One-step extrusion of concentrated lidocaine lipid nanocarrier (LNC) dispersions

Lipid nanocarriers (LNCs) have been successfully produced by many methods including high pressure homogenization, sonication and microemulsification, but it remains very difficult to produce dispersions with greater than 30% LNCs, volume average particle diameter less than 150 nm, and concentration of drugs useful for topical products. This research is the first to propose and demonstrate extrusion to manufacture highly concentrated drug containing LNC dispersions continuously and economically in a single step. By treating crude emulsions in a twin-screw extruder which has sections for homogenizing, mixing and fast-cooling inside the extruder, lidocaine-loaded LNC dispersions were successfully generated with lipid concentration up to 60% and particle diameters less than 50 nm. Electrical conductivity and birefringence measurements indicate that in the lidocaine system, lamellar microemulsions are intermediate structures and compositions with low lipid concentrations that do not present evidence of lamellar structures fail to give nanoparticles when processed. This paper also presents a new method for measuring kinetics of drug release from nanoparticles based on pH stat titration. Sufficiently precise data from pH stat titration allows determination of rate laws for release occurring on a time scale of minutes versus hours or days. The release rate of lidocaine from extruded 35% lipid nanoparticles was constant (zero order release kinetics) through the first hour (40% of drug release), a valuable property for drug delivery.