ADVANTAGES OF LIPOSOMAL DELIVERY SYSTEMS

4. ADVANTAGES OF LIPOSOMAL DELIVERY SYSTEMS

Since liposomes can be constructed with a range of properties (particle size, lamellarity, drug loading, drug release characteristics, etc.) depending on the method of manufac-

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ture, the choice of lipids, and other excipients, etc., they can

be easily manipulated to suit a wide range of drug delivery applications. Liposomal encapsulation of drugs offers several advantages over their conventional direct administration in vivo.

4.1. Liposomes for Solubilizing Drugs Liposomes can serve as efficient solubilizing vehicles for drugs

with poor solubility in pharmaceutically acceptable solvents. Such a strategy has been used to improve drug solubility for

a wide range of compounds including alphaxalone (48), camp- tothecin (49), tacrolimus (50), econazole (51), and paclitaxel (52). Entrapment of drugs can also be used to reduce in vivo degradation and thus enhance the biological half-life of a drug;

a feature that has been extremely useful for preserving and prolonging the pharmacological activity of nucleic acid therapeu- tics such as antisense oligonucleotides and plasmid DNA (26,27).

4.2. Liposomes for Tissue Targeting Liposomes can be used for passive or active tissue targeting

by virtue of their size or by the incorporation of immunorecog- nition motifs in the liposomal bilayer, respectively (6,7,53). Upon intravenous (i.v.) administration, liposomes larger than 200 nm are quickly cleared from the systemic circulation due to rapid uptake by phagocytic macrophages and other compo- nents of the reticuloendothelial system (53). The rate at which conventional liposomes are cleared from the circulation is dependent on their particle size, charge, and fluidity (54). Negative charge, larger size, and high fluidity all increase clearance (54,55). The adsorption of plasma proteins on the liposome surface, also known as opsonization, promotes reticuloendothelial uptake of liposomes (55,56). The negative charge of conventional liposomes facilitates opsonization (54). Due to this characteristic preferential uptake, liposomes larger than 200 nm can be used to target and deliver drugs into macrophages for diseases that involve these cells (56,57).

Liposomes smaller than 100 nm can escape phagocytic macrophage uptake and thus have higher circulation times

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in vivo compared to those of larger liposomes (58,59). Small liposomes can extravasate into tissues if the space in between cells surrounding the vasculature is significantly large. Under physiological conditions, extravasation is restricted to the liver and spleen tissue; however, the vasculature of tumors and tissues under inflammatory conditions is uneven and the intercellular spaces are abnormally wide (53,60,61). Very small liposomes can easily exit ‘‘leaky’’ vasculatures and are selectively accumulated in such tissues. This phenomenon is known as the enhanced permeability and retention (EPR) effect (53,60,61). The EPR effect of small liposomes having long circulation times in the systemic circulation has been used to achieve targeted delivery of anticancer drugs into tumors (53,62), and antifungal (63) as well as radiocontrast agents (64) into pathological sites in the liver and the spleen. Since drugs are released in desired tissues, their therapeutic potential can be significantly enhanced and side effects dra- matically reduced (7). AmBisome, a liposomal antifungal pro- duct, has been shown to avoid uptake by the mononuclear phagocytic cells and thus a prolonged circulation time as a consequence of it small particle size (80 nm) (15).

Active targeting using liposomes has been accomplished by attaching target-specific moieties onto the surface of liposomes. These ligands, such as antibodies (65), immunoglobulins (66), lectins (67), transferrin (68), sterylglucoside (69), folates (70), peptides (71), and polysaccharides (mannan) (72), have specific recognition receptors in tissues that facilitate selectively inter- nalization into target cells.

4.3. Liposomes for Immunopotentiation Liposomes have been used as potent adjuvants to augment the

immune response to recombinant protein vaccines (73,74). Immunopotentiating reconstituted influenza virosomes, used in commercially marketed vaccine formulations such as Inflexal and Epaxal, contain structural determinants that are responsible for enhanced immunogenic potential. Virosomes, due to their characteristic membrane bilayer structure, can mimic the natural mechanisms of antibody pre-

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sentation and processing. Additionally, surface glycoproteins hemagglutinin and neuraminidase in virosomes promote cel- lular fusion with antigen-presenting cells of the immune sys- tem. Consequently, a robust T-cell and B-cell response is generated when antigens are delivered via virosomes (75,76). Liposomal adjuvants are biodegradable, have low toxi- city, and do not stimulate the production of antiphospholipid antibodies (74). These adjuvants are well tolerated and safe for repeated use compared to traditionally used aluminum salt-based adjuvants in protein formulations (23,76).

4.4. Liposomes for Modified Release Liposomal vesicles can be used to develop controlled release

formulations due to delayed release of drug molecules com- plexed and =or entrapped within liposome compartments. Controlled release liposomal formulations have been devel- oped for many drugs such as progesterone (77) and cisplatin (78) among others. The commercially licensed formulations DepoDur and DepoCyt are based on the DepoFoam technol- ogy (79) that involves encapsulating drugs into multivescicu- lar liposomes composed of mixtures of cholesterol, triolein, 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DOPC), and 1,2-dipalmitoyl-sn-glycero-3-[phospho-rac-1-glycerol] (DPPG). These lipid bilayer membranes can serve as an efficient bar- rier to the permeation of entrapped drugs and can be pro- grammed to release the drug over extended periods of time.

4.5. Transdermal Drug Delivery Using Liposomes Although the focus of this book is on i.v. delivery, transdermal

applications of liposomal formulations merit discussion due to the significant advances that have occurred recently in this rapidly developing field (80–82). Liposomal encapsulation for transdermal use is intended for localized delivery and has the following two major advantages: (i) ability to circum- vent systemic administration and thus increase local activity and prevent toxic side effects, a feature that is particularly important for potent glucocorticosteroids and retinoids (81),

260 Patil and Burgess

and (ii) targeted site-specific delivery that is especially useful for selective treatment of tissues, a feature practical in phar- macotherapy of psoriasis, acne, and genital warts, as well as stimulation of hair growth. Liposomes can be a non-toxic sub- stitute for dermal penetration enhancers such as dimethyl- sulfoxide to improve localized drug transport into skin (83). They are believed to release entrapped drugs upon interaction with cells, by fusion and =or endocytosis (80,83). Some of the liposomal formulations commercially available for transder- mal applications include Pevaryl Lipogel Õ (51), which con- tains econazole and is indicated for dermatomycosis and gynecological fungal infections; and L.M.X.4 Õ (formerly known as ELA-Max Õ ) (84), which contains lidocaine and is indicated for local anesthesia and itch relief. See Table 1 for additional information on approved dermatologic liposomal products.