title: Characterization of a novel intraocular drug-delivery system using crystalline lipid antiviral prodrugs of ganciclovir and cyclic cidofovir.
abstract: OBJECTIVE
  In an earlier study, a novel intraocular drug-delivery system was reported in which hexadecyloxypropyl-phospho-ganciclovir (HDP-P-GCV) was used as a prototype. The hypothesis was that many biologically effective compounds could be modified to crystalline lipid prodrugs and could be delivered directly into the vitreous in a long-lasting, slow-release form. This study was undertaken to characterize this new drug-delivery system further, by using small particles of HDP-P-GCV and hexadecyloxypropyl-cyclic cidofovir (HDP-cCDV).
  
  
  METHODS
  HDP-P-GCV was microfluidized into 4.4-microm (median) particles, injected into rabbit vitreous. The vitreous drug level was then measured at different time points. Crystalline HDP-cCDV was synthesized, suspended in 5% dextrose, and injected into the rabbit's vitreous at 10, 55, 100, 550, or 1000 microg in 50 microL vehicle per eye, to determine the highest nontoxic dose. The dose, 100 microg, was injected into 24 rabbit eyes, to evaluate pharmacokinetics; into 14 rabbit eyes with established HSV retinitis, to evaluate its efficacy; and into 58 rabbit eyes before herpes simplex virus (HSV) infection to evaluate its intraocular antiviral duration.
  
  
  RESULTS
  Microfluidized particles of HDP-P-GCV showed an increased drug release rate compared with the large-particle drug formulation, with area under concentration-time curve (AUC) of 219.8 +/- 114.1 (n=3) versus 108.3 +/- 47.2 (n=3) for unmodified HDP-P-GCV during the 12-week period after a 2.8-micromole intravitreal injection. There was a 103% increase of the drug released from the microfluidized formulation of HDP-P-GCV versus the unmodified formulation. Intravitreal injections of HDP-cCDV at doses of 100 microg/eye or lower were not toxic. After the 100 microg/eye injections, HPLC analysis showed a vitreous HDP-cCDV level of 0.05 microM at week 5, which declined to 0.002 microM at week 8. The concentration at week 8 (0.002 microM) remained above the IC50 for cytomegalovirus (0.0003 microM). The pretreatment study demonstrated an antiviral effect that lasted 100 days after a single intravitreal injection.
  
  
  CONCLUSIONS
  This crystalline lipid prodrug intravitreal delivery system is an effective approach to achieving sustained, therapeutic drug levels in the eye. Small microfluidized particles of HDP-P-GCV provide more rapid dissolution and higher vitreous drug levels.
authors.affiliation: Shiley Eye Center, University of California San Diego, La Jolla, California 92093-0946, USA. cheng@eyecenter.ucsd.edu
authors.forename: Lingyun
authors.initials: L
authors.lastname: Cheng
authors.forename: Karl Y
authors.initials: KY
authors.lastname: Hostetler
authors.forename: Jeffery
authors.initials: J
authors.lastname: Lee
authors.forename: Hyoung Jun
authors.initials: HJ
authors.lastname: Koh
authors.forename: James R
authors.initials: JR
authors.lastname: Beadle
authors.forename: Kenichiro
authors.initials: K
authors.lastname: Bessho
authors.forename: Mitsuko
authors.initials: M
authors.lastname: Toyoguchi
authors.forename: Kathy
authors.initials: K
authors.lastname: Aldern
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Bovet
authors.forename: William R
authors.initials: WR
authors.lastname: Freeman
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000633:toxicity; D019540:Area Under Curve; D001682:Biological Availability; D002851:Chromatography, High Pressure Liquid; D003596:Cytosine / Q000008:administration & dosage* / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000633:toxicity; D016503:Drug Delivery Systems; D015828:Eye Infections, Viral / Q000378:metabolism / Q000517:prevention & control* / Q000821:virology; D015774:Ganciclovir / Q000008:administration & dosage* / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000633:toxicity; D006561:Herpes Simplex / Q000378:metabolism / Q000517:prevention & control* / Q000821:virology; D018259:Herpesvirus 1, Human / Q000502:physiology; D008081:Liposomes; D044085:Microfluidics; D063065:Organophosphonates / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000633:toxicity; D011355:Prodrugs / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000633:toxicity; D011817:Rabbits; D012160:Retina / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D012173:Retinitis / Q000378:metabolism / Q000517:prevention & control* / Q000821:virology; D014822:Vitreous Body / Q000187:drug effects / Q000378:metabolism / Q000473:pathology
chemical_list: C407662:1-O-hexadecyl-propanediol-3-phospho-ganciclovir; D000998:Antiviral Agents; D008081:Liposomes; D063065:Organophosphonates; D011355:Prodrugs; C493733:hexadecyloxypropyl-cyclic cidofovir; D003596:Cytosine; D015774:Ganciclovir