CN103961457A - Medicine composition for treating colporrhagia in woman climacterium and preparation method of composition - Google Patents
Medicine composition for treating colporrhagia in woman climacterium and preparation method of composition Download PDFInfo
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Abstract
The invention provides medicine composition for treating colporrhagia in woman climacterium. The medicine composition comprises a first active component, namely, components of a Kuntai capsule and a second active component, namely, mifepristone, wherein the Kuntai capsule comprises cooked rehmannia roots, rhizoma coptidis, radix paeoniae alba, radix scutellariae, ass-hide glue and poria cocos. Through combined application of the Kuntai capsule and the mifepristone of the composition, the composition is obvious superior to a singleprescription of the same dosage in effect of treating the colporrhagia in the woman climacterium, the fact indicates that the two medicines have synergistic effects when being combined for usage, and meanwhile, the composition is free of obvious toxicity and side effects and more significant in treatment effect.
Description
Technical field
The present invention relates to the pharmaceutical composition of a kind of vaginal hemorrhage for the treatment of Woman climacteric, more specifically, the invention still further relates to preparation method and and the application in the medicine for the treatment of Woman climacteric vaginal hemorrhage by the prepared medicine of this preparation method of said composition.
Background technology
Climacteric there will be vaginal hemorrhage, and different individualities often there will be dizziness, numb limbs and tense tendons, hand tremor, hypomnesis, sleepy, irritability, excitement and adaptive capacity reduces and the syndrome such as Increased sensitivity.Serious time, can cause life danger.
Kuntai capsule is made up of Radix Rehmanniae Preparata, Rhizoma Coptidis, the Radix Paeoniae Alba, Radix Scutellariae, Colla Corii Asini, Poria composition, and it has nourishing YIN and clearing away heat, the relieving restlessness of calming the nerves.Hyperactivity of fire caused by deficiency of YIN person, disease sees that hectic fever is flushing, spontaneous sweating, vexed peaceful, insomnia and dreamful sleep, dizziness and tinnitus, soreness of the waist and knees, feverish sensation in the palms and soles; The curative effect that women's ovary deterioration climacteric syndrome is shown in above-mentioned shower.Effectively control vaginal hemorrhage but can't form clinically.
Mifepristone is acceptor levels onapristone, has termination of early pregnancy, anti-implantation, induction menstruation and promotes the effects such as cervix maturation, reaches the effect of antagonism progesterone with progesterone competition receptor, also has certain adhesion with glucocorticoid receptor (GR).Mifepristone can obviously increase the sensitivity of gravid uterus to prostaglandin.The sequential merging prostaglandins of low dose mifepristone administration medicine, can obtain satisfied termination of early pregnancy effect.
Also do not have at present a kind of specific medicament to go effective prevention, alleviate and/or treat climacteric in the world and there will be vaginal hemorrhage
Based on inventor's knowledge, do not report that Kuntai capsule and Mifepristone plus are applied to more effectively the vaginal hemorrhage that prevents, alleviates and/or treat treatment Woman climacteric at present.
Summary of the invention
The object of the invention has been to provide the pharmaceutical composition of a kind of vaginal hemorrhage that is used for the treatment of Woman climacteric, and it is Kuntai capsule and the second active component mifepristone that this pharmaceutical composition contains the first active component.Because two medicine mechanism of action and two medicines have share synergism, its effect is obviously better than the folk prescription of same dose.In addition, by the consumption of the mifepristone in choose reasonable compositions, make compositions in the vaginal hemorrhage that effectively reduces Woman climacteric again without obvious toxic and side effects, the while, this compositions only needed medication once on 1st, medication is convenient, and this will improve patient's compliance greatly.
Based on above-mentioned technical problem, the present invention solves by following scheme: the invention provides a kind of compositions for the treatment of hyperlipidemia, said composition comprises two kinds of active component, and first active component is Kuntai capsule, and second active component is mifepristone.
In one aspect of the invention, the percentage by weight that in the first active component Kuntai capsule, each component accounts for total charges is:
Described each component is taken, be ground into fine powder, add starch and the magnesium stearate in above-mentioned table, measured to mix, then pour in hopper, open granulation coating machine, pour celphere into, pelletize, pelletize speed 1-10rpm, rotary speed 100-500rpm, after spray 7%PVP solution, dry discharging and become described Kuntai capsule.
An aspect of of the present present invention, the present invention screens the weight ratio of two kinds of active component as an example of mifepristone example, the weight ratio that draws by experiment Kuntai capsule and mifepristone is 10～1000:1, and preferred ratio is 20～500:1, and further preferred ratio is 250:1.
Another aspect of the present invention, described compound preparation can be oral formulations, external preparation, suction preparation, through nasal preparation, per rectum preparation, percutaneous preparation or ejection preparation.Be preferably oral formulations.
The oral formulations dosage form of the pharmaceutical preparation of the present composition, comprise the solid preparations such as tablet, capsule, granule, pill, drop pill, can be according to general formulation method preparation well known in the art, Kuntai capsule content is equivalent to when by compositions administration the approximately daily dose of 200～750mg, and mifepristone content is equivalent to the daily dose of 0.25～2mg.
Another aspect of the present invention, described purposes also comprises uses to experimenter the compositions of the present invention that prevents and/or treats effective dose.Preferably described experimenter behaves.
Another aspect of the present invention, described effective dose comprises uses the medicine of about 0.1mg/kg to about 10000mg/kg body weight every day to people.
Another aspect of the present invention, described medicine also comprises and contains the Kuntai capsule that mixes with the diluent or carrier pharmaceutically accepted and the pharmaceutical composition of mifepristone, in described pharmaceutical composition, Kuntai capsule and mifepristone proportion, by weight, the gross weight that accounts for whole preparation is 10%～80%.
In the world, inventor uses from screening Kuntai capsule and mifepristone and has obtained a present composition without any side effects, effectively accomplishes first Scientific Usage of Drugs, shoots the arrow at the target.Also be this function of having found first the compositions of Kuntai capsule and mifepristone, filled up Chinese herbal medicine modern domestic, international blank, be beneficial to Rehabilitation.
Detailed description of the invention
In order to provide substantive understanding of the present invention, with different the level of details, some aspect of the present invention, pattern, embodiment, modification and feature are described hereinafter.
In enforcement process of the present invention, medical science, clinical medicine, protein biochemistry, cytobiology, immunology, microbiology, pharmacology are used, a lot of conventional arts of toxicology, pharmacopedics and pharmaceutical technology aspect.These technology are known, and in pertinent literature, are illustrated respectively.The definition of some terms that use in this description, except as otherwise noted, all technology used herein and scientific words have the meaning equivalent in meaning of conventionally understanding with those skilled in the art conventionally.
The preventive use of the present composition and therapeutic use
In an embodiment of the invention, first prepare pharmaceutical composition of the present invention, described compositions comprises: a) the first active component: Kuntai capsule; B) the second active component: mifepristone.Described Kuntai capsule is made up of Radix Rehmanniae Preparata, Rhizoma Coptidis, the Radix Paeoniae Alba, Radix Scutellariae, Colla Corii Asini, Poria.Each component of above-mentioned Kuntai capsule can be taken out from the capsule preparing, or buys individually each combination, is then mixed, with mifepristone moulding preparation.
In another embodiment of the present invention, in described Kuntai capsule, each component accounts for the percentage by weight of total charges and is:
Described each component is taken, be ground into fine powder, add starch and the magnesium stearate in above-mentioned table, measured to mix, then pour in hopper, open granulation coating machine, pour celphere into, pelletize, pelletize speed 1-10rpm, rotary speed 100-500rpm, after spray 7%PVP solution, dry discharging and become described Kuntai capsule.
In the detailed description of the invention of preparation pharmaceutical composition of the present invention, by weight, the proportionate relationship of the interpolation of mifepristone and Kuntai capsule can be 1:1～10000, is preferably 1:20～500; More preferably 1:50～500; Further preferred ratio is 1:250.
Term used herein " treatment " or refer to treatment treatment measures and measure prevention or that prevent, wherein, prevents or slows down (weakening) experimenter's the pathological symptom of suffering from or imbalance.If accepted according to the present composition of the therapeutic dose of method as herein described, experimenter's symptom succeed " treatment ", experimenter shows, can observe and/or be measured to one or more signs of symptom and symptom and reduce and disappear.It is also understood that treatment described herein or prevent that the various patterns of medical conditions are intended to represent " significantly ", it comprises whole treatments or prevention and is less than whole treatments or prevention, has wherein reached and has been correlated with or the relevant result of medical science certain biology.
In various embodiments, carry out that suitable external test or in vivoassay are measured the effect of the medicine based on the specific present composition and whether administration is suitable for treatment.In various embodiments, can carry out external test to the related representative cell of experimenter's disease, measure the given medicine based on the present composition and whether described cell type has been produced to the effect of expecting.If accepted according to the present composition of the therapeutic dose of method as herein described, experimenter's symptom is succeeded and is treated, be that experimenter shows, one or more signs and the symptom that can observe and/or be measured to above-mentioned pathological symptom or disease reduce and disappear.It is also understood that treatment described herein or prevent that the various patterns of medical conditions are intended to represent " significantly ", it comprises whole treatments or prevention and is less than whole treatments or prevention, has wherein reached and has been correlated with or the relevant result of medical science certain biology.
In a specific embodiment of the present invention, experimenter is used to the medicine that contains the present composition that prevents and/or treats effective dose.
Before human experimenter is tested, can in suitable animal model system, test candidate compound used in treatment, described animal subjects model system for example, including, but not limited to non-human primates (baboon, orangutan, monkey); Such as the pet animals of cat, Canis familiaris L., Serpentis etc.; The farm-animals of pig, horse, cattle, goat etc.; Such as any animal of the laboratory animals of rat, mice, monkey, rabbit etc.In one embodiment, by the present composition be administered to suffer from or danger in above-mentioned pathological symptom or disease in the experimenter of (state of this symptom that is easy to get), attempt to improve the one or more factors that cause this pathological symptom or disease.
Term used herein " effective dose " refers to be enough to obtain the required effect that treats and/or prevents, for example, cause prevention or alleviate and the amount of the symptom of pathological symptom or disease.Be administered to experimenter's the amount of compositions by depending on the type of disease and seriousness and individual character, such as health condition, age, sex, body weight and the tolerance to medicine at ordinary times.Described amount also depends on ill degree, seriousness and type.Those skilled in the art can according to these factors and other be because usually determining suitable dosage.Described compositions also can be carried out administration in conjunction with one or more other treatment compound.In method described herein, compound of the present invention can be administered to has one or more signs of pathological symptom or the experimenter of pathological symptom.For example, " treatment effective dose " refers to the minimally average level of the physiological action of mitigation symptoms.
Conventionally, described dosage can prevent or alleviate seriousness or the expansion for the treatment of situation or indication.Correct dosage will depend on environment, situation, administration time table, the described compound for example treated whether use separately or be combined with another kind of therapeutic agent use, the plasma half-life of described compound and experimenter's holistic health.
Can adopt comprise oral, external, suck, per nasal, per rectum, percutaneous or injection method of application to experimenter's medication.
In a specific embodiment of the present invention, prepare and contained for described pharmaceutical composition disclosed herein, dosage scheme was about 0.1mg/kg to about 10000mg/kg body weight, was preferably about 1mg/kg to about 10000mg/kg body weight, more preferably 1mg/kg, to about 5000mg/kg, most preferably is 1mg/kg to about 2000mg/kg body weight every day.Can use every day 1 to 6 time, preferably use 2 or 3 times every day.Interval can be also irregular, those skilled in the art generally acknowledge that compound or the optimised quantity of its pharmaceutically acceptable salt and the interval of single-dose are by the nature and extent by situation to be treated, form, approach and the site of administration and the experimenter's who treats concrete condition and determining, and can determine most preferably scheme by routine techniques.Those skilled in the art be also to be understood that the optimum process for the treatment of, and the compound that give every day in given natural law or the administration quantity of its pharmaceutically acceptable salt can be utilized conventional treatment method of testing and be determined by those skilled in the art.In treatment application, in relatively short interval, there is relatively high dosage sometimes to need, until the process of disease slows down or stops, and preferably until experimenter display section or fully improved described disease or pathological symptom.Therefore, patient can be to the administering mode of effecting prevention property of patient.Those skilled in the art will recognize that, some factor can affect dosage and the time of effectively treating an experimenter, including, but not limited to the order of severity of disease or imbalance, previous treatment, health condition and/or experimenter's age and the Other diseases of existence.And, utilize the treatment reference composition for the treatment of effective dose described herein to treat an experimenter and can comprise single therapy or a series for the treatment of.
Compositions of the present invention can be together with at least one other compound administering therapeutic climacteric vaginal hemorrhage.Herein only as an example, for example comprise with the common compounds of following treatment the antibioticses such as Phenylbutazone, miltown, sodium phenobarbital, rifampicin, phenytoin Sodium, chlordiazepoxide, desoxyphenobarbital, carbamazepine, ethosuximide, carbamazepine, hydrocortisone, clomiphene, estradiol valerate, Progesterone, human chorionic gonadotropin (hCG), penicillins, Tetracyclines, chloromycetin, erythromycin, estrogen, progestogen, erythromycin and and bactrim, but be not limited to use together.It will be appreciated by those skilled in the art that the above-claimed cpd of using can make a choice according to described various disease or pathological symptom together with compositions of the present invention.
Compound of the present invention can be used together with at least one other Chinese herbal medicine.Chinese patent medicine can be selected Fructus Chaenomelis Pilulae, DAHUOLUO DAN, XIAOHUOLUO DAN, Radix Bupleuri, Radix Salviae Miltiorrhizae, Ramulus Cinnamomi, the Radix Paeoniae Alba, Pericarpium Citri Reticulatae, Rhizoma Pinelliae, Herba speranskiae tuberculatae, Rhizoma Et Radix Notopterygii, Radix Rehmanniae, Radix Platycodonis, Rhizoma Cyperi, Semen Sinapis Albae, Radix Aconiti Kusnezoffii, RADIX ACONITI LATERALIS PREPARATA, Caulis Lonicerae, Radix Gentianae Macrophyllae, Ramulus Mori, Poria, Radix Ginseng, the Radix Astragali, the Rhizoma Atractylodis Macrocephalae, Radix Angelicae Sinensis, Radix Rehmanniae Preparata, Fructus Corni, Colla Corii Asini, Herba Schizonepetae, Rhizoma Cyperi, Auricularia charcoal, Radix Glycyrrhizae, Radix Angelicae Sinensis, the Radix Rehmanniae, the Radix Paeoniae Alba, Radix Scrophulariae, Cortex Phellodendri, Fructus Ligustri Lucidi, the Radix Rehmanniae, the Radix Paeoniae Alba, Radix Scrophulariae, Fructus Ligustri Lucidi, Cortex Moutan, Cortex Phellodendri, Herba Ecliptae, Herba Schizonepetae, Fructus Atriplicis Sibiricae, Radix Polygoni Multiflori, Rhizoma Smilacis Glabrae, raw Semen Coicis, Semen Plantaginis, Herba Scutellariae Barbatae, Herba Hedyotidis Diffusae, Radix Angelicae Sinensis, Radix Paeoniae, Fructus Evodiae, Radix Et Rhizoma Rhei, Rhizoma Zingiberis, Radix Aconiti Lateralis Preparata, Herba Asari, Rhizoma Chuanxiong, Cortex Moutan, Tabanus, Hirudo, Cortex Magnoliae Officinalis, Semen Persicae, Ramulus Cinnamomi, Radix Angelicae Sinensis, Radix Paeoniae Rubra, Rhizoma Chuanxiong, Ramulus Cinnamomi, Tabanus, Hirudo, Rhizoma Zingiberis, Herba Asari, RADIX PEUCEDANI, firewood guest, continuous careless Rhizoma Nelumbinis, Herba Gendarussae, Cortex Syingae Amurensis, Herba pterocephali, Medulla Stachyuri (Medulla Helwingiae), Flos Bombacis Malabarici, dragon brush leaf, Herba Polygoni cymosi, recklessly reed the sixth of the twelve Earthly Branches, emblic in, Herba Potentillae Discoloris, Flos Rhododendri Mollis, Semen Litchi, Rhizoma Saururi (Herba Saururi), Caulis Lonicerae, Cortex Phellodendri, dried meat is looked sidelong in sea, meaning Hui Ren, night Siberian cocklebur, Herb Gynostemmae Pentaphylli, Rhizoma Polygoni Cuspidati, Fructus Aurantii, Semen Astragali Complanati, Herba Hedyotidis Diffusae, Herba Scutellariae Barbatae, Ramulus Uncariae Cum Uncis, Indigo Naturalis, Radix Salviae Miltiorrhizae, Flos Chrysanthemi, Fructus Cnidii, Semen Persicae, my art, Ganoderma, the Rhizoma Atractylodis Macrocephalae, Radix Paeoniae Rubra, Cortex Phellodendri, Radix Bupleuri, the Radix Aucklandiae, Flos Carthami, Semen Persicae, Radix Angelicae Sinensis, Scolopendra, Scorpio, Armadillidium, Flos Lonicerae, Fructus Citri Sarcodactylis, Caulis Spatholobi, Herba Hedyotidis Diffusae, Herba Lobeliae Chinensis, Gekko Swinhonis, Herba Duchesneae Indicae, Rhizoma Paridis, Herba Violae, Fructus Forsythiae, Rhizoma Sparganii, Rhizoma Curcumae, Rhizoma Corydalis, Radix et Rhizoma Rhei (stir-fried with wine), Eupolyphaga Seu Steleophaga, Poria, Radix Notoginseng, the Pseudobulbus Bletillae (Rhizoma Bletillae), Herba Leonuri, Herba Artemisiae Scopariae, Herba Houttuyniae, stir-baked SQUAMA MANITIS, Fructus Aurantii Immaturus, Herba Salviae Chinensis, Herba Cirsii, Radix Sanguisorbae, Fructus Lycii, the Radix Astragali, Fructus Ligustri Lucidi, Spica Prunellae, the blue or green bat of Radix Glycyrrhizae and Folium Et Cacumen Murrayae.
Described compound or Chinese herbal medicine can be used as independent preparation or use in unit dosage forms with combination of compositions of the present invention simultaneously, or use in turn.Under any circumstance, multiple therapeutic agent can be with any order or administration even simultaneously.If side by side, described multiple therapeutic agent can be provided as single, unified form or with multiple forms (for example,, as single tablet or two of tablet or capsule kinds of different preparations independently separately).A kind of therapeutic agent in described therapeutic agent may provide with multiple dose type, or wherein two kinds can be used as multiple dose type and provide.If not side by side, the interval between multidose can be from being greater than 0 week to being less than approximately 1 week, be less than approximately 2 weeks, be less than approximately 4 weeks, be less than approximately 2 months, be less than approximately 4 months or be even less than the scope of about half a year and change.
In the another embodiment of the present invention, can be by the first active component and the second active component simultaneously, use continuously and respectively.
Term used herein " unit dosage forms " refers to the unit separating being physically suitable as for humans and animals experimenter's unit dose, the compound that each unit comprises independent scheduled volume or with other agent combination, its amount is enough to as calculated and pharmaceutically acceptable diluent, carrier or media mix produce desired effects.
In the specific embodiment of the present invention, the pharmaceutical composition of compositions or derivatives thereof that preparation contains Kuntai capsule and mifepristone, it is used for the treatment of and/or prevent and increases and make collagen protein relevant pathological symptom or the disease of improving of degrading by suppressing human cathepsin K activity.It plays a role to experimenter's administration by modes such as oral, external, inhalations.Therefore pharmaceutical composition of the present invention can be prepared into various dosage forms, for example, can be the prepared product of capsule, tablet, powder, granule, buccal tablet, effervescent tablet, syrup, emulsion, controlled release, rapidly-soluble prepared product, liquid oral dosage form etc. for the compositions of oral medication; Compositions for external medication can be liniment type medicine, cream, external application, ointment, lotion, the gentle spray of liquid spray etc.Compositions for inhalation administration can be solution, dispersion liquid, dry powder etc.; Also can from red bayberry spp.ing plant and vitis spp, extract the composition compounds of highly purified Kuntai capsule and mifepristone, the nanometer Kuntai capsule of preparation liposome and the compositions of mifepristone, be prepared into ejection preparation and slow releasing pharmaceutical dosage form.In described pharmaceutical composition, the compositions of Kuntai capsule and mifepristone or its derivant proportion, the gross weight that accounts for whole preparation taking weight is 1.0%～99.0%, preferably 10%～90%, be more preferably 10%～75%, most preferably be 25～70%.
In pharmaceutical preparation of the present invention, taking oral formulations as example, pharmaceutically acceptable adjuvant used is including, but not limited to lubricant, as magnesium stearate, calcium stearate, or zinc stearate, stearic acid, Glyceryl Behenate, sodium stearyl fumarate, Talcum, silica gel; Disintegrating agent, as starch, cyclodextrin, carboxymethyl cellulose, cross-linked carboxymethyl cellulose, crospolyvinylpyrrolidone; Diluent or compression agent, as lactose, sucrose, mannitol xylitol, erythritol, Sorbitol, microcrystalline Cellulose; Flavouring agent or other composition, as Fructus Fragariae Ananssae, Fructus Citri tangerinae, Fructus Musae, Herba Menthae, Mel.
Carrier granular can be crystal or the spheroid of lactose or sucrose; Or composite sphere or granule, as by with starch as binding agent make sucrose granulate form sugared spheroid, by starch as binding agent form calcium carbonate spheroid or maltodextrin.Carrier granular can be also the granule of any other medical acceptable excipient, as hydroxy propyl cellulose crude granule, guar gum granule, xanthan gum granule.Carrier can have various ways, and the adjustment of all these selections and amount is obviously in those skilled in the art's limit of power.
By per os approach, can comprise and be dissolved in food or health product liquid according to the compound of the compositions or derivatives thereof of Kuntai capsule of the present invention and mifepristone or its compositions, as being dissolved in alternatively liquid or the water～alcohol solution of aqueous of seasoning.It can be included into the solid excipient that can swallow, for example, in the form of particle form, pill, tablet, enteric coatel tablets.It also can be placed in the liquid in food or health product, and itself optional condition is in swallowable capsule.For swallowing, can be multiple Orally administered composition embodiment, particularly, can be the accrete Orally administered composition embodiment of food.Manufacture enteric coatel tablets, colloid capsule, gel, emulsion, tablet, capsule or solution and preparation by conventional method.Particularly, can include any other form of dietary supplement ingredient or condensed food or health product according to activating agent of the present invention, for example food or health product rod, or among compression or incompressible powder.These powder can dilute with water, can be at soda, and dilute with water in salt cheese production or soybean derivatives, maybe can bring in food or health product.
Record by following embodiment, understand better the present invention, but be not limited to this embodiment.
Embodiment
Embodiment 1: capsule-type preparation
a、
| Activating agent | Addition (g) |
| Kuntai capsule | 200 |
| Excipient | |
| Starch | 200 |
| Magnesium stearate | 3 |
Kuntai capsule compositions for the embodiment of the present invention can be the Kuntai capsule of drug purchase, and its composition is poured out from capsule.Or the proportioning of each component of the Kuntai capsule that therefrom herb store buys, take respectively Radix Rehmanniae Preparata 143g, Rhizoma Coptidis 35g, Radix Paeoniae Alba 13g, Radix Scutellariae 3.5g, Colla Corii Asini 2.5g, Poria 3.0g, be ground into fine powder.This component is crossed to 120 mesh sieves, take, add starch and the magnesium stearate in above-mentioned table, measured to mix, then pour in hopper.Open granulation coating machine, enter wind pressure O.6bar, enter 30 DEG C of air temperatures, spray gun pressure (CYL) 3b cylinder, atomizing pressure (CAP1) 0.8bar, pour 250g celphere into, pelletize, pelletize speed 4rpm, the pump 12% of wriggling, rotary speed 145rpm, the 7%PVP solution (solvent is 90% ethanol) of spray 200g.After pelletize finishes, 50 DEG C of oven dry, discharging.
b、
| Activating agent | Addition (g) |
| Mifepristone | 1.0g |
| Excipient | |
| Starch | 200 |
| Magnesium stearate | 3 |
Preparation technology: mifepristone is crossed to 120 mesh sieves, and recipe quantity takes, adds starch and the magnesium stearate in above-mentioned table, measured to mix, and pours in hopper.Open granulation coating machine, enter wind pressure 0.5bar, enter 30 DEG C of air temperatures, CYL:3bar, CAP1:0.8bar, pours the celphere of 30g, pelletize, blanking velocity 4rpm into, the pump 6% of wriggling, rotary speed 160, sprays the 7%PVP solution (solvent is 90% ethanol) of 30g.Pelletize finishes, 50 DEG C of oven dry, discharging.
C, the piller that a and b are made adopt hard capsule medicine filling machine to fill and prepare the capsule that contains Kuntai capsule and mifepristone according to being respectively 200mg and 0.5mg containing Kuntai capsule and the amount of mifepristone in every two capsules.
Embodiment 2 tablets prepare a,
| Activating agent | Addition (g) |
| Kuntai capsule | 300 |
| Excipient | |
| Tapioca | 30 |
| Galactose | 20 |
| Microcrystalline Cellulose | 30 |
Preparation technology: take respectively Kuntai capsule component: Radix Rehmanniae Preparata 214g, Rhizoma Coptidis 53g, Radix Paeoniae Alba 20g, Radix Scutellariae 5.5g, Colla Corii Asini 3.0g, Poria 4.5g, cross 100 mesh sieves, tapioca, galactose, microcrystalline Cellulose are crossed 80 mesh sieves, mix homogeneously, add the 6%PVP ethanol solution of 100g to granulate in right amount, 60 DEG C dry, and the dry granule of 18 mesh sieve integer adds the magnesium stearate of 2g in dry granule.
b、
| Activating agent | Addition (g) |
| Mifepristone | 1.0 |
| Excipient | |
| Starch | 50 |
| Maltose alcohol | 50 |
| Xylose | 40 |
| Silica particles | 5 |
Preparation technology: mifepristone is crossed 100 mesh sieves, starch, maltose alcohol, xylose, silica particles are crossed 80 mesh sieves, take mifepristone and the mix homogeneously of recipe quantity, add the ethanol solution of 6%PVP to granulate in right amount, 60.C is dry, the whole dry granule of 16 mesh sieve, adds 1g wych-elm acid glycerol vinegar in dry granule.
C, by above-mentioned a, two kinds of components of b adopt bi-layer tablet press stamping to obtain double-layer tablet, the every amount containing Kuntai capsule and mifepristone calcium is respectively 200mg and lmg.
Embodiment 3. mixed type capsule-type controlled release preparations
The preparation of a, active medicated core
| Activating agent | Addition (g) |
| Kuntai capsule component | 200 |
| Mifepristone | 1.0g |
| Excipient | |
| Starch | 200 |
| Magnesium stearate | 3 |
| Adhesive | |
| Glucose | 2 |
| Maltodextrin | 3 |
| Vinylacetic acid ester copolymer | 1.5 |
Kuntai capsule component or mifepristone for the embodiment of the present invention can be the Kuntai capsules of drug purchase, and its composition is poured out from capsule.Or therefrom herb store buy, take respectively Kuntai capsule component: Radix Rehmanniae Preparata 214g, Rhizoma Coptidis 53g, Radix Paeoniae Alba 20g, Radix Scutellariae 5.5g, Colla Corii Asini 3.0g, Poria 4.5g, be ground into fine powder.This component is crossed to 120 mesh sieves, take, add starch, magnesium stearate, glucose, maltodextrin and the vinylacetic acid ester copolymer in above-mentioned table, measured to mix, cross 250 mesh sieves, then pour in hopper.Open granulation coating machine, enter wind pressure O.6bar, enter 30 DEG C of air temperatures, spray gun pressure (CYL) 3b cylinder, atomizing pressure (CAP1) 0.8bar, pour 250g celphere into, pelletize, pelletize speed 4rpm, the pump 12% of wriggling, rotary speed 145rpm, the 7%PVP solution (solvent is 90% ethanol) of spray 200g.After pelletize finishes, 50 DEG C of oven dry, discharging.
The preparation of b, coating
| Coating composition | Addition (g) |
| Methacrylic acid and ethyl acetate copolymer | 90 |
| Methacrylic acid and methylmethacrylate copolymer | 135 |
| Ethyl cellulose | 180 |
| Triethyl citrate | 450 |
In room temperature, in fluid bed, with acetone/isopropanol/aqueous mixtures (54/36/10, percentage by weight) dissolve 90g methacrylic acid and ethyl acetate copolymer, 135g methacrylic acid and methylmethacrylate copolymer, 180g ethyl cellulose and the dissolving of 45g triethyl citrate, be coated with this mixture the particulate obtaining in a of 450g simultaneously.After injection, obtain coated microgranule.Average diameter is 270 μ m.
C, the piller that a and b are made adopt hard capsule medicine filling machine to fill and prepare capsule according to the particulate being coated, and obtain the mixed type controlled release capsule preparation of the present invention that contains the female safe component of 0.5g and mifepristone.
The preparation of embodiment 4 controlled release tablets of the present invention
a、
| Activating agent | Addition (g) |
| Kuntai capsule component | 200 |
| Mifepristone | 1.0g |
| Excipient | |
| Tapioca | 30 |
| Galactose | 20 |
| Microcrystalline Cellulose | 30 |
Preparation technology: take respectively Kuntai capsule component: Radix Rehmanniae Preparata 214g, Rhizoma Coptidis 53g, Radix Paeoniae Alba 20g, Radix Scutellariae 5.5g, Colla Corii Asini 3.0g, Poria 4.5g, mifepristone 1.0g cross 100 mesh sieves, tapioca, galactose, microcrystalline Cellulose are crossed 80 mesh sieves, mix homogeneously, add the 6%PVP ethanol solution of 100g to granulate in right amount, 60 DEG C dry, the dry granule of 18 mesh sieve integer, adds the magnesium stearate of 2g in dry granule.
The preparation of b, coating
| Coating composition | Addition (g) |
| Methacrylic acid and ethyl acetate copolymer | 90 |
| Methacrylic acid and methylmethacrylate copolymer | 135 |
| Ethyl cellulose | 180 |
| Triethyl citrate | 450 |
In room temperature, in fluid bed, with acetone/isopropanol/aqueous mixtures (54/36/10, percentage by weight) be dissolved to 90g methacrylic acid and ethyl acetate copolymer, 135g methacrylic acid and methylmethacrylate copolymer, 180g ethyl cellulose and the dissolving of 45g triethyl citrate, be coated with this mixture the particulate obtaining in a of 450g simultaneously.After injection, obtain coated microgranule.Average diameter is 270 μ m.In order to obtain the coating of multilamellar, on original coating basis, again spray, repeatedly carry out above-mentioned steps and just can obtain required multilamellar controlled release layer.
C, by above-mentioned a, two kinds of components of b adopt bi-layer tablet press stamping to obtain double-layer tablet, every containing female safe component 0.5g and mifepristone 2.5mg.
The preparation of the injection type of embodiment 5 present compositions
Formula: 10g Kuntai capsule, 50mg mifepristone, 20g mannitol
Take respectively Kuntai capsule component: Radix Rehmanniae Preparata 7.5g, Rhizoma Coptidis 1.5g, Radix Paeoniae Alba 0.5g, Radix Scutellariae 0.1g, Colla Corii Asini 0.2g, Poria 0.2g, mifepristone 50mg, be mixed with 1000ml solution with water for injection, aseptic filtration, by every 1ml fill, lyophilization, tamponade, rolls lid and obtains finished product injection.
Embodiment 6: coated tablets preparation
| Activating agent | Addition (g) |
| Kuntai capsule | 300 |
| Mifepristone | 1.0 |
| Excipient | |
| Microcrystalline Cellulose coating | 70 |
| Coating | 60 |
| Magnesium stearate | 3 |
| Colloidal silica anhydrous | 1 |
| Coating agent | |
| Resina Toxicodendri | 5 |
| Talcum | 60 |
| Sucrose | 50 |
| N-vinyl butyrate lactam | 6 |
| Titanium dioxide | 0.3 |
| Coloring agent | 5 |
The animal safety evaluation of embodiment 6 compound preparations of the present invention
6.1 laboratory animal kind and features
BALB/C mice, 9 weeks～10 weeks age, body weight 20g left and right, male and female half and half.
6.2 raising conditions
Animal Lab. air timing ventilation, illumination are good, keep laboratory room temperature.Every cage is raised 5 animals, feeds the expanded pellet diet of making as mice taking specially, freely drinks water.Before experiment starts, observe animal feed, active situation and feces thereof etc. one week, the mouse of a unsoundness is chosen as next step experiment.
6.3 acute toxicity testing
First-selection, uses acute toxicity test to carry out safety evaluatio to the compositions of Kuntai capsule and mifepristone, to provide foundation for the application of the compositions of Kuntai capsule and mifepristone.This experiment adopts acute toxicity test maximum tolerated dose method, first chooses 20 of the healthy BALB/C mice of body weight 20g left and right, male and female half and half.The route of administration of clinical plan use is oral, therefore this experiment has adopted administration by gavage administration.Take each component of Kuntai capsule and mifepristone according to arbitrary formula of embodiment 1-6, the powder of Kuntai capsule and mifepristone is modulated into grume with distilled water, with 160g/kg dosage, in one day, gavage and be administered once and in one day, gavage administration 2 times or gavage 3 days (be equivalent to respectively 320,640 times of a clinical daily dose and add up 960 times) of successive administration that be administered once every day to mice (320 milligrams of left and right of every Mus), animal overnight fasting before gavage, freely drinks water.After gavage, give normal diet, observe poisoning symptom, death condition, weigh weekly once, the observation period is 2 weeks.Under similarity condition, get the normal diet feeding that does not add medicament and observe as a control group with batch mouse.By the observation of 7 days, mice appetite, spontaneous activity, outward appearance, feces, growth promoter be all without abnormal, none animal dead.Be that experimental result shows that all mices are any poisoning symptom of appearance, prove that compositions of the present invention belongs to innocuous substance.
6.4 long term toxicity test
Same as 6.3, powder in Kuntai capsule and mifepristone powder are modulated into grume with distilled water, 25g/Kg, 12.5g/Kg, 5.0g/Kg(are equivalent to respectively 50,25 and 5 times of clinical daily dose respectively) to the continuous gavage of rat 180 days, the growth promoter (body weight gain) to rat, hemopoietic function, blood biochemical were learned all without obvious toxic effect; The weight of the main organs such as the heart to rat, liver, spleen, lung, kidney: absolute weight, relative weight are except indivedual internal organs have been compared significant difference with matched group, all have no significant effect, and the tectology inspection of above-mentioned main organs is also found no to obvious damaging toxicity variation, illustrate that compound preparation long-term taking toxicity is lower, quantity is safe.
The therapeutic effect of embodiment 7 present compositions to hot flushes in rats
In order to verify that the present composition is for the preparation of prevention, alleviate and/or treat involutional ovary and endometrial impact, we with involutional rat as laboratory animal, verified the therapeutic effect of the present composition to hot flushes in rats, the compositions of having investigated Kuntai capsule and mifepristone by performance term rat treatment and the preventive effect of clinical disease.
7.1 involutional rat models build
First, strain and the source of selection and embodiment 2 animals, on all four 50 the healthy SD rats of raising condition.Wherein, 10 2.5 monthly ages, every (275.8 ± 6.5) g of weight average, normal feeding, as Normal group.40 12 monthly ages, be equivalent to after mankind's climacteric and menopause early stage, also it is " climacteric " stage, average weight 350-400g left and right, be divided at random 3 groups: model control group climacteric group, folk prescription group are respectively Kuntai capsule group (female safe group), or mifepristone group (non-group of rice), compound recipe group (female rice group): i.e. compositions group, 10 every group; 10 2.5 months old rats are young group.Raise by clean grade standard, freely drink water and standard particle feedstuff.
7.2 medication
Medication: climacteric group gives every of normal saline gavage 1ml every day; Simultaneously according to folk prescription Kuntai capsule: 2.5gkg
～1d
～1group, mifepristone: 10mgkg
～1d
～1, pharmaceutical composition of the present invention: 2.5gkg
～1d
～1and 10mgkg
～1d
～1gavage, wherein Kuntai capsule is made up of Radix Rehmanniae Preparata, Rhizoma Coptidis, the Radix Paeoniae Alba, Colla Corii Asini, Radix Scutellariae, Poria, and every capsules content is 0.5g, takes out the interior powder of capsule separately or makes aqueous solution with mifepristone.
7.3 processing methods:
7.3.1. leaving and taking of tissue specimen: after experiment 3 months, taken a blood sample by heart, separated serum, put to death all experiment mices simultaneously.All rat carotid artery intubate sacrificed by exsanguination, blood specimen centrifuging and taking serum ,～20 DEG C of preservations.Claim uterus weight in wet base, get rat both ovaries and one-sided uterus and be dipped in respectively with 4% formaldehyde and fix 24 hours, then use the EDTA(pH7.4 of 500 mMs) carry out decalcification processing, prepare paraffin section by conventional method, with dyeing in haematoxylin/Yihong.
7.3.2. ovary and the morphologic observation of uterine cancer cell pathological section: routine paraffin wax embedded section, both ovaries specimen is got respectively maximum vertical section, and uterus specimen is got cross section, one-sided uterus.
7.3.3 ovary and uterus histomorphology quantitative analysis: adopt Chinese IMS cell automated image analysis system (Japanese Panasonic, model: MV～CP410); Microscope is Japanese OLYMPUS product; Image analysis software is Shanghai Shenteng Information Technology Co., Ltd.'s product.Testing index: the maximum longitudinal section area of (1) ovary (mm
2, bilateral); (2) corpus luteum number (individual, bilateral); (3) cavity of uterus epithelial thickness (um): get measurement point every 0.2mm distance, calculating mean value represents 1 sample value; (4) uterus interstitial thickness (um): cross section, each uterus is got 6 equidistant points and measured, and gets its mean as 1 sample value; (5) endometrium thickness (um), gets above sum of the two and represents 1 sample value; (6) uterine cancer cell cross-sectional area (mm
2): record respectively cross section, uterus area coverage and cavity of uterus area except peripheral placenta percreta, the two subtracts each other.
7.4 experimental result
First,, by rat ovary corpus luteum number and endometrium thickness are analyzed and measured, experimental result is as shown in table 1.
Table 1 each group rat ovary corpus luteum number and endometrium thickness
Note: with the comparison of climacteric group,
*p<0.01,
*p<0.05; With the comparison of mifepristone group,
##p<0.01,
#p<0.05; Compare with female safe group,
The rat ovary tissue slice of the present embodiment display application based Controlled-release Drug treatment of the present invention is observed, and shows corpus luteum growth better, and corpus luteum number is increased.Compared with the Kuntai capsule group of folk prescription, its corpus luteum number and endometrium thickness are able to remarkable increase, illustrate through the rat corpus luteum number of this treatment and endometrium thickness all close to adolescent rat, illustrates that the degeneration of hot flushes in rats ovary rehabilitates.
The impact of embodiment 8 present compositions on climacteric vaginal hemorrhage patient
For further checking present composition people experimenter's the therapeutic effect to climacteric vaginal hemorrhage, this experiment is by the compositions of the present invention of having used that occurs climacteric vaginal hemorrhage patient (=people experimenter), and clinical therapeutic efficacy by within 3 months, observing (height, body weight, appetite), ask that the anti-symptom that records improves situation, routine blood test and detect, excess syndrome the present composition climacteric vaginal hemorrhage patient's treatment is had to obvious advantage.
The selection of 8.1 cases
According to aspiration principle, it is the women in the menopause in 48-60 year that the present invention has selected the age of 120, has climacteric vaginal hemorrhage patient simultaneously, is divided at random four groups, every group of 30 people.Be that climacteric group is not carried out Drug therapy; Kuntai capsule group: at 30 minutes after meal sooner or later every day is oral twice, and totally four, every contains 0.5 gram of female safe composition; Mifepristone group: take with Kuntai capsule, at 30 minutes after meal sooner or later every day is oral twice simultaneously, and totally two, every contains 5 milligrams of mifepristones; 30 minutes after meal sooner or later every day of present composition group (=female rice group) is oral twice, and each one, every contains 5 milligrams of 1 gram of female safe composition and mifepristones.
8.1 experimental technique
8.1.1 visual observations
Patient's height, body weight, blood pressure, heart beating are measured, before and after treatment, between each group, be there is no notable difference.But in climacteric group, having 4 examples cannot stand the state of an illness, also there are respectively 2 example and 3 routine dyspeptic situations and gave up halfways in Kuntai capsule group and mifepristone group.To monitoring hematuria routine, hepatic and renal function, blood fat, blood glucose before medication and when medication 3 months, blood pressure, body weight are also measured simultaneously, and result shows no significant difference equally.
8.1.2 estradiol level (E2) detects
Adopt Electrochemiluminescince respectively at before taking medicine, take medicine and measure serum E 3 months time
2, test kit is purchased from Roche company.Before blood drawing, patient does not eat too greasy, high protein diet in one day, avoids heavy drinking; After 8 o'clock evenings of health check-up the previous day, should start fasting 12 hours, in order to avoid affect testing result. blood is got on an empty stomach in the morning 8～10 o'clock, in all sample sets, measures.
8.1.3 the observation of endometrium thickness
Utilize the method for transvaginal sonography, use Toshiba's 380 type colorful ultrasonic instrument, ultrasonic probe is 7.5MHz, and the thickness in uterus before and after treatment is detected.
8.2 experimental result
The experimental result of embodiment 8.1.1-3 is summarized in to table 3,
The comparison of the different group therapeutic effect of table 3
From table 3, be easy to find out, compare with matched group with other folk prescription group with the patient of present composition treatment, estradiol level (E2) and Endometrium thickness are increased simultaneously, and cure rate is up to 90%(28/30) more than.Therefore can reach a conclusion, two active component in the present composition, compositions has significant curative effect to treatment vaginal hemorrhage.
The invention has the beneficial effects as follows: the compositions of Kuntai capsule and mifepristone can suppress climacteric vaginal hemorrhage symptom.
The present invention does not limit to the specific implementations of describing in this application, as the unitary declaration of independent aspect of the present invention.It will be understood by those skilled in the art that in the situation of the spirit and scope that can not depart from the application and carry out various amendments and change.According to above description, except enumerating herein, the purposes being equal in the function in the scope of the present disclosure is obvious for those skilled in the art of this area.Such change and amendment are intended to fall within the scope of the appended claims.The disclosure be only subject to claims and with such claim the four corner that is equal to of scope limit.Should be appreciated that the disclosure is not limited to specific method, reagent, compositions and biosystem, certainly, described method, reagent, compositions and biosystem can change.It can also be appreciated that term used herein is only for describing specific embodiment, it is restrictive not being used for.
In addition, in the case of describe in the mode of Ma Kushi group feature of the present disclosure or aspect, the disclosure that one of skill in the art will appreciate that of this area is also described in the arbitrary single member in Ma Kushi group or subgroup member's mode.
All patents, patent application, earlier application and publication referred herein or that quote are incorporated to herein by reference and in full, comprise all forms, and they are not contradicted with the clearly instruction of this description.Other embodiment is proposed within the scope of claim.
Claims (11)
1. a pharmaceutical composition for the treatment of the vaginal hemorrhage of Woman climacteric, is characterized in that, described compositions comprises: a) the first active component: Kuntai capsule; B) the second active component: mifepristone.
2. pharmaceutical composition as claimed in claim 1, is characterized in that, described Kuntai capsule is made up of Radix Rehmanniae Preparata, Rhizoma Coptidis, the Radix Paeoniae Alba, Radix Scutellariae, Colla Corii Asini, Poria.
3. pharmaceutical composition as claimed in claim 1, is characterized in that, in described Kuntai capsule, each component accounts for the percentage by weight of total charges and is:
Described each component is taken, be ground into fine powder, add starch and the magnesium stearate in above-mentioned table, measured to mix, then pour in hopper, open granulation coating machine, pour celphere into, pelletize, pelletize speed 1-10rpm, rotary speed 100-500rpm, after spray 7%PVP solution, dry discharging and become described Kuntai capsule.
4. pharmaceutical composition as claimed in claim 1 or 2, is characterized in that, the weight ratio of described Kuntai capsule and mifepristone is 20～500:1.
5. pharmaceutical composition as claimed in claim 3, is characterized in that, the weight ratio of described Kuntai capsule and mifepristone is 20～250:1.
6. a method of preparing the pharmaceutical composition as described in as arbitrary in claim 1-4, is characterized in that, described preparation method comprises at least one step: the first active component and the second active component are mixed.
7. the preparation of method pharmaceutical compositions as claimed in claim 6, is characterized in that, the preparation of described pharmaceutical composition is oral formulations, external preparation, suction preparation, through nasal preparation, per rectum preparation, percutaneous preparation or ejection preparation.
8. a purposes that prevents and/or treats climacteric vaginal hemorrhage, is characterized in that: described method also comprises uses to people the pharmaceutical composition that prevents and/or treats climacteric vaginal hemorrhage effective dose.
9. purposes as claimed in claim 8, is characterized in that: described effective dose comprises uses the medicine of about 0.1mg/kg to about 10000mg/kg body weight every day to people.
10. purposes as claimed in claim 9, it is characterized in that: described medicine also comprises and contains the ampelopsin that mixes with the diluent or carrier pharmaceutically accepted and the pharmaceutical composition of derivant thereof, in described pharmaceutical composition, Kuntai capsule and mifepristone proportion, by weight, the gross weight that accounts for whole preparation is 10%-80%.
11. purposes as claimed in claim 9, is characterized in that: described purposes also comprises the first active component and the second active component while, uses continuously and respectively.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1500507A (en) * | 2002-11-12 | 2004-06-02 | 贵阳新天药业股份有限公司 | Compound formulation of traditional Chinese medicine for climacteric syndrome and preparation method |
| CN103432275A (en) * | 2013-08-30 | 2013-12-11 | 贵阳新天药业股份有限公司 | Sustained-release nano-capsules for improving endometrial receptivity and application thereof |
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2013
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1500507A (en) * | 2002-11-12 | 2004-06-02 | 贵阳新天药业股份有限公司 | Compound formulation of traditional Chinese medicine for climacteric syndrome and preparation method |
| CN103432275A (en) * | 2013-08-30 | 2013-12-11 | 贵阳新天药业股份有限公司 | Sustained-release nano-capsules for improving endometrial receptivity and application thereof |
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| 国家食品药品监督管理局: "<<国家药品标准-新药转正标准中药第五十四册>>", 31 December 2003, article "坤泰胶囊", pages: 36 * |
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