Ganciclovir release rates in vitreous from different formulations of 1-O-hexadecylpropanediol-3-phospho-ganciclovir.
OBJECTIVE
To determine the optimal formulation of lipid prodrug, 1-O-hexadecyloxypropyl-phospho-ganciclovir (HDP-P-GCV), for intravitreal delivery.


METHODS
Equal concentrations of crystalline or liposomal HDP-P-GCV were exposed to rabbit whole vitreous, core vitreous, peripheral vitreous, human plasma, and heat inactivated rabbit vitreous, and the samples were incubated at 37 degrees C for one week. Aliquots were taken at day 1, 2, 3, and 7 and subjected to HPLC analysis for conversion to GCV.


RESULTS
The resultant concentration of GCV from crystalline HDP-P-GCV in vitreous was 198 +/- 49 microM (n = 3) at day 1 and 1253 +/- 248 microM (n = 3) at day 7. The resultant concentration of GCV from the liposomal formulation of HDP-P-GCV in vitreous was much lower, yielding a concentration of 66 +/- 7 microM (n = 3) at day 1 and 243 +/- 39 microM (n = 3) at day 7 (P < 0.001, t Test). When the crystalline HDP-P-GCV was incubated with heat-inactivated vitreous, the detectable GCV concentrations were low (22 microM) and did not increase over time. The concentration of GCV detected from the crystalline HDP-P-GCV in the core vitreous was 19.69 +/- 3.84 microM (n = 3) at day 1 and 1537.36 +/- 177.14 microM (n = 3) at day 7. The concentration of GCV released from crystalline HDP-P-GCV in peripheral vitreous was 32.86 +/- 5.07 microM (n = 3) at day 1 and 1805.78 +/- 327.94 microM (n = 3) at day 7. Detectable GCV concentration from both core and peripheral vitreous samples increased over time, however, the magnitude of GCV release from peripheral vitreous samples was higher (P < 0.05, t Test).


CONCLUSIONS
In vitreous, HDP-P-GCV as a crystalline formulation was converted to GCV more rapidly than liposomal formulation of HDP-P-GCV. Vitreous cells may play an important role in the metabolism of either formulation of HDP-P-GCV delivered into vitreous.
Cheng
Lingyun
L
Department of Ophthalmology, Shiley Eye Center, University of California, San Diego, La Jolla, CA 92093-0946, USA. cheng@eyecenter.ucsd.edu
Hostetler
Karl Y
KY
Toyoguchi
Mitsuko
M
Beadle
James R
JR
Rodanant
Nuttawut
N
Gardner
Michael F
MF
Aldern
Kathy A
KA
Bergeron-Lynn
Germaine
G
Freeman
William R
WR
D000818:Animals; D003460:Crystallization; D015774:Ganciclovir / Q000008:administration & dosage* / Q000031:analogs & derivatives* / Q000378:metabolism*; D006801:Humans; D008081:Liposomes; D009994:Osmolar Concentration; D011817:Rabbits; D013997:Time Factors; D014822:Vitreous Body / Q000166:cytology / Q000378:metabolism*
C407662:1-O-hexadecyl-propanediol-3-phospho-ganciclovir; D008081:Liposomes; D015774:Ganciclovir