Manufacturing Strategies for Liposome and Proliposome-Based Drug Delivery Systems
摘要
In this chapter, various methods of preparing liposomes were reviewed with respect to the desired liposome characteristics such as size and number of bilayers. Thin-film hydration technique is the universally recognized method for preparing multilamellar liposome vesicles (MLVs), while subsequent sonication or extrusion can be used to generate small unilamellar liposome vesicles (SUVs) or large unilamellar liposome vesicles (LUVs), respectively. Liposomes made using the traditional techniques (e.g. thin-film hydration) have a range of instabilities such as phospholipid hydrolysis and oxidation, with subsequent vesicle aggregation and loss of the originally entrapped material from the liposomes. This is further complicated by the possible microbial contamination of the liposome formulations. Freeze-drying has been suggested as a method to stabilize liposomes through producing a lyophilized powder of the vesicles. Unfortunately, the stressful effect of freeze-drying may damage the liposome structures, causing them to aggregate or fuse during rehydration with concomitant loss of the originally entrapped material. Cryoprotectant materials (e.g. carbohydrates) have been included in the liposome formulations prior to freeze-drying in order to protect the liposomes from the deleterious effects of freeze-drying. As an alternative to freeze-drying, proliposome technologies are stable phospholipid formulations that are either particulate-based or solvent-based, and can generate liposomes upon addition of water just before administration. As for traditional liposomes, vesicles generated from proliposomes can be further processed to generate nano-sized vesicles (e.g. by probe-sonication). Liposomes generated from proliposomes can be produced at a larger scale using methods like high-pressure homogenization. An approach employing fluid-bed coating to manufacture proliposome granules consisting of sugar coated with lipids and steroid, followed by hydration and high-pressure homogenization to generate SUVs, has been introduced in our laboratory. This was followed by freeze-drying of the self-cryoprotected SUVs to generate stable lyophilized formulations offering high drug entrapment efficiency. Overall, further work on scaling up liposomes generated from proliposomes is needed to unlock the full potential of proliposome technologies for developing novel inhalable formulations.