CN1672685A - New contraception medicine - Google Patents
New contraception medicine Download PDFInfo
- Publication number
- CN1672685A CN1672685A CNA2004100296007A CN200410029600A CN1672685A CN 1672685 A CN1672685 A CN 1672685A CN A2004100296007 A CNA2004100296007 A CN A2004100296007A CN 200410029600 A CN200410029600 A CN 200410029600A CN 1672685 A CN1672685 A CN 1672685A
- Authority
- CN
- China
- Prior art keywords
- estradione
- acetylene
- preparation
- estradiol
- corpus luteum
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Classifications
-
- 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
-
- 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
- A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
-
- 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
- A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
- A61K31/567—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in position 17 alpha, e.g. mestranol, norethandrolone
-
- 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
- A61P15/18—Feminine contraceptives
-
- 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
- A61P5/30—Oestrogens
-
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- General Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Organic Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Endocrinology (AREA)
- Engineering & Computer Science (AREA)
- Epidemiology (AREA)
- Diabetes (AREA)
- Gynecology & Obstetrics (AREA)
- Reproductive Health (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to of new kind of contraception medicine, and is especially the method of using low dosage estrogen and progesterone as long term oral contraceptive, compound oral contraceptive preparation containing low dosage of estrogen and progesterone and combined low dosage oral contraceptive of estrogen and progesterone packed separately.
Description
Technical field:
The present invention relates to a kind of application of contraceptive, particularly use low dose estrogen (estrogen) and Progesterone (progesterone) method as long-term oral contraceptive, contain the COC thing preparation of low dose estrogen class material and corpus luteum letones and packing respectively, unite the packing medicine box of the oral contraceptive of the low dose estrogen class material of use and corpus luteum letones.
Background technology:
The cycle of ovary/menstruation is the process of a complexity.Its basic feature can be divided into follicular phase of being rich in estrogen (estrogen) and the luteal phase of being rich in Progesterone (progesterone) after ovulation.Follicular phase and luteal phase, each continued about 14 days, therefore formed 28 days menstrual cycle.Endometrium can change with the change of periphery hormone.
Begin with menstruation first day initial as menstrual cycle, at nogestational menstrual cycle, death comes off because Progesterone stops secretion in 5-7 days time on the endometrium top layer that last menstrual cycle forms.The well-regulated maturation of follicle causes the rising of estrogen level in the peripheral circulation in the ovary, and then causes new endometrial differentiation again.
In the interstage of menstrual cycle, generally be 12-16 days at menstrual cycle, most of follicles are engaged in the ovulation activity, and are that the main secretion Progesterone that changes into is main (corpus luteum) from secretion estrogen.Because the increase of Progesterone level in the blood makes the endometrium of propagation change into secretor state.In this state, the propagation of tissue obviously reduces, and endometrial gland forms.After become pregnant 6-8 days, the fertilized egg cell of existence continues embryo's division, and endometrial secreting gland and conceptus can interact and produce implantation (implantation).
If implantation produces conceived, the embryo will adhere to and be embedded in endometrial secreting gland, begin to produce human chorionic gonadotropin (HCG).The function of human chorionic gonadotropin and then stimulation corpus luteum for example, is kept the level of Progesterone, does not have menstrual onset at the menstrual cycle of becoming pregnant, and becomes pregnant successfully.
At the non-menstrual cycle of becoming pregnant, the level of Progesterone descends and causes coming off of endometrial tissue in the blood, thereby begins new menstrual cycle.Because endometrial propagation is to prepare for gestation subsequently, so can be by the regulation and control of hormone and uterus environment being played the effect of contraception, for example, known estrogen can reduce the secretion of follicule-stimulating hormone (FSH) (follicle stimulating hormone) by negative feedback.Under certain certain conditions, estrogen can also suppress the secretion of luteotropic hormone (luteinizing hormone), also is that negative feedback is regulated.In the ordinary course of things, only the estrogenic peak value that detects in blood circulation before ovulation can make the release of promoting sexual gland hormone (gonadotropic hormones), causes ovulation.Take heavy dose of estrogen after the sexual intercourse immediately and can play contraceptive efficacy, its mechanism is the implantation that has disturbed sperm.
Progesterone also can play the effect of contraception.Endogenous Progesterone behind the progestogen can make pregravidic endometrium and cervix uteri and vaginal cell/organize periodically to change.Take Progesterone and make that the mucus of cervical orifice is dense, thereby stop sperm to pass through.Progesterone take the secretion that has also suppressed interstitialcellstimulating hormone (ICSH) (luteinizing hormone) simultaneously, stop ovulation.
The most general contraceptive device is to comprise estrogen and Progesterone in tablet simultaneously, so be called " COC ".
In addition, contraceptive can only comprise Progesterone.Yet the contraceptive that only contains Progesterone has bigger side effect than compound preparation, the especially easier massive hemorrhage that causes.So " COC " remains the first-selected contraceptive (Sheth et al., Contraception 25:243,1982) of today.
When taking dose was big, 21 days traditional oral contraceptives add drug withdrawal in 7 days or placebo has effect preferably at interval.When reducing dosage, estrogen and Progesterone all can increase bleeding problems, early stage at oral contraceptive particularly, and can have the longer time in this influence of some patients.
Since occur the Estrogen-Progesterone compound formulation as oral contraceptive since, estrogenic every day, consumption constantly reduced.Simultaneously, the dose of Progesterone also when reducing, continues based on androgen.Do such cooperation in the prescription and be used among the multiple therapy, comprise single and three-stage treatment.Each therapy all has its pluses and minuses.Consider the sickness rate and the seriousness of the blood coagulation disorders that causes because of estrogen, and lipophilic Progesterone is in the advantage of keeping blood circulation middle-high density lipoprotein, the oral contraceptive of all things considered today is safer.
U.S. Patent No. 4,390,531 have set forth a kind of three-stage treatment, the about 20-40mcg acetylene of each issue use estradione (ethinyl estradiol), first phase and three phases are used 0.3-0.8 norethindrone (norethindrone), and the second phase doubles the consumption of norethindrone.Three phases took 21 days in 28 day cycle altogether.The application patent 0 226 279 of European publication is thought, because there is dependency in the sudden massive hemorrhage of this therapy and high incidence, so use the acetylene estradione (10-50 μ g) of relatively low dosage and the norethindrone (0.5-1.5mg) of higher dosage to replace three-stage treatment, estrogen is in the consumption difference of any two phases.Use this therapy in the remaining other about 7 day time.
U.S. Patent No. 5,098,714 have lectured a kind of infiltrative oral contraceptive.Though take a slice every day, in fact every administration remains many phases.Administering mode comprises estrogen and the Progesterone that begins to give pulsed dosage, gives follow-up additional estrogen subsequently.
The patent of European publication is used 0 253 607 and has been described single contraceptive instructions of taking, every variant (desogestrel, or a great deal of) that contains 0.008-0.03mg acetylene estradione and 0.025-0.1mg was taken 23-25 days continuously, best 24 days, days drug withdrawal of 2-5 subsequently.The purpose of this therapy is treatment and the contraception protection that hormone replacement is provided for women before the menopause, because they need supply with the estrogen of low dosage and the progestogen of very low dose.
For oral contraceptive to premenopausal (35-50 year) healthy non-smoking women low dosage, the healthy Drug Counseling of the reproduction of united states drug and food control office and mother committee is according to the data of accumulation, and suggestion oral contraceptive every day contains 20-35.mu.g estrogen.Japan estimates safety, effect and the social acceptance level of oral contraceptive first.
U.S. Patent No. 5,552,394 have described a kind of female contraception method.Its feature is in 28 day cycle, continuously singlely takes the Estrogen-Progesterone compound recipe 23-25 days, and the dosage of every day is equivalent to 5-35mcg ethinylestradiol and about 0.025 approximately to the 10mg norethindrone acetate, and weight ratio is 1: 45.The sickness rate that it is characterized in that breakthrough bleeding descends.
When setting up Estrogen-Progesterone oral contraception method, must be in the face of two main problems.The first, must keep effect, the second, must avoid endometrial hemorrhage.In general, the commercial contraceptive of lowest dose level can possess the contraception effect, and still along with the reduction of dosage, bleeding problems rises, as breakthrough bleeding or amenorrhea (the withdrawal amenorrhea in drug withdrawal week.)
The purpose of this invention is to provide a kind of new Estrogen-Progesterone COC, both preserved the effectiveness of medicine, controlled endometrial hemorrhage again.Therapy has strengthened the adaptability in uterus by the conversion that stopped several times/begin in a year, the anemia patient has been reduced lose blood.Menstruation minimizing has at interval made things convenient for life.By following specific descriptions, it is very obvious that the target of these inventions can become.
Summary of the invention:
The invention provides a kind of composite contraception pharmaceutical preparation that contains estrogenic chemicals and corpus luteum letones, said preparation is made up of estrogenic chemicals and corpus luteum letones and medicine acceptable carrier, the content of estrogenic chemicals calculates the amount that equals 5-35mcg acetylene estradione with the acetylene estradione in each preparation unit, the content of corpus luteum letones calculates the amount of the SH 420 equal 0.025-0.150mg with SH 420, and other are the medicine acceptable carrier.Composite contraception pharmaceutical preparation of the present invention, wherein the amount of estrogens medicine and corpus luteum ketone medicine also can be other specification dosage, make every day taking dose estrogens medicine and the corpus luteum ketone medicine amount that equals the SH 420 of the amount of 5-35mcg acetylene estradione and 0.025-0.150mg get final product, preparation as the ingredient estrogen class medicine in the preparation and corpus luteum ketone medicine being made the amount 1/2 of SH 420 of 1/2 and 0.025-0.150mg of amount that each preparation unit dose equals 5-35mcg acetylene estradione respectively, when taking, take each two dosage every day and get final product.
The present invention also provides a kind of drug packages box, and this packing box intermediate package has two kinds of medicines, estrogens medicine and corpus luteum ketone medicine, and recombinant was packaging together after two kinds of medicines were packed respectively, became combination box of the present invention.Estrogens medicine wherein and each preparation unit dose of corpus luteum ketone medicine equal the amount of the SH 420 of the amount of 5-35mcg acetylene estradione and 0.025-0.150mg respectively, each medicine is respectively obeyed a preparation unit when taking, took continuously 180-360 days, withdrew in 3-5 days subsequently.Drug packages box of the present invention, wherein estrogens medicine and corpus luteum ketone medicine also can be made the unit formulation of other specification dosage, make every day taking dose estrogens medicine and the corpus luteum ketone medicine amount that equals the SH 420 of the amount of 5-35mcg acetylene estradione and 0.025-0.150mg get final product, as estrogens medicine and corpus luteum ketone medicine being made the amount 1/2 of SH 420 of 1/2 and 0.025-0.150mg that each preparation unit dose equals the amount of 5-35mcg acetylene estradione respectively, when taking, take each two dosage every day and get final product.The above estrogens medicine and corpus luteum ketone medicine can be oral formulations, and as tablet or capsule preparations, these medicines and preparation are to use the preparation method of conventional pharmaceutical preparation to prepare.
The present invention has also described a kind of female contraception method, and it is the feature that is reduced to the menstruation number of times in women every year.It is relevant with the female contraception method.This method comprises that estrogenic chemicals of taking every day and corpus luteum letones equal the amount of the SH 420 of 5-35mcg acetylene estradione and 0.025-0.150mg approximately respectively, takes continuously 180-360 days, withdraws in 3-5 days subsequently.The method according to this invention, 180 days rule take medicine and drug withdrawal in 3 days in, have only every year and treat and menstrual cycle for 1-2 time.Above contraceptive method can be by taking compound medicinal formulation of the present invention or drug packages box of the present invention is implemented.
The estrogenic chemicals that contains in compound contraceptive medicament preparation of the present invention and the drug packages box can be selected from following material: the fat of estradiol, estrone and ethinyl estradiol, the salt that comprises them is acetate for example, sulfate, valerate or benzoate, the analog of estrogen (conjugated equine estrogens, agnostic anti-estrogens), and selective estrogen receptor modulators, as: estradiol, estrone, estriol, estradiol benzoate, estradiol valerate, estradiol cypionate, ethinylestradiol, quinestrol, nilestriol, conjugated estrogens, diethylstilbestrol, chlorotrianisene, mestranol, the female ether in general Shandong, stilbestrol dipropionate, dimoestrol, hexestrol, hexestrole bromoacetate.
The corpus luteum letones that contains in compound contraceptive medicament preparation of the present invention and the drug packages box can be selected from following material: Progesterone, medroxyprogesterone, ethisterone, cyproterone, promegestone, nomegestrol, norethindrone, megestrol, norgestrel, levonorgestrel, desogestrel, norgestimate, gestodene, quingestanol, gestrinone, anorethindrane dipropionate, chlormadinone, methylenechlormadinoni acetas, Cymegesolate, hydroxyprogesterone, norethisterone oenanthate,
Preferred estrogenic chemicals of the present invention and corpus luteum letones are acetylene estradione (ethinylestradiol) and SH 420 (levonorgestrel).The weight ratio of these two kinds of active component was at least 1: 5.The amount of preferred acetylene estradione is 10-20mcg, and the amount of SH 420 is 0.05-0.150mg.The consumption of other estrogenic chemicals is equivalent to the acetylene estradione.For example, 30mcg acetylene estradione is equivalent to the 17-beta-estradiol of 60mcg ethinylestradiol methanol or 2000mg approximately.Identical therewith, other corpus luteum letones should be equivalent to SH 420, and for example, the 3.5mg SH 420 approximates 1mg (desogestrel) and (3-ketodesogestre) l and approximately (gestodene) of 0.7mg.The dependency that estrogenic chemicals and corpus luteum letones are renderd a service is known.Given above is acetylene estradione and SH 420 data, if use other estrogenic chemicals and corpus luteum letones, according to the principle of equivalence, used in amounts adjusts.
Preparation in compound contraceptive medicament preparation of the present invention or the drug packages box is taken in a conventional manner, comprises that oral and subcutaneous injection is to keep the activity of medicine.Most estrogen have Orally active, so recommend to make in this way.
The dosage form that is fit to take that compound contraceptive medicament preparation of the present invention can be made into is selected from: tablet, sugar coated tablet, film coated tablet, enteric coated tablet, capsule, hard capsule, soft capsule, oral liquid, suck agent, granule, electuary, pill, powder, sublimed preparation, suspensoid, powder, injection of solution agent, exsiccant injectable powder.
Preparation in compound contraceptive medicament preparation of the present invention or the drug packages box can add when making preparation and physiologically acceptable carrier (adjuvant).Described physiologically acceptable carrier is selected from following material: mannitol, sorbitol, sodium pyrosulfite, sodium sulfite, sodium thiosulfate, cysteine hydrochloride, TGA, methionine, vitamin C, the EDTA disodium, EDTA calcium sodium, the alkali-metal carbonate of monovalence, acetate, phosphate or its aqueous solution, hydrochloric acid, acetic acid, sulphuric acid, phosphoric acid, aminoacid, sodium chloride, potassium chloride, sodium lactate, xylitol, maltose, glucose, fructose, dextran, glycine, starch, sucrose, lactose, mannitol, silicon derivative, cellulose and derivant thereof, alginate, gelatin, polyvinylpyrrolidone, glycerol, soil temperature 80, agar, calcium carbonate, calcium bicarbonate, surfactant, Polyethylene Glycol, cyclodextrin, beta-schardinger dextrin-, the phospholipid material, Kaolin, Pulvis Talci, calcium stearate, magnesium stearate etc.
Preparation of the present invention if oral, contains excipient commonly used, such as binding agent, filler, diluent, lubricant, disintegrating agent, coloring agent, flavoring agent, wetting agent, antiseptic, cosolvent.
The filler that is suitable for comprises cellulose, mannitol, lactose and other similar filler.Suitable disintegrating agent comprises starch, polyvinylpyrrolidone and starch derivatives, for example sodium starch glycollate.Suitable lubricant comprises, for example magnesium stearate, Pulvis Talci.The acceptable wetting agent of appropriate drug comprises sodium lauryl sulphate.
Can fill by mixing, the method that tabletting etc. are commonly used prepares solid oral composition.Mix repeatedly active component is distributed in those preparations of a large amount of filleies of whole use.
The form of oral liquid for example can be aqueous or oily suspensions, solution, Emulsion, syrup or elixir, perhaps can be a kind of available water before use or other suitable composite dry products of carrier.This liquid preparation can contain conventional additive, such as suspending agent, for example sorbitol, syrup, methylcellulose, gelatin, hydroxyethyl-cellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenation edible fat, emulsifying agent, for example lecithin, anhydro sorbitol monooleate or arabic gum; Non-aqueous carrier (they can comprise edible oil), for example almond oil, fractionated coconut oil, such as oily ester, propylene glycol or the ethanol of the ester of glycerol; Antiseptic, for example para hydroxybenzene methyl ester or propyl p-hydroxybenzoate or sorbic acid, and if desired, can contain conventional flavouring agent or coloring agent.
For injection, the liquid unit dosage forms of preparation contains active substance of the present invention and sterile carrier.According to carrier and concentration, this chemical compound can be suspended or dissolving.The preparation of solution is normally passed through medicine dissolution in a kind of carrier, filter-sterilized before it is packed into a kind of suitable bottle or ampoule, sealing then.For example a kind of local anesthetic of adjuvant, antiseptic and buffer agent also can be dissolved in this carrier.In order to improve its stability, can be after the bottle of packing into that this compositions is freezing, and under vacuum, water is removed.
Prepare the parenteral suspension with essentially identical mode,, and before it is suspended in sterile carrier, it is carried out disinfection with oxirane except being is suspended in carrier with reactive compound rather than with its dissolving.Surfactant or wetting agent can be included in this preparation, are beneficial to the uniform distribution of this reactive compound.
Composite contraception pharmaceutical preparation of the present invention is tablet or capsule preparations, and each sheet/grain contains the SH 420 of 5-35mcg acetylene estradione and 0.025-0.150mg.
Drug packages box of the present invention, specifically can be, two Packaging Bottle are arranged in every box, in one of them bottle 175-355 unit of SH 420 preparation arranged, in another bottle 175-355 unit of acetylene estradione preparation arranged, acetylene estradione preparation wherein, the acetylene estradione of 5-35mcg is contained in each preparation unit, the SH 420 preparation, the SH 420 of 0.025-0.150mg is contained in each preparation unit.Drug packages box for tablet or capsule preparations, two Packaging Bottle are arranged in every box, in one of them bottle SH 420 tablet or capsule 175-355 sheet/grain are arranged, in another bottle acetylene estradione tablet or capsule 175-355 sheet/grain are arranged, acetylene estradione preparation wherein, each sheet/grain contains the acetylene estradione of 5-35mcg, SH 420 sheet/grain, and each sheet/grain contains the SH 420 of 0.025-0.150mg.
Pharmaceutical methods can be with reference to various documents, for example, and " modern pharmaceutical " (Banker ﹠amp; Rhodes, MarcelDekker, Inc.1979; " Goodman ﹠amp; Oilman ' s The Pharmaceutical Basis ofTherapeutics ", 6th Edition, MacMillan Publishing Co., New York 1980) or the like can be for referencial use.
The form supply that compound medicinal formulation of the present invention can use boxed.Every box recommends to contain 175 tablets of medicines, can as many as 355, and for taking continuously.The instructions about how to take medicine of recommending are to take estrogen and Progesterone tablet every day, continuous at least 175 days,
For combination box of the present invention, every box recommends to contain 175 of estrogens medicines, can as many as 355, and 175 of corpus luteum ketone medicines can as many as 355, takes continuously for The combined.The instructions about how to take medicine of recommending are to take estrogen and Progesterone tablet every day, continuous at least 175 days,
Below data are further set forth beneficial effect of the present invention by experiment.
Experimental example 1
The animal that use meets the requirements is tested.Standard meets NIH's " laboratory animal application guide ", U.S. public health service portion " laboratory animal using standard ".
10 of experimental selection have the adult female macaque (macaca fasicularis) of normal menstrual cycle (research beginning previous month 28.9+3.1 days).Their spontaneous menstrual phase is 3.4+1.4 days.Average weight is 4.9+1.1kg (X.+.SEM).(12 hours of light and23.degree.C.) raises separately in the environment of control.The commercial Primate feedstuff of feeding (Purina, St.Louis, Mo.) and water.
Monkey is divided into two groups (N=5each) at random.Research is from pretreated menstrual cycle.At the spontaneous menstrual onset of the next one, accepted the very low dose oral contraceptive continuously 60 days, stop treatment in 3 days, or take 84 days continuously, stop 7 days.This therapy is carried out 3 times continuously.
Collect the blood of femoral artery every day, the freezing preservation of serum.Use radioimmunity (RIA) methods analyst estradiol, Progesterone, FSH and LH be each concentration of the 3rd day before treatment, in treatment back and the treatment cycle.The interval of taking medicine, do not done analysis.Use every day the vagina cotton swab to detect hemorrhage feature to differentiate spontaneous menstruation, menstruation moisture regain, breakthrough bleeding or living in retirement property menolipsis.Breakthrough bleeding is defined as in the end takes contraceptive or at the spontaneous menstrual cycle of non-treatment, 8 days outer visible blood of vagina of pro-.
Because purpose is the ultralow metering of test oral contraceptive, medicine is adjusted to and is suitable for the laboratory primate littler than the people.Acetylene estradione dosage is 1.2ug/ days, and the dosage of SH 420 is 0.06mg/ days.(Loestrin 1/20, Parke Davis, Morris Plains with commercial single tablet in experiment, N.J.) clay into power, former medicine contains every of the acetylene estradione of the SH 420 of 1mg and 20.mu.g, is packaged as 21 days dosage, is rich in 7 days iron content placebo.
In order to have comparability with the people, the acceptable dose (body weight of monkey is about 5kg, and women's body weight is about 50kg) of monkey every day is approximately 12.mu.g acetylene estradione and 0.6mg SH 420.So the Estrogen-Progesterone contraceptive of this ultra low-volume has reduced by 40% than the estrogen oral contraceptive of the lowest dose level of existing US and European marketingization.
Consider that continuous 84 days ultra low-volumes add 7 days drug withdrawal interval, compare that have more 63 every year, annual dosage has reduced 26% with 21 days therapies of traditional commercial Loestrin 1/20.
Experimental example 2-5
The experiment of experimental example 1 uses following estrogen and Progesterone combination to obtain repetition:
Experimental example estrogenic chemicals corpus luteum letones treatment natural law
2 mestranol SH 420s 84
(mestranol) (levonorgestrel)
3 17-beta-estradiol 3-keto-desogestrel 110
e thinyl
4 Estradiol?ethinyl?Desogestrel 80
5 Estradiol?mestranol Gestodone 60
The method that the present invention stated, preparation and composition can be with any clinical, medical science and pharmaceutical technology method validations.Concrete experiment described above is in order to set forth this invention.Various modifications are carried out in various changes under the prerequisite of following its basic thought and scope.
The specific embodiment:
Further specify the present invention by the following examples.Just explanation rather than of the effect of these embodiment in order to limit range of application of the present invention.
Embodiment 1
Every contains the SH 420 of 0.025mg and 25mg SH 420 and 5mg acetylene estradione are got in the preparation of 5mcg acetylene estradione tablet, add starch 50g, carboxymethyl cellulose 50g, usefulness progression method mix homogeneously, 75% ethanol is wetting agent, mixing, wet granulation, oven dry, granulate, add 1% magnesium stearate, the mixing tabletting extrudes 1000.
Embodiment 2
Contain the SH 420 of 0.150mg and the preparation of 35mcg acetylene estradione capsule and get 150mg SH 420 and 35mg acetylene estradione, add starch 50g, carboxymethyl cellulose 50g, usefulness progression method mix homogeneously, 75% ethanol is wetting agent, mixing, wet granulation, oven dry, granulate, add 1% magnesium stearate, encapsulated 1000.
Embodiment 3
Contain the SH 420 of 0.150mg and the preparation of 35mcg acetylene estradione sugar coated tablet and get 150mg SH 420 and 35mg acetylene estradione, add starch 50g, carboxymethyl cellulose 50g, usefulness progression method mix homogeneously, 75% ethanol is wetting agent, mixing, wet granulation, oven dry, granulate, add 1% magnesium stearate, the mixing tabletting extrudes 1000.Use sucrose syrup, Pulvis Talci, after food coloring mixes, the coating pan sugar coating.
Embodiment 4
Contain the SH 420 of 0.025mg and the preparation of 5mcg acetylene estradione enteric coated tablet and get 25mg SH 420 and 5mg acetylene estradione, add starch 50g, carboxymethyl cellulose 50g, usefulness progression method mix homogeneously, 75% ethanol is wetting agent, mixing, wet granulation, oven dry, granulate add 1% magnesium stearate, the mixing tabletting, extrude 1000, enteric coated.
Embodiment 5
The preparation of combination box has two Packaging Bottle in every box, 175 in the SH 420 tablet of 0.025mg is arranged in one of them bottle, in another bottle 175 in 5mcg acetylene estradione tablet is arranged.
Embodiment 6
The preparation of combination box has two Packaging Bottle in every box, 175 in the SH 420 tablet of 0.150mg is arranged in one of them bottle, in another bottle 175 in 35mcg acetylene estradione tablet is arranged.
Embodiment 7
The preparation of combination box has three Packaging Bottle in every box, 175 in the SH 420 tablet of 0.025mg is arranged in one of them bottle, in another bottle 175 in 5mcg acetylene estradione tablet is arranged, and in the 3rd bottle 3 tablets of placebo is arranged.
Embodiment 8
The preparation of combination box has three Packaging Bottle in every box, 355 in the SH 420 tablet of 0.025mg is arranged in one of them bottle, in another bottle 355 in 5mcg acetylene estradione tablet is arranged, and in the 3rd bottle 5 tablets of placebo is arranged.
Embodiment 9
Every preparation that contains the SH 420 tablet of 0.025mg
Get the 25mg SH 420, add starch 50g, carboxymethyl cellulose 50g, usefulness progression method mix homogeneously, 75% ethanol is wetting agent, mixing, wet granulation, oven dry, granulate add 1% magnesium stearate, and the mixing tabletting extrudes 1000.
Embodiment 10
Every preparation that contains 5mcg acetylene estradione tablet
Get 5mg acetylene estradione, add starch 50g, carboxymethyl cellulose 50g, usefulness progression method mix homogeneously, 75% ethanol is wetting agent, mixing, wet granulation, oven dry, granulate add 1% magnesium stearate, and the mixing tabletting extrudes 1000.
Claims (10)
1. composite contraception pharmaceutical preparation that contains estrogenic chemicals and corpus luteum letones, said preparation is made up of estrogenic chemicals and corpus luteum letones and medicine acceptable carrier, the content of estrogenic chemicals calculates the amount that equals 5-35mcg acetylene estradione with the acetylene estradione in each preparation unit, the content of corpus luteum letones calculates the amount of the SH 420 equal 0.025-0.150mg with SH 420, and other are the medicine acceptable carrier.
2. the composite contraception pharmaceutical preparation of claim 1, wherein estrogenic chemicals is selected from: the acetylene estradione, the fat of estradiol, estrone, ethinyl estradiol, estradiol, estrone, estriol, estradiol benzoate, estradiol valerate, estradiol cypionate, ethinylestradiol, quinestrol, nilestriol, conjugated estrogens, diethylstilbestrol, chlorotrianisene, mestranol, the female ether in general Shandong, stilbestrol dipropionate, dimoestrol, hexestrol, hexestrole bromoacetate or their acetate, sulfate, valerate or benzoate, the corpus luteum letones is selected from: SH 420, Progesterone, medroxyprogesterone, ethisterone, cyproterone, promegestone, nomegestrol, norethindrone, megestrol, norgestrel, levonorgestrel, desogestrel, norgestimate, the gestodene, quingestanol, gestrinone, anorethindrane dipropionate, chlormadinone, methylenechlormadinoni acetas, Cymegesolate, hydroxyprogesterone, norethisterone oenanthate.
3. the composite contraception pharmaceutical preparation of claim 1 is oral drug preparation, and the SH 420 of 5-35mcg acetylene estradione and 0.025-0.150mg is contained in each preparation unit.
4. the composite contraception pharmaceutical preparation of claim 1 is tablet or capsule preparations, and each sheet/grain contains the SH 420 of 5-35mcg acetylene estradione and 0.025-0.150mg.
5. drug packages box, two kinds of pharmaceutical preparatioies are housed in this packing box, a kind of pharmaceutical preparation for making by estrogenic chemicals, the pharmaceutical preparation that another kind is made for the corpus luteum letones, two kinds of pharmaceutical preparatioies are separately packed, recombinant formation combination box packaging together, the content of each preparation unit of estrogens medicine wherein calculates the amount that equals 5-35mcg acetylene estradione with the acetylene estradione, and the content of each preparation unit of corpus luteum ketone medicine calculates the amount of the SH 420 that equals 0.025-0.150mg with SH 420.
6. the packing box of claim 5, wherein estrogenic chemicals is selected from: the acetylene estradione, the fat of estradiol, estrone, ethinyl estradiol, estradiol, estrone, estriol, estradiol benzoate, estradiol valerate, estradiol cypionate, ethinylestradiol, quinestrol, nilestriol, conjugated estrogens, diethylstilbestrol, chlorotrianisene, mestranol, the female ether in general Shandong, stilbestrol dipropionate, dimoestrol, hexestrol, hexestrole bromoacetate or their acetate, sulfate, valerate or benzoate, the corpus luteum letones is selected from: SH 420, Progesterone, medroxyprogesterone, ethisterone, cyproterone, promegestone, nomegestrol, norethindrone, megestrol, norgestrel, levonorgestrel, desogestrel, norgestimate, the gestodene, quingestanol, gestrinone, anorethindrane dipropionate, chlormadinone, methylenechlormadinoni acetas, Cymegesolate, hydroxyprogesterone, norethisterone oenanthate.
7. the packing box of claim 5, two Packaging Bottle are arranged in every box, in one of them bottle 175-355 unit of SH 420 preparation arranged, in another bottle 175-355 unit of acetylene estradione preparation arranged, acetylene estradione preparation wherein, the acetylene estradione of 5-35mcg is contained in each preparation unit, the SH 420 preparation, and the SH 420 of 0.025-0.150mg is contained in each preparation unit.
8. the packing box of claim 5, two Packaging Bottle are arranged in every box, in one of them bottle SH 420 tablet or capsule 175-355 sheet/grain are arranged, in another bottle acetylene estradione tablet or capsule 175-355 sheet/grain are arranged, acetylene estradione preparation wherein, each sheet/grain contains the acetylene estradione of 5-35mcg, SH 420 sheet/grain, and each sheet/grain contains the SH 420 of 0.025-0.150mg.
9. the packing box of claim 5, wherein also packing has placebo.
10. female contraception method, this method comprises, estrogenic chemicals of taking every day and corpus luteum letones equal the amount of the SH 420 of the amount of 5-35mcg acetylene estradione and 0.025-0.150mg respectively, take continuously 180-360 days, withdraw in 3-5 days subsequently.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2004100296007A CN1672685A (en) | 2004-03-26 | 2004-03-26 | New contraception medicine |
| PCT/CN2004/000348 WO2005092346A1 (en) | 2004-03-26 | 2004-04-14 | Using combination of estrogen and progestin with ultra low dose for long term oral contraception |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2004100296007A CN1672685A (en) | 2004-03-26 | 2004-03-26 | New contraception medicine |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1672685A true CN1672685A (en) | 2005-09-28 |
Family
ID=35045627
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2004100296007A Pending CN1672685A (en) | 2004-03-26 | 2004-03-26 | New contraception medicine |
Country Status (2)
| Country | Link |
|---|---|
| CN (1) | CN1672685A (en) |
| WO (1) | WO2005092346A1 (en) |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102302779A (en) * | 2011-07-29 | 2012-01-04 | 岳中瑾 | Cream preparation used for treating phimosis, and application thereof |
| CN101848716B (en) * | 2007-11-05 | 2012-11-28 | 拜耳先灵医药股份有限公司 | Use of a gestagen in combination with an estrogen and one or more pharmaceutically tolerable excipients/carriers for lactose-free oral contraceptive |
| CN101455644B (en) * | 2008-02-05 | 2013-05-01 | 北京紫竹药业有限公司 | Long-acting composite contraception microspheres and preparation method thereof |
| CN107995864A (en) * | 2015-05-18 | 2018-05-04 | 敏捷治疗公司 | Composition for contraception and the method for improving efficiency and adjusting side effect |
| CN114259498A (en) * | 2021-12-02 | 2022-04-01 | 南通联亚药业有限公司 | Pharmaceutical composition containing desogestrel and ethinylestradiol, and preparation method and application thereof |
| WO2022246634A1 (en) * | 2021-05-25 | 2022-12-01 | Zhejiang Jiachi Development Pharmaceuticals Ltd. | Compositions for treating insomnia and uses thereof |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20070111975A1 (en) * | 2004-10-07 | 2007-05-17 | Duramed Pharmaceuticals, Inc. | Methods of Hormonal Treatment Utilizing Ascending-Dose Extended Cycle Regimens |
| JP2011507853A (en) * | 2007-12-20 | 2011-03-10 | テバ ウィメンズ ヘルス インコーポレイテッド | Dosage regimens and pharmaceutical compositions and packages for emergency contraception |
-
2004
- 2004-03-26 CN CNA2004100296007A patent/CN1672685A/en active Pending
- 2004-04-14 WO PCT/CN2004/000348 patent/WO2005092346A1/en active Application Filing
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101848716B (en) * | 2007-11-05 | 2012-11-28 | 拜耳先灵医药股份有限公司 | Use of a gestagen in combination with an estrogen and one or more pharmaceutically tolerable excipients/carriers for lactose-free oral contraceptive |
| CN101455644B (en) * | 2008-02-05 | 2013-05-01 | 北京紫竹药业有限公司 | Long-acting composite contraception microspheres and preparation method thereof |
| CN102302779A (en) * | 2011-07-29 | 2012-01-04 | 岳中瑾 | Cream preparation used for treating phimosis, and application thereof |
| CN107995864A (en) * | 2015-05-18 | 2018-05-04 | 敏捷治疗公司 | Composition for contraception and the method for improving efficiency and adjusting side effect |
| WO2022246634A1 (en) * | 2021-05-25 | 2022-12-01 | Zhejiang Jiachi Development Pharmaceuticals Ltd. | Compositions for treating insomnia and uses thereof |
| CN114259498A (en) * | 2021-12-02 | 2022-04-01 | 南通联亚药业有限公司 | Pharmaceutical composition containing desogestrel and ethinylestradiol, and preparation method and application thereof |
| CN114259498B (en) * | 2021-12-02 | 2023-04-28 | 南通联亚药业股份有限公司 | Pharmaceutical composition containing desogestrel and ethinyl estradiol as well as preparation method and application thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2005092346A1 (en) | 2005-10-06 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US5108995A (en) | Hormone preparation and method | |
| US5585370A (en) | Hormone preparation and method | |
| EP0559240B1 (en) | Contraceptive packages containing oestrogen and progestin | |
| CN1137691C (en) | heterogeneous contraception preparation based on natural estrogen | |
| CA2256977C (en) | Methods of extended use oral contraception | |
| US5256421A (en) | Hormone preparation and method | |
| KR100847346B1 (en) | Methods and preparations for treating female sexual dysfunction | |
| US4855305A (en) | Compositions and methods of effecting contraception utilizing melatonin | |
| KR100849919B1 (en) | Combination of an estrogen and an androgen for treating hormonal deficiencies in women undergoing estrogen replacement therapy | |
| JP2015163646A (en) | Pharmaceutical composition and treatment method for emergency contraception | |
| CN1678324A (en) | Estrogen Replacement Therapy Programs | |
| US20030191096A1 (en) | Method of hormonal therapy | |
| CN1672685A (en) | New contraception medicine | |
| CA2392841A1 (en) | Ultra low dose oral contraceptives with sustained efficacy and induced amenorrhea | |
| JP2001523639A (en) | Progestogen-anti-progestogen regimen | |
| EP0472628A1 (en) | Use of melatonin derivatives for effecting contraception | |
| CA1332228C (en) | Formulation and method for estrogen replacement therapy | |
| JP2007197459A (en) | Ultra low dose contraceptive with less menstrual bleeding and sustained efficacy | |
| IE83631B1 (en) | Hormone preparation and method | |
| IE84449B1 (en) | Contraceptive packages containing oestrogen and progestin | |
| CA2596416A1 (en) | Methods of extended use oral contraception |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
| WD01 | Invention patent application deemed withdrawn after publication |