WO2013060275A1 - 楹树提取物在制备治疗胃溃疡药物中的应用 - Google Patents

楹树提取物在制备治疗胃溃疡药物中的应用 Download PDF

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WO2013060275A1
WO2013060275A1 PCT/CN2012/083458 CN2012083458W WO2013060275A1 WO 2013060275 A1 WO2013060275 A1 WO 2013060275A1 CN 2012083458 W CN2012083458 W CN 2012083458W WO 2013060275 A1 WO2013060275 A1 WO 2013060275A1
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extract
eucalyptus
osbeck
chinensis
merr
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PCT/CN2012/083458
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English (en)
French (fr)
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庾石山
张建军
马双刚
徐瑞明
冀呈雪
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中国医学科学院药物研究所
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Application filed by 中国医学科学院药物研究所 filed Critical 中国医学科学院药物研究所
Priority to CN201280052172.2A priority Critical patent/CN103906525B/zh
Priority to JP2014537478A priority patent/JP6076361B2/ja
Priority to EP12843553.4A priority patent/EP2772264B8/en
Priority to RU2014116582A priority patent/RU2651750C2/ru
Priority to US14/353,926 priority patent/US9393277B2/en
Publication of WO2013060275A1 publication Critical patent/WO2013060275A1/zh

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    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D11/00—Solvent extraction
    • B01D11/02—Solvent extraction of solids
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • 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

  • the present invention relates to an extract of Eucalyptus chinensis (Osbeck) Mem] and a preparation method thereof, and to a pharmaceutical use of a eucalyptus extract as a proton pump inhibitor for the preparation of a medicament for treating gastric ulcer and acid-related diseases,
  • Osbeck Eucalyptus chinensis
  • Gastric ulcer is a common disease in the digestive system and is prone to recurrence. With the rapid pace of modern life, increased mental stress and increased work pressure, the incidence of gastric ulcers is on the rise, jeopardizing people's physical and mental health. At present, the most widely used anti-ulcer western medicines are ranitidine and omeprazole. Although the recent curative effect of western medicine is obvious, it has adverse reactions and side effects after taking the medicine. Therefore, people began to develop new and highly effective anti-ulcer drugs. Based on the long-term clinical practice and drug history of traditional Chinese medicine, it is innately advantageous and has a wide clinical application value to find and excavate natural active ingredients or effective components with anti-gastric ulcer from traditional Chinese herbal medicine.
  • Albizia chinensis (Osbeck) Mem is a plant of the genus Albizia. Its medicinal part is bark, and the bark contains enamel. It has the effect of solidifying diarrhea, astringent and stimulating muscles, and attending enteritis, diarrhea and dysentery.
  • Chinese herbal medicine compilation National Chinese Herbal Medicine Compilation Group, Second Edition, Volume 2, 1986, PP768). It is also reported that bark of eucalyptus contains triterpenoid saponins (also known as Acacia oxytocin) and has the function of contracting the uterus (Chinese Dictionary of Traditional Chinese Medicine, edited by Jiangsu New Medical College, 1998, vol. 1, PP937).
  • the technical problem to be solved by the present invention is to provide a new class of drugs for treating gastric ulcer and acid-related diseases, namely, eucalyptus chinensis (Osbeck) Me extract.
  • the eucalyptus chinensis (Osbeck) Me extract of the present invention can be used as a proton pump inhibitor for the preparation of a medicament for treating gastric ulcer and acid-related diseases.
  • Another technical problem to be solved by the present invention is to provide a method for preparing a eucalyptus extract and an eucalyptus extract obtained by the method.
  • Still another technical problem to be solved by the present invention is to provide a pharmaceutical composition
  • a pharmaceutical composition comprising eucalyptus extract as an active ingredient and a carrier commonly used in the pharmaceutical field.
  • the present invention adopts the following technical solutions:
  • the invention relates to a eucalyptus extract which can be used for preparing a proton pump inhibitor for treating gastric ulcer and acid-related diseases, and the preparation method thereof is as follows:
  • the eucalyptus original medicinal material is pulverized and extracted with a solvent, and the extract is concentrated to obtain a eucalyptus extract.
  • a preferred eucalyptus medicinal material is eucalyptus bark.
  • the original eucalyptus medicinal material is dried and appropriately pulverized to increase the contact area with the solvent to improve the efficiency.
  • an alcohol solvent or a mixed solvent of water and an alcohol can be used.
  • Preferred alcohols include methanol, ethanol, isopropanol, butanol, and the like, with ethanol being most preferred.
  • the ethanol concentration may be 50 to 100% by volume; the preferred concentration is 80 to 95% by volume.
  • the solvent used in the extraction is a volume/weight ratio (unit: liter/kg) of the solvent volume to the weight of the original medicinal material: 3 to 10: 1, preferably 3 to 5:1.
  • the extraction can be carried out under static or dynamic conditions, preferably under dynamic conditions, such as agitation.
  • dynamic conditions such as agitation.
  • ultrasonic waves or the like can be used.
  • the temperature to be extracted is from room temperature (e.g., 20 ° C) to the reflux temperature of the solvent, and the preferred temperature is the temperature at which the solvent is refluxed.
  • the extraction can be carried out continuously or intermittently, and the batch extraction can be repeated 1 to 5 times, preferably 2-4 times.
  • the extraction time is 1-5 hours, preferably 2-3 hours.
  • the preparation method of the eucalyptus extract is as follows: Weigh the smashed eucalyptus bark medicinal material, and reflux 3-5 times with 3-5 liters of 80-95% ethanol per kilogram, 2-3 hours each time; The extracts were combined and the extract was concentrated under reduced pressure to give an extract of Albizia chinensis (Osbeck Merr).
  • Eucalyptus extract is further purified by polyamide column chromatography and eluted by an alcohol solvent gradient to obtain eucalyptus extract.
  • the eucalyptus extract is dissolved in 10-30% ethanol, preferably 20% ethanol.
  • the polyamide sorbent dry powder is used in an amount of 20 to 40 times, preferably 25 to 30 times, by volume (liter) to the weight of the medicinal extract extract (kg).
  • the eluent may be a mixed solvent of an alcohol and water; a preferred alcohol solvent is methanol and ethanol, and most preferably the alcohol solvent is ethanol.
  • the elution solvent is used in an amount of 3 to 10 times the volume of the polyamide dry powder, and preferably the eluent is used in an amount of 4 to 5 times the volume of the polyamide dry powder.
  • the gradient was eluted with 10-30% ethanol and 40-80% ethanol in turn, and 40-80% ethanol eluate was recovered under reduced pressure to obtain eucalyptus extract.
  • the preferred polyamide column chromatography purification step comprises: dissolving the eucalyptus extract in 10-30% ethanol, and adding to the polyamide column of 30-90 mesh [the amount of the polyamide adsorbent dry powder in volume (liter) and the medicinal material The weight of the extracted extract (kg) is 25-30], and the gradient elution is carried out by 10-30% ethanol and 40-80% ethanol in sequence.
  • the elution solvent is 3-5 times of polyamide dry powder. Volume, concentrated 40-80% ethanol eluate to obtain eucalyptus extract.
  • the present invention relates to a pharmaceutical composition comprising an extract of eucalyptus extracted by the method of the present invention and a pharmaceutically acceptable carrier.
  • the present invention also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising the extract of the present invention as an active ingredient and a conventional pharmaceutical excipient or adjuvant.
  • the pharmaceutical composition of the present invention contains 0.1 to 95% by weight of the extract of the present invention.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising as an active ingredient an eucalyptus extract and/or eucalyptus extracted by the method of the present invention as a active ingredient and a pharmaceutically acceptable carrier.
  • Pharmaceutical compositions of the extracts of the invention can be prepared according to methods well known in the art. For this purpose, if desired, the extract of the invention may be combined with one or more solid or liquid pharmaceutical excipients and/or adjuvants to form a suitable form of administration for use as a human or veterinary drug or Dosage form.
  • the extract of the present invention or the pharmaceutical composition containing the same may be administered in a unit dosage form, which may be enterally or parenterally, such as oral, intravenous, intramuscular, subcutaneous, intraperitoneal, nasal, oral mucosa, Mouth, lungs and respiratory tract, skin, vagina, rectum, etc., are preferably administered orally.
  • the dosage form can be a liquid dosage form, a solid dosage form or a semi-solid dosage form.
  • Liquid dosage forms can be solutions (including true and colloidal solutions), emulsions (including o/w, w/o and double emulsions), suspensions, injections (including water injections, powder injections and infusions), eye drops Agents, nasal drops, lotions and tinctures.
  • the solid dosage form may be a tablet (including a common tablet, an enteric tablet, a tablet, a dispersible tablet, a chewable tablet, an effervescent tablet, an orally disintegrating tablet), a capsule (including a hard capsule, a soft capsule, an enteric capsule), and a granule.
  • semisolid dosage forms may be ointments, gels, pastes, and the like.
  • the extract of the present invention can be prepared into a common preparation, a sustained release preparation, a controlled release preparation, a targeted preparation, and various microparticle delivery systems.
  • diluents may be starch, dextrin, sucrose, glucose, lactose, mannitol, sorbitol, xylitol, microcrystalline cellulose, calcium sulfate, calcium hydrogen phosphate, calcium carbonate, etc.
  • the humectant may be water, ethanol, or different Propyl alcohol, etc.
  • binders may be, starch syrup, dextrin, syrup, honey, glucose solution, microcrystalline cellulose, gum arabic, gelatin syrup, sodium carboxymethylcellulose, methylcellulose, hydroxypropyl Methyl cellulose, ethyl cellulose, acrylic resin, carbomer, polyvinylpyrrolidone, polyethylene glycol, etc.
  • disintegrant can be dry starch, microcrystalline cellulose,
  • a carrier for example, a diluent and an absorbent such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, polyvinylpyrrolidone, lauric acid polyethylene glycol glyceride, kaolin, talc, etc.; , such as gum arabic, yellow peat, gelatin, ethanol, honey, liquid sugar, rice paste or batter; etc.; disintegrating agents, such as agar powder, dried starch, alginate, sodium dodecyl sulfonate, methyl fiber , ethyl cellulose, etc.
  • a diluent and an absorbent such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, polyvinylpyrrolidone, lauric acid polyethylene glycol glyceride, kaolin, talc, etc.
  • disintegrating agents such as agar powder, dried starch, alginate, sodium dodecyl sulfonate, methyl
  • the carrier are, for example, polyethylene glycol, lecithin, cocoa butter, higher alcohols, esters of higher alcohols, gelatin, semi-synthetic glycerides and the like.
  • the active ingredient extract of the present invention is mixed with the above various carriers, and the thus obtained mixture is placed in a hard gelatin capsule or soft capsule.
  • the active ingredient of the present invention may also be formulated into a microcapsule, suspended in an aqueous medium to form a suspension, or may be enclosed in a hard capsule or used as an injection.
  • the extract of the present invention is formulated into an injectable preparation such as a solution, a suspension solution, an emulsion, or a lyophilized powder injection, which may be aqueous or non-aqueous, and may contain one type and/or more A pharmaceutically acceptable carrier, diluent, binder, lubricant, preservative, surfactant or dispersing agent.
  • the diluent may be selected from the group consisting of water, ethanol, polyethylene glycol, 1, 3-propanediol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, polyoxyethylene sorbitan fatty acid ester, and the like.
  • an appropriate amount of sodium chloride, glucose or glycerin may be added to the preparation for injection, and a conventional cosolvent, a buffer, a pH adjuster or the like may be added. These excipients are commonly used in the art.
  • coloring agents may also be added to the pharmaceutical preparations as needed.
  • the pharmaceutical or pharmaceutical composition of the present invention can be administered by any known administration method for the purpose of enhancing the therapeutic effect for the purpose of administration.
  • the dosage of the pharmaceutical composition of the extract of the present invention depends on a number of factors, such as the nature and severity of the disease to be prevented or treated, the sex, age, weight, personality and individual response of the patient or animal, the route of administration, the number of doses
  • the purpose of treatment therefore the treatment of the present invention
  • the therapeutic dose can vary widely.
  • the dosages of the pharmaceutical ingredients employed in the present invention are well known to those skilled in the art.
  • the amount of the actual drug contained in the final preparation in the extract composition of the present invention can be appropriately adjusted to achieve the therapeutically effective amount thereof, and the prophylactic or therapeutic purpose of the present invention can be accomplished.
  • a suitable dosage range per day for the extract of the present invention is from 0.001 to 150 mg/kg body weight, preferably from 0.1 to 100 mg/kg body weight, more preferably from 1 to 60 mg/kg body weight, most preferably from 0.001 to 150 mg/kg body weight. 2 ⁇ 50 mg/Kg body weight.
  • the above dosages may be administered in a single dosage form or divided into several, for example two, three or four dosage forms, which are limited by the clinical experience of the administering physician and the dosing regimen including the use of other therapeutic means.
  • the total dose required for each treatment can be divided into multiple or single dose administrations.
  • the extract or composition of the present invention can be administered alone or in combination with other therapeutic or symptomatic drugs and adjusted in dosage.
  • the present invention proves that the eucalyptus extract has a significant anti-gastric ulcer effect by inhibiting the activity of sputum extract on gastric H+/K+-ATPase and the effect of pylorus ligation on gastric ulcer in rats, and the mechanism is through inhibition. H+/K+-ATPase activity.
  • Beneficial technical effect
  • Figure 2 Protective effect of eucalyptus extract on chronic acetic acid-type gastric ulcer in rats.
  • Example 1 Preparation method of eucalyptus extract
  • H+/K+-ATPase activity assay The purified porcine gastric mucosal vesicles were diluted with buffer. After dosing, incubate in a 37 °C water bath for 20 min, add 20 mg/kg ATP and incubate for 30 min, add 10%. The TCA stopped the reaction and was centrifuged at 6000 rpm for 10 min. The quantitative supernatant was used to determine the inorganic phosphorus content released by hydrolysis of H+/K+-ATPase at 660 nm. Calculate enzyme activity.
  • mice Male rats that were fasted for 48 hours were randomly divided into 3 groups. The pylorus ligation was performed under ether anesthesia. 100 and 500 mg/kg of eucalyptus extract were administered by duodenum, and normal rats were given normal saline. The animals were sacrificed 20 hours after surgery, and the stomach was removed, and the number of ulcers in the stomach was counted. Results The difference significance test was performed using One-way ANOVA.
  • the rats were fasted for 24 hours, anesthetized with sodium pentobarbital, and the glandular stomach was injected with 20% acetic acid 20 ul by the pyloric side. Animals were randomized and administered on the second day after surgery, once daily for 10 consecutive days. The stomach was removed and fixed, the stomach was flattened on a glass plate, photographed with a digital camera, and the image was treated with spot advanced software to determine the ulcer area.

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Abstract

一种楹树提取物及其制备方法，所述楹树提取物用于制备质子泵抑制剂和治疗酸相关性疾病，如胃溃疡和慢性胃炎的药物。

Description

楹树提取物在制备治疗胃溃疡药物中的应用 技术领域
本发明涉及一种楹树 chinensis (Osbeck) Mem] 中提取物及 其制备方法， 本发明还涉及楹树提取物作为质子泵抑制剂在制备治疗 胃溃疡和酸相关性疾病药物中的医药用途， 医药技术领域， 。 背景技术
胃溃疡是消化系统常见的疾病， 且易复发。 随着现代生活节奏加 快， 精神紧张和工作压力增大， 使得胃溃疡的发病率呈上升趋势， 危 害及人们的身心健康。 目前临床上应用较多的抗溃疡西药主要为雷尼 替丁、 奥美拉唑等药物， 虽然西药近期疗效明显， 但其存在服药后出 现不良反应和毒副作用。 因此， 人们开始研发高效、 低毒的新型的抗 溃疡药物。 基于我国传统中药的长期临床实践和用药历史， 从传统中 草药中寻找和挖掘具有抗胃溃疡的天然活性成分或有效组分， 具有先 天优势和广阔的临床应用价值。
Albizia chinensis (Osbeck) Mem为豆科合欢属 (Albizia )植物， 其药用部位为树皮， 树皮含鞣质， 有固涩止泻、 收敛生肌之功效， 主 治肠炎、 腹泻、 痢疾 （全国中草药汇编， 全国中草药汇编编写组编， 第二版， 下册， 1986年， PP768)。 另有记载楹树皮含三萜皂苷 （又称 合欢催产素），有收缩子宫的作用（中药大辞典，江苏新医学院编， 1998 年， 上册， PP937)。 近年来， 我们从楹树皮中分离得到一系列结构复 杂的具有肿瘤细胞毒活性的三萜皂苷 U. Nat. Prod. 2009, 72, 632 - 639; Carbohydr. Res. 2010, 345, 1877 - 1881 )。此外，我们还发现楹树 chinensis 提取物具有镇静催眠的活性 （中国专利公开号 CN 101766676A )。迄今为止尚未见有关楹树皮提取物在抑制质子泵活性和 治疗胃溃疡或慢性胃炎方面的药理活性研究的报道。 发明内容
本发明要解决的技术问题是， 提供一类新的治疗胃溃疡和酸相关 性疾病的药物， 即楹树 chinensis (Osbeck) Me 提取物。 本发明 的楹树 chinensis (Osbeck) Me 提取物可作为质子泵抑制剂， 用 于制备治疗胃溃疡和酸相关性疾病药物。
本发明要解决的另一个技术问题是提供制备楹树提取物的方法以 及这种方法获得的楹树提取物。
本发明要解决的又一个技术问题是提供一种药物组合物， 包括作 为活性成分的楹树提取物及制药领域中常用的载体。
本发明要解决的再一个技术问题是提供楹树提取物
chinensis (Osbeck) Me 在制备治疗胃溃疡和酸相关性疾病药物中的应 用。
解决本发明的技术问题， 本发明采取如下的技术方案：
本发明涉及一种可用于制备质子泵抑制剂治疗胃溃疡和酸相关性 疾病药物的楹树提取物， 其制备方法为：
( 1 ) 将楹树原药材粉碎并用溶剂提取， 提取液浓缩得楹树浸膏。 优选的楹树原药材是楹树茎皮。楹树原药材经干燥并适当的粉碎， 以利增大与溶剂的接触面积提高效率。
原药材的提取溶剂可以使用醇类溶剂或水与醇类的混合溶剂。 优选的醇类包括甲醇、 乙醇、 异丙醇、 丁醇等， 最优选的是乙醇。 乙醇浓度可以是体积比 50- 100% ; 优选的浓度为体积比 80〜95%。 提取时溶剂使用量是溶剂体积与原药材重量的体积 /重量比（单位: 升 /公斤） 为 3〜10： 1， 优选是 3〜5： 1。
提取可以在静态或动态下进行， 优选在动态条件下， 例如搅拌。 为了提高提取的效率， 可以使用超声波等。
提取的温度是从室温 (例如 20°C )到溶剂回流温度的范围内，优选的 温度是溶剂回流的温度下。
提取可连续或间歇进行， 间歇提取时可重复 1〜5次， 优选 2-4次。 提取时间是 1-5小时， 优选为 2-3小时。 合并提取液， 在常压或减压加热浓缩成膏状， 优选在减压条件下 浓缩。
优选楹树浸膏的制备方法如下： 称量粉碎的楹树茎皮药材， 以药 材重量计每公斤用 3-5升的 80-95%乙醇回流 2-4次， 每次 2-3小时； 合并提取液， 提取液经减压浓缩得到楹树 （Albizia chinensis (Osbeck) Merr) 浸膏。
(2)楹树浸膏进一步通过聚酰胺柱色谱，通过醇类溶剂梯度洗脱， 精制纯化得到楹树提取物。
楹树浸膏以 10-30%的乙醇溶解， 优选 20%的乙醇溶解。
聚酰胺吸附剂干粉的用量以体积（升）与药材提取浸膏的重量（公 斤） 的比例为 20〜40倍， 优选 25〜30倍。
洗脱剂可以醇类与水的混合溶剂； 优选的醇类溶剂为甲醇和乙醇， 最优选醇类溶剂为乙醇。
洗脱溶剂的用量为聚酰胺干粉的体积 3-10倍，优选洗脱剂用量为聚 酰胺干粉的体积 4-5倍。
依次用 10-30%的乙醇、 40-80%的乙醇进行梯度洗脱， 40-80%的乙 醇洗脱液减压回收得到楹树提取物。
优选的聚酰胺柱色谱纯化步骤包括： 将楹树浸膏以 10-30%的乙醇 溶解后，加到 30〜90目的聚酰胺柱上 [聚酰胺吸附剂干粉的用量以体积 (升）与药材提取浸膏的重量（公斤） 的比例为 25-30] , 依次用 10-30% 的乙醇、 40-80%的乙醇进行梯度洗脱， 洗脱溶剂的用量为 3-5倍聚酰胺 干粉的体积， 浓缩 40-80%的乙醇洗脱液得到楹树提取物。 本发明涉及了一种药物组合物， 包括以本发明所述的方法提取的 楹树提取物及药学上可接受的载体。
本发明还涉及含有作为活性成份的本发明提取物和常规药物赋形 剂或辅剂的药物组合物。 通常本发明药物组合物含有 0.1〜95%重量的 本发明提取物。
本发明还提供一种药物组合物， 它包括药物有效剂量的， 作为活 性成分的如本发明方法提取的楹树提取物和 /或楹树及药学上可接受的 载体。 本发明提取物的药物组合物可根据本领域公知的方法制备。 用于 此目的时， 如果需要， 可将本发明提取物与一种或多种固体或液体药 物赋形剂和 /或辅剂结合， 制成可作为人药或兽药使用的适当的施用形 式或剂量形式。
本发明提取物或含有它的药物组合物可以单位剂量形式给药， 给 药途径可为肠道或非肠道， 如口服、 静脉注射、 肌肉注射、 皮下注射、 腹腔注射、 鼻腔、 口腔粘膜、 目艮、 肺和呼吸道、 皮肤、 阴道、 直肠等， 优选口服给药。
给药剂型可以是液体剂型、 固体剂型或半固体剂型。 液体剂型可 以是溶液剂 （包括真溶液和胶体溶液） 、 乳剂 （包括 o/w型、 w/o型和 复乳） 、 混悬剂、 注射剂 （包括水针剂、 粉针剂和输液） 、 滴眼剂、 滴鼻剂、 洗剂和搽剂等。 固体剂型可以是片剂 （包括普通片、 肠溶片、 含片、 分散片、 咀嚼片、 泡腾片、 口腔崩解片） 、 胶囊剂 （包括硬胶 囊、 软胶囊、 肠溶胶囊） 、 颗粒剂、 散剂、 微丸、 滴丸、 栓剂、 膜剂、 贴片、 气 （粉） 雾剂、 喷雾剂等； 半固体剂型可以是软膏剂、 凝胶剂、 糊剂等。
本发明提取物可以制成普通制剂、 也可以是缓释制剂、 控释制剂、 靶向制剂及各种微粒给药系统。
为了将单位给药剂型制成片剂， 可以广泛使用本领域公知的各种 赋形剂， 包括稀释剂、 黏合剂、 润湿剂、 崩解剂、 润滑剂、 助流剂。 稀释剂可以是淀粉、 糊精、 蔗糖、 葡萄糖、 乳糖、 甘露醇、 山梨醇、 木糖醇、 微晶纤维素、 硫酸钙、 磷酸氢钙、 碳酸钙等； 湿润剂可以是 水、 乙醇、 异丙醇等； 粘合剂可以是， 淀粉浆、 糊精、 糖浆、 蜂蜜、 葡萄糖溶液、 微晶纤维素、 阿拉伯胶浆、 明胶浆、 羧甲基纤维素钠、 甲基纤维素、 羟丙基甲基纤维素、 乙基纤维素、 丙烯酸树脂、 卡波姆、 聚乙烯毗咯垸酮、 聚乙二丙醇等； 崩解剂可以是干淀粉、 微晶纤维素、 低取代羟丙基纤维素、 交联聚乙烯毗咯垸酮、 交联羧甲基纤维素钠、 羧甲基淀粉钠、 碳酸氢钠与构椽酸、 碳酸钙、 聚氧乙烯山梨糖醇脂肪 酸酯、 十二垸基磺酸钠； 润滑剂和助流剂可以是滑石粉、 二氧化硅、 硬脂酸盐、 酒石酸、 液体石蜡、 聚乙二醇等。 还可以将片剂进一步制成包衣片， 例如糖包衣片、 薄膜包衣片、 肠溶包衣片， 或双层片和多层片。
为了将给药单元制成丸剂， 可以广泛使用本领域公知的各种载体。 关于载体的例子是， 例如稀释剂与吸收剂， 如葡萄糖、 乳糖、 淀粉、 可可脂、 氢化植物油、 聚乙烯吡咯垸酮、 月桂酸聚乙二醇甘油酯、 高 岭土、 滑石粉等； 粘合剂， 如阿拉伯胶、 黄菩胶、 明胶、 乙醇、 蜂蜜、 液糖、 米糊或面糊等； 崩解剂， 如琼脂粉、 干燥淀粉、 海藻酸盐、 十 二垸基磺酸钠、 甲基纤维素、 乙基纤维素等。
为了将给药单元制成栓剂， 可以广泛使用本领域公知的各种载体。 关于载体的例子是， 例如聚乙二醇、 卵磷脂、 可可脂、 高级醇、 高级 醇的酯、 明胶、 半合成甘油酯等。
为了将给药单元制成胶囊， 将有效成分本发明提取物与上述的各 种载体混合， 并将由此得到的混合物置于硬的明胶胶囊或软胶囊中。 也可将有效成分本发明提取物制成微囊剂， 混悬于水性介质中形成混 悬剂， 亦可装入硬胶囊中或制成注射剂应用。
例如， 将本发明提取物制成注射用制剂， 如溶液剂、 混悬剂溶液 剂、 乳剂、 冻干粉针剂， 这种制剂可以是含水或非水的， 可含一种和 / 或多种药效学上可接受的载体、 稀释剂、 粘合剂、 润滑剂、 防腐剂、 表面活性剂或分散剂。 如稀释剂可选自水、 乙醇、 聚乙二醇、 1, 3-丙二 醇、 乙氧基化的异硬脂醇、 多氧化的异硬脂醇、 聚氧乙烯山梨醇脂肪 酸酯等。 另外， 为了制备等渗注射液， 可以向注射用制剂中添加适量 的氯化钠、 葡萄糖或甘油， 此外， 还可以添加常规的助溶剂、 缓冲剂、 pH调节剂等。 这些辅料是本领域常用的。
此外， 如需要， 也可以向药物制剂中添加着色剂、 防腐剂、 香料、 矫味剂、 甜味剂或其它材料。
为达到用药目的， 增强治疗效果， 本发明的药物或药物组合物可 用任何公知的给药方法给药。
本发明提取物药物组合物的给药剂量取决于许多因素， 例如所要 预防或治疗疾病的性质和严重程度， 患者或动物的性别、 年龄、 体重、 性格及个体反应， 给药途径、 给药次数、 治疗目的， 因此本发明的治 疗剂量可以有大范围的变化。 一般来讲， 本发明中药学成分的使用剂 量是本领域技术人员公知的。 可以根据本发明提取物组合物中最后的 制剂中所含有的实际药物数量， 加以适当的调整， 以达到其治疗有效 量的要求， 完成本发明的预防或治疗目的。 本发明提取物的每天的合 适剂量范围本发明的提取物的用量为 0.001〜150 mg/Kg体重， 优选为 0.1〜100 mg/Kg体重， 更优选为 1〜60 mg/Kg体重， 最优选为 2〜50 mg/Kg体重。上述剂量可以单一剂量形式或分成几个， 例如二、三或四 个剂量形式给药这受限于给药医生的临床经验以及包括运用其它治疗 手段的给药方案。 每一种治疗所需总剂量可分成多次或按一次剂量给 药。 本发明的提取物或组合物可单独服用， 或与其他治疗药物或对症 药物合并使用并调整剂量。 本发明通过楹树提取物对胃 H+/K+-ATP酶抑制活性和对幽门结扎 致大鼠胃溃疡的作用的研究， 证明， 楹树提取物具有显著的抗胃溃疡 作用， 其机理是通过抑制 H+/K+-ATP酶活性。 有益技术效果
本发明楹树提取物作用物质基础和作用机理明确， 制备工艺简单， 适合工业化生产。
为治疗胃溃疡以及慢性胃炎的提供了一种新的药物。 附图说明 图 1、 楹树提取物的制备实施例 1的流程图。
图 2、 楹树提取物对大鼠慢性醋酸型胃溃疡的保护作用。
具体实施方式
下面的实施例及药物活性实验用来进一步说明本发明， 实施例仅 用于说明， 不能限制本发明的范围。 实施例 1楹树提取物的制备方法
称取楹树茎皮粗粉 1 Kg, 用 3.5升（以每公斤药材 3.5升提取溶剂 计）的 95%乙醇回流三次，每次 3小时；提取液经减压浓缩得浸膏 130g， 再以 20%的乙醇溶解， 加到 3200ml的聚酰胺 （30〜60 目） 柱上， 依 次用 12升 20%的乙醇、 12 升 60%的乙醇进行梯度洗脱，浓缩 60%的 乙醇洗脱液至干， 即得到楹树提取物 8.0 g。 药理实验
试验例 1 楹树提取物抑制胃 H+/K+-ATP酶活性
实验方法：
H+/K+-ATP酶活性测定：将纯化的猪胃黏膜囊泡加缓冲液稀释，加 药后在 37°C水浴温孵 20 min， 加入 20 mg/kg ATP继续温孵 30 min， 加入 10% TCA终止反应， 6000 rpm离心 10 min。取定量上清液用定磷 试剂盒于 660 nm测定 H+/K+-ATP酶水解释放的无机磷含量。计算酶活 力。
结果：
数据见表 1。 楹树提取物 （1和 10 mg/L) 对猪胃 H+/K+-ATP酶活 性的抑制率分别为 28%和 73%。 提示楹树提取物对 H+/K+-ATP酶活性 具有较强的抑制作用。 表 1 楹树提取物对猪胃 H+/K+-ATP酶活性的影响
Figure imgf000008_0001
试验例 2 楹树提取物对幽门结扎致大鼠胃溃疡的保护作用
实验方法：
取禁食 48小时的雄性大鼠， 随机分为 3组。 乙醚麻醉下行幽门结 扎术，术时经十二指肠给予 100和 500 mg/kg的楹树提取物，对照组大 鼠给予生理盐水。 术后 20小时处死动物， 取出胃， 计前胃部溃疡数。 结果用 One-way ANOVA进行差异显著性检验。
结果：
数据见表 2。楹树提取物在 100和 500 mg/kg剂量下对幽门结扎致 大鼠胃溃疡的抑制率分别为 43%和 86% (p<0.05 ) o 提示楹树提取物对 幽门结扎溃疡模型有很好的保护作用。
Figure imgf000009_0001
Figure imgf000009_0002
试验例 3 楹树提取物对大鼠慢性醋酸型胃溃疡的保护作用
实验方法：
大鼠禁食 24小时，戊巴比妥钠麻醉， 腺胃部靠幽门侧注射 30%醋酸 20 ul。 动物随机 分组，术后第二天开始给药， 每日一次， 连续 10天。 取出胃并固定， 将胃平展于玻 璃板上，用数码相机照像， 图像用 spot advanced软件处理，测定溃疡面积。
结果：
数据见表 3。 楹树提取物在 100 和 30 mg/kg 剂量下对大鼠慢性醋酸型溃疡的有效 率分别为 49. 7%和 57. 2% (p〈0. 01 ) 。 提示楹树提取物对慢性醋酸型溃疡有很好的 保护作用。
表 3 楹树提取物对大鼠慢性醋酸型溃疡的影响
Figure imgf000009_0003

Claims

权 利 要 求 书
1、 一种楹树（Albizia chinensis (Osbeck) Merr)提取物的制备方法， 其 特征在于， 包括如下步骤：
A. 楹树 （Albizia chinensis (Osbeck) Merr) 药材采用溶剂提取，
B. 通过聚酰胺柱色谱， 溶剂梯度洗脱精制纯化得到楹树提取物。
2、 根据权利要求 1所述的制备方法， 其特征在于， 步骤 A中所述的溶剂 选自醇类或水与醇类的混合溶剂。
3、 根据权利要求 2所述的制备方法， 其特征在于， 步骤 A包括如下步 骤： 粉碎楹树 lbizia chinensis (Osbeck) Merr) 茎皮， 以药材重量计 每公斤用 3-5升的 80-95%乙醇回流 2-4次， 每次 2-3小时； 合并提取 液， 提取液经减压浓缩得到楹树 lbizia chinensis (Osbeck) Merr ) 浸
4、 根据权利要求 1所述的制备方法， 其特征在于， 步骤 B为将步骤 A 中获得的楹树浸膏以 10-30%的乙醇溶解后， 加到 30〜90 目的聚酰胺 柱上， 聚酰胺干粉的体积用量为以浸膏重量计 25-30升 /每公斤， 依次 用 10-30%的乙醇、40-80%的乙醇进行梯度洗脱，洗脱溶剂的用量为 3-5 倍聚酰胺干粉的体积， 浓缩 40-80%的乙醇洗脱液得到所述的楹树提取
5、权利要求 1-4中任一项制备的楹树（Albizia chinensis (Osbeck) Merr) 提取物。
6、 一种药物组合物， 其特征在于， 含有作为有效成分的权利要求 5的 楹树 (Mbizia chinensis (Osbeck) Merr ) 提取物， 及药学上可接受的载 体。
7、 权利要求 5的楹树 lbizia chinensis (Osbeck) Merr) 提取物作为质 子泵抑制剂的应用。
8、 权利要求 5的楹树 lbizia chinensis (Osbeck) Merr) 提取物在制备 治疗酸相关性疾病药物中的应用。
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