Sustained-release formulation development for tetracaine encapsulated in ionic gradient liposomes

Abstract

Encapsulation of Local Anesthetics (LA) in ionic gradient liposomes (IGL) aspiring to increase the time of analgesia and decrease the side effects, by maintaining the drug in the site of action for a longer time, has been quite encouraging and prolific. Mowat et al (Anesthesiol. 85:635, 1996) reported the use of IGL with an acidic inner aqueous compartment (300 mM citrate at pH 4.0) and external pH of 7.4 to encapsulate bupivacaine. Their large unilamellar vesicles, composed of dioleoyl PC/chol (55:45 molar ratio), were able to upload up to 2% bupivacaine with high encapsulation efficiency (%EE = 64-82%), and sustained release (9-14 h) after intradermal administration in guinea pigs. Intradermal administration of large multivesicular vesicles IGL prepared with (NH4)2SO4 in a human volunteer achieved up to 19, 38, and 48 h of successful anesthesia with 0.5, 1, and 2% drug respectively (Grant et al., Anesthesiol 101:133, 2004). Our group has recently reported large (up to 2%) amounts of LA ropivacaine (RVC) entrapped (%EE~70%) in egg PC/chol/alpha-tocopherol 4/3/0.07 mole % IGL with a sustained release (~25 h) (Silva et al., J Lip. Res.26:1, 2015). Also, a significant increase in the sensory block duration (27 h) in rats was achieved with a 0.012% formulation of dibucaine in IGL (prepared with sulfate and citrate), in comparison to an equivalent DBC solution (11 h) (Couto V.M., Master thesis, Unicamp, 2015). Tetracaine (TTC) is also a potent LA of the ester series. It finds extensive use in ophthalmology and topical anesthesia. However its encapsulation and anesthetic potential in IGL, to the best of our knowledge, yet remains to be explored. The aim of the present study would therefore be to increase the resident time of TTC at the site of injection, prolonging its anesthetic effect through a pharmaceutical formulation suitable for use in the treatment of burn injuries (topical) or long-lasting anesthesia (surgical procedures and postoperative period in ophthalmology). In that way we propose to prepare, to characterize and to test the in vitro and in vivo the activity of TTC-in IGL, in comparison to plain tetracaine. (AU)