ORAL DELIVERY of small molecules and proteins

Due to the inferior stability of conventional liposomes in the gastrointestinal tract, they can only be applied parenteral (non-oral). The major advantages of NovoArc’s liposomes are:

• protection against gastrointestinal hydrolysis, enzymatic lipolysis and agglomeration
• increased shelf-life at room temperature
• increased bioavailability after oral administration.

Vancomycin is a potent glycopeptide antibiotic used to treat serious infections caused by gram-positive bacteria. It inhibits bacterial cell wall synthesis through binding of essential peptidoglycans, thus disrupting cell wall synthesis. Due to its poor oral bioavailability (not efficiently absorbed in the gastrointestinal tract) Vancomycin is currently only administered intravenously (IV). To overcome this massive drawback, we wanted to improve the oral bioavailability of vancomycin by encapsulation with NovoArc’s liposomes. Free vancomycin (reference) and encapsulated Vancomycin were administered to wistar rats intravenously and by oral gavage. Vancomycin levels were periodically determined in plasma samples.

We could demonstrate that the bioavailability of the oral formulation increased up to 3.5-fold compared to the reference (6.5% vs. 1.9%).

When encapsulated and free vancomycin were administered intravenously, a lower clearance rate was observed (30-fold higher blood levels after 8h).

To demonstrate the improved storage stability of API’s formulated with NovoArc’s liposomes, the light and oxidation sensitive model compound cannabidiol (CBD) was encapsulated.
An accelerated degradation study (40°C, basic conditions, oxidative environment) was performed and the CBD degradation was monitored.. NovoArc’s liposomes significantly slowed down the degradation process compared to conventional liposomes and free CBD (Figure A).

After storage at room temperature and light exposure for 4 months a significantly higher CBD content was observed in NovoArc’s liposomes compared to formulation with conventional ones (Figure B).

In an assay simulating the environment of GI tract, 20% less degradation of NovoArc’s encapsulated CBD, compared to conventional liposomes was found.

Investigation of cellular uptake in vitro in Caco2 cells confirmed a 12-fold higher uptake of NovoArc’s liposomes compared to conventional ones.

Several other in vivo studies highlighting the potential of tetraether lipids for oral drug delivery:

• Insulin (Diabetes)
  Li, Z. Investigation of archaeosomes as carriers for oral delivery of peptides. Biochemical and Biophysical Research Communications 394, 412–417 (2010).
• Vaccines and Gene Delivery
  van Hoogevest, P. Review – An update on the use of oral phospholipid excipients. European Journal of Pharmaceutical Sciences 108, 1–12 (2017).
• Vancomycin (Peptide Antibiotic)
  Uhl, P. Oral delivery of vancomycin by tetraether lipid liposomes. European Journal of Pharmaceutical Sciences 108, 111–118 (2017).
• Octreotide (Cancer Treatment)
  Parmentier, J. Oral peptide delivery by tetraether lipid liposomes. International Journal of Pharmaceutics 415, 150–157 (2011).
• Myrcludex B (Hepatitis B and D)
  Uhl, P. A liposomal formulation for the oral application of the investigational hepatitis B drug Myrcludex B. European Journal of Pharmaceutics and Biopharmaceutics 103, 159–166 (2016).
• Griseofulvin (Antifungal Medication)
  Ong, S. Influence of the Encapsulation Efficiency and Size of Liposome on the Oral Bioavailability of Griseofulvin-Loaded Liposomes. Pharmaceutics 8, 25 (2016).
• Human Growth Hormone
  Parmentier, J. Improved Oral Bioavailability of Human Growth Hormone by a Combination of Liposomes Containing Bio-Enhancers and Tetraether Lipids and Omeprazole. Journal of Pharmaceutical Sciences 103, 3985–3993 (2014)