The role of drug-lipid interactions on the disposition of liposome-formulated opioid analgesics in vitro and in vivo

Although liposome encapsulation prolongs the duration of action of epidural ly administered drugs, little is known about how liposome encapsulation aff ects opioids differently, or about how lipid content of liposomes alters th e bioavailability of epidurally-administered opioids. To address these issu es, morphine, alfentanil, fentanyl, and sufentanil were loaded into D-a-dip almitoyl phosphatidylcholine multilamellar liposomes, and incorporation eff iciency and in vitro release rates were determined. We then determined epid ural morphine and sufentanil lipo somes, at two different lipid/opioid rati os, in vivo in a pig model in which epidural and intrathecal spaces were co ntinuously sampled via microdialysis. Liposome encapsulation efficiency was significantly more for sufentanil (100%) than for the other opioids (25%-3 0%). The in vitro release rate was slowest for morphine, intermediate for f entanyl and alfentanil, and fastest for sufentanil. In vivo, morphine was r eleased more slowly than sufentanil. It is most important to note that incr easing the Lipid content of morphine liposomes increased the proportion of drug reaching the intrathecal space. In contrast, increasing the lipid cont ent of sufentanil liposomes did not alter intrathecal movement but did decr ease movement into plasma. Therefore, increasing drug hydrophobicity and li pid content of the liposomes modulates drug distribution in vivo.