Abstract
Nowadays, the freeze-drying of liposome dispersions is still necessary to provide a solid dosage form intended for different routes of administration (i.e., parenteral, oral, nasal and/or pulmonary). However, after decades of studies the optimization of process conditions remains still challenging since the freezing and the dehydration destabilize the vesicle organization with the concomitant drug leakage. Starting from the thermal properties of phospholipids, this work reviews the main formulation and process parameters which can guarantee a product with suitable characteristics and increase the efficiency of the manufacturing process. In particular, an overview of the cryo- and/or lyo-protective mechanisms of several excipients and the possible use of co-solvent mixtures is provided. Attention is also focused on the imaging methods recently proposed to characterize the appearance of freeze-dried products and liposome dispersions upon reconstitution. The combination of such data would allow a better knowledge of the factors causing inter-vials variability in the attempt to improve the quality of the final medicinal product.
Highlights
Over the past decades, liposomes have evolved from models for artificial cells due to their structural similarity to biological membranes, to very attractive drug delivery systems
1. definitTioonoobftatihneatawreglel-tdpesriogdnufrceteqzeu-adlriytiyngprporfioclees, s, the application of Quality by Design (QbD) 2. deptearmadingmatisohnouoldf tbheealcsroitaipcaplieqdubaalisteydaotntrtihbeufotellsow(CinQgAassp)eacntsd[8c8r]i:tical process parameters (CPPs), 3. ris1k. assdeesfisnmitieonnto, f the target product quality profile, 4. de23v..elodrpiesmtkeeramsnstiensoasftmiaoennntoe,fxtpheercirmitiecanltqaul adlietsyiagtntriabiumteisn(gCQtoAisn) vanedstcigriatitcealthpreoicmesps paacrtaomfeCtePrsP(sCoPnPsC), QAs and est4a.blidshevaeldopemsiegnnt ospf aanceexperimental design aiming to investigate the impact of CPPs on CQAs and 5. designeastnadbliismh pa ldeemsigenntsaptaicoen of a control strategy to ensure a continuous improvement
After decades of studies in this field, no “rules of thumbs” can be proposed to make the design and development of a freeze-dried liposomal formulation easier. It is not just a matter of the type and location of protectant or the definition of process parameters, but it is the intricate relation among such variables and bilayer composition which determines the success of lyophilization to stabilize liposomes in a dried state
Summary
Liposomes have evolved from models for artificial cells due to their structural similarity to biological membranes, to very attractive drug delivery systems. Depending on the hydration level, hydrocarbon chains can be tilted or not tilted; the angle of tilt increases with the increase of water content, obtaining a thin bilayer [19] Other factors, such as the type of phospholipid polar head or the presence of cholesterol, may influence the chain tilt [20]. Differential scanning calorimetry (DSC) and microcalorimetry analyses are often used to study the response of the lipid membrane to formulation additives and/or external factors, being either a drug or an environmental stress These techniques can be applied only on very simplified formulations, since for example the presence of cholesterol significantly decreases the enthalpy variation associated Tm and, at high concentrations, hinders the transition [22]. ◦bbCeecc[aa3uu6ss,3ee7tt]hhceeanbbiibllaaeyyaeedrrduuenndddteeorrwwreeednnuttcaae the intrinsic stochasticity in this step
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