Cholesteryl ester vesicles loading peptides, proteins and nucleic acids into chylomicrons and body cells

摘要

The present invention is directed to one or more macromolecules in a lipid vesicle oral formulation which targets intracellular receptors, in particular for peptides, proteins, nucleic acids and mixtures thereof, optionally in combination with small molecules. The invention encapsulates said macromolecules in a neutral lipid vesicle comprised of one or more cholesteryl esters. Unique properties of macromolecules encapsulated in said vesicles include high oral bioavailability, defined herein as in at least 50%, i.e., often in excess of 50% on the basis of oral to parenteral AUC. Non-limiting examples are provided, for large hydrophilic molecules such as peptides, proteins and nucleic acids which heretofore have been very poorly absorbed by the mammalian intestine. In prior art; said molecules are generally less than 25% bioavailable, even with protective coatings and optionally absorption enhancing component substances in the formulation. An additional feature of the present invention is high tissue concentrations after oral use, a result of rapid uptake of cholestosomes delivered by chylomicrons to body cells. A preferred embodiment is disclosed for insulin, where with eholestosome encapsulation oral bioavailability is at least 66%. Prior to the present invention, oral bioavailability of insulin and other peptides and proteins was maximally 25% and usually between 5% and 10%. Additional preferred examples are provided for one or more macromolecules useful in the treatment of cancer and in particular intracellular targeting in the practice of cancer immunotherapeutics.