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| 米托蒽醌脂质体处方筛选与工艺优化
摘要
脂质体是由磷脂与胆固醇组成的磷脂双分子层结构的囊泡。脂质体用于包封实体分子具有很多的优势，改善化合物溶解性，改善体内代谢动力学分布，能被动或主动靶向于病变组织，增加被包封物质稳定性等作用。因此，脂质体可以作为药物的优良载体。本论文以制备粒径小，单分布的脂质体用于包封米托蒽醌药物为出发点，搭建具备产业化生产潜力的脂质体药物制剂开发平台以及筛选具有合适释放速率的米托蒽醌脂质体制剂。本论文主要包括以下三部分：
关键词：脂质体；改良乙醇注入法；制备工艺；米托蒽醌
Abstract
Liposomes are vesicles with a phospholipid bilayerstructure composed of phospholipids and cholesterol. Liposomes have many advantages for encapsulating solid molecules,improving the solubility of compounds and the distribution of metabolic kinetics in the body, being able to passively or actively target diseased tissues and increasing the stability of the encapsulated substances. Therefore, liposomes can be used as excellent carriers for drugs.In this thesis, to prepare small particle size,single-distributed liposomes for encapsulatingmitoxantrone drugs, this study build a liposome drug formulation development platform with industrial production potential and screen for mitoxantrone liposome preparations with a suitable release rate. This paper mainly includes the following three parts:
The first chapter reviewed the prescription and technology of liposome drugs that have been on the market. Liposomes are widely used in drug carriers, and are now used in a variety of drugs,including anti-tumor drugs, anti-infectives, analgesics, local anesthetics and other different fields. The marketed liposomes are divided into two types: active drug-loading and passive drug-loading.In the last part, the significance and innovation of this paper are introduced.
The second chapter developed a liposome preparation platform for preparing liposomes of different particle sizes and narrow distribution by smallpore size tangential flow injection method combined with extrusion method. Firstly, ethanol injection method is selected.Subsequently, the organic phase water ratio of the ethanol injection method,the lipid concentration, the injection rate,and the influence of the stirring rate on the particle size were optimized,and a small pore tangential flow injection method that can be used for scale-up production was designed, and its preparation effect was better than that of direct ethanol inject and reduce the amount of ethanol. In order to further reduce the particle size and improve the particle size distribution, the effects of ultrasonic dispersion method,high-pressure homogenization method, and high-pressure extrusion method on particle size reduction are compared. The influence of different factors on particle size reduction of high-pressure homogenization method and high-pressure extrusion method were investigated. Finally, it is concluded that high-pressure homogenization is suitable for liposomes with large particle size and very uneven distribution,and high-pressure extrusion is suitable for liposomes with small initial particle size and need to increase particle size distribution. Finally, liposomes are prepared by small pore tangential flow injection and extrusion.The preparation process can be scaled up linearly.This platform can be used for the development of various nano-liposome preparations.
The third chapter screened out the mitoxantrone liposome formulation with suitable release rate.First, a tangential flow filtration system was used to construct a pH gradient.This method also has advantages that replacing the external water phase,removing the ethanol in the system, and diluting or concentrating to the desired concentration. The effects of drug loading temperature, drug loading time,and drug-to-lipid ratio on the encapsulation efficiency of mitoxantrone were investigated. The subsequent drug release optimization was carried out for prescription screening,and the liposome particle size, drug-to-lipid ratio, and dilution effect on the release were investigated. Finally, a liposome formulation of mitoxantrone with a particle size of 70nm and a drug-to-lipid ratio of 1:15 was optimized. It was released from a plasma sample and had a suitable release rate, which could be used for follow-up research.
Key words: Liposome,Improved ethanol injection method, Preparation technology, Mitoxantrone
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