DERIVATIZED PHOSPHOLIPIDS


Liposomes: Definition & Structure

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 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 phospholipid bilayer.

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 Multivesicular Vesicles (MVV).

Liposomes for Drug Delivery

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.

Phospholipids are composed of one or more fatty acids (long chains of hydrogen and carbon molecules), which are attached to a glycerol 'head'.

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 been well documented as having pharmaceutical advantages including increased 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.

animated drawing of a Lipid Nanoparticle

To view our animated drawing of
a Lipid Nanoparticle – click here.

Stability of Liposomes

Several factors that have an influence on liposomal system stability, such as liposomal composition (e.g., lipids, phospholipids 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).

liposome-lipid-bilayer-graphic

Want to experiment with an
immersive liposome lipid bilayer
created from our 3D model?

Our Derivatized Phospholipid Offering

CordenPharma’s expert lipid manufacturers have mastered the chemical total synthesis of complex phospholipid derivatives from multi-gram to multi-kilogram scale and are renowned for their contract lipid and phospholipid molecule manufacturing expertise. Our large-scale proprietary cGMP manufacturing processes start with (S)-1,2-isopropylideneglycerol ((S)-IPG) and extend over a cascade of optimised and fully-scalable conversions leading to a wide range of phospholipid examples such as, but not limited to:



Lipids


CAS N°


Structure


DMF
DMPC 18194-24-6
DOPE 4004-05-1
DPPA, Na 169051-60-9
POPC 26853-31-6
DPPC 63-89-8
DSPC 816-94-4
DSPG, Na 124011-52-5
DPPG, Na 200880-41-7
DMPG, Na 200880-40-6
DMPE 998-07-2
1,2-POPE 26662-94-2
SCS 2864-50-8

Derivatized Phospholipid Manufacturing

  • >> Highly efficient, quality excipients
  • >> Adherence to the latest guidelines of the International Pharmaceutical Excipient Council (IPEC)
  • >> cGMP certified supplier of high quality liposomal excipients additives
  • >> Aid development of target delivery drugs
  • >> Emphasis on Quality by Design (QbD) & Process Analytical Technology (PAT) for controlled raw materials & lower net costs
  • >> Comply with Pharmacopeia standards: USP, BP, EU & IP (where a monography is established)
  • >> Comply with the GMP API requirements (Eudralex Vol 4, part II)
  • >> Bovine Spongiform Encephalopathy (BSE) & Transmissible Spongiform Encephalopathies (TSEs) free certification
  • >> Well-established specification sheets, quality control & test procedures
  • >> Functionality with lot-to-lot consistency

MPEG-Conjugated Lipid Manufacturers

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 phospholipid examples for sensitive liposome formulation processes.



Lipids


CAS N°


Structure


DMF
MPEG-2000-DMPE 384835-59-0
MPEG-750-DSPE 147867-65-0
MPEG-2000-DSPE 147867-65-0
MPEG-5000-DSPE 147867-65-0
MPEG-2000-DPPE 205494-72-0

In addition, standard cationic phospholipids such as DODMA and DOTAP can be made available in cGMP and R&D grade qualities.

Ionizable Lipids & Lipid Nanoparticles: Initiatives like C12-200 Allow Lower Dose

Significant effort has been applied to discover and develop vehicles which can guide small interfering siRNA through the many barriers guarding the interior of target cells. Improvements in delivery efficacy were required to fulfill the broadest potential of RNA interference therapeutics. Through the combinatorial synthesis and screening of a different class of materials, a formulation has been identified that enables siRNA-directed liver gene silencing in mice at doses below 0.01 mg∕kg. The potential of this formulation was further validated in non-human primates, where high levels of knockdown of the clinically relevant gene transthyretin were observed at doses as low as 0.03 mg∕kg.

A screening of different tails and amine groups was evaluated, reporting interesting structure-activity results. With respect to tail length, most of the top performing structures possessed tails consisting of 14-carbons in length. Additionally, no compounds with tails less than 12-carbons in length mediated silencing greater than 30%.

Regarding amine head groups, a tertiary amine was present in the top performing compounds. With the top 3 lipids, an in vivo delivery of siRNA to hepatocytes in mice was conducted and a dose dependent gene silencing was obtained. One compound in particular, C12-200, demonstrated over two orders-of-magnitude higher potency when compared to LNP01.

We developed a manufacturing process for C12‑200, which is now ready for evaluation by potential customers looking for a breakthrough in LNP and IP free lipid vehicles. C12‑200 is available with high purity and a process robust enough to allow for a GMP campaign.

Please refer to CordenPharma’s Phospholipid Brochure for more details.

A wide selection of Readily Available Derivatized Phospholipids suitable for Research & Discovery is available for purchase in convenient 1 g and 10 g pack sizes (please refer to our Lipid List for more details).

CordenPharma has the additional capability to provide the development and manufacturing of Complex Carbohydrates along the value chain ranging from clinical activities through process development, scale-up and GMP manufacturing, for a wide range of applications.

Integrated Supply

CordenPharma’s ability to develop and manufacture Active Pharmaceutical Ingredients (APIs), Finished Dosage and Packaging in our network of facilities allows clients full access to integrated services resulting in a simplified supply chain, reduced risk and cost associated with technology transfers, and ultimately faster production and delivery timelines.


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