Drug release and pharmacokinetics of intravitreal liposomal injections: a case study with cyclic guanosine monophosphate derivative

Retinitis pigmentosa (RP) is an inherited retinal dystrophy that leads to blindness at an early age. Although no effective drug treatment of RP exists, administration of cyclic guanosine monophosphate analogue 8- bromo- β- phenyl- 1, N²- ethenoguanosine- 3', 5'- cyclic monophosphorothioate, Rp- isomer (CN03) has shown preclinical promise in the treatment of the RP nevertheless, fast drug clearance from vitreous may reduce its clinical applicability. To prolong intravitreal injection intervals of CN03, we investigated CN03 release from liposomes and the pharmacokinetics of intravitreally injected liposomes in rabbits. CN03 was encapsulated into pegylated (5 mol%) liposomes with different phospholipid compositions (18:0 PC, 18:1 PC, and 20:1 PC), achieving varying encapsulation efficiencies of 10.7 ± 1.0%, 84.8 ± 3.4%, and 65.1 ± 2.3%, respectively. The longest release half-life of CN03 was obtained with 20:1 PC liposomes (62.7 ± 4.6 h), whereas 18:1 PC (22.9 ± 2.9 h) and 18:0 PC (2.3 ± 0.6 h) liposomes showed shorter half-lives of release in isolated bovine vitreous humor. Thus, the CN03 release was slowed down by monounsaturated alkyl chains and longer carbon chains of the alkyls in the lipids. The vitreal half-life of CN03 in solution was 4.8 h in rabbit eyes, whereas pegylated 18:1 PC liposomes had a half-life of 6.9 days. A pharmacokinetic simulation model was used to estimate free CN03 concentration in the rabbit and human vitreous humor during drug release from the liposomes. In conclusion, drug loading capacity, CN03 clearance, and vitreal retention of liposomes set limits to the extended injection interval with liposomes. Overall, we present herein a process for in vitro - in vivo extrapolation for intravitreal drug delivery systems.