熊果酸及其衍生物纳米晶的研究

发布时间：2018-01-15 01:12

本文关键词：熊果酸及其衍生物纳米晶的研究　出处：《中国医药工业研究总院》2016年博士论文　论文类型：学位论文

【摘要】：天然活性成分熊果酸(Ursolic Acid,UA)具有多种药理活性,特别是抗肿瘤活性备受关注,具有潜在成药价值。由于其溶解性和渗透性差,生物利用度低,影响药效发挥。改善UA的溶解性,优化其药动学属性,研究多种给药途径的适用性,提高生物利用度很有必要。纳米晶(Nanocrystals,NC)技术或纳米混悬(Nanosuspension,NS)技术,能够明显改善难溶性药物的溶解度和溶出速率,且适用于包括注射、口服在内的多种给药途径,纳米晶或纳米混悬制剂具有独特的药代动力学属性,有很好的应用前景。因此,本文采用纳米晶技术解决UA生物利用度问题,提出两种研究策略:设计口服UA-NC,提高UA的口服生物利用度;研究注射给药途径,设计具有缓释特性的UA衍生物-NC,通过肌肉注射给药实现缓慢释药,提高UA生物利用度。本文首先以提高口服生物利用度为目标,以纳米晶技术为手段,探讨不同处方工艺所制备的UA-NC对UA口服吸收的影响。分别采用溶剂沉淀(Solvent Precipitation,SP)法和高压均质(High Pressure Homogenization,HPH)法制备UA-NC,确定了不同制备方法的较优工艺参数和条件。采用星点设计-效应面法对高压微射流均质法进行了影响因素考察,确定了影响因素泊洛沙姆188含量、均质压力、均质时间对UA-NC的平均粒径、粒径分布和Zeta电位等指标的关系。初步考察了UA-NC的冻干条件以及冻干再分散性。扫描电镜结果表明,HPH法所得UA-NC呈细小的短杆形,而SP法所得UA-NC为近球形不规则颗粒。差示扫描量热和粉末X射线结果均表明,在HPH过程中,有部分UA转化为无定形态,而SP法UA-NC全部以无定形态存在。体外溶出试验表明UA-NC显著提高了UA的溶出速率。以50 mg/kg的剂量灌胃给以不同工艺制备的UA-NC后,HPH组和SP组Cmax分别为UA原药组的2.4和3.5倍,AUC0-∞分别是原药的2.5倍和3.8倍,显著增加了UA的口服生物利用度。同时,消除速率显著降低,体内滞留时间延长。其次,本文以研究UA长效注射给药制剂为目标,通过设计和制备UA衍生物NC,探讨UA及其衍生物NC长效注射给药的适用性以及化合物结构对UA及其衍生物NC体内药代动力学的影响。分别合成了C-3位衍生物乙酰氧基熊果酸(AUA)和辛酰氧基熊果酸(OUA)以及C-28位衍生物熊果酸乙酯(UAA)和熊果酸辛酯(UAO)。采用HPH法制备的衍生物NC,药物粒子以无定形态存在于混悬介质中,平均粒径约为300 nm。四种不同衍生物NC大鼠肌注给药的药代动力学结果表明,与等剂量UA-NC肌注给药相比,AUA和OUA组Tmax相近,Cmax明显降低。UAA和UAO组,Tmax显著延长,Cmax显著降低,AUC0-∞显著提高,血浆清除率CL/F显著降低,具有较UA-NC更为明显的缓释特征。四种衍生物肌注给药后大鼠体内的UA暴露量均较低,且随着衍生化碳链增加而呈进一步降低的趋势,有待进一步研究。
[Abstract]:Natural active ingredients of ursolic acid (Ursolic Acid UA) has a variety of pharmacological activities, especially the antitumor activity of concern, with potential medicine value. Because of its solubility and poor permeability, low bioavailability, affect the efficacy of play. To improve the solubility of UA, optimize its pharmacokinetic properties and applicability to research a variety of ways of drug and improve the bioavailability is necessary. Nanocrystalline (Nanocrystals, NC) or nanosuspension (Nanosuspension, NS) technology, can significantly improve the solubility of insoluble drugs and dissolution rate, and is suitable for injection, including a variety of oral route of administration, nanocrystalline or nano suspension preparation has unique pharmacokinetic properties, has good application prospects. Therefore, this paper uses UA technology to solve the problem of nano biological utilization, put forward two research methods: Design of oral UA-NC, improve the oral bioavailability of UA; research The injection route, UA derivatives -NC design has the characteristic of sustained release, by intramuscular administration achieve slow release, improve the bioavailability of UA. Firstly, in order to improve the oral bioavailability of the target, using nanocrystalline technology as a means to investigate the effects of different prescription prepared UA-NC UA oral absorption by using solvent precipitation. Respectively (Solvent Precipitation, SP) and high pressure homogenization (High Pressure Homogenization, HPH) UA-NC prepared by different preparation methods, the optimal process parameters and conditions are determined. The influence factors of high pressure microfluidization method using central composite design response surface method, determine the influencing factors of Bo poloxamer 188 content, homogenization pressure, homogenization time of average particle size of UA-NC, the relationship between particle size distribution and Zeta potential index. The preliminary investigation of freezing and freeze drying conditions of UA-NC redispersible. Scanning electron microscope The results show that the HPH method of the UA-NC is small short rod, and the UA-NC SP method is nearly spherical particles are irregular. DSC and X ray powder. The results show that in the process of HPH, part of UA transformed into amorphous, and SP UA-NC all existed in a form of indefinite test. Show that UA-NC significantly improves the dissolution rate of UA dissolution in vitro. At a dose of 50 mg/kg by gavage with different preparation methods of UA-NC, HPH group and SP group Cmax respectively UA TC was 2.4 and 3.5 times, respectively AUC0- - TC is 2.5 times and 3.8 times, significantly increased UA oral bioavailability. At the same time, the elimination rate is significantly reduced, prolong the retention time in vivo. Secondly, based on the research of UA long-acting injection preparations as the goal, through the design and preparation of UA derivative NC system, discusses the applicability and compound administration structure of UA and its derivative NC and its derivative UA NC long-acting injection Influence of the pharmacokinetics of C-3 derivatives were synthesized. Acetoxy ursolic acid (AUA) and Xin Xianyang (OUA) and ursolic acid C-28 ester derivatives of ursolic acid (UAA) and ursolic acid ester (UAO). Using HPH preparation of derivatives of NC, drug particles in amorphous form in the mix the suspension medium, the average particle size is about 300 nm. of four kinds of derivatives of NC rats administered intramuscularly pharmacokinetics results showed that with the dose of UA-NC administered intramuscularly as compared to AUA group and OUA group were similar to Tmax,.UAA and Cmax decreased significantly in UAO group, Tmax was significantly prolonged, Cmax significantly decreased significantly, AUC0- 2 increased plasma clearance rate of CL/F was significantly decreased, UA-NC has a more significant sustained release characteristics. Four kinds of derivatives of intramuscular injection in rats UA after drug exposure was low, and with the derivatization of carbon chain increased further decreased, require further research.

【学位授予单位】：中国医药工业研究总院
【学位级别】：博士
【学位授予年份】：2016
【分类号】：R943

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