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WO2018133110A1 - Ziyuglycoside ii solid dispersion and preparation method therefor - Google Patents

Ziyuglycoside ii solid dispersion and preparation method therefor Download PDF

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Publication number
WO2018133110A1
WO2018133110A1 PCT/CN2017/072230 CN2017072230W WO2018133110A1 WO 2018133110 A1 WO2018133110 A1 WO 2018133110A1 CN 2017072230 W CN2017072230 W CN 2017072230W WO 2018133110 A1 WO2018133110 A1 WO 2018133110A1
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saponin
solid dispersion
solution
povidone
preparation
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PCT/CN2017/072230
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Chinese (zh)
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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/CN2017/072230 priority Critical patent/WO2018133110A1/en
Publication of WO2018133110A1 publication Critical patent/WO2018133110A1/en

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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/70Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A61K31/704Compounds 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
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/14Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00Drugs for disorders of the blood or the extracellular fluid
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00Drugs for disorders of the blood or the extracellular fluid
    • A61P7/06Antianaemics

Definitions

  • the invention relates to a solid dispersion of saponin II and a preparation method 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.
  • Diltiazem II is a mantle from the genus Rosaceae or A pharmacologically active compound is extracted from the roots of the longleaf mantle.
  • CN101119740A discloses the use of saponin II in the preparation of a medicament for increasing red blood cells and hemoglobin.
  • saponin II is not effective, and it is often difficult to obtain a better blood cell level and a bone marrow suppression treatment when used alone. Therefore, there is an urgent need to improve the efficacy of the saponin II and promote the clinical application of the drug.
  • the present invention provides a solid dispersion of saponin II which is prepared from the following raw materials by weight ratio: 1 part of saponin II and 4-30 parts of povidone.
  • the povidone is PVP K30.
  • the invention provides a preparation method of the solid dispersion, comprising the following steps:
  • organic solvent described in step a is anhydrous ethanol.
  • the mass to volume ratio of the saponin II to the solvent in the saponin II solution described in step a is 1:100; the mass to volume ratio of povidone to solvent in the povidone solution is (1: 4) ⁇ (5:1).
  • step c was carried out by placing the mixture in a 60 ° C water bath and evaporating the solvent.
  • the present invention provides the use of the solid dispersion for the preparation of a medicament for increasing the number of blood cells and hemoglobin.
  • the present invention provides the use of the solid dispersion for the preparation of a medicament for the treatment and/or prevention of myelosuppression.
  • the present invention provides a method of increasing the number of blood cells and hemoglobin using the solid dispersion.
  • the present invention provides a method of treating and/or preventing myelosuppression using the solid dispersion.
  • the reason that the effect of the saponin II on raising the blood cell level is poor is that the solubility is low and the gastrointestinal absorption rate is small, resulting in low bioavailability of the drug and limiting the exertion of its efficacy.
  • the invention uses the povidone as a carrier material to prepare the saponin II as a solid dispersion, which can significantly improve the solubility of the drug, and the dissolution rate of the solid dispersion is as high as 85%.
  • the solid dispersion of the saponin II of the present invention can significantly increase the number of WBC, RBC, PLT, NEUT and HGB in the peripheral blood, and the drug effect is obviously superior to that of the saponin II drug, indicating that the present invention
  • the invention can improve the bioavailability of the main drug and increase the blood cell number and prevent bone marrow suppression by preparing the saponin II into a solid dispersion.
  • 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.
  • PEG 8000, PEG 6000, PEG 4000, F68 were purchased from Chengdu Kelon Chemical Reagent Factory; PVP K30 was purchased from Sinopharm Chemical Reagent Co., Ltd.
  • Dissolution method Take one tablet of each batch, according to the dissolution method ("Chinese Pharmacopoeia" Appendix XC second method), with pH 6.8PBS 1 000mL as the dissolution medium, the rotation speed is 100r ⁇ min -1 , temperature ( 37 ⁇ 0.5)°C, sample 5mL at 0, 5, 15, 20, 25min, filter with 0.45 ⁇ m microporous membrane, place the filtrate in a 100mL volumetric flask, dilute to the mark with pH 6.8PBS, shake well, UV- Visible spectrophotometry (Chinese Pharmacopoeia Appendix IVA) measured absorbance at 345nm wavelength; after 25min sampling, the whole solution was transferred to a beaker, heated and stirred at 100 ° C for 2 ⁇ 3min, cooled to 37 ° C, according to the above method After sampling and dilution, the absorbance measured by the eluate after treatment at 100 ° C was the denominator, and the absorbance measured at each time point was taken as
  • the solubility of the saponin II drug in the early stage of the experiment was determined to be only 0.032 mg/ml. It can be seen from Table 1 that when the solid dispersion of the saponin II is prepared by using the povidone-based carrier material of the present invention, the solubility of the drug can be significantly improved, and the dissolution degree is highest; if other carrier materials, such as poloxamer, are used, With polyethylene glycol and the like, the dissolution rate of the solid dispersion is greatly reduced, and the solubility of the drug is not as obvious as that of PVP K30.
  • Test drug saponin II solid dispersion (prepared according to Example 2), saponin II.
  • tool drugs cyclophosphamide.
  • mice All animals were fed ad libitum for 1 week and were randomly divided into: blank group; model group; saponin II solid dispersion group, which were formulated into 0.5 mg ⁇ kg -1 , 5 mg ⁇ kg -1 , 10 mg ⁇ kg -1 .
  • the suspension was prepared before use; the saponin II group was formulated into a 10 mg ⁇ kg -1 suspension and 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, 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 normal 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

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Abstract

A ziyuglycoside II solid dispersion, a preparation method therefor and a use thereof. The solid dispersion is prepared by the following raw and auxiliary materials in weight proportion: 1 part of ziyuglycoside II and 4-30 parts of polyvinylpyrrolidone, and can be used for preparing medicines for increasing the count of blood cells and hemoglobin and for preparing medicines for treating and/or preventing myelosuppression. The solid dispersion can improve the solubility of the ziyuglycoside II and achieves a dissolution rate of 85%.

Description

一种地榆皂苷Ⅱ固体分散体及其制备方法Earthworm saponin II solid dispersion and preparation method thereof 技术领域Technical field
本发明涉及一种地榆皂苷Ⅱ固体分散体及其制备方法,属于医药领域。The invention relates to a solid dispersion of saponin II and a preparation method thereof, and belongs to the field of medicine.
背景技术Background technique
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尚缺乏有效的治疗手段,亟需开发出药效较好的治疗药物。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. Lack of granulocytes can cause serious infections; a marked reduction in red blood cells can cause severe anemia; a marked drop in platelets causes severe bleeding and even death. At present, there is still no effective treatment for bone marrow suppression in the clinic, and it is urgent to develop a therapeutic drug with better efficacy.
地榆皂苷Ⅱ,化学名:3-O-α-L-阿拉伯糖基-19α-羟基乌索-12烯-28-羧酸(ziyu-glycosideⅡ),是从蔷薇科地榆属植物地榆或长叶地榆的根中提取得到的具有药理活性的化合物。CN101119740A公开了地榆皂苷Ⅱ在制备升高红细胞和血红蛋白的药物中的用途。然而,实际使用中发现,地榆皂苷Ⅱ药效欠佳,单独使用时往往难以取得较好的升高血细胞水平、治疗骨髓抑制的效果。因此,亟需提高地榆皂苷Ⅱ的药效,促进该药物在临床上的应用。Diltiazem II, chemical name: 3-O-α-L-arabino-19-carboxylic acid (ziyu-glycoside II), is a mantle from the genus Rosaceae or A pharmacologically active compound is extracted from the roots of the longleaf mantle. CN101119740A discloses the use of saponin II in the preparation of a medicament for increasing red blood cells and hemoglobin. However, in actual use, it has been found that saponin II is not effective, and it is often difficult to obtain a better blood cell level and a bone marrow suppression treatment when used alone. Therefore, there is an urgent need to improve the efficacy of the saponin II and promote the clinical application of the drug.
发明内容Summary of the invention
本发明的目的在于提供一种地榆皂苷Ⅱ固体分散体及其制备方法。 It is an object of the present invention to provide a solid dispersion of saponin II and a process for the preparation thereof.
本发明提供了一种地榆皂苷Ⅱ固体分散体,它是由下述重量配比的原辅料制备而成:地榆皂苷Ⅱ1份、聚维酮4~30份。The present invention provides a solid dispersion of saponin II which is prepared from the following raw materials by weight ratio: 1 part of saponin II and 4-30 parts of povidone.
进一步的,它是由下述重量配比的原辅料制备而成:地榆皂苷Ⅱ1份、聚维酮4~10份。Further, it is prepared from the following raw materials by weight ratio: 1 part of saponin II and 4-10 parts of povidone.
进一步的,它是由下述重量配比的原辅料制备而成:地榆皂苷Ⅱ1份、聚维酮8份。Further, it is prepared from the following raw materials by weight ratio: 1 part of saponin II and 8 parts of povidone.
进一步的,所述的聚维酮为PVP K30。Further, the povidone is PVP K30.
本发明提供了一种所述固体分散体的制备方法,包括如下步骤:The invention provides a preparation method of the solid dispersion, comprising the following steps:
a、分别将地榆皂苷Ⅱ、聚维酮溶解于有机溶剂中,得到地榆皂苷Ⅱ溶液、聚维酮溶液,备用;a. Dissolving saponin II and povidone in an organic solvent respectively to obtain a solution of saponin II and povidone, and use;
b、将地榆皂苷Ⅱ溶液加入到聚维酮溶液中,混合均匀;b, adding the saponin II solution to the povidone solution, and mixing uniformly;
c、除去b步骤所得混合物中的有机溶剂,粉碎,即得。c. The organic solvent in the mixture obtained in the step b is removed and pulverized.
进一步的,a步骤所述的有机溶剂为无水乙醇。Further, the organic solvent described in step a is anhydrous ethanol.
进一步的,a步骤所述的地榆皂苷Ⅱ溶液中地榆皂苷Ⅱ与溶剂的质量体积比为1:100;所述的聚维酮溶液中聚维酮与溶剂的质量体积比为(1:4)~(5:1)。Further, the mass to volume ratio of the saponin II to the solvent in the saponin II solution described in step a is 1:100; the mass to volume ratio of povidone to solvent in the povidone solution is (1: 4) ~ (5:1).
进一步的,c步骤将混合物置于60℃水浴锅上蒸干溶剂。Further, step c was carried out by placing the mixture in a 60 ° C water bath and evaporating the solvent.
本发明提供了所述固体分散体在制备升高血细胞、血红蛋白数量的药物中的用途。The present invention provides the use of the solid dispersion for the preparation of a medicament for increasing the number of blood cells and hemoglobin.
本发明提供了所述固体分散体在制备治疗和/或预防骨髓抑制的药物的用途。The present invention provides the use of the solid dispersion for the preparation of a medicament for the treatment and/or prevention of myelosuppression.
本发明提供了一种使用所述固体分散体升高血细胞、血红蛋白数量的方法。 The present invention provides a method of increasing the number of blood cells and hemoglobin using the solid dispersion.
本发明提供了一种使用所述固体分散体治疗和/或预防骨髓抑制的方法。发明人在研究过程中发现,地榆皂苷II升高血细胞水平效果欠佳的原因在于其溶解度低、胃肠吸收率小,导致该药物的生物利用度较低,限制其药效的发挥。本发明以聚维酮为载体材料将地榆皂苷Ⅱ制备成固体分散体,可显著提高药物溶解度,且固体分散体溶出度高达85%。药效实验中,与模型组比较,本发明地榆皂苷Ⅱ固体分散体能显著升高外周血WBC、RBC、PLT、NEUT和HGB数量,且药效明显优于地榆皂苷Ⅱ原药,表明本发明将地榆皂苷Ⅱ制备成固体分散体后能够提高主药的生物利用度,增强其升高血细胞数量、防治骨髓抑制的作用。The present invention provides a method of treating and/or preventing myelosuppression using the solid dispersion. During the research, the inventors found that the reason that the effect of the saponin II on raising the blood cell level is poor is that the solubility is low and the gastrointestinal absorption rate is small, resulting in low bioavailability of the drug and limiting the exertion of its efficacy. The invention uses the povidone as a carrier material to prepare the saponin II as a solid dispersion, which can significantly improve the solubility of the drug, and the dissolution rate of the solid dispersion is as high as 85%. In the pharmacodynamic experiment, compared with the model group, the solid dispersion of the saponin II of the present invention can significantly increase the number of WBC, RBC, PLT, NEUT and HGB in the peripheral blood, and the drug effect is obviously superior to that of the saponin II drug, indicating that the present invention The invention can improve the bioavailability of the main drug and increase the blood cell number and prevent bone marrow suppression by preparing the saponin II into a solid dispersion.
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。It is apparent that various other modifications, substitutions and changes can be made in the form of the above-described embodiments of the present invention.
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。The above content of the present invention will be further described in detail below by way of specific embodiments in the form of embodiments. However, the scope of the above-mentioned subject matter of the present invention should not be construed as being limited to the following examples. Any technique implemented based on the above description of the present invention is within the scope of the present invention.
具体实施方式detailed description
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。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.
PEG 8000、PEG 6000、PEG 4000、F68,均购自成都市科龙化工试剂厂;PVP K30购于国药集团化学试剂有限公司。PEG 8000, PEG 6000, PEG 4000, F68 were purchased from Chengdu Kelon Chemical Reagent Factory; PVP K30 was purchased from Sinopharm Chemical Reagent Co., Ltd.
实施例1本发明地榆皂苷Ⅱ固体分散体的制备Example 1 Preparation of the solid dispersion of saponin II of the present invention
取地榆皂苷Ⅱ1.0g,加100ml的无水乙醇超声至溶解,得溶液1。另取5.0g的PVP K30,加入20ml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加热至熔融,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固体分散体。1.0 g of saponin II was taken and added to 100 ml of absolute ethanol to dissolve to obtain a solution 1. Another 5.0 g of PVP K30 was added, and 20 ml of absolute ethanol was added to ultrasonicate to dissolve to obtain a solution 2. Put solution 2 The mixture was heated to melt 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 solid dispersion.
实施例2本发明地榆皂苷Ⅱ固体分散体的制备Example 2 Preparation of the solid dispersion of saponin II of the present invention
取地榆皂苷Ⅱ1.0g,加100ml的无水乙醇超声至溶解,得溶液1。另取8.0g的PVP K30,加入32ml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加热至熔融,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固体分散体。1.0 g of saponin II was taken and added to 100 ml of absolute ethanol to dissolve to obtain a solution 1. Another 8.0 g of PVP K30 was added, and 32 ml of absolute ethanol was added to ultrasonicate to dissolve to obtain a solution 2. Solution 2 was heated to melt on a thermostatic magnetic stirrer while solution 1 was slowly added to solution 2 with a dropper. After solution 1 was all 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 solid dispersion.
实施例3本发明地榆皂苷Ⅱ固体分散体的制备Example 3 Preparation of the solid dispersion of saponin II of the present invention
取地榆皂苷Ⅱ1.0g,加100ml的无水乙醇超声至溶解,得溶液1。另取20.0g的PVP K30,加入4ml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加热至熔融,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固体分散体。1.0 g of saponin II was taken and added to 100 ml of absolute ethanol to dissolve to obtain a solution 1. Another 20.0 g of PVP K30 was added to the solution by adding 4 ml of absolute ethanol to dissolve to obtain a solution 2. Solution 2 was heated to melt on a thermostatic magnetic stirrer while solution 1 was slowly added to solution 2 with a dropper. After solution 1 was all 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 solid dispersion.
以下通过实验例证明本发明的有益效果。The beneficial effects of the present invention are exemplified below by experiments.
溶出度测定方法:取各批片剂1片,照溶出度测定法(《中国药典》附录ⅩC第二法),以pH 6.8PBS 1 000mL为溶出介质,转速为100r·min-1,温度(37±0.5)℃,于0、5、15、20、25min各取样5mL,用0.45μm微孔滤膜过滤,滤液置100mL量瓶中,加pH 6.8PBS稀释至刻度,摇匀, 照紫外-可见分光光度法(《中国药典》附录ⅣA)在345nm波长处测定吸光度;25min取样后,将溶出液全部转移至烧杯中,于100℃加热搅拌2~3min,放冷至37℃,按前述方法取样及稀释,以100℃处理后溶出液测得的吸光度为分母,以各时间点测到的吸光度为分子,计算累积溶出率。Dissolution method: Take one tablet of each batch, according to the dissolution method ("Chinese Pharmacopoeia" Appendix XC second method), with pH 6.8PBS 1 000mL as the dissolution medium, the rotation speed is 100r·min -1 , temperature ( 37±0.5)°C, sample 5mL at 0, 5, 15, 20, 25min, filter with 0.45μm microporous membrane, place the filtrate in a 100mL volumetric flask, dilute to the mark with pH 6.8PBS, shake well, UV- Visible spectrophotometry (Chinese Pharmacopoeia Appendix IVA) measured absorbance at 345nm wavelength; after 25min sampling, the whole solution was transferred to a beaker, heated and stirred at 100 ° C for 2 ~ 3min, cooled to 37 ° C, according to the above method After sampling and dilution, the absorbance measured by the eluate after treatment at 100 ° C was the denominator, and the absorbance measured at each time point was taken as a molecule, and the cumulative dissolution rate was calculated.
实验例1采用不同载体材料制备地榆皂苷Ⅱ固体分散体的质量评价Experimental Example 1 Quality Evaluation of Preparation of Diosgenin II Solid Dispersion Using Different Carrier Materials
本实验设置5个实验组。分别取地榆皂苷Ⅱ1.0g,加100ml的无水乙醇超声至溶解,得溶液1。另取8.0g的不同高分子材料PVP K30、泊洛沙姆188(F68)、聚乙二醇(PEG)8000、聚乙二醇(PEG)6000、聚乙二醇(PEG)4000,加入4ml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加热至熔融,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固体分散体。测定固体分散体溶解度及溶出度,结果见表1。Five experimental groups were set up in this experiment. 1.0 g of saponin II was separately taken and ultrasonically added to 100 ml of anhydrous ethanol to dissolve to obtain a solution 1. Another 8.0g of different polymer materials PVP K30, poloxamer 188 (F68), polyethylene glycol (PEG) 8000, polyethylene glycol (PEG) 6000, polyethylene glycol (PEG) 4000, add 4ml The anhydrous ethanol was sonicated to dissolve to obtain a solution 2. Solution 2 was heated to melt on a thermostatic magnetic stirrer while solution 1 was slowly added to solution 2 with a dropper. After solution 1 was all 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 solid dispersion. The solubility and dissolution of the solid dispersion were measured, and the results are shown in Table 1.
表1 地榆皂苷Ⅱ固体分散体溶解度及溶出度测定结果Table 1 Determination of Solubility and Dissolution of Diquat Saponin II Solid Dispersion
Figure PCTCN2017072230-appb-000001
Figure PCTCN2017072230-appb-000001
实验前期对地榆皂苷Ⅱ原药的溶解度进行测定,仅为0.032mg/ml。由表1可知,采用本发明聚维酮类载体材料制备地榆皂苷Ⅱ固体分散体时,可显著提高药物溶解度,且溶出度达到最高;若使用其它载体材料,如泊洛沙姆、 聚乙二醇等,固体分散体溶出度大幅下降,药物溶解度的提升亦不如PVP K30明显。The solubility of the saponin II drug in the early stage of the experiment was determined to be only 0.032 mg/ml. It can be seen from Table 1 that when the solid dispersion of the saponin II is prepared by using the povidone-based carrier material of the present invention, the solubility of the drug can be significantly improved, and the dissolution degree is highest; if other carrier materials, such as poloxamer, are used, With polyethylene glycol and the like, the dissolution rate of the solid dispersion is greatly reduced, and the solubility of the drug is not as obvious as that of PVP K30.
以上结果表明,以聚维酮为载体材料制备得到的地榆皂苷Ⅱ固体分散体质量最佳。The above results show that the quality of the solid dispersion of saponin II prepared by using povidone as the carrier material is the best.
实验例2载体材料用量对地榆皂苷Ⅱ固体分散体质量的影响Experimental Example 2 Effect of the Amount of Support Material on the Quality of Diquat Saponin II Solid Dispersion
本实验设置6个实验组。分别取地榆皂苷Ⅱ1.0g,加100ml的无水乙醇超声至溶解,得溶液1。另外分别按照如表2所示的质量比例称取PVP K30(固定地榆皂苷Ⅱ质量为1份,PVP K30质量随比例变化),加入4ml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加热至熔融,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固体分散体。测定固体分散体溶解度及溶出度,结果见表2。Six experimental groups were set up in this experiment. 1.0 g of saponin II was separately taken and ultrasonically added to 100 ml of anhydrous ethanol to dissolve to obtain a solution 1. Further, PVP K30 (1 part by mass of saponin II and 1 part by mass of PVP K30) was weighed according to the mass ratio shown in Table 2, and ultrasonically dissolved in 4 ml of anhydrous ethanol to dissolve to obtain a solution 2. Solution 2 was heated to melt on a thermostatic magnetic stirrer while solution 1 was slowly added to solution 2 with a dropper. After solution 1 was all 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 solid dispersion. The solubility and dissolution of the solid dispersion were measured, and the results are shown in Table 2.
表2 地榆皂苷Ⅱ固体分散体溶解度及溶出度测定结果Table 2 Determination of Solubility and Dissolution of Diquat Saponin II Solid Dispersion
Figure PCTCN2017072230-appb-000002
Figure PCTCN2017072230-appb-000002
实验结果:载体材料PVP K30用量为地榆皂苷Ⅱ4-30倍时均能得到质量较好的固体分散体:药物溶解度提高至0.594mg/mL,溶出度达到64%以上;PVP K30用量为地榆皂苷Ⅱ4-10倍时,制剂质量得到了进一步优化,药物溶解度提高至0.4mg/mL以上,溶出度不低于70%;其中,在地榆皂苷Ⅱ:PVP K30质量比为1:8的条件下,制备得到的固体分散体溶解度及溶出度最高。Experimental results: When the amount of PVP K30 as carrier material is 4-30 times of saponin, a good solid dispersion can be obtained: the solubility of the drug is increased to 0.594 mg/mL, the dissolution is more than 64%; the amount of PVP K30 is mantle. When the saponin II is 4-10 times, the quality of the preparation is further optimized, the solubility of the drug is increased to 0.4 mg/mL or more, and the dissolution is not less than 70%; wherein the mass ratio of the saponin II: PVP K30 is 1:8. The prepared solid dispersion has the highest solubility and dissolution.
实验例3地榆皂苷Ⅱ固体分散体的药效实验Experimental Example 3 Efficacy Experiment of Diquat Saponin II Solid Dispersion
1、实验材料、试剂、仪器1. Experimental materials, reagents and instruments
1.1、受试药物:地榆皂苷Ⅱ固体分散体(根据实施例2制备)、地榆皂苷Ⅱ。1.1. Test drug: saponin II solid dispersion (prepared according to Example 2), saponin II.
1.2、工具药物:环磷酰胺。1.2, tool drugs: cyclophosphamide.
1.3、实验动物KM-小鼠:18.5~22.5g。1.3. Experimental animal KM-mouse: 18.5-22.5 g.
1.4、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, experimental equipment: automatic blood cell analyzer; BS-600L electronic balance: specifications: 600g / 0.1g, Shanghai Yousheng Weighing Apparatus Co., Ltd.
2、统计方法2, statistical methods
用SPSS 17.0软件进行统计分析。数据以均数±标准差(
Figure PCTCN2017072230-appb-000003
)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。
Statistical analysis was performed using SPSS 17.0 software. Data in mean ± standard deviation (
Figure PCTCN2017072230-appb-000003
), one-way analysis of variance was used between groups, LSD test was performed between groups with variance, and Tamhane's T2 test was performed for those with irregular variance.
3、实验方法3. Experimental methods
3.1、实验动物分组及模型制备3.1, experimental animal grouping and model preparation
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固体分散体组,分别配制成0.5mg·kg-1,5mg·kg-1,10mg·kg-1混悬液,临用前配制;地榆皂苷Ⅱ组,配制成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。 All animals were fed ad libitum for 1 week and were randomly divided into: blank group; model group; saponin II solid dispersion group, which were formulated into 0.5 mg·kg -1 , 5 mg·kg -1 , 10 mg·kg -1 . The suspension was prepared before use; the saponin II group was formulated into a 10 mg·kg -1 suspension and prepared before use. On the first day of the experiment, except for the blank group, 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.
3.2、给药3.2, administration
各实验组自实验第1天开始按剂量、灌胃给予相应药物,空白组和模型组小鼠灌胃给药等体积生理盐水,连续7天。The experimental groups were given the corresponding drugs by dose and gavage from the first day of the experiment. The mice in the blank group and the model group were intragastrically administered with the same volume of normal saline for 7 consecutive days.
3.3、标本采集3.3, specimen collection
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。On the 8th day of the experiment, blood was taken from the eye of each experimental group and collected with a 0.5 ml EP tube containing EDTA anticoagulant.
3.4、检测指标及方法3.4. Test indicators and methods
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。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.
4、实验结果4. Experimental results
表3 各实验组小鼠外周血象检测结果Table 3 Results of peripheral blood test results of mice in each experimental group
Figure PCTCN2017072230-appb-000004
Figure PCTCN2017072230-appb-000004
注:与模型组比较,*P<0.05,**P<0.01;与地榆皂苷Ⅱ组比较,△P<0.05,△△P<0.01。 Note: Compared with the model group, *P<0.05, **P<0.01; compared with the saponin II group, △P<0.05, △△P<0.01.
由表3可知,与模型组比较,地榆皂苷Ⅱ固体分散体各组小鼠外周血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固体分散体各组小鼠外周血WBC、RBC、PLT数量均有显著升高(P<0.05)。As can be seen from Table 3, compared with the model group, the number of WBC, RBC and PLT in the peripheral blood of each group of the saponin II solid dispersion was significantly increased (P<0.05), and there was no significant difference in the saponin II group. Compared with the saponin II group, the number of WBC, RBC and PLT in the peripheral blood of the mice in the solid dispersion of saponin II was significantly increased (P<0.05).
表4 各实验组小鼠外周血象检测结果Table 4 Results of peripheral blood test results of mice in each experimental group
Figure PCTCN2017072230-appb-000005
Figure PCTCN2017072230-appb-000005
注:与模型组比较,*P<0.05,**P<0.01;与地榆皂苷Ⅱ组比较,△P<0.05,△△P<0.01。Note: Compared with the model group, *P<0.05, **P<0.01; compared with the saponin II group, △P<0.05, △△P<0.01.
由表4可知,与模型组比较,地榆皂苷Ⅱ固体分散体组小鼠外周血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固体分散体组小鼠外周血NEUT和HGB数量均有显著升高(P<0.05)。As can be seen from Table 4, compared with the model group, the NEUT and HGB numbers in the peripheral blood of the saponin II solid dispersion group were significantly increased (P<0.05), and there was no significant difference in the saponin II group; Compared with the saponin II group, the NEUT and HGB numbers in the peripheral blood of the saponin II solid dispersion group were significantly increased (P<0.05).
以上实验结果表明,根据本发明制剂处方将地榆皂苷Ⅱ制备成固体分散体后,可显著提高药物升高血细胞水平的作用,能有效防治骨髓抑制。 The above experimental results show that the preparation of the saponin II as a solid dispersion according to the formulation of the present invention can significantly improve the blood cell level of the drug, and can effectively prevent bone marrow suppression.

Claims (12)

  1. 一种地榆皂苷Ⅱ固体分散体,其特征是:它是由下述重量配比的原辅料制备而成:地榆皂苷Ⅱ 1份、聚维酮4~30份。A solid dispersion of saponin II characterized in that it is prepared from the following raw materials by weight ratio: 1 part of saponin II and 4-30 parts of povidone.
  2. 如权利要求1所述的固体分散体,其特征是:它是由下述重量配比的原辅料制备而成:地榆皂苷Ⅱ 1份、聚维酮4~10份。The solid dispersion according to claim 1, which is prepared from a raw material of the following weight ratio: 1 part of saponin II and 4 to 10 parts of povidone.
  3. 如权利要求2所述的固体分散体,其特征是:它是由下述重量配比的原辅料制备而成:地榆皂苷Ⅱ 1份、聚维酮8份。The solid dispersion according to claim 2, which is prepared from the following raw materials by weight ratio: 1 part of saponin II and 8 parts of povidone.
  4. 如权利要求1~3任意一项所述的固体分散体,其特征是:所述的聚维酮为PVP K30。The solid dispersion according to any one of claims 1 to 3, wherein the povidone is PVP K30.
  5. 一种权利要求1~4任意一项所述固体分散体的制备方法,其特征是:包括如下步骤:A method for preparing a solid dispersion according to any one of claims 1 to 4, which comprises the steps of:
    a、分别将地榆皂苷Ⅱ、聚维酮溶解于有机溶剂中,得到地榆皂苷Ⅱ溶液、聚维酮溶液,备用;a. Dissolving saponin II and povidone in an organic solvent respectively to obtain a solution of saponin II and povidone, and use;
    b、将地榆皂苷Ⅱ溶液加入到聚维酮溶液中,混合均匀;b, adding the saponin II solution to the povidone solution, and mixing uniformly;
    c、除去b步骤所得混合物中的有机溶剂,粉碎,即得。c. The organic solvent in the mixture obtained in the step b is removed and pulverized.
  6. 如权利要求5所述的制备方法,其特征是:a步骤所述的有机溶剂为无水乙醇。The preparation method according to claim 5, wherein the organic solvent in the step a is anhydrous ethanol.
  7. 如权利要求5或6所述的制备方法,其特征是:a步骤所述的地榆皂苷Ⅱ溶液中地榆皂苷Ⅱ与溶剂的质量体积比为1:100;所述的聚维酮溶液中聚维酮与溶剂的质量体积比为(1:4)~(5:1)。The preparation method according to claim 5 or 6, wherein the mass ratio of the saponin II to the solvent in the solution of the saponin II in the step a is 1:100; in the povidone solution The mass to volume ratio of povidone to solvent is (1:4) to (5:1).
  8. 如权利要求5所述的制备方法,其特征是:c步骤将混合物置于60℃水浴锅上蒸干溶剂。The process according to claim 5, wherein the step c is carried out by placing the mixture in a 60 ° C water bath and evaporating the solvent.
  9. 权利要求1~4任意一项所述固体分散体在制备升高血细胞、血红蛋 白数量的药物中的用途。The solid dispersion according to any one of claims 1 to 4 for preparing elevated blood cells and blood red eggs Use in white quantities of drugs.
  10. 权利要求1~4任意一项所述固体分散体在制备治疗和/或预防骨髓抑制的药物的用途。Use of the solid dispersion according to any one of claims 1 to 4 for the preparation of a medicament for the treatment and/or prevention of myelosuppression.
  11. 一种升高血细胞、血红蛋白数量的方法,其特征是:使用权利要求1~4任意一项所述固体分散体。A method for raising the number of blood cells and hemoglobin, which comprises using the solid dispersion according to any one of claims 1 to 4.
  12. 一种治疗和/或预防骨髓抑制的方法,其特征是:使用权利要求1~4任意一项所述固体分散体。 A method for treating and/or preventing myelosuppression, which comprises using the solid dispersion according to any one of claims 1 to 4.
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CN106539763A (en) * 2015-09-18 2017-03-29 四川英路维特医药科技有限公司 II solid dispersion of a kind of sanguisorbin and preparation method thereof

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