WO2006072213A1 - Preparations anti-depressives - Google Patents

Preparations anti-depressives Download PDF

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Publication number
WO2006072213A1
WO2006072213A1 PCT/CN2005/002432 CN2005002432W WO2006072213A1 WO 2006072213 A1 WO2006072213 A1 WO 2006072213A1 CN 2005002432 W CN2005002432 W CN 2005002432W WO 2006072213 A1 WO2006072213 A1 WO 2006072213A1
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Prior art keywords
extract
psoralen
pharmaceutical composition
water
solution
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PCT/CN2005/002432
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English (en)
Chinese (zh)
Inventor
Hsiang-Fu Kung
Ling-Dong Kong
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Hong Kong Jockey Club Institute Of Chinese Medicine Limited
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Priority claimed from US11/029,121 external-priority patent/US20060147569A1/en
Application filed by Hong Kong Jockey Club Institute Of Chinese Medicine Limited filed Critical Hong Kong Jockey Club Institute Of Chinese Medicine Limited
Publication of WO2006072213A1 publication Critical patent/WO2006072213A1/fr

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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
    • A61K36/06—Fungi, e.g. yeasts
    • A61K36/07—Basidiomycota, e.g. Cryptococcus
    • A61K36/076—Poria
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A61K31/366—Lactones having six-membered rings, e.g. delta-lactones
    • A61K31/37—Coumarins, e.g. psoralen
    • 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
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • 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
    • A61K36/487—Psoralea
    • 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 the field of pharmaceutical compositions, nutritional supplements, health foods, and other related components.
  • the present invention relates to a formulation comprising an herbal extract for alleviating depression and related conditions.
  • BACKGROUND The references cited in this disclosure are not necessarily prior art. Therefore, references to these references do not imply that such references are prior art in any jurisdiction. Depression is a common and frequently-occurring disease that seriously endangers the physical and mental health of human beings. With the increasing social competition, the physical and psychological pressures on people are increasing, and the incidence of depression is on the rise. The latest statistics from the World Health Organization show that the global prevalence rate is about
  • a pharmaceutical composition for treating depression characterized in that the pharmaceutical composition comprises an extract of a leguminous psoralen and an extract of a polyporaceae fungus.
  • the pharmaceutical composition consists essentially of an extract of the leguminous psoralen and an extract of the Polyporaceae fungus.
  • the pharmaceutical composition consists of an extract of the leguminous psoralen and an extract of the Polyporaceae fungus.
  • the pharmaceutical composition is composed of an extract of psoralen (dried mature fruit of leguminous psoralen) and an extract of sputum (dried sclerotia of polyporaceae fungus).
  • the weight ratio of the psoralen extract to the alfalfa extract is about 1:1 to 1:7.
  • the weight ratio of the psoralen extract to the alfalfa extract is from about 1 : 1 to about 1:3.
  • the weight ratio of the psoralen extract to the anthraquinone extract is about 1:1 to 1:2.
  • the weight ratio of the psoralen extract to the alfalfa extract is about 1:1.5.
  • the psoralen extract comprises 80-99% furanocoumarin, wherein the furocoumarin comprises 4-12% psoralen and about 3-11 % of the psoralen. In a more preferred embodiment, the psoralen extract comprises 95% furocoumarin, wherein the furocoumarin contains about 7-9% psoralen and 6-8% different Psoralen.
  • the alfalfa extract contains about 57-62% of the Lycium barbarum polysaccharide.
  • the pharmaceutical composition does not comprise a Chinese herbal medicine selected from the group consisting of ginseng, astragalus, scorpion, salvia miltiorrhiza, Polygonum multiflorum, Ophiopogon japonicus, Codonopsis, Atractylodes, Chonglou, Xiangfu, Atractylodes, Windproof, medlar, medlar, comfrey, licorice.
  • the content ratio of the psoralen, isopsoralen and scorpion polysaccharide is from 7 to 9:6 to 8:86 to 93.
  • psoralen and strontium are prepared by the following weight ratios: psoralen 1 to 2 parts, ⁇ 1 to 2 parts.
  • the psoralen and bismuth are prepared by the following weight ratios: 1-2 parts of psoralen, 1 part of ⁇ .
  • the psoralen and strontium are prepared by the following weight ratios: 2 parts of psoralen, 1 part.
  • step a. extracting the psoralen further comprises:
  • the first extract is ethanol, methanol or acetone and the second extract is ethyl acetate, diethyl ether, chloroform or dichloromethane.
  • the first extract is 55-75% (v/v) ethanol and the second extract is 80-100% ethyl acetate.
  • the first extract is 65% (v/v) ethanol and the second extract is 100% acetic acid B Ester.
  • the extracting of the step b. ⁇ further comprises:
  • step i) further comprising:
  • the precipitate is separated and dried to form a water soluble extract of hydrazine.
  • the precipitate in step C. is formed by the addition of an alcohol.
  • the alcohol is 80-100% (v/v) ethanol. In a most preferred embodiment, the alcohol is 95% (v/v) ethanol.
  • step (ii) further comprises:
  • the precipitate is separated and dried to obtain the lysine-soluble extract.
  • the alkaline solvent is 1 M NaOH.
  • the precipitation is obtained by the addition of an alcohol.
  • the alcohol is 80-100% (v/v) ethanol. In a most preferred embodiment, the alcohol is 95% (v/v) ethanol.
  • a nutritional supplement comprising a psoralen extract and a sputum extract.
  • the weight ratio of the psoralen extract to the anthraquinone extract is about 1:1 to 1:7.
  • the weight ratio of the psoralen extract to the alfalfa extract is about 1:1 to 1:3.
  • the weight ratio of the psoralen extract to the alfalfa extract is about 1:1-1:2.
  • the weight ratio of the psoralen extract to the extract of the mash is about 1:1.5.
  • a health food comprising psoralen extract and sputum extract.
  • the weight ratio of the psoralen extract to the sputum extract is about 1:1 to 1:7.
  • the weight ratio of the psoralen extract to the alfalfa extract is about 1:1 to 1:3.
  • the weight ratio of the psoralen extract to the alfalfa extract is about 1:1 to 1:2.
  • the weight ratio of the psoralen extract to the extract of the mash is about 1:1.5.
  • the weight ratio of the psoralen extract to the alfalfa extract is from 1:1 to 1:7. In a more preferred embodiment, the weight ratio of the psoralen extract to the alfalfa extract is from 1:1 to 1:3. In a more preferred embodiment, the weight ratio of the psoralen extract to the alfalfa extract is from about 1:1 to 1:2. In a most preferred embodiment, the weight ratio of the psoralen extract to the alfalfa extract is about 1:1.5.
  • Figure 1 shows a process for preparing a mash extract provided in accordance with one aspect of the present invention.
  • Figure 2 shows the HPLC chromatogram of standard psoralen and isostoral fat.
  • Figure 3 shows an HPLC chromatogram of a psoralen extract prepared in accordance with another aspect of the invention.
  • Figure 4 shows HPLC and UV spectra of a sample of psoralen mixture
  • FIG. 5 shows the HPLC and UV spectra of psoralen (BGZ-1).
  • Psoralen is a dry and mature fruit of Psoral corylifolia L., which is a commonly used traditional Chinese medicine for warming kidney and aphrodisiac. Its sexual taste is Xin Wen, into the kidney, the main five labors and seven injuries, warm kidney yang, cure kidney effusion, through the door, warm dantian, convergence spirit. Wenshen Zhuangyang Chinese medicine can achieve the effect of "tonifying kidney” and “centering” by regulating HPA axis function and immune function.
  • psoralen contains coumarins, flavonoids, volatile oils, etc., which regulates the central nervous system, neuroendocrine system, enhances immunity, fights cancer, and inhibits nitric oxide synthase.
  • psoralen is often used to treat menopausal syndrome.
  • Foreign clinical studies have confirmed that coumarin in the psoralen can treat seasonal affective disorder by inhibiting melatonin metabolism.
  • extract refers to an active ingredient that is extracted from a plant by the general methods or equivalent methods described herein.
  • water The soluble extract refers to a water-soluble extract.
  • Alkali-soluble extract refers to an extract soluble in an alkaline solvent.
  • psoralen extract refers to a composition which is isolated and extracted from the dried fruit of the psoralen plant or the psoralen by a specific extraction method in a general case.
  • the composition is isolated from the dried fruit of the psoralen plant by a specific extraction method.
  • This extract contains furocoumarin, psoralen, and psoralen.
  • ⁇ is a polyporaceae fungus ⁇ ⁇ ' cocos (Schw.) Wolf. Dry sclerotia. In the Han Dynasty, Zhongjing Fangzhong reused it to achieve the goal of "Ningxin and God".
  • ⁇ mainly contains ⁇ polysaccharides, triterpenoid organic acids and other ingredients.
  • the hydrophobic extract has a calming effect on the central nervous system. Hydrophobic extract can correct the intracellular calcium level to provide a scientific basis for the treatment of central nervous system diseases. Lycium barbarum polysaccharides have immunomodulatory functions such as enhancing killer cell activity of natural killer cells and lymphokine activation, regulating cytokine levels, and inhibiting tumor necrosis factor.
  • sputum extract refers to a specific extraction process, which is isolated from the dried sclerotium, mycelium, or other parts of the fungus of the genus Polyporus. Active composition. Preferred are active compositions which are isolated from the dried sclerotia of the fungus sputum by a specific extraction process.
  • This extract includes lycium polysaccharide. The lycium polysaccharide contains gluten, dextran, sucrose, sucrose and the like.
  • ⁇ polysaccharide refers to a polysaccharide extracted from alfalfa.
  • highly polar solvent refers to an organic solvent having a Snyder polarity index greater than 5.
  • Low polar solvent refers to an organic solvent having a Snyder polarity index of less than 5.
  • Tail Suspension Test (TST), Forced swimming Test (FST) and chronic mild stress model (Chronic Mild) Stress, CMS) was used to study the antidepressant effect of the pharmaceutical composition.
  • TST Tail Suspension Test
  • FST Forced Swimming Test
  • CST Chronic mild stress model
  • CMS Chronic Mild Stress
  • mice were forced to swim in a confined space. They first showed the motivational behavior of struggling and trying to escape, and then in a state of immobility called "desperation.”
  • the immobility referred to here reflects a state called “behaviour despair and variant” or “failure to adapt to stress", which is a negative Unmotivated desperate state.
  • the anti-depressant effect of the drug on mice can be measured. (The shorter the immobility time, the more significant the antidepressant effect of the drug is shown).
  • the desperate model of forced swimming behavior in mice is sensitive to most antidepressants, and its operation is simple and fast, so it is widely used in the screening of such drugs.
  • Chronic Mild Stress (CMS) model is sensitive to most antidepressants, and its operation is simple and fast, so it is widely used in the screening of such drugs.
  • rats were stimulated with a chronic mild procedure to observe recovery of sucrose intake, inhibition of brain monoamine oxidase-A (MAO-A) and monoamine oxidase-B (MAO-B) activity, and cortisol. The degree of reduction in content is used to determine the effectiveness of antidepressants.
  • MAO-A brain monoamine oxidase-A
  • MAO-B monoamine oxidase-B
  • mice received multiple mild stimuli in sequence within a few weeks.
  • the effect of chronic mild stimulation on the behavior of rats was evaluated by using a rat to reduce the intake of sweet solution.
  • Antidepressants antagonize this effect, which increases the sucrose intake of rats in chronic mild stimulation models.
  • Further studies have shown that chronic mild stimuli can cause damage to the biochemical and physiological processes in rats.
  • Administration of antidepressants such as tricyclic antidepressants, selective serotonin reuptake inhibitors, monoamine oxidase inhibitors, etc., can improve the damage of chronic mild irritations to animals, while non-depressant drugs are ineffective in this model.
  • Example 1 Chronic mild stimulation reduces sucrose intake in animals and increases the activity of brain monoamine oxidase-A (MAO-A) and monoamine oxidase-B (MAO-B) as well as serum cortisol levels. Therefore, an agent that restores sucrose intake to animals, inhibits the activity of brain MAO-A and MAO-B, and lowers serum cortisol levels is considered to be an effective antidepressant.
  • MAO-A brain monoamine oxidase-A
  • MAO-B monoamine oxidase-B
  • Rotary vacuum concentrator Purchased from Buchi LabortechnikAQ Switzerland. Grind 100 g of dried psoralen into powder, add 65% ethanol and 75 mL and mix well. After suffocating for 2 h, the powder should be evenly filled into the percolating tube. Soak in 65 % ethanol 200 mL for 24 h, then add 1300 ml of 65 % ethanol to the percolating tube. 1500.0 mL of percolate was collected at a rate of 1.5 mL/min. Concentrate under reduced pressure at 60 ° C until the percolate has no ethanol flavor, and obtain 2'50.0 mL of the drug solution. The solution was extracted 8 times with 250 ml of 100% ethyl acetate.
  • Flask (2000ml): purchased from Nanjing Sanai Glass Instrument Co., Ltd.
  • Product Code 1117 ⁇
  • Spherical Condensing Tube Purchased from Beijing Glass Instrument Factory.
  • Product Code yq230503.
  • Infiltration tube 1000ml: Purchased from Tianjin Youfeng Technical Glass Co., Ltd.
  • Product number 119-02-10.
  • HY30-01 Electronic vacuum drying oven: purchased from Taijiang Medical Instrument Factory, Fuzhou, China.
  • HH-S electric thermostatic water bath purchased from Dongtai Electrical Appliance Factory, Jiangsu province, Jiangsu province, China.
  • 100 g of sputum is ground into a coarse powder, and 1000 mL of distilled water is added to the mashed powder in step A, soaked for 0.5 h, and then decocted at 95-100 ° C for 2 hours, and filtered to obtain an aqueous solution of hydrazine (I).
  • ⁇ residue (1) the hydrazine residue (1) is extracted in the same manner as in the step ,, to obtain an aqueous solution of hydrazine ( ⁇ ), (III) and hydrazine residue (11).
  • step C the aqueous hydrazine solutions (1), (?), and (III) are combined to form an aqueous hydrazine solution (IV).
  • the hydrazine aqueous solution (IV) was concentrated in a step D using a rotary evaporator to obtain 300 ml of a concentrated aqueous hydrazine solution.
  • step E 840 ml of 95% ethanol is stirred and added to the concentrated hydrazine solution. The final ethanol concentration was 70% (v/v), and it was allowed to stand at 4 °C for 24 h to form a precipitate.
  • step F the residue (II) is soaked in 1000 ml of 1 M sodium hydroxide solution for 10 hours (room temperature), and then filtered to obtain a sodium hydroxide extraction solution (I) (filtrate) and an antimony residue (IV) in the step.
  • step G the hydrazine residue (IV) is further extracted twice by the method of the step F to obtain a hydrazine residue (V) and a sodium hydroxide extraction solution (11), (111) of hydrazine.
  • step H the combined sodium hydroxide extraction solutions (1), ( ⁇ ), and (III) were combined to form 2900 ml of a sodium hydroxide extraction solution (IV).
  • the solution (IV) was extracted with sodium hydroxide of 10% acetic acid to pH-6, and then 8120 ml of 95% ethanol was added thereto with stirring, and allowed to stand at 4 ° C for 24 hours to form a precipitate. Filtration, and the resulting precipitate was dried under reduced pressure at 60 ° C to obtain 35.69 g of a dry powdery bismuth extract VI.
  • the components of the psoralen extract (psoralen and isopsoralen) prepared in Example 1 were analyzed by high performance liquid chromatography (HPLC) in combination with ultraviolet detection. This method has a lower detection limit and good accuracy, accuracy, and linearity. Medicine
  • Spectral grade acetonitrile and methanol were purchased from the International Laboratory (USA). Purified water was prepared by the Mili-Q system (Millipore). The standard psoralen and isopsoralen were purchased from the China National Institute for the Control of Pharmaceutical and Biological Products. The standard psoralen and isopsoralen were dissolved in methanol solution to form a standard solution, which was used as an external standard solution. Instrument and chromatographic conditions
  • the mobile phase was eluted with acetonitrile-water (40:60, v/v) at a flow rate of 1.0 ml/min.
  • the injection volume was 1.0 1, and the detection wavelength was 246 nm. All chromatographic analyses were carried out at 22 °C.
  • FIG. 2 shows the HPLC chromatogram of the standard psoralen and isopsoralen.
  • Figure 3 is an HPLC chromatogram of psoralen extract. There were no other impurity peak interferences at the control retention time. Comparing Fig. 2 with Fig. 3, according to the retention time of the standard and the corresponding position of the sample peak, it can be seen that the psoralen extract contains psoralen and isopsoralen.
  • the psoralen extract prepared according to Example 1 contained about 8.01% psoralen and 6.86% isopsoralen.
  • the hydrazine component was analyzed by the phenol-suli ric acid method.
  • the phenol sulfuric acid method (Dubosis et al., 1956) is a colorimetric reaction. Due to its simplicity, it is commonly used to determine sugars, oligosaccharides, polysaccharides and their derivatives in samples. Medicine
  • D-Glucose purchased from Sigma-Aldrich (St Louis, MO, USA). Product Code: G5250.
  • Glucose is selected as the standard. The measurement was carried out according to the basic operating procedure of Dubosis et al. (1956). Precisely measure 0.2 g, dl, 0.6, 0.8, 1 and 1.2 ml of 10 g/dl glucose solution. Add the tubes separately and add water to make up the final volume of 2ml (containing 20-120 mg of glucose). An additional 1 ml of a 5% (w/v) phenol solution was added. Then, 5 ml of concentrated sulfuric acid was quickly added along the surface of the liquid to achieve a good mixing effect.
  • the tube was allowed to stand for 10 minutes, shaken, and placed in a 25-30 ° C water bath for 15 minutes, and the absorbance was measured at 490 nm. Take a blank with distilled water. Taking the glucose reference quantity as the abscissa and the absorbance as the ordinate, the least squares method was used for data regression.
  • _y absorbance value
  • ⁇ : glucose amount (111 ⁇ )
  • ⁇ correlation coefficient
  • the polysaccharide of the alfalfa extract was determined by the phenol sulfuric acid method. Standard curves were prepared using different concentrations of D-glucose (20-120 mg) as standard solutions. Accurately measure 2 ml of the sputum extract solution and add them to the test tube. Same as above, add 1 ml of 5% (w/v) phenol solution. Then, 5 ml of concentrated sulfuric acid was quickly added. After standing for 10 minutes, the mixture was shaken, placed in a 25-30 ° C water bath for 15 minutes, and the absorbance was measured at 490 nm. The blank sample is replaced by distilled water. Distilled water was used as a blank control.
  • compositions were prepared in this example:
  • ICR mice male, 26 ⁇ 2g, provided by the Jiangsu Experimental Animal Center, housed in a 25 ⁇ 2 oC room, fed with free water for one week. All animal testing procedures are in accordance with the regulations of the China Animal Management Committee.
  • Fluoxetine hydrochloride purchased from Sigma-Aldrich, (St. Louis MO, USA), product number: F132
  • mice The mode and dose of each group of mice to be administered are as follows:
  • Bakuchi extract group 80mg/kg/day, 50 mg/kg/day, 28.5 mg/kg/day
  • composition Group I 200 mg/kg/day
  • composition Group II 200 mg/kg/day
  • composition Group III 200 mg/kg/day
  • mice were fasted for 1.5 hours before dosing.
  • the above drug is dissolved or suspended in physiological saline to prepare the concentration. According to the mouse weight drug.
  • Tables 3 and 4 the mice were administered for 3 days and 7 days, respectively. No abnormalities in the mice were observed during the administration. Behavioral experiments were performed 1 hour after the last administration.
  • Table 3 affects the time of mouse tail suspension
  • composition prepared from the psoralen extract and the alfalfa extract in an appropriate ratio can effectively reduce the immobility time of the tailed mice and the forced swimming mice at a suitable dose.
  • composition 1 Composition 1 > Composition 11 > Composition III.
  • composition I Same as used in Experiment 1.
  • Gp, psoralen extract: ⁇ extract 1:1.5
  • 5-Hydroxytrptamine (5-HT) for monoamine oxidase-A (MAO-A) specific substrate, purchased from Sigma-Aldrich (St. Louis, MO, USA), product number: H 9523
  • P-phenylethylamine ( ⁇ - ⁇ ) for monoamine oxidase-B (MAO-B) specific substrate, purchased from Sigma-Aldrich (St Louis, MO, USA), product number: P 2641
  • Fluoxetine hydrochloride purchased from Sigma-Aldrich (St. Louis, MO, USA), product number: F132
  • the sucrose aqueous solution l% (w/v) is made of 10 g of sucrose dissolved in 1000 ml of water.
  • Bovine serum albumin purchased from Sigma-Aldrich (St.
  • Disodium hydrogen phosphate purchased from Nanjing Chemical Reagent Co., Ltd., product number: 1370503101
  • WH-3 Micro Oscillator It is a product of Shanghai Huxi Analytical Instrument Factory.
  • HH-S electric thermostatic water bath It is a product of Jiangsu Dongtai Electric Appliance Factory.
  • Model saline group (stimulated by CMS): 10 ml/kg/day
  • composition Group I 200 mg/kg/day
  • composition Group I 150 mg/kg/day
  • sucrose intake was basically stable after 3 weeks. (How to calculate sucrose intake: The weight of the container before ingestion (g) - The weight of the container after ingestion (g)) In the following experiment, the sucrose intake was measured once a week (9: 00a. Rn.-10: 00 am), the method is the same as above.
  • the rats were randomized into two groups, the empty group (not stimulated by CMS) and the model group (stimulated by CMS).
  • the model group underwent a 4-week low-intensity mild stimulus.
  • the stimulation included: deprivation of food or water, oblique cage 45 °C, interval illumination (alternating light/dark/2 h), contaminated squirrel cage (200 mL water added to the bottom), pairing Feeding, low intensity strobe lighting (150 times / mim). Stimulate twice a week in the above order, 12 to 14 hours each time.
  • the blank group was housed in another room, and there was no contact with the animals in the stimulation group, except for the determination of sucrose intake after 14 hours of deprivation of food and water, and free drinking water.
  • composition (I) group dose 200 mg/kg/day composition (I)
  • composition (I) group dose 150 mg/kg/day composition (I)
  • Fluoxetine hydrochloride group dose of 10 mg/kg/day fluoxetine hydrochloride (positive control group)
  • Model saline group Dose 10 ml/kg/day saline (negative control group) All routes of administration were oral. All animals were dosed once daily at 10 am for 6 weeks. Except for the blank group animals, each group was stimulated during the administration period, and each was performed. 4. Blood and brain tissue sampling
  • sucrose intake After the last determination of sucrose intake for 24 h, the whole blood was immediately decapitated during 10 a.m.-l la.m., centrifuged at 3000 °C for 10 min at 4 °C, and serum was taken at -20 °. C storage for cortisol determination. The whole brain was quickly taken on an ice table, and the blood was washed with frozen physiological saline and stored at -80 °C for the activity of monoamine oxidase A and B (MAO-A and MAO-B).
  • MAO-A and MAO-B monoamine oxidase A and B
  • the mitochondrial part of the rat brain was prepared as described by Schurr and Livne (1976).
  • the whole brain MAO-A and MAO-B activity assays were performed by reference to the method of spectrophotometry by Yu et al. (2002).
  • the mitochondria fraction was suspended in 9 volumes of cold sodium dihydrogen phosphate buffer (10 mM, pH 7.4, containing 320 mM sucrose) at 4. Mix and stir for 20 minutes under C. The resulting mixture was centrifuged at 4000 rpm for 10 minutes at 4 ° C, and the resulting supernatant was centrifuged again at 15000 rpm for 30 minutes at 4 ° C to obtain a protein precipitate. The precipitate was resuspended in the same buffer. The protein concentration was adjusted to 1 mg/ml. The protein content was determined by the modified Lowry (1951) method. Bovine serum albumin is used as a standard.
  • Cortisol content was determined by radioimmunoassay.
  • follow the instructions of the manufacturer (manufacturer: Beijing Furui Biotechnology Co., Ltd., product number: FR-FJ-055).
  • composition I (1:1.5) and fluoxetine reversed rat sucrose intake to varying degrees compared with week 0. The amount is reduced.
  • the composition 200 mg/kg significantly increased the sucrose intake of the model group (CMS) and returned to normal after 4 weeks of administration.
  • the composition 150 mg/kg significantly increased the sucrose intake after 3 weeks of administration, and returned to normal after 5 weeks of administration. It takes 6 weeks for fluoxetine to restore sucrose intake to animals. It was shown that composition I (1:1.5) was more effective than fluoxetine in model group (CMS) animals. Table 5. Effect of composition I on sucrose intake
  • CMS can significantly increase serum cortisol levels in rats.
  • Oral administration of psoralen extract and alfalfa extract composition I (1:1.5) can significantly reduce serum cortisol levels in CMS animals, wherein the composition 200 mg/kg can be Cortisol levels in CMS rats returned to normal.
  • fluoxetine failed to significantly change serum cortisol levels in CMS rats.
  • the psoralen extract and alfalfa extract composition can effectively restore the sucrose intake of CMS-stimulated rats at a suitable ratio and dose, and there is a statistically significant difference compared with the saline group.
  • the psoralen extract and alfalfa extract composition can effectively inhibit the increase of MAO-A and MAO-B activity in rats induced by CMS at a suitable ratio and dosage, and have statistically significant differences compared with the saline group. .
  • the psoralen extract and alfalfa extract composition can effectively reduce the increase of cortisol level in rats induced by CMS at a suitable ratio and dosage, and have statistically significant differences compared with the saline group.
  • Oral Composition I can reverse the abnormalities in behavior and biochemical indicators produced by CMS-stimulated rats. Significantly increased sucrose intake, resulting in significant antidepressant effects.
  • the composition may achieve antidepressant effects by inhibiting the activity of MAO-A and MAO-B and down-regulating the function of the hypothalamic-pituitary-adrenal axis (HPA axis).
  • Composition I with antidepressant effect is more effective for treating senile depression.
  • Example 1 demonstrates a method of preparing a psoralen extract
  • there are many other methods for obtaining a psoralen extract For example, 100 g of dried psoralen is ground into powder, placed in a 2500 ml round bottom bottle, and added with 800 mL of 65% ethanol, and extracted three times in a water bath at 85-90 ° C for 1.5 h each time to obtain a psoralen extraction solution. . The resulting extract was concentrated under reduced pressure at 60 ° C (rotary pressure concentrator: Buchi Labortechnik AG, Switzerland) to obtain 250 ml of a drug solution.
  • 60 ° C rotary pressure concentrator: Buchi Labortechnik AG, Switzerland
  • the compound is prepared by combining 2:1 compatibility with psoralen and medicinal materials, and then extracting with water and ethanol according to the conventional method.
  • the above-mentioned composition I is a psoralen medicine and a medicinal material, respectively, and is combined together.
  • the water extract and the ethanol extract of the three substances were formed by extracting the compound, psoralen and sputum with ethanol and water, respectively.
  • psoralen ethanol extract and then petroleum ether ' Extraction with chloroform, ethyl acetate and n-butanol.
  • the sample names of various extracts are abbreviated as follows: Compound ethanol extract: Compound alcohol;
  • Psoralen ethanol extract supplemental alcohol
  • Petroleum ether extraction site of psoralen ethanol extract supplemental phenol
  • Chloroform extraction site of psoralen ethanol extract supplemental alcohol chlorine
  • n-butanol extraction site of the psoralen ethanol extract supplemental alcohol
  • Water extract water
  • Ethanol extract sterol.
  • the above extraction and extraction methods are carried out in a conventional manner.
  • (2) The yield of the extract sample, and the determination results of its psoralen and isopsoralen are shown in Table, Table 8, Table C and Table D.
  • the amount of Chinese herbal medicines is calculated in the same way as the previous method.
  • mice Male ICR mice (clean grade, body weight 20-25g). The animal room temperature is controlled at 22 ⁇ 2 V. Maintain a 12 hour light and dark interval. Dosage at 14: 00 daily. Free water food. Adapted to support for 4 days, Remove abnormal animals. The administration time was one, three, seven, and fourteen days, respectively. One hour after the last administration, a mouse forced swimming test (FST) and a tail suspension experiment (TST) were performed. The behavior observation time is from 9: 00 to 15: 30 of the day.
  • FST mouse forced swimming test
  • TST tail suspension experiment
  • mice were placed in a beaker having a depth of 10 cm (20 cm in height and 14 cm in diameter) at a water temperature of 25 °C. After 6 minutes of observation, the immobility time of the mice in the administration group and the control group was compared within 4 minutes.
  • mice 2 cm of the tail of the mouse was adhered to a horizontal wooden stick, and the head was placed upside down. The head was about 5 cm away from the table, and the sides of the line of sight of the mouse were blocked by a plate. After 6 min of suspension, the immobility time of the mice in the administration group and the control group was compared within 4 min.
  • the animal suspension time was shortened to some extent after 3 and 7 days of administration. After 14 days of administration, the compound ethanol extract was stronger than the water extract, and the low dose group was slightly stronger than the high dose group.
  • the compound ethanol extract was stronger than the water extract after 3 days of administration, and the dose relationship was not obvious. After 7 days of administration, the high-dose group of the compound water extract was slightly stronger than the low-dose group of the ethanol extract. After 14 days of administration, the low-dose group of the compound ethanol extract was stronger than the water extract group, and the high-dose group was basically equivalent. In general, the compound ethanol extract acts stronger than its water extract.
  • the active ingredient in the compound alcohol extract may be derived from psoralen.
  • the water extract of the single miso was stronger after 3 days of administration. After 14 days of administration, the high and low dose effects of the aqueous extract of the single miso were comparable to those of the combined aqueous extract.
  • the active ingredient in the compound water extract may be derived from strontium.
  • the alkaline extract of the residue after hydrophobic extraction was slightly stronger on the TST in the animal FST experiment. It was further confirmed that the residue alkali extract after the hydrophobic extraction had antidepressant activity.
  • the n-butanol extraction site of the psoralen ethanol extract and the psoralen residue had no effect.
  • the petroleum ether extraction site, the chloroform extraction fraction and the ethyl acetate extraction site of the psoralen ethanol extract were effective after 3 days, 7 days and 14 days of administration, and the dose relationship was obvious.
  • the high dose effect of the low-dose, chloroform extraction site and ethyl acetate extraction site of the petroleum ether extract of psoralen ethanol extract was particularly significant. After 14 days of administration, the high-dose effect of the chloroform extraction site and the ethyl acetate extraction site of the psoralen ethanol extract was stronger than that of the psoralen extract.
  • the psoralen ethanol extract was extracted in stages by organic solvent, and the chloroform extraction site was mainly concentrated in the content of psoralen and isopsoralen.
  • the water extract and alkali extract samples derived from the high total sugar content of the cockroach have a strong antidepressant effect.
  • the TLC test conditions were as follows: Silica gel GF 254 prefabricated plate, observed with cyclohexane-ethyl acetate (3:1) as a developing solvent under a 365 nm UV lamp.
  • HPLC conditions were as follows: Column: Zorbax XDB RP-C 18 (4.6 mm 250 mm, 5 m); Mobile phase: Methanol-water (40: 60); Flow rate: lO mL . min' 1 ; Detection wavelength: 246 Wake up .
  • the TLC test conditions were as follows: Silica gel GF 254 prefabricated plate, observed with cyclohexane-ethyl acetate (3:1) as a developing solvent under a 365 nm UV lamp.
  • HPLC conditions were as follows: Column: Zorbax XDB RP-C 18 (4.6 mm 250 mm, 5 m) ; mobile phase: methanol-water (65: 35); flow rate: lO mL . min' 1 ; detection wavelength: 340 nm . Take psoralen to 0.2g. Light yellow powder (acetone), identified as 1 phloem by 1 H NMR and MS spectroscopy, HPLC (chromatographic conditions are the same as Chapter 1), UV spectrum is shown in Figure 5.
  • Cortex significantly increases cortical CRF levels. After 1 day of administration, each dose group significantly decreased the increase in cortical CRF levels caused by FST. After 3, 7 and 14 days of dosing, there was a trend to reduce cortical CRF levels in each dose group, but there was no significant effect.
  • Hippocampus FST increases hippocampal CRF levels.
  • the dose group of 20-60 mg/kg significantly reversed the increase in CRF levels in the hippocampus caused by FST, and there was substantially no significant effect in each dose group after 3, 7 and 14 days of administration.
  • FST does not substantially affect striatum CRF levels. There was also no significant effect in each dose group after administration.
  • Medulla oblongata FST can significantly increase the level of CRF in the medulla oblongata. Both the 1 and 3 day low dose groups significantly reduced the elevation of CMR caused by FST. After 7 and 14 days of dosing, each dose group substantially reduced the medullary CRF level.
  • hypothalamus FST can significantly increase hypothalamic CRP levels. After 14 days of administration, each dose group substantially reduced hypothalamic CRF levels.
  • Serum FST increases serum CRF levels. After 3 days of administration, each dose group had a certain decrease in serum CRF levels caused by FST.
  • FST increases serum cortisol levels. After 1, 7, and 14 days of dosing, each dose group significantly reduced the increase in serum cortisol levels caused by FST.
  • FST has the effect of lowering serum ACTH levels. There was essentially no significant effect after administration.
  • Psoralen, fluoxetine and amitriptyline were administered orally for 1, 3, 7, and 14 days, respectively.
  • CRP ng/ml
  • ACTH pg/ml
  • Cortisol ng/ml
  • Psoralen, fluoxetine and amitriptyline were orally administered 1, 3, 7, and 14, respectively.
  • BGZ-1 (20 mg/kg) is slightly stronger than fluoxetine, but Weak than amitriptyline.
  • BGZ-1 (20 mg/kg) was weaker than fluoxetine and amitriptyline.
  • Amitriptyline 10 40.38 ⁇ 5.74
  • BGZ-1 administration significantly reduced serum CRF, serum cortisol and ACTH levels after 3 days of administration, and had a dose-effect relationship. See Table G.
  • Table G Effect of BGZ-1 on serum CRF levels, cortisol levels, and ACTH levels in ICR mice that were not stimulated and stimulated by FST a
  • the mixture of psoralen and isopsoralen has different effects on the function of the sacral axis in different brain regions, and there is a quantitative and time-dependent relationship.
  • the mixture of psoralen and isopsoralen can reverse the serum CRF caused by FST There is a quantitative and time-dependent relationship with elevated serum cortisol levels.
  • Buguzhiding can reverse serum-related HPA axis function indicators.
  • Part III Proportion of different extract ratios 1. Compatible samples Converted according to human dose
  • the plant and fungal materials disclosed herein are also specific plant and fungal parts according to the Pharmacopoeia of the People's Republic of China.
  • the active ingredient may also be present in other parts of the same plants and fungi. Therefore, it is within the scope of the invention to extract relevant active ingredients from other parts of the same plants and fungi.
  • many plant species within a genus belong to the same plant, and plants of different species within the same genus can sometimes be substituted for each other.
  • the general extraction process involves reducing the volume of the herb material and then extracting it with a suitable extract, for example, by reflux.
  • the herb extract can be obtained by immersing the whole plant of psoralen or sputum, the leaves, stems, roots, sclerotia, mycelium and/or fruit of the plant in an extract, or refluxing the extract .
  • the type of extract is not limited.
  • Usable extracts such as organic solvents such as methanol, ethanol, propanol, butanol, propanol, ... 1,3 butanediol, glycerol, acetone, butanone, ethyl acetate, diethyl ether, chloroform, dichloromethane And water.
  • the solvent may be used singly or in combination.
  • a preferred embodiment of the invention is the use of methanol, ethanol, ethyl acetate or a mixture of these solvents with water.
  • a more preferred embodiment is the use of ethanol or a mixture of water and ethanol, which is considered to be safe for organisms (low toxicity).
  • the reduction in the volume of the herb can be, but is not limited to, achieved by: cutting, damage, shearing, twisting, twisting, mashing, grinding, pulverizing, and the like. As long as it is reduced, it can increase the surface area of the herb. All materials and methods for achieving such objectives are within the scope of the invention.
  • a dose lower than the lowest dose described herein is far enough. In other cases, even if the dose used is higher than the highest dose, it will not cause harmful side effects, as long as it will be higher before administration.
  • the dose is divided into multiple smaller doses in one day and administered in multiple doses.
  • the active ingredient may be administered alone or in admixture with other pharmaceutically acceptable carriers or diluents. Administration can be carried out one or more times.
  • the active ingredient can be administered in a number of different dosage forms, such as pills, capsules, troches, tablets, hard candies, powders, sprays, creams, ointments, suppositories, gels, gels, pastes, lotions, Ointments, suspensions, injectable solutions, medicinal liquors, canes and the like.
  • Carriers include solid diluents or fillers, sterile aqueous vehicles, various non-toxic organic solvents, and the like.
  • the oral pharmaceutical composition may also be suitably sweetened or flavored.
  • the concentration of active compound in these dosage forms is from about 5.0% to about 70%.
  • the pill When administered orally, the pill may contain various excipients such as microcrystalline cellulose, sodium citrate, calcium carbonate, dicalcium phosphate, glycine, or may be used together with various disintegrating agents, such as starch (preferably Corn, potato, tapioca starch, alginic acid, and specific silicides may also be mixed with granulation binders such as polyvinylpyrrolidone, sucrose, bone glue and gum arabic.
  • a lubricant such as magnesium stearate, sodium lauryl sulfate, talc or the like may be added, which is a good adjuvant for preparing the pellet.
  • a similar solid composition can also be added to the capsule as a filler.
  • Preferred materials include lactose, milk sugar, and polymeric polyethylene glycol.
  • the active compounds may be mixed with a plurality of sweetening, flavoring, colouring or colouring agents. And, if necessary, it can be mixed with an emulsifier and/or a suspending agent. It may also be mixed with a diluent such as water, ethanol, propanol, glycerin or the like.
  • the active ingredient can be dissolved in sesame oil and peanut oil.
  • the aqueous solution must be suitably buffered (preferably at a pH greater than 8) and the liquid used for dilution must be isostatic.
  • the aqueous solution is suitable for intravenous injection.
  • the oil solution is suitable for intra-articular, intramuscular or subcutaneous injection. All of the above solutions are prepared under sterile conditions and follow standard pharmaceutical techniques well known to those of ordinary skill in the art.
  • the active compound can be administered topically.
  • Useful means include: creams, gels, gels, pastes, ointments, ointments and the like, prepared by standard pharmaceutical techniques well known to those of ordinary skill in the art.
  • the active compound in the case of administration to animals other than humans, such as cattle or poultry livestock, can be administered orally, for example, by means of a drug.
  • the active compound can also be administered via a liposome delivery system, such as a single layer of small vesicles, a single layer of large vesicles, multiple layers of vesicles, and the like.
  • the vesicles can be formed from a variety of phospholipids, such as cholesterol, stearylamine, or phosphatidylcholine.

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Abstract

La présente invention décrit des préparations pour le traitement de la dépression et des symptômes associés à partir d’extrait de Psoralea corylifolia et d’extrait de Poria cocos.
PCT/CN2005/002432 2005-01-03 2005-12-31 Preparations anti-depressives WO2006072213A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US11/029,121 US20060147569A1 (en) 2005-01-03 2005-01-03 Anti-depression formulations
US11/029,121 2005-01-03
CNA2005100595060A CN1799574A (zh) 2005-01-03 2005-03-25 治疗抑郁症的药物
CN200510059506.0 2005-03-25

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111693641A (zh) * 2020-07-20 2020-09-22 江苏弘典中药产业研究院有限公司 一种仁术健胃颗粒的薄层鉴别的方法

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1401381A (zh) * 2002-09-05 2003-03-12 南京大学 抗抑郁组合物及其制备方法
CN1539497A (zh) * 2002-09-05 2004-10-27 �Ϻ���ͨ��ѧ 一种治疗抑郁症的药物组合物及其制备方法
CN1628692A (zh) * 2003-12-15 2005-06-22 成都三明药物研究所 一种抗抑郁中药及其用途

Patent Citations (3)

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Publication number Priority date Publication date Assignee Title
CN1401381A (zh) * 2002-09-05 2003-03-12 南京大学 抗抑郁组合物及其制备方法
CN1539497A (zh) * 2002-09-05 2004-10-27 �Ϻ���ͨ��ѧ 一种治疗抑郁症的药物组合物及其制备方法
CN1628692A (zh) * 2003-12-15 2005-06-22 成都三明药物研究所 一种抗抑郁中药及其用途

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111693641A (zh) * 2020-07-20 2020-09-22 江苏弘典中药产业研究院有限公司 一种仁术健胃颗粒的薄层鉴别的方法

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