Edition 1 / March 2020
Since the discovery of liposomes by Bangham and Horne in 1964, the use of phospholipids as critical excipients / pharmaceutical additives or Active Pharmaceutical Ingredients (APIs) in the pharmaceutical and biotech industries is an expanding area. Potential of liposomes as drug delivery carriers has been extensively explored via versatile administrative routes such as parenteral, oral, pulmonary, nasal, ocular and transdermal. In 1974, AmBisome®, a formulation of amphotericin B, became the first injectable liposome product to be licensed.
Not long after that (in the 1980s), the evolution of the development, manufacturing, supply and formulation of Lipid Nanoparticles (LNP) with lipids and critical excipients led CordenPharma’s cGMP facility in Liestal, Switzerland to specialize in the creation of derivatized phospholipid manufacturing technologies, processes and dedicated resources to support the Pharma & Biotech industry.
A liposome is a spherical vesicle of concentric self-assembling lipid bilayers. The liposome can be used as a vehicle for administration of pharmaceutical drugs or nutrients. Liposomes are most often composed of biocompatible and biodegradable lipids excipients such as sphingomyelin, phosphatidylcholine, glycerophospholipids and cholesterols, but may also include other lipids excipients, so long as they are compatible with the lipid bilayer structure. Cholesterol, another pharmaceutical additive, can increase stability of a liposome and prevent leakage of a bilayer because its hydroxyl group can interact with the polar heads of the bilayer phospholipids.
According to the structure of lipid bilayers and the size of the vesicles, liposomes are commonly classified into Large Unilamellar Vesicles (LUV), Small Unilamellar Vesicles (SUV), Multilamellar Vesicles (MLV) and Mutivesicular Vesicles (MVV).
Phospholipids are regulated as APIs or highly controlled pharmaceutical critical excipients with stringent quality specifications due to their drug activity-enhancing function. Phospholipid molecules, and in particular phosphatidylcholines (PC), have well-documented pharmaceutical advantages including increasing solubility, protection against degradation, prolonged circulation time, and passive / active target delivery.
Nevertheless, primitive parenteral liposomes have one severe drawback: they are always cleared from blood very quickly and end up in organs and tissues in the Reticulo-Endothelial System (RES, e.g., liver, spleen, and lung). The clearing occurs by plasma opsonization and subsequent sequestration from circulation. By pegylation, a process of coating with long-chain Polyethylene Glycols (PEG), liposomes are camouflaged with layers of hydrophilic coatings to evade RES clearance and achieve long circulation in the body. The successful marketing of Doxil®, a pegylated liposomal doxorubicin product, represents a milestone in the development of parenteral liposomes.
Several factors that have an influence on liposomal system stability, such as liposomal composition (e.g., phospholipids-lipids with high phase transition temperatures), fatty acid side-chains, polar head chemistry, chain length, and the degree of unsaturation, are preferred to maintain liposomal rigidity and phospholipid:cholesterol molar ratio (crucial for the liposomal stability and controlling drug release). Briuglia et al. (2015) demonstrated that a 70:30 molar ratio of phospholipids (using 1,2-Dimyristoyl-sn-glycero-3-phosphocholine (DMPC), dipalmitoyl phosphatidylcholine (DPPC), and distearoyl phosphatidylcholine (DSPC)) to cholesterol achieved a liposomal formulation that can guarantee the stability and control over drug release and surface potential (high surface potential is directly related to the liposomal physical stability, as it helps to reduce the rate of fusion and aggregation).
For thirty years, CordenPharma’s scientists have mastered the chemical total synthesis of complex derivatized phospholipids from multi-gram to multi-kilogram scale, and are renowned for their contract lipid and phospholipid manufacturing expertise. Our large-scale proprietary cGMP manufacturing processes start with (S)-1,2-isopropylideneglycerol ((S)-IPG) and extend over a cascade of optimized and fully-scalable conversions, leading to a wide range of phospholipids such as, but not limited to:
CordenPharma also pioneered the chemistry and large-scale manufacture of MPEG-conjugated phospholipids, which can be accessed through the same synthesis cascade, rendering them superior quality products in sensitive liposome formulation processes.
In addition, standard cationic phospholipids such as DODMA and DOTAP can be made available in cGMP and R&D grade qualities.
Please refer to CordenPharma’s Phospholipid Brochure for more details.
A wide selection of Readily Available Derivatized Phospholipids suitable for Research & Discovery is also available for purchase in convenient 1g and 10 g pack sizes (please refer to our Lipid List for more details).
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