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WO2008148303A1 - Composition destinée à traiter le syndrome de la dystonie végétative, préparation pharmaceutique de ladite composition et application de celle-ci - Google Patents

Composition destinée à traiter le syndrome de la dystonie végétative, préparation pharmaceutique de ladite composition et application de celle-ci Download PDF

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Publication number
WO2008148303A1
WO2008148303A1 PCT/CN2008/001071 CN2008001071W WO2008148303A1 WO 2008148303 A1 WO2008148303 A1 WO 2008148303A1 CN 2008001071 W CN2008001071 W CN 2008001071W WO 2008148303 A1 WO2008148303 A1 WO 2008148303A1
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Prior art keywords
filtered
solvent
group
ferulate
syndrome
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Ceased
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PCT/CN2008/001071
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English (en)
Chinese (zh)
Inventor
Shouzhu Hao
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Beijing Century Biocom Pharmaceutical Technology Co Ltd
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Beijing Century Biocom Pharmaceutical Technology Co Ltd
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Publication of WO2008148303A1 publication Critical patent/WO2008148303A1/fr
Anticipated expiration legal-status Critical
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/12—Drugs for genital or sexual disorders; Contraceptives for climacteric disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J75/00—Processes for the preparation of steroids in general

Definitions

  • compositions, therapeutic preparation and use thereof for treating autonomic dysfunction Composition, therapeutic preparation and use thereof for treating autonomic dysfunction
  • the present invention relates to a treatment for autonomic disorders, menopausal syndrome, primary dysmenorrhea, premenstrual tension, periodic psychosis, vascular headache, head trauma syndrome, gastrointestinal disorders, hyperlipidemia
  • Autonomic disorders are usually caused by trauma and long-term stress and fatigue, leading to a decrease in the function of the cerebral cortex, causing transitional excitement and rapid fatigue.
  • the disease is characterized by a wide onset of symptoms. Common ones are: headache, dizziness, dizziness, tinnitus, insomnia, multiple dreams, lack of concentration, memory loss, chest tightness, bloating, loss of appetite, indigestion, constipation, diarrhea, etc.; , nervous or lack of energy, back pain, fatigue, weakness, palpitations, sweating, cold and cold limbs.
  • This disease causes many inconveniences to the patient's physical and mental health and the family, and the recurrence rate of the disease is high.
  • Menopausal syndrome refers to cardiovascular, neurological, and endocrine system dysfunction caused by decreased estrogen and progesterone levels in women after menopause, leading to functional uterine bleeding, paroxysmal hot flashes and sweating, vulva and vaginal atrophy, and bone mass. Symptoms such as looseness and personality changes. Menopause is a period of great change in a person's life. It is also the time when life is the only way to live, which accounts for 1/3-2/5 of the life of the whole life. Especially in women, when the ovarian endocrine secretion in the body has a significant decline, and the organ function is gradually declining, some symptoms such as irritability, impatience, depression, anxiety, anger and temper are easily generated.
  • dysmenorrhea refers to the absence of organic lesions in the reproductive organs.
  • Premenstrual stress refers to a group of clinical syndromes in which anxiety is the main clinical manifestation of irritability, irritability, headache, insomnia, breast tenderness, and bloating.
  • anxiety is the main clinical manifestation of irritability, irritability, headache, insomnia, breast tenderness, and bloating.
  • the prevalence of premenstrual stress is high and the performance is complex, which directly affects the physical and mental health of women.
  • Oryzanol is currently the most commonly used drug for the treatment of these conditions, and is also used in functional foods to improve the body's constitution and prevent the above-mentioned conditions.
  • the raw material is derived from the extract of rice bran oil.
  • the carrageenan ferulate is a trace bioactive substance present in rice bran oil. It was discovered by Tsuchiya Tatsuro in 1953, and it was named as oryzanol after extraction. It is composed of a dozen alcohols and triterpene alcohol. The ester is mixed.
  • the composition of the raw materials is complex, the current production process is confusing, and the proportion of its constituents varies.
  • the sum of the percentages of the main components of the cycloartol ferulate and the 24-methylene ring-buckylan ferulate is only about 70%, and contains a large amount of other components. . Due to the large number of ingredients, the quality of oryzanol is difficult to control and the water solubility is extremely poor.
  • oryzanol is an oral preparation with poor bioavailability.
  • the oryzanol injection preparation on the market is an oil-soluble injection, which is only used for intramuscular injection. After the injection, the patient is prone to cause side effects such as pain at the injection site and even muscle necrosis, and the patient compliance is poor.
  • Patent 02135610.6 discloses a process for purifying 60-70% pure oryzanol by solvent extraction, but the oryzanol mentioned is of low purity.
  • Patent 00122929.X discloses a therapeutic treatment of oryzanol injection, but does not further study the purification of oryzanol.
  • Oryzanol and its application in functional foods comprehensively described the nutritional effects and disease prevention of oryzanol, but did not discuss the purification of oryzanol and the application of specific ingredients.
  • the applicant removed the ingredients of the non-cyclo-bambolan alcohol ferulic acid ester in most of the oryzanol raw materials by means of modern separation and purification means on the basis of a large number of studies, so that the ring in the present invention
  • the sum of the percentages of wood pineappenol ferulate and 24-methylene cyclobolinol ferulate increased from 70% to over 90% (including 90%).
  • the purified and purified carrageenan alcohol ferulate composition (the sum of the percentages of the cycloartol ferulate and the 24-methylene cyclopentyl alcohol ferulate) is 90% or more) It can be further prepared into a water-soluble injection solution and a lyophilized powder preparation for intravenous injection, which solves the problem of poor water solubility of the product.
  • the preparation prepared by using the composition of the present invention has greatly reduced irritation and markedly enhanced drug efficacy.
  • the preparation process adopted by the invention has low cost, is easy to operate, has good controllability, and is suitable for industrial large-scale production.
  • the present invention provides a pharmaceutical composition in which the sum of the percentages of the active ingredients cyclopentylenol ferulate and 24-methylenecyclo-bambolanol ferulate is increased from 70% to 90% (containing 90%) or more, preferably 95%, more preferably 99%.
  • the content ratio of the cycloartipenol ferulate to the 24-methylenecyclo-bambolanol ferulate in the composition of the present invention is 4: 1-1: 4, preferably 2: 1-1: 2, more Preferably 1.5: 1 -1 : 1.5.
  • Vegetable oil Alcohol ferulic acid ester 10 ⁇ 12 0 ⁇ 0.5 Soybean meal ferulic acid ester Bu 2 0 ⁇ 0.2 Triterpene alcohol ferulic acid ⁇ ⁇
  • Ringwood pineapple alcohol ferulate 8 ⁇ 10 0 ⁇ 2
  • the present invention further provides a method for preparing a pharmaceutical composition comprising a cyclic wood pineolinol ferulate, 24-methylenecyclo-bambolanol ferulate, for intravenous injection, comprising the steps of:
  • the sum of the percentages of commercially available oryzanol raw materials is about 70-75%, referred to as "purity 70-75". %", the same below), the first solvent and the second solvent mixed solution are reflux-dissolved, filtered, and the filtrate is allowed to stand, crystallized, filtered, and dried.
  • the dried crystals are reconstituted with a first solvent, filtered, allowed to stand, crystallized, filtered, and dried.
  • the crystal obtained in the step 4 is dissolved in a first solvent under reflux, filtered, allowed to stand, crystallized, filtered, and dried.
  • step 7 The crystallization obtained in step 7 is recrystallized in the same manner as in step 5.
  • the first solvent is selected from the group consisting of ethyl acetate and acetone, preferably ethyl acetate
  • the second solvent is selected from the group consisting of anhydrous ethanol, methanol, preferably anhydrous ethanol.
  • the mixing ratio of the first solvent and the second solvent is 1:200-200:1; preferably, the ratio of the two is 1:100-100:1; more preferably, the ratio of the two is 1: 50-50: 1; Most preferably, the ratio of the two is 1: 1 - 50: 1.
  • the reflux of each step is preferably heated under reflux at a temperature of from 40 to 90 ° C, preferably from 50 to 80 ° C.
  • the amount of the solvent to be added during recrystallization is 1 to 50 times, preferably 1 to 10 times, preferably 2 to 8 times the mass of the solution.
  • the invention also provides a pharmaceutical formulation comprising the above pharmaceutical composition and a pharmaceutically acceptable carrier.
  • the pharmaceutical preparation may be an oral preparation such as a tablet, a capsule, a powder, a granule or a pill, and an injection, particularly a preparation for intravenous injection, more particularly a non-oil-soluble injection for intravenous injection. .
  • the injection of the present invention contains the pharmaceutical composition of the present invention and a surfactant
  • the surfactant may be an anionic, cationic or nonionic surfactant, including but not limited to polyoxyethylene sorbitan esters, for example, polyoxygen Ethylene sorbitan fatty acid ester, polyethylene glycol, sodium lauryl sulfate, sodium dodecyl sulfate, lithium dodecyl sulfate, chenodeoxycholic acid, sodium deoxycholate, glycodeoxycholic acid Sodium, N-lauryl sarcosine, hexadecanoyl chloride, phospholipids.
  • Preferred surfactants are Tween, polyethylene glycol or mixtures thereof.
  • the Tween may be Tween 20, 40, 60, 80; the polyethylene glycol may be polyethylene glycol 200, 400, 600, 800, 1000, 2000, 4000, 8000 or a mixture thereof, preferably polyethylene glycol 200, 400, 800 or a mixture thereof; most preferred is Tween 80, polyethylene glycol 400 or a mixture thereof.
  • the injection of the present invention may also optionally further comprise other pharmaceutically acceptable excipients such as excipients, antioxidants, pH adjusting agents, preservatives, isotonic agents, and the like.
  • excipient may be selected from, but not limited to, one or more of mannitol, lactose, glucose, sorbitol, sodium chloride, hydrolyzed gelatin, dextran, sucrose, glycine, polyvinylpyrrolidone, etc.; preferably mannitol Or glucose.
  • the preservative may be selected from, but not limited to, one or more of phenol, cresol, tri-tert-butanol, benzyl alcohol, and paraben.
  • the stabilizer may be selected from, but not limited to, sodium sulfite, sodium hydrogen sulfite, sodium metabisulfite, sodium thiosulfate, thiourea, vitamin C, tert-butyl p-hydroxyanisole, dibutyl phenol, propyl gallate, tocopherol, One or more of ascorbyl palmitate, ethylenediaminetetraacetic acid, and disodium edetate.
  • the pH adjusting agent may be a pharmaceutically acceptable organic acid, an organic base, an inorganic acid, an inorganic base, including but not limited to hydrochloric acid, citric acid, tartaric acid, phosphoric acid, metaphosphoric acid, polymetaphosphoric acid, acid, sulfuric acid, nitric acid, acetic acid, Sodium hydroxide, potassium hydroxide, sodium citrate, potassium citrate, sodium hydrogencarbonate, potassium hydrogencarbonate, ammonium carbonate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, ethanolamine, diethanolamine, triethanolamine, 1, 2 - already diamine, carbonic acid One or more of sodium, potassium sodium tartrate, potassium metaphosphate, potassium polymetaphosphate, and sodium metaphosphate.
  • the injection provided by the present invention may be a water-soluble injection, an infusion, a lyophilized powder injection, preferably a water-soluble injection liquid and a lyophilized powder injection, and most preferably a lyophilized powder injection.
  • the injection of the present invention can be produced by a method of preparing a conventional injection in the art.
  • the present invention also provides the use of the above pharmaceutical compositions and pharmaceutical preparations for the preparation of a medicament for the treatment of autonomic dysfunction, primary dysmenorrhea, menopausal syndrome, premenstrual tension and the like.
  • Example 1
  • the mother liquor which has been recrystallized in the step 1 is recovered and recovered to a volume twice the volume of the solute contained, and then allowed to stand, crystallized, filtered, and dried.
  • step 2 The crystals in step 2 (purity of about 85-87%) were refluxed with 8 times the amount of ethyl acetate, filtered, allowed to stand, crystallized, filtered, and dried. Repeat the above recrystallization step 3-5 times.
  • step 4 The mother liquor filtered out after recrystallization in step 3 is combined and recovered to a volume twice the volume of the solute contained, and then allowed to stand, crystallized, filtered, and dried.
  • step 4 The crystal obtained in step 4 (purity is about 85-87%) is recrystallized in the same manner as in step 3.
  • (40: 60) is the mobile phase; the flow rate is L5ml/min; the detection wavelength is 327nm; the sensitivity is 0.005AUFS.
  • the number of theoretical plates should be no less than 2000.
  • test solution Weigh accurately the commercially available oryzanol raw material, 10mg of the raw material of the invention, into a 10ml volumetric flask, add water to dissolve and make up to volume, and shake well, that is, the test solution. 3. Determination: Precision extraction of the test solution ⁇ , injection into the liquid chromatograph, recording the chromatogram, the area content normalization method to check the percentage of each component.
  • the raw material of the invention 20g is the raw material of the invention 20g.
  • the washed and sterilized vials, rubber stoppers and fine filtrates are introduced into the filling room, and the filling volume is determined according to the content to be filled and half-filled.
  • Example 4 The sampled vials are placed in a freeze-dried tray, placed in a freeze-drying tray, lyophilized, lyophilized, the gel plug is completely pressed into the vial, and finally the atmosphere is taken out, and the lyophilized sample is taken out. That is, the lyophilized powder for injection of the present invention is obtained.
  • Example 4 The sampled vials are placed in a freeze-dried tray, placed in a freeze-drying tray, lyophilized, lyophilized, the gel plug is completely pressed into the vial, and finally the atmosphere is taken out, and the lyophilized sample is taken out. That is, the lyophilized powder for injection of the present invention is obtained.
  • Example 4 Example 4
  • mice initial weight 18-22 g , were randomly divided into 7 groups, 10 in each group: 1 blank control group; 2 Inventive material group I (25 mg/kg); 3 Inventive material group II (50 mg/ Kg); 4 The present invention group III (100 mg / kg); 5 stability group (2 mg / kg); 6 oryzanol group (100 mg / kg); 7 oryzanol group (200 mg / kg;).
  • mice Each group of mice was intragastrically administered for 3 consecutive days, and the blank group was given an equal volume of vehicle. On the 5th day after the last administration (in the stable group, intraperitoneal injection of diazepam), lh barbital sodium (20mg/kg) was intraperitoneally injected, the dosage volume was 0.1ml/10g, and the corrective reflex disappeared in each group within 15 minutes. The number of animals.
  • mice initial weight 18-22 g, were randomly divided into 7 groups, 10 in each group: 1 blank control group; 2 Inventive material group I (25 mg/kg); 3 Inventive material group II (50 mg/kg) 4; the present invention raw material group III (100mg / kg); 5 stability group (2mg / kg); 6 oryzanol group UOOmg / kg); 7 oryzanol group (200mg / kg).
  • mice Each group of mice was intragastrically administered for 3 consecutive days, and the blank group was given an equal volume of vehicle. On the 4th day after the last administration of lh (after the intraperitoneal injection of diazepam for 20 minutes), the mice were placed in an autonomous activity box for 5 minutes, and the number of spontaneous activities within 10 minutes was recorded. Results - The sedative and hypnotic effects of the freeze-dried powder needle of the present invention were examined by two experiments of autonomous activity and sub-threshold sleep of pentobarbital. The results are shown in Table 1. The raw materials of the present invention exhibited significant sedative and hypnotic effects in two different tests, significantly reducing the number of spontaneous activities of the mice, and increasing the number of sleeping animals in the subthreshold sleep test.
  • mice 96 female ICR mice were randomly divided into 19 cages according to body weight, 5-6 per cage, 10 randomly selected as sham operation group, and the remaining 86 mice were used as model animals. The mice were anesthetized by abdominal cavity to remove bilateral ovaries ( The sham operation group only cut open, did not remove the ovaries. After suturing, the injection was treated with penicillin sodium for 4 days.
  • mice On the fourth day after surgery, the mice were given chronic unpredictable stress in the following order: (1) electric shock foot: 36V alternating current, stimulated every lmin for 10s, 15 times; (2) ice water swimming: 4° C, 5min; (3) Thermal stimulation: 45 ° C, 5 min; (4) Shake: 140 times / min, 1.5 hr ; (5) Tail: lcm from the base of the tail, lmin; (6) Water ban: 24 hr; (7) Fasting: 24hr ; (8) Upside down: 24hr; 3 times for each stimulus.
  • mice after chronic stress were randomly divided into 7 groups (10 in each group): 1 model group, 2 Nilestriol group (0.25 mg/kg/d), 3 inventive material group I (25 mg/kg); 4 The raw material of the present invention group II (50 mg/kg); 5 The raw material mash group of the invention (100 mg/kg); 6; the oryzanol group (100 mg/kg); 7 the oryzanol group (200 mg/kg).
  • mice were intragastrically administered twice a day in a volume of 20 ml/kg (the sham-operated group and the model group were given only the vehicle) for 16 days. After 45 minutes of the last administration, the mice were bled for blood, and the serum was separated to measure E2 and FSH. After that, the brain was quickly decapitated, and the uterus and adrenal gland were weighed to calculate the organ index. The results were statistically processed (t-test).
  • the uterus index of the model group was significantly decreased (PO.01). Compared with the model group, the uterine weight and index of the positive drug nylestriol and oryzanol (200 mg/kg/d) were significantly increased (P ⁇ 0.01 After the administration of the raw materials of the present invention by intragastric administration, the uterus index of the high dose group (100 mg/kg/d) was significantly increased (PO.01), as shown in Table 4. Effect on uterus and adrenal index of menopausal model mice ( ⁇ SD)
  • mice were injected subcutaneously with diethylstilbestrol O. lmg/only once daily for 10 days, and the first day and the last day were doubled. Ten days later, intragastric administration was started for 3 consecutive days. On the fourth day after the last administration, lh, intraperitoneal injection of oxytocin 0.5u/only, the writhing test was performed immediately, and the first writhing time and the number of writhing times were calculated and calculated in 20 minutes. The average number of twists.
  • the analgesic effect of the raw material of the present invention was examined by using a dysmenorrhea mouse model modeled by oxytocin. The results are shown in Table 5.
  • the raw material of the invention especially high dose, can significantly reduce the number of writhing in dysmenorrhea mice, prolong the incubation period, and High writhing inhibition rate. The effect is significantly better than oryzanol raw materials.
  • the lyophilized powder needle prepared in Example 2 was subjected to irritation of animal blood vessels.
  • the method was to take 6 healthy rabbits with no ear damage and randomly divided into two groups according to body weight, namely the experimental group and the sodium chloride injection control group.
  • the dosage of rabbits was designed based on the dose of oryzanol oil-soluble injection in clinical adults.
  • the rabbits were given a slow bolus injection from the left ear vein of the rabbit, and the control group was given an equal volume of sodium chloride injection for 5 consecutive days.
  • the results of the test showed that, compared with the sodium chloride injection group, the lyophilized powder needle prepared by using the raw material of the present invention was administered intravenously, and no red blood vessels and surrounding tissues were observed by the naked eye after the administration and 24 hours after the last administration.
  • the tissue section examination showed that the structure of the rabbit ear vein was clear, the individual blood vessels were dilated, the wall thickness was uniform, the inner wall was smooth, and there was no inflammatory exudate around the tube. It is indicated that the lyophilized powder prepared by using the raw material of the present invention under the experimental conditions has no obvious stimulating effect on the rabbit ear vein.
  • the commercially available oryzanol oil-soluble injection was also used as a irritant test.
  • the results showed that the injection site and its surrounding tissues were red and swollen, and induration was observed.
  • the tissue section showed obvious vasodilation, and there was inflammatory exudate around the tube, indicating that the valley under experimental conditions Vitamin E oil-soluble injection has a significant stimulating effect on the muscle injection site.

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Abstract

La présente invention concerne une composition contenant un ester d'acide férulique de cycloarténol et un ester d'acide férulique de 24-méthylènecycloaltanol en tant que composants actifs. L'invention concerne également la préparation pharmaceutique et l'application de cette composition. Le pourcentage massique des deux composants actifs dans la composition est supérieur à 90 %. Ladite composition peut se présenter sous la forme d'injections, de poudres lyophilisées ou de préparations solides orales. Elle peut être utilisée dans le traitement du syndrome de la dystonie végétative, du syndrome climatérique, de la dysménorrhée essentielle, du syndrome prémenstruel, de la psychose circulaire, de la céphalée vasculaire, du syndrome des blessures crâniennes, du syndrome du déréglage estomac-intestin-système nerveux, de l'hyperlipidémie etc.
PCT/CN2008/001071 2007-05-31 2008-05-30 Composition destinée à traiter le syndrome de la dystonie végétative, préparation pharmaceutique de ladite composition et application de celle-ci Ceased WO2008148303A1 (fr)

Applications Claiming Priority (2)

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CN200710099845.0 2007-05-31
CN200710099845 2007-05-31

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WO2008148303A1 true WO2008148303A1 (fr) 2008-12-11

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CN105233029A (zh) * 2015-10-16 2016-01-13 岳永磊 一种用于月经周期性精神病的中西药复方制剂
CN113689931B (zh) * 2021-08-25 2024-01-26 首都医科大学宣武医院 一种服药辅助系统及方法
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