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WO2013087042A1 - 预防或治疗淀粉样β肽相关疾病或状况的医药组合物 - Google Patents

预防或治疗淀粉样β肽相关疾病或状况的医药组合物 Download PDF

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Publication number
WO2013087042A1
WO2013087042A1 PCT/CN2012/086796 CN2012086796W WO2013087042A1 WO 2013087042 A1 WO2013087042 A1 WO 2013087042A1 CN 2012086796 W CN2012086796 W CN 2012086796W WO 2013087042 A1 WO2013087042 A1 WO 2013087042A1
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Prior art keywords
pharmaceutical composition
polar solvent
water
ethanol
disease
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PCT/CN2012/086796
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English (en)
French (fr)
Inventor
林汉钦
苏慕寰
黄永名
唐静静
Original Assignee
杏辉天力（杭州）药业有限公司
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Application filed by 杏辉天力（杭州）药业有限公司 filed Critical 杏辉天力（杭州）药业有限公司
Priority to KR1020147018051A priority Critical patent/KR102048289B1/ko
Priority to SG11201403265VA priority patent/SG11201403265VA/en
Priority to EP12856624.7A priority patent/EP2792361B1/en
Priority to US14/365,404 priority patent/US20150087606A1/en
Priority to AU2012350437A priority patent/AU2012350437B2/en
Priority to JP2014546303A priority patent/JP6134331B2/ja
Priority to CA2859227A priority patent/CA2859227C/en
Publication of WO2013087042A1 publication Critical patent/WO2013087042A1/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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7032—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a polyol, i.e. compounds having two or more free or esterified hydroxy groups, including the hydroxy group involved in the glycosidic linkage, e.g. monoglucosyldiacylglycerides, lactobionic acid, gangliosides
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23G—COCOA; COCOA PRODUCTS, e.g. CHOCOLATE; SUBSTITUTES FOR COCOA OR COCOA PRODUCTS; CONFECTIONERY; CHEWING GUM; ICE-CREAM; PREPARATION THEREOF
    • A23G4/00—Chewing gum
    • A23G4/06—Chewing gum characterised by the composition containing organic or inorganic compounds
    • A23G4/10—Chewing gum characterised by the composition containing organic or inorganic compounds characterised by the carbohydrates used, e.g. polysaccharides
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L2/00—Non-alcoholic beverages; Dry compositions or concentrates therefor; Their preparation
    • A23L2/52—Adding ingredients
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/105—Plant extracts, their artificial duplicates or their derivatives
    • 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
    • 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)
    • A61K36/64—Orobanchaceae (Broom-rape family)
    • 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
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • composition for preventing or treating amyloid beta peptide-related diseases or conditions comprising: preventing or treating amyloid beta peptide-related diseases or conditions
  • the present invention relates to a pharmaceutical composition for preventing or treating an amyloid ⁇ -peptide-related disease or condition, which comprises as an active ingredient a lutein and a heterophylloside, the active ingredient It is capable of inhibiting the production, accumulation or aggregation of amyloid beta peptide.
  • U.S. Patent No. 7,087,252, ⁇ 2 discloses a 25-50 wt% echinacoside and 5-15 wt% amygdalin (acteoside) prepared from the fleshy stem of Tubulosa (Schenk) Wight).
  • Formulations useful for anti-Alzheimer's disease (senile dementia) Heterophyllin and a variety of other phenylethanoid glycosides are known to be included in the formulation.
  • heterologous lutein or a pharmaceutically acceptable salt thereof for inhibiting the production, accumulation or aggregation of amyloid beta peptides, and the preparation thereof for the prevention or treatment of amyloid beta peptides is disclosed in WO 201 1/157059 A1.
  • the use of a drug for a disease or condition is disclosed in WO 201 1/157059 A1.
  • amyloid beta peptides and aggregates thereof are susceptible to eliciting various diseases or conditions in vivo
  • a pharmaceutical composition for inhibiting the production, accumulation or aggregation of amyloid beta peptides which can be used as Food, drink, chew, patch, skin care product or other additive.
  • Another object of the present invention is to provide a pharmaceutical composition for preventing or treating an amyloid beta peptide-related disease or condition.
  • a pharmaceutical composition for preventing or treating a disease or condition associated with an amyloid beta peptide according to the present invention comprises, as an active ingredient, a lutein and a heterophylloside, wherein the heterologous leaf cohosh
  • the weight ratio of the glycoside to the leaf scutellin is from 4:1 to 1:4.
  • the weight ratio of the isoflavones to the leaf-like aglycone in the pharmaceutical composition is 4: 1 to 2:3.
  • the pharmaceutical composition does not contain echinacoside.
  • the pharmaceutical composition is capable of inhibiting the production, accumulation or aggregation of the amyloid beta peptide.
  • the pharmaceutical composition is capable of inhibiting the extracellular production, accumulation or aggregation of the amyloid beta peptide.
  • the pharmaceutical composition is capable of inhibiting the damage or apoptosis of the amyloid beta peptide, thereby retaining, improving or restoring learning and memory.
  • the disease or condition associated with amyloid beta peptide is Alzheimer's disease, mild cognitive impairment, Lewis dementia, Down's syndrome, Dutch-type amyloidosis, Guam Parkinson Syndrome - dementia complex, cerebral amyloid angiopathy, inclusion body inflammation, frontotemporal dementia, age-related macular degeneration or Pick disease.
  • the pharmaceutical composition is for the treatment of Alzheimer's disease.
  • the pharmaceutical composition is for preventing or delaying an organism suffering from Alzheimer's disease.
  • the effective amount of the pharmaceutical composition to the human body is equivalent to 0.2 mg to 4 mg of the active ingredient per kg of body weight per day.
  • the pharmaceutical composition comprises a plant extracting phenylethanoid glycoside as a source of the active ingredient, wherein the preparation comprises phylloside and heterophylloside as the main phenylethyl alcohol component, and is heterogeneous.
  • the content of scutellarin is greater than that of the leaf scutellin.
  • the formulation comprises 12-32% flavonoids and 26-46% isophylloside, based on the weight of the formulation.
  • the plant is a Cistanche tubulosa.
  • the preparation is prepared by a process comprising the following steps:
  • step b) the extract obtained in step a) is concentrated and added to a column containing a hydrophobic macroporous polymer, so that the phenylethanoid is adsorbed on the polymer;
  • the first polar solvent is water, sterol, ethanol, a mixture of water and sterol a solvent, or a mixed solvent of water and ethanol
  • the second polar solvent is water
  • the third polar solvent is decyl alcohol, ethanol, a mixed solvent of water and sterol, or a mixed solvent of water and ethanol, and the third The polar solvent is less polar than the second polar solvent; e) concentrating the phenylethanoid glycoside-containing eluate obtained in step d) and redissolving it in water, and the resulting aqueous solution is contacted with a macroporous resin such that the phenylethanoid glycoside is adsorbed on the macroporous resin;
  • the fourth polar solvent is a 25 to 35% aqueous solution of ethanol
  • the fifth polar solvent is a 35 to 45% aqueous solution of ethanol.
  • Figure 1 shows the pharmaceutical composition of drug A (Cymenoside), I (heterologin), C (control group, drug-free) and different ratios of A and I in the accumulation of ⁇ 1-40 outside the cell. Impact.
  • Figure 2 shows the pharmaceutical composition of the drug ⁇ (C. sinensis), I (heterophyllin), C (control group, drug-free) and different ratios of A and I to ⁇ -42 oligomerization Impact. The best way to implement the invention
  • amyloid beta peptide aggregates may be present, for example, in the form of fibers or plaques, and precipitated in the system, organ, tissue or body fluid of the organism, thereby causing various diseases or conditions. If it can effectively inhibit the production, accumulation or aggregation of amyloid ⁇ -peptide, it should avoid various diseases or conditions caused by the formation of aggregates of amyloid ⁇ -peptide, which should be used as an effective prevention or treatment of amyloid ⁇ -peptide related diseases or conditions.
  • preventing is meant avoiding or delaying the appearance of a disease or condition in an organism, and said “treating” means slowing or preventing the progression of the disease or condition, or returning the condition of the organism to a better or normal condition. status.
  • amyloid beta peptide-associated disease or condition means that the occurrence of the disease or condition is usually associated with the production, accumulation or aggregation of amyloid beta peptide, and in particular that the occurrence of the disease or condition is caused by amyloid beta peptide. .
  • amyloid beta peptide-associated disease or condition means that the occurrence of the disease or condition is usually associated with the production, accumulation or aggregation of amyloid beta peptide, and in particular that the occurrence of the disease or condition is caused by amyloid beta peptide. .
  • amyloid beta peptide-associated disease or condition means that the occurrence of the disease or condition is usually associated with the production, accumulation or aggregation of amyloid beta peptide, and in particular that the occurrence of the disease or condition is caused by amyloid beta peptide. .
  • the disease or condition may also be considered. It is related to amyloid beta peptide.
  • the aggregation of the amyloid beta peptide is similar to the
  • the wild type human neuroblastoma SH-SY5Y was cultured in Eagle's Minimum essential Medium (EMEM)/Ham's F12 medium (1:1 mixture) (containing 10% FBS, 10 units/ml penicillin, 10 g/ml)
  • EMEM Eagle's Minimum essential Medium
  • Ham's F12 medium (1:1 mixture) (containing 10% FBS, 10 units/ml penicillin, 10 g/ml)
  • MEM minimum essential medium
  • Example 2 Accumulation test of ⁇ 1-40 outside the cells for each sample
  • the medium of the native human neuroblastoma SH-SY5Y in Example 1 was replaced with a chemical medium (EMEM/F12 medium (Cat. No. 12500-062), Hepes 5 mM, glucose 0.6%, NaHC0 3 3 mM, branamide 2.5 mM, insulin 25 g/ml, Transferin 100 g/ml, Progestrone 20 nM, Putrescine 60 ⁇ , sartite (Sodium selenite) 30 nM, Heparin 2 g/ml). Each well has lxlO 5 SH-SY5Y cells with a medium volume of 300 ⁇ l.
  • test samples shown in Table 1 were separately added to different wells at a total concentration of 50 g/ml for 24 hours, and then the culture medium of each well was analyzed with Human ⁇ 1-40 Immunoassay kits (Catalog # KHB3482 Invitrogen). middle ⁇ 1-40 content.
  • the human neuroblastoma SH-SY5Y accumulates ⁇ in the extracellular medium, while Figure 1 shows the percentage of ⁇ 1-40 in the culture medium after the SH-SY5Y well was treated with each test sample.
  • the control group (C) added to any test sample treatment was used as a baseline. The results are shown as the mean standard error, while the statistical differences between the control and test sample groups are indicated as: *** indicates ⁇ ⁇ 0.001.
  • test sample ⁇ (C. sinensis) reduced the ⁇ 1-40 content in the medium by about 10%
  • test sample ⁇ : ⁇ 40: 10 (C. sinensis 40 g/ml + heterologous leaf Ascoside 10 g/ml) reduced the ⁇ 1-40 content in the medium by about 22%
  • the remaining test samples reduced the ⁇ 1-40 content in the medium by about 80%.
  • the test sample of the glycoside (D) with the test sample of the heterologous leaf asparagine 50 g/ml, had an excellent activity for significantly reducing the extracellular accumulation of ⁇ 1 -40.
  • Example 3 Experiment of oligomerization of ⁇ 1-42 by each test sample
  • the dried Human ⁇ 1-42 was taken out from the refrigerator to room temperature, and 1,1,1,3,3,3-Hexa-fluro-2-propanol (HFIP) was added to dissolve ⁇ 1-42 to a concentration of 1 mM, and then at room temperature. Let stand for 1 hour.
  • HFIP 1,1,1,3,3,3-Hexa-fluro-2-propanol
  • the HFIP-treated ⁇ 1-42 was dissolved in PBS, and subjected to a test sample AD at a concentration of 5 ( ⁇ g/ml, respectively, and shake-treated at 4 ° C for 24 hours to prepare an oligoomer of ⁇ 1-42,
  • Figure 2 shows the effect of the test samples in Table 1 on ⁇ 1-42 oligomerization, and the results are shown as a percentage and based on the control group (C) not treated with any test sample.
  • the active ingredient of ⁇ is formed, accumulated or aggregated, and it is expected that the pharmaceutical composition can effectively inhibit ⁇ -induced neuronal damage or apoptosis, thereby further retaining, improving or restoring learning and memory ability.
  • the ⁇ -related disease or condition may include, but is not limited to, Alzheimer's disease, mild cognitive impairment, Louis's dementia, Down's syndrome, Dutch-type amyloidosis, Guam Parkinson's disease - loss Syndrome complex, cerebral amyloid angiopathy, inclusion body myositis, frontotemporal dementia, age-related macular degeneration, Pico disease and others.
  • the ⁇ is exemplified by the largest amount of ⁇ 1-40 in ⁇ or ⁇ 1-42 having high fiber formation, other amino acid fragments may be contained.
  • a method for preparing a Cistanche tubulosa preparation containing phenylethanoid glycoside is described in the following U.S. Patent No. 7,087,252, which comprises the following steps: a) The underground portion of the Cistanche tubulosa (Flesh Stem) Extracting with a first polar solvent; b) adding the extract obtained in step a) to a column containing a hydrophobic macroporous polymer such that the phenylethanoid is adsorbed onto the polymer; c) using the second The polar solvent elutes the column as a mobile phase stream wash to remove free compounds, while substantially all of the phenylethanoside remains adsorbed on the polymer; and d) the phenylethanoid glycoside is removed from the third polar solvent The polymer is eluted to obtain an eluate containing phenylethanoid, which is less polar than the second polar solvent.
  • the first polar solvent of the above step a) may be, for example, water or a mixed solvent of water and ethanol.
  • the second polar solvent of step c) is water.
  • the third polar solvent of the step d) may, for example, comprise decyl alcohol, ethanol, a mixed solvent of water and decyl alcohol, or a mixed solvent of water and ethanol, and the third polar solvent is preferably a mixed solvent of water and ethanol.
  • the present invention provides a further purification method, which directly purifies the above-described phenylethanoid glycoside preparation, to obtain a pharmaceutical combination containing only phenylethanoids of phylloside and heterophylloside Things.
  • the further purification method comprises the steps of: e ) purifying the Cistanche tubulosa preparation containing a plurality of phenylethanoids with a macroporous resin; f) sequentially performing the macroporous resin separately with the fourth polar solvent and the fifth polar solvent Elution, wherein the polarity of the fourth polar solvent is lower than that of the fifth polar solvent, so that the phenylethanoid glycoside eluted through the fifth polar solvent substantially only contains the flavonoids and the heterophylloside .
  • the fourth polar solvent may be, for example, a 25 to 35% aqueous solution of ethanol
  • the fifth polar solvent may be, for example, a 35 to 45% aqueous solution of ethanol.
  • the hydrophobic macroporous polymer and the macroporous resin are crosslinked polyaromatic materials, more preferably crosslinked polystyrene, or crosslinked styrene and divinylbenzene copolymers, such as D-101. Type or AB-8 type material.
  • Example 4 A pharmaceutical combination containing only the isophylloside and the phenylethanoids of the genus Phytophthoside, 10 kg of Cistanche tubulosa, cut into pieces, and immersed in 8 times the amount of water for 1 hour and then decoction for 2 hours. , filtered, and the filtrate is ready for use. The dregs were further extracted twice with 6 times water, and filtered for 1 hour each time.
  • the filtrate was combined three times, concentrated under reduced pressure to a specific gravity of 1.10 (50 ° C), ethanol was added to an alcohol content of 60%, and refrigerated for 12 hours. The supernatant was decanted, and the remaining suspension was filtered, and the supernatant and filtrate were combined. The extract was concentrated under reduced pressure and ethanol was recovered to a specific gravity of 1.10 (50 ° C) to obtain an extract.
  • the extract extract 6 kg plus 1 times the amount of water is heated and dissolved, and slowly injected into the treated macroporous adsorption resin column, first eluted with water, and collected 4 times the amount of the water eluate for use; and then eluted with 40% ethanol. Collect 5 times the amount of 40% ethanol eluate for use.
  • the water eluate is re-injected into the macroporous adsorption resin column, first eluted with 3 times the amount of water, and the water eluate is discarded; and then eluted with 40% ethanol to collect the drug 4 times 40% ethanol eluate spare.
  • the 40% ethanol eluate was combined twice, concentrated, and dried to obtain 1107 g of a preparation containing phenylethanoid.

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Abstract

一种含有类叶升麻苷与异类叶升麻苷的医药组合物，其能够抑制一淀粉样β肽生成、累积或聚集，于是可以用于预防或治疗与一淀粉样β肽相关的一疾病或状况，其中异类叶升麻苷对该类叶升麻苷的重量比为4：1至1：4。

Description

预防或治疗淀粉样 β肽相关疾病或状况的医药组合物 技术领域
本发明系有关于一种用于预防或治疗一种与淀粉样 β肽相关性疾病或 状况之医药组合物， 其含有作为有效成分的类叶升麻苷与异类叶升麻苷， 该有效成分能够抑制淀粉样 β肽生成、 累积或聚集。 背景技术
美国专利 7,087,252 Β2揭示了一种从管花肉苁蓉 tubulosa (Schenk) Wight)的肉质茎所制备之含 25-50 wt%松果菊苷 (echinacoside)及 5- 15 wt%类叶升麻苷（acteoside)的制剂， 其可用于抗老年痴呆症（senile dementia) 异类叶升麻苷及多种其它苯乙醇苷类（phenylethanoid glycosides) 已知被包含于该制剂中。
申请人前于 WO 201 1/157059 A1揭示了异类叶升麻苷或其医药学上 可接受盐于抑制淀粉样 β肽生成、 累积或聚集之用途， 以及其于制备预防 或治疗淀粉样 β肽相关之疾病或状况的药物之用途。
美国专利 7,087,252 Β2及 WO 201 1/157059 A1的全部内容通过参考方 式被并入本案。
于本申请案中发明人延续 WO 201 1/157059 A1 的研究并获得一相关 的发明成就。 发明内容
有鉴于淀粉样 β肽和其聚集体，容易于生物体内引发各种疾病或状况， 因此本发明之一目的为提供一种抑制淀粉样 β肽生成、 累积或聚集的医药 组合物， 其可作为食品、 饮品、 咀嚼物、 贴片、 皮肤保养品或其他的一添 加剂。 本发明之另一目的则提供一种预防或治疗淀粉样 β肽相关之疾病或 状况的医药组合物。
本发明的又一目的为提供一种医药组合物于制备预防或治疗淀粉样 β 肽相关之疾病或状况的药物之用途。
依本发明内容所完成的一种预防或治疗与一淀粉样 β肽相关之一疾病 或状况的医药组合物包含作为有效成分的类叶升麻苷与异类叶升麻苷， 其 中异类叶升麻苷对该类叶升麻苷的重量比为 4: 1至 1 :4。
较佳的， 该医药组合物中的异类叶升麻苷对该类叶升麻苷的重量比为 4: 1至 2:3。
较佳的， 该医药组合物不含有松果菊苷。
较佳的， 该医药组合物能够抑制该淀粉样 β肽的生成、 累积或聚集。 较佳的， 该医药组合物能够抑制该淀粉样 β肽细胞外的生成、 累积或 聚集。
较佳的， 该医药组合物能够抑制该淀粉样 β肽导致神经元的损伤或凋 亡， 进而保留、 改善或恢复学习与记忆能力。
较佳的， 该与淀粉样 β肽相关之疾病或状况为阿滋海默氏症、 轻度认 知障碍、 路易氏体失智症、 唐氏症、 荷兰型类淀粉变性症、 关岛帕金森氏 症-失智症复合症、 大脑淀粉样血管病、 包涵体几炎、 额颞叶型失智症、 年 龄相关性黄斑变性或皮克病。
较佳的， 该医药组合物是用于治疗阿滋海默氏症。
较佳的， 该医药组合物是用于避免或延迟一生物体罹患阿滋海默氏 症。
较佳的，该医药组合物对人体的有效剂量系相当于每日每公斤体重 0.2 毫克至 4毫克之该有效成分。
较佳的， 该医药组合物包含一种萃取自植物的苯乙醇苷制剂作为该有 效成分的来源， 其中该制剂包含类叶升麻苷与异类叶升麻苷为主要的苯乙 醇成分， 且异类叶升麻苷的含量大于该类叶升麻苷。
较佳的， 该制剂包含 12-32%类叶升麻苷及 26-46%的异类叶升麻苷， 以该制剂的重量为基准。
较佳的， 该植物为一管花肉苁蓉。
较佳的， 该制剂系经过一包含以下步骤的方法所制备：
a)将该管花肉苁蓉的肉质茎以一第一极性溶剂加予萃取；
b)将步骤 a)获得的萃取物于浓缩后加到装有疏水大孔隙聚合物的柱 中， 使得苯乙醇苷吸附在聚合物上；
c)用第二极性溶剂作为流动相流洗液洗脱该柱以除去游离的化合物， 而实质上大部份的苯乙醇苷仍然吸附在聚合物上； 以及
d)用第三极性溶剂将苯乙醇苷从聚合物上洗脱下来， 得到含有苯乙醇 苷的洗脱液， 其中第一极性溶剂为水、 曱醇、 乙醇、 水与曱醇的混合溶剂、 或水与乙醇的混合溶剂； 第二极性溶剂为水； 及第三极性溶剂为曱醇、 乙 醇、 水与曱醇的混合溶剂、 或水与乙醇的混合溶剂， 且该第三极性溶剂与 第二极性溶剂相比极性较低； e)将步骤 d)获得的含有苯乙醇苷的洗脱液浓缩再溶于水中， 所得到的 水溶液与一大孔树脂接触使得其中的苯乙醇苷吸附在大孔树脂上； 及
f)依序以一第四极性溶剂和一第五极性溶剂分别对该大孔树脂进行洗 脱， 其中该第五极性溶剂的极性较该第四极性溶剂为低， 使得以该第四极 性溶剂洗脱而得的洗脱液不含有类叶升麻苷与异类叶升麻苷， 而以该第四 极性溶剂洗脱而得的洗脱液仅包含类叶升麻苷与异类叶升麻苷， 其中第四 极性溶剂及第五极性溶剂为水与曱醇的混合溶剂、 或水与乙醇的混合溶 剂。
较佳的， 该第四极性溶剂为 25~35%乙醇水溶液， 而该第五极性溶剂 则为 35~45%乙醇水溶液。
为让本发明之上述和其他目的、 特征、 和优点能更明显易懂， 下文特 举出实施例， 并配合所附图式， 作详细说明。 附图的简要说明
图 1显示药物 A (类叶升麻苷）、 I (异类叶升麻苷）、 C (控制组， 不含 药物)及不同比例之 A与 I的医药组合物对 Αβ1-40在细胞外累积的影响。
图 2显示显示药物 Α (类叶升麻苷)、 I (异类叶升麻苷)、 C (控制组， 不含药物)及不同比例之 A与 I的医药组合物对 Αβΐ -42寡聚化的影响。 实施发明的最佳方式
许多由淀粉样 β肽引发的疾病均具有一种共通的特征-淀粉样 β肽聚集 体的形成。 这些淀粉样 β肽聚集体可以例如纤维或斑块的形态出现， 并且 沉淀在生物体的系统、 器官、 组织或体液中， 进而引发各种疾病或状况。 如能有效抑制淀粉样 β肽的生成、 累积或聚集， 应可避免淀粉样 β肽形成 聚集体而引发的各种疾病或状况， 其应可作为有效预防或治疗淀粉样 β肽 相关疾病或状况的方式之一。
所述"预防"意指避免或延迟疾病或状况在生物体中出现， 而所述 "治 疗"则指减緩或阻止疾病或状况的发展， 又或者使生物体的状况回复至较 佳或正常的状态。
所述"淀粉样 β肽相关性疾病或状况 "指此疾病或状况的发生通常与淀 粉样 β肽的生成、 累积或聚集相关， 且尤其指此疾病或状况的发生为淀粉 样 β肽所导致。 而当在具有某种疾病或状况之一定比例上的生物体上发现 有淀粉样 β肽的不正常生成、 累积或聚集现象时， 亦可认为此疾病或状况 为淀粉样 β肽相关。 另外， 当淀粉样 β肽的聚集处与疾病或状况所发生的 病理特征影响位置相近时， 亦可认为此疾病或状况为淀粉样 β肽相关。
在下列实施例中， 利用表一所提供之测试样品进行 Αβ试验， 并且与 未加入任何测试样品处理的对照组 (Vehicle)进行比较。 表一： 进行试验之样品
Figure imgf000005_0001
实施例一： 神经瘤母细胞株之培养
将原生型（wild type)人类神经瘤母细胞 SH-SY5Y 培养于 Eagle's Minimum essential Medium (EMEM)/Ham's F12 medium (1 : 1混合物) (含 10% FBS, 10 units/ml penicillin, 10 g/ml Streptomycin)中， 而原生型小鼠神 经瘤母细胞 Neuro-2a则培养于 minimum essential medium (MEM)培养基 (含 10% FBS, 10 units/ml penicillin, 10 g/ml Streptomycin)中。 实施例二： 各样品对 Αβ1-40于细胞外的累积测试
将实施例一中的原生型人类神经瘤母细胞 SH-SY5Y之培养基置换成 化学成份培养基 (EMEM/F12 medium (Cat.No.12500-062), Hepes 5 mM, 葡 萄糖 0.6%, NaHC03 3 mM, 麸酰胺 2.5 mM, 胰岛素 25 g/ml, Transferin 100 g/ml, Progestrone 20 nM, Putrescine 60 μΜ, 亚石西酸 ] (Sodium selenite) 30 nM, Heparin 2 g/ml)。 每个井 (well)具有 lxlO5个 SH-SY5Y细胞， 而培 养基体积为 300 μ1。 30分钟后， 将表一中所示之测试样品分别以 50 g/ml 的总浓度加入至不同井中处理 24 小时， 接着以 Human Αβ1-40 Immunoassay kits(Catalog # KHB3482 Invitrogen)分析各井之培养基中的 Αβ1-40含量。
人类神经瘤母细胞 SH-SY5Y会累积 Αβ于细胞外的培养基中， 而图 1 显示 SH-SY5Y井分别经各测试样品处理后， Αβ1-40于培养基中的含量百 分比，其系以未加入任何测试样品处理的对照组 (C)为比较基准。结果显示 为平均值士标准误差， 而对照组和测试样品组间之统计差异标示为： ***表 示 Ρ<0.001。
参考图 1所示， 测试样品 Α (类叶升麻苷)减少培养基中的 Αβ1-40含 量约 10%, 测试样品 Α:Ι 40: 10 (类叶升麻苷 40 g/ml +异类叶升麻苷 10 g/ml)则减少培养基中的 Αβ1-40含量约 22%,而其余测试样品则减少培养 基中的 Αβ1-40含量约 80%。图 1结果显示类叶升麻苷 +异类叶升麻苷 = 30 g/ml + 20 g/ml; 20 g/ml + 30 g/ml; 及 10 g/ml + 40 g/ml异类叶升麻 苷 (D)的测试样品， 与异类叶升麻苷 50 g/ml 的测试样品具有显著降低 Αβ 1 -40于细胞外累积的极佳活性。 实施例三： 各测试样品对 Αβ1-42寡聚化的实验
将干燥的 Human Αβ1-42 自 冰箱取出 平衡至室温， 加入 1,1,1 ,3 ,3 ,3 -Hexa-fluro-2-propanol (HFIP)溶解 Αβ1-42至浓度为 ImM, 而之 后在室温下静置 1小时。以 Hamilton注射器将上述 ΑβΙ-42/HFIP容易进行 分装， 并且以氮气将 HFIP 吹干， 接着存放于 -20。C。 将 HFIP 处理后的 Αβ1-42以 PBS溶解， 并分别以浓度 5(^g/ml的测试样品 A-D且于 4°C下 振荡处理 24小时， 以制备 Αβ1-42之寡聚物 (oligomer), 并利用 thioflavine T结合荧光 (Ex=450 nm, Em=482 nm)以分析 Αβ1-42的寡聚化程度。
图 2显示表 1 中的测试样品分别对 Αβ1-42寡聚化 (oligomerization)的 影响， 结果以百分比显示， 并以未加入任何测试样品处理的对照组 (C)为基 准。 图 2结果显示表 1中的各测试样品均具有抑制 Αβ1-42寡聚化的活性， 其中以类叶升麻苷+异类叶升麻苷 = 30 g/ml + 20 g/ml; 20 g/ml + 30 g/ml; 及 10 g/ml + 40 g/ml异类叶升麻苷 (D)的测试样品， 与异类叶升 麻苷 50 g/ml的测试样品对降低 Αβ1-42的寡聚化具有较佳的活性， 进而 可抑制 Αβ形成纤维丝或老年斑块。
综合上述结果， 异类叶升麻苷及类叶升麻苷的医药组合物可作为抑制
Αβ生成、 累积或聚集之有效成份， 预计此医药组合物可有效抑制 Αβ导致 神经元的损伤或凋亡， 以进而保留、 改善或恢复学习与记忆能力。 此外， 所述 Αβ相关疾病或状况可包含但不限于阿滋海默氏症、 轻度认知障 碍、 路易氏体失智症、 唐氏症、 荷兰型类淀粉变性症、 关岛帕金森氏症- 失智症复合症、 大脑淀粉样血管病、 包涵体肌炎、 额颞叶型失智症、 年龄 相关性黄斑变性、皮克病以及其他。另，所述 Αβ虽以 Αβ中最大量的 Αβ1-40 或具有高度纤维形成性的 Αβ1-42为例， 然亦可包含其他胺基酸片段。
图 1及 2的结果显示异类叶升麻苷具有较佳的活性，但在实际应用上， 异类叶升麻苷为一种含糖分子， 不易以化学合成方式制备。 以植物来源获 得高纯度异类叶升麻苷的成本亦极高。 由于图 1及 2的结果亦显示类叶升 麻苷和异类叶升麻苷的混合物作为淀粉样 β肽抑制剂具有可比拟于纯异类 叶升麻苷的活性， 因此假使一医药组合物可包含适当组成比的类叶升麻苷 和异类叶升麻苷， 则可在兼顾经济效益和医疗功效等实际应用面考量上， 将此医药组合物用于代替纯化之异类叶升麻苷于预防或治疗淀粉样 β肽相 关的疾病或^大况。
在本发明的下列实施例中， 首先参考美国专利案 US7,087,252所述制 备含有苯乙醇苷的管花肉苁蓉制剂之方法， 其包括下列步骤： a)将管花肉 苁蓉的地下部分（肉质茎）以一第一极性溶剂加予萃取； b)将步骤 a)获得的 萃取物加到装有疏水大孔隙聚合物的柱中， 使得苯乙醇苷被吸附在聚合物 上； c)用第二极性溶剂作为流动相流洗液洗脱该柱以除去游离的化合物， 而实质上大部份的苯乙醇苷仍然吸附在聚合物上； 以及 d)用第三极性溶剂 将苯乙醇苷从聚合物上洗脱下来， 得到含有苯乙醇苷的洗脱液， 该第三极 性溶剂与第二极性溶剂相比极性较低。
上述步骤 a)的第一极性溶剂可例如为水、 或水与乙醇的混合溶剂。 步 骤 c)的第二极性溶剂为水。 步骤 d)的第三极性溶剂则可例如包含曱醇、 乙 醇、 水与曱醇的混合溶剂、 或水与乙醇的混合溶剂， 而第三极性溶剂较佳 为水与乙醇的混合溶剂。
本发明提供了一种进一步纯化方法， 其系直接将上述含苯乙醇苷的管 花肉苁蓉制剂经进一步纯化， 以得到仅含有类叶升麻苷与异类叶升麻苷之 苯乙醇苷的医药组合物。 此进一步纯化方法包括步骤： e)将含有多种苯乙 醇苷的管花肉苁蓉制剂以大孔树脂进行纯化； f)依序以第四极性溶剂与第 五极性溶剂分别对大孔树脂进行洗脱， 其中第四极性溶剂的极性较第五极 性溶剂为低， 使经由第五极性溶剂洗脱而出的苯乙醇苷大抵仅包含类叶升 麻苷与异类叶升麻苷。在一较佳实施例中，第四极性溶剂可例如为 25~35% 乙醇水溶液， 而第五极性溶剂则可例如为 35~45%乙醇水溶液。 较佳的， 该疏水大孔隙聚合物及大孔树脂为交联聚芳族物质， 更佳的 为交联的聚苯乙烯， 或交联的苯乙烯和二乙烯苯共聚物， 例如 D-101型或 AB-8型的材料。
将上述经第五极性溶剂洗脱后的洗脱液进行浓缩或干燥， 即可直接得 到实质上仅含异类叶升麻苷与类叶升麻苷之苯乙醇苷的医药组合物。 实施例四： 仅含有异类叶升麻苷与类叶升麻苷之苯乙醇苷的医药组合 将管花肉苁蓉药材 10 kg, 切成饮片， 加 8倍量水浸泡 1小时后煎煮 提取 2小时， 过滤， 滤液备用。 药渣再加 6倍量水煎煮提取 2次， 每次 1 小时， 过滤。 合并三次滤液， 减压浓缩至比重 1.10 (50°C) , 加乙醇至含醇 量达 60%, 冷藏 12小时， 倾出上清液， 将残留的悬浊液过滤， 合并上清 液和滤液， 减压浓缩并回收乙醇至比重 1.10 (50°C), 得提取浸膏。
将提取浸膏 6 kg加 1倍量水加热溶解，徐徐注入已处理好的大孔吸附 树脂柱内， 先用水洗脱， 收集药材 4倍量水洗脱液备用； 再用 40%乙醇洗 脱， 收集药材 5倍量 40%乙醇洗脱液备用。 将水洗脱液再注入大孔吸附树 脂柱中， 先用药材 3倍量水洗脱， 弃去水洗脱液； 再用 40%乙醇洗脱， 收 集药材 4倍量 40%乙醇洗脱液备用。 合并 2次 40%乙醇洗脱液， 浓缩， 干 燥， 即得含有苯乙醇苷的制剂 1107 g。
以高效液相色谱法测定， 溶剂 A: 含 0.1 %曱酸的乙腈（acetonitrile,
CAN),溶剂 B: 含 0.1%曱酸的 MQ-H20,柱: Agilent Zorbax SB-C18柱， 2.1 X 150 mm, 5μηι; 流速： 0.3 ml/min; UV波长： 333 nm。 上述苯乙醇苷制剂 中的松果菊苷、 类叶升麻苷以及异类叶升麻苷之含量， 经计算后所得之结 果分别为 33.6 wt%、 3.65 wt %以及 6.05 wt %。
将 200公克上述含苯乙醇苷的制剂溶于 800克水中， 以一溶液形式流 经大孔树脂以便进行纯化。接着依序先后分别以 30%乙醇和 40%乙醇进行 洗脱。 ， 在薄层析片（聚酰胺 (Polyamide))以 UV 365nm检测个别的洗脱液， 其中 30%乙醇的洗脱液中未包含类叶升麻苷与异类叶升麻苷， 而 40%乙醇 的洗脱液中则仅包含类叶升麻苷与异类叶升麻苷之苯乙醇苷 23.6 g。 在此 实施例中， 所测得洗脱液中的类叶升麻苷为 22.5 wt%, 而异类叶升麻苷为 36.4 wt%。
虽然本发明已以数个较佳实施例揭露如上， 然其并非用以限定本发明， 任 何熟习此技艺者， 在未脱离本发明所揭示之精神下所完成之等效改变或修 饰， 均应包含在下述之权利要求内。

Claims

权 利 要 求
1. 一种预防或治疗与一淀粉样 β 肽相关的一疾病或状况的医药组合 物， 其包含作为有效成分的类叶升麻苷与异类叶升麻苷， 其中异类叶升麻 苷对该类叶升麻苷的重量比为约 4: 1至约 1 :4。
2. 如权利要求 1所述的医药组合物，其中异类叶升麻苷对该类叶升麻 苷的重量比为约 4: 1至约 2:3。
3. 如权利要求 1所述的医药组合物， 其不含有松果菊苷。
4. 如权利要求 1所述的医药组合物，其中该医药组合物能够抑制该淀 粉样 β肽的生成、 累积或聚集。
5. 如权利要求 1所述的医药组合物，其中该医药组合物能够抑制该淀 粉样 β肽细胞外的生成、 累积或聚集。
6. 如权利要求 1所述的医药组合物，其中该医药组合物能够抑制该淀 粉样 β肽导致神经元的损伤或凋亡， 进而保留、 改善或恢复学习与记忆能 力。
7. 如权利要求 1所述的医药组合物，其中该与淀粉样 β肽相关的疾病 或状况为阿滋海默氏症、 轻度认知障碍、 路易氏体失智症、 唐氏症、 荷兰 型类淀粉变性症、 关岛帕金森氏症-失智症复合症、 大脑淀粉样血管病、 包 涵体肌炎、 额颞叶型失智症、 年龄相关性黄斑变性或皮克病。
8. 如权利要求 1所述的医药组合物，其中该医药组合物是用于治疗阿 滋海默氏症。
9. 如权利要求 1所述的医药组合物，其中该医药组合物是用于避免或 延迟一生物体罹患阿滋海默氏症。
10. 如权利要求 1所述的医药组合物， 其中该医药组合物对人体的有 效剂量系相当于每日每公斤体重 0.2毫克至 4毫克的该有效成分。
11. 如权利要求 3所述的医药组合物， 其包含一种萃取自植物的苯乙 醇苷制剂作为该有效成分的来源， 其中该制剂包含类叶升麻苷与异类叶升 麻苷为主要的苯乙醇成分， 且异类叶升麻苷的含量大于该类叶升麻苷。
12. 如权利要求 11所述的医药组合物， 其中该制剂包含 12-32%类叶 升麻苷及 26-46%的异类叶升麻苷， 以该制剂的重量为基准。
13. 如权利要求 12所述的医药组合物， 其中该植物为一管花肉苁蓉。
14. 如权利要求 13所述的医药组合物，其中该制剂系经过一包含以下 步骤的方法所制备： a)将该管花肉苁蓉的肉质茎以一第一极性溶剂加予萃取； b)将步骤 a)获得的萃取物于浓缩后加到装有疏水大孔隙聚合物的柱 中， 使得苯乙醇苷吸附在聚合物上；
c)用第二极性溶剂作为流动相流洗液洗脱该柱以除去游离的化合物， 而实质上大部份的苯乙醇苷仍然吸附在聚合物上； 以及
d)用第三极性溶剂将苯乙醇苷从聚合物上洗脱下来， 得到含有苯乙醇 苷的洗脱液， 其中第一极性溶剂为水、 曱醇、 乙醇、 水与曱醇的混合溶剂、 或水与乙醇的混合溶剂； 第二极性溶剂为水； 及第三极性溶剂为曱醇、 乙 醇、 水与曱醇的混合溶剂、 或水与乙醇的混合溶剂， 且该第三极性溶剂与 第二极性溶剂相比极性较低；
e)将步骤 d)获得的含有苯乙醇苷的洗脱液浓缩再溶于水中， 所得到的 水溶液与一大孔树脂接触使得其中的苯乙醇苷吸附在大孔树脂上； 及
f)依序以一第四极性溶剂和一第五极性溶剂分别对该大孔树脂进行洗 脱， 其中该第五极性溶剂的极性较该第四极性溶剂为低， 使得以该第四极 性溶剂洗脱而得的洗脱液不含有类叶升麻苷与异类叶升麻苷， 而以该第四 极性溶剂洗脱而得的洗脱液仅包含类叶升麻苷与异类叶升麻苷， 其中第四 极性溶剂及第五极性溶剂为水与曱醇的混合溶剂、 或水与乙醇的混合溶 剂。
15. 如权利要求 14 所述的医药组合物， 其中该第四极性溶剂为 25~35%乙醇水溶液， 而该第五极性溶剂则为 35~45%乙醇水溶液。
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