WO2018133104A1 - 地榆皂苷II羟丙基β-环糊精包合物及其制备方法和用途 - Google Patents

地榆皂苷II羟丙基β-环糊精包合物及其制备方法和用途 Download PDF

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WO2018133104A1
WO2018133104A1 PCT/CN2017/072224 CN2017072224W WO2018133104A1 WO 2018133104 A1 WO2018133104 A1 WO 2018133104A1 CN 2017072224 W CN2017072224 W CN 2017072224W WO 2018133104 A1 WO2018133104 A1 WO 2018133104A1
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saponin
hydroxypropyl
cyclodextrin
solution
preparation
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PCT/CN2017/072224
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杨世林
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四川英路维特医药科技有限公司
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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
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
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    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • 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
    • A61P7/06—Antianaemics

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  • the invention relates to a saponin II hydroxypropyl ⁇ -cyclodextrin inclusion compound, a preparation method thereof and use thereof, and belongs to the field of medicine.
  • the saponin II is a compound which has obvious activity from the mantle of the genus Rosaceae.
  • the chemical name is 3-O- ⁇ -L-arabinosyl-19 ⁇ -hydroxy-Uso-12--28-carboxylic acid. (ziyu-glycoside II), its structural formula is:
  • saponin II has a good effect on raising blood cells.
  • saponin II is usually used in combination with other drugs, and no reports of use alone have been reported.
  • the present invention provides a saponin II hydroxypropyl ⁇ -cyclodextrin inclusion compound comprising the preparation of the following raw materials: saponin II, hydroxypropyl ⁇ -cyclodextrin fine.
  • the weight ratio of the saponin II to the hydroxypropyl ⁇ -cyclodextrin is 1:1 to 1:20.
  • the pharmaceutically acceptable solvent is at least one of absolute ethanol, n-butanol and diethyl ether.
  • the invention also provides a method of preparing the aforementioned clathrate comprising the steps of:
  • step a the saponin II is taken according to the ratio, the solvent is added, and the volume-to-weight ratio of the solvent to the saponin II is 100 mL: 1 g;
  • step b according to the ratio of taking hydroxypropyl ⁇ -cyclodextrin, adding solvent, the volume ratio of solvent to hydroxypropyl ⁇ -cyclodextrin is 10mL: 1g;
  • step c the mixture was stirred for 4 h and evaporated to dryness at 60 °C.
  • the present invention also provides the use of the aforementioned clathrate for the preparation of a medicament for raising blood cells.
  • the drug is a drug that increases peripheral blood leukocytes, neutrophils, red blood cells, platelets, and/or hemoglobin.
  • the invention also provides a preparation of the saponin II, which is prepared by using the saponin II hydroxypropyl ⁇ -cyclodextrin inclusion compound as an active ingredient, adding a pharmaceutically acceptable auxiliary or auxiliary component. preparation.
  • the preparation is a powder, a tablet, a pill, a granule, a powder injection, an injection or a capsule.
  • the present invention also provides a method of raising blood cells which is treated using the aforementioned clathrate.
  • mantle saponin II has problems such as low solubility and low oral absorption rate, which results in low oral bioavailability of the component, which limits the effect of the component on blood cell growth.
  • the inventors have solved the problem of low solubility of saponin II and improved the bioavailability of saponin II by studying the dosage form and its formulation by using the saponin II hydroxypropyl ⁇ -cyclodextrin inclusion compound prepared by the invention. Degree, and thus improve its efficacy in raising blood cells, is of great significance for the better clinical application of saponin II.
  • Figure 1 is a comparison of bone marrow hematopoietic stem cell counts in mice of each experimental group.
  • the preparation method is as follows:
  • the saponin II was taken according to the ratio, and ultrasonically added to 50 ml of anhydrous ethanol to dissolve to obtain a solution 1. Further, hydroxypropyl ⁇ -cyclodextrin was taken according to the ratio, and 10 ml of absolute ethanol was added thereto to ultrasonically dissolve to obtain a solution 2.
  • the solution 2 was stirred on a thermostatic magnetic stirrer while the solution 1 was slowly added to the solution 2 with a dropper. After the solution 1 was all added to the solution 2, the mixture was stirred on a thermostatic magnetic stirrer for four hours. The mixture was poured into an evaporating dish, placed in a 60 ° C water bath, evaporated to dryness, and the dried product was finely ground to obtain a clathrate.
  • the preparation method is as follows:
  • the saponin II was taken according to the ratio, and ultrasonically added to 1000 ml of anhydrous ethanol to dissolve to obtain a solution 1. Further, hydroxypropyl ⁇ -cyclodextrin was taken according to the ratio, and 200 ml of absolute ethanol was added to ultrasonicate to dissolve to obtain a solution 2.
  • the solution 2 was stirred on a thermostatic magnetic stirrer while the solution 1 was slowly added to the solution 2 with a dropper. After the solution 1 was all added to the solution 2, the mixture was stirred on a thermostatic magnetic stirrer for four hours. The mixture was poured into an evaporating dish, placed in a 60 ° C water bath, evaporated to dryness, and the dried product was finely ground to obtain a clathrate.
  • the following materials were weighed into the following materials: 5 g of saponin II and 10 g of the clathrate.
  • the preparation method is as follows:
  • a certain amount of saponin II was taken and ultrasonically added to 100 times the amount of absolute ethanol to dissolve to obtain a solution 1.
  • the inclusion material was further taken, and 10 times of anhydrous ethanol was added thereto to ultrasonically dissolve to obtain a solution 2.
  • the solution 2 was stirred on a thermostatic magnetic stirrer while the solution 1 was slowly added to the solution 2 with a dropper. After the solution 1 was all added to the solution 2, the mixture was stirred on a thermostatic magnetic stirrer for four hours.
  • the mass of saponin II / the quality of saponin II administration ⁇ 100%) the results are shown in Table 1.
  • the saponin II hydroxypropyl ⁇ -cyclodextrin inclusion compound prepared by using the inclusion material hydroxypropyl ⁇ -cyclodextrin of the invention has high inclusion rate and good inclusion effect.
  • the results showed that only the saponin II hydroxypropyl ⁇ -cyclodextrin inclusion complex prepared using the inventive inclusion material hydroxypropyl ⁇ -cyclodextrin was of the highest quality.
  • the saponin II hydroxypropyl ⁇ -cyclodextrin inclusion compound can be obtained only when the present invention is used as a carrier material in the range of saponin II: hydroxypropyl ⁇ -cyclodextrin;
  • the saponin II: hydroxypropyl ⁇ -cyclodextrin is in the range of 1:1 to 1:20, and the inclusion ratio is over 90%, indicating that the hydroxypropyl ⁇ -cyclodextrin has a good inclusion effect on the saponin II. .
  • Test drug saponin II-H- ⁇ -CD clathrate (prepared according to Example 1), saponin II, cyclophosphamide.
  • mice All animals were fed ad libitum for 1 week and were randomly divided into: blank group; model group; saponin II-H- ⁇ -CD inclusion complex, formulated into 0.5mg ⁇ kg-1, 2.5mg ⁇ kg-1 , 10mg ⁇ kg-1 suspension, prepared before use; saponin II group; dissolved in 10% DMSO-physiological saline, formulated into 0.5mg ⁇ kg-1, 2.5mg ⁇ kg-1, 10mg ⁇ kg- 1 suspension, prepared before use.
  • the other groups of mice were intraperitoneally injected with cyclophosphamide physiological saline solution at a dose of 50 mg ⁇ kg -1 for 3 consecutive days.
  • the blank group of mice was injected with an equal volume of normal saline in the tail vein.
  • mice in the blank group and the model group were intragastrically administered with the same volume of physiological saline for 7 consecutive days.
  • Peripheral blood test Peripheral blood leukocytes (WBC), neutrophils (NEUT) red blood cells (RBC), platelets (PLT), and hemoglobin (HGB) were counted in each experimental group by an automatic blood cell counter.
  • WBC Peripheral blood leukocytes
  • NUT neutrophils
  • RBC red blood cells
  • PHT platelets
  • HGB hemoglobin
  • Bone marrow hematopoietic stem cell count (based on bone marrow cell CD34+ antigen expression), the right femur bone marrow cells were pulverized with PBS buffer containing 0.2% bovine serum albumin, 106 cells were removed, the supernatant was discarded, and 30 ⁇ L was added. Normal mouse serum was blocked with non-specific binding sites, 10 ⁇ L of FITC-labeled rat anti-mouse CD34+ antibody was added, 10 ⁇ L of the corresponding control antibody was added to the control tube, and the reaction was protected from light for 30 min at 4 °C.
  • the saponin II hydroxypropyl ⁇ -cyclodextrin inclusion compound prepared by the invention solves the problem of low solubility of the saponin II, improves the bioavailability of the saponin II, and further increases the increase thereof.
  • the efficacy of blood cells is of great significance for the better clinical application of saponin II.

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Abstract

一种地榆皂苷II羟丙基β-环糊精包合物、其制备方法及其在制备升高血细胞的药物中的用途。所述地榆皂苷II羟丙基β-环糊精包合物包含地榆皂苷II 0.5-10份和羟丙基β-环糊精1-20份。

Description

地榆皂苷II羟丙基β-环糊精包合物及其制备方法和用途 技术领域
本发明涉及一种地榆皂苷II羟丙基β-环糊精包合物及其制备方法和用途，属药物领域。
背景技术
地榆皂苷II是从蔷薇科地榆属地榆中提取制备有明显活性作用的化合物，化学名：3-O-α-L-阿拉伯糖基-19α-羟基乌索-12烯-28-羧酸(ziyu-glycoside II)，其结构式为：
Figure PCTCN2017072224-appb-000001
现代研究表明，地榆皂苷II具有良好地升高血细胞的作用。目前，地榆皂苷II通常与其他药物联合使用，未见单独使用的报道。
发明内容
为解决上述问题，本发明提供了一种地榆皂苷II羟丙基β-环糊精包合物，它包含下述原料制备而成的制剂：地榆皂苷II、羟丙基β-环糊精。
进一步地，它是由下述重量配比的原料加上药学上可接受的溶剂制备而成：地榆皂苷II0.5-10份、羟丙基β-环糊精1-20份。
进一步地，所述地榆皂苷II与羟丙基β-环糊精的重量配比为1:1～1:20。
进一步地，所述的药学上可接受的溶剂为无水乙醇、正丁醇、乙醚中至少一种。
本发明还提供了制备前述的包合物的方法，包括下述步骤：
a.按配比取地榆皂苷II，加入药学上可接受的溶剂，溶解，得溶液1；
b.按配比取羟丙基β-环糊精，加入药学上可接受的溶剂，溶解，得溶液2；
c.边搅拌溶液2边向其中加入溶液1，全部加入后，搅拌、蒸干、研磨，即得包合 物。
进一步地，步骤a中，按配比取地榆皂苷II，加入溶剂，溶剂与地榆皂苷II的体积重量比为100mL：1g；
步骤b中，按配比取羟丙基β-环糊精，加入溶剂，溶剂与羟丙基β-环糊精的体积重量比为10mL：1g；
步骤c中，搅拌4h，60℃蒸干。
本发明还提供了前述的包合物在制备升高血细胞的药物中的用途。
进一步地，所述的药物是升高外周血白细胞、中性粒细胞、红细胞、血小板和/或血红蛋白的药物。
本发明还提供了一种地榆皂苷II制剂，它是由地榆皂苷II羟丙基β-环糊精包合物为活性成分，加入药学上可接受的辅料或辅助性成分制备而成的制剂。
进一步地，所述的制剂为散剂、片剂、丸剂、颗粒剂、粉针剂、注射剂或胶囊剂.
本发明还提供了一种升高血细胞的方法，它是使用前述的包合物进行治疗。
发明人前期研究发现，地榆皂苷II存在溶解度低、口服胃肠吸收率小等问题，造成该成分口服生物利用度低，限制了该成分升高血细胞效果的发挥。
发明人经过对剂型及其配方的研究，通过本发明制备的地榆皂苷II羟丙基β-环糊精包合物解决了地榆皂苷II溶解度低的问题，提高了地榆皂苷II生物利用度，进而提高其升高血细胞的疗效，对地榆皂苷II更好的临床应用具有十分重要的意义。
显然，根据本发明的上述内容，按照本领域的普通技术知识和惯用手段，在不脱离本发明上述基本技术思想前提下，还可以做出其它多种形式的修改、替换或变更。
以下通过实施例形式的具体实施方式，对本发明的上述内容再作进一步的详细说明。但不应将此理解为本发明上述主题的范围仅限于以下的实例。凡基于本发明上述内容所实现的技术均属于本发明的范围。
附图说明
图1为各实验组小鼠骨髓造血干细胞计数比较。
具体实施方式
实施例1本发明包合物的制备
按下述配比称取原料：
地榆皂苷II0.5g、羟丙基β-环糊精1g。
制备方法如下：
按配比取地榆皂苷II，加入50ml的无水乙醇超声至溶解，得溶液1。另按配比取羟丙基β-环糊精，加入10ml的无水乙醇超声至溶解，得溶液2。将溶液2放在恒温磁力搅拌器上搅拌，同时用滴管将溶液1缓慢加入溶液2中，当溶液1全部加入溶液2之后，让其混合液在恒温磁力搅拌器上搅拌四小时。将混合液倒入蒸发皿中，放在60℃水浴锅上，蒸干，取蒸干物研细即得到包合物。
实施例2本发明包合物的制备
按下述配比称取原料：
地榆皂苷II 10g、羟丙基β-环糊精20g。
制备方法如下：
按配比取地榆皂苷II，加1000ml无水乙醇超声至溶解，得溶液1。另按配比取羟丙基β-环糊精，加入200ml的无水乙醇超声至溶解，得溶液2。将溶液2放在恒温磁力搅拌器上搅拌，同时用滴管将溶液1缓慢加入溶液2中，当溶液1全部加入溶液2之后，让其混合液在恒温磁力搅拌器上搅拌四小时。将混合液倒入蒸发皿中，放在60℃水浴锅上，蒸干，取蒸干物研细即得到包合物。
以下通过具体实验证明本发明的有益效果。
实验例1采用不同包合材料制备地榆皂苷II包合物的质量评价
本研究根据地榆皂苷II的性质，选择β-环糊精、甲基β-环糊精、羟丙基β-环糊精为载体材料制成地榆皂苷II包合物。
下述配比称取原料：地榆皂苷II 5g、包合材料10g。
制备方法如下：
取一定量的地榆皂苷II，加100倍量的无水乙醇超声至溶解，得溶液1。另取包合材料，加入10倍量的无水乙醇超声至溶解，得溶液2。将溶液2放在恒温磁力搅拌器上搅拌，同时用滴管将溶液1缓慢加入溶液2中，当溶液1全部加入溶液2之后，让其混合液在恒温磁力搅拌器上搅拌四小时。将混合液倒入蒸发皿中，放在60℃水浴锅上，蒸干，取蒸干物研细即得到包合物，测其包合率(包合率(％)＝包合物中地榆皂苷II的质量/地榆皂苷II投药质量×100％)，结果见表1。
表1 不同包合材料制备地榆皂苷II包合物的质量评价
Figure PCTCN2017072224-appb-000002
实验结果：采用本发明包合材料羟丙基β-环糊精制备的地榆皂苷II羟丙基β-环糊精包合物，包合率高，包合效果好。结果表明仅有在使用本发明包合材料羟丙基β-环糊精制备的地榆皂苷II羟丙基β-环糊精包合物质量最佳。
实验例2采用不同量羟丙基β-环糊精载体材料制备地榆皂苷II羟丙基β-环糊精包合物的质量评价
分别称取不同比例的地榆皂苷II、羟丙基β-环糊精，按下述方法试验：取一定量的地榆皂苷II，加100倍量的无水乙醇超声至溶解，得溶液1。另按配比取羟丙基β-环糊精，加入10倍量的无水乙醇超声至溶解，得溶液2。将溶液2放在恒温磁力搅拌器上搅拌，同时用滴管将溶液1缓慢加入溶液2中，当溶液1全部加入溶液2之后，让其混合液在恒温磁力搅拌器上搅拌四小时。将混合液倒入蒸发皿中，放在60℃水浴锅上，蒸干，取蒸干物研细即得到包合物，测其包合率。结果见表2。
表2 不同量羟丙基β-环糊精载体材料制备地榆皂苷II羟丙基β-环糊精包合物的包合率
Figure PCTCN2017072224-appb-000003
实验结果：仅在采用本发明数地榆皂苷II：羟丙基β-环糊精范围内作为载体材料时，才能得到地榆皂苷II羟丙基β-环糊精包合物；其中，采用地榆皂苷II：羟丙基β-环糊精为1:1-1:20范围内，包合率达到90％以上，表明羟丙基β-环糊精对地榆皂苷II包合效果好。
实验例3本发明地榆皂苷II羟丙基β-环糊精包合物药效学研究
1.实验材料
1.1受试药物：地榆皂苷II-H-β-CD包合物(按照实施例1制备)、地榆皂苷II、环磷酰胺。
1.2实验动物：KM-小鼠：18.5～22.5g。
1.3实验仪器：全自动血球分析仪；BS-600L电子天平：规格：600g/0.1g，上海友声衡器有限公司。
1.4统计方法
用SPSS 17.0软件进行统计分析。数据以均数±标准差
Figure PCTCN2017072224-appb-000004
表示，组间采用单因素方差分析，方差齐者组间进行LSD检验，方差不齐者进行Tamhane’s T2检验。
2.实验方法
2.1实验动物分组及模型制备
所有动物适应性喂养1周后按体重随机分为：空白组；模型组；地榆皂苷II-H-β-CD包合物组，配制成0.5mg·kg-1、2.5mg·kg-1、10mg·kg-1混悬液，临用前配制；地榆皂苷II组；用10％DMSO-生理盐水溶解，配制成0.5mg·kg-1、2.5mg·kg-1、10mg·kg-1混悬液，临用前配制。实验第1天，除空白组外，其余各组小鼠按50mg·kg-1剂量腹腔注射环磷酰胺生理盐水溶液，连续3天，空白组小鼠尾静脉注射等体积生理盐水。
2.2给药
各实验组自实验第1天开始按剂量、给药方式给予相应药物，空白组和模型组小鼠灌胃给药等体积生理盐水，连续7天。
2.3标本采集
实验第8天，各实验组小鼠眼眶取血，用装有EDTA抗凝剂的0.5mlEP管收集待测。
2.4检测指标及方法
外周血象检测：采用全自动血球计数仪对各实验组小鼠外周血白细胞(WBC)、中性粒细胞(NEUT)红细胞(RBC)、血小板(PLT)、血红蛋白(HGB)进行计数。
骨髓造血干细胞计数(以骨髓细胞CD34+抗原表达量计)用含牛血清白蛋白浓度为0.2％的PBS缓冲液冲出小鼠右侧股骨骨髓细胞，取出106个细胞离心，弃上清，加入30μL正常小鼠血清以封闭非特异结合位点，再加入10μL FITC标记的大鼠抗小鼠CD34+抗体，对照管加入10μL相应对照抗体，4℃避光反应30min。加入2mL红细胞裂解液，作用5min，洗细胞2次，加入终浓度为3μg/mL的PI染液，采用流式细胞仪检测骨髓细胞CD34+抗原表达。
3.实验结果
3.1外周血主要血细胞计数比较，见表1、表2。
表1 各实验组小鼠外周血血细胞数量
Figure PCTCN2017072224-appb-000005
注：与模型组比较，*P<0.05，**P<0.01；注：与地榆皂苷II组比较，△P<0.05，△△P<0.01。
结果显示，与模型组比较，地榆皂苷II-H-β-CD包合物组小鼠外周血WBC、RBC、PLT数量均有显著升高(P<0.05)，地榆皂苷II组无显著性差异；与地榆皂苷II组比较，地榆皂苷II-H-β-CD包合物组小鼠外周血WBC、RBC、PLT数量均有显著升高(P<0.05)。
表2 各实验组小鼠外周血血细胞数量
Figure PCTCN2017072224-appb-000006
注：与模型组比较，*P<0.05，**P<0.01；注：与地榆皂苷II组比较，△P<0.05，△△P<0.01。
结果显示，与模型组比较，地榆皂苷II-H-β-CD包合物组小鼠外周血NEUT和HGB数量均有显著升高(P<0.05)，地榆皂苷II组无显著性差异；与地榆皂苷II组比较，地榆皂苷II-H-β-CD包合物组小鼠外周血NEUT和HGB数量均有显著升高(P<0.05)。
综上所述，本发明制备的地榆皂苷II羟丙基β-环糊精包合物解决了地榆皂苷II溶解度低的问题，提高了地榆皂苷II生物利用度，进而提高其升高血细胞的疗效，对地榆皂苷II更好的临床应用具有十分重要的意义。

Claims (11)

  1. 一种地榆皂苷II羟丙基β-环糊精包合物，其特征在于：它包含下述原料制备而成的制剂：地榆皂苷II、羟丙基β-环糊精。
  2. 根据权利要求1所述的包合物，其特征在于：它是由下述重量配比的原料加上药学上可接受的溶剂制备而成：
    地榆皂苷II 0.5-10份、羟丙基β-环糊精1-20份。
  3. 根据权利要求1或2所述的包合物，其特征在于：所述地榆皂苷II与羟丙基β-环糊精的重量配比为1:1～1:20。
  4. 根据权利要求2或3所述的包合物，其特征在于：所述的药学上可接受的溶剂为无水乙醇、正丁醇、乙醚中至少一种。
  5. 制备权利要求1-4任意一项所述的包合物的方法，其特征在于：包括下述步骤：
    a.按配比取地榆皂苷II，加入药学上可接受的溶剂，溶解，得溶液1；
    b按配比取羟丙基β-环糊精，加入药学上可接受的溶剂，溶解，得溶液2；
    c.边搅拌溶液2边向其中加入溶液1，全部加入后，搅拌、蒸干、研磨，即得包合物。
  6. 根据权利要求5所述的方法，其特征在于：
    步骤a中，按配比取地榆皂苷II，加入溶剂，溶剂与地榆皂苷II的体积重量比为100mL：1g；
    步骤b中，按配比取羟丙基β-环糊精，加入溶剂，溶剂与羟丙基β-环糊精的体积重量比为10mL：1g；
    步骤c中，搅拌4h，60℃蒸干。
  7. 权利要求1-4任意一项所述的包合物在制备升高血细胞的药物中的用途。
  8. 根据权利要求7所述的用途，其特征在于：所述的药物是升高外周血白细胞、中性粒细胞、红细胞、血小板和/或血红蛋白的药物。
  9. 一种地榆皂苷II制剂，其特征在于：它是由地榆皂苷II羟丙基β-环糊精包合物为活性成分，加入药学上可接受的辅料或辅助性成分制备而成的制剂。
  10. 根据权利要求9所述的制剂，其特征在于：所述的制剂为散剂、片剂、丸剂、颗粒剂、粉针剂、注射剂或胶囊剂。
  11. 一种升高血细胞的方法，其特征在于：它是使用权利要求1-4任意一项所述的包合物进行治疗。
PCT/CN2017/072224 2017-01-23 2017-01-23 地榆皂苷II羟丙基β-环糊精包合物及其制备方法和用途 WO2018133104A1 (zh)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1593436A (zh) * 2003-09-08 2005-03-16 成都地奥制药集团有限公司 乌索烷型三萜皂苷在制备升高白细胞和/或血小板药物中的应用
CN101119740A (zh) * 2004-12-14 2008-02-06 成都地奥制药集团有限公司 中药地榆及其提取物在制备升高红细胞和血红蛋白药物中的应用
CN103830740A (zh) * 2012-11-28 2014-06-04 青岛百草汇中草药研究所 人参皂苷Rg3羟丙基－β－环糊精包合物及制剂和制备方法
CN106540269A (zh) * 2015-09-18 2017-03-29 四川英路维特医药科技有限公司 地榆皂苷II羟丙基β‑环糊精包合物及其制备方法和用途

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1593436A (zh) * 2003-09-08 2005-03-16 成都地奥制药集团有限公司 乌索烷型三萜皂苷在制备升高白细胞和/或血小板药物中的应用
CN101119740A (zh) * 2004-12-14 2008-02-06 成都地奥制药集团有限公司 中药地榆及其提取物在制备升高红细胞和血红蛋白药物中的应用
CN103830740A (zh) * 2012-11-28 2014-06-04 青岛百草汇中草药研究所 人参皂苷Rg3羟丙基－β－环糊精包合物及制剂和制备方法
CN106540269A (zh) * 2015-09-18 2017-03-29 四川英路维特医药科技有限公司 地榆皂苷II羟丙基β‑环糊精包合物及其制备方法和用途

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