A Review of Liposomes as a Drug Delivery System: Current Status of Approved Products, Regulatory Environments, and Future Perspectives

Abstract

Liposomes have been considered promising and versatile drug vesicles. Compared with traditional drug delivery systems, liposomes exhibit better properties, including site-targeting, sustained or controlled release, protection of drugs from degradation and clearance, superior therapeutic effects, and lower toxic side effects. Given these merits, several liposomal drug products have been successfully approved and used in clinics over the last couple of decades. In this review, the liposomal drug products approved by the U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA) are discussed. Based on the published approval package in the FDA and European public assessment report (EPAR) in EMA, the critical chemistry information and mature pharmaceutical technologies applied in the marketed liposomal products, including the lipid excipient, manufacturing methods, nanosizing technique, drug loading methods, as well as critical quality attributions (CQAs) of products, are introduced. Additionally, the current regulatory guidance and future perspectives related to liposomal products are summarized. This knowledge can be used for research and development of the liposomal drug candidates under various pipelines, including the laboratory bench, pilot plant, and commercial manufacturing.

Keywords: drug delivery; drug loading; lipid excipient; liposomes; marketed products.

Figure 1

Categories and structures of liposomal drug delivery system. (a) Structural illustration of liposome composition. The size of a typical phospholipid bilayer is 4.5 nm, which is much smaller than the one of the inner aqueous core; (b) Classification of liposomal vesicles according to their lamellarity/compartment and particle size; (c) The size and lamellarity of different types of liposomes; (d,e) The cryo-transmission electron microscopy of Doxil [35] and Vyxeos [36]; (f,g) The electron micrographs of DepoFoam^TM particles with a typical diameter of 1–100 μm (e.g., DepoCyt) and MLVs with a typical diameter of 0.2–5 μm (e.g., Mepact) [37].

Figure 2

(a) Structural illustration of glycerolphospholipid. R1 and R2 can be saturated or unsaturated fatty acids, such as decanoic acid, lauric acid, palmitic acid, oleic acid, myristic acid, stearic acid, and erucic acid. R3 can be phosphatidylcholine (PC), phosphatidyl ethanolamine (PE), phosphatidyl serine (PS), phosphatidyl inositols (PI), phosphatidic acid (PA), phosphatidylglycerol (PG), and cardiolipin; (b) Structure of sphingomyelin. (c) Structure of cholesterol.

Figure 3

The potential manufacturing processes of the marketed liposomal products, summarized based on the related patents or publications.

Figure 4

Different mechanisms of remote drug loading. (a) Doxil: DOX-loaded by transmembrane gradient of (NH₄)₂SO₄ concentration [35]; (b) Myocet, Marqibo, and DaunoXome: drug loaded by transmembrane gradient of pH; (c) Mepact: MDP chemically conjugated to PE through a peptide spacer, then formed liposomes with other phospholipids. (d) Onivyde: irinote can loaded by transmembrane gradient of the concentration of sucrosofate triethylammonium salt (TEA-SOS). One molecule of SOS can bind 8 molecules of irinotecan.

Figure 5

The phase transition of liposomal bilayer dispersed in aqueous solution. Heating above the melting temperature (T_m), the phase of bilayer transits from “solid” gel phase (L_β: hexagonal lattice untitled chain or L_β’: quasi hexagonal array with titled chain) (ordered state) to liquid crystalline phase (L_α) (disordered state). Cooling below T_c, the phase of bilayer transits from “solid” gel phase (L_β or L_β’) (ordered state) to subgel phase or crystalline phase (L_c) (ordered state).

Figure 6

The comparison profiles of publications using setting TITLE-ABS-KEY as “liposome”, “(liposome AND medicine) or (liposome AND drug)”, “(nano AND liposomes AND medicine) or (nano AND liposomes AND drug) and “(nano AND medicine) or (nano AND drug)” in the year range between 1970 and 2020 in Scopus.