CN101623287B - Novel drospirenone analogue medicinal composition for treating menopausal syndrome - Google Patents
Novel drospirenone analogue medicinal composition for treating menopausal syndrome Download PDFInfo
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Abstract
The invention discloses a novel drospirenone analogue medicinal composition for treating menopausal syndrome, which consists of a compound shown as a formula (I) used as a first active ingredient, one or more synthetic estrogen used as a second active ingredient and one or more medicinal carriers or excipients, wherein the content of the compound shown as the formula (I) is equivalent to daily dose of 1 to 5mu g/kg; and the content of the estrogen is equivalent to daily dose of 10 to 40mu g/kg. The medicinal composition is used for preparing human or primate hormone replacement therapy (HRT) treatment medicaments.
Description
Technical field
The present invention relates to a kind of with the drospirenone analogue as progestogen be active component be used to prepare Hormone Replacement Therapy (HRT, hormone replacement therapy) pharmaceutical composition.
Background technology
Drospirenone (Drospirenone; DRSP) be the derivant of a kind of 17 α-spironolactone; Be a kind of synthetic progestogen and progestational hormone seemingly, with progesterone receptor, mineralcorticoid receptor have the height affinity; Very low with androgen receptor and glucocorticoid receptor (GR) affinity, do not combine with estrogen receptor.It combines the pharmacological characteristics of progestogen, anti mineralocorticoid and androgen antagonist, and this makes biochemistry and the pharmacological properties of DRSP and natural progestogen quite similar, and it is active to have a not available progesterone of other synthetic hormones.Therefore drospirenone is used to treat climacteric syndrome; The European Union and the U.S. also have been distributed in and had ratified that German schringAG produces in 2003 and 2004; By 0.5mg DRSP and 1mgE2 (estradiol; Estradiol) forms the oral formulations that is used to treat climacteric syndrome of commodity Angeiq by name.The analog of a kind of drospirenone of chemical formula (I)---18-methyl-6 α is disclosed at one Chinese patent application CN200580048680.3,7 α-15 β, 16 β-dimethylene-3-oxo-19-is nor--pregnant-4 alkene-21 of 17-, the 17-lactone:
This application also discloses a series of general formula compounds that comprise in formula (I) chemical compound and has had the gestagen receptor affinity higher than drospirenone; Yet in this application; Specifically do not provide the gestagen receptor affinity data that formula (I) chemical compound is compared with drospirenone, and in this application, only to have provided the daily dose of general formula compound in the contraception medicament be 0.1-20mg, from prior art, learn; The treatment of climacteric syndrome mainly is to adopt Hormone Replacement Therapy (HRT); Mainly be to adopt estrogen and progestogen to treat in this therapy, wherein estrogen action is to improve the climacteric syndrome symptom, prevents and treats osteoporosis; Reduce the cardiovascular disease incidence rate; But research shows that simultaneously taking the estrogen meeting merely significantly increases the risk of suffering from carcinoma of endometrium and breast carcinoma, and the method that an amount of progestogen are taken in therefore frequent clinically employing is simultaneously prevented the generation of these side effect.Therefore because progestogen itself also have certain side effect,, when clinical use, need the accurate dosage of confirming progestogen to reach the generation of avoiding side effect in the therapeutic effect like depression, irritability, mazalgia and edema.
Summary of the invention
In order to overcome defective of the prior art, in the research to formula (I) chemical compound, we have unexpectedly found the optimal daily dose as people or primates Hormone Replacement Therapy (HRT) medicine of this chemical compound.
We provide a kind of is the pharmaceutical composition of active component with formula (I) chemical compound; Said composition is by constituting as formula (I) chemical compound of first kind of active component with as one or more estrogen and one or more pharmaceutically useful carriers or excipient of second kind of active component; The content of its Chinese style (I) chemical compound is equivalent to the daily dose of 1 μ g/kg～5 μ g/kg, and the content of synthetic estrogen is equivalent to the daily dose of 10 μ g/kg～40 μ g/kg.
Pharmaceutical composition preferred formula of the present invention (I) compounds content is equivalent to the daily dose of 1 μ g/kg～3 μ g/kg.
Pharmaceutical composition of the present invention also preferably is equivalent to the daily dose of 10 μ g/kg～30 μ g/kg as second kind of active component for estrogenic content.
The daily dose that especially preferably is equivalent to 20 μ g/kg as second kind of active estrogenic content.
The content of the also preferred described formula of Pharmaceutical composition of the present invention (I) chemical compound is equivalent to the daily dose of 1 μ g/kg, and said estrogenic content is equivalent to the daily dose of 20 μ g/kg.
The content of the also preferred described formula of Pharmaceutical composition of the present invention (I) chemical compound is equivalent to the daily dose of 3 μ g/kg, and said estrogenic content is equivalent to the daily dose of 20 μ g/kg.
Pharmaceutical composition according to the invention is the application in preparation human contraceptive preferably, and body weight for humans is in 50kg when calculating dosage.
In the Pharmaceutical composition of the present invention; Used estrogen is as preferred; Like estradiol (EE), sulfamic acid estradiol, estradiol valerate, estradiol benzoate, ethinylestradiol, estrone, estriol, styptanon and CE; Comprise the combination premarin; Like OES, 17 beta estradiol sulfuric esters, 17-alpha estradiol sulfuric ester, sulphuric acid 1,3,5,7-estratetraen-3-ol-17-one, 17 β-dihydroequilin sulfuric ester and 17 α-dihydroequilin sulfuric ester or their mixture; Preferred estradiol, sulfamic acid estradiol, estradiol valerate, estradiol benzoate, estrone, OES or their mixture, preferred especially estradiol, estradiol valerate, most preferably estradiol.
Before pharmaceutical composition of the present invention can also be used to prepare treatment menopause, the medicine of menopause and PMS, and the medicine that is used to prepare hormone replacement therapy (HRT).
Formula in the pharmaceutical composition of the present invention (I) chemical compound and/or estradiol preferably adopt micronized form to provide, and described micronization is meant mean diameter D
50(meso-position radius, rate all just was the corresponding particle size values in 50% place under promptly sieve was gone up rate and sieved)≤5 μ m, special, D
90(sieve is rate 90% corresponding particle diameter down)≤10 μ m, the medicine of described micronization form helps formula (I) chemical compound and when oral, can dissolve in vivo rapidly, improves the oral administration biaavailability of said formula (I) chemical compound.Can also adopt to be dissolved in organic solvent and to spray to the method on the blank micropill core then, described method of micronization can adopt known breaking method, pulverizes like fluid energy mill.
Pharmaceutical composition of the present invention can be prepared according to method known to those skilled in the art; Be about to formula (I) chemical compound, prepare, and process the peroral dosage form that needs as the synthetic estrogen of second kind of active component and pharmaceutically useful carrier or excipient.
Described dosage form includes but are not limited to tablet, coated tablet, capsule, pill, granule or suspensoid, implants, cutaneous permeable agent; The preferred oral preparation includes but are not limited to tablet, pill, coated tablet, granule, capsule, suspensoid.Special preferred tablet, capsule, granule.
Comprise in the pharmaceutical composition of the present invention that pharmaceutically useful carrier that known oral formulations is used or excipient are to include but are not limited in filler, wetting agent and binding agent, disintegrating agent, lubricant, coloring agent, the correctives one or more,
Described pharmaceutically useful carrier or excipient can be selected from but be not limited only in the following material one or more:
Starch includes but are not limited to corn starch, wheaten starch, potato starch; Saccharide, preferred sucrose, glucose, the lactose of pulverizing; Sugar alcohols, preferred mannitol, sorbitol, xylitol; Dextrin, preferred beta-schardinger dextrin-; Cellulose derivative comprises methylcellulose (MC), hydroxypropyl cellulose (HPC), hydroxypropyl emthylcellulose (HPMC), sodium carboxymethyl cellulose (CMC-Na), ethyl cellulose (EC); And gelatin, polyvinylpyrrolidone (PVP), Polyethylene Glycol (PEG, PEG4000 commonly used or PEG6000), carboxymethyl starch sodium (CMS-Na), low-substituted hydroxypropyl cellulose (L-HPC), cross-linking sodium carboxymethyl cellulose (CCNa), crospolyvinylpyrrolidone (PVPP), magnesium stearate, micropowder silica gel, Pulvis Talci, purified water, ethanol, microcrystalline Cellulose, pregelatinized Starch.
Especially, pharmaceutical composition of the present invention can also be processed enteric coated tablet, enteric coated capsule with the method for conventional enteric coated preparation.As adopt credulity to restrain
TM(EASCOL
TM, Tianjin Aileyi Medicine Materials Co., Ltd. produces) and serial enteric coating agents carries out coating, makes enteric coated tablet or enteric coated particles, enteric coated capsule etc.Also can process the general thin garment piece (the HPMC coating, as, be prone to release beautiful
TM, Tianjin Aileyi Medicine Materials Co., Ltd. produces), conventional capsule, plain particles agent.
Pharmaceutical composition according to the invention can provide in order to following method: micronized formula (I) chemical compound that will make fully mixes with the pharmaceutically acceptable auxiliaries as carrier or excipient; Add dissolving or pulverize the binding agent in solvent or dispersant; Carry out pelletize, then with the granule tabletting, optional added proper amount of lubricating agent or fluidizer; Also can granule be irritated capsule and make capsule
Pharmaceutical composition according to the invention also can provide in order to following method: micronized formula (I) chemical compound that will make fully mixes with the pharmaceutically acceptable auxiliaries as carrier or excipient, then powder is directly carried out direct compression.Also can well-mixed pastille powder directly pour into capsule and make capsule, the tablet of gained or capsule also all can carry out coating.
Pharmaceutical composition of the present invention can also provide in order to following method: with formula (I) chemical compound and/or as in the suitable organic solvent of being dissolved in of second kind of medicinal ingredient synthetic estrogen; Like in methanol, ethyl acetate, the ethanol etc. one or more; And will be sprayed onto on blank micropill nuclear core or the coated tablet label; Obtain pastille micropill or pastille label; Described celphere can be preferably a kind of in the sucrose ball core of the commercially available definition that meets American Pharmacopeia 25 editions, microcrystalline Cellulose ball core, starch ball core, the diameter of described celphere is 0.1mm～1mm.Adopt the method for fluidized bed coating or pan coating, preferably pastille label or pastille micropill are carried out coating, obtain enteric coated micropill or enteric coatel tablets with above-mentioned enteric coating agents; Enteric coated micropill is poured into capsule promptly get capsule; Described coating method is with reference to (development of verapamil hydrochloride pulse controlled release micro pill, Chinese Journal of Pharmaceuticals, 2003.34 (5) such as Zhang Yu; 236～237) the virtuous grade of the He Lianggui (development of diltiazem hydrochloride colon patch; Chinese Journal of Pharmaceuticals, 2003.34 (5), 233～235) disclosed method.
Can also with the coating that makes or not the pastille micropill of coating add an amount of disintegrating agent such as in the microcrystalline Cellulose one or more; Filler such as starch, sugar, dextrin, in one or more, pregelatinized Starch; Binding agent such as polyvinylpyrrolidone (PVP), cellulose derivative are as comprising methylcellulose (MC), hydroxypropyl cellulose (HPC), hydroxypropyl emthylcellulose (HPMC), sodium carboxymethyl cellulose (CMC-Na), ethyl cellulose (EC), Macrogol 4000 (PEG4000), polyethylene glycol 6000 (PEG6000); In disintegrating agent carboxymethyl base Starch Sodium (CMS-Na), low-substituted hydroxypropyl cellulose (L-HPC), cross-linking sodium carboxymethyl cellulose (CCNa), the crospolyvinylpyrrolidone (PVPP) one or more, lubricant such as magnesium stearate.Adopt known compressing dry granulation or wet method tabletting method to make tablet, and preferably the tablet that makes is carried out coating, described coating can be an enteric coating, also can be the coating of common cellulose derivative film.
Can also this pastille micropill of not coating directly be poured in the capsule and to capsule and carry out coating, described coating can be an enteric coating, also can be the coating of common cellulose derivative film.
Described pastille micropill is at coating or all can not be prepared under the situation of coating and be used for directly oral granule.
Described pharmaceutical composition can also adopt with micronized formula as first kind of active component (I) chemical compound with as one or more of the synthetic estrogen of second kind of active component and replace above-mentioned pastille micropill; Directly make tablet, capsule; Made capsule and tablet preferably carry out coating; Described coating can be an enteric coating, also can be the coating of common cellulose derivative film.
The oral formulations that described pharmaceutical composition is processed; Wherein enteric coated preparation meets 2005 editions appendix XD of Chinese Pharmacopoeia drug release determination method; 2 hours release degree≤5% in the hydrochloric acid solution of pH=1; 45 minutes release degree>=70% in the phosphate buffer of pH=6.8, non-enteric coated preparation meet 2005 editions appendix XC of Chinese Pharmacopoeia dissolution method, 45 minutes dissolution>=70% in the hydrochloric acid solution of pH=1.
The content that this drug oral compositions can be processed said formula (I) chemical compound is equivalent to the daily dose (0.05～0.25mg/d people's body weight is in 50kg) of 1 μ g/kg～5 μ g/kg, and estrogenic content is equivalent to the oral formulations of the daily dose of 10 μ g/kg～40 μ g/kg.(0.5～2.0mg/d, people's body weight is in 50kg)
The content of preferably processing formula (I) chemical compound is equivalent to the pharmaceutical preparation of the daily dose of 1 μ g/kg～3 μ g/kg (0.05～0.15mg/d, people's body weight is in 50kg)
What also preferably be made as second kind of active component is the pharmaceutical preparation that estrogenic content is equivalent to the daily dose of 14～30 μ g/kg.(0.7～1.5mg/d, people's body weight is in 50kg)
What especially preferably be made as second kind of active component is the pharmaceutical preparation that estrogenic content is equivalent to the daily dose of 20 μ g/kg.(1.0mg/d, people's body weight is in 50kg).
More preferably process the oral formulations that the synthetic estrogen of 0.05 to 0.15mg formula (I) chemical compound and 0.7～1.5mg is contained in each daily dose unit, the preferred estradiol of described estrogen.
Above-mentioned oral formulations, preferably formula (I) chemical compound of 0.05mg and the estrogen of 1mg, the preferred estradiol of described estrogen are contained in each daily dose unit.
Above-mentioned oral formulations, preferably formula (I) chemical compound of 0.15mg and the estrogen of 1mg, the preferred estradiol of described estrogen are contained in each daily dose unit.
According to known drug use method (body weight for humans is in 50kg), Pharmaceutical composition of the present invention can also process by the cycle administration by at least 21 single phase preparations or the multistage preparation that in the administration cycle, constitutes that contain described two kinds of active component and 7 or the single preparation that does not contain formula (I) chemical compound (tablet, capsule, pill) still less by the single preparation that contains the different activities component content (tablet, capsule, pill).Thus; Pharmaceutical composition of the present invention can be processed the pharmaceutical preparation of being made up of a plurality of independent packagings and the daily dose unit that can take out separately; Described daily dose unit places in the packaging unit; Be used for oral administration in the continuous at least 21 days time; Formula (I) chemical compound of 0.05～0.25mg and the estrogen of 0.5～2.0mg are contained in wherein said each daily dose unit, and preferably formula (I) chemical compound of 0.05～0.25mg and the estrogen of 0.7～1.5mg, the preferred estradiol of described estrogen are contained in each daily dose unit.
As improvement to above-mentioned preparation, Pharmaceutical composition of the present invention also can process by the cycle administration by at least 21 contain described two kinds of active component and 7 or still less only contain estrogen or barren single preparation (tablet, capsule, pill) single phase preparation or in the administration cycle by the multistage preparation of the single preparation that contains the different activities composition (tablet, capsule, pill).Thus; Pharmaceutical composition of the present invention can be processed the pharmaceutical preparation of being made up of a plurality of independent packagings and the daily dose unit that can take out separately; Described daily dose unit places in the packaging unit;, formula (I) chemical compound of 0.05～0.25mg and the estrogen of 0.5～2.0mg are contained in described each each daily dose unit of wherein containing two kinds of active component, preferably contain formula (I) chemical compound of 0.05～0.15mg and the estrogen of 0.7～1.5mg; The described daily dose unit of only containing synthetic estrogen, it contains the estrogen of 0.5～2.0mg, preferably contains 0.7～1.5mg estrogen, especially preferably contains 1.0mg estrogen, the preferred estradiol of described estrogen.
Single phase that described Pharmaceutical composition is processed or multistage preparation; Containing active component daily dose unit can be 21～24; The single preparation that does not contain formula (I) chemical compound as active component is 4～7, and each administration cycle is at least 28 days, the described multistage; Can be 2～4 stages, also can be the more stage.
Compositions of the present invention can also be the form of parenteral formulation; For example subcutaneous implant or percutaneous preparation; In order to prepare implant, can be with active component with for example polysiloxane polymer, ethylene vinyl acetate, polyethylene or polypropylene preparation of one or more conjugates that can corrode gradually in use or degrade.
When relating to percutaneous preparation, can percutaneous preparation be processed skeleton, film or the liquid in oil or hydrogel or the form of thickness preparation.For the percutaneous patch; Should comprise can with the binding agent of skin-compatible for example polyacrylate, polyorganosiloxane adhesive or polyisobutylene, and the lining of processing by for example polyethylene, polypropylene, ethylene vinyl acetate, polrvinyl chloride, polyvinylidene chloride or polyester and by for example polyester or be coated with polysiloxane or the protection that can remove lining that fluoropolymer polymer is processed.When preparation percutaneous solution or gel, can make water or organic solvent or its mixture.The percutaneous gel can also contain one or more suitable gellant or thickening agent for example polysiloxanes, tragcanth, starch or starch derivatives, cellulose or cellulose derivative or polyacrylic acid or derivatives thereof.Percutaneous preparation can also suitably contain one or more can promote the material through skin absorbs, for example bile salt or derivatives thereof and/or phospholipid.Suitable percutaneous preparation can according to WO94/04157 in the similar mode of the method for preparing the 3-keto-desogestrel percutaneous preparation described prepare.Perhaps, percutaneous preparation can be according to for example BWBarry, " Dermatological Formulations; Percutaneous Absorption ", Marcel Dekker Inc., NewYork-Basel; 1983 or YW Chien, " Transdermal Controlled Systemic Medications ", Marcel DekkerInc.; New York-Basel, disclosed method preparation in 1987.
The specific embodiment
The following specific embodiment is in order better to explain and to understand technical scheme of the present invention, can not be interpreted as by any way the qualification to the claimed technical scheme of the present invention.
FORMULATION EXAMPLE
Embodiment 1
The label that has following composition through following method preparation: (label is 100mg)
Micronized formula (I) chemical compound 0.05mg
Micronized estradiol 1.0mg
Lactose monohydrate 61.40mg
Corn starch 19.10mg
Pregelatinized Starch starch 1500 12.9mg
Polyvinylpyrrolidone K25 (mean molecule quantity 30000) 500mg
Magnesium stearate 0.57mg
Feed intake to prepare 10000; To add fluidized bed pelletizer except that the above-mentioned mixing of materials of the recipe quantity polyvinylpyrrolidone, the magnesium stearate; Start fluid bed; The polyvinylpyrrolidone of recipe quantity is made into the spraying and carry out drying and granulating through the mode of heated fluidized bed continuously on fluid bed of 20% aqueous solution, and the magnesium stearate with recipe quantity of granulating when finishing sucks fluidized bed pelletizer and fully mixes, and the granule that obtains is carried out tabletting obtain label.Adopt commercially available HPMC coating materials (to be prone to release beautiful
TM, Tianjin Aileyi Medicine Materials Co., Ltd. produces) carry out coating and obtain desired Film coated tablets.The coating materials consumption is by heavy 6% the feeding intake of sheet, and every contains formula (I) chemical compound 0.05mg, estradiol 1.0mg.
Embodiment 1-1
Obtain label among the embodiment 1, adopt commercially available enteric coating agents (trade name: credulity gram
TM(EASCOL
TM, Tianjin Aileyi Medicine Materials Co., Ltd. produces) carry out coating and obtain enteric coated tablet, the coating materials consumption is by heavy 6% the feeding intake of sheet.Every contains formula (I) chemical compound 0.05mg, estradiol 1.0mg.
Embodiment 1-2
With the granule that obtains among the embodiment 1, adopt No. 4 capsules to irritate capsule and obtain 10000 of capsules.Every contains formula (I) chemical compound 0.05mg, estradiol 1.0mg.
Embodiment 1-3
The capsule that embodiment 1-2 is obtained adopts the coating materials of implementing among the 1-1 to carry out coating, obtains 10000 of enteric coated capsules.Every contains formula (I) chemical compound 0.05mg, estradiol 1.0mg.
Embodiment 2 (every or every capsule)
Micronization formula (I) chemical compound 0.15mg
Estradiol micronized 1.0mg
60～80 commercially available purpose celphere (like the XYT-MCC60/80 type microcrystalline Cellulose ball core of the special Science and Technology Ltd. in Xinyi, Shenzhen production) 15.0mg
Pregelatinized Starch starch 1500 15.2mg
Lactose monohydrate 4.5mg
Magnesium stearate 0.28mg
Feed intake according to 10000 of preparations, formula (I) chemical compound of recipe quantity and estradiol are dissolved in obtain medicinal liquid in the ethanol, the celphere adding coating machine with recipe quantity makes the pastille micropill with medicine liquid spray on celphere.
With the adjuvant mixing direct compression of pastille micropill, and adopt the method for embodiment 1 that it is wrapped film-coat with other recipe quantities.Make Film coated tablets.Every contains formula (I) chemical compound 0.15mg, estradiol 1.0mg.
Embodiment 2-1
The label that embodiment 2 is made carries out coating by the enteric coating agents that adopts embodiment 1-1 and makes 10000 of enteric coated tablet.Every contains formula (I) chemical compound 0.15mg, estradiol 1.0mg.
Embodiment 2-2
With the pastille micropill that embodiment 2-2 makes, adopt No. 4 capsules to irritate capsule and obtain 10000 of capsules.Every contains formula (I) chemical compound 0.15mg, estradiol 1.0mg.
Embodiment 2-3
The capsule that embodiment 2-2 is made adopts the coating materials among the embodiment 1-1 to carry out coating, obtains 10000 every of enteric coated capsule and contains formula (I) chemical compound 0.15mg, estradiol 1.0mg.
Embodiment 3
Coating materials among the pastille micropill employing embodiment 1-1 that makes among the embodiment 2 is carried out coating obtain enteric coated micropill; Enteric coated micropill is carried out tabletting according to the prescription of other adjuvants among the embodiment 2; Obtain 10000 of sheets, every contains formula (I) chemical compound 0.15mg, estradiol 1.0mg.
Embodiment 3-1
Every content of dispersion is by the prescription of implementing 2, and the enteric coated micropill that embodiment 3 is made pours into capsule and obtains 10000 of capsules.Every contains formula (I) chemical compound 0.15mg, estradiol 1.0mg.
Embodiment 4
The stripping of effective ingredient and release
The enteric coated preparation that embodiment 1-1, embodiment 1-3, embodiment 2-1, embodiment 2-3, embodiment 3, embodiment 3-1 make is respectively got 6 (grains); Measure formula (I) chemical compound release degree according to the assay method of the second method method 1 in 2005 editions appendix XD of Chinese Pharmacopoeia drug release determination respectively; The non-enteric coated preparation that embodiment 1,1-2,2,2-2 make is respectively got 6 (grains) assay method mensuration formula (I) chemical compound dissolution according to first method in 2005 editions appendix XC of Chinese Pharmacopoeia dissolution method; All enteric coated preparation are 2 hours release degree≤5% in the hydrochloric acid solution of pH=1; 45 minutes release degree>=70% in the phosphate buffer of pH=6.8; All non-enteric coated preparation are 45 minutes dissolution>=70% in the hydrochloric acid solution of pH=1, meet the regulation of appendix XD and appendix XC in the Chinese Pharmacopoeia 2005 editions respectively.
The same method is surveyed the dissolution of estradiol, also meets the regulation of appendix XD and appendix XC in the Chinese Pharmacopoeia 2005 editions respectively
Embodiment 5
To the bone amount of ovariectomized rat, the influence in uterus
In the prior art, be the effect of check HRT medicine, the situation that the hormone secretion amount descends when often using ovariectomized rat to simulate climacteric syndrome.
The contrast medicine,
(1) adopt micronized drospirenone (DRSP) replace in embodiment 2 prescriptions formula (I) chemical compound; Process enteric coating pastille micropill by the method among the embodiment 3, the pastille micropill that the blank micropill of every 15mg makes contains 0.5mg drospirenone, 1.0mg estradiol as matched group 3 medications.(promptly being the drospirenone of " Angeliq " and the compound recipe of estradiol) according to the commercially available commodity that are used to treat climacteric syndrome in the prior art are bright
(2) adopt of the administration of micronized estradiol as matched group 4.
(3) the blank micropill that adopts embodiment 3 to adopt is produced enteric coating pastille micropill, as matched group 2 medications (blank)
According to the method for embodiment 3, produce every 15mg celphere respectively and contain:
Experimental group 1:0.05mg formula (I) chemical compound 1.0mg estradiol
Experimental group 2:0.15mg formula (I) chemical compound 1.0mg estradiol
Experimental group 3:0.25mg formula (I) chemical compound 1.0mg estradiol
Experimental group 4:0.05mg formula (I) chemical compound 2.0mg estradiol
Experimental group 5:0.15mg formula (I) chemical compound 2.0mg estradiol
5 groups of enteric coating pastille micropills, respectively as the medication of experimental group 1～5.Successive administration 90d.
Laboratory animal: adopt 90 of the female Wister rats of 6-7 monthly age healthy adult, body weight 199.8 ± 20.1g.Be divided into 9 groups at random, be divided into sham operated rats (Sham)---matched group 1, oophorectomize group (OVX)---matched group 2, oophorectomize administration group, wherein administration group administration grouping situation sees the following form
Experimental technique: all laboratory animals are in anesthesia, under the aseptic condition, and excision bilateral ovaries, sham operated rats are only carried out the switch art, the postoperative water of normally ingesting, 1 week each administration group of back give oral administration, matched group 1,2 only gives the blank micropill of feeding.Administration was weighed after 10 weeks, put to death whole rats, isolated from rat uterus, accurate weighing weight in wet base, right side femur.And carry out bone density (BMD) and measure.Experimental result sees the following form
Experiment conclusion:
Above-mentioned experiment shows; Compare with ovariectomized matched group 2; The bone density of experimental group 1～5, matched group 3～4 (BMD) all has significance (P＜0.05); And compare in twos between experimental group 1～5, the matched group 3～4; Bone density does not have significance (P＞0.05), and the matched group 3 of the prescription that the drospirenone of commodity " Angeliq " by name is identical with the estradiol compound recipe in the experimental group 1～5 that employing formula (I) chemical compound is described and employing and the prior art is compared, and when the osteoporosis that the treatment laboratory animal causes because of spay, can produce identical effect.
And through the measurement to laboratory animal uterus weight and endometrium thickness; Compare with matched group 4; The uterus weight of experimental group 1～5, contrast 4 and endometrium thickness all significantly reduce (P＜0.05), explain that technical scheme of the present invention can overcome simple use estrogen and cause endometrial hyperplasia.And under the identical situation of amount of estrogen; Adopt the experimental group 1 of 1 μ g/ (kgd) formula (I) chemical compound suitable with the outgrowth inhibition effect of 3 pairs of endometrium of matched group that adopts 10 μ g/ (kgd) drospirenones; And when adopting formula (I) chemical compound of 3～5 μ g/ (kgd); More remarkable to the outgrowth inhibitory action of endometrium, in the experimental group 4～5 that the estradiol consumption doubles, formula (I) chemical compound of 1～3 μ g/ (kgd) also has the effect of significant inhibition endometrial hyperplasia.Explanation thus; Compare as the compound preparation with estrogen is formed of the treatment climacteric syndrome of progestogen with use drospirenone in the prior art; Technical scheme of the present invention can be used the formula as progestogen (I) chemical compound still less, reaches the identical effect of more drospirenone.
Claims (14)
1. a formula (I) chemical compound is the pharmaceutical composition of active component; By constituting as formula (I) chemical compound of first kind of active component with as one or more synthetic estrogens of second kind of active component and one or more pharmaceutically useful carriers or excipient; The content of described formula (I) chemical compound is equivalent to the daily dose of 1 μ g/kg, and described estrogenic content is equivalent to the daily dose of 10 μ g/kg～40 μ g/kg
2. pharmaceutical composition as claimed in claim 1 is characterized in that said estrogen content is equivalent to the daily dose of 14g/kg～30 μ g/kg.
3. pharmaceutical composition as claimed in claim 2 is characterized in that said estrogen content is equivalent to the daily dose of 20 μ g/kg.
4. pharmaceutical composition as claimed in claim 1 is characterized in that the preferred estradiol of described estrogen (EE), sulfamic acid estradiol, estradiol valerate, estradiol benzoate, ethinylestradiol, estrone, estriol, styptanon, OES, 17 beta estradiol sulfuric esters, 17-alpha estradiol sulfuric ester, sulphuric acid 1,3,5,7-estratetraen-3-ol-17-one, 17 β-dihydroequilin sulfuric ester and 17 α-dihydroequilin sulfuric ester or their mixture.
5. pharmaceutical composition as claimed in claim 1 is characterized in that the preferred estradiol of described estrogen (EE), sulfamic acid estradiol, estradiol valerate, estradiol benzoate, ethinylestradiol, estrone, estriol, styptanon, combination premarin or their mixture.
6. pharmaceutical composition as claimed in claim 5 is characterized in that the preferred estradiol of described estrogen, sulfamic acid estradiol, estradiol valerate, estradiol benzoate, estrone, OES or their mixture.
7. pharmaceutical composition as claimed in claim 6 is characterized in that the preferred estradiol of described estrogen, estradiol valerate.
8. like arbitrary described pharmaceutical composition in the claim 1 to 3; It is characterized in that described formula (I) chemical compound and/or estrogen preferably adopt micronization or is dissolved in organic solvent sprays to the method administration on the blank micropill core then, and described micronization is meant mean diameter D
50≤5 μ m.
9. pharmaceutical composition as claimed in claim 1 is characterized in that described pharmaceutical composition can process tablet, capsule, pill, granule, suspensoid, implants, cutaneous permeable agent.
10. pharmaceutical composition as claimed in claim 9; Can process oral formulations; The content of described oral formulations Chinese style (I) chemical compound is equivalent to the daily dose of 1 μ g/kg, and estrogenic content is equivalent to the daily dose of 10 μ g/kg～40 μ g/kg, and described estrogen is estradiol.
11. pharmaceutical composition as claimed in claim 10, estrogenic content are equivalent to the daily dose of 14 μ g/kg～30 μ g/kg.
12. pharmaceutical composition as claimed in claim 10 is characterized in that preferably formula (I) chemical compound of 0.05mg and the estrogen of 0.7～1.5mg are contained in each daily dose unit, described estrogen is estradiol.
13. pharmaceutical composition as claimed in claim 10 is characterized in that preferably formula (I) chemical compound of 0.05mg and the estrogen of 1mg are contained in each daily dose unit, described estrogen is estradiol.
14. pharmaceutical composition as claimed in claim 1, the preferred oral pharmaceutical formulation is following:
More than be the label prescription,
The HPMC coating materials, the coating materials consumption is by heavy 6% the feeding intake of sheet.
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| CN2008100537641A CN101623287B (en) | 2008-07-07 | 2008-07-07 | Novel drospirenone analogue medicinal composition for treating menopausal syndrome |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1395488A (en) * | 2000-01-18 | 2003-02-05 | 先灵公司 | Drospirenone for hormone replacement therapy |
| CN101128476A (en) * | 2004-12-30 | 2008-02-20 | 舍林股份公司 | 18-methyl-19-nor-17-pregn-4-en-21,17-carbolactones and pharmaceutical preparations comprising the same |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1395488A (en) * | 2000-01-18 | 2003-02-05 | 先灵公司 | Drospirenone for hormone replacement therapy |
| CN101128476A (en) * | 2004-12-30 | 2008-02-20 | 舍林股份公司 | 18-methyl-19-nor-17-pregn-4-en-21,17-carbolactones and pharmaceutical preparations comprising the same |
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| CN101623287A (en) | 2010-01-13 |
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