WO2002085392A1 - Procedes d'utilisation d'un extrait de puerariae radix, flavone de puerariae radix et preparation contenant une puerarine pour la prevention et le traitement de nouvelles indications - Google Patents

Procedes d'utilisation d'un extrait de puerariae radix, flavone de puerariae radix et preparation contenant une puerarine pour la prevention et le traitement de nouvelles indications Download PDF

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WO2002085392A1
WO2002085392A1 PCT/CN2002/000276 CN0200276W WO02085392A1 WO 2002085392 A1 WO2002085392 A1 WO 2002085392A1 CN 0200276 W CN0200276 W CN 0200276W WO 02085392 A1 WO02085392 A1 WO 02085392A1
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puerarin
pueraria
senile
flavonoids
treatment
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PCT/CN2002/000276
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English (en)
French (fr)
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Weilin Wang
Shiying Lu
Xinyong Wang
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Weilin Wang
Shiying Lu
Xinyong Wang
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Publication of WO2002085392A1 publication Critical patent/WO2002085392A1/zh

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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
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • 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
    • A61K36/488—Pueraria (kudzu)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/08—Drugs for disorders of the urinary system of the prostate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/10—Drugs for disorders of the urinary system of the bladder
    • 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
    • A61P15/02—Drugs for genital or sexual disorders; Contraceptives for disorders of the vagina
    • 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
    • A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
    • 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
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/10—Anti-acne agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/14—Drugs for dermatological disorders for baldness or alopecia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • 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
    • A61P25/20—Hypnotics; Sedatives
    • 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
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/10—Ophthalmic agents for accommodation disorders, e.g. myopia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/12—Ophthalmic agents for cataracts
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/16—Otologicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid

Definitions

  • the present invention relates to a method for preventing and treating new indications by using pueraria root, pueraria flavonoid extract and puerarin preparation. More specifically, the present invention relates to puerarin, puerarin flavonoid extract and puerarin preparations for the prevention and treatment of osteoporosis and disorders related to endocrine disorders, such as menopause syndrome, premenstrual syndrome, irregular menstruation, breast Hyperplasia, undersized or undersized breasts with secondary sexual characteristics, male hair loss, acne, and the following aging-related conditions, such as: loss or memory of senile memory, dementia, senile sleep disorders, senile deafness, Loss or decline in vision in the elderly, cataracts, chronic prostatic hypertrophy, senile vaginitis, cystitis, urethritis, vulvar dryness, and skin aging (senile plaques, dry skin in the elderly, itchy skin in the elderly, insufficient collagen in the skin Low skin elasticity, increased
  • Puerariae Radix is the dried root of the legume Pueraria Lobata Willd Ohwi or Pueraria Thamsonii Benth. Pueraria is widely sourced from China, the Korean Peninsula, Japan, Southeast Asia, and North America. Traditional Chinese medicine Pueraria is commonly used to treat colds, fever, neck back pain, diarrhea, and drunkenness. In recent years, the puerarin flavonoids and puerarin have been used to dilate blood vessels, reduce blood pressure, improve cardio-cerebral blood circulation, reduce myocardial oxygen consumption, used for dizziness, headache, stroke, coronary heart disease, angina pectoris, Myocardial infarction. Summary of the Invention
  • the present invention finds pueraria pueraria, pueraria flavonoid extract and puerarin preparation through in-depth research It can be used clinically to prevent and treat the following new indications: osteoporosis, disorders related to endocrine disorders, such as menopause syndrome, premenstrual syndrome, irregular menstruation, hyperplasia of the breast, insufficient development of secondary sexual characteristics Of breasts that are too small or too small, male hair loss, acne, and the following aging-related conditions, such as: decreased or lower memory in the elderly, dementia, sleep disorders in the elderly, deafness in the elderly, decreased vision in the elderly, or cataract , Chronic prostatic hypertrophy, senile vaginitis, cystitis, urethritis, vulvar dryness, and skin aging (senile plaques, dry skin in the elderly, itchy skin in the elderly, insufficient collagen fibers in the skin and low skin elasticity, increased wrinkles, skin Thinning).
  • the invention also relates to the use of pueraria pueraria,
  • Pueraria root is the dried root of leguminous kudzu or kudzu, as described above, and it can be used for the new indications described in the present invention as long as it contains puerarin, regardless of whether there is a variety improvement or variation. Roots can be dried by natural drying under natural ventilation and shade, or by mechanical drying. After the root is dried, it can be processed into slices or powder by mechanical crushing.
  • Pueraria flavonoid extract can be extracted by mechanically crushed pueraria slices or powder with water or alcohol.
  • the main chemical component in the extract is puerarin, which accounts for about 50% of puerarin flavonoids.
  • Others include daidzein, awn Phylocanthin-7-0-glucoside, daidzein, 3, -methoxypuerarin, puerarin B, daidzein-8-C-celerysyl- (1-6) -glucoside, 3, -Hydroxypuerarin, puerarin xyloside, daidzein-7,4, -0-diglucoside, puerarin-4, -0-glucoside, puerarin C, etc.
  • the method of extracting pueraria flavonoids with alcohol is to add crushed pueraria root slices or powder to 20 ⁇ 90% ethanol solvent, fully immerse, then add more than equal volume of solvent, stir the mixture to warm up to 20 ⁇ 7 0 ⁇ , and continue stirring for 0.5 ⁇ 3 hours, solid-liquid separation, remove the solvent, and concentrate It can be made into a paste or dried; or it can be prepared according to the extraction method of clear cream during the preparation of the 2000 edition of Yufeng Ningxin Tablets; or it can be extracted according to Chinese Patent Publication (publication number) 1172808, 1176818, or 1326932.
  • Puerarin is a known, single-component compound extracted from puerarin. Its chemical name is 4, 7, 7-dihydroxy, 8- &-0 glucose isoflavones. Its molecular formula is C 21 H 2Q 0 9 .
  • the method can be extracted as described in Chinese Patent Publication (publication number) 1163127 or 1154849, or it can be synthesized by chemical methods.
  • the dose required for prevention and treatment is related to many factors, such as the symptoms of the disease, the mode of administration, and the age and physical condition of the recipient.
  • Pueraria, Pueraria flavonoid extract and puerarin preparations are generally used for administration.
  • the dosage is based on the amount of puerarin.
  • the dosage is 30mg ⁇ 1500mg, the typical dosage is 100mg ⁇ 500mg. It is preferably 150 mg to 300 mg.
  • the raw materials for preparing the medicine or food preparation of the present invention for treating and preventing the indication may be pueraria, pueraria flavonoids or puerarin, and physiologically acceptable salts of puerarin and derivatives thereof.
  • the above-mentioned ingredients can also be used in combination with other therapeutic active agents that are well known to those skilled in the art to treat and prevent the diseases described in the present invention.
  • the agent includes preparations of other Chinese herbal medicines or western medicine ingredients for preventing and treating the diseases described in the present invention; or alternatively, it further includes inorganic or organic calcium, magnesium or other minerals, organic chitin or polyamide, sulfuric acid Chondroitin, collagen, vitamins such as vitamins D and K, or functional ingredients such as antioxidants, anti-aging, gastrointestinal functions, analgesics and antispasmodics.
  • inactive pharmaceutically or food commonly used carriers or excipients can also be added.
  • the carrier or excipient can be solid or liquid, or both.
  • the type of carrier or excipient can be selected according to the dosage form used.
  • a preparation containing pueraria as a main component and other functional Chinese herbal medicines as auxiliary components may be used.
  • the content of pueraria may be in
  • a preparation containing puerarin or puerarin as a main component may be used, and the amount of puerarin is used as a standard, and the content is 0.1% to 100% by weight.
  • the formulations of the invention can be prepared using any well-known pharmaceutical technique.
  • the puerarin salt in the present invention refers to a non-toxic base salt formed by puerarin and a pharmaceutically acceptable base, or a non-toxic acid addition salt formed by puerarin and a pharmaceutically acceptable acid.
  • the non-toxic base salts include, but are not limited to, from pharmaceutically acceptable cations such as alkali metal cations (such as potassium and sodium) and alkaline earth metal cations (such as calcium and magnesium), ammonium or water-soluble amine addition salts such as N-methyl Glucosamine (Meglumine) and lower alkanolammonium derived salts and other pharmaceutically acceptable organic amine base salts.
  • the non-toxic acid addition salt refers to a non-toxic acid addition salt formed by a compound and an organic or inorganic acid.
  • salts containing pharmacologically acceptable anions such as hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphonate, acid salt, acetate, lactic acid Salt, citrate, acid citrate, tartrate, tartrate, succinate, maleate, fumarate, gluconate, saccharic acid, benzoate, mesylate Acid salts, ethanesulfonic acid salts, benzenesulfonic acid salts, p-toluenesulfonic acid salts and naphthenate salts.
  • Puerarin derivatives according to the present invention include, for example, 3'-methoxypuerarin, puerarin B, 3'-hydroxypuerarin, puerarin xyloside, puerarin-4'-D-glucoside , Puerarin C and so on.
  • the preparation of the present invention has very low toxicity and side effects, and is a safe osteoporosis for humans or animals and a therapeutic and preventive agent for the above-mentioned diseases.
  • the animals are, for example, pets and domestic animals (such as dogs, cats, chickens, cows, horses, etc.), or bones used to strengthen competitive animals (such as horses for horse racing).
  • the method of administration can be oral or non-oral, and oral preparations are preferred.
  • the pharmaceutically acceptable carrier in the present invention refers to a pharmaceutically acceptable carrier that does not affect the activity of each active ingredient and has no toxic or side effects on the human body.
  • the pharmaceutical preparation of the present invention can be made orally
  • the form of administration is, for example, an emotional diluent or an assimilated edible carrier, or it can be encapsulated in a hard or soft shell capsule, or it can be compressed into tablets.
  • the active compound can be combined with excipients, ingestible oral solutions, powders, powders, granules, ointments, emulsions, suspensions, tablets, pills, buccal tablets, granules Dosage, lozenge, tincture, tincture, suppository, syrup, glutinous rice paper tincture and other dosage forms are used.
  • the amount of active compound in such therapeutically useful compositions makes it possible to obtain suitable dosages.
  • Tablets, lozenges, pills, capsules, etc. may also contain the following components: binders, such as gum, gum arabic, corn starch, or gelatin; excipients, such as dicalcium phosphate; disintegrants, such as corn starch , Potato starch, alginic acid, etc .; lubricants, such as magnesium stearate; sweeteners, such as sucrose, lactose, or saccharin, or flavoring agents, such as mint, wintergreen, or cherry flavoring agents.
  • binders such as gum, gum arabic, corn starch, or gelatin
  • excipients such as dicalcium phosphate
  • disintegrants such as corn starch , Potato starch, alginic acid, etc .
  • lubricants such as magnesium stearate
  • sweeteners such as sucrose, lactose, or saccharin
  • flavoring agents such as mint, wintergreen, or cherry flavoring agents.
  • tablets, pills or capsules can be coated with shellac, sugar or both.
  • Syrups or elixirs may contain the active compound, sucrose as a sweetener, methyl parabens and propyl esters as preservatives, and dyes and flavoring agents such as cherry or orange flavoring agents.
  • Any raw material used to prepare any unit dosage form should be pharmaceutically pure and substantially non-toxic at the dosages used.
  • the active ingredient may be incorporated in a sustained-release preparation.
  • Formulations suitable for injection include sterile aqueous solutions (as long as they are water soluble) and sterile powders for the temporary preparation of sterile injectable solutions. They must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms, such as bacteria and fungi.
  • the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils.
  • polyol for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like
  • suitable mixtures thereof and vegetable oils.
  • the use of various antibacterial and antifungal agents can prevent the action of microorganisms, such as parabens, chlorobutanol, phenol, sorbitol, and the like. In many cases, It will be preferable to include isotonic agents, for example,
  • Sterile injectable solutions are prepared by mixing the required amount of the active ingredient in a suitable solvent with the various other ingredients listed above and, if necessary, subsequently sterilizing by filtration or other appropriate means. Dispersions are also targeted by the present invention. They can be prepared by incorporating a variety of sterile active ingredients in a sterile carrier that contains a basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders used in the preparation of sterile injectable solutions, the preferred method of preparation includes vacuum drying and freeze drying techniques to obtain a powder of the active ingredient plus any additional required ingredients, the additional ingredients from the previous sterile filtration The solution.
  • Pharmaceutically acceptable carriers and / or diluents include any of all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like.
  • the use of these media and agents for pharmaceutically active substances is well known in the art. Except for those which are incompatible with the active ingredient in conventional media or reagents, the present invention is directed to their use in therapeutic formulations.
  • unit dosage forms for oral administration, so that administration is easy and the dosage is uniform.
  • the unit dosage form used herein refers to physically discrete units, suitable as a single dose for treatment; each unit contains a predetermined amount of active substance associated with a desired drug carrier, and the content is calculated to produce the desired therapeutic effect.
  • the description of the unit dosage form of the present invention depends on and directly depends on (a) the unique properties of the active substance and the specific therapeutic effect to be achieved, and (b) the limitations inherent in the field of formulation.
  • the formulations of the present invention may be provided in the form of food, for example, by addition, mixing or other means to food.
  • Food is broadly defined, such as health food. Best Mode of the Invention
  • Preparation method Use 10g of puerarin powder produced by Beijing Xiehe Pharmaceutical Factory as raw materials, add water to dissolve, adjust pH 4. 5-7. 0, and then add 0.5% phenol as bacteriostatic agent, set volume to 2000ml, ultrafiltration , Filling, welding and sterilization.
  • Treatment Example 1 Recent studies have shown that bone density is closely related to cardiovascular disease. For example, in patients with coronary heart disease, bone density decreases with increasing disease duration, which is negatively correlated. The invention is used for the treatment of osteoporosis, and is discovered through the treatment of patients with coronary heart disease with a preparation containing puerarin. 18 female patients aged 52-61 years and 13 male patients aged 54-66 years with coronary heart disease and osteoporosis with waist and leg pain.
  • Puerarin extract preparation prepared in the formulation example 1 containing puerarin daily. Oral, three times a day, each dose is equivalent to 200-450mg containing puerarin. Bone found in female patients after taking 3 months Density increased by an average of 2.18%, an average increase of 2.72% after 6 months; male patients increased an average of 1.83% after taking 3 months, and an average increase of 2.31% after 6 months, and The symptoms of waist and leg pain have also improved. It was found that pueraria root, pueraria flavonoid extract, and puerarin preparations have the effect of inhibiting the decrease of bone density and increasing bone density, and can be used to prevent and treat osteoporosis, or to enhance bone quality. Treatment Example 2.
  • each preparation contains 200-450 mg of puerarin (Yufeng Ningxin Tablets: Beijing Tongrentang Chinese Medicine Refinery; each tablet contains pueraria total 60mg of flavonoids, 3-5 tablets at a time, 2-3 times a day)
  • pueraria a preparation contains pueraria total 60mg of flavonoids, 3-5 tablets at a time, 2-3 times a day
  • During treatment 9 people's facial neck and neck fever, nausea, insomnia, fatigue, and moodiness were significantly improved in 2 weeks, effective 75.0%. It was found that pueraria, pueraria flavonoid extract, and puerarin preparations can be used to prevent and treat menopause syndrome.
  • Treatment Example 3 Treatment Example 3.
  • kudzu root, pueraria flavonoid extract, and puerarin preparations can be used to prevent and treat irregular menstruation, premenstrual syndrome and breast hyperplasia.
  • pueraria, pueraria flavonoid extract and puerarin preparations can be used to prevent and treat male hair loss and acne.
  • Treatment Example 5 For a 49-56-year-old female patient with coronary heart disease accompanied by dry skin, itching of the skin, itching of the vulva, frequent urination, and dryness of the genitals, oral administration of a preparation containing 200-450 mg of puerarin daily The oral solution described in Example 3, 2 to 3 times a day) After treatment, the symptoms of dry skin, itching of the skin, itching of the vulva, frequent urination, and dryness of the vagina were significantly improved after 3 weeks. After 20 weeks, the above symptoms were significantly improved.
  • pueraria, pueraria flavonoid extract, and puerarin preparations can be used to prevent and treat senile earrings, vision loss or depression in the elderly, and cataracts.
  • Treatment Example 7 Nine 68-76-year-old male patients with sleep disturbance, memory loss, mild Alzheimer's disease, and chronic prostate hypertrophy, orally taking a preparation containing 200-450 mg of puerarin daily (Yufengning Heart tablets: Beijing Tongrentang Traditional Chinese Medicine Refinery; each tablet contains 60mg of pueraria flavonoids, 3-5 tablets at a time, 2-3 times a day) During treatment, 1 month later, 6 people found that their sleep disturbance, memory loss, Alzheimer's disease, urinary tract obstruction, and frequent urination were also significantly improved, with an effective rate of 66.6%. It was found that pueraria, pueraria flavonoid extract, and puerarin preparations can be used to prevent and treat senile sleep disorders, aged memory loss or depression, dementia, and chronic prostate hypertrophy.
  • Example 8 Thirty-two female mice of 8 weeks of age were randomly divided into 4 groups of 8 mice each. Experimental settings: sham operation group, ovariectomy model control group (OVX), 0VX + 10% Puerariae group, 0VX + 20% Puerariae group. Under 1% pentobarbital sodium anesthesia and sterile operation, except for the sham operation group where the ovaries were not removed and the sham operation was performed, the other groups were excised from both sides of the mouse, resulting in experimental bone caused by estrogen deficiency. Osteoporosis. After the operation, the sham operation group and the 0VX group were given ordinary feed.
  • OVX ovariectomy model control group
  • the OVX + 10% pueraria group and the 0VX + 20% pueraria group were given ordinary feed containing 10% and 20% pueraria powder, respectively. Then, remove the right femur, pick out soft tissues such as muscles, soak in 70% alcohol, dry, weigh them, and perform X-ray photography to analyze the bone mineral content. Results 1 Femoral bone weight was significantly reduced after ovariectomy. The 0VX + 10% Puerariae group completely inhibited the reduction of bone weight caused by oophorectomy.
  • the 0VX + 20% Puerariae group not only completely suppressed the reduction of bone weight caused by ovariectomy, but also The bone weight was larger than that in the sham operation group, indicating that Pueraria can not only suppress the decrease in bone weight caused by estrogen deficiency, but also increase bone weight (Table 1).
  • Osteoblasts come from 0.1% Collagenase solution to digest the skull of newborn ddY mice. Bone marrow cells are derived from the tibia of mice at 6-8 weeks. 5ml ⁇ 2xl0 5 bone marrow cells and 2xl0 4 osteoblasts were added to a 24-well plate containing 10% FBS (calf serum) a- MEM culture medium, so that the final volume was 0.5 ml. After cultured for one day in a 5% C0 2 at 37 ° C in an incubator, remove 0.
  • FBS calf serum
  • the number of osteoclast induced by active vitamin D 3 is 100%, the 10-8 to 10-puerarin dose-dependent manner inhibits the formation of osteoclasts, 10- 3 ⁇ 41 puerarin inhibition rate of up to 91.7% ( p ⁇ 0.05). It indicates that puerarin, puerarin extract or puerarin preparations can inhibit the low bone density, and are used to prevent and treat osteoporosis, which is related to puerarin's inhibition of osteoclast formation.

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Description

葛根、 葛根黄酮提取物以及葛根素制剂用于
预防和治疗新的适应症的方法 技术领域
本发明涉及葛根、 葛根黄酮提取物以及葛根素制剂用于预防和 治疗新的适应症的方法。 更具体地说， 本发明涉及葛根、 葛根黄酮 提取物以及葛根素制剂用于预防和治疗骨质疏松症， 与内分泌失调 相关的病症， 如更年期综合症、 经前期综合症、 月经不调、 乳腺增 生、 第二性征发育不足的乳房过小或偏小、 男性脱发、 痤疮， 以及 以下与老化相关的病症， 例如：老年记忆力的减退或低下、 老年痴呆 症、 老年睡眠障碍、 老年性耳聋、 老年视力的减退或低下、 白内障、 慢性前列腺肥大、 老年性阴道炎、 膀胱炎、 尿道炎、 女阴干燥症、 以及皮肤老化（老年斑， 老年皮肤干燥， 老年皮肤搔痒， 皮肤胶原纤 维不足而导致的皮肤弹性低下， 皱紋增多， 皮肤变薄）。 背景技术
葛根 (Puerariae Radix)为豆科植物野葛 (Pueraria Lobata Willd Ohwi)或甘葛（Pueraria Thamsonii Benth)的干燥根。 葛 根广泛取材于我国、 朝鲜半岛、 曰本、 东南亚以及北美等地。 通常 使用中药葛根治疗感冒发热、 项背疼痛、 泄泻、 醉酒等。 近年来， 使用其提取物葛根黄酮和葛根素（Puerarin ) 用于扩张血管、 降低 血压、 改善心脑血液循环、 降低心肌耗氧、 用于高血压头晕、 头疼， 脑中风， 冠心病， 心绞痛， 心肌梗塞。 发明内容
本发明经深入研究发现葛根、 葛根黄酮提取物以及葛根素制剂 在临床上可以用于预防和治疗下列新的适应症： 骨质疏松症， 与内 分泌失调相关的病症， 如更年期综合症、 经前期综合症、 月经不调、 乳腺增生、 第二性征发育不足的乳房过小或偏小， 男性脱发， 痤疮， 以及以下与老化相关的病症， 例如：老年记忆力的減退或低下、 老年 痴呆症、 老年睡眠障碍、 老年性耳聋、 老年视力的减退或低下、 白 内障、 慢性前列腺肥大、 老年性阴道炎、 膀胱炎、 尿道炎、 女阴干 燥症、 以及皮肤老化（老年斑， 老年皮肤干燥， 老年皮肤搔痒， 皮肤 胶原纤维不足而导致的皮肤弹性低下， 皱纹增多， 皮肤变薄）。 本发 明还涉及葛根、 葛根黄酮提取物以及葛根素制剂用于制备治疗和预 防上述疾病的药物或食品增补剂的用途。
葛根是如前所述的豆科植物野葛或甘葛的干燥的根， 不论是否 有品种的改良或变异只要含有葛根素， 即可用于本发明中所述的新 的适应症。 根的干燥方法可以采用在自然通风、 阴凉下自然干燥， 也可以采用机械式干燥。 根干燥后可通过机械破碎加工成切片或粉 末等。
可以将机械破碎加工后的葛根切片或粉末等用水或醇等溶剂提 取得到葛根黄酮浸膏， 提取物中主要化学成份为葛根素， 约占葛根 黄酮的 50%, 其他还包括黄豆甙元、 芒柄花素 -7-0-葡萄糖甙、 黄豆 甙、 3， -甲氧基葛根素、 葛甙 B、 黄豆甙元 -8- C-芹菜糖基 - (1-6) - 葡萄糖甙、 3， -羟基葛根素、 葛根素木糖甙、 黄豆甙元- 7, 4， - 0- 二葡萄糖甙、 葛根素 -4， -0-葡萄糖甙、 葛甙 C 等（中国专利公告 1176117)。 用水提取葛根黄酮的方法与普通煎中药一样， 例如， 将 粉碎葛根切片或粉末， 加水充分浸泡后， 再加入相等体积以上的水， 加热沸腾后改为小火， 煎煮 30分钟以上至水溶性物质充分溶出后， 固液分离， 液体浓缩成膏状， 或再进行干燥。 用醇提取葛根黄酮的 方法， 例如用水-已醇提取， 是将粉碎葛根切片或粉末， 加入 2 0 ~ 9 0 %的乙醇溶剂， 充分浸泡后， 再加入相等体积以上的溶剂， 搅拌 下使混合物升温至 2 0 ~ 7 0 Ό， 并继续搅拌 0. 5 ~ 3小时， 固液分 离， 除去溶剂， 浓缩成膏状， 或再进行干燥；或者按照中国药典 2000 年版愈风宁心片的制备过程中清膏的提取方法进行制备； 或者按中 国专利公告 (公开号） 1172808， 1176818, 或 1326932提取。
葛根素是从葛根中提取的已知的、 单一成份的化合物， 其化学 名为 4， ，7-二羟基，8- & -0葡萄糖异黄酮， 其分子式是 C21H2Q09, 其 制造方法是可按中国专利公告 (公开号） 1163127或 1154849所述提 取， 或者可以用化学方法合成。
预防和治疗所需的剂量与许多因素有关， 例如疾病症状、 给药 方式以及接受治疗者的年龄、 身体状况等。 通常用于给药的剂量， 葛根、 葛根黄酮提取物以及葛根素制剂都以含有葛根素的量为标准， 曰剂量为 30mg ~ 1500mg,典型的剂量为 lOOmg ~ 500mg。优选 150mg ~ 300mg。
用于制备治疗和预防所述适应症的本发明药品或食品制剂的原 料可以是葛根、 葛根黄酮或葛根素以及葛根素的生理上可接受的盐 以及其衍生物。 可选择地， 在本发明的治疗方法和本发明制剂中还 可以将上述成分与本领域技术人员熟知的治疗和预防本发明所述疾 病的其它治疗活性剂一起联合应用， 所述的其它治疗活性剂包括预 防和治疗本发明所述疾病的其他的中草药或西药成分的制剂；或可 选择地， 进一步包括无机或有机的钙、 镁或其他的矿物质， 有机的 甲壳素或聚酰氨， 硫酸软骨素， 胶原蛋白， 维生素类如维生素 D，K, 或有抗氧化、 抗衰老、 整胃肠功能， 镇痛解痉等功能性成分。 除上 述活性成分之外， 还可以加入其他的非活性的药学上或食品上常用 的载体或赋形剂等成分。 载体或赋形剂可以是固体或液体， 或者两 者都是。 可以根据所用剂型对载体或赋型剂的类型进行选择。 在本发明的实施方案中， 可以采用以葛根为主要成分， 其他功 能性的中草药为辅助性成分的制剂， 其中葛根的含有量可以在
22-100%。 在本发明的实施方案中， 可以采用以葛根黄酮或葛根素为 主要成分的制剂， 以含有葛根素的量为标准， 其含量为 0. 1%—100% 重量。 本发明中的制剂可以使用任何熟知的药学技术来制备。
本发明所述的葛根素盐是指葛根素与可药用碱形成的无毒碱盐， 或者是葛根素与可药用酸形成的无毒酸加成盐。 所述的无毒碱盐包 括但不仅限于， 从可药用阳离子如碱金属阳离子（例如钾和钠）和 碱土金属阳离子（例如钙和镁）、铵或水溶性胺加成盐如 N-甲基葡糖 胺（葡甲胺）和低级链烷醇铵衍生的盐和其它可药用有机胺的碱盐。 所述的无毒酸加成盐是指化合物与有机或无机酸生成的无毒酸加成 盐。 即含有药理学上可接受的阴离子的盐， 例如盐酸盐、 氢溴化物、 氢碘化物、 硝酸盐、 硫酸盐、 硫酸氢盐、 鱗酸盐、 酸式 酸盐、 乙 酸盐、 乳酸盐、 柠檬酸盐、 酸式柠檬酸盐、 酒石酸盐、 酒石酸氢盐、 琥珀酸盐、 马来酸盐、 富马酸盐、 葡糖酸盐、 糖二酸盐、 苯甲酸盐、 甲磺酸盐、 乙磺酸盐、 苯磺酸盐、 对甲苯磺酰酸盐和朴酸盐。
本发明所述的葛根素的衍生物包括， 例如： 3' -甲氧基葛根素、 葛甙 Β、 3' -羟基葛根素、 葛根素木糖甙、 葛根素 -4' -D-葡萄糖甙、 葛甙 C等。
本发明的制剂， 毒性， 副作用非常低， 是人或动物的安全的骨质 疏松症以及上述各疾患的治疗和预防剂。 所说的动物， 例如宠物和 家养动物（例如狗、 猫、 鸡、 牛、 马等）， 或用于增强竟技动物的骨 庸（例如赛马所用的马等）。 给药方式， 采用口 JI良、 非口服都可以， 优选口服制剂。
本发明所述的药学上可接受的载体是指不影响各活性成分的活 性且对人体无毒副作用的药用载体。 本发明药物制剂可以制成口服 给药的形式， 例如与情性稀释剂或可同化的食用载体， 或者它可以 被包封在硬壳或软壳胶嚢内， 或者它可以被压制成片。 关于胃肠道 给药治疗给药， 活性化合物可以与赋形剂结合， 以可摄取的口 溶 液、 粉剂、 散剂、 冲剂、 膏剂、 乳剂、 悬浊剂、 片剂、 丸剂、 口含 片、 颗粒剂、 锭剂、 胶嚢剂、 酏剂、 栓剂、 糖浆剂、 糯米纸嚢剂等 剂型加以使用。 活性化合物在这种治疗学上有用的组合物中的含量 使获得适合的剂量成为可行。
片剂、 锭剂、 丸剂、 胶嚢剂等还可以含有下列组分： 粘合剂， 例 如树胶、 阿拉伯胶、 玉米淀粉或明胶； 赋形剂， 例如磷酸二钙； 崩 解剂， 例如玉米淀粉、 马铃薯淀粉、 藻酸等； 润滑剂， 例如硬脂酸 镁； 可以加入甜味剂， 例如蔗糖、 乳糖或糖精， 或矫味剂， 例如薄 荷、 冬青油或櫻桃调味剂。 若单位剂型是胶嚢剂， 则除了上述类型 原料以外， 还可以含有液体载体。 还可以存在各种其它原料， 作为 包衣， 或者改变单位剂型的物理形状。 例如， 片剂、 丸剂或胶嚢剂 可以用虫胶、 糖或二者包衣。 糖浆剂或酏剂可以含有活性化合物， 还含有蔗糖作为甜味剂、含有对羟基苯甲酸甲酯与丙酯作为防腐剂、 含有染剂和调味剂， 例如櫻桃或橙味剂。 用于制备任何单位剂型的 任何原料都应当是药学纯的， 并且在所用剂量下是基本无毒的。 另 外， 活性成分可以结合在緩释制剂中。
适合于注射用途的制剂包括无菌水溶液（只要是水溶性的）和无 菌粉末， 用于无菌可注射溶液的临时性制备。 它们在生产和贮存条 件下必须是稳定的， 并且必须加以保护不受微生物的污染作用， 例 如细菌和真菌。 载体可以是溶剂或分散介质， 例如含有水、 乙醇、 多元醇（例如甘油、 丙二醇和液体聚乙二醇等）、 它们的适当混合物 和植物油。 利用各种抗细菌剂和抗真菌剂可以防止微生物的作用， 例如对羟基苯甲酸酯、 氯丁醇、 苯酚、 山梨醇等。 在很多情况下， 将优选包括等渗剂， 例如糖或氯化钠。
无菌可注射溶液是这样制备的，将在适当溶剂中的所需量活性成 分与上文列举的各种其它成分混合， 根据需要， 随后例如进行过滤 灭菌或其它适当方式的灭菌。 分散系也是本发明所针对的， 它们可 以这样制备， 将各种无菌活性成分结合在无菌载体内， 载体含有基 本分散介质和所需的上文列举的其它成分。 在用于无菌可注射溶液 制备的无菌粉末的情况下， 优选的制备方法包括真空干燥和冷冻干 燥技术， 得到活性成分加任何另外的所需成分的粉末， 另外的成分 来自以前无菌过滤的溶液。
药学上可接受的载体和 /或稀释剂包括任何所有的溶剂、 分散介 质、 包衣、 抗细菌与抗真菌剂、 等渗与吸收延迟剂等。 这些介质和 试剂对药学上的活性物质的用途是本领域所熟知的。 除了在常规介 质或试剂药围内与活性成分不相容的以外， 本发明所针对的是其在 治疗制剂中的用途。
尤为有利的是配制成口^^给药的单位剂型， 以便给药容易、 剂量 统一。 这里所用的单位剂型指物理上离散的单元， 适合作为单一剂 量用于治疗； 每个单元含有与所需药物载体締合的预定量的活性物 质， 含量经过计算可产生所需的治疗效果。 关于本发明的单位剂型 的说明取决于并且直接依赖于（a)活性物质的独特性质和所要达到 的特定治疗效果， （b)制剂领域固有的限制。
本发明的制剂可以以食品的形式提供， 例如以加入、 混合或其 他途径加到食品中去。 食品是从广义上讲的， 例如健康食品。 本发明的最佳实施方式
本发明的进一步特征更加充分地描述在下列实施例中。不过不言 而喻的是， 包括这些详细说明的目的仅仅在于对本发明进行例证。 制剂实施例 1、 浸膏
[制法]取葛根 150g, 粉碎成细粉， 另取葛根 850g, 用 80%~ 90% 乙醇加热回流三次， 第一次 4小时， 第二、 三次各 3小时， 滤过， 合并滤液， 回收乙醇， 减压浓缩至相对密度为 1. 40 (50°C )的清膏。
制剂实施例 2、 片剂
[制法]取制剂实施例 1中所述清膏， 与葛根细粉混匀， 干燥， 粉 碎， 制成颗粒， 干燥， 压制成约 1000片， 包糖衣或薄膜衣， 即得。
制剂实施例 3、 口服液
[制法]取制剂实施例 1中所述清膏，加入蔗糖、矫味剂和水适量， 调节 pH4. 5 - 7. 0, 加水至 1000ml, 灌装， 灭菌， 即得。
制剂实施例 4、 食品增补剂 （冲剂）
[制法]取制剂实施例 1中所迷清膏， 喷雾干燥， 制成干浸膏粉， 加乳糖适量， 混匀， 制粒， 干燥。
制剂实施例 5、 注射剂
[制法]用北京协和制药厂生产的葛根素粉末 10g作原料，加入水 溶解， 调 pH4. 5-7. 0, 再加入苯酚 0. 5%作抑菌剂， 定容至 2000ml, 超滤， 灌装， 熔封， 灭菌。 治疗实施例 1. 最近的研究表明骨密度与心血管疾病有密切关 系。 如冠心病患者随着病程的增加而骨密度降低， 呈显箸负相关。 本发明用于治疗骨质疏松症， 是通过用含有葛根素的制剂对冠心病 患者进行治疗过程中而发现的。 患有冠心病伴有腰腿疼痛的骨质疏 松症的 52-61岁女性患者 18人和 54-66岁男性患者 13人每日以含 有葛根素的制剂实施例 1 中制备的葛根浸膏制剂口服， 每日三次， 每次剂量相当于含葛根素 200-450mg。发现女性患者服用 3个月后骨 密度平均增加了 2. 18 % , 6个月后平均增加了 2. 72%; 男性患者服 用 3个月后骨密度平均增加 1. 83 % , 6个月后平均增加了 2. 31%, 并且腰腿疼痛的症状也有良好的改善。 由此发现葛根、 葛根黄酮提 取物以及葛根素制剂有抑制骨密度的低下、 并有使骨密度增加的作 用， 可以用来预防和治疗骨庸疏松症， 或用于增强骨质。 治疗实施例 2. 对更年期综合症的 46-52岁女性患者 12人，每 曰口服含有 200-450 mg葛根素的制剂 （愈风宁心片： 北京同仁堂中 药提炼厂；规格每片含葛根总黄酮 60mg， 一次 3-5片， 一曰 2- 3次） 对其进行治疗时， 2周内， 9人面颈红热、 恶心、 失眠、 易疲劳、 情 绪不安等症状得到明显改善， 有效率 75. 0%。 由此发现葛根、 葛根黄 酮提取物以及葛根素制剂可以用来预防和治疗更年期综合症。 治疗实施例 3. 对月经不调、 经前期综合症、 轻度乳腺增生的 42-49岁女性患者 13人， 每曰口服含有 130m g - 200mg葛根素的制 剂 （愈风宁心片：河北宽城制药厂； 规格每片含葛根素不少于 13mg, 一次 5片，一日 2-3次）对其进行治疗时， 3周后 9人月经周期紊乱、 经前期综合症得到明显改善， 有效率 69. 2%, 12周后， 8人乳腺增生 也得到很好的改善， 有效率 61. 5%。 由此发现葛根、 葛根黄酮提取物 以及葛根素制剂可以用来预防和治疗月经不调、 经前期综合症以及 乳腺增生。 治疗实施例 4. 对脱发伴有痤疮的 18-29岁未婚男性患者 8人， 每曰注射葛根素制剂（葛根素注射液， 渐洒康恩贝制药有限公司生 产， 10mg/2ml, —次 5支， 加入注射用葡萄糖水溶液中， 静脉滴注）， 1周后， 5人痤疮得到明显改善， 4周后， 脱发得到明显改善， 有效 率 62, 5%。 由此发现葛根、 葛根黄酮提取物以及葛根素制剂可以用来 预防和治疗男性脱发、 痤疮。 治疗实施例 5. 对冠心病伴有皮肤干燥、皮肤搔痒、外阴搔痒、 尿频及女阴干燥症的 49-56岁女性患者 10人,每日口服含有 200-450 mg葛根素的制剂 （制剂实施例 3所述口服液， 一日 2- 3次） 对其进 行治疗时， 3周后， 7人皮肤干燥、 皮肤搔痒、 外阴搔痒、 尿频以及 阴道干燥的症状得到明显改善， 20周后， 上述的症状进一步得到改 善外， 皮肤弹性增强， 皱紋減少， 第二性征的胸乳外观也得到很好 的改善， 有效率 70. 0%。 由此发现葛根、 葛根黄酮提取物以及葛根素 制剂可以用来预防和治疗皮肤老化、 老年性阴道炎、 膀胱炎、 尿道 炎、 女阴干燥症以及改善胸乳外观。 治疗实施例 6. 对老年性耳聋、 老年视力的减退、 白内障的 61-72岁患者 9人， 每日口服约含有 200- 450 mg葛根素的制剂 （愈 风宁心片： 北京同仁堂中药提炼厂；规格每片含葛根总黄酮 60mg, — 次 3- 5片， 一日 2-3次）对其进行治疗时， 4周后，发现 5人其耳聋、 视力减退的症状得到明显改善， 6个月后， 5人除上述的症状进一步 得到改善外， 白内障也得到好转， 有效率 55. 5%。 由此发现葛根、 葛 根黄酮提取物以及葛根素制剂可以用来预防和治疗老年性耳章、 老 年视力的减退或低下以及白内障。 治疗实施例 7. 对伴有睡眠障碍、 记忆力的减退、 轻度老年痴 呆症、 慢性前列腺肥大的 68-76 岁男性患者 9人， 每日口服含有 200-450 mg 葛根素的制剂 （愈风宁心片： 北京同仁堂中药提炼厂； 规格每片含葛根总黄酮 60mg, —次 3-5片， 一曰 2- 3次）对其进行 治疗时， 1个月后， 6人发现其睡眠障碍、 记忆力的減退、 老年痴呆 症、 尿路梗阻和尿频等症状也得到明显改善， 有效率 66. 6%。 由此发 现葛根、 葛根黄酮提取物以及葛根素制剂可以用来预防和治疗老年 睡眠障碍、 老年记忆力的減退或低下、 老年痴呆症、 慢性前列腺肥 大。
实施例 8. 8周龄的雌性小鼠 32只，随机分为 4组，每组 8只。 实验设： 假手术組， 卵巢切除模型对照组（OVX) , 0VX +10%葛根组， 0VX +20%葛根組。 在 1%戊巴比妥钠麻醉和无菌搡作下， 除假手术组 未切除卵巢施行假手术外， 其它各組均切除小鼠双侧卵巢， 造成由 雌激素缺乏而引起的实验性骨质疏松症。 术后， 假手术组和 0VX组 给予普通饲料， OVX +10%葛根組、 0VX +20%葛根组分别给予含有 10%、 20%葛根粉末的普通饲料， 饲养 4周， 麻醉下心脏取血死亡后， 取出 右侧股骨， 剔净付着肌肉等软組织， 置 70%酒精浸泡后， 干燥， 秤取 其重量， 并进行 X射线摄影， 分析其骨矿质的含有程度。 结果①卵 巢切除后股骨重量显著降低， 0VX +10%葛根组完全抑制了卵巢切除 所致的骨重的减少； 0VX +20%葛根組不仅完全抑制了卵巢切除所致的 骨重的减少， 而且比假手术組的骨重还大， 说明葛根不仅能够抑制 雌激素缺乏所导致的骨重减少， 并能够增加骨重 （表 1)。 ② X射线 照片显示， 卵巢切除后股骨远心端海绵骨的骨矿质的含量下降； 0VX +10%葛根组完全抑制了这种下降； 0VX +20%葛根組不仅完全抑制了 这种下降， 而且比假手术组骨矿质的含量还高， 说明葛根不仅能够 抑制雌激素缺乏所导致的骨矿质的含量下降， 并能够增加骨中矿质 的含量（附图 1: 照片）。 综上所述， 葛根不仅有可能用来预防和治 疗骨质疏松症， 而且有可能用来增强骨质。 表 1. 葛根对卵巢切除后小鼠股骨重量的影响
組别 股骨重量 （mg) 假手术組 53. 7 ±1. 1 *
0VX組 50. 4 ±1. 0
0VX +10%葛根組 56. 1 ±1. 2 **
0VX +20%葛根组 57. 1 ±1. 1 ** #
与 0VX組比， * P < 0. 05, ** P < 0. 01。
与假手术组比， # P < 0. 01。 实施例 9. 成骨细胞由 0. l%Collagenase液消化新生 ddY小鼠 的颅骨而来。 骨髓细胞来源于 6 ~ 8周的小鼠的胫骨。 2xl05骨髓细 胞与 2xl04成骨细胞加入含有 10%FBS (小牛血清）的 a- MEM培养液的 24孔板中， 使最终体积为 0. 5ml。 在 37度 C的 5%的 C02培养箱内培 养一天后， 去掉 0. 4ml培养液， 再加入活性维生素 D3 (使其最终浓度 为 10—8Μ) ,或再加入各种浓度的葛根素（使其最终浓度为 10— 8 ~ 10— 5M)， 各組标本培养 3天后， 换以新的各培养液再培养 3天。 然后去掉培 养液， 用 10%PBS清洗， 放室温干燥后， 加入酸性祷酸酶染色， 光学 显微镜下观察， 其中有 3个核以上的细胞计为破骨细胞。 以活性维 生素 D3诱导的破骨细胞数为 100%计算， 10— 8 ~ 10— 葛根素用量依存 地抑制了破骨细胞的形成， 10— ¾1 葛根素的抑制率最高达 91. 7% ( p 〈0. 05)。 说明葛根， 葛根浸膏或葛根素制剂抑制骨密度的低下， 用 于预防和治疗骨质疏松症， 是与葛根素抑制破骨细胞的形成作用有 关。

Claims

权 利 要 求
1. 葛根、 葛根黄酮以及葛根素用于治疗或预防骨质疏松症、 与内 分泌失调相关的病症以及与老化相关的病症的方法。
2. 根据权利要求 1的方法， 其中所述与内分泌失调相关的病症是 更年期综合症， 经前期综合症， 月经不调， 乳腺增生， 第二性征发 育不足的乳房过小或偏小、 男性脱发、 痤疮。
3. 根据权利要求 1的方法， 其中所述与老化相关的病症为老年记 忆力的減退或低下， 老年痴呆症， 老年睡眠障碍， 老年性耳章， 老 年视力的减退或白内障， 慢性前列腺肥大， 老年性阴道炎、 膀胱炎、 尿道炎， 女阴干燥症以及皮肤老化。
4. 根据权利要求 1的方法， 其中所述葛根作为治疗剂。
5. 根据权利要求 1-4的方法， 其中使用葛根黄酮提取物作为治疗 剂。
6. 根据权利要求 1-4的方法， 其中使用葛根素作为治疗剂。
7. 根据权利要求 1-4的方法， 其中所用的葛根、 葛根黄酮、 葛根 素的量以葛根素计为每日 30mg-1500mg, 优选 100-500mg， 更优选 150-300mg。
8. 葛根、 葛根黄酮以及葛根素用于制备治疗或预防骨质疏松症、 与内分泌失调相关的病症以及与老化相关的病症的药物制剂的用 途。
9. 根据权利要求 8的用途， 其中药物制剂， 以葛根为主要成分。
10. 根据权利要求 9的用途， 其中葛根的含量为 22- 100%重量。
11. 根据权利要求 8的用途， 其中药物制剂以葛根黄酮或葛根素为 成分。
12- 根据权利要求 11的用途， 其中以含有葛根素的量为标准， 葛 根黄酮或葛根素的量为 0. 1-100%重量。
13. 根据权利要求 8-11的用途， 其中所述药物制剂为口服液、 片 剂、 浸膏、 粉剂、 散剂、 丸剂、 冲剂、 口含片、 颗粒剂、 锭剂、 胶 嚢剂、 糖浆剂、 糯米纸嚢剂、 注射剂。
14. 葛根、 葛根黄酮以及葛根素用于制备改善或预防骨质疏松症、 与内分泌失调相关的病症以及与老化相关的病症的食品增补剂的用 途。
PCT/CN2002/000276 2001-04-23 2002-04-23 Procedes d'utilisation d'un extrait de puerariae radix, flavone de puerariae radix et preparation contenant une puerarine pour la prevention et le traitement de nouvelles indications WO2002085392A1 (fr)

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