技术领域technical field
the
本发明属于医药技术领域，涉及一种聚合物包覆齐墩果酸脂质体及其制备方法。The invention belongs to the technical field of medicine, and relates to a polymer-coated oleanolic acid liposome and a preparation method thereof.
背景技术Background technique
齐墩果酸（oleanolic acid，OA）广泛分布于自然界中，为五环三萜类化合物，是从天然植物中提取出的有效活性单体，以游离形式或苷的形式存在。OA可改善肝细胞结构和功能，抑制肝细胞线粒体过氧化脂质形成，临床已作为肝病辅助治疗的OTC药物用于急性化学性肝损伤、慢性肝硬化和肝纤维化，还具有免疫双向调节作用及抗癌等药理作用。OA主要以被动扩散方式吸收，然而其在水中溶解度和溶出速度极差、肠细胞（Caco-2单层细胞）表观渗透系数仅为1.1×10-6-1.3×10-6cm/s，因此限制了其在胃肠道的溶出与吸收，导致OA口服吸收差，在大鼠体内的绝对生物利用度仅为0.7%。为了改善OA的体外溶出和提高体内口服生物利用度，构建稳定性高、促进药物跨膜吸收的口服新剂型是目前研究的热点。Oleanolic acid (OA) is widely distributed in nature and is a pentacyclic triterpenoid compound. It is an effective active monomer extracted from natural plants and exists in free form or in the form of glycosides. OA can improve the structure and function of liver cells, inhibit the formation of lipid peroxidation in the mitochondria of liver cells, and has been clinically used as an OTC drug for adjuvant treatment of liver diseases for acute chemical liver injury, chronic liver cirrhosis and liver fibrosis, and also has two-way immune regulation and anti-cancer pharmacological effects. OA is mainly absorbed by passive diffusion, but its solubility and dissolution rate in water are extremely poor, and the apparent permeability coefficient of enterocytes (Caco-2 monolayer cells) is only 1.1×10-6 -1.3×10-6 cm/s, Therefore, its dissolution and absorption in the gastrointestinal tract is limited, resulting in poor oral absorption of OA, and the absolute bioavailability in rats is only 0.7%. In order to improve the in vitro dissolution of OA and increase the oral bioavailability in vivo, constructing new oral dosage forms with high stability and promoting drug transmembrane absorption is a current research hotspot.
脂质体制剂口服给药安全、生物利用度提高、患者顺应性强，包覆脂质体作为一种新型的膜修饰脂质体，优点在于通过囊泡间静电作用、空间阻力作用、亲水性等，增加了脂质体双层膜的稳定性，从而提高了脂质体的体内外稳定性；包覆层的存在使药物能够缓慢释放；包覆材料的选择可以达到延长脂质体体内滞留及循环时间、促进药物跨膜吸收的目的。将包覆脂质体混悬液制备为前体脂质体，不仅提高了脂质体的长期稳定性，而且在包装、贮存和运输中更为方便。Liposomal preparations are safe for oral administration, with improved bioavailability and strong patient compliance. As a new type of membrane-modified liposome, coated liposomes have the advantages of electrostatic interaction between vesicles, steric resistance, and hydrophilicity. properties, etc., which increase the stability of the liposome bilayer membrane, thereby improving the in vivo and in vitro stability of the liposome; the existence of the coating layer enables the drug to be released slowly; the selection of the coating material can prolong the liposome in vivo. The residence and circulation time, and the purpose of promoting drug transmembrane absorption. Preparing the coated liposome suspension as proliposome not only improves the long-term stability of the liposome, but also is more convenient in packaging, storage and transportation.
发明内容Contents of the invention
本发明的目的在于提供一种使齐墩果酸体内滞留及循环时间延长、跨膜吸收提高、并且便于包装、贮存和运输的聚合物包覆齐墩果酸脂质体及其制备方法，使齐墩果酸的体内生物利用度提高，使用更方便。The object of the present invention is to provide a kind of polymer-coated oleanolic acid liposome and preparation method thereof that make oleanolic acid stay in the body and prolong the circulation time, improve transmembrane absorption, and be convenient for packaging, storage and transportation. The in vivo bioavailability of oleanolic acid is improved and it is more convenient to use.
本发明的技术方案是：一种聚合物包覆齐墩果酸脂质体及其制备方法，其特征是，所述制备方法包括以下步骤：The technical scheme of the present invention is: a kind of polymer coating oleanolic acid liposome and preparation method thereof, it is characterized in that, described preparation method comprises the following steps:
(1) 制备药物脂质体混悬液：以齐墩果酸、磷脂、胆固醇、复合乳化剂溶于有机溶剂中作为油相，磷酸盐缓冲液作为水相（若后续采用冷冻干燥法制备前体脂质体，在此处应加入冻干保护剂），采用薄膜分散法、乙醇注入法、逆相蒸发法、复乳法或熔融法，在水浴条件下进一步乳化，方法包括高压均质机匀化乳化、高速剪切搅拌乳化、超声乳化或胶体磨乳化，制备药物的脂质体混悬液；(1) Preparation of drug liposome suspension: oleanolic acid, phospholipids, cholesterol, and complex emulsifiers are dissolved in an organic solvent as the oil phase, and phosphate buffer as the water phase (if the subsequent freeze-drying method is used to prepare Body liposome, here should add freeze-drying protective agent), using film dispersion method, ethanol injection method, reverse phase evaporation method, double emulsion method or melting method, further emulsification under water bath conditions, methods include high-pressure homogenizer Homogenizing emulsification, high-speed shear emulsification, ultrasonic emulsification or colloid mill emulsification to prepare liposome suspension of drugs;
(2) 制备聚合物包覆脂质体混悬液：将(1)制得混悬液与聚合物的磷酸盐缓冲液相互混合，10℃搅拌混匀60min，即得聚合物包覆齐墩果酸脂质体混悬液；(2) Preparation of polymer-coated liposome suspension: mix the suspension prepared in (1) with the polymer phosphate buffer, stir and mix at 10°C for 60 minutes, and obtain the polymer-coated liposome AHA liposome suspension;
(3) 采用喷雾干燥或冷冻干燥制备聚合物包覆齐墩果酸前体脂质体，即将聚合物包覆脂质体混悬液经喷雾干燥（进风温度为140-220℃，出风温度为70-100℃）或冷冻干燥（预冻时间7-12h，预冻温度-70℃，冷冻干燥时间为24-38h，冷冻干燥温度-50℃）制备聚合物包覆齐墩果酸前体脂质体。(3) Prepare polymer-coated oleanolic acid proliposomes by spray drying or freeze-drying, that is, the polymer-coated liposome suspension is spray-dried (inlet air temperature is 140-220°C, The temperature is 70-100°C) or freeze-drying (pre-freezing time 7-12h, pre-freezing temperature -70°C, freeze-drying time 24-38h, freeze-drying temperature -50°C) before preparing polymer-coated oleanolic acid body liposomes.
(4) 将喷干或冻干后制得的包覆齐墩果酸前体脂质体根据需要，加入适量蒸馏水，经振荡、超声或搅拌水合后重新得到聚合物包覆脂质体混悬液。(4) Add an appropriate amount of distilled water to the coated oleanolic acid proliposomes obtained after spray drying or lyophilization as needed, and obtain polymer-coated liposome suspension again after shaking, ultrasonication or stirring for hydration liquid.
以齐墩果酸为模型药，试验结果表明包封率可达85%-99%，口服生物利用度得到显著提高。Using oleanolic acid as a model drug, the test results show that the encapsulation rate can reach 85%-99%, and the oral bioavailability has been significantly improved.
本发明所述的聚合物包覆齐墩果酸脂质体的组分及其质量百分比为：齐墩果酸0.01%-20%、包覆材料0.2%-20%、磷脂2%-85%、胆固醇0.5%-25%、复合乳化剂0%-5%、冻干保护剂0%-6%。The components of the polymer-coated oleanolic acid liposome according to the present invention and their mass percentages are: 0.01%-20% of oleanolic acid, 0.2%-20% of coating materials, and 2%-85% of phospholipids , cholesterol 0.5%-25%, compound emulsifier 0%-5%, lyoprotectant 0%-6%.
本发明所述聚合物包覆材料为聚乙二醇2000、聚乙二醇4000、聚乙二醇6000、聚乙烯醇、环糊精、壳聚糖、壳寡糖、羧甲基壳聚糖、三甲基壳聚糖中的一种或几种。The polymer coating material of the present invention is polyethylene glycol 2000, polyethylene glycol 4000, polyethylene glycol 6000, polyvinyl alcohol, cyclodextrin, chitosan, chitosan oligosaccharide, carboxymethyl chitosan , one or more of trimethyl chitosan.
本发明所述磷脂选自大豆磷脂、蛋黄卵磷脂、二棕榈酰磷脂酰胆碱、磷脂酰肌醇、磷脂酰乙醇胺、磷脂酰甘油或磷脂酰胆碱中的一种或几种。The phospholipids in the present invention are selected from one or more of soybean lecithin, egg yolk lecithin, dipalmitoylphosphatidylcholine, phosphatidylinositol, phosphatidylethanolamine, phosphatidylglycerol or phosphatidylcholine.
本发明所述复合乳化剂为吐温85、吐温80、吐温60、苄泽、卖泽、司盘80、司盘60、聚氧乙烯蓖麻油、聚氧乙烯氢化蓖麻油、泊洛沙姆、辛酸癸酸聚乙二醇甘油酯中的一种或几种。The composite emulsifier of the present invention is Tween 85, Tween 80, Tween 60, Benze, Maize, Span 80, Span 60, polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, poloxa One or several kinds of macrogol glyceride caprylic acid and caprylic acid.
本发明所述冻干保护剂为甘露醇、乳糖、山梨醇、海藻糖、葡萄糖、氯化钠、右旋糖苷、环糊精、蔗糖、麦芽糖、果糖中的一种或几种。The lyoprotectant of the present invention is one or more of mannitol, lactose, sorbitol, trehalose, glucose, sodium chloride, dextran, cyclodextrin, sucrose, maltose and fructose.
本发明的有益效果是：聚合物包覆齐墩果酸脂质体除具有普通脂质体的优点外，还具有以下优点：（1）包覆脂质体提高了药物的稳定性，克服了普通脂质体聚集、沉降和渗漏等不稳定现象；（2）延长了制剂的体内滞留时间、循环时间，促进药物的跨膜吸收；（3）所述包覆脂质体显著提高齐墩果酸的生物利用度，该齐墩果酸固态粉剂便于包装、贮存和运输，使用更方便。The beneficial effect of the present invention is: polymer coated oleanolic acid liposome has the following advantages except having the advantage of common liposome: (1) coating liposome has improved the stability of medicine, has overcome Unstable phenomena such as aggregation, sedimentation and leakage of ordinary liposomes; (2) prolong the residence time and circulation time of the preparation in vivo, and promote the transmembrane absorption of drugs; (3) the coated liposomes significantly improve the The bioavailability of the fruit acid, the oleanolic acid solid powder is convenient for packaging, storage and transportation, and is more convenient to use.
为了更好地理解本发明，下面结合实施例进一步阐明本发明的内容，但本发明的内容不仅仅局限于下面的实施例。In order to better understand the present invention, the content of the present invention is further illustrated below in conjunction with the examples, but the content of the present invention is not limited to the following examples.
实施例 1 一种聚合物包覆齐墩果酸脂质体及其制备方法，它包括如下步骤：Embodiment 1 A kind of polymer-coated oleanolic acid liposome and preparation method thereof, it comprises the steps:
采用乙醇注入法，取齐墩果酸0.1g、大豆卵磷脂2g、胆固醇0.5mg、吐温800.1g溶于乙醇中作为油相，使药物与脂质完全溶解，快速滴入到恒温搅拌下的甘露醇磷酸盐缓冲液50ml中（5%，w/v，pH6.8），持续恒温（50±2℃）搅拌至乙醇挥发完全。在冰水浴条件下超声处理（超声功率80%，超声时间4min），即得齐墩果酸脂质体混悬液。将制得混悬液缓慢滴入季铵度65%的三甲基壳聚糖的磷酸盐缓冲液（1%，w/v）50ml中，10℃搅拌混匀60min，即得三甲基壳聚糖包覆齐墩果酸脂质体混悬液，采用喷雾干燥（进风温度为140-220℃，出风温度为70-100℃）制备三甲基壳聚糖包覆前体脂质体，包封率为94.8%，临用前根据需要，加入适量蒸馏水，即得三甲基壳聚糖包覆齐墩果酸脂质体混悬液。Using the ethanol injection method, take 0.1g of oleanolic acid, 2g of soybean lecithin, 0.5mg of cholesterol, and 800.1g of Tween dissolved in ethanol as the oil phase, so that the drug and lipid are completely dissolved, and quickly drop into the liquid under constant temperature stirring. In 50ml of mannitol phosphate buffer solution (5%, w/v, pH 6.8), keep stirring at constant temperature (50±2°C) until ethanol evaporates completely. Ultrasonic treatment (ultrasonic power 80%, ultrasonic time 4min) under the condition of ice-water bath, obtains oleanolic acid liposome suspension. Slowly drop the prepared suspension into 50ml of trimethyl chitosan phosphate buffer (1%, w/v) with a quaternary ammonium degree of 65%, and stir and mix for 60 minutes at 10°C to obtain trimethyl chitosan Glycan-coated oleanolic acid liposome suspension was spray-dried (inlet air temperature 140-220°C, outlet air temperature 70-100°C) to prepare trimethyl chitosan-coated precursor lipids body, the encapsulation rate was 94.8%, before use, according to the need, add appropriate amount of distilled water to obtain trimethyl chitosan-coated oleanolic acid liposome suspension.
实施例 2 一种聚合物包覆齐墩果酸脂质体及其制备方法，它包括如下步骤：Embodiment 2 A kind of polymer coated oleanolic acid liposome and preparation method thereof, it comprises the following steps:
采用薄膜分散法，取齐墩果酸0.3g、大豆卵磷脂4.1g、胆固醇2g，吐温800.06g，泊洛沙姆1880.07g溶于乙醇中作为油相，使用旋转蒸发仪35℃蒸干成膜，除去乙醇，停止旋转保持真空继续抽吸2h后停止，加入右旋糖酐的磷酸盐缓冲液50ml中（5%，w/v，pH6.8），剧烈振摇40min，洗膜后在4℃条件下高压均质机匀化（均质压力80Mpa，循环次数5次），即得齐墩果酸脂质体混悬液。将制得混悬液缓慢滴入羧甲基壳聚糖的磷酸盐缓冲液（1%，w/v）50ml中，10℃搅拌混匀60min，即得羧甲基壳聚糖包覆齐墩果酸脂质体混悬液，采用喷雾干燥（进风温度为140-220℃，出风温度为70-100℃）制备羧甲基壳聚糖包覆前体脂质体，包封率为85.3%，临用前根据需要，加入适量蒸馏水，即得羧甲基壳聚糖包覆齐墩果酸脂质体混悬液。Using the film dispersion method, take 0.3g of oleanolic acid, 4.1g of soybean lecithin, 2g of cholesterol, 800.06g of Tween, and 1880.07g of poloxamer dissolved in ethanol as the oil phase, and evaporate to dryness at 35°C using a rotary evaporator. Remove the ethanol from the membrane, stop the rotation and keep the vacuum for 2 hours, then stop, add 50ml of dextran phosphate buffer solution (5%, w/v, pH6.8), shake vigorously for 40min, wash the membrane at 4°C Homogenize with a high pressure homogenizer (homogenization pressure 80Mpa, cycle times 5 times) to obtain oleanolic acid liposome suspension. Slowly drop the prepared suspension into 50ml of carboxymethyl chitosan phosphate buffer (1%, w/v), stir and mix at 10°C for 60min to obtain carboxymethyl chitosan-coated oleoresin Fruit acid liposome suspension, prepared by spray drying (inlet air temperature 140-220°C, outlet air temperature 70-100°C) to prepare carboxymethyl chitosan-coated proliposomes, encapsulation efficiency 85.3%, according to needs before use, add appropriate amount of distilled water to obtain carboxymethyl chitosan-coated oleanolic acid liposome suspension.
实施例 3 一种聚合物包覆齐墩果酸脂质体及其制备方法，它包括如下步骤：Embodiment 3 A kind of polymer-coated oleanolic acid liposome and preparation method thereof, it comprises the steps:
采用逆相蒸发法，取蛋黄卵磷脂3.5g、胆固醇0.9g溶于乙醚中作为油相，加入3.1ml乳糖、甘露醇（1：1，w/w）的混合磷酸盐缓冲液，超声5min得到乳浊液，使用旋转蒸发仪25℃除去乙醚至胶态，加入含有0.2g齐墩果酸的乙醇溶液7ml，35℃旋转蒸发至干，停止旋转保持真空继续抽吸2h后停止，加入乳糖、甘露醇（1：1，w/w）的混合磷酸盐缓冲液50ml中（5%，w/v，pH6.8），剧烈振摇40min，洗膜后在冰水浴条件下超声处理（超声功率80%，超声时间4min），即得齐墩果酸脂质体混悬液。将制得混悬液缓慢滴入环糊精的磷酸盐缓冲液（7%，w/v）50ml中，10℃搅拌混匀60min，即得环糊精包覆齐墩果酸脂质体混悬液，采用冷冻干燥（预冻时间7-12h，预冻温度-70℃，冷冻干燥时间为24-38h）制备环糊精包覆前体脂质体，包封率为90.7%，临用前根据需要，加入适量蒸馏水，即得环糊精包覆齐墩果酸脂质体混悬液。Using the reverse phase evaporation method, take 3.5g of egg yolk lecithin and 0.9g of cholesterol dissolved in ether as the oil phase, add 3.1ml of lactose and mannitol (1:1, w/w) mixed phosphate buffer solution, and ultrasonicate for 5min to obtain For the emulsion, use a rotary evaporator at 25°C to remove ether to a colloidal state, add 7ml of ethanol solution containing 0.2g oleanolic acid, and evaporate to dryness at 35°C, stop the rotation and keep vacuuming for 2 hours, then stop, add lactose, Mix mannitol (1:1, w/w) in 50ml of phosphate buffer (5%, w/v, pH 6.8), shake vigorously for 40min, wash the membrane and sonicate it in an ice-water bath (ultrasonic power 80%, ultrasonic time 4min), that is, oleanolic acid liposome suspension. Slowly drop the prepared suspension into 50ml of cyclodextrin-containing phosphate buffer (7%, w/v), stir and mix at 10°C for 60min to obtain cyclodextrin-coated oleanolic acid liposome mixture. The suspension was freeze-dried (pre-freezing time 7-12h, pre-freezing temperature -70°C, freeze-drying time 24-38h) to prepare cyclodextrin-coated proliposomes, the encapsulation efficiency was 90.7%, and it was used immediately According to need, add appropriate amount of distilled water to obtain cyclodextrin-coated oleanolic acid liposome suspension.
实施例 4 一种聚合物包覆齐墩果酸脂质体及其制备方法，它包括如下步骤：Embodiment 4 A kind of polymer-coated oleanolic acid liposome and preparation method thereof, it comprises the following steps:
采用熔融法，取蛋黄卵磷脂5.2g溶于海藻糖（3%，w/v，pH6.8）的磷酸盐缓冲液，倾入熔融的胆固醇2.8g中，搅拌均匀后加入0.6g齐墩果酸的乙醇溶液7ml，恒温搅拌倾入海藻酸（3%，w/v，pH6.8）的磷酸盐缓冲液50ml中，持续恒温（68±2℃）挥发30min，超声处理（超声功率80%，超声时间4min），即得齐墩果酸脂质体混悬液。将制得混悬液缓慢泵入聚乙二醇2000的磷酸盐缓冲液（10%，w/v）50ml中，10℃搅拌混匀60min，即得聚乙二醇2000包覆齐墩果酸脂质体混悬液，采用冷冻干燥（预冻时间7-12h，预冻温度-70℃，冷冻干燥时间为24-38h，冷冻干燥温度-50℃）制备聚乙二醇2000包覆前体脂质体，包封率为87.2%，临用前根据需要，加入适量蒸馏水，即得聚乙二醇2000包覆齐墩果酸脂质体混悬液。Using the melting method, take 5.2g of egg yolk lecithin dissolved in phosphate buffer solution of trehalose (3%, w/v, pH6.8), pour it into 2.8g of molten cholesterol, stir well and add 0.6g of olean 7ml of ethanol solution of acid, stirred at constant temperature, poured into 50ml of phosphate buffer solution of alginic acid (3%, w/v, pH6.8), volatilized at constant temperature (68±2°C) for 30min, ultrasonic treatment (ultrasonic power 80%) , ultrasonic time 4min), that is, oleanolic acid liposome suspension. Slowly pump the prepared suspension into 50ml of phosphate buffer solution (10%, w/v) of polyethylene glycol 2000, stir and mix at 10°C for 60 minutes to obtain polyethylene glycol 2000-coated oleanolic acid Liposome suspension, prepared by freeze-drying (pre-freezing time 7-12h, pre-freezing temperature -70°C, freeze-drying time 24-38h, freeze-drying temperature -50°C) to prepare polyethylene glycol 2000 coated precursor The liposome has an encapsulation rate of 87.2%. Before use, an appropriate amount of distilled water is added to obtain a polyethylene glycol 2000-coated oleanolic acid liposome suspension.
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| CN104622808A (en)* | 2014-09-16 | 2015-05-20 | 江西中医药大学 | Polymer-coated cyanidin and glucoside lipidosome for eyes and preparation method of polymer-coated cyanidin and glucoside lipidosome |
| CN104814928A (en)* | 2015-04-29 | 2015-08-05 | 江西省科学院应用化学研究所 | Preparation method of dihydromyricetin-carried ternary complex liposome |
| CN104984339A (en)* | 2015-06-26 | 2015-10-21 | 燕山大学 | Oleanolic acid liposome coated with nanogold spherical shell and preparation method thereof |
| CN104983684A (en)* | 2015-07-09 | 2015-10-21 | 钟志容 | Oleanolic acid polycystic lipidosome and preparation method and application thereof |
| CN112999197A (en)* | 2021-03-05 | 2021-06-22 | 浙江医药高等专科学校 | Chitosan-coated solid lipid nanoparticle for promoting pentacyclic triterpenoid drug absorption and preparation method thereof |
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104622808A (en)* | 2014-09-16 | 2015-05-20 | 江西中医药大学 | Polymer-coated cyanidin and glucoside lipidosome for eyes and preparation method of polymer-coated cyanidin and glucoside lipidosome |
| CN104814928A (en)* | 2015-04-29 | 2015-08-05 | 江西省科学院应用化学研究所 | Preparation method of dihydromyricetin-carried ternary complex liposome |
| CN104814928B (en)* | 2015-04-29 | 2017-06-13 | 江西省科学院应用化学研究所 | A kind of preparation method for carrying dihydromyricetin tri compound liposome |
| CN104984339A (en)* | 2015-06-26 | 2015-10-21 | 燕山大学 | Oleanolic acid liposome coated with nanogold spherical shell and preparation method thereof |
| CN104984339B (en)* | 2015-06-26 | 2017-11-24 | 燕山大学 | A kind of oleanolic acid liposome of nano gold spherical shell cladding and preparation method thereof |
| CN104983684A (en)* | 2015-07-09 | 2015-10-21 | 钟志容 | Oleanolic acid polycystic lipidosome and preparation method and application thereof |
| CN104983684B (en)* | 2015-07-09 | 2018-04-03 | 钟志容 | Oleanolic acid multivesicular liposome, preparation method and applications |
| CN112999197A (en)* | 2021-03-05 | 2021-06-22 | 浙江医药高等专科学校 | Chitosan-coated solid lipid nanoparticle for promoting pentacyclic triterpenoid drug absorption and preparation method thereof |
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| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
| WD01 | Invention patent application deemed withdrawn after publication | Application publication date:20131106 |