WO2010069139A1

WO2010069139A1 - Pharmaceutical composition and preparation method thereof

Info

Publication number: WO2010069139A1
Application number: PCT/CN2009/001467
Authority: WO
Inventors: 郝守祝; 焦玉焕
Original assignee: 北京世纪博康医药科技有限公司
Priority date: 2008-12-17
Filing date: 2009-12-16
Publication date: 2010-06-24
Also published as: CN101480403B; CN101480403A

Abstract

The present invention discloses a pharmaceutical composition containing a complex of cycloartenyl ferulate and 24-methylene cycloartanyl ferulate, phospholipids, cholic acids and/or salts thereof. The water-solubility and the stability of the complex of cycloartenyl ferulate and 24-methylene cycloartanyl ferulate have been effectively improved by being made into the pharmaceutical composition of the present invention. And the particle diameter and the stability of the said pharmaceutical composition are superior to that of the existing products. Furthermore, the present invention provides an injectable fluid, an injectable lyophilized powder and a kit containing the pharmaceutical composition as well as the preparation methods thereof.

Description

一种药用组合物及其制备方法 Pharmaceutical composition and preparation method thereof

技术领域 Technical field

本发明涉及一种药用组合物，具体地说本发明公开了一种供注射用的药物组合物及其制备方法，属于医药领域。 The present invention relates to a pharmaceutical composition, and more particularly to a pharmaceutical composition for injection and a method for preparing the same, which belong to the field of medicine.

背景技术 Background technique

谷维素是以环木菠萝醇类为主体的阿魏酸酯和醇类的阿魏酸酯所组成的一种天然混合物，外观为白色至淡黄色晶体粉末、无味、有特异香味。谷维素主要存在于米糠油及其油脚中，在米糠油谷维素中，环木菠萝醇类阿魏酸酯含量约为 70〜80%。经过长期研究，研究人员发现谷维素具有多种生理功能。主要包括：降低血脂、降低胆固醇的吸收、降低血清胆固醇、防止脂质氧化和预防心血管疾病。除此之外，谷维素还可以缓和女性进入更年期之后的各种身体障碍状态和自律神经失调症，改善间脑视床底部功能失调。 Oryzanol is a natural mixture of ferulic acid esters and ferulic acid esters of alcohols, which are mainly composed of white to pale yellow crystal powder, odorless and specific flavor. Oryzanol is mainly found in rice bran oil and its oil feet. In the rice bran oil, the content of ferulic acid ferulate is about 70~80%. After long-term research, the researchers found that oryzanol has many physiological functions. It mainly includes: lowering blood lipids, lowering cholesterol absorption, lowering serum cholesterol, preventing lipid oxidation and preventing cardiovascular diseases. In addition, oryzanol can also alleviate the various physical disorders and autonomic nervous disorders after menopause, and improve the dysfunction of the bottom of the cerebral ventricle.

在谷维素应用中存在的问题是谷维素难溶于水、易氧化，这导致在很难将谷维素做成一种稳定的制剂。谷维素中含有很多活性成分，当通过技术手段分离出单一成分时，溶解度和稳定性问题变得更为严峻。极低的溶解度和易氧化的特点不仅导致实际应用时吸收率低，同时也导致在生产中质量难以控制。为了解决这些问题，本领域研究人员进行了一定的摸索。中国专利 CN123428公开了一种谷维素的植物油溶制剂，提高了生物利用度，临床效果优于一般片剂。但是由.于油溶制剂临床应用时必须肌肉注射，病人痛苦感比较强，且易导致肌肉结块。同时油溶制剂起效缓慢，需要大约一个月的时间进行持续的肌肉注射。中国专利申请 2007100156403 为了解决采用植物油制剂带来的易沉淀、不稳定问题，采用油酸乙酯代替植物油做成谷维素的油溶制剂，从而达到稳定、不易产生沉淀的效果。但是该发明依旧没有从本质上解决油溶制剂带来的肌肉注射易导致病人痛苦、肌肉结块、依从性差的弊端。中国专利申请 2004100945568公开了谷维素原料与胆固醇、磷脂结合制备为脂质体的技术方案，应用该发明技术方案的制剂克服谷维素口服效果差、生物利用率低的问题。但是制备脂质体是一个成本很高的工艺流程，生产过程质量不易控制，无法获得质量稳定可靠的谷维素脂质体。专利 CN100386082C公开了谷维素的一种注射制剂，该发明通过将谷维素与表面活性剂、助溶剂同时结合第二表面活性剂的方法，获得了一种注射制剂。但是该方案获得的注射剂为注射乳剂，必须包括油相，而且制备的乳液粒径比较难控制、稳定性相对不佳，在制备时需乳均机等设备，操作较为复杂、成本高。 A problem in the application of oryzanol is that oryzanol is hardly soluble in water and easily oxidized, which makes it difficult to make oryzanol into a stable preparation. Oryzanol contains many active ingredients, and when a single component is separated by technical means, the solubility and stability problems become more severe. The extremely low solubility and oxidative characteristics not only result in low absorption rates in practical applications, but also lead to difficult quality control in production. In order to solve these problems, researchers in the field have made some groping. Chinese patent CN123428 discloses a vegetable oil-soluble preparation of oryzanol, which improves bioavailability and has a clinical effect superior to that of a general tablet. However, it must be injected intramuscularly in the clinical application of oil-soluble preparations, and the patient feels more painful and easily causes muscle agglomeration. At the same time, the oil-soluble preparation is slow to take, and it takes about one month for continuous intramuscular injection. Chinese Patent Application 2007100156403 In order to solve the problem of easy precipitation and instability caused by the use of vegetable oil preparations, ethyl oleate is used instead of vegetable oil to prepare an oil-soluble preparation of oryzanol, thereby achieving a stable and less prone to precipitation. However, the invention still does not substantially solve the disadvantages of intramuscular injection caused by oil-soluble preparations, which may lead to patient suffering, muscle agglomeration, and poor compliance. Chinese Patent Application No. 2004100945568 discloses a technical solution for preparing a oryzanol raw material in combination with cholesterol and a phospholipid to prepare a liposome, and the preparation of the technical solution of the present invention overcomes the problem of poor oral efficacy and low bioavailability of oryzanol. However, the preparation of liposomes is a costly process, the quality of the production process is not easy to control, and the stable or reliable oryzanol liposomes cannot be obtained. Patent CN100386082C discloses an injection preparation of oryzanol which is obtained by a method in which oryzanol is simultaneously combined with a surfactant and a co-solvent to a second surfactant. However, the injection obtained by the solution is an injection emulsion, which must include an oil phase, and the prepared emulsion has a relatively difficult particle size control and relatively poor stability. In the preparation, a milk homogenizer or the like is required, and the operation is complicated and costly.

因此，现有技术中仍需要一种制备工艺简单、使用方便、治疗效果良好、副作用小的环木菠萝醇类阿魏酸酯注射剂。 Therefore, there is still a need in the prior art for a ring having a simple preparation process, convenient use, good therapeutic effect, and small side effects. Wood pineapple alcohol ferulic acid ester injection.

发明内容 Summary of the invention

本发明中， "注射剂"是指可用于静脉输注或推注的制剂，包括但不限于注射液、输液、冻干粉针等。 In the present invention, "injection" means a preparation which can be used for intravenous infusion or bolus injection, including but not limited to injection, infusion, lyophilized powder, and the like.

本发明中， "冻干制剂"是指任何经过冻干，即水溶液的冷冻干燥得到的具体物质，水溶液中可以含有非水溶剂。 In the present invention, the "lyophilized preparation" means any specific substance obtained by freeze-drying, that is, lyophilization of an aqueous solution, and the aqueous solution may contain a nonaqueous solvent.

本发明中， "药物组合物"是指任何足以使其有作为药物产品实用性和稳定性的组合物形太 ' 本发明中， "有效治疗量"或 "治疗有效量"是指在某种程度上减轻被治疗病症的一种或多种症状的被给药的量。即将本发明组合物应用的时候针对所对应病症，起到了治疗效果的药物组合物中的复合物的量。 In the present invention, "pharmaceutical composition" means any composition which is sufficient to make it useful and stable as a pharmaceutical product. In the present invention, "effective therapeutic amount" or "therapeutically effective amount" means in some kind The amount administered to alleviate one or more symptoms of the condition being treated. The amount of the complex in the pharmaceutical composition which provides a therapeutic effect against the corresponding condition when the composition of the present invention is applied.

本发明中， "药学上可接受的"是指用于药物组合物的成分不导致不可接受的药理活性丧失或者不可接受的副作用。 In the present invention, "pharmaceutically acceptable" means that the ingredients used in the pharmaceutical composition do not cause unacceptable loss of pharmacological activity or unacceptable side effects.

在发明人的前期研究中，通过将谷维素所含成分进行有效的分离，获得了环木菠萝烯醇阿魏酸酯和 24-亚甲基环木菠萝醇阿魏酸酯的含量不低于 90%的复合物，并对此复合物申请了专利（中国专利申请 200810097493.X ) , 此专利申请被全文引入本文，作为参考。随后申请人对其实际应用进行了研究，证实其在治疗植物神经失调症、更年期综合症、原发性痛经、经前紧张症、周期性精神病、血管性头痛、头部外伤综合症、胃肠神经失调症、高脂血症等方面均有广泛的应用价值。本发明中所采用的活性成分为环木菠萝烯醇阿魏酸酯和 24-亚甲基环木菠萝醇阿魏酸酯组合物，其中这两种物质的含量之和占总成分的 90%以上，以重量百分比计。在本申请中，称以上组合物为环木菠萝烯醇阿魏酸酯和 24-亚甲基环木菠萝醇阿魏酸酯复合物。本发明的环木菠萝烯醇阿魏酸酯和 24-亚甲基环木菠萝醇阿魏酸酯复合物可以按中国专利申请 200810097493.x所公开方法进行制备，也可以采用现有技术公开的其它方法进行制备。在研究该复合物制剂过程中，发明人意外地发现，在制剂中加入一定量的磷脂与胆汁酸和 /或其盐可以显著地提高该复合物在水中的溶解度，形成澄清、性质稳定的溶液。将磷脂类物质和胆汁酸类物质混合使用，能够显著增加环木菠萝烯醇阿魏酸酯和 24-亚甲基环木菠萝醇阿魏酸酯复合物在水中的溶解度，其效果远远好于二者单独使用，可大大减少副作用、并且节约成本。该组合物为澄清胶体溶液，其中没有油相成分，也不形成乳剂，粒径在 20nm 以下，接近真溶液，有效地解决了乳剂粒径难以控制、不稳定、成本高、操作复杂的问题。所制备的组合物，在室温条件下能保持澄清 8小时以上。所得组合物在使用前不需要采用有机溶媒稀释，直接加入注射用水或葡萄糖注射液、生理盐水即可使用，简化了操作。同时本发明公开的冻千制剂最大限度地减少了或者避免了吐温的使用，防止了潜在的溶血问题。相对于现有的解决方案，本发明辅料用量明显减少，降低了药物的副作用。 In the preliminary study of the inventors, by effectively separating the components contained in oryzanol, the content of the cycloartenol ferulate and the 24-methylenecyclo-bambolanol ferulate was not less than 90. % of the composite, and a patent for this composite (Chinese Patent Application No. 200810097493.X), which is incorporated herein in its entirety by reference. Subsequently, the applicant studied its practical application and confirmed that it is in the treatment of autonomic dysfunction, menopausal syndrome, primary dysmenorrhea, premenstrual tension, periodic psychosis, vascular headache, head trauma syndrome, gastrointestinal Neurological disorders, hyperlipidemia and other aspects have a wide range of applications. The active ingredients used in the present invention are cycloartenol ferulate and 24-methylenecyclo-cinnamol ferulate composition, wherein the sum of the two substances accounts for 90% of the total composition. Above, in weight percent. In the present application, the above composition is referred to as cycloartenol ferulate and 24-methylenecyclo-coniferin ferulate complex. The cycloartenol ferulate and the 24-methylene cyclo-bambolan ferulate complex of the present invention can be prepared according to the method disclosed in Chinese Patent Application No. 200810097493.x, or can be disclosed by the prior art. Other methods are used for the preparation. In the study of the complex preparation, the inventors have unexpectedly discovered that the addition of a certain amount of phospholipids and bile acids and/or their salts to the formulation can significantly increase the solubility of the complex in water, forming a clear, stable solution. . The combination of phospholipids and bile acids can significantly increase the solubility of cycloartenol ferulate and 24-methylene cyclopentyl alcohol ferulate complex in water, and the effect is far better. When used alone, it can greatly reduce side effects and save costs. The composition is a clarified colloidal solution, which has no oil phase component and does not form an emulsion. The particle size is below 20 nm, which is close to the true solution, and effectively solves the problem that the emulsion particle size is difficult to control, unstable, high in cost, and complicated in operation. The prepared composition was kept clear for more than 8 hours at room temperature. The resulting composition does not require organic use prior to use. The solvent is diluted and directly added to the water for injection or glucose injection, and the physiological saline can be used, which simplifies the operation. At the same time, the disclosed frozen preparation minimizes or avoids the use of Tween and prevents potential hemolysis problems. Compared with the existing solutions, the amount of the auxiliary materials of the invention is significantly reduced, and the side effects of the drugs are reduced.

本发明一方面提供了一种药物组合物，包括环木菠萝烯醇阿魏酸酯和 24-亚甲基环木菠萝醇阿魏酸酯复合物、磷脂、以及胆汁酸和 /或其盐。其中，环木菠萝烯醇阿魏酸酯和 24-亚甲基环木菠萝醇阿魏酸酯复合物、胆汁酸和 /或其盐、磷脂质量比可以是 1 : 1-100： 1-500；优选的，复合物、胆汁酸和 /或其盐、磷脂质量比可以是 1 : 1-50： 1-100；更优选的，复合物、胆汁酸和 /或其盐、磷脂质量比可以是 1 : 5-40： 5-80。该组合物可以是固体状态，还可以是' 液体。其中的液体还可以是胶束溶液形式。 In one aspect, the invention provides a pharmaceutical composition comprising a cycloartipenol ferulate and a 24-methylene cyclopentanol ferulate complex, a phospholipid, and a bile acid and/or a salt thereof. Wherein, the mass ratio of the cycloartenol ferulate and the 24-methylene cyclopentanol ferulate complex, the bile acid and/or the salt thereof, and the phospholipid may be 1: 1-100: 1-500 Preferably, the mass ratio of the complex, the bile acid and/or the salt thereof, and the phospholipid may be 1: 1-50: 1-100; more preferably, the mass ratio of the complex, the bile acid and/or the salt thereof, and the phospholipid may be 1 : 5-40: 5-80. The composition may be in a solid state and may also be a liquid. The liquid therein may also be in the form of a micellar solution.

另一方面，本发明还提供了一种冻干粉针剂，其含有治疗有效量的环木莰萝烯醇阿魏酸酯和 24-亚甲基环木菠萝醇阿魏酸酯复合物、胆汁酸和 /或其盐、以及磷脂，其中，所述环木菠萝烯醇阿魏酸酯和 24-亚甲基环木菠萝醇阿魏酸酯复合物中环木菠萝烯醇阿魏酸酯和 24-亚甲基环木菠萝醇阿魏酸酯质量百分含量不低于 90%。其中，环木菠萝烯醇阿魏酸酯和 24-亚甲基环木菠萝醇阿魏酸酯复合物、胆汁酸和 /或其盐、磷脂质量比可以是 1 : 1-100： 1-500；优选的，复合物、胆汁酸和 /或其盐、磷脂质量比可以是 1 : 1-50： 1-100；更优选的，复合物、胆汁酸和 /或其盐、磷脂质量比可以是 1 : 5-40： 5-80。 In another aspect, the present invention provides a lyophilized powder injection comprising a therapeutically effective amount of cyclocarolene ferulate ferulic acid ester and 24-methylene cyclo-coniferin ferulate complex, bile An acid and/or a salt thereof, and a phospholipid, wherein the cycloartipenol ferulate and the 24-methylenecyclopentanol ferulic acid ester complex are cyclopentalenol ferulate and 24 - The mass percentage of methylene ringwood pineapple alcohol ferulate is not less than 90%. Wherein, the mass ratio of the cycloartenol ferulate and the 24-methylene cyclopentanol ferulate complex, the bile acid and/or the salt thereof, and the phospholipid may be 1: 1-100: 1-500 Preferably, the mass ratio of the complex, the bile acid and/or the salt thereof, and the phospholipid may be 1: 1-50: 1-100; more preferably, the mass ratio of the complex, the bile acid and/or the salt thereof, and the phospholipid may be 1 : 5-40: 5-80.

本发明还提供了一种试剂盒，包含两种单位制剂，其中第一种单位制剂中包括治疗有效量的环木菠萝烯醇阿魏酸酯和 24-亚甲基环木菠萝醇阿魏酸酯复合物、胆汁酸和 /或其盐、以及磷脂；第二种单位制剂为溶剂。第一单位制剂中的环木菠萝烯醇阿魏酸酯和 24-亚甲基环木菠萝醇阿魏酸酯复合物、胆汁酸和 /或其盐、磷脂质量比可以是 1 : 1-100： 1-500；优选的，复合物、胆汁酸和 /或其盐、磷脂质量比可以是 1 : 1-50： 1-100；更优选的，复合物、胆汁酸和 /或其盐、磷脂质量比可以是 1 : 5-40： 5-80。第二种制剂中的溶剂为水溶液或非水溶液，优选水溶液，例如是注射用水、含有醇的水溶液，或含有注射剂常规用辅料的水溶液。其中所述注射剂常规用辅料选自等张调节剂、稳定剂、抗氧剂、 PH调节剂、防腐剂、赋形剂、增溶剂中的一种和 /或一种以上的混合物。试剂盒中还可以包括指导如何使用的说明书。 The invention also provides a kit comprising two unit preparations, wherein the first unit preparation comprises a therapeutically effective amount of cycloartenol ferulate and 24-methylenecyclo-coniferin ferulic acid An ester complex, a bile acid and/or a salt thereof, and a phospholipid; the second unit preparation is a solvent. The mass ratio of the cycloartipenol ferulate and the 24-methylenecyclopentanol ferulate complex, the bile acid and/or its salt, and the phospholipid in the first unit preparation may be 1: 1-100. Preferably, the mass ratio of the complex, the bile acid and/or its salt, and the phospholipid may be 1: 1-50: 1-100; more preferably, the complex, the bile acid and/or its salt, the phospholipid The mass ratio can be 1: 5-40: 5-80. The solvent in the second preparation is an aqueous solution or a non-aqueous solution, preferably an aqueous solution, for example, water for injection, an aqueous solution containing an alcohol, or an aqueous solution containing a conventional excipient for injection. Wherein the auxiliary for injection is conventionally selected from the group consisting of an isotonic regulator, a stabilizer, an antioxidant, a pH adjuster, a preservative, an excipient, a solubilizing agent, and/or a mixture of more than one. Instructions for how to use it can also be included in the kit.

本发明还进一步地提供了以上制剂盒的使用方法，包括将第一种制剂和第二种制剂混合的步骤。 The present invention still further provides a method of using the above kit, comprising the step of mixing the first formulation with the second formulation.

本发明所用的磷脂可以选自大豆磷脂、蛋黄磷脂、大豆鞘磷脂、蛋黄鞘磯脂、氢化大豆憐脂、氢化蛋黄磷脂、磷脂酰胆碱、磷脂酰乙醇胺、磷脂酰丝氨酸、磷脂酰甘油、磷脂酰肌醇、二棕榈磷脂酰胆碱、二棕榈磷脂酰乙醇胺、二硬脂磷脂酰胆碱、二棕榈磷脂酰甘油脂、二棕榈磷脂酰丝氨酸、二肉豆蔻酰磷脂酰胆碱、二肉豆蔻酰磷脂酰甘油、二肉豆蔻酰磷脂酰乙醇胺、二亚油酰磷脂酰胆碱、二亚油酸甘油脂磷脂酰胆碱、二亚油酸甘油脂磷脂酰乙醇胺、二亚油酸甘油脂磷脂酰甘油的一种和 /或一种以上的混合物。优选大豆磷脂、蛋黄磷脂、大豆鞘磷脂、蛋黄鞘磷脂、氢化大豆磷脂、氢化蛋黄磷脂、磷脂酰胆碱、磷脂酰乙醇胺、磷脂酰丝氨酸、磷脂酰甘油、磷脂酰肌醇，最优选大豆磷脂、蛋黄磷脂、磷脂酰胆碱、磷脂酰乙醇胺。 The phospholipid used in the present invention may be selected from the group consisting of soybean phospholipid, egg yolk phospholipid, soybean sphingomyelin, egg yolk sheath, sulphate, hydrogenated egg yolk phospholipid, phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylglycerol, phospholipid Acylsitol, dipalmitoylphosphatidylcholine, dipalmitoylphosphatidylethanolamine, distearylphosphatidylcholine, dipalmitophosphatidylglyceride, Dipalmitoylphosphorylserine, dimyristoylphosphatidylcholine, dimyristoylphosphatidylglycerol, dimyristoylphosphatidylethanolamine, dilinoleoylphosphatidylcholine, dilinoleic acid glycerolipid phosphatidylcholine And one or more than one mixture of dilinoleic acid glycerylphosphatidylethanolamine, dilinoleic acid glycerol phosphatidylglycerol. Preferred are soybean phospholipids, egg yolk phospholipids, soybean sphingomyelin, egg sphingomyelin, hydrogenated soybean phospholipids, hydrogenated egg yolk phospholipids, phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylglycerol, phosphatidylinositol, most preferably soybean phospholipids, Egg yolk phospholipid, phosphatidylcholine, phosphatidylethanolamine.

胆汁酸和 /或其盐加入后可以显著增加本发明组合物的稳定性。本发明所用的胆汁酸选自游离胆汁酸、结合胆汁酸或其混合物，所述的胆汁酸盐是胆汁酸成盐后的产物。其中，胆汁酸包括游离胆汁酸、' 结合胆汁酸或二者的混合物，游离胆汁酸包括胆酸、石胆酸、去氧胆酸、鹅去氧胆酸、熊去氧胆酸、猪去氧胆酸等，优选为胆酸、去氧胆酸、鹅去氧胆酸、猪去氧胆酸；结合胆汁酸为上述游离胆汁酸中的羧醛与甘氨酸（H₂NCH₂C00H)或牛磺酸（H₂NCH₂CH₂S0₃H) 或其他含有氨基的化合物中的氨基形成酰胺键后的产物，优选为甘氨胆酸、甘氨去氧胆酸、甘氨鵝去氧胆酸、甘氨熊去氧胆酸、牛磺胆酸、牛磺去氧胆酸、牛磺鹅去氧胆酸、牛磺熊去氧胆酸；胆汁酸盐包括但不限于钾盐、钠盐、钙盐、镁盐、锌盐、硒盐、铁盐等，优选为钠盐和钾盐。 The addition of bile acids and/or their salts can significantly increase the stability of the compositions of the invention. The bile acid used in the present invention is selected from the group consisting of free bile acids, bound bile acids or mixtures thereof, which are products of bile acids after salt formation. Wherein, bile acids include free bile acids, 'bound bile acids or a mixture of the two, free bile acids including cholic acid, lithocholic acid, deoxycholic acid, chenodeoxycholic acid, ursodeoxycholic acid, hyodeoxycholic acid Acid or the like, preferably cholic acid, deoxycholic acid, chenodeoxycholic acid, hyodeoxycholic acid; combined bile acid is the carboxaldehyde in the above free bile acid with glycine (H ₂ NCH ₂ C00H) or taurine ( H ₂ NCH ₂ CH ₂ S0 ₃ H) or an amino group-containing compound in which the amino group forms an amide bond, preferably glycocholic acid, glycodeoxycholic acid, glycine chenodeoxycholic acid, glycine Ursodeoxycholic acid, taurocholic acid, taurodeoxycholic acid, taurochenodeoxycholic acid, tauroursodeoxycholic acid; bile salts include, but are not limited to, potassium salts, sodium salts, calcium salts, A magnesium salt, a zinc salt, a selenium salt, an iron salt or the like is preferably a sodium salt and a potassium salt.

同时，本发明的组合物、冻干粉针、试剂盒中的制剂还可任选地含有其它辅料，包括但不限于助溶剂、等张调节剂、稳定剂、抗氧剂、 PH 调节剂、防腐剂、赋形剂中的一种和 /或一种以上的混合物，可以提高药物的稳定性，有利于药品质量的控制。在下述辅料用量上，可以根据实际应用进行调节。 Meanwhile, the composition of the present invention, the lyophilized powder needle, and the preparation in the kit may optionally further contain other excipients, including but not limited to a solubilizer, an isotonic regulator, a stabilizer, an antioxidant, a pH adjuster, One of the preservatives, excipients and/or more than one mixture can improve the stability of the drug and facilitate the control of the quality of the drug. In the following amount of auxiliary materials, it can be adjusted according to the actual application.

所述的助溶剂包括但不限于吐温、聚乙二醇、丙二醇、甘氨酸，优选甘氨酸。 The cosolvents include, but are not limited to, Tween, polyethylene glycol, propylene glycol, glycine, preferably glycine.

所述的等张调节剂包括但不限于 0.9%氯化钠溶液、 5%葡萄糖溶液，优选 5%葡萄糖溶液。所述的稳定剂包括但不限于亚硫酸钠、亚硫酸氢钠、焦亚硫酸钠、硫代硫酸钠、硫脲、维生素 C、叔丁基对羟基茴香醚、二丁基苯酚、没食子酸丙酯、生育酚、甲硫氨酸、盐酸半胱氨酸、乙酰半胱氨酸、 N-乙酰 -DL-甲硫氨酸、抗坏血酸棕榈酸酯、乙二胺四乙酸、乙二胺四乙酸二钠中的一种或一种以上的混合物，优选亚硫酸氢钠、维生素（：、没食子酸丙酯、抗坏血酸棕榈酸酯中的一种或其任意混合物，优选维生素 C。 The isotonicity adjusting agents include, but are not limited to, 0.9% sodium chloride solution, 5% dextrose solution, preferably 5% dextrose solution. The stabilizers include, but are not limited to, sodium sulfite, sodium hydrogen sulfite, sodium metabisulfite, sodium thiosulfate, thiourea, vitamin C, t-butyl p-hydroxyanisole, dibutyl phenol, propyl gallate, tocopherol , one of methionine, cysteine hydrochloride, acetylcysteine, N-acetyl-DL-methionine, ascorbyl palmitate, ethylenediaminetetraacetic acid, disodium edetate One or more mixtures, preferably one of sodium hydrogen sulfite, vitamins (:, propyl gallate, ascorbyl palmitate or any mixture thereof, preferably vitamin C.

所述的抗氧剂包括但不限于无水亚硫酸钠、焦亚硫酸钠、亚硫酸氢钠、硫代硫酸钠、叔丁基对羟基茴香醚，优选无水亚硫酸钠、焦亚硫酸钠、亚硫酸氢钠，最优选无水亚硫酸钠。 The antioxidants include, but are not limited to, anhydrous sodium sulfite, sodium metabisulfite, sodium hydrogen sulfite, sodium thiosulfate, t-butyl p-hydroxyanisole, preferably anhydrous sodium sulfite, sodium metabisulfite, sodium hydrogen sulfite, most preferably. Anhydrous sodium sulfite.

所述的 PH调节剂包括但不限于盐酸、枸橼酸、酒石酸、磷酸、偏磷酸、聚偏磷酸、碳酸、氢氧化钠、氢氧化钾、枸橼酸钠、枸橼酸钾、碳酸氢钠、碳酸氢钾、碳酸胺、磷酸氢二钠、磷酸氢二钾、乙醇胺、二乙醇胺、三乙醇胺、 1，2-已二胺、碳酸钠、酒石酸钠钾、偏磷酸钾、聚偏磷酸钾、偏磷酸钠中的一种或几种，优选氢氧化钠、碳酸氢钠、盐酸、磷酸，最优选氢氧化钠、碳酸氢钠。 The pH adjusting agent includes, but not limited to, hydrochloric acid, citric acid, tartaric acid, phosphoric acid, metaphosphoric acid, polymetaphosphoric acid, carbonic acid, sodium hydroxide, potassium hydroxide, sodium citrate, potassium citrate, sodium hydrogencarbonate. , potassium bicarbonate, amine carbonate, hydrogen phosphate II One or more of sodium, dipotassium hydrogen phosphate, ethanolamine, diethanolamine, triethanolamine, 1,2-hexanediamine, sodium carbonate, potassium sodium tartrate, potassium metaphosphate, potassium polymetaphosphate, sodium metaphosphate, Sodium hydroxide, sodium hydrogencarbonate, hydrochloric acid, phosphoric acid are preferred, and sodium hydroxide or sodium hydrogencarbonate is most preferred.

所述的防腐剂包括但不限于苯酚、甲酚、三叔丁醇、苯甲醇、尼泊金中的一种或几种，优选甲酚、苯甲醇、尼泊金，最优选尼泊金。 The preservatives include, but are not limited to, one or more of phenol, cresol, tri-tert-butanol, benzyl alcohol, and paraben, preferably cresol, benzyl alcohol, paraben, and most preferably paraben.

所述的赋形剂包括但不限于甘露醇、乳糖、葡萄糖、山梨醇、氯化钠、水解明胶、右旋糖酐、蔗糖、甘氨酸、聚乙烯吡咯垸酮等中的一种或几种，优选甘露醇、乳糖、甘氨酸、葡萄糖、山梨醇或其任意混合物，更优选甘露醇、甘氨酸或其混合物，最优选甘露醇。 The excipient includes, but is not limited to, one or more of mannitol, lactose, glucose, sorbitol, sodium chloride, hydrolyzed gelatin, dextran, sucrose, glycine, polyvinylpyrrolidone, etc., preferably mannitol Lactose, glycine, glucose, sorbitol or any mixture thereof, more preferably mannitol, glycine or a mixture thereof, most preferably mannitol.

优选地，本发明组合物、冻干粉针、试剂盒里的制剂中还可以加入增溶剂用于进一步改善环木菠萝悌醇阿魏酸酯和 24-亚甲基环木菠萝醇阿魏酸酯复合物的溶解度。所述增溶剂选自聚乙二醇、乙二醇、丙二醇、吐温、丙三醇、聚乙二醇十二位羟基硬脂酸酯、羟丙基 β环糊精、聚维酮中的一种和 /或其任意混合物。所述吐温选自吐温 -20，吐温 -40，吐温 -60，吐温 -80，优选为吐温 -80。所述的聚乙二醇，优选平均分子量为 200〜10000的聚乙二醇，更优选聚乙二醇 -200、聚乙二醇 -400、聚乙二醇 -800。所用增溶剂的量为磷脂与胆汁酸和 /或其盐质量和的 0〜2倍，以质量计。 Preferably, the composition of the present invention, the lyophilized powder needle, and the preparation in the kit may further contain a solubilizing agent for further improving the ringwood pineapple sterol ferulate and the 24-methylene ring wood pine alcohol ferulic acid. The solubility of the ester complex. The solubilizing agent is selected from the group consisting of polyethylene glycol, ethylene glycol, propylene glycol, Tween, glycerol, polyethylene glycol t-hydroxystearate, hydroxypropyl beta cyclodextrin, povidone One and / or any mixture thereof. The Tween is selected from the group consisting of Tween-20, Tween-40, Tween-60, Tween-80, preferably Tween-80. The polyethylene glycol is preferably polyethylene glycol having an average molecular weight of 200 to 10,000, more preferably polyethylene glycol-200, polyethylene glycol-400 or polyethylene glycol-800. The amount of the solubilizing agent used is 0 to 2 times the mass of the phospholipid and the bile acid and/or its salt, by mass.

本发明的产品可以是溶液形式、冻干粉针形式、或由第一单位制剂和液体状态的第二单位制剂组成的组合产品形式。当产品是溶液形式时，其为澄清的胶束溶液，可作为注射液直接注射给药；当其是冻干粉针时，冻干粉针剂在加入注射用水、葡萄糖溶液、氯化钠溶液复溶后，为澄清状态，然后给药；当其是由第一单位制剂和液体状态的第二单位制剂组成的组合产品形式时，将两种制剂混合，振摇均匀后使用。 The product of the present invention may be in the form of a solution, a lyophilized powder, or a combination product consisting of a first unit preparation and a second unit preparation in a liquid state. When the product is in the form of a solution, it is a clear micelle solution, which can be directly injected as an injection; when it is a freeze-dried powder, the lyophilized powder is added to the water for injection, glucose solution, sodium chloride solution. After dissolution, it is in a clarified state and then administered; when it is in the form of a combination product consisting of a first unit preparation and a second unit preparation in a liquid state, the two preparations are mixed, shaken and used uniformly.

在所述注射液中、冻干粉针冷冻干燥前的溶液中、.或组合产品中两种制剂混合后的溶液中，复合物的浓度为 lmg〜100mg/ml，磷脂的浓度为 lmg〜1000mg/ml，胆汁酸和 /或其盐浓度为 lmg~500mg/mlo In the injection solution, in the solution before freeze-drying of the freeze-dried powder, or in the solution of the two preparations in the combined product, the concentration of the complex is 1 mg to 100 mg/ml, and the concentration of the phospholipid is 1 mg to 1000 mg. /ml, bile acid and / or its salt concentration is lmg ~ 500mg / mlo

本发明的药物组合物的 pH不大于 10，优选 pH为 6 - 9。 The pharmaceutical composition of the present invention has a pH of not more than 10, preferably a pH of 6 - 9.

最后，本发明提供了以上产品的制备方法，包括将环木菠萝烯醇阿魏酸酯和 24-亚甲基环木菠萝醇阿魏酸酯复合物、磷脂与胆汁酸和 /或其盐混合、搅泮的步骤。具体包括如下步骤： Finally, the present invention provides a process for the preparation of the above product, which comprises mixing a cycloartenol ferulate and a 24-methylene cyclopentyl alcohol ferulate complex, a phospholipid with a bile acid and/or a salt thereof. The steps of stirring up. Specifically, the following steps are included:

①将复合物、憐脂、胆汁酸和 /或其盐溶解于有机溶剂中，搅拌，形成澄清溶液，减压蒸馏，从而得到本发明组合物的有机相； 1 dissolving the complex, pity, bile acid and/or its salt in an organic solvent, stirring to form a clear solution, and distilling under reduced pressure to obtain an organic phase of the composition of the present invention;

②将本发明药物组合物所用的辅料溶解于水中，从而得到水相。 2 The auxiliary material used in the pharmaceutical composition of the present invention is dissolved in water to obtain an aqueous phase.

③ A.注射液：将步骤①的有机相溶解于步骤②的水相中充分搅拌混匀。 B. 冻干粉针：按照常规方法将①所得到的有机相溶解于步骤②所得水相中，搅拌混匀，然后分装。例如，将①蒸馏后所得的有机相溶液溶解于水中，在 30O〜80°C条件下高速搅拌 0. 5〜1小时，形成澄清溶液，加入 pH调节剂调节至 pH6〜9，分装。在溶液中加入注射用活性碳滤膜精滤、冷冻干燥，得到本发明冻干粉针。 3 A. Injection: Dissolve the organic phase of step 1 in the aqueous phase of step 2 and mix well. B. Lyophilized powder needle: The organic phase obtained in 1 is dissolved in the aqueous phase obtained in the step 2 according to a conventional method, stirred and mixed, and then dispensed. For example, the organic phase solution obtained by the distillation of 1 is dissolved in water, and stirred at a high speed of 30 to 80 ° C for 0.5 to 1 hour to form a clear solution, adjusted to pH 6 to 9 by adding a pH adjuster, and dispensed. The activated carbon filter for injection is finely filtered and freeze-dried in the solution to obtain a freeze-dried powder needle of the present invention.

C.试剂盒：将步骤①所得有机相用 0. 22um微孔滤膜进行精滤，分装至西林瓶，为第一单位制剂；将步骤②所得水相溶液加入 0. 05%注射用活性碳搅拌三十分钟，脱碳过滤后， 0. 22um微孔滤膜进行精滤，分装至西林瓶，为第二单位制剂，本发明的试剂盒。在临床使用时，将第二单位制剂加入第一单位制剂中，振摇混匀后即可使用。 O. Injectable activity of the aqueous phase solution obtained in step 2 is added to the vial solution. The carbon was stirred for 30 minutes, and after decarburization filtration, a 0.22 μm microporous membrane was finely filtered and dispensed into a vial to prepare a second unit preparation, the kit of the present invention. In clinical use, the second unit preparation is added to the first unit preparation, shaken and mixed, and then used.

在步骤①中，所述的有机溶剂泛指可以溶解复合物、磷脂、胆汁酸和 /或其盐的药学上可接受的有机溶剂，包括但不限于乙醇、乙酸乙酯、氯仿、丙二醇中的一种和 /或一种以上的混合物。复合物、磷脂、胆汁酸和 /或其盐可以以任意先后顺序或者同时加入到有机溶剂中。可以根据需要，在本步骤的任何分步骤加入其他药用辅料。例如，助溶剂、稳定剂、抗氧化剂等。例如，可以将复合物溶解于乙醇中，搅匀后加入磷脂、胆汁酸和 /或其盐混合物。还可以将复合物、磷脂、胆汁酸和 /或 ^盐、助溶剂分别溶解于有机溶剂中，加入到一个容器里混匀搅拌得到本发明药物组合物有机相。在本步骤中，为了提高溶解速度，溶液应处于 50〜100 °C加热搅拌状态。 In the step 1, the organic solvent generally refers to a pharmaceutically acceptable organic solvent which can dissolve the complex, phospholipid, bile acid and/or its salt, including but not limited to ethanol, ethyl acetate, chloroform, propylene glycol. One and/or more than one mixture. The complex, phospholipid, bile acid and/or its salt may be added to the organic solvent in any order or simultaneously. Other pharmaceutical excipients may be added at any substep of this step as needed. For example, cosolvents, stabilizers, antioxidants, and the like. For example, the complex may be dissolved in ethanol, and after stirring, a mixture of phospholipid, bile acid and/or a salt thereof may be added. The complex, the phospholipid, the bile acid and/or the salt, and the co-solvent may each be dissolved in an organic solvent, added to a container, and stirred to obtain an organic phase of the pharmaceutical composition of the present invention. In this step, in order to increase the dissolution rate, the solution should be heated and stirred at 50 to 100 °C.

在所述步骤②中，按照常规或者己知的方法制备含有辅料的水相。各种辅料可以以任意顺序加入或者同时加入。例如可以将等张调节剂加入水中，然后加入抗氧化剂、稳定剂，搅拌混匀。 In the step 2, an aqueous phase containing an adjuvant is prepared according to a conventional or known method. Various excipients can be added in any order or simultaneously. For example, an isotonic conditioning agent can be added to the water, followed by the addition of an antioxidant, a stabilizer, and agitation.

在所述步骤③中，注射液的制备方法可按照常规方法将①的有机溶液中有机溶剂挥发以后溶解于步骤②所得水相中，搅拌混匀，然后分装。例如，将①蒸馏后所得有机相溶解于水中，在 30°C〜8(TC条件下高速搅拌 0. 1〜1小时，形成胶体溶液，加入 PH调节剂调节至 PH6〜 9，分装。 In the step 3, the preparation method of the injection solution can be carried out by volatilizing the organic solvent in the organic solution of 1 according to a conventional method, and then dissolving in the aqueous phase obtained in the step 2, stirring and mixing, and then dispensing. For example, the organic phase obtained after the distillation of 1 is dissolved in water, and stirred at a high temperature of 30 ° C to 8 (TC conditions for 0.1 to 1 hour to form a colloidal solution, and adjusted to pH 6 to 9, by adding a pH adjuster.

具体实施方式 detailed description

下面将通过实施例来说明实现本发明的技术方案，这些实施方式并不用来限制本发明。本领域技术人员根据现有知识对本发明进行等同替换或相应的逻辑改进，属于本发明的范围。实施例 1 环木菠萝烯醇阿魏酸酯和 24-亚甲基环木菠萝醇阿魏酸酯复合物的制备 The technical solutions for carrying out the invention will be described below by way of examples, which are not intended to limit the invention. It is within the scope of the invention to make equivalent substitutions or corresponding logical improvements to the invention in light of the prior art. Example 1 Preparation of Cycloartenol Ferulate and 24-Methylene Cyclobarcanol Ferulate Complex

1.取市售谷维素原料（纯度为 70%) lkg, 用 5倍量比例为 20: 1的乙酸乙酯及无水乙醇混合溶液回流溶解，过滤，静置，将析出结晶过滤，干燥。将干燥的结晶（纯度约为 84%)用 8 倍量的乙酸乙酯回流复溶，过滤，静置，将析出的结晶过滤，干燥。以上重结晶步骤重复 3-5次。 1. Commercially available oryzanol raw material (purity: 70%) lkg, dissolved in a mixture of ethyl acetate and absolute ethanol in a ratio of 5:1 in a ratio of 5 times, filtered, and allowed to stand, and the precipitated crystals were filtered and dried. The dried crystals (purity of about 84%) were reconstituted with 8 times of ethyl acetate under reflux, filtered, and allowed to stand, and the precipitated crystals were filtered and dried. Repeat the above recrystallization step 3-5 times.

2. 将步骤 1中重结晶后滤出的母液合并回收至体积为所含溶质的 2倍后，静置，将析出的结晶过滤、干燥。 2. The mother liquor which has been recrystallized in the step 1 is recovered and recovered to a volume twice the volume of the solute contained therein, and then allowed to stand, and the precipitated crystals are filtered and dried.

3. 将步骤 2中的结晶（纯度约为 85-87%)用 8倍量的乙酸乙酯回流溶解，过滤，静置，将析出的结晶过滤、干燥。重复以上重结晶步骤 3-5次。 3. The crystals in step 2 (purity of about 85-87%) were dissolved in 8 times of ethyl acetate under reflux, filtered, and allowed to stand, and the precipitated crystals were filtered and dried. Repeat the above recrystallization step 3-5 times.

4. 将步骤 3中重结晶后滤出的母液合并回收至体积为所含溶质的 2倍后，静置，将析出的结晶过滤、干燥。 4. The mother liquor which has been recrystallized in the step 3 is recovered and recovered to a volume twice the volume of the solute contained, and then allowed to stand, and the precipitated crystals are filtered and dried.

5. 将步骤 4中所得的结晶（纯度约为 85-87%)做重结晶处理，方法同步骤 3。 5. The crystal obtained in step 4 (purity is about 85-87%) is recrystallized in the same manner as in step 3.

6. 将步骤 1， 3， 5中所得的结晶混合，得到环木菠萝烯醇阿魏酸酯和 24-亚甲基环木菠萝醇阿魏酸酯复合物。 6. The crystals obtained in the steps 1, 3, and 5 are mixed to obtain a cyclopentylenol ferulate and a 24-methylenecyclopentalin ferulate complex.

通过高效液相检测方法，证实环木菠萝烯醇阿魏酸酯、 24-亚甲基环木菠萝醇阿魏酸酯的百分含量之和由原来的 70%提高到 93%。复合物中环木菠萝烯醇阿魏酸酯与 24-亚甲基环木菠萝醇阿魏酸酯的含量比为 1. 16： 1。 By the high-performance liquid phase detection method, it was confirmed that the sum of the percentages of the cycloartenol ferulate and the 24-methylene cyclobolinol ferulate increased from 70% to 93%. The content ratio of the cycloartenol ferulate in the complex to the 24-methylene ringwood pineapple ferulate is 1. 16:1.

以下实施例 2-15、对比实施例 1-3中所述复合物均是指按照实施例 1所制备的环木菠萝烯醇阿魏酸酯和 24-亚甲基环木菠萝醇阿魏酸酯复合物。在下述实施例中，加入甘露醇等赋形剂是满足制备成冻干剂型的需要。如果在实际应用中，直接使用组合物胶体溶液可以不加入赋形剂。 The composites described in the following Examples 2-15 and Comparative Examples 1-3 all refer to the cycloartenol ferulate and the 24-methylenecyclolaurin ferulic acid prepared according to Example 1. Ester complex. In the following examples, the addition of an excipient such as mannitol is required to prepare a lyophilized dosage form. If in practice, the composition colloidal solution is used directly without the addition of excipients.

实施例 2 Example 2

复合物 10mg Compound 10mg

大豆磷脂 50mg Soybean phospholipid 50mg

猪脱氧胆酸 50mg Porcine deoxycholic acid 50mg

甘露醇 80mg Mannitol 80mg

注射用水 . 至 10ml Water for injection . to 10ml

将复合物、大豆磷脂、猪脱氧胆酸溶解于 3ml乙酸乙酯中，加热至 80Ό搅拌，至充分溶解。采用减压蒸发的方法蒸馏，得到有机相。在以上有机相中加入已经溶解了甘露醇的注射用水全量， 60°C下充分搅拌混匀，即可得本发明组合物注射液。用氢氧化钠溶液调节 PH到 7. 3, 加入 0. 05%注射用活性碳搅拌三十分钟，脱碳过滤后， 0. 22um微孔滤膜进行精滤，分装至西林瓶。 The complex, soybean phospholipid, and porcine deoxycholic acid were dissolved in 3 ml of ethyl acetate, and heated to 80 ° with stirring until fully dissolved. The organic phase was obtained by distillation under reduced pressure. To the above organic phase, the whole amount of water for injection in which mannitol has been dissolved is added, and the mixture is thoroughly stirred and mixed at 60 ° C to obtain the composition injection of the present invention. The pH was adjusted to 7. 3 with sodium hydroxide solution, and the mixture was stirred for 30 minutes with activated carbon for 30 minutes. After decarburization filtration, the 0.222 μm microporous membrane was finely filtered and dispensed into a vial.

实施例 3 Example 3

复合物 40mg 大豆磷脂 200mg Compound 40mg Soybean phospholipid 200mg

鹅脱氧胆酸 300mg Chenodeoxycholic acid 300mg

甘氨酸 lOOmg Glycine lOOmg

注射用水至 10ml Water for injection to 10ml

将复合物、鹅脱氧胆酸、大豆磷脂溶解于 5ml丙二醇中，加热至 80°C搅拌，至充分溶解。采用减压蒸发的方法蒸馏，得到有机相。在以上有机相中加入已经溶解了甘氨酸的注射用水至全量， 70°C下充分搅拌混匀，即可得本发明组合物注射液。用氢氧化钠溶液调节 PH到 9. 0，加入 0. 05%注射用活性碳搅拌三十分钟，脱碳过滤后， 0. 22_Um微孔滤膜进行精滤，分装至西林瓶。 The complex, chenodeoxycholic acid, and soybean phospholipid were dissolved in 5 ml of propylene glycol, and heated to 80 ° C to be stirred until fully dissolved. The organic phase was obtained by distillation under reduced pressure. To the above organic phase, water for injection in which glycine has been dissolved is added to the whole amount, and the mixture is thoroughly stirred and mixed at 70 ° C to obtain the composition injection of the present invention. The pH was adjusted to 9.0 with a sodium hydroxide solution, and the mixture was stirred for 30 minutes with activated carbon for 30 minutes. After decarburization filtration, a _{0.22 Um} microporous membrane was finely filtered and dispensed into a vial.

实施例 4 Example 4

复合物 lmg Compound lmg

大豆鞘磷脂 500mg Soy sphingomyelin 500mg

石胆酸 lOOmg Phytic acid lOOmg

葡萄糖 200mg Glucose 200mg

注射用水至 10ml Water for injection to 10ml

将复合物、大豆鞘磷脂、石胆酸溶解于 10ml乙酸乙酯中，加热至 60°C搅拌，至充分溶解。采用减压蒸发的方法蒸馏，得到有机相。在以上有机相中加入已经溶解了葡萄糖的注射用水至全量， 60°C下充分搅拌混匀，即可得本发明组合物注射液。用氢氧化钠溶液调节 PH到 6. 6，加入 0. 05%注射用活性碳搅拌三十分钟，脱碳过滤后， 0. 22um微孔滤膜进行精滤，分装至西林瓶。 The complex, soybean sphingomyelin and lithocholic acid were dissolved in 10 ml of ethyl acetate, and heated to 60 ° C to stir until fully dissolved. The organic phase was obtained by distillation under reduced pressure. To the above organic phase, water for injection in which glucose has been dissolved is added to the whole amount, and the mixture is thoroughly stirred and mixed at 60 ° C to obtain the composition injection of the present invention. The pH was adjusted to 6. 6 with sodium hydroxide solution, and 0. 05% of the injection was stirred for 30 minutes with activated carbon. After decarburization filtration, the 0.222 μm microfiltration membrane was finely filtered and dispensed into a vial.

实施例 5 Example 5

复合物 10mg Compound 10mg

甘氨胆酸 lOOmg Glycocholic acid lOOmg

氢化蛋黄磷脂 400mg Hydrogenated egg yolk phospholipid 400mg

甘氨酸 200mg Glycine 200mg

甘露醇 200mg Mannitol 200mg

注射用水至 10ml Water for injection to 10ml

将复合物、甘氨胆酸、氢化蛋黄磷脂溶解于 2ml乙酸乙酯中，加热至 60Ό搅拌，加热混匀，至充分溶解。采用减压蒸发的方法蒸馏，得到有机相。在以上有机相中加入已经溶解了甘露醇和甘氨酸的注射用水至全量， 60°C下充分搅拌混匀，即可得本发明组合物注射液。用氢氧化钠溶液调节 PH到 6. 0，加入 0. 05%注射用活性碳搅拌三十分钟，脱碳过滤后， 0. 45um 微孔滤膜进行精滤，罐装，然后分装至西林瓶。 The complex, glycocholic acid, and hydrogenated egg yolk phospholipid were dissolved in 2 ml of ethyl acetate, heated to 60 Torr, stirred, and heated to be fully dissolved. The organic phase was obtained by distillation under reduced pressure. To the above organic phase, water for injection in which mannitol and glycine have been dissolved is added to the whole amount, and the mixture is thoroughly stirred and mixed at 60 ° C to obtain the composition injection of the present invention. use The sodium hydroxide solution was adjusted to a pH of 6.0, and the mixture was stirred for 30 minutes with activated carbon for 30 minutes. After decarburization filtration, the 0. 45um microporous membrane was finely filtered, canned, and then dispensed into a vial. .

实施例 6 Example 6

复合物 50mg Complex 50mg

甘氨去氧胆酸 lOOmg Glycerol deoxycholate lOOmg

磷脂酰乙醇胺 60mg Phosphatidylethanolamine 60mg

硫代甘油 2mg Thioglycerol 2mg

亚硫酸钠 lmg Sodium sulfite lmg

山梨醇 80mg Sorbitol 80mg

注射用水至 10ml Water for injection to 10ml

将复合物、甘氨去氧胆酸、磷脂酰乙醇胺溶解于 8ml乙酸乙酯中，加热至 8(TC搅拌，然后加入硫代甘油加热混匀，至充分溶解。采用减压蒸发的方法蒸馏，得到有机相。在以上有机相中加入已经溶解了亚硫酸钠和山梨醇的注射用水至全量， 60°C下充分搅拌混匀，即可得本发明组合物注射液。加入 0. 05%注射用活性碳搅拌三十分钟，脱碳过滤后， 0. 22um微孔滤膜进行精滤，分装至西林瓶。 Dissolve the complex, glycodeoxycholic acid, phosphatidylethanolamine in 8 ml of ethyl acetate, heat to 8 (TC stirring, then add thioglycerol to heat and mix until fully dissolved. Distillation by evaporation under reduced pressure, The injectable activity is added to the present invention. The injection of the composition of the present invention is added to the above-mentioned organic phase. The carbon was stirred for 30 minutes, and after decarburization filtration, a 0.22 μm microporous membrane was finely filtered and dispensed into a vial.

实施例 7 Example 7

复合物 50mg Complex 50mg

脱氧胆酸 250mg Deoxycholic acid 250mg

大豆磷脂 400mg Soybean phospholipid 400mg

聚乙二醇- 800 10mg Polyethylene glycol - 800 10mg

羟丙基 P环糊精 20mg Hydroxypropyl P cyclodextrin 20mg

乳糖 150mg Lactose 150mg

注射用水至 10ml Water for injection to 10ml

将复合物、脱氧胆酸、大豆磷脂、聚乙二醇 -800溶解于 5ml乙醇中，加热至 60°C搅拌，至充分溶解。采用减压蒸发的方法蒸镏，得到有机相。在以上有机相中加入已经溶解了羟丙基 β环糊精和乳糖的注射用水至全量， 60 下充分搅拌混匀，即可得本发明注射液。用氢氧化钠溶液调节 ΡΗ至 7. 5，加入 0. 05%注射用活性碳搅拌三十分钟，脱碳过滤后， 0. 22um微孔滤膜进行精滤，分装至西林瓶。 The complex, deoxycholic acid, soybean phospholipid, and polyethylene glycol-800 were dissolved in 5 ml of ethanol, and heated to 60 ° C to be stirred until fully dissolved. The organic phase was obtained by evaporation under reduced pressure. To the above organic phase, water for injection in which hydroxypropyl β-cyclodextrin and lactose have been dissolved is added to the whole amount, and the mixture is thoroughly stirred and mixed under 60 to obtain the injection of the present invention. The sodium hydroxide solution was adjusted to 7.5, and the mixture was stirred for 30 minutes with activated carbon for 30 minutes. After decarburization filtration, the 0.222 μm microfiltration membrane was finely filtered and dispensed into a vial.

实施例 8 Example 8

复合物 lmg 磷脂酰甘油 20mg Compound lmg Phosphatidylglycerol 20mg

甘氨去氧胆酸钠 10mg . Sodium glycobionate 10mg .

吐温- 80 3mg Tween - 80 3mg

甘露醇 20mg Mannitol 20mg

注射用水至 10ml Water for injection to 10ml

将复合物、磷脂酰甘油、甘氨去氧胆酸钠、吐温- 80溶解于 2ml乙酸乙酯中，加热至 60 °C搅拌，至充分溶解。采用减压蒸发的方法蒸馏，得到有机相。在以上有机相中加入已经溶解了甘露醇的注射用水至全量， 60'C下充分搅拌混匀，即可得本发明注射液。加入 0. 05%注射用活性碳搅拌三十分钟，脱碳过滤后， 0. 22um微孔滤膜进行精滤，分装至西林瓶。 The complex, phosphatidylglycerol, sodium glycodeoxycholate, and Tween-80 were dissolved in 2 ml of ethyl acetate, and heated to 60 ° C to stir until fully dissolved. The organic phase was obtained by distillation under reduced pressure. To the above organic phase, water for injection in which mannitol has been dissolved is added to the whole amount, and the mixture is thoroughly stirred and mixed at 60 ° C to obtain the injection of the present invention. After adding 0. 05% injection, the mixture was stirred for 30 minutes with activated carbon. After decarburization filtration, a 0.22 μm microporous membrane was finely filtered and dispensed into a vial.

实施例 9 Example 9

复合物 10mg Compound 10mg

磷脂酰胆碱 lOOmg Phosphatidylcholine lOOmg

牛磺胆酸 80mg Taurocholic acid 80mg

维生素 E 15mg Vitamin E 15mg

葡萄糖 lOOmg Glucose lOOmg

注射用水至 10ml Water for injection to 10ml

将复合物、磷脂酰胆碱、牛磺胆酸溶解于 4ml乙酸乙酯中，加热至 75°C搅拌，至充分溶解。采用减压蒸发的方法蒸馏，得到有机相。在以上有机相中加入已经溶解了维生素 E和葡萄糖的注射用水至全量， 60°C下充分搅拌混匀，即可得本发明注 ^:射液。加入 0. 05%注射用活性碳搅拌三十分钟，脱碳过滤后， 0. 22um微孔滤膜进行精滤，分装至西林瓶。 The complex, phosphatidylcholine, and taurocholic acid were dissolved in 4 ml of ethyl acetate, and the mixture was heated to 75 ° C and stirred until fully dissolved. The organic phase was obtained by distillation under reduced pressure. In the above organic phase was added vitamin E had been dissolved and water for injection to the total amount of glucose, 60 ° C for sufficient mixing with stirring, to obtain the present invention ^NOTE: injection. 05% injection was stirred with activated carbon for 30 minutes, after decarburization filtration, 0. 22um microporous membrane was finely filtered and dispensed into a vial.

实施例 10 Example 10

复合物 20mg Compound 20mg

磷脂酰胆碱 200mg Phosphatidylcholine 200mg

甘氨胆酸 300mg Glycocholic acid 300mg

甘露醇 lOOmg Mannitol lOOmg

注射用水至 10ml Water for injection to 10ml

将复合物、磷脂酰胆碱、甘氨胆酸溶解于 5ml乙酸乙酯中，加热至 75°C搅拌，至充分溶解。采用减压蒸发的方法蒸馏，得到有机相。在有机相中加入已经溶解了甘露醇的注射用水至全量， 60°C下充分搅拌混匀，然后采用氢氧化钠溶液调节 PH至 8，即可得本发明注射液。加入 0. 05%注射用活性碳搅拌三十分钟，脱碳过滤后， 0. 22um微孔滤膜进行精滤，分装至西林瓶。 The complex, phosphatidylcholine, and glycocholic acid were dissolved in 5 ml of ethyl acetate, and the mixture was heated to 75 ° C and stirred until fully dissolved. The organic phase was obtained by distillation under reduced pressure. The injection water which has dissolved mannitol is added to the organic phase to the whole amount, and the mixture is thoroughly stirred and mixed at 60 ° C, and then the pH is adjusted to 8 by using a sodium hydroxide solution to obtain the injection of the present invention. 05% injection with activated carbon for 30 minutes, after decarburization filtration, 0. 22um microporous membrane for fine filtration, dispensing to the west Forest bottle.

实施例 11 Example 11

复合物 15mg Complex 15mg

磷脂酰胆碱 180mg Phosphatidylcholine 180mg

脱氧胆酸 200mg Deoxycholic acid 200mg

维生素 E 15mg Vitamin E 15mg

甘氨酸 lOOmg Glycine lOOmg

葡萄糖 lOOmg Glucose lOOmg

注射用水至 10ml Water for injection to 10ml

将复合物、磷脂酰胆碱、牛磺胆酸、维生素 E溶解于 5ml乙醇中，加热至 70°C搅拌，至充分溶解。采用减压蒸发的方法蒸馏，得到有机相。加入已经溶解了甘氨酸和葡萄糖的注射用水至全量， 60°C下充分搅拌混匀，然后采用氢氧化钠溶液调节 PH至 7，即可得本发明注射液。加入 0. 05%注射用活性碳搅拌三十分钟，脱碳过滤后， 0. 22um微孔滤膜进行精滤，分装至西林瓶。 The complex, phosphatidylcholine, taurocholic acid, and vitamin E were dissolved in 5 ml of ethanol, and heated to 70 ° C to be stirred until fully dissolved. The organic phase was obtained by distillation under reduced pressure. The injection water having dissolved glycine and glucose was added to the whole amount, and the mixture was thoroughly stirred and mixed at 60 ° C, and then the pH was adjusted to 7, by using a sodium hydroxide solution to obtain the injection of the present invention. After adding 0. 05% of the injection, the activated carbon was stirred for 30 minutes, and after decarburization filtration, the 0.222 μm microporous membrane was finely filtered and dispensed into a vial.

实施例 12 Example 12

复合物 15mg Complex 15mg

磷脂酰胆碱 180mg Phosphatidylcholine 180mg

甘氨胆酸纳 200mg Glycyrrhizinate 200mg

甘氨酸 lOOmg Glycine lOOmg

甘露醇 120mg Mannitol 120mg

丙二醇 lOmg Propylene glycol lOmg

注射用水至 10ml Water for injection to 10ml

将复合物、磷脂酰胆碱、甘氨胆酸钠、丙二醇溶解于 3ml乙醇中，加热至 70°C搅拌，至充分溶解。采用减压蒸发的方法蒸馏，得到有机相。在以上有机相中加入已经溶解了甘酸酸和甘露醇的注射用水至全量， 60Ό下充分搅拌混匀，即可得本发明注射液。加入 0. 05%注射用活性碳搅拌三十分钟，脱碳过滤后， 0. 22ura微孔滤膜进行精滤，分装至西林瓶。 The complex, phosphatidylcholine, sodium glycocholate, and propylene glycol were dissolved in 3 ml of ethanol, and heated to 70 ° C to be stirred until fully dissolved. The organic phase was obtained by distillation under reduced pressure. To the above organic phase, water for injection in which the acid and mannitol have been dissolved is added to the whole amount, and the mixture is thoroughly stirred and mixed under 60 Torr to obtain the injection of the present invention. 05% injection After stirring for 30 minutes with activated carbon, after decarburization filtration, the 0.222 ura microporous membrane was finely filtered and dispensed into a vial.

实施例 13 Example 13

复合物 15mg Complex 15mg

蛋黄磷脂 180mg 牛磺胆酸钾 150mg Egg yolk phospholipid 180mg Potassium taurocholate 150mg

丙三醇 15mg Glycerol 15mg

山梨醇 lOOmg Sorbitol lOOmg

葡萄糖 50mg Glucose 50mg

注射用水至 10ml Water for injection to 10ml

将复合物、蛋黄磷脂、牛磺胆酸溶解于 3ml乙酸乙酯中，加热至 70°C搅拌，至充分溶解。采用减压蒸发的方法蒸馏，得到有机相。在以上有机相中加入已经溶解了丙三醇、山梨醇和葡萄糖的的注射用水至全量， 60°C下充分搅拌混匀，然后采用碳酸氢钠溶液调节 PH至 8即可得本发明注射液。加入 0. 05%注射用活性碳搅拌二十分钟，脱碳过滤后， 0. 22um微孔滤膜进行精滤，分装至西林瓶。 The complex, egg yolk phospholipid, and taurocholic acid were dissolved in 3 ml of ethyl acetate, and heated to 70 ° C to stir until fully dissolved. The organic phase was obtained by distillation under reduced pressure. To the above organic phase, water for injection in which glycerin, sorbitol, and glucose have been dissolved is added to the whole amount, and the mixture is thoroughly stirred and mixed at 60 ° C, and then the pH is adjusted to 8 by using a sodium hydrogencarbonate solution to obtain the injection of the present invention. 0. 05% of the injection was stirred with activated carbon for 20 minutes. After decarburization filtration, the 0.222 μm microporous membrane was finely filtered and dispensed into a vial.

实施例 14 Example 14

复合物 10mg Compound 10mg

磷脂酰胆碱 180mg Phosphatidylcholine 180mg

牛磺胆酸 200mg Taurocholic acid 200mg

丙二醇 10mg Propylene glycol 10mg

丙三醇 lOmg Glycerol lOmg

注射用水至 10ml 将复合物、磷脂酰胆碱、牛磺胆酸、丙三醇溶解于 2.5ml乙醇中，加热至 70°C搅拌，至充分溶解。采用减压蒸发的方法蒸馏，得到有机相。在以上有机相中加入已经溶解了丙二醇和乳糖的的注射用水至全量， 60°C下充分搅拌混匀，即可得本发明注射液。加入 0. 05%注射用活性碳搅拌三十分钟，脱碳过滤后， 0. 22u_m微孔滤膜进行精滤，分装至西林瓶。 Water for injection to 10 ml The complex, phosphatidylcholine, taurocholic acid, and glycerin were dissolved in 2.5 ml of ethanol, and heated to 70 ° C to stir until fully dissolved. The organic phase was obtained by distillation under reduced pressure. To the above organic phase, water for injection in which propylene glycol and lactose have been dissolved is added to the whole amount, and the mixture is thoroughly stirred and mixed at 60 ° C to obtain the injection of the present invention. 05% injection with activated carbon for 30 minutes, decarburization filtration, 0. 22u _m microporous membrane for fine filtration, dispensing into a vial.

实施例 15 Example 15

复合物 lOmg Compound lOmg

大豆磷脂酰胆碱 180mg Soy phosphatidylcholine 180mg

脱氧胆酸钠 200mg Sodium deoxycholate 200mg

丙二醇 lOmg Propylene glycol lOmg

丙三醇 lOmg Glycerol lOmg

甘露醇 120mg Mannitol 120mg

注射用水至 10ml 将复合物、大豆磷脂酰胆碱、牛磺胆酸钠溶解于 2.5ml乙醇中，加热至 70Ό搅拌，至充分溶解。采用减压蒸发的方法蒸馏，得到有机相。在以上有机相中加入已经溶解了丙二醇、丙三醇和甘露醇的注射用水至全量， 60°C下充分搅拌混匀，即可得本发明注射液。加入 0. 05% 注射用活性碳搅拌二十五分钟，脱碳过滤后， 0. 22um微孔滤膜进行精滤，分装至西林瓶。实施例 16 Water for injection to 10ml The complex, soybean phosphatidylcholine, and sodium taurocholate were dissolved in 2.5 ml of ethanol, and heated to 70 Torr to be stirred until fully dissolved. The organic phase was obtained by distillation under reduced pressure. To the above organic phase, water for injection in which propylene glycol, glycerin, and mannitol have been dissolved is added to the whole amount, and the mixture is thoroughly stirred and mixed at 60 ° C to obtain the injection of the present invention. 05% 05% injection with activated carbon for 25 minutes, decarburization filtration, 0. 22um microporous membrane for fine filtration, dispensing into a vial. Example 16

第一单位制剂 First unit preparation

复合物 10mg Compound 10mg

磷脂酰胆碱 lOOmg Phosphatidylcholine lOOmg

牛磺胆酸 80mg 第二单位制剂 Taurocholic acid 80mg second unit preparation

维生素 C 15mg Vitamin C 15mg

注射用水 10ml 将复合物、磷脂酰胆碱、牛磺胆酸溶解于 5ml丙酮中， 60°C下充分搅拌下采用减压蒸干的方法除去溶液中的丙酮，用 0. 22um微孔滤膜进行精滤，分装至西林瓶，标号为 A; O. 22微米微孔滤膜 The acetone in the solution was removed by a method of decomposing under reduced pressure, and the acetone was removed by evaporation under reduced pressure at a temperature of 60 ° C. Perform fine filtration and dispense into a vial, labeled A;

将维生素 C溶解于 10ml水中，然后加入 0. 05%注射用活性碳搅拌三十分钟，脱碳过滤后， 0. 22um微孔滤膜进行精滤，分装至西林瓶，标号为 B。 The vitamin C was dissolved in 10 ml of water, and then added with 0.5% of the activated carbon for 30 minutes. After decarburization filtration, the 0.22 μm microporous membrane was finely filtered and dispensed into a vial, designated B.

在临床使用时，将 B瓶中的溶液加入到 A瓶中，充分振摇使其混匀成澄清溶液后使用。实施例 17 In clinical use, add the solution in the B bottle to the A bottle, shake it thoroughly and mix it into a clear solution for use. Example 17

第一单位制剂 First unit preparation

复合物 20mg Compound 20mg

磷脂酰胆碱 200mg Phosphatidylcholine 200mg

甘氨胆酸 300mg 第二单位制剂 Glycocholic acid 300mg second unit preparation

甘氨酸 10mg Glycine 10mg

注射用水 10ml 将复合物、磷脂酰胆碱、甘氨胆酸溶解于 15ml 乙醇中， 60°C下充分搅拌下采用减压等干的方法除去溶液中的乙醇，用 0. 22um微孔滤膜进行精滤，分装至西林瓶，标号为 A; The iodine filter is removed by a dry process such as decompression, and the solution is dried under reduced pressure. Perform fine filtration and dispense into a vial, labeled A;

将甘氨酸溶解于 10ml水中，然后加入 0. 05%注射用活性碳搅拌三十分钟，脱碳过滤后， 0. 22um微孔滤膜进行精滤，分装至西林瓶，标号为 B。 The glycine was dissolved in 10 ml of water, and then added with 0.5% of the activated carbon for 30 minutes. After decarburization filtration, the 0.222 μm microfiltration membrane was finely filtered and dispensed into a vial, designated B.

在临床使用时，将 B瓶中的溶液加入到 A瓶中，充分振摇使其混匀成澄清溶液后使用。实施例 18 In clinical use, the solution in the B bottle is added to the A bottle, shaken well and mixed to form a clear solution for use. Example 18

第一单位制剂 First unit preparation

复合物 15mg Complex 15mg

磷脂酰胆碱 150mg Phosphatidylcholine 150mg

脱氧胆酸 200mg Deoxycholic acid 200mg

维生素 E lOmg 第二单位制剂 Vitamin E lOmg second unit preparation

甘氨酸 lOOmg Glycine lOOmg

注射用水 10ml 将复合物、磷脂酰胆碱、脱氧胆酸、维生素 E溶解于 15ml乙醇中， 60Ό下充分搅拌下采用减压蒸干的方法除去溶液中的乙醇，用 0. 22um微孔滤膜进行精滤，分装至西林瓶，标号为 A; The iodine filter is removed by a method of removing the ethanol in the solution, using a solution of 0. 22 um microporous membrane. The solution is immersed in a solution of 0. 22 um microporous membrane. Perform fine filtration and dispense into a vial, labeled A;

将甘氨酸溶解于 10ml水中，然后加入 0. 05%注射用活性碳搅拌三十分钟。加入氢氧化钠溶液调节 pH到 8. 0。脱碳过滤后， 0. 22um微孔滤膜进行精滤，分装至西林瓶，标号为 B。 The glycine was dissolved in 10 ml of water, and then 0. 05% of the injection was stirred with activated carbon for thirty minutes. Add sodium hydroxide solution to adjust the pH to 8.0. After decarburization filtration, the 0.22 μm microporous membrane was finely filtered and dispensed into a vial, designated B.

在临床使用时，将 B瓶中的溶液加入到 A瓶中，充分振摇使其混匀成澄清溶液后使用。实施例 19 In clinical use, add the solution in the B bottle to the A bottle, shake it thoroughly and mix it into a clear solution for use. Example 19

第一单位制剂 First unit preparation

复合物 15mg Complex 15mg

磷脂酰胆碱 180mg Phosphatidylcholine 180mg

甘氨胆酸纳 200mg Glycyrrhizinate 200mg

丙二醇 lOmg 第二单位制剂 Propylene glycol lOmg second unit preparation

丙三醇 20mg Glycerol 20mg

甘氨酸 lOOmg Glycine lOOmg

注射用水 10ml 将复合物、磷脂酰胆碱、甘氨胆酸钠和丙二醇溶解于 10ml三氯甲垸中， 60°C下充分搅拌下采用减压蒸干的方法除去溶液中的三氯甲烷，用 0. 22um微孔滤膜进行精滤，分装至西林瓶，标号为 A; 10 ml of water for injection The complex, phosphatidylcholine, sodium glycocholate and propylene glycol were dissolved in 10 ml of trichloromethane, and the chloroform in the solution was removed by evaporation under reduced pressure at 60 ° C under agitation. Fine filtration with a 0.22 μm microporous membrane, and dispensed into a vial, labeled A;

将丙三醇、甘氨酸溶解于 10ml水中，然后加入 0. 05%注射用活性碳搅拌三十分钟。加入碳酸氢钠溶液调节 pH到 8。脱碳过滤后， 0. 22um微孔滤膜进行精滤，分装至西林瓶，标号为 B。 The glycerol and glycine were dissolved in 10 ml of water, and then 0. 05% of the injection was stirred with activated carbon for thirty minutes. The pH was adjusted to 8 by the addition of sodium bicarbonate solution. After decarburization filtration, the 0. 22um microporous membrane was finely filtered and dispensed into a vial, labeled B.

在临床使用时，将 B瓶中的溶液加入到 A瓶中，充分振摇使其混匀成澄清溶液后使用。实施例 20 In clinical use, add the solution in the B bottle to the A bottle, shake it thoroughly and mix it into a clear solution for use. Example 20

第一单位制剂 First unit preparation

复合物 15mg Complex 15mg

蛋黄磷脂 180mg Egg yolk phospholipid 180mg

牛磺胆酸钾 150mg 第二单位制剂 Potassium taurocholate 150mg second unit preparation

丙三醇 15mg Glycerol 15mg

注射用水 10ml 将复合物、蛋黄磯脂、牛磺胆酸钾溶解于 10ml二氯甲烷中， 60Ό下充分搅拌下采用减压蒸干的方法除去溶液中的二氯甲烷，用 0. 22um微孔滤膜进行精滤，分装至西林瓶，标号为 A; The diatom of the solution was removed by using a solution of 0. 22 um micropores. The solution was dissolved in a solution of 0. 22 um micropores. The filter membrane is finely filtered and dispensed into a vial, labeled A;

将丙三醇溶解于 10ml水中，然后加入 0. 05%注射用活性碳搅拌三十分钟。加入碳酸氢钠溶液调节 pH到 9。脱碳过滤后， 0. 22um微孔滤膜进行精滤，分装至西林瓶，标号为 B。 The glycerol was dissolved in 10 ml of water, and then 0. 05% of the injection was stirred with activated carbon for thirty minutes. The pH was adjusted to 9 by the addition of sodium bicarbonate solution. After decarburization filtration, the 0.22 μm microporous membrane was finely filtered and dispensed into a vial, designated B.

在临床使用时，将 B瓶中的溶液加入到 A瓶中，充分振摇使其混勾成澄清溶液后使用。实施例 21 In clinical use, add the solution in the B bottle to the A bottle, shake it thoroughly and mix it into a clear solution for use. Example 21

第一单位制剂 First unit preparation

复合物 10mg Compound 10mg

磷脂酰胆碱 180mg Phosphatidylcholine 180mg

牛黄胆酸 200mg Bovine cholic acid 200mg

丙三醇 10mg 第二单位制剂 Glycerol 10mg second unit preparation

丙二醇 lOmg Propylene glycol lOmg

乳糖 lOmg Lactose lOmg

注射用水 10ml 将复合物、磷脂酰胆碱、牛黄胆酸和丙三醇溶解于 10ml 乙醇中， 60Ό下充分搅拌下采用减压蒸干的方法除去溶液中的乙醇，用 0. 22um微孔滤膜进行精滤，分装至西林瓶，标号为 A; The immersion in the solution was carried out by using a solution of 0. 22 um microporous filtration. The solution was dissolved in 10 ml of ethanol. The membrane is finely filtered and dispensed into a vial, labeled A;

将丙二醇、乳糖溶解于 10ml水中，然后加入 0. 05%注射用活性碳搅拌三十分钟，脱碳过滤后， 0. 22um微孔滤膜进行精滤，分装至西林瓶，标号为 B。 Dissolve propylene glycol, lactose in 10 ml of water, then add 0. 05% of the injection with activated carbon for 30 minutes, decarburization After filtration, the 0. 22 um microporous membrane was finely filtered and dispensed into a vial, designated B.

在临床使用时，将 B瓶中的溶液加入到 A瓶中，充分振摇使其混匀成澄清溶液后使用。实施例 22 In clinical use, add the solution in the B bottle to the A bottle, shake it thoroughly and mix it into a clear solution for use. Example 22

第一单位制剂 First unit preparation

复合物 10mg Compound 10mg

大豆磷脂酰胆碱 180mg Soy phosphatidylcholine 180mg

脱氧胆酸钠 200mg Sodium deoxycholate 200mg

丙三醇 10mg Glycerol 10mg

第二单位制剂 Second unit preparation

丙二醇 lOmg Propylene glycol lOmg

维生素 C 2mg Vitamin C 2mg

注射用水 10ml 将复合物、大豆磷脂酰胆碱、脱氧胆酸钠、丙三醇溶解于 10ml丙酮中， 60°C下充分搅拌下采用减压蒸干的方法除去溶液中的丙酮，用 0. 22um微孔滤膜进行精滤，分装至西林瓶，标号为 A; 10 ml of water for injection, the complex, soybean phosphatidylcholine, sodium deoxycholate, glycerol was dissolved in 10 ml of acetone, and the acetone in the solution was removed by evaporation under reduced pressure at 60 ° C under a sufficient stirring. The 22um microporous membrane is finely filtered and dispensed into a vial, labeled A;

将丙二醇、维生素 C溶解于 10ml水中，然后加入 0. 05%注射用活性碳搅拌三十分钟，脱碳过滤后， 0. 22um微孔滤膜进行精滤，分装至西林瓶，标号为 B。 The propylene glycol and vitamin C were dissolved in 10 ml of water, and then added with 0.5% of the activated carbon for 30 minutes. After decarburization filtration, the 0.222 μm microfiltration membrane was finely filtered and dispensed into a vial, labeled B. .

在临床使用时，将 B瓶中的溶液加入到 A瓶中，充分振摇使其混匀成澄清溶液后使用。实施例 23 In clinical use, add the solution in the B bottle to the A bottle, shake it thoroughly and mix it into a clear solution for use. Example 23

第一单位制剂 First unit preparation

复合物 lOmg Compound lOmg

大豆磷脂 80mg Soybean phospholipid 80mg

甘氨胆酸 60mg Glycocholic acid 60mg

丙三醇 15mg 第二单位制剂 Glycerol 15mg second unit preparation

赖氨酸 5mg Lysine 5mg

维生素 E 2mg Vitamin E 2mg

注射用水 10ml 将复合物、大豆磷脂、甘氨胆酸、丙三醇溶解于 10ml三氯甲烷中， 60°C下充分搅拌下采用减压蒸干的方法除去溶液中的三氯甲垸，用 0. 221 微孔滤膜进行精滤，分装至西林瓶，标号为 A; 10 ml of water for injection The complex, soybean phospholipid, glycocholic acid, and glycerin were dissolved in 10 ml of chloroform, and the solution of trichloromethane was removed by evaporation under reduced pressure at 60 ° C under a sufficient agitation. 0. 221 microporous membrane for fine filtration, dispensed into vials, Labeled as A;

将赖氨酸、维生素 E溶解于 10ml水中，然后加入 0. 05%注射用活性碳搅拌三十分钟，脱碳过滤后， 0. 22um微孔滤膜进行精滤，分装至西林瓶，标号为 B。 The lysine and the vitamin E were dissolved in 10 ml of water, and then the mixture was stirred for 30 minutes with activated carbon for 30 minutes. After decarburization filtration, the 0.22 μm microporous membrane was finely filtered and dispensed into a vial, labeled For B.

在临床使用时，将 B瓶中的溶液加入到 A瓶中，充分振摇使其混匀成澄清溶液后使用。 In clinical use, add the solution in the B bottle to the A bottle, shake it thoroughly and mix it into a clear solution for use.

实施例 2〜23制的溶液澄清度判断方法 Method for judging the clarity of solution of Example 2~23

上述实施例制备的溶液、或者实施例制备的临床使用时的溶液，依据《中国药典 2005年版（二部)》附录 IX B方法，将制备的溶液与等量的浊度标准液分别置于配对的比浊用玻璃管中，在浊度标准液制备 5分钟后，在暗室内垂直同置于伞棚灯下，照度为 lOOOLx, 从水平方向观察、比较，制备的溶液澄清，不深于 1号浊度标准液。 The solution prepared in the above examples, or the solution prepared in the clinical use of the examples, according to the Chinese Pharmacopoeia 2005 edition (Part 2) Appendix IX B method, the prepared solution and the equivalent amount of turbidity standard solution are respectively paired The turbidity is measured in a glass tube, and after 5 minutes of preparation in the turbidity standard solution, it is placed vertically under the umbrella lamp in the dark room, and the illuminance is lOOOLx. The solution is clarified from the horizontal direction, and is not deeper than 1 No. turbidity standard solution.

将实施例 2〜15制的溶液按照下述方法进行冷冻干燥 The solutions prepared in Examples 2 to 15 were freeze-dried as follows.

预冻：制品温度下降至一 45°C，保温 3小时后即可以进行升华干燥； Pre-freezing: The temperature of the product drops to a temperature of 45 ° C, and the sublimation drying can be carried out after 3 hours of heat preservation;

升华干燥：升华干燥温度控制在一 12Ό以下； ' Sublimation drying: Sublimation drying temperature is controlled below 12 ;; '

再干燥：再干燥阶段最高温度控制在 35Ό，干燥失重应符合规定； Re-drying: The maximum temperature in the re-drying stage is controlled at 35 Ό, and the weight loss on drying should meet the requirements;

干燥结束后，箱内压胶塞，出箱锁铝盖，成品检验合格后包装即得。对比实施例 1 After the drying is finished, the rubber plug is pressed in the box, and the aluminum cover is released from the box. After the finished product is inspected, the package is obtained. Comparative Example 1

复合物 20mg Compound 20mg

磷脂酰胆碱 260mg Phosphatidylcholine 260mg

注射用水至 10ml Water for injection to 10ml

将复合物、磷脂酰胆碱溶解于乙醇中，加热至 70Ό搅拌，至充分溶解。采用减压蒸发的方法蒸馏乙醇，得到胶状的固体，加入注射用水至全量， 60°C下充分搅拌混匀，结果形成颗粒度很大的乳状物，不澄清。对比实施例 2 The complex and phosphatidylcholine were dissolved in ethanol, and heated to 70 ° with stirring until fully dissolved. The ethanol was distilled by a method of evaporation under reduced pressure to obtain a colloidal solid, and water for injection was added to the whole amount, and the mixture was thoroughly stirred and mixed at 60 ° C to form a milk having a large particle size, which was not clarified. Comparative Example 2

复合物 20mg Compound 20mg

牛磺胆酸 lOOmg Taurocholic acid lOOmg

注射用水至 10ml Water for injection to 10ml

将复合物、牛磺胆酸溶解于乙醇中，加热至 70Ό搅拌，至充分溶解。采用减压蒸发的方法蒸馏乙醇，得到胶状的固体，加入注射用水至全量， 60'C下充分搅拌混匀，结果形成颗粒度很大的乳状物，不澄清。对比实施例 3 The complex and taurocholic acid were dissolved in ethanol, and heated to 70 Torr to be stirred until fully dissolved. Using reduced pressure evaporation The ethanol was distilled to obtain a colloidal solid, and water for injection was added to the whole amount, and the mixture was thoroughly stirred and mixed at 60 ° C to form a milk having a large particle size, which was not clarified. Comparative Example 3

复合物 5mg Complex 5mg

胆酸 150mg Cholic acid 150mg

磷脂 20mg Phospholipid 20mg

维生素 E 5mg Vitamin E 5mg

注射用水至 10ml Water for injection to 10ml

：将复合物和胆酸加热溶于 5mol/L氢氧化钠溶液中，用 lmol/L盐酸调 PH值至 7. 0，加入磷脂、维生素 E搅拌溶解，加注射用水至全量。形成有很多大颗粒的混悬液，并且在短时间内药品成份迅速析出。 : The complex and bile acid are heated and dissolved in a 5 mol/L sodium hydroxide solution, and the pH value is adjusted to 7.0 with 1 mol/L hydrochloric acid, and the phospholipid and vitamin E are added to stir and dissolve, and water for injection is added to the whole amount. A suspension of many large particles is formed, and the components of the drug are rapidly precipitated in a short period of time.

对比实验例 4 Comparative experiment example 4

复合物 4. 5mg Complex 4. 5mg

大豆油 30mg Soybean oil 30mg

大豆磷脂 llmg Soy lecithin llmg

维生素 E 0. lmg Vitamin E 0. lmg

甘油 2. 5mg Glycerin 2. 5mg

注射用水至 10ml Water for injection to 10ml

将大豆油、复合物加入容器中，将此容器置于油浴中，加热至 100°C，搅拌至药物溶解，降温至 80°C。然后加入大豆磷脂、维生素，搅拌至磷脂溶解形成均匀油相。将注射用水 80ml 置于另一容器中，加入甘油于 80°C下搅拌溶解形成水相。将油相在搅拌下加入水相中，继续搅拌 40分钟形成初乳，用氢氧化钠调节 PH至 8。加注射用水至 100ml,将初乳用高压匀质机或超声探头匀化。 The soybean oil and the compound were placed in a container, and the container was placed in an oil bath, heated to 100 ° C, stirred until the drug was dissolved, and the temperature was lowered to 80 ° C. Soybean phospholipids, vitamins are then added and stirred until the phospholipids dissolve to form a homogeneous oil phase. 80 ml of water for injection was placed in another container, and glycerin was added thereto to dissolve at 80 ° C to form an aqueous phase. The oil phase was added to the aqueous phase with stirring, stirring was continued for 40 minutes to form colostrum, and pH was adjusted to 8 with sodium hydroxide. Add water for injection to 100 ml and homogenize the colostrum with a high pressure homogenizer or ultrasonic probe.

实施例 24 Example 24

取实施例 10制备的注射用冻干粉针在阴凉处贮藏半年，观察其理化性质变化，记录为下列表格 The lyophilized powder for injection prepared in Example 10 was stored in a cool place for half a year, and its physical and chemical properties were observed and recorded as the following table.

室温留样观察结果 Sample retention at room temperature

时间（月） 0 1 2 4 6 Time (month) 0 1 2 4 6

外观类白色类白色类白色类白色类白色含量 100 99. 93 99. 92 99. 81 99. 87 PH 8. 30 8. 27 8. 33 8. 31 8. 25 由上述数据可见，本发明组合物质量稳定。 Appearance class white white white white white content 100 99. 93 99. 92 99. 81 99. 87 PH 8. 30 8. 27 8. 33 8. 31 8. 25 From the above data, it can be seen that the composition of the present invention is stable in quality.

从其复溶后的溶液外观判断，所得组合物溶液澄清，放置两天未见药物析出，目视观察无乳光。依据《中国药典 2005年版（二部）》附录 IX B方法，将制备的溶液与等量的浊度标准液分别置于配对的比浊用玻璃管中，在浊度标准液制备 5分钟后，在暗室内垂直同置于伞棚灯下，照度为 lOOOLx, 从水平方向观察、比较，制备的溶液澄清，不深于 1号浊度标准液。实施例 25粒径检测 Judging from the appearance of the solution after reconstitution, the obtained composition solution was clarified, and no drug was precipitated for two days, and no opalescence was visually observed. According to the method of Appendix IX B of the Chinese Pharmacopoeia 2005 Edition (Part 2), the prepared solution and the equal amount of turbidity standard solution were placed in a paired turbidity glass tube, respectively, after 5 minutes of preparation of the turbidity standard solution, Vertically placed under the umbrella shed lamp in the dark room, the illuminance is lOOOLx. When viewed from the horizontal direction, the prepared solution is clarified and not deeper than the No. 1 turbidity standard solution. Example 25 Particle Size Detection

将对比实验例 3和 4与本发明实施例 2制备的注射液进行了粒径检测，所得结果如下表。粒径 1代表本发明实施例 2的注射液，粒径 2为对比实验例 4的组合物、粒径 3为对比实验例 3的组合物。 Comparative Examples 3 and 4 and the injection prepared in Example 2 of the present invention were subjected to particle size measurement, and the results obtained are shown in the following table. The particle size 1 represents the injection liquid of Example 2 of the present invention, the particle size 2 is the composition of Comparative Experimental Example 4, and the particle size 3 is the composition of Comparative Experimental Example 3.

粒径观察结果 Particle size observation

由上述结果可知，本发明注射用溶液粒径明显小于对比实验例 3和 4制备的组合物。同时本发明注射液粒径属于胶束溶液，在粒径上接近于真溶液，稳定性优于现有技术制备的乳剂和注射液。 From the above results, the particle size of the solution for injection of the present invention was significantly smaller than that of the compositions prepared in Comparative Examples 3 and 4. At the same time, the particle size of the injection of the present invention belongs to a micelle solution, which is close to the true solution in particle size, and the stability is superior to the emulsion and the injection prepared in the prior art.

实施例 26 Example 26

将按照实施例 10 方法制得的冻干产物复溶后进行动物血管的刺激性试验。方法是取健康、耳缘无损伤家兔 40只，按体重随机分为两组，即注射用复合物试验组和氯化钠注射液对照组。以临床成人拟用剂量为依据设计家兔给药剂量，从家兔左侧耳缘静脉缓慢推注给药，对照组给予等容积氯化钠注射液，连续给予 5天。试验结果表明，与氯化钠注射液组相比，静脉推注给予注射用复合物，给药期间及末次给药 24小时后，肉眼观察未见血管及周围组织红肿，组织切片检査可见兔耳静脉结构清晰，个别血管扩张明显，管壁厚薄均匀，内壁平滑，管周无炎性渗出物。表明实验条件下注射用复合物对家兔耳缘静脉无明显刺激作用。 The lyophilized product prepared according to the method of Example 10 was reconstituted and subjected to an animal blood vessel irritation test. The method was to take 40 healthy rabbits with no ear damage and randomly divided into two groups according to body weight, namely, the injection compound test group and the sodium chloride injection control group. Rabbits were dosed according to the clinical adult dose, and were injected slowly from the left ear vein of rabbits. The control group was given an equal volume of sodium chloride injection for 5 consecutive days. The results of the test showed that compared with the sodium chloride injection group, the injection compound was administered by intravenous bolus injection. After the administration and 24 hours after the last administration, no red blood vessels and surrounding tissues were observed by the naked eye. The structure of the ear vein is clear, the individual blood vessels are dilated, the wall thickness is uniform, the inner wall is smooth, and there is no inflammatory exudate around the tube. It indicated that the injection compound had no obvious stimulating effect on rabbit ear veins under the experimental conditions.

Claims

权利要求书 Claim

1. 一种药物组合物，包含治疗有效量的环木菠萝烯醇阿魏酸酯和 24-亚甲基环木菠萝醇阿魏酸酯复合物、胆汁酸和 /或其盐、磷脂，其中，所述环木菠萝烯醇阿魏酸酯和 24-亚甲基环木菠萝醇阿魏酸酯复合物中环木菠萝烯醇阿魏酸酯和 24-亚甲基环木菠萝醇阿魏酸酯质量百分含量不低于 90%。 A pharmaceutical composition comprising a therapeutically effective amount of cycloartipenol ferulate and 24-methylenecyclopentanol ferulate complex, bile acid and/or a salt thereof, a phospholipid, wherein , the cycloartenol ferulate and the 24-methylene cyclotree pineappel alcohol ferulic acid ester complex, the cyclopentenol ferulate and the 24-methylene cyclopentanol ferulic acid The ester mass percentage is not less than 90%.

2. 根据权利要求 1的药物组合物，其中复合物、胆汁酸和 /或其盐、磷脂质量比是 1 : 1-100： 1-500。 The pharmaceutical composition according to claim 1, wherein the mass ratio of the complex, the bile acid and/or its salt, and the phospholipid is 1: 1-100: 1-500.

3. 根据权利要求 2的药物组合物，其中复合物、胆汁酸和 /或其盐、磷脂质量比是 1 : 1-50： 1-100。 The pharmaceutical composition according to claim 2, wherein the mass ratio of the complex, the bile acid and/or its salt, and the phospholipid is 1: 1-50: 1-100.

4. 根据权利要求 3的药物组合物，复合物、胆汁酸和 /或其盐、磷脂质量比是 1 : 5-40： 5-80。 The pharmaceutical composition according to claim 3, wherein the mass ratio of the complex, bile acid and/or its salt to phospholipid is 1: 5-40: 5-80.

5. 根据权利要求 1〜4中任一项权利要求的药物组合物，其制备方法包括以下步骤：将复合物、磷脂、胆汁酸和 /或其盐混合、搅拌、溶解于有机溶剂中，挥发有机溶剂。 The pharmaceutical composition according to any one of claims 1 to 4, which comprises the steps of: mixing, stirring, dissolving a complex, a phospholipid, a bile acid and/or a salt thereof in an organic solvent, and volatilizing Organic solvents.

6. . 根据权利要求 1〜4中任一项权利要求的药物组合物，在溶液状态，所述复合物的浓度为 lmg~ 100mg/mL The pharmaceutical composition according to any one of claims 1 to 4, wherein the concentration of the complex is from 1 mg to 100 mg/mL in a solution state.

7. 根据权利要求 1〜4 中任一项权利要求的药物组合物，在溶液状态，所述磷脂的浓度为 The pharmaceutical composition according to any one of claims 1 to 4, wherein the concentration of the phospholipid is in a solution state

1 mg〜 1000mg/ml。 1 mg ~ 1000 mg / ml.

8. 根据权利要求 1 ~4中任一项权利要求的药物组合物，在溶液状态，所述胆汁酸和 /或其盐的浓度为 lmg〜500mg/ml。 The pharmaceutical composition according to any one of claims 1 to 4, wherein the concentration of the bile acid and/or its salt is from 1 mg to 500 mg/ml in a solution state.

9. 根据权利要求 1〜4中任一项权利要求的药物组合物，所述磷脂选自大豆磷脂、蛋黄磷脂、大豆鞘磷脂、蛋黄鞘磷脂、氢化大豆磷脂、氢化蛋黄磷脂、磷脂酰胆碱、磷脂酰乙醇胺、磷脂酰丝氨酸、磷脂酰甘油、磷脂酰肌醇、二棕榈磷脂酰胆碱、二棕榈磷脂酰乙醇胺、二硬脂磷脂酰胆碱、二棕榈磷脂酰甘油脂、二棕榈磷脂酰丝氨酸、二肉豆蔻酰磷脂酰胆碱、二肉豆蔻酰磷脂酰甘油、二肉豆蔻酰磷脂酰乙醇胺、二亚油酰磷脂酰胆碱、二亚油酸甘油脂磷脂酰胆碱、二亚油酸甘油脂磷脂酰乙醇胺、二亚油酸甘油脂磷脂酰甘油的一种和 /或一种以上的混合物。 The pharmaceutical composition according to any one of claims 1 to 4, wherein the phospholipid is selected from the group consisting of soybean phospholipid, egg yolk phospholipid, soybean sphingomyelin, egg sphingomyelin, hydrogenated soybean phospholipid, hydrogenated egg yolk phospholipid, phosphatidylcholine , phosphatidylethanolamine, phosphatidylserine, phosphatidylglycerol, phosphatidylinositol, dipalmitoylphosphatidylcholine, dipalmitoylphosphatidylethanolamine, distearylphosphatidylcholine, dipalmitophosphatidylglyceride, dipalmitophosphatidyl Serine, dimyristoyl phosphatidylcholine, dimyristoyl phosphatidylglycerol, dimyristoyl phosphatidylethanolamine, dilinoleoylphosphatidylcholine, dilinoleic acid glycerol phosphatidylcholine, di arsenic One and/or more than one mixture of glycerylphosphatidylphosphatidylethanolamine, dilinoleic acid glycerol phosphatidylglycerol.

10. 根据权利要求 1〜4中任一项权利要求的药物组合物，所述胆汁酸选自游离胆汁酸、结合胆汁酸或二者的混合物；所述胆汁酸盐是胆汁酸成盐后的产物。 The pharmaceutical composition according to any one of claims 1 to 4, wherein the bile acid is selected from the group consisting of a free bile acid, a bound bile acid or a mixture of the two; the bile acid salt is a salt of bile acid product.

1 1. 根据权利要求 10的药物组合物，其中的游离胆汁酸为胆酸、石胆酸、去氧胆酸、鹅去氧胆酸、熊去氧胆酸、猪去氧胆酸或其混合物；结合胆汁酸为上述游离胆汁酸中的羧醛与甘氨酸或牛磺酸或其他含有氨基的化合物中的氨基形成酰胺键后的产物或其混合物。 1 1. The pharmaceutical composition according to claim 10, wherein the free bile acid is cholic acid, lithocholic acid, deoxycholic acid, chenodeoxycholic acid, ursodeoxycholic acid, hyodeoxycholic acid or a mixture thereof; The bile acid is a product obtained by forming an amide bond between a carboxaldehyde in the above free bile acid and an amino group in a glycine or taurine or other amino group-containing compound, or a mixture thereof.

12. 根据权利要求 11的药物组合物，其中的游离胆汁酸为胆酸、去氧胆酸、鹅去氧胆酸、熊去氧胆酸、猪去氧胆酸或其混合物；其中的结合胆汁酸为甘氨胆酸、甘氨去氧胆酸、甘氨鹅去氧胆酸、甘氨熊去氧胆酸、甘氨猪去氧胆酸、牛磺胆酸、牛磺去氧胆酸、牛磺鹅去氧胆酸、牛磺熊去氧胆酸、牛磺猪去氧胆酸或其混合物。 12. The pharmaceutical composition according to claim 11, wherein the free bile acid is cholic acid, deoxycholic acid, chenodeoxycholic acid, ursodeoxycholic acid, hyodeoxycholic acid or a mixture thereof; wherein the bile acid is combined For glycocholic acid, glycodeoxycholic acid, Gan Amino chenodeoxycholic acid, glycine ursodeoxycholic acid, glycine hyodeoxycholic acid, taurocholic acid, taurodeoxycholic acid, taurochenodeoxycholic acid, tauroursodeoxycholic acid, Taurine hyodeoxycholic acid or a mixture thereof.

13. 根据权利要求 10的药物组合物，其中的胆汁酸盐为胆汁酸的钾盐、钠盐、钙盐、镁盐、锌盐、硒盐、铁盐或其混合物。 13. The pharmaceutical composition according to claim 10, wherein the bile acid salt is a potassium salt, a sodium salt, a calcium salt, a magnesium salt, a zinc salt, a selenium salt, an iron salt or a mixture thereof of the bile acid.

14. 根据权利要求 1 的药物组合物，还包含增溶剂，所述增溶剂选自吐温、聚乙二醇十二位羟基硬脂酸酯、聚乙二醇、丙三醇、丙二醇、乙二醇、羟丙基 P环糊精、聚维酮中的一种和 /或一种以上的混合物。 14. The pharmaceutical composition according to claim 1, further comprising a solubilizing agent selected from the group consisting of Tween, polyethylene glycol t-dodecyl hydroxystearate, polyethylene glycol, glycerol, propylene glycol, and B. One of diol, hydroxypropyl P cyclodextrin, povidone, and/or a mixture of more than one.

15. 根据权利要求 14 的药物组合物，所需增溶剂的量为磷脂和胆汁酸和 /或其盐质量之和的 0〜2倍。 The pharmaceutical composition according to claim 14, wherein the amount of the solubilizing agent is 0 to 2 times the sum of the mass of the phospholipid and the bile acid and/or its salt.

16. 根据权利要求 1 的药物组合物，还包含药学上可以接受的辅料，所述的辅料包括等张调节剂、稳定剂、抗氧剂、 PH调节剂、防腐剂、赋形剂中的一种和 /或一种以上的混合物。 16. The pharmaceutical composition according to claim 1, further comprising a pharmaceutically acceptable excipient, the excipient comprising one of an isotonic modifier, a stabilizer, an antioxidant, a pH adjuster, a preservative, and an excipient And/or more than one mixture.

17. 一种冻干粉针剂，其含有治疗有效量的环木菠萝烯醇阿魏酸酯和 24-亚甲基环木菠萝醇阿魏酸酯复合物、胆汁酸和 /或其盐、以及磷脂，其中，所述环木菠萝烯醇阿魏酸酯和 24- 亚甲基环木菠萝醇阿魏酸酯复合物中环木菠萝烯醇阿魏酸酯和 24-亚甲基环木菠萝醇阿魏酸酯质量百分含量不低于 90%。 17. A lyophilized powder injection comprising a therapeutically effective amount of cycloartenol ferulate and 24-methylenecyclo-bambolanol ferulate complex, bile acid and/or a salt thereof, and a phospholipid, wherein the cycloartipenol ferulate and the 24-methylene cyclopentanol ferulic acid ester complex are cyclopentalenol ferulate and 24-methylene cyclotree The ferulic acid ester content is not less than 90% by mass.

18. 根据权利要求 17的冻干粉针剂，其中复合物、胆汁酸和 /或其盐、磷脂质量比是 1 : 1-100： 1-500。 The lyophilized powder injection according to claim 17, wherein the mass ratio of the complex, the bile acid and/or its salt, and the phospholipid is 1: 1-100: 1-500.

19. 根据权利要求 18的冻干粉针剂，其中复合物、胆汁酸和 /或其&、磷脂质量比是 1 : 1-50： 1-100。 The lyophilized powder injection according to claim 18, wherein the mass ratio of the complex, the bile acid and/or its &, phospholipid is 1: 1-50: 1-100.

20. 根据权利要求 19的冻干粉针剂，复合物、胆汁酸和 /或其盐、磷脂质量比是 1 : 5-40： 5-80。 The lyophilized powder injection according to claim 19, wherein the mass ratio of the complex, the bile acid and/or the salt thereof, and the phospholipid is 1: 5-40: 5-80.

21. 根据权利要求 17〜20 中任一项权利要求的药物组合物，其制备方法包括以下步骤：将复合物、磷脂、胆汁酸和 /或其盐混合、搅拌、溶解于有机溶剂中，挥发有机溶剂。 The pharmaceutical composition according to any one of claims 17 to 20, which comprises the steps of: mixing, stirring, dissolving the complex, phospholipid, bile acid and/or a salt thereof in an organic solvent, and volatilizing Organic solvents.

22. 根据权利要求 17〜20中任一项权利要求的冻干粉针剂，所述冻干粉针冷冻干燥前的溶液中，复合物的浓度为 lmg〜100mg/ml。 The lyophilized powder injection according to any one of claims 17 to 20, wherein the concentration of the complex in the solution before freeze-drying of the freeze-dried powder is from 1 mg to 100 mg/ml.

23. 根据权利要求 17〜20中任一项权利要求的药物组合物，所述冻干粉针冷冻干燥前的溶液中，憐脂的浓度为 lmg〜1000mg/ml。 The pharmaceutical composition according to any one of claims 17 to 20, wherein the concentration of the pity is from 1 mg to 1000 mg/ml in the solution before freeze-drying of the freeze-dried powder.

24. 根据权利要求 17〜20中任一项权利要求的冻干粉针剂，所述冻干粉针冷冻干燥前的溶液中，胆汁酸和 /或其盐的浓度为 lmg〜500mg/ml。 The lyophilized powder injection according to any one of claims 17 to 20, wherein the concentration of the bile acid and/or its salt in the solution before freeze-drying of the freeze-dried powder needle is from 1 mg to 500 mg/ml.

25. 根据权利要求 17〜20中任一项权利要求的冻干粉针剂，所述磷脂选自大豆磷脂、蛋黄磷月旨、大豆鞘磷脂、蛋黄鞘磷脂、氢化大豆磷脂、氢化蛋黄磷脂、磷脂酰胆碱、磷脂酰乙醇胺、磷脂酰丝氨酸、磷脂酰甘油、磷脂酰肌醇、二棕榈磯脂酰胆碱、二棕榈磷脂酰乙醇胺、二硬脂磷脂酰胆碱、二棕榈磷脂酰甘油脂、二棕榈磷脂酰丝氨酸、二肉豆蔻酰磷脂酰胆碱、二肉豆蔻酰磷脂酰甘油、二肉豆蔻酰磷脂酰乙醇胺、二亚油酰磷脂酰胆碱、二亚油酸甘油脂憐脂酰胆碱、二亚油酸甘油脂磷脂酰乙醇胺、二亚油酸甘油脂磷脂酰甘油的一种和 /或一种以上的混合物。 The lyophilized powder injection according to any one of claims 17 to 20, wherein the phospholipid is selected from the group consisting of soybean phospholipid, egg yolk phosphorus, soybean sphingomyelin, egg sphingomyelin, hydrogenated soybean phospholipid, hydrogenated egg yolk phospholipid, phospholipid Acylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylglycerol, phosphatidylinositol, dipalmitoylcholine, dipalmitoylphosphatidyl Alcoholamine, distearylphosphatidylcholine, dipalmitophosphatidylglyceride, dipalmitoylphosphorylserine, dimyristoylphosphatidylcholine, dimyristoylphosphatidylglycerol, dimyristoylphosphatidylethanolamine, two a linoleoyl phosphatidylcholine, dilinoleic acid glyceryl lipoyl choline, dilinoleic acid glycerol phosphatidylethanolamine, dilinoleic acid glycerol phosphatidylglycerol, and/or a mixture of more than one .

26. 根据权利要求 17〜20中任一项权利要求的冻干粉针剂，所述胆汁酸选自游离胆汁酸、结合胆汁酸或二者的混合物；所述胆汁酸盐是胆汁酸成盐后的产物。 The lyophilized powder injection according to any one of claims 17 to 20, wherein the bile acid is selected from the group consisting of free bile acids, bound bile acids or a mixture of the two; the bile acid salt is a bile acid salt Product.

27. 根据权利要求 26的冻干粉针剂，其中的游离胆汁酸为胆酸、石胆酸、去氧胆酸、鹅去氧胆酸、熊去氧胆酸、猪去氧胆酸或其混合物；结合胆汁酸为上述游离胆汁酸中的羧醛与甘氨酸或牛磺酸或其他含有氨基的化合物中的氨基形成酰胺键后的产物或其混合物。 27. The lyophilized powder injection according to claim 26, wherein the free bile acid is cholic acid, lithocholic acid, deoxycholic acid, chenodeoxycholic acid, ursodeoxycholic acid, hyodeoxycholic acid or a mixture thereof; The bile acid is a product obtained by forming an amide bond between a carboxaldehyde in the above free bile acid and an amino group in a glycine or taurine or other amino group-containing compound, or a mixture thereof.

28. 根据权利要求 27的冻干粉针剂，其中的游离胆汁酸为胆酸、去氧胆酸、鹅去氧胆酸、熊去氧胆酸、猪去氧胆酸或其混合物；其中的结合胆汁酸为甘氨胆酸、甘氨去氧胆酸、甘氨鹅去氧胆酸、甘氨熊去氧胆酸、甘氨猪去氧胆酸、牛磺胆酸、牛磺去氧胆酸、牛磺鹅去氧胆酸、牛磺熊去氧胆酸、牛磺猪去氧胆酸或其混合物。 28. The lyophilized powder injection according to claim 27, wherein the free bile acid is cholic acid, deoxycholic acid, chenodeoxycholic acid, ursodeoxycholic acid, hyodeoxycholic acid or a mixture thereof; wherein the bile is combined Acids are glycocholic acid, glycodeoxycholic acid, glycine chenodeoxycholic acid, glycine ursodeoxycholic acid, glycine hyodeoxycholic acid, taurocholic acid, taurodeoxycholic acid, cattle Sulfonodeoxycholic acid, tauroursodeoxycholic acid, taurode hyodeoxycholic acid or a mixture thereof.

29. 根据权利要求 26的冻干粉针剂，其中的胆汁酸盐为胆汁酸的钾盐、钠盐、钙盐、镁盐、锌盐、硒盐、铁盐或其混合物。 29. The lyophilized powder injection according to claim 26, wherein the bile acid salt is a potassium salt, a sodium salt, a calcium salt, a magnesium salt, a zinc salt, a selenium salt, an iron salt or a mixture thereof of the bile acid.

30. 根据权利要求 17的冻干粉针剂，还包含增溶剂，所述增溶剂选自吐温、聚乙二醇十二位羟基硬脂酸酯、聚乙二醇、甘油、丙二醇、乙二醇、羟丙基 P环糊精、聚维酮中的一种和 /或一种以上的混合物。 30. The lyophilized powder injection according to claim 17, further comprising a solubilizing agent selected from the group consisting of Tween, polyethylene glycol dodecahydroxy hydroxystearate, polyethylene glycol, glycerin, propylene glycol, ethylene glycol One of an alcohol, hydroxypropyl P cyclodextrin, povidone, and/or a mixture of more than one.

31. 根据权利要求 30 的冻干粉针剂，所需增溶剂的量为磷脂和胆汁酸和 /或其盐质量之和的 0〜2倍。 The lyophilized powder injection according to claim 30, wherein the amount of the solubilizing agent is 0 to 2 times the sum of the mass of the phospholipid and the bile acid and/or the salt thereof.

32. 根据权利要求 17的冻干粉针剂，还包含药学上可以接受的辅料，所述的辅料包括等张调节剂、稳定剂、抗氧剂、 PH调节剂、防腐剂、赋形剂中的一种和 /或一种以上的混合物。 32. The lyophilized powder injection according to claim 17, further comprising a pharmaceutically acceptable excipient, wherein the excipient comprises an isotonic regulator, a stabilizer, an antioxidant, a pH adjuster, a preservative, an excipient One and/or more than one mixture.

33. 一种试剂盒，包含两种单位制剂，其中第一种单位制剂中包括治疗有效量的环木菠萝烯醇阿魏酸酯和 24-亚甲基环木菠萝醇阿魏酸酯复合物、胆汁酸和 /或其盐、以及磷脂；第二种单位制剂为溶剂。 33. A kit comprising two unit preparations, wherein the first unit preparation comprises a therapeutically effective amount of cycloartenol ferulate and 24-methylenecyclopentanol ferulate complex , bile acids and/or salts thereof, and phospholipids; the second unit formulation is a solvent.

34. 根据权利要求 33的试剂盒，第一种制剂中复合物、胆汁酸和 /或其盐、磷脂质量比是 1 : 34. The kit according to claim 33, wherein the mass ratio of the complex, the bile acid and/or its salt, and the phospholipid in the first preparation is 1:

1-100： 1-500。 1-100: 1-500.

35. 根据权利要求 34的试剂盒，第一种制剂中复合物、胆汁酸和 /或其盐、磷脂质量比是 1 : 35. The kit according to claim 34, wherein the mass ratio of the complex, the bile acid and/or its salt, and the phospholipid in the first preparation is 1:

1-50： 1-100。 1-50: 1-100.

36. 根据权利要求 35的试剂盒，第一种制剂中复合物、胆汁酸和 /或其盐、磷脂质量比是 1 : 36. The kit according to claim 35, wherein the mass ratio of the complex, the bile acid and/or its salt, and the phospholipid in the first preparation is 1:

5-40： 5-80。 5-40: 5-80.

37. 根据权利要求 33 的试剂盒，其第一种制剂的制备方法包括以下步骤：将其中的组分混合、搅拌、溶解于有机溶剂中，挥发有机溶剂。 The kit according to claim 33, wherein the preparation method of the first preparation comprises the steps of: mixing, stirring, dissolving the components therein in an organic solvent, and volatilizing the organic solvent.

38. 根据权利要求 33的试剂盒，第二种制剂中的溶剂为水溶液。 38. A kit according to claim 33, wherein the solvent in the second formulation is an aqueous solution.

39. 根据权利要求 38的试剂盒，第二种制剂中的溶剂为水。 39. The kit according to claim 38, wherein the solvent in the second formulation is water.

40. 根据权利要求 38的试剂盒，第二种制剂中的溶剂为含有注射剂常规用辅料的水溶液。 The kit according to claim 38, wherein the solvent in the second preparation is an aqueous solution containing a conventional excipient for injection.

41. 根据权利要求 40的试剂盒，所述注射剂常规用辅料选自等张调节剂、稳定剂、抗氧剂、 PH调节剂、防腐剂、赋形剂、增溶剂中的一种和 /或一种以上的混合物。 The kit according to claim 40, wherein the auxiliary for injection is selected from the group consisting of an isotonic regulator, a stabilizer, an antioxidant, a pH adjuster, a preservative, an excipient, a solubilizer, and/or More than one mixture.

42. 根据权利要求 33〜41中任一项权利要求的试剂盒，试剂盒中的二种制剂混合均匀后，所述复合物的浓度为 lmg〜100mg/ml。 The kit according to any one of claims 33 to 41, wherein the concentration of the complex is from 1 mg to 100 mg/ml after the two preparations in the kit are uniformly mixed.

43. 根据权利要求 33〜41中任一项权利要求的试剂盒，试剂盒中的二种制剂混合均匀后，所述磷脂的浓度为 lmg〜1000mg/ml。 The kit according to any one of claims 33 to 41, wherein the concentration of the phospholipid is from 1 mg to 1000 mg/ml after the two preparations in the kit are uniformly mixed.

44. 根据权利要求 33〜41中任一项权利要求的试剂盒，试剂盒中的二种制剂混合均匀后，所述胆汁酸和 /或其盐的浓度为 lmg〜500mg ml。 The kit according to any one of claims 33 to 41, wherein the concentration of the bile acid and/or its salt is from 1 mg to 500 mg ml after the two preparations in the kit are uniformly mixed.

45. 根据权利要求 33的试剂盒，所述磷脂选自大豆磷脂、蛋黄磷脂、大豆鞘磷脂、蛋黄鞘磷月旨、氢化大豆磷脂、氢化蛋黄磷脂、磷脂酰胆碱、磷脂酰乙醇胺、磷脂酰丝氨酸、磷脂酰甘油、磷脂酰肌醇、二棕榈磷脂酰胆碱、二棕榈磷脂酰乙醇胺、二硬脂磷脂酰胆碱、二棕榈磷脂酰甘油脂、二棕榈磷脂酰丝氨酸、二肉豆蔻酰磷脂酰胆碱、二肉豆蔻酰磷脂酰甘油、二肉豆蔻酰磷脂酰乙醇胺、二亚油酰磷脂酰胆碱、二亚油酸甘油脂磷脂酰胆碱、二亚油酸甘油脂磷脂酰乙醇胺、二亚油酸甘油脂磷脂酰甘油的一种和 /或一种以上的混合物。 45. The kit according to claim 33, wherein the phospholipid is selected from the group consisting of soybean phospholipid, egg yolk phospholipid, soybean sphingomyelin, egg yolk sheath phosphorus, hydrogenated soybean phospholipid, hydrogenated egg yolk phospholipid, phosphatidylcholine, phosphatidylethanolamine, phosphatidyl Serine, phosphatidylglycerol, phosphatidylinositol, dipalmitoylphosphatidylcholine, dipalmitoylphosphatidylethanolamine, distearylphosphatidylcholine, dipalmitophosphatidylglyceride, dipalmitophosphatidylserine, dimyristoyl phospholipid Acylcholine, dimyristoyl phosphatidylglycerol, dimyristoyl phosphatidylethanolamine, dilinoleoylphosphatidylcholine, dilinoleic acid glycerylphosphatidylcholine, dilinoleic acid glycerolipid phosphatidylethanolamine, One and/or more than one mixture of dilinoleic acid glycerol phosphatidylglycerol.

46. 根据权利要求 33的试剂盒，所述胆汁酸选自游离胆汁酸、结合胆汁酸或二者的混合物；所述胆汁酸盐是胆汁酸成盐后的产物。 46. The kit according to claim 33, wherein the bile acid is selected from the group consisting of free bile acids, bound bile acids, or a mixture of the two; the bile acid salt is a product of bile acid salt formation.

47. 根据权利要求 46的试剂盒，其中的游离胆汁酸为胆酸、 '石胆酸、去氧胆酸、鹅去氧胆酸、熊去氧胆酸、猪去氧胆酸或其混合物；结合胆汁酸为上述游离胆汁酸中的羧醛与甘氨酸或牛磺酸或其他含有氨基的化合物中的氨基形成酰胺键后的产物或其混合物。 47. The kit according to claim 46, wherein the free bile acid is cholic acid, 'lithocholic acid, deoxycholic acid, chenodeoxycholic acid, ursodeoxycholic acid, hyodeoxycholic acid or a mixture thereof; The bile acid is a product of a carboxaldehyde in the above free bile acid and an amide bond with glycine or an amino group in a taurine or other amino group-containing compound, or a mixture thereof.

48. 根据权利要求 47的试剂盒，其中的游离胆汁酸为胆酸、去氧胆酸、鹅去氧胆酸、熊去氧胆酸、猪去氧胆酸或其混合物；其中的结合胆汁酸为甘氨胆酸、甘氨去氧胆酸、甘氨鹅去氧胆酸、甘氨熊去氧胆酸、甘氨猪去氧胆酸、牛磺胆酸、牛磺去氧胆酸、牛磺鹅去氧胆酸、牛磺熊去氧胆酸、牛磺猪去氧胆酸或其混合物。 48. The kit according to claim 47, wherein the free bile acid is cholic acid, deoxycholic acid, chenodeoxycholic acid, ursodeoxycholic acid, hyodeoxycholic acid or a mixture thereof; wherein the bile acid is bound Glycocholic acid, glycodeoxycholic acid, glycine chenodeoxycholic acid, glycine ursodeoxycholic acid, glycine hyodeoxycholic acid, taurocholic acid, taurodeoxycholic acid, tauro geese Deoxycholic acid, tauroursodeoxycholic acid, taurode hyodeoxycholic acid or a mixture thereof.

49. 根据权利要求 46的试剂盒，其中的胆汁酸盐为胆汁酸的钾盐、钠盐、钙盐、镁盐、锌盐、硒盐、铁盐或其混合物。 49. The kit according to claim 46, wherein the bile acid salt is a potassium salt, a sodium salt, a calcium salt, a magnesium salt, a zinc salt, a selenium salt, an iron salt or a mixture thereof of the bile acid.

50. 根据权利要求 33的试剂盒，所述第一种制剂中还包含增溶剂，所述增溶剂选自吐温、聚乙二醇十二位羟基硬脂酸酯、聚乙二醇、甘油、丙二醇、乙二醇、羟丙基 β环糊精、聚维酮中的一种和 /或一种以上的混合物。 50. The kit according to claim 33, wherein said first preparation further comprises a solubilizing agent selected from the group consisting of Tween, polyethylene glycol dodecahydroxy hydroxystearate, polyethylene glycol, glycerin And one or more than one or more of propylene glycol, ethylene glycol, hydroxypropyl beta cyclodextrin, povidone.

51. 根据权利要求 50的试剂盒，所需增溶剂的量为磷脂和胆汁酸和 /或其盐质量之和的 0〜2 倍。 51. The kit according to claim 50, wherein the amount of the solubilizing agent is 0 to 2 times the sum of the mass of the phospholipid and the bile acid and/or its salt.

52. 根据权利要求 33的试剂盒，其中还包括指导如何使用的说明书。 52. A kit according to claim 33, further comprising instructions for instructions on how to use.

53. 权利要求 1〜16所述的药物组合物的制备方法，包括将环木菠萝烯醇阿魏酸酯和 24-亚甲基环木菠萝醇阿魏酸酯复合物与磷脂、胆汁酸和 /或其盐溶解于有机溶剂、减压蒸馏的步骤。 53. A process for the preparation of a pharmaceutical composition according to any of claims 1 to 16 comprising a mixture of cycloartenol ferulate and 24-methylenecyclo-bambolanol ferulate complex with phospholipids, bile acids and / The step of dissolving the salt thereof in an organic solvent and distilling under reduced pressure.

54. 根据权利要求 53所述药物组合物的制备方法，有机溶剂选自乙醇、乙酸乙酯、二氯甲垸、三氯甲垸、丙二醇中的一种和 /或一种以上的混合物。 54. A process for the preparation of a pharmaceutical composition according to claim 53 wherein the organic solvent is selected from the group consisting of ethanol, ethyl acetate, dichloromethane, trichloromethane, propylene glycol and/or a mixture of more than one.

55. 权利要求 17〜32所述的冻干粉针的制备方法，包括将环木菠萝烯醇阿魏酸酯和 24-亚甲基环木菠萝醇阿魏酸酯复合物与憐脂、胆汁酸和 /或其盐溶解于有机溶剂、减压蒸馏的步骤。 55. A method for preparing a lyophilized powder needle according to any of claims 17 to 32, which comprises a mixture of cycloartenol ferulate and 24-methylenecyclo-bambolanol ferulate, and pity, bile The step in which the acid and/or its salt are dissolved in an organic solvent and distilled under reduced pressure.

56. 根据权利要求 55所述的冻干粉针的制备方法，有机溶剂选自乙醇、乙酸乙酯、二氯甲烷、三氯甲垸、丙二醇中的一种和 /或一种以上的混合物。 56. A method of preparing a lyophilized powder needle according to claim 55, wherein the organic solvent is selected from the group consisting of ethanol, ethyl acetate, dichloromethane, trichloromethane, propylene glycol, and/or a mixture of more than one.

57. 根据权利要求 55或 56所述冻干粉针的制备方法，包括以下步骤： ①将复合物、磷脂、胆汁酸和 /或其盐混合、搅拌，减压蒸馏，得到有机相； ② 以注射用水或蒸馏水作为水相，如还有其它的药学辅料，也加入到水相中； ③ 将步骤①的有机相溶解于步骤②的水相中充分搅拌混匀。 57. A method for preparing a lyophilized powder needle according to claim 55 or 56, comprising the steps of: 1 mixing, stirring, and distilling the complex, phospholipid, bile acid and/or its salt to obtain an organic phase; Water for injection or distilled water is used as the aqueous phase, and if other pharmaceutical adjuvants are also added to the aqueous phase; 3 The organic phase of step 1 is dissolved in the aqueous phase of step 2 and thoroughly stirred and mixed.

58. 根据权利要求 57所述的冻干粉针制备方法，其中还包括将步骤③所得产品加入活性炭、过滤、除菌，冷冻干燥的步骤。 The method for preparing a lyophilized powder needle according to claim 57, further comprising the step of adding the product obtained in the step 3 to the activated carbon, filtering, sterilizing, and freeze-drying.

59. 权利要求 33〜52所述试剂盒的制备方法，包括将环木菠萝烯醇阿魏酸酯和 24-亚甲基环木菠萝醇阿魏酸酯复合物与磷脂、胆汁酸和 /或其盐溶解于有机溶剂、减压蒸馏的步骤。 59. A method of preparing a kit according to claims 33 to 52, comprising reacting cycloartenol ferulate and 24-methylenecyclo-bambolanol ferulate complex with phospholipids, bile acids and/or The salt is dissolved in an organic solvent and distilled under reduced pressure.

60. 根据权利要求 59所述的制备方法，有机溶剂选自乙醇、乙酸乙酯、二氯甲垸、三氯甲烷、丙二醇中的一种和 /或一种以上的混合物。 60. The production method according to claim 59, wherein the organic solvent is one selected from the group consisting of ethanol, ethyl acetate, dichloromethane, chloroform, propylene glycol, and/or a mixture of more than one.

61. 权利要求 33〜52所述试剂盒的使用方法，包括将第一种制剂和第二种制剂混合的步骤。 61. A method of using a kit according to claims 33 to 52, comprising the step of mixing the first formulation with the second formulation.