title: Micelle formulation of hexadecyloxypropyl-cidofovir (HDP-CDV) as an intravitreal long-lasting delivery system.
abstract: There still is an unmet need for a safe and sustained intravitreal drug delivery system. In this study we are proposing and characterizing a micelle based, clear-media intravitreal drug delivery system using the lipid derivatized nucleoside analog, hexadecyloxypropyl-cidofovir (HDP-CDV, CMX 001). HDP-CDV forms micelles in water and in vitreous supernatant with the critical micelle concentration of 19 μg/mL and 9 μg/mL, respectively at 37 °C. The formed micelles had the average size of 274.7 nm and the Zeta potential of -47.1 mV. Drug release study in the excised rabbit vitreous showed a sustained release profile with a half-life of 2.7 days. The micelle formulation of HDP-CDV demonstrated a good safety profile in two animal species (rabbit and guinea pig) following intravitreal injection. The sustained efficacy was tested in a pretreatment study design and the drug potency was tested in an ongoing herpes simplex virus (HSV-1) retinitis model. The pretreatment studies using single intravitreal injection and later HSV-1 infection revealed at least 9 weeks of vitreous presence and therapeutic level of HDP-CDV, with 71% eyes protection from infection. The treatment study demonstrated that intravitreal administration halted active HSV-1 retinitis in 80% of the infected eyes while cidofovir (CDV) treatment failed to suppress active HSV-1 retinitis. In summary, lipid derivatized nucleoside analogs can be formulated as a micelle intravitreal injection and provides a sustained drug release in vitreous for chronic retinal diseases.
authors.affiliation: Jacobs Retina Center at Shiley Eye Center, UCSD, La Jolla, CA, USA.
authors.forename: Feiyan
authors.initials: F
authors.lastname: Ma
authors.affiliation: Jacobs Retina Center at Shiley Eye Center, UCSD, La Jolla, CA, USA.
authors.forename: Kaihui
authors.initials: K
authors.lastname: Nan
authors.affiliation: Jacobs Retina Center at Shiley Eye Center, UCSD, La Jolla, CA, USA.
authors.forename: SuNa
authors.initials: S
authors.lastname: Lee
authors.affiliation: Department of Medicine, San Diego VA Healthcare System and UCSD, La Jolla, CA, USA.
authors.forename: James R
authors.initials: JR
authors.lastname: Beadle
authors.affiliation: Jacobs Retina Center at Shiley Eye Center, UCSD, La Jolla, CA, USA.
authors.forename: Huiyuan
authors.initials: H
authors.lastname: Hou
authors.affiliation: Jacobs Retina Center at Shiley Eye Center, UCSD, La Jolla, CA, USA.
authors.forename: William R
authors.initials: WR
authors.lastname: Freeman
authors.affiliation: Department of Medicine, San Diego VA Healthcare System and UCSD, La Jolla, CA, USA.
authors.forename: Karl Y
authors.initials: KY
authors.lastname: Hostetler
authors.affiliation: Jacobs Retina Center at Shiley Eye Center, UCSD, La Jolla, CA, USA. Electronic address: l1cheng@ucsd.edu.
authors.forename: Lingyun
authors.initials: L
authors.lastname: Cheng
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage / Q000737:chemistry; D002626:Chemistry, Pharmaceutical / Q000379:methods; D003596:Cytosine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry; D003692:Delayed-Action Preparations / Q000008:administration & dosage* / Q000737:chemistry*; D016503:Drug Delivery Systems / Q000379:methods; D006168:Guinea Pigs; D006207:Half-Life; D006561:Herpes Simplex / Q000188:drug therapy; D018259:Herpesvirus 1, Human / Q000187:drug effects; D058449:Intravitreal Injections / Q000379:methods; D008823:Micelles; D063065:Organophosphonates / Q000008:administration & dosage* / Q000737:chemistry*; D011355:Prodrugs / Q000008:administration & dosage / Q000737:chemistry; D011817:Rabbits; D012160:Retina / Q000187:drug effects / Q000821:virology; D014822:Vitreous Body / Q000187:drug effects* / Q000821:virology
chemical_list: D000998:Antiviral Agents; D003692:Delayed-Action Preparations; D008823:Micelles; D063065:Organophosphonates; D011355:Prodrugs; C525733:brincidofovir; D003596:Cytosine
keywords: 2-Propanol (PubChem CID: 3776); Cidofovir; Cidofovir (PubChem CID: 60613); Dextrose (PubChem CID: 5793); Disodium hydrogen phosphate (PubChem CID: 24203); Formaldehyde (PubChem CID: 712); Formic acid (PubChem CID: 284); Glutaraldehyde (PubChem CID: 3485); Guinea pig eye; Herpes simplex virus-1 retinitis; Hexadecyloxypropyl-cidofovir (PubChem CID: 483477); Intravitreal drug delivery; Lipid prodrug; Methanol (PubChem CID: 887); Micelles formulation; Pentane (PubChem CID: 8003); Rabbit eye