Name: Phospholipids
CAS No: See Table II.
None adopted.
Coatsome; glycerol phosphatides; Lipoid; phosphatides; phosphatidic acid; phosphatidylcholine; phosphatidylethanolamine; phosphatidylglycerol; phosphatidylinositol; phosphatidylserine; phosphoglycerides; PhosphoLipid; purified egg yolk PC; sphingomyelin. See also Table I.
See Table II.
Phospholipids are formed from two combinations of apolar and ‘backbone’ moieties: a glycerol (or other polyol) moiety substituted with one or two acyl or alkyl chains; or an N-acylated sphingoid base (a ceramide).(1) Typically, the molecular weights range from 600 to 5000. See also Table III.
See Table IV.
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).
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.
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Phospholipids are amphiphilic, surface-active molecules with a high tendency to form aggregates (phases) both in the dry state and when fully hydrated. The temperature of transition from crystalline to mesomorphic (liquid crystalline) state is the transition temperature (Tm).(9) See Table V. Most phospholipids are freely soluble in organic solvents.
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)
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Phospholipids can be manufactured from naturally occurring materials, especially soybean and egg. The manufacturing process typically involves extraction, fractionation, and purification. They can also be synthesized chemically by reacting glycerol phosphocholine (PC), glycerol phosphoglycerol (PG), glycerol phosphoserine (PS), glycerol phosphoethanolamine (PE), or glycerol phosphoinositol (PI) with purified fatty acids.(15)
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.
Observe normal precautions appropriate to the circumstances and quantity of the material handled. Eye protection and gloves are recommended.
Included in the FDA Inactive Ingredient Database (oral, otic, buccal, vaginal, topical, epidural, intravenous, intramuscular, and inhalation aerosol). A number of phospholipids such as DPPG and DOPC are present in approved products in Europe and the USA.
Lecithin.
The fatty acid content of egg phospholipids depends on the types of fat in the diets of the hen as well as the strain of hen.(24) Likewise, the composition of soy is known to vary.(25) To ensure batch-tobatch reproducibility, phospholipids from synthetic sources are commonly used.