Integrity plus injectors4/28/2023 ![]() ![]() Conversely, few examples of in silico rationalization of such excipient are available in the literature. Excipients are usually selected on calorimetric studies focused on the thermotropic pattern of phospholipids in their presence. In order to obtain a uniform lyo-cake, cryo- and/or lyo-protectants may be combined to other excipients acting as bulking agents, which are necessary to assure a suitable physical structure. According to literature data, the choice of excipients suitable for liposome lyophilization is limited mainly to monosaccharides and disaccharides, which can either replace water molecules in stable hydrogen bonds with lipid head groups and/or form a glassy matrix spacing between adjacent lipid bilayers, thus avoiding fusion and mechanical disruption. In general, adding cryo-protectants and/or lyo-protectants leads to effective preservation of the liposomes and allows easy reconstitution of the lyo-cake. Therefore, formulation design and lyo-cycle conditions should be specifically studied. However, freeze-drying can cause structural changes to liposomes as a result of freezing and dehydration stresses: ice crystals can damage bilayer membranes through mechanical stress, whereas water removal can induce fusion and/or aggregation phenomena. Lyophilization has the potential to yield a dried product in a single operation with the concomitant advantages of facilitating transportation, storage and prolonging shelf-life. However, the elimination of residual ethanol may be problematic because of the formation of an azeotropic ethanol/water mixture. Among them, the ethanol injection method allows to achieve a good control over the physical properties of liposomes and can be scaled-up at the industrial level. Due to the increasing interest, preparation methods have been evolving from conventional laboratory scale techniques based on top-down approaches which require post-processing steps (e.g., thin film hydration method) to bottom-up technologies enabling to tailor liposome size with a good reproducibility and scalability. Nevertheless, it should be also underlined that cakes blew out at an ethanol concentration higher than 1% v/ v, probably due to the poor cohesion within the cake and solvent vapour pressure upon sublimation.īeing among the most versatile carriers to effectively deliver active substances, liposomes have been investigated for a wide range of applications in the food, cosmetic and pharmaceutic industries. Differently from the other tested protectants, the selected trehalose/PVP combination allows to preserve liposome size, even in the presence of 6% ethanol, as demonstrated by Nanoparticle Tracking Analysis (NTA). The effect further improved in the presence of PVP. Overall data suggested a stronger cryo-protectant effect of trehalose, compared with sucrose, due to stronger interactions with the DPPC bilayer and the formation of highly ordered clusters around the lipids. The freeze-drying protocol was based on calorimetric results. The interactions among vesicles and protectants were preliminary screened by Molecular Dynamics (MD) simulations, which have been proved useful in rationalizing the selection of protectant(s). This work aimed to investigate the effects of possible protectants, namely sucrose, trehalose and/or poly(vinyl pyrrolidone) (PVP), on the main features of the dried product using a 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC)-based liposomal dispersion prepared by ethanol injection and containing ethanol up to 6%, as a model. The freeze-drying of complex formulations, such as liposomes, is challenging, particularly if dispersions contain residual organic solvents.
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