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WO2018133105A1 - 地榆皂苷元羟丙基β-环糊精包合物及其制备方法和用途 - Google Patents

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

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WO2018133105A1
WO2018133105A1 PCT/CN2017/072225 CN2017072225W WO2018133105A1 WO 2018133105 A1 WO2018133105 A1 WO 2018133105A1 CN 2017072225 W CN2017072225 W CN 2017072225W WO 2018133105 A1 WO2018133105 A1 WO 2018133105A1
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saponin
hydroxypropyl
cyclodextrin
solution
pharmaceutically acceptable
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PCT/CN2017/072225
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English (en)
French (fr)
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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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Priority to PCT/CN2017/072225 priority Critical patent/WO2018133105A1/zh
Publication of WO2018133105A1 publication Critical patent/WO2018133105A1/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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—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
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • 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
    • 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

Definitions

  • the invention relates to a saponin hydroxypropyl ⁇ -cyclodextrin inclusion compound, a preparation method thereof and use thereof, and belongs to the field of medicine.
  • Myelosuppression is a clinically common hematopoietic disease that can occur in radiation therapy and/or chemotherapy of various systemic neoplastic diseases, radiation damage caused by ionizing radiation, viral hepatitis, parvovirus infection or drugs (chloramphenicol). , benzene, sulfonamides, anti-epileptic drugs, sedatives, anti-thyroid drugs, anti-diabetes drugs, anti-malaria, sleeping pills and other factors. Myelosuppression can cause damage to the bone marrow microenvironment, hematopoietic stem cells, hematopoietic growth factors, etc., and the granulosa, red, and megakaryocyte systems are inhibited.
  • the saponin is extracted from the roots of Sanguisorba officinalis L. or S. officinalis L. var. longifolia (Bertol.) Yu et Li.
  • the active ingredient is an aglycon of saponin I and saponin II, chemical name: 3 ⁇ , 19 ⁇ -hydroxy-Uso-12--28-carboxylic acid, and its structural formula is as follows:
  • the technical proposal of the present invention provides a saponin hydroxypropyl ⁇ -cyclodextrin inclusion compound, a preparation method thereof and use thereof.
  • the present invention provides a saponin hydroxypropyl ⁇ -cyclodextrin inclusion compound prepared from the following stoichiometric starting materials plus a pharmaceutically acceptable solvent:
  • Hydroxypropyl ⁇ -cyclodextrin H- ⁇ -CD.
  • the pharmaceutically acceptable solvent is at least one of absolute ethanol, n-butanol and diethyl ether.
  • the present invention also provides a method of preparing the above clathrate, comprising the steps of:
  • the pharmaceutically acceptable solvent is at least one of absolute ethanol, n-butanol and diethyl ether;
  • the stirring time was 4 hours, and the evaporation to dryness was 60 °C.
  • the invention also provides the use of the above clathrate for the manufacture of a medicament for the treatment and/or prevention of myelosuppression.
  • the drug is a drug for treating and/or preventing bone marrow suppression caused by a chemical substance.
  • the present invention also provides the use of the above clathrate for the preparation of a medicament for increasing the number of one or more of peripheral blood leukocytes, neutrophils, red blood cells, platelets, hemoglobin, bone marrow hematopoietic stem cells.
  • the present invention also provides a saponin preparation which is prepared by using a saponin 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 treating and/or preventing myelosuppression, in particular, using the aforementioned clathrate.
  • the method is a method of treating and/or preventing bone marrow suppression caused by a chemical substance.
  • the present invention also provides a method for increasing the amount of one or more of peripheral blood leukocytes, neutrophils, red blood cells, platelets, hemoglobin, bone marrow hematopoietic stem cells, in particular, using the aforementioned clathrate.
  • the saponin hydroxypropyl ⁇ -cyclodextrin inclusion compound prepared by the invention can significantly improve the solubility and dissolution of the drug, and significantly increase the peripheral blood leukocytes, neutrophils, red blood cells, platelets, hemoglobin and bone marrow hematopoietic stem cells.
  • the quantity, with obvious therapeutic and/or prevention of myelosuppression, is of great significance for the clinical application of saponin.
  • the raw materials and equipment used in the specific embodiments of the present invention are known products and are obtained by purchasing commercially available products.
  • the preparation method is as follows:
  • the saponin was taken according to the ratio, and 50 ml of anhydrous ethanol was added thereto to ultrasonically dissolve to obtain a solution 1. Further, H- ⁇ -CD was taken according to the ratio, and 15 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 preparation method is as follows:
  • the saponin was taken according to the ratio, and 150 ml of absolute ethanol was added to dissolve to dissolve to obtain a solution 1.
  • Another H- ⁇ -CD was taken according to the ratio, and 50 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 preparation method is as follows:
  • the saponin was taken according to the ratio, and 250 ml of absolute ethanol was added to dissolve to dissolve to obtain a solution 1. Further, H- ⁇ -CD was taken according to the ratio, and 100 ml 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 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 was taken according to the ratio, and 450 ml of anhydrous ethanol was added to dissolve to dissolve to obtain a solution 1. Further, H- ⁇ -CD was taken according to the ratio, and 450 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 preparation method is as follows:
  • the saponin was taken according to the ratio, and 650 ml of absolute ethanol was added to ultrasonicate to dissolve to obtain a solution 1. Further, H- ⁇ -CD was taken according to the ratio, and 165 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 preparation method is as follows:
  • the saponin was taken according to the ratio, and 850 ml of absolute ethanol was added to dissolve to dissolve to obtain a solution 1. Further, H- ⁇ -CD was taken according to the ratio, and 350 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 was taken according to the ratio, and 1000 ml of absolute ethanol was added to ultrasonicate to dissolve to obtain a solution 1. Further, H- ⁇ -CD was taken according to the ratio, and 450 ml of absolute ethanol was added to ultrasonicate to dissolve to obtain a solution 2.
  • Stir the solution 2 on a constant temperature magnetic stirrer while slowly adding the solution 1 to the solution 2 with a dropper. After all of Solution 1 was added to 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 and weighed: 5 g of saponin and 15 g of clathrate.
  • the preparation method is as follows:
  • the saponin was weighed and added with 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 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.
  • inclusion ratio mass of saponin in the inclusion compound / mass of saponin administration ⁇ 100%
  • the saponin hydroxypropyl ⁇ -cyclodextrin inclusion complex can be obtained only in the proportion of the saponin: hydroxypropyl ⁇ -cyclodextrin of the present invention; wherein, the saponin is used Element: Hydroxypropyl ⁇ -cyclodextrin is in the range of 1:1 to 1:20, and the inclusion ratio is over 90%, which is significantly different from that of hydroxypropyl ⁇ -cyclodextrin 1:0.5 (P ⁇ 0.05), indicating hydroxypropyl ⁇ -cyclodextrin to saponin pack The effect is good.
  • Test drug saponin-H- ⁇ -CD clathrate (prepared according to Examples 1 to 7), saponin, cyclophosphamide.
  • mice All animals were fed ad libitum for 1 week and were randomly divided into: blank group; model group; saponin-H- ⁇ -CD inclusion complex group, prepared according to Examples 1-7, formulated into 2.5 mg ⁇ kg - 1 suspension, set to sample groups 1 to 7, respectively, saponin group; dissolved in 10% DMSO-physiological saline, formulated into a 2.5mg ⁇ kg -1 suspension.
  • 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, and the blank mice were injected with the same 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 number of hematopoietic stem cells in the saponin hydroxypropyl ⁇ -cyclodextrin inclusion compound group of the present invention was significantly increased (P ⁇ 0.05), and the saponin group was absent.
  • the number of hematopoietic stem cells in the saponin hydroxypropyl ⁇ -cyclodextrin inclusion compound group of the present invention was significantly increased (P ⁇ 0.05).
  • the saponin inclusion complex prepared by the invention effectively solves the problem of low solubility of the saponin, improves the bioavailability of the saponin, can effectively raise blood cells, and effectively prevent and treat bone marrow suppression.
  • the clinical application of sapogenin is of great significance.

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Abstract

一种地榆皂苷元羟丙基β-环糊精包合物及其制备方法和用途，所述地榆皂苷元羟丙基β-环糊精包合物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的制剂：地榆皂苷元0.5-10份、羟丙基β-环糊精1-20份。

Description

地榆皂苷元羟丙基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元羟丙基β-环糊精包合物及其制备方法和用途，属于药物领域。
背景技术
骨髓抑制是临床上常见的造血系统疾病，它可发生于各系统肿瘤性疾病的放射治疗及(或)化学治疗、电离辐射引起的放射损伤、病毒性肝炎、微小病毒感染或药物(氯霉素、苯、磺胺、抗癫痈药、镇静剂、抗甲状腺药、抗糖尿病药、抗疟疾、安眠药)等因素。骨髓抑制可引起骨髓微环境、造血干细胞、造血细胞生长因子等的损伤，粒、红、巨核细胞系统一系、二系或三系细胞受抑制。粒细胞缺乏会引起严重感染；红细胞明显减少会引起严重贫血；血小板明显下降引起严重出血，甚至导致死亡。目前，临床上对于骨髓抑制，尤其是放化疗引起的骨髓抑制，尚缺乏有效的治疗手段，亟需开发出药效较好的治疗药物。
地榆皂苷元是从蔷薇科地榆属植物地榆(Sanguisorba officinalis L.)或长叶地榆[S.officinalis L.var.longifolia(Bertol.)Yu et Li]的根中提取得到的一种活性成分，是地榆皂苷I和地榆皂苷II的苷元，化学名：3β，19α-羟基乌索-12烯-28-羧酸，其结构式如下所示：
Figure PCTCN2017072225-appb-000001
目前尚未见以地榆皂苷元为活性成分制备环糊精包合物，用于治疗和/或预防骨髓抑制的公开报道。
发明内容
本发明的技术方案是提供了一种地榆皂苷元羟丙基β-环糊精包合物及其制备方法和用途。
本发明提供了一种地榆皂苷元羟丙基β-环糊精包合物，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：
地榆皂苷元0.5-10份、羟丙基β-环糊精1-20份。
羟丙基β-环糊精：H-β-CD。
其中，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：
地榆皂苷元1份、羟丙基β-环糊精1-30份。
其中：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：
地榆皂苷元2.5份、羟丙基β-环糊精10份；
或地榆皂苷元1份、羟丙基β-环糊精10份。
其中，所述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上述包合物的方法，包括下述步骤：
a.按配比取地榆皂苷元，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。
其中，步骤a和/或b中，所述药学上可接受的溶剂为无水乙醇、正丁醇、乙醚中至少一种；
步骤c中，搅拌的时间为4h，蒸干的温度为60℃。
本发明还提供了上述包合物在制备治疗和/或预防骨髓抑制的药物的用途。
其中，所述的药物是治疗和/或预防化学物质导致的骨髓抑制的药物。
本发明还提供了上述包合物在制备升高外周血白细胞、中性粒细胞、红细胞、血小板、血红蛋白、骨髓造血干细胞中一种或几种的数量的药物中的用途。
本发明还提供了一种地榆皂苷元制剂，它是由地榆皂苷元羟丙基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。
其中，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治疗和/或预防骨髓抑制的方法，具体是采用前述的包合物进行治疗。
其中，所述方法是治疗和/或预防化学物质导致的骨髓抑制的方法。
本发明还提供了一种升高外周血白细胞、中性粒细胞、红细胞、血小板、血红蛋白、骨髓造血干细胞中一种或几种的数量的方法，具体是采用前述的包合物进行治疗。
本发明制备的地榆皂苷元羟丙基β-环糊精包合物，可显著提高药物溶解度及溶出度，显著提高外周血白细胞、中性粒细胞、红细胞、血小板、血红蛋白和骨髓造血干细胞的数量，具有明显的治疗和/或预防骨髓抑制的作用，对地榆皂苷元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各实验组小鼠骨髓造血干细胞计数比较
具体实施方式
本发明具体实施方式中使用的原料、设备均为已知产品，通过购买市售产品获得。
实施例1本发明包合物的制备
按下述配比称取原料：
地榆皂苷元0.5g、羟丙基β-环糊精1.5g。
制备方法如下：
按配比取地榆皂苷元，加50ml的无水乙醇超声至溶解，得溶液1。另按配比取H-β-CD，加入15ml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：
地榆皂苷元1.5g、羟丙基β-环糊精5g。
制备方法如下：
按配比取地榆皂苷元，加150ml的无水乙醇超声至溶解，得溶液1。另 按配比取H-β-CD，加入50ml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3本发明包合物的制备
按下述配比称取原料：
地榆皂苷元2.5g、羟丙基β-环糊精10g。
制备方法如下：
按配比取地榆皂苷元，加250ml的无水乙醇超声至溶解，得溶液1。另按配比取H-β-CD，加入100ml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4本发明包合物的制备
按下述配比称取原料：
地榆皂苷元4.5g、羟丙基β-环糊精45g。
制备方法如下：
按配比取地榆皂苷元，加450ml的无水乙醇超声至溶解，得溶液1。另按配比取H-β-CD，加入450ml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5本发明包合物的制备
按下述配比称取原料：
地榆皂苷元6.5g、羟丙基β-环糊精16.5g。
制备方法如下：
按配比取地榆皂苷元，加650ml的无水乙醇超声至溶解，得溶液1。另按配比取H-β-CD，加入165ml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6本发明包合物的制备
按下述配比称取原料：
地榆皂苷元8.5g、羟丙基β-环糊精35g。
制备方法如下：
按配比取地榆皂苷元，加850ml的无水乙醇超声至溶解，得溶液1。另按配比取H-β-CD，加入350ml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7本发明包合物的制备
按下述配比称取原料：
地榆皂苷元10g、羟丙基β-环糊精45g。
制备方法如下：
按配比取地榆皂苷元，加1000ml的无水乙醇超声至溶解，得溶液1。另按配比取H-β-CD，加入450ml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包合物的质量评价
本研究根据地榆皂苷元的性质，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元包合物。
下述配比称取原料：地榆皂苷元5g、包合材料15g。
制备方法如下：
称取地榆皂苷元，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(％)＝包合物中地榆皂苷元的质量/地榆皂苷元投药质量×100％)，结果见表1。
表1 不同包合材料制备地榆皂苷元包合物的质量评价
Figure PCTCN2017072225-appb-000002
注：与β-环糊精组相比，*P<0.05。
由表1可见，采用本发明包合材料羟丙基β-环糊精制备的地榆皂苷元羟丙基β-环糊精包合物，包合率高，包合效果好。而使用其它包合材料制备的包合物包合率差。
结果表明，仅在使用本发明包合材料羟丙基β-环糊精制备的地榆皂苷元羟丙基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元羟丙基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元、羟丙基β-环糊精，按下述方法试验：取一定量的地榆皂苷元，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元羟丙基β-环糊精包合物的包合率
Figure PCTCN2017072225-appb-000003
注：与1:0.5组相比，*P<0.05。
由表2可见，仅在采用本发明地榆皂苷元：羟丙基β-环糊精比例范围内才能得到地榆皂苷元羟丙基β-环糊精包合物；其中，采用地榆皂苷元：羟丙基β-环糊精为1:1-1:20范围内，包合率达到90％以上，与羟丙基β-环糊精为1:0.5相比，差异显著(P<0.05)，表明羟丙基β-环糊精对地榆皂苷元包 合效果好。
实验例3本发明地榆皂苷元羟丙基β-环糊精包合物药效学研究
1.实验材料
1.1受试药物：地榆皂苷元-H-β-CD包合物(按照实施例1～7制备)、地榆皂苷元、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 PCTCN2017072225-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；地榆皂苷元-H-β-CD包合物组，按照实施例1～7制备,配制成2.5mg·kg-1混悬液，分别设置为样品1～7组，地榆皂苷元组；用10％DMSO-生理盐水溶解，配制成2.5mg·kg-1混悬液。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3-4。
表3 各实验组小鼠外周血血细胞数量
Figure PCTCN2017072225-appb-000005
注：与模型组比较，*P<0.05，**P<0.01；注：与地榆皂苷元组比较，△P<0.05，△△P<0.01。
由表3可见，与模型组比较，地榆皂苷元组无显著性差异，地榆皂苷元-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)；与地榆皂苷元组比较，地榆皂苷元-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)。其中样品3组具有极显著升高(P<0.01)。
表4 各实验组小鼠外周血血细胞数量
Figure PCTCN2017072225-appb-000006
注：与模型组比较，*P<0.05，**P<0.01；注：与地榆皂苷元组比较，△P<0.05，△△P<0.01。
由表4可见，与模型组比较，地榆皂苷元组无显著性差异，地榆皂苷元-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)；与地榆皂苷元组比较，地榆皂苷元-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)。其中样品3组具有极显著升高(P<0.01)。
3.2骨髓造血干细胞计数比较
见图1。
从图1可知，与模型组比较，本发明地榆皂苷元羟丙基β‐环糊精包合物组小鼠造血干细胞数量均有显著升高(P<0.05)，地榆皂苷元组无显著性差异；与地榆皂苷元组比较，本发明地榆皂苷元羟丙基β‐环糊精包合物组小鼠造血干细胞数量均有显著升高(P<0.05)。
以上实验结果表明，本发明地榆皂苷元羟丙基β‐环糊精包合物可以有效升高血细胞，而直接用地榆皂苷元原药无效果。
综上，本发明制备的地榆皂苷元包合物有效解决了地榆皂苷元溶解度低的问题，提高了地榆皂苷元生物利用度，可以有效升高血细胞，有效防治骨髓抑制，对地榆皂苷元的临床应用具有十分重要的意义。

Claims (13)

  1. 一种地榆皂苷元羟丙基β-环糊精包合物，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：
    地榆皂苷元0.5-10份、羟丙基β-环糊精1-20份。
  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：
    地榆皂苷元1份、羟丙基β-环糊精1-30份。
  3. 根据权利要求1或2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：
    地榆皂苷元2.5份、羟丙基β-环糊精10份；
    或地榆皂苷元1份、羟丙基β-环糊精10份。
  4. 根据权利要求1-3任意一项所述的包合物，其特征在于：所述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.按配比取地榆皂苷元，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和/或b中，所述药学上可接受的溶剂为无水乙醇、正丁醇、乙醚中至少一种；
    步骤c中，搅拌的时间为4h，蒸干的温度为60℃。
  7. 权利要求1-4任意一项所述的包合物在制备治疗和/或预防骨髓抑制的药物的用途。
  8. 根据权利要求7所述的用途，其特征在于：所述的药物是治疗和/或预防化学物质导致的骨髓抑制的药物。
  9. 权利要求1-4任意一项所述的包合物在制备升高外周血白细胞、中性粒细胞、红细胞、血小板、血红蛋白、骨髓造血干细胞中一种或几种的数量的药物中的用途。
  10. 一种地榆皂苷元制剂，其特征在于：它是由地榆皂苷元羟丙基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。
  11. 一种治疗和/或预防骨髓抑制的方法，其特征在于：采用权利要求1-4任意一项所述的包合物进行治疗。
  12. 根据权利要求11所述的方法，其特征在于：所述方法是治疗和/或预防化学物质导致的骨髓抑制的方法。
  13. 一种升高外周血白细胞、中性粒细胞、红细胞、血小板、血红蛋白、骨髓造血干细胞中一种或几种的数量的方法，其特征在于：采用权利要求1-4任意一项所述的包合物进行治疗。
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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
CN1788758A (zh) * 2004-12-14 2006-06-21 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
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CN106606504A (zh) * 2015-10-16 2017-05-03 四川英路维特医药科技有限公司 地榆皂苷元羟丙基β‑环糊精包合物及其制备方法和用途

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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
CN1788758A (zh) * 2004-12-14 2006-06-21 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
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