WO2006099783A1 - Préparation pharmaceutique pour le traitement de la dépression et méthode d'élaboration de ladite préparation - Google Patents

Préparation pharmaceutique pour le traitement de la dépression et méthode d'élaboration de ladite préparation Download PDF

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Publication number
WO2006099783A1
WO2006099783A1 PCT/CN2005/001796 CN2005001796W WO2006099783A1 WO 2006099783 A1 WO2006099783 A1 WO 2006099783A1 CN 2005001796 W CN2005001796 W CN 2005001796W WO 2006099783 A1 WO2006099783 A1 WO 2006099783A1
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Prior art keywords
extract
weight
parts
pharmaceutical composition
ginseng
Prior art date
Application number
PCT/CN2005/001796
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English (en)
French (fr)
Inventor
Zuoguang Zhang
Original Assignee
Beijing Wonner Biotech Ltd. Co.
Priority date (The priority date 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 date listed.)
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Publication date
Priority to CA2601790A priority Critical patent/CA2601790C/en
Priority to AU2005329710A priority patent/AU2005329710B2/en
Application filed by Beijing Wonner Biotech Ltd. Co. filed Critical Beijing Wonner Biotech Ltd. Co.
Priority to US11/909,087 priority patent/US20090232914A1/en
Priority to EP05806436A priority patent/EP1862158B8/en
Priority to PL05806436T priority patent/PL1862158T3/pl
Priority to BRPI0520141-1A priority patent/BRPI0520141A2/pt
Priority to BR122017003461-8A priority patent/BR122017003461B1/pt
Priority to JP2008502222A priority patent/JP2008533180A/ja
Priority to SI200531630T priority patent/SI1862158T1/sl
Priority to ES05806436T priority patent/ES2394609T3/es
Priority to NZ562641A priority patent/NZ562641A/en
Priority to MX2007011713A priority patent/MX2007011713A/es
Priority to DK05806436.1T priority patent/DK1862158T5/da
Publication of WO2006099783A1 publication Critical patent/WO2006099783A1/zh
Priority to NO20074753A priority patent/NO338015B1/no
Priority to IL186127A priority patent/IL186127A/en
Priority to HK08106212.1A priority patent/HK1111631A1/xx
Priority to US14/076,861 priority patent/US9572827B2/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/25—Araliaceae (Ginseng family), e.g. ivy, aralia, schefflera or tetrapanax
    • A61K36/258—Panax (ginseng)
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7076—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/48—Fabaceae or Leguminosae (Pea or Legume family); Caesalpiniaceae; Mimosaceae; Papilionaceae
    • A61K36/484—Glycyrrhiza (licorice)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/72—Rhamnaceae (Buckthorn family), e.g. buckthorn, chewstick or umbrella-tree
    • A61K36/725—Ziziphus, e.g. jujube
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/43—Enzymes; Proenzymes; Derivatives thereof
    • A61K38/51—Lyases (4)
    • 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
    • A61P25/24—Antidepressants

Definitions

  • the present invention relates to a pharmaceutical composition, particularly a pharmaceutical composition which is mainly effective in the treatment of depression.
  • the present invention also relates to a method of preparing a pharmaceutical composition which is mainly effective in the treatment of depression. Background technique
  • Depression is a common disease. According to statistics, about 25% of women in the general population have experienced depression in their lifetime, and about 10% of men have experienced depression (Zhang Chunxing: Modern Psychology). Information provided by the World Health Organization: The incidence of depression in the world is about 11%. There are currently about 340 million people with depression in the world, and this number is still on the rise. The survey found that depression will rise in the next 20 years. It is the second most common disease in the world.
  • antidepressant drugs in the domestic and international markets are mainly serotonin reuptake inhibitors (SSRIs) such as Baiyoujie, Selot, Zoloft, etc.
  • SSRIs serotonin reuptake inhibitors
  • the mechanism of action is to increase the content of serotonin in human nervous media. Relieve depressive symptoms.
  • These drugs have varying degrees of side effects. Studies have shown that "the complex ampoules contained in these drugs have a role in balancing the body's functions, but more often, they still cannot calm the patients.” Whether drugs are harmful has become a serious social problem.
  • Selot has been found to have potential safety hazards as early as 1996. Since 2001, it has been recalled from the market.
  • the present invention relates to a pharmaceutical composition for treating depression as a main effect (1), characterized by comprising a group selected from the group consisting of:
  • the group (A) or (B) may further include:
  • a preferred composition of the pharmaceutical composition of the present invention comprises: 9 parts by weight of ginseng and 6 parts by weight of licorice, or 9 parts by weight of ginseng water extract or ethanol extract and 6 parts by weight of water extract or ethanol extract licorice.
  • the present invention also relates to a pharmaceutical composition (2) for treating depression mainly, comprising 3 to 10 parts by weight of ginseng ethanol extract or water extract, 0.2 to 0.8 parts by weight of glycyrrhizic acid or licorice
  • a pharmaceutical composition (2) for treating depression comprising 3 to 10 parts by weight of ginseng ethanol extract or water extract, 0.2 to 0.8 parts by weight of glycyrrhizic acid or licorice
  • the hypoacid wherein it is preferred that the ethanol extract of ginseng contains 20-40% ginseng total saponin, and the purity of glycyrrhizic acid or glycyrrhetinic acid is 80-98%.
  • the pharmaceutical composition (2) of the present invention may further comprise: 0.05 to 0.2 parts by weight of jujube ethanol extract or water extract, wherein preferably the jujube ethanol extract contains 0.5 to 3% jujube cAMP 0
  • Another object of the present invention is to provide a process for the preparation of the above-mentioned pharmaceutical composition which is mainly based on antidepressant.
  • the present invention relates to a process for the preparation of the above pharmaceutical composition (1), characterized in that it comprises the following steps:
  • the method further comprises the steps of: extracting 3 to 14 parts by weight of jujube in 60-75% ethanol solution, and separating and purifying by chromatography to obtain a third extract, which is added to the drug.
  • the composition further comprises the steps of: extracting 3 to 14 parts by weight of jujube in 60-75% ethanol solution, and separating and purifying by chromatography to obtain a third extract, which is added to the drug.
  • the composition further comprises the steps of: extracting 3 to 14 parts by weight of jujube in 60-75% ethanol solution, and separating and purifying by chromatography to obtain a third extract, which is added to the drug.
  • the composition further comprises the steps of: extracting 3 to 14 parts by weight of jujube in 60-75% ethanol solution, and separating and purifying by chromatography to obtain a third extract, which is added to the drug.
  • the present invention also relates to a method of the above pharmaceutical composition (2), which comprises the steps of 0.2 to 0.8 parts by weight of a purity of 80 to 98% glycyrrhizic acid or glycyrrhetinic acid, and 3 to 10 parts by weight of 20-40.
  • the ginseng extract of ginseng total saponin is mixed and pulverized to obtain the pharmaceutical composition.
  • the method for preparing the pharmaceutical composition (2) further comprises the steps of: adding 0.05 to 0.2 part by weight of the jujube extract containing 1% jujube cAMP with ⁇ -cyclodextrin and obtaining jujube extract and
  • the jujube extract package and body are added to the pharmaceutical composition.
  • the pharmaceutical composition of the present invention has only 2 to 3 flavors: ginseng, licorice, (and jujube).
  • Ginseng contains adenylate cyclase (AC) stimulating adenosine and contains phosphodiesterase inhibitors, which have a multiplicative effect, which together increase intracellular cAMP; ginseng can also promote Amphetamine crosses the blood-brain barrier and promotes the synthesis of dopamine (DA) and norepinephrine (E), thereby increasing the concentration of DA and NE in the brain.
  • AC adenylate cyclase
  • phosphodiesterase inhibitors which have a multiplicative effect, which together increase intracellular cAMP
  • ginseng can also promote Amphetamine crosses the blood-brain barrier and promotes the synthesis of dopamine (DA) and norepinephrine (E), thereby increasing the concentration of DA and NE in the brain.
  • DA dopamine
  • E norepinephrine
  • Jujuba contains a large amount of cAMP-like substances, and this exogenous non-hydrolyzed cAMP can participate in the metabolism of cAMP in the body, which can mimic the action of hormones and increase the intracellular cAMP content.
  • the combination of ginseng, licorice and jujube, the contract function increases the concentration of cAMP in the brain cells by activating adenylate activating enzyme (AC); and reduces the degradation of cAMP by inhibiting cAMP phosphodiesterase
  • AC adenylate activating enzyme
  • cAMP phosphodiesterase
  • the synthesis and release of neurotransmitters such as NE can be increased (for details, see the related book on the formation of catecholamine CAs by cAMP). This process is the modern pharmacological mechanism of action that can prevent depression.
  • the present invention proposes the following preferred parts by weight. 1. Group one:
  • Ginseng ethanol extract (containing 20-40% ginseng total saponin) 3 ⁇ 10 parts
  • Jujube ethanol extract (containing 0.5-3% jujube cAMP) 0.05 ⁇ 0.2 parts of the formula, preferably an agent made of the following weight ratio raw materials: ginseng ethanol extract (containing 30% ginseng total) ⁇ , ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ Share.
  • a pulverized material of ginseng and licorice can be directly used in accordance with a prescribed composition weight ratio to directly prepare a pharmaceutical composition.
  • a dry powder of jujube was added to prepare another pharmaceutical composition.
  • the pharmaceutical composition of the present invention may be prepared by using a dry powder of at least one raw material according to the weight ratio of the components defined in the composition, adding an aqueous extract or an alcohol extract of other ingredients, or at least one raw material of water.
  • the extract or the alcohol extract is prepared by adding dry powder of other ingredients.
  • the preparation method of the pharmaceutical composition of the invention comprises:
  • the first extract obtained in the step 1 and the second extract obtained in the step 2 are mixed and pulverized, and sieved to obtain the pharmaceutical composition (1) of the present invention.
  • 9 parts by weight of ginseng and 6 parts by weight of licorice are preferred.
  • 3 to 14 parts by weight, preferably 6 parts by weight, of the jujube may be further added, and the ethanol solution is decomposed, purified by chromatography, and packaged with ⁇ -cyclodextrin and the jujube extract package and body, and The first extract and the second extract are mixed and pulverized to obtain the pharmaceutical composition of the present invention.
  • the jujube extract package and the body are mixed and pulverized with 0.2 to 0.8 parts by weight of 90% pure glycyrrhetinic acid, 3 to 10 parts by weight of 30% pure ginseng extract to obtain the pharmaceutical composition of the present invention.
  • the preferred parts by weight of each component are:
  • a jujube extract containing 1% jujube cAMP containing 9 times the amount of ⁇ -cyclodextrin
  • 5 parts by weight of ginseng extract containing 30% ginseng total saponin 5 parts by weight of ginseng extract containing 30% ginseng total saponin, and licorice having a purity of 90% 0.4 parts by weight of hypoacid.
  • the solution of the botanical composition of the invention is based on the treatment of "depression” in traditional Chinese medicine, combined with the treatment mechanism of depression in modern medicine and pharmacology, and developed an anti-depression effect.
  • Botanical composition It is characterized in that all raw materials are both medicine and food, the combination of medicine and taste is simple (only 2 to 3 flavors), the mechanism of action is clear (in accordance with the mechanism of action of modern pharmacology), the functional ingredients can be quantified, the curative effect is obvious and the administration is safe.
  • This pharmaceutical composition using a combination of medicine and food as a raw material has a non-toxic (secondary) action and can be used as a medicine for treating depression for a long time.
  • the pharmaceutical composition of the present invention can be administered in a unit dosage form, which can be enterally or parenterally, such as orally.
  • the pharmaceutical preparations such as tablets, capsules, dropping pills, pills, powders, solutions, suspensions, emulsions, granules and the like may be common preparations, sustained release preparations, controlled release preparations, and various microparticle delivery systems.
  • various carriers well known in the art can be widely used.
  • the carrier examples include, for example, a diluent and an absorbent such as starch, dextrin, calcium sulfate, lactose, mannitol, sucrose, sodium chloride, glucose, urea, calcium carbonate, kaolin, microcrystalline cellulose, silicic acid.
  • a diluent and an absorbent such as starch, dextrin, calcium sulfate, lactose, mannitol, sucrose, sodium chloride, glucose, urea, calcium carbonate, kaolin, microcrystalline cellulose, silicic acid.
  • wetting agents and binders such as water, glycerin, polyethylene glycol, ethanol, propanol, starch syrup, dextrin, syrup, honey, glucose solution, gum arabic, gelatin syrup, sodium carboxymethyl cellulose , shellac, Methylcellulose, potassium phosphate, polyvinylpyrrolidone, etc.
  • disintegrating agents such as dried starch, alginate, agar powder, brown algae starch, sodium bicarbonate and tannic acid, calcium carbonate, polyoxyethylene sorbitan fatty acid Ester, sodium dodecyl sulfonate, methyl cellulose, ethyl cellulose, etc.
  • disintegration inhibitors such as sucrose, glyceryl tristearate, cocoa butter, hydrogenated oil, etc.
  • absorption enhancers such as quaternary ammonium Salt, sodium lauryl sulfate, etc.
  • lubricants such as talc, silica, corn starch,
  • Tablets may also be further formulated into coated tablets, such as sugar coated tablets, film coated tablets, enteric coated tablets, or bilayer tablets and multilayer tablets.
  • various carriers known in the art can be widely used.
  • the carrier are, for example, a diluent and an absorbent such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, polyvinylpyrrolidone, Gelucire, kaolin, talc, etc.; binders such as gum arabic, jaundice Glue, gelatin, ethanol, honey, liquid sugar, rice paste or batter; etc.; disintegrating agents, such as agar powder, dried starch, alginate, sodium dodecyl sulfate, methyl cellulose, ethyl cellulose, etc.
  • compositions or extracts of the present invention are mixed with the various carriers described above, and the resulting mixture is placed in a hard gelatin capsule or soft capsule.
  • the compositions or extracts of the present invention may also be formulated as microcapsules, suspended in an aqueous medium to form a suspension, or may be incorporated into a hard capsule.
  • coloring agents may also be added to the pharmaceutical preparations as needed.
  • FIG. 1 is a process flow 1 of the process of the present invention.
  • Figure 2 is a process flow 2 of the process of the present invention.
  • FIG. 3 is a process flow 3 of the method of the present invention. detailed description
  • Example 1 The present invention is primarily directed to the preparation of the pharmaceutical compositions of the present invention using methods well known to those skilled in the art in conjunction with the various aspects of the present invention.
  • the following examples are for illustrative purposes only and are not intended to limit the invention.
  • lg jujube extract (containing 1% jujube cAMP) was coated with 9 g of P cyclodextrin and 10 g of the package; 10 g of the package and 50 g of ginseng extract (containing 30% ginsenoside) 4g of glycyrrhetinic acid (90% purity) was mixed and pulverized to obtain the group III drug of the present invention.
  • Example 4 lg jujube extract (containing 1% jujube cAMP) was coated with 9 g of P cyclodextrin and 10 g of the package; 10 g of the package and 50 g of ginseng extract (containing 30% ginsenoside) 4g of glycyrrhetinic acid (90% purity) was mixed and pulverized to obtain the group III drug of the present invention.
  • Example 5 4 kg of ginseng and 3 kg of licorice are pulverized into a dry powder, and the obtained dry powder is mixed by a preparation method known to a person skilled in the art, and then a medicinal binder such as honey is added to prepare a honey pill.
  • a medicinal binder such as honey
  • composition of the present invention was prepared in the same manner as in Example 4, except that 18 kg of ginseng and 14 kg of licorice were used.
  • Example 6
  • the commercially available 4 kg ginseng, 3 kg licorice is pulverized into a dry powder, using the common technology in the field.
  • the dry powder obtained by the skilled person is mixed, and then 0.2 kg of jujube% ethanol extract and a pharmaceutically acceptable carrier such as starch or dextrin are added to prepare a tablet.
  • a pharmaceutically acceptable carrier such as starch or dextrin
  • Example 9 4 kg of ginseng, 14 kg of licorice aqueous extract obtained by the method of Example 1; pulverized into a dry powder, and the obtained dry powder was mixed by a preparation method known to those skilled in the art, and then added by the method of Example 2
  • the 14 kg of 70% jujube water extract is added to a pharmaceutically acceptable carrier such as starch or dextrin to prepare a tablet.
  • a pharmaceutically acceptable carrier such as starch or dextrin
  • Example 10 A commercially available 3 kg of ginseng ethanol extract containing 40% ginseng total saponin and 0.2 kg of glycyrrhetinic acid were mixed to obtain a mixture, and a drug dropping pill was prepared by a method known to those skilled in the art.
  • Example 10 A commercially available 3 kg of ginseng ethanol extract containing 40% ginseng total saponin and 0.2 kg of glycyrrhetinic acid were mixed to obtain a mixture, and a drug dropping pill was prepared by a method known to those skilled in the art.
  • Example 10 A commercially available 3 kg of ginseng ethanol extract containing 40% ginseng total saponin and 0.2 kg of glycyrrhetinic acid were mixed to obtain a mixture, and a drug dropping pill was prepared by a method known to those skilled in the art.
  • Example 10 A commercially available 3 kg of ginseng ethanol extract containing 40% ginseng total saponin and 0.2 kg of glycyrrhe
  • a commercially available 4 kg of ginseng ethanol extract containing 20% ginseng total saponin was mixed with 0.8 kg of glycyrrhizic acid to obtain a mixture, and a soft drug capsule was prepared by a method known to those skilled in the art.
  • mice per group ⁇ Inventive Example 3 drug high dose group (188.5 mg/kg), 2 inventive Example 3 drug middle dose group (94.25 mg/kg), 3 invention Example 3 drug low dose group (47.125 Mg/kg), Qijieyu pill group (650mg/kg), 3 paroxetine group (16.7mg/kg), and 6 saline group. (10 mice per group)
  • Example 3 of the present invention has an antidepressant function.
  • Experimental Example 2 Reserpine induced body temperature drop experiment
  • Embodiment 3 of the present invention Provided by Onar Bioengineering Technology Co., Ltd.
  • mice per group ⁇ Inventive Example 3 drug high dose group (188.5 mg/kg), (2) Inventive Example 3 drug medium dose group (94.25 mg/kg), 3 Inventive Example 3 drug low dose group (47.125mg/kg), Qiyu Yuwan group (650mg/kg), 3 paroxetine group (16.7mg/kg), ® saline group. (10 mice per group)
  • the above aqueous solution of the drug is administered by intragastric administration of 0.2 ml/10 g body weight twice a day for 7 days.
  • mice The anal temperature of the mice was measured after the last administration, and then the reserpine was injected intraperitoneally with 2 mg/kg, and then the anus temperature was measured 2, 3, 4, 5, 6, and 7 hours after the injection of reserpine.
  • Example 3 of the present invention has an effect against the hypothermia of mice caused by reserpine, and the middle dose group is compared with the saline group (model group). There is a very significant difference, and it can be inferred that Example 3 of the present invention has an antidepressant function.

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Description

治疗抑郁症的药物组合物及其制法 技术领域
本发明涉及一种药物组合物， 特别是以治疗抑郁症为主功效的药 物组合物。 本发明还涉及一种以治疗抑郁症为主功效的药物组合物的 制备方法。 背景技术
抑郁症是一种常见的疾病。 据统计在一般人口中大约有 25%女性 在其一生中经历过抑郁症， 男性中约有 10%左右经历过抑郁症 （张春 兴着： 《现代心理学》）。 世界卫生组织提供的资料： 抑郁症在全世界的 发病率约为 11%， 目前全球约有 3.4亿精神抑郁患者，而且这个数字仍 成上升趋势， 调查发现在今后 20年， 抑郁症将会上升为全球第二大常 见疾病。
目前国内外市场上抗抑郁症药物中基本以百优解、 赛洛特、 左洛 复等 5羟色胺再摄取抑制剂（SSRIs)为主， 其作用机理是通过增加人 体神经介质内 5羟色胺成分含量缓解抑郁症状。 这类药物都有不同程 度的副作用， 研究表明 "这些药品中含有的复安栓对平衡人体机能有 作用， 但更多时候， 它们还是无法让患者平静下来。"近年来百优解等 抑郁症药物是否有害已成为严重的社会问题， 其中赛洛特更是早在 1996年就被发现存在有安全隐患， 自 2001 年开始已陆续从市场上召 回。 2004年 6月， 美国纽约州总检察长指控英国葛兰素史克公司为了 获取利润， 欺骗性隐瞒了服用赛洛特与 "增加青少年自杀倾向及行为 的风险"之间有联系的研究报告。 在这种背景下， 如何研发生产新一 代副作用小又能有明显抗郁作用的药物已成为全球医药界所关注的问 题。 发明内容
为了克服现有技术的不足， 本发明的目的在于提供一种以抗抑郁 症为主功效的植物药组合物。
具体而言， 本发明涉及一种治疗抑郁症为主功效的药物组合物 ( 1 )， 其特征在于包括选自以下组方：
(A) 4〜18重量份人参， 3〜14重量份甘草；
(B) 4〜18重量份人参的水提取物或者乙醇提取物， 3〜14重量份甘 草的水提取物或者乙醇提取物；
(C) 4〜18重量份人参， 3〜14重量份甘草的水提取物或者乙醇提取 物；或者
(D) 3〜14重量份甘草， 4〜18重量份人参的水提取物或者乙醇提取 物。
在上述药物组合物 （1 ) 组方 （A)或者 (B)中还可以进一步包括：
(E) 3〜14重量份大枣； 或者
(F) 3〜14重量份大枣水提取物或者乙醇提取物。
本发明的药物组合物优选的组方包括： 9重量份人参和 6重量份甘 草， 或者 9重量份人参水提取物或者乙醇提取物和 6重量份水提取物 或者乙醇提取物甘草。
在上述的优选组方中还可以包括： 6重量份大枣， 或者 6重量份水 提取物或者乙醇提取物大枣。
本发明还涉及一种治疗抑郁症为主功效的药物组合物 （2)， 其特 征在于， 包括 3〜10重量份的人参乙醇提取物或者水提取物， 0.2〜0.8 重量份的甘草酸或者甘草次酸， 其中优选的是人参乙醇提取物含 20-40%人参总皂甙， 甘草酸或者甘草次酸纯度为 80— 98%。
本发明的药物组合物 （2) 还可以进一步包括 :0.05〜0.2重量份的大枣 乙醇提取物或者水提取物， 其中优选的是大枣乙醇提取物含 0.5— 3% 大枣 cAMP0
本发明的另一目的是提供上述以抗抑郁症为主功效的药物组合物 的制备方法。
本发明涉及一种制备上述药物组合物（1 ) 的方法， 其特征在于包 括以下步骤：
( 1 )将 4〜18重量份人参用 60-75%乙醇溶液煎提， 经层析分离纯化， 得第一提取物；
(2) 将 3〜14重量份甘草用水煎提， 浓缩、 干燥得第二提取物；
(3)将步骤 1得到的第一提取物和步骤 2得到的第二提取物混合粉碎， 过筛， 得所述的药物组合物。
在上述的制备方法中还进一步包括以下步骤： 将 3〜14重量份大 枣在 60-75%乙醇溶液提取， 再经层析分离纯化后， 得第三提取物， 将 其加入所述的药物组合物中。
本发明还涉及一种上述药物组合物（2) 的方法， 其特征在于包括 以下步骤将 0.2〜0.8重量份纯度为 80— 98%甘草酸或者甘草次酸、 3〜 10重量份含 20-40%人参总皂甙的人参提取物混合粉碎，得所述的药物 组合物。
在制备药物组合物 （2) 的方法中， 其还可以包括以下步骤： 将 0.05〜0.2重量份含 1%大枣 cAMP的大枣提取物用 β环糊精包和得大 枣提取物包和体； 将大枣提取物包和体加入所述的药物组合物中。 具体而言， 本发明的药物组合物中只有 2〜3味： 人参、 甘草、 （和大 枣）。
人参 （ginseng): 人参中含有腺苷酸环化酶 （AC) 剌激腺苷， 并 含有磷酸二酯酶抑制剂， 两者有相乘作用， 共同使细胞内 cAMP升高； 人参还能促使苯丙胺酸透过血脑屏障， 增进多巴胺（DA)和去甲肾上 腺素 （ E) 的合成， 从而提高了脑内 DA和 NE的浓度。
甘草 （liquorice): 甘草中的甘草酸和甘草次酸， 是 cAMP磷酸二 酯酶强抑制剂， 而通过抑制 cAMP磷酸二酯酶则可减少 cAMP降解， 从而提高大脑中枢系统 cAMP的利用度。
大枣 （jujuba): 大枣中含有大量 cAMP样物质， 而这种外源性非 水解类 cAMP能参与机体中 cAMP的代谢过程， 能模拟激素作用， 使 得细胞内 cAMP含量增高。
本发明组方中人参、 甘草、 大枣三者配伍， 合同作用， 通过激活 腺苷酸活化酶 （AC)， 增加脑细胞内 cAMP的浓度； 通过抑制 cAMP 磷酸二酯酶， 减少了 cAMP的降解， 提高 cAMP的利用度； 而 cAMP 的浓度和活性增强， 则可增加 NE等神经递质的合成与释放（详见《神 经科学原理》上册关于 cAMP对儿茶酚胺 CAs生成作用的有关论述）。 这个过程， 即是本方能够抗抑郁的现代药理学作用机理。
换言之， 为了完成本发明的目的， 本发明提出以下重量份优选的组 方。 1、 组方一：
人参 4〜18份 甘草 3〜14份
更优选的为由下述重量配比的原料制成的药剂：
人参 9份 甘草 6份
2、 组方二：
人参 4〜18份 甘草 3〜14份 大枣 3〜14份
更优选的为由下述重量配比的原料制成的药剂：
人参 9份 甘草 6份 大枣 6份
3、 组方三：
人参乙醇提取物 （含 20-40%人参总皂甙） 3〜10份
甘草次酸（80-98%纯度） 0.2〜0.8份
大枣乙醇提取物 （含 0.5— 3%大枣 cAMP) 0.05〜0.2份 组方三中， 优选的为由下述重量配比的原料制成的药剂： 人参乙 醇提取物 （含 30%人参总皂甙）、 甘草次酸 （90%纯度）、 大枣乙醇提 取物（含 1%大枣 cAMP):其中 人参乙醇提取物 5份,甘草次酸 0. 4份, 大枣乙醇提取物 0. 1份。
为了制备本发明的药物组合物， 可以直接按照规定的组方重量配 比使用人参和甘草的粉碎物， 直接制成药物组合物。 而在此组方的基 础上加入大枣的干粉制成另一种药物组合物。
此外， 本发明的药物组合物还可以按照组方中限定的成分重量配 比采用至少一种原料的干粉， 加入其他成分的水提取物或者醇提取物 来制成， 或者至少一种原料的水提取物或者醇提取物， 加入其他成分 干粉的来制成。
本发明药物组合物的制作方法包括：
方法一：
1、 将 4〜18重量份人参用 60-75%乙醇溶液煎提， 经层析分离纯 化， 得第一提取物；
2、 将 3〜14重量份甘草用水煎提， 浓缩、 干燥得第二提取物；
3、将步骤 1得到的第一提取物和步骤 2得到的第二提取物混合粉 碎， 过筛， 得本发明组方药物组合物（1 )。 在上述的方法中优选为人参 9重量份， 甘草 6重量份。
方法二：
方法一中可以再加入大枣 3〜14重量份， 优选为 6重量份， 乙醇 溶液煎提， 经层析分离纯化， 用 β环糊精包和得大枣提取物包和体， 将其与第一提取物、 第二提取物混合粉碎， 得本发明组方药物组合物
(2)。
方法三：
1、将 0.05〜0.2重量份含 1%大枣 cAMP的大枣提取物用 β环糊精 包和得大枣提取物包和体；
2、将大枣提取物包和体与 0.2〜0.8重量份 90%纯度甘草次酸、 3〜 10重量份 30%纯度人参提取物混合粉碎，得本发明组方三药物组合物。 在上述方法中各组份优选重量份为：
含 1%大枣 cAMP的大枣提取物 0. 1重量份（用 9倍量的 β环糊精 包和），含 30%人参总皂甙的人参提取物 5重量份， 纯度为 90%的甘草 次酸 0.4重量份。
本发明植物药组合物的解决方案， 是在中医学关于治疗 "郁症" 的基础上， 结合现代医学、 药理学关于抑郁症的治疗机理， 研制开发 出来的一种以抗抑郁症为主功效的植物药组合物。 其特点是所有原料 均系药食兼用植物， 药味组合简单（只有 2〜3味）， 作用机理明确（符 合现代药理学的作用机理），功效成份可以量化，疗效明显且服用安全。 这种以药食兼用植物为原料的药物组合物， 无毒 （副） 作用， 可以用 来作为治疗抑郁症的药物长期服用。
本发明的的药物组合物可以单位剂量形式给药， 给药途径可为肠 道或非肠道， 如口服等。 给药剂型例如片剂、 胶囊、 滴丸、 丸剂、 粉 剂、 溶液剂、 混悬剂、 乳剂、 颗粒剂等， 可以是普通制剂、 缓释制剂、 控释制剂及各种微粒给药系统。 为了将单位给药剂型制成片剂， 可以 广泛使用本领域公知的各种载体。 关于载体的例子是， 例如稀释剂与 吸收剂， 如淀粉、 糊精、 硫酸钙、 乳糖、 甘露醇、 蔗糖、 氯化钠、 葡 萄糖、 尿素、 碳酸钙、 白陶土、 微晶纤维素、 硅酸铝等； 湿润剂与粘 合剂， 如水、 甘油、 聚乙二醇、 乙醇、 丙醇、 淀粉浆、 糊精、 糖浆、 蜂蜜、 葡萄糖溶液、 阿拉伯胶浆、 明胶浆、 羧甲基纤维素钠、 紫胶、 甲基纤维素、 磷酸钾、 聚乙烯吡咯烷酮等； 崩解剂， 例如干燥淀粉、 海藻酸盐、 琼脂粉、 褐藻淀粉、 碳酸氢钠与枸橼酸、 碳酸钙、 聚氧乙 烯山梨糖醇脂肪酸酯、 十二垸基磺酸钠、 甲基纤维素、 乙基纤维素等; 崩解抑制剂， 例如蔗糖、 三硬脂酸甘油酯、 可可脂、 氢化油等； 吸收 促进剂， 例如季铵盐、 十二烷基硫酸钠等； 润滑剂， 例如滑石粉、 二 氧化硅、 玉米淀粉、 硬脂酸盐、 硼酸、 液体石蜡、 聚乙二醇等。 还可 以将片剂进一步制成包衣片， 例如糖包衣片、 薄膜包衣片、 肠溶包衣 片， 或双层片和多层片。 为了将给药单元制成丸剂， 可以广泛使用本 领域公知的各种载体。 关于载体的例子是， 例如稀释剂与吸收剂， 如 葡萄糖、乳糖、淀粉、可可脂、氢化植物油、聚乙烯吡咯垸酮、 Gelucire, 高岭土、 滑石粉等； 粘合剂， 如阿拉伯胶、 黄蓍胶、 明胶、 乙醇、 蜂 蜜、 液糖、 米糊或面糊等； 崩解剂， 如琼脂粉、 干燥淀粉、 海藻酸盐、 十二烷基磺酸钠、 甲基纤维素、 乙基纤维素等。 为了将给药单元制成 栓剂， 可以广泛使用本领域公知的各种载体。 关于载体的例子是， 例 如聚乙二醇、 卵磷脂、 可可脂、 高级醇、 高级醇的酯、 明胶、 半合成 甘油酯等。 为了将给药单元制成胶囊， 将本发明组合物或者提取物与 上述的各种载体混合， 并将由此得到的混合物置于硬的明胶胶囊或软 胶囊中。 也可将本发明组合物或者提取物制成微囊剂， 混悬于水性介 质中形成混悬剂， 亦可装入硬胶囊中应用。
此外， 如需要， 也可以向药物制剂中添加着色剂、 防腐剂、 香料、 矫味剂、 甜味剂或其它材料。 附图说明
附图 1为本发明方法的工艺流程 1。
附图 2为本发明方法的工艺流程 2。
附图 3为本发明方法的工艺流程 3。 具体实施方式
以下将结合附图和实施例进一步说明本发明。 本发明主要是采用 本领域技术人员公知的方法结合本发明的组方特征制备本发明所述的 药物组合物。 以下实施例仅仅是为了说明， 并非限定本发明。 实施例 1
参见附图 1， 采用本领域技术人员公知的方法， 将 9公斤人参用 75%纯度的乙醇煎提， 经上柱层析分离纯化，得第一提取物， 该提取物 含有 40%人参总皂甙； 将 6公斤甘草用水溶液煎煮、 过滤、 浓縮、 干 燥， 得第二提取物； 将第一提取物与第二提取物混合， 粉碎得本发明 组方一药物。 实施例 2
参见附图 2，使用 60%的乙醇对 9公斤人参进行醇提，经上柱层析 分离纯化， 得第一提取物； 将 6公斤甘草用水溶液煎煮、 过滤、 浓缩、 干燥， 得第二提取物； 采用 75%乙醇醇提 6公斤大枣， 经上柱层析分 离纯化， 得第三提取物， 将其用 9倍量的 β环糊精包和， 得一包和物； 将第一提取物、 第二提取物与第三提取物的包和体混合粉碎， 得本发 明组方二药物。 实施例 3
参见附图 3， 将 lg大枣提取物 （含 1%大枣 cAMP) 用 9g P环糊 精包和得 10g包和物； 将 10g包和物与 50g人参提取物 （含 30%人参 皂甙）、 4g甘草次酸 （90%纯度） 混合粉碎， 得本发明组方三药物。 实施例 4
将 4公斤人参， 3公斤甘草粉碎成干粉，采用本领域普通技术人员 公知的制备方法将得到的干粉混合后， 加入蜂蜜等药用粘合剂制成蜜 丸。 实施例 5
采用实施例 4相同的方法制备本发明组合物， 不同的是采用 18公 斤的人参和 14公斤的甘草。 实施例 6
将市售的 4公斤人参， 3公斤甘草粉碎成干粉，采用本领域普通技 术人员公知的制备方法将得到的干粉混合后， 加入 0.2公斤的大枣％ 乙醇提取物以及淀粉、 糊精等药用载体制成片剂。 实施例 7
将 14公斤甘草， 18公斤人参的水提取物（市售）粉碎成干粉， 采 用本领域普通技术人员公知的制备方法将得到的千粉混合后， 加入淀 粉、 糊精等药用载体制成片剂。 实施例 8
将 4公斤份人参， 14公斤经实施例 1的方法得到的甘草水提取物; 粉碎成干粉， 采用本领域普通技术人员公知的制备方法将得到的干粉 混合后，再加入经实施例 2方法得到的 14公斤 70 %大枣水提取物加入 淀粉、 糊精等药用载体制成片剂。 实施例 9
将市售的 3公斤含有 40%人参总皂甙的人参乙醇提取物， 0.2公斤 的甘草次酸混合后得一混合物， 采用本领域技术人员公知的方法制成 药物滴丸。 实施例 10
将市售的 4公斤含有 20%人参总皂甙的人参乙醇提取物， 与 0.8 公斤甘草酸混合后得一混合物， 采用本领域技术人员公知的方法制成 药物软胶囊。
实验例 本发明物的抗抑郁实验
实验例 1 : 小鼠悬尾实验
实验动物： ICR小鼠
实验药品：
本发明实施例 3药物： 欧纳尔生物工程技术有限公司提供
解郁丸： 郑州豫密药业股份有限公司产品
帕罗西汀 （赛乐特）： 中美天津史克制药有限公司产品 实验方法：
一、分组： Φ本发明实施例 3药物大剂量组（188.5mg/公斤）、②本 发明实施例 3药物中剂量组（94.25mg/公斤）、 ③本发明实施例 3药物 小剂量组 （47.125mg/公斤）、 Θ解郁丸组 （650mg/公斤）、 ③帕罗西汀 组（16.7mg/公斤）、 ⑥生理盐水组。 （每组 10只小鼠）
二、给药：上述药物水溶液按 0.2ml/10g体重灌胃给药，每天 2次， 共 7天， 最后一次给药后 1小时进行悬尾实验。
三、 悬尾实验： 将小鼠尾 （距尾尖 lcm处）用胶布粘在高山台面 5cm的木条上悬吊 6分钟， 记录后 5分钟内小鼠的不动时间。 实验结果：
实验结果用 SPSS11.5 统计软件进行方差分析计算与模型组比较的 P 值。
Figure imgf000010_0001
结论- 根据以上实验， 可以看出本发明实施例 3大、 中剂量组和帕罗西 汀组均可减少小鼠悬尾后的不动时间， 与生理盐水组 （模型组） 相比 有显著性差异， 从而可以推断本发明物实施例 3有抗抑郁功能。 实验例 2: 利血平诱导体温下降实验
实验动物： ICR小鼠
实验药品：
本发明实施例 3 : 欧纳尔生物工程技术有限公司提供
利血平： 上海复旦华药业有限公司产品
解郁丸： 郑州豫密药业股份有限公司产品
帕罗西汀 （赛乐特）： 中美天津史克制药有限公司产品 实验方法：
一、分组： Φ本发明实施例 3药物大剂量组（188.5mg/公斤）、（2)本 发明实施例 3药物中剂量组（94.25mg/公斤）、 ③本发明实施例 3药物 小剂量组 （47.125mg/公斤）、 Θ解郁丸组 （650mg/公斤）、 ③帕罗西汀 组（16.7mg/公斤）、 ®生理盐水组。 （每组 10只小鼠）
二、给药：上述药物水溶液按 0.2ml/10g体重灌胃给药，每天 2次， 共 7天。
三、 最后一次给药后测定小鼠肛温， 然后经腹腔注射利血平 2mg/ 公斤， 然后于注射利血平后 2、 3、 4、 5、 6、 7小时分别测定小鼠肛温。 实验结果：
实验结果用 SPSS11.5统计软件进行方差分析计算与生理盐水组比 较的 P值。 动 物 2 小时 P值 3 小时 P值 4小时肛 组别 肛温下 肛温下 温下降 P值
'( H ) 降 值 值（度）
(度） (度）
生理盐水组 （模 10 2.63±0. 2.33±0. 2.84±0.8 型组） 56 85 4 帕罗西汀组 10 1.29士0. 0.00 1.08±0. 0.0 1.55±0.6 0.00
47 1 35 01 4 1 解郁丸组 10 2.03±0. 0.00 2.67±0. 0.2 2.88±0.6 0.88 55 3 48 01 5 2 本发明实施例 3 10 0.00 1.77士0. 0.0 2.92±0.5 0.76 药物大剂量组 1 51 38 1 7 本发明实施例 3 10 0.90±0. 0.00 0.48士 0. 0.0 0.85±0.2 0.00 药物中剂量组 44 1 36 01 1 1 本发明实施例 3 10 2.63±0. 0.81 2.04士 0. 0.2 1.45±0.5 0.00 药物小剂量组 43 5 77 75 5 1
∞
屮
o
Figure imgf000012_0001
结论- 根据以上结果， 可以看出本发明实施例 3大、 中、 小剂量组均有 对抗由于利血平引起的小鼠体温降低的作用， 中剂量组与生理盐水组 (模型组） 相比有极显著性差异， 由此可以推断本发明物实施例 3有 抗抑郁功能。

Claims

权利要求书
1一种治疗抑郁症药物组合物， 其特征在于包括选自以下组方：
(A) 4〜18重量份人参， 3〜14重量份甘草；
(B) 4〜18重量份人参的水提取物或者乙醇提取物， 3〜14重量份甘 草的水提取物或者乙醇提取物；
(C) 4〜18重量份人参， 3〜14重量份甘草的水提取物或者乙醇提取 物； 或者
(D) 3〜14重量份甘草， 4〜18重量份人参的水提取物或者乙醇提取 物。
2.根据权利要求 1所述的药物组合物， 其特征在于还包括：
(E) 3〜14重量份大枣； 或者
(F) 3〜14重量份大枣水提取物或者乙醇提取物。
3. 根据权利要求 1所述的药物组合物， 其特征在于包括：
9重量份人参和 6重量份甘草， 或者
9重量份人参水提取物或者乙醇提取物和 6重量份甘草水提取物或 者乙醇提取物。
4.根据权利要求 2所述的药物组合物， 其特征在于还包括： 6重量份大 枣， 或者 6重量份大枣水提取物或者乙醇提取物。
5 .一种治疗抑郁症药物组合物， 其特征在于， 包括 3〜10重量份的人 参乙醇提取物或者水提取物， 0.2〜0.8重量份的甘草酸或者甘草次酸。
6.根据权利要求 5所述的药物组合物， 其特征在于人参乙醇提取物含 20-40%人参总皂甙， 甘草酸或者甘草次酸纯度为 80— 98%。
7.根据权利要求 5或 6所述的药物组合物，其特征在于还包括: 0.05〜0.2 重量份的大枣乙醇提取物或者水提取物。
8.根据权利要求 7所述的药物组合物， 其特征在于大枣乙醇提取物含
0.5 -- 3%大枣 cAMP
9.根据权利要求 8所述的药物组合物， 其特征在于包括人参乙醇提取 物含 30%人参总皂甙、甘草次酸为 90%纯度、大枣乙醇提取物含 1%大 枣 cAMP， 而且人参乙醇提取物为 5重量份， 甘草次酸为 0. 4重量份， 大枣乙醇提取物为 0. 1重量份。
10. 一种权利要求 1 药物组合物的制备方法， 其特征在于包括以下步 骤：
( 1 )将 4〜 18重量份人参用 60-75%乙醇溶液煎提， 经层析分离纯化， 得第一提取物；
(2) 将 3〜14重量份甘草用水煎提， 浓缩、 干燥得第二提取物；
(3)将步骤 1得到的第一提取物和步骤 2得到的第二提取物混合粉碎， 过筛， 得所述的药物组合物。
11.根据权利要求 10药物组合物的制备方法， 其特征在于包括以下步 骤： 将 3〜14重量份大枣在 60-75%乙醇溶液提取， 再经层析分离纯化 后， 得第三提取物， 将其加入所述的药物组合物中。
12. 一种权利要求 5药物组合物的制备方法， 其特征在于包括以下步 骤： 将 0.2〜0.8 重量份纯度为 80— 98%甘草酸或者甘草次酸、 3〜10 重量份含 20-40%人参总皂甙的人参提取物混合粉碎， 得所述的药物组 合物。
13. 根据权利要求 12药物组合物的制备方法， 其特征在于包括以下步 骤： 将 0.05〜0.2重量份含 1%大枣 cAMP的大枣提取物用 β环糊精包 和得大枣提取物包和体； 将大枣提取物包和体加入所述的药物组合物 中。
PCT/CN2005/001796 2005-03-25 2005-10-31 Préparation pharmaceutique pour le traitement de la dépression et méthode d'élaboration de ladite préparation WO2006099783A1 (fr)

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JP2008502222A JP2008533180A (ja) 2005-03-25 2005-10-31 抑鬱症治療用の薬物組成物及びその製法
US11/909,087 US20090232914A1 (en) 2005-03-25 2005-10-31 Pharmaceutical composition for treating depression and method for preparation thereof
EP05806436A EP1862158B8 (en) 2005-03-25 2005-10-31 A pharmaceutical composition for treating depression and method for preparation thereof
PL05806436T PL1862158T3 (pl) 2005-03-25 2005-10-31 Kompozycja farmaceutyczna do leczenia depresji oraz sposób jej przygotowywania
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BR122017003461-8A BR122017003461B1 (pt) 2005-03-25 2005-10-31 Composição farmacêutica para tratar uma depressão e método de preparação de uma composição farmacêutica.
CA2601790A CA2601790C (en) 2005-03-25 2005-10-31 A pharmaceutical composition for treating depression and method for preparation thereof
SI200531630T SI1862158T1 (sl) 2005-03-25 2005-10-31 Farmacevtski sestavek za zdravljenje depresije in postopek za njegovo pripravo
NZ562641A NZ562641A (en) 2005-03-25 2005-10-31 A pharmaceutical composition for treating depression and method for preparation thereof
ES05806436T ES2394609T3 (es) 2005-03-25 2005-10-31 Una composición farmacéutica para tratar la depresión y procedimiento para la preparación de la misma
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