Functional Category
Anionic surfactant; biodegradable material; cationic surfactant; dispersing agent; emulsifying agent; emulsion stabilizer; membraneforming agent; nonionic surfactant; solubilizing agent; suspending agent; wetting agent.
Applications in Pharmaceutical Formulation
Phospholipids are amphiphilic molecules and are the major component of most cell membranes.(2) They are able to selfassociate and form a variety of structures, including micelles and liposomes.(3) Numerous pharmaceutical formulations use phospholipids to form various types of liposomes, including unilamellar (one bilayer membrane surrounding an aqueous chamber), multilamellar (two or more concentric membranes, each surrounding an aqueous chamber), and multivesicular (numerous aqueous chambers joined in a honeycomb-like arrangement) liposomes.(4) Modified phospholipids have been used to enhance the properties of the resulting liposomes. The covalent attachment of polyethylene glycol (PEG) to the phospholipid, or PEGylation, provides steric hindrance to the surface of the liposomes, resulting in decreased uptake by the reticuloendothelial system (RES), also known as the mononuclear phagocyte system, and a prolonged circulation half-life following intravenous administration; the so-called ‘stealth liposomes.’ (5) Conjugation with antibodies produces immunoliposomes, which are able to target specific cell types and deliver a payload of encapsulated drug.(6) Phospholipids can be anionic, cationic, or neutral in charge. Because of their amphiphilic nature, phospholipids will associate at hydrophobic/hydrophilic interfaces. The charged lipids can be used to provide electrostatic repulsion and physical stability to suspended particles. Thus, they have been used to physically stabilize emulsions and suspensions.(7,8) Phospholipids have also been used in formulations administered as lung surfactants, in intravenous fat emulsions, and in oral solutions (e.g. Rapamune).
Description
Phospholipids occur as white powders. They are sometimes supplied as clear, nearly colorless chloroform or methylene chloride solutions. Phosphatidylglycerols, phosphatidic acids, and phosphatidylserines are available as sodium or ammonium salts. Phospholipids can be purified from natural sources, such as eggs or soybeans, or can be chemically synthesized. Lecithins are partially purified mixtures of naturally occurring phospholipids.
Stability and Storage Conditions
Phospholipids are stable in the solid state if protected from oxygen, heat, and light. Chloroform or dichloromethane solutions are also stable. Both the solid-state and solution forms should be stored at 208C. Liposomal phospholipids are known to degrade via oxidation and hydrolysis. To minimize oxidation, liposomes can be prepared under oxygen-free environments and antioxidants, such as butylated hydroxytoluene (BHT), can be added.(11,12) To minimize hydrolysis, water can be removed from liposomes by lyophilization. In cases where liposomes are unstable to lyophilization, long-term storage at 2–88C is recommended. The ester hydrolysis of phospholipids in liposomes typically follows a Vshaped curve, with the minimum at around pH 6.5.(13,14)
Safety
Generally, phospholipids have little or no acute toxicity (i.e. they are well tolerated even when administered at doses in the g/kg range).(16) The clearance of most phospholipids occurs by wellknown metabolic pathways.(17) Liposomes containing stearylamines (cationic liposomes) have been found to induce cytotoxicity through apoptosis in the macrophage-like cell line RA W2647(18) and inhibit the growth of cells in vitro. (19,20) In nine cancer-derived cell lines and one normal cultured human cell line, stearylamine- and cardiolipin-containing liposomes were toxic (LD50) at 200 mM liposomal lipid concentration or less, whereas PG- and PS-containing liposomes were toxic in the range 130–3000 mM. (21) Positively charged lipids such as stearylamine can increase the toxicity of liposomes.(22) These studies reported an LD50 (IV) of 1.1 g/kg and 7.5 g/kg with and without stearylamine, respectively. The safety of phospholipids delivered by the intravenous route is complicated by their tendency to form particles that are recognized by macrophages of the RES.(23) Uptake by the RES is dependent on particle size and composition.