ProNano-Liposphers (PNL) for improved oral bioavailability of cyclosporine

Many dispersion systems are currently in use as carriers of substances, particularly biologically active compounds. One of the in situ methods of preparation of solid lipid nanoparticles was developed by using a dispersible pre-concentrate system. This delivery system, termed pro-nanoliposphere (PNL), is based on a solution containing the drug, triglyceride, phospholipid, surfactants, and a water miscible organic solvent. This solution spontaneously forms nanoparticles when gently mixed in an aqueous media, such as the upper GI lumen content. When given orally, a drug is absorbed into the enterocytes monolayer in the basolateral side of the intestine. From the apical side of the enterocytes the drug is delivered via the portal vein to the liver and thereafter into the systemic blood circulation. Bioavailability is defined as the fraction of an administered dose of unchanged drug that reaches the systemic circulation. Bioavailability is one of the essential tools in pharmacokinetics, as it must be considered when calculating dosages for none intravenous routes of administration.

This study utilized cyclosporine, which is a cyclic polypeptide containing eleven amino acids and used as immunosuppressive, as a model drug. It is is classified as a BCS IV drug due to its physicochemical properties, including high lipophilicity, polar surface area, and molecular weight. The factors impeding the absorption of cyclosporine include the narrow absorption window in the upper gut, P-glycoprotein efflux from enterocytes, and extensive pre-systemic metabolism in the wall and liver. To date, how to improve its in-vivo performance has been a widespread concern. We developed oral formulations for cyclosporine with improved bioavailability using the PNL technology. Improved PNL formulations were created using GRAS components which dissolved the drug and enhance oral bioavailability. The PNL pre-concentrate with high load drug (50-100 mg per capsule), which can be packed in soft gelatine capsules, composed of lipidic and emulsifying excipients of GRAS status, upon addition to aqueous media, such as stomach liquids, spontaneously form nano-droplets of 400 nm or below, preferably below 50 nm. The solvent, type of the triglyceride, surfactants and their ratios are some of the most effective parameters. This formulation possesses improved oral bioavailability when given to animal or human.