Characterization of a Novel Intraocular Drug-Delivery System Using Crystalline Lipid Antiviral Prodrugs of Ganciclovir and Cyclic Cidofovir

Cheng, Lingyun; Hostetler, Karl Y.; Lee, Jeffery; Koh, Hyoung Jun; Beadle, James R.; Bessho, Kenichiro; Toyoguchi, Mitsuko; Aldern, Kathy A.; Bovet, Jean-Marc; Freeman, William R.

doi:10.1167/iovs.04-0064

Cited by 39 publications

(58 citation statements)

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“…We have noted that it is inevitable that the RPE will more or less come with the retina when the retina is detached from the complex of RPE-Bruch's membranechoroid. 14,16 In contrast, one can get a very clean Bruch's membrane-choroid-sclera complex by completely scraping the single layer RPE off from Bruch's membrane under an ophthalmic surgical microscope. To use the Bruch's membrane-choroid-sclera complex without the RPE layer in this study meant to reduce the variation from the possible variable amount of RPE remaining on the Bruch's membrane.…”

Section: Methodsmentioning

confidence: 99%

The Effect of Ocular Pigmentation on Transscleral Delivery of Triamcinolone Acetonide

Sun

et al. 2013

Journal of Ocular Pharmacology and Therapeutics

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Purpose: To determine the capacity and kinetics of the binding between triamcinolone acetonide (TA) and the ocular pigment for a better understanding of the transscleral delivery. Methods: In the in vitro study, natural melanin (sepia officinalis, Sigma-Aldrich) was incubated at 37°C with different concentrations of TA and the binding capacity/binding affinity was measured. The TA releasing profile from the melanin was also studied through repeated incubation of TA-melanin in fresh phosphate-buffed saline. In the ex vivo study, the effect of the choroidal pigment on the trans sclera/choroid permeability of TA was investigated through Franz-type vertical diffusion cells using both a TA suspension and a saturated TA solution.Results: The amount of TA bound to melanin increases with the increase of the TA concentration and with an increase in the incubation time. A Scatchard analysis revealed that the maximum number of moles of TA bound to melanin is predicted to be 22.43 nmol/mg, with a binding affinity of K = 2.4 · 10 -5 nM -1 . TA released from a pigment showed a fast phase within the first 24 h and a slow phase thereafter. About 40% of the bound TA released in the first day and 73.94% of accumulative release was observed after 5 days. The TA suspension showed more TA penetration through the scleral-choroid complex than the saturated solution (P = 0.0104). The apparent permeability coefficients for the suspension across the sclera-choroid of pigmented and albino rabbits are 7.48 -1.53 · 10 -6 cm/s and 10.78 -2.49 · 10 -6 cm/s, respectively. Conclusions: TA can bind to and release from the ocular pigment, which may extend the TA ocular half-life and therapeutic duration when TA is delivered through a subtenon injection. A further in vivo study is warranted to validate the findings and to quantitate the magnitude of the difference between pigmented and albino animals.

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Section: Methodsmentioning

confidence: 99%

The Effect of Ocular Pigmentation on Transscleral Delivery of Triamcinolone Acetonide

Sun

et al. 2013

Journal of Ocular Pharmacology and Therapeutics

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“…In accordance with our published data with HDP-cCDV, 100 mg per rabbit eye was the highest nontoxic dose. 9 Therefore, 100 mg/eye was chosen to do a 4-week confirmation toxicity study on 3 rabbits before the pharmacokinetic study. The right eyes were injected with 100 mg ODE-cCDV and the left eyes were injected with the equivalent volume (50 mL) of 5% dextrose.…”

Section: Preparation Of 14 C-ode-ccdvmentioning

confidence: 99%

“…7 We previously reported an intravitreal drug delivery system that conjugates a longchain alkoxyalkyl moiety to a candidate compound to render it lipophilic with low solubility in vitreous, achieving a long intravitreal half-life. 8,9 Alkoxyalkyl prodrugs penetrate cell membrane easily and are cleaved inside cells by phosphatases of the phospholipase C type, releasing the parent drug. 10 Our previous pretreatment studies demonstrated a period of 100 to 140 days of herpes simplex virus (HSV) retinitis prevention after a single intravitreal injection of alkoxyalkyl-derivatized cidofovir or GCV.…”

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“…10 Our previous pretreatment studies demonstrated a period of 100 to 140 days of herpes simplex virus (HSV) retinitis prevention after a single intravitreal injection of alkoxyalkyl-derivatized cidofovir or GCV. 9,11 Due to the poor water solubility of lipid-derivatized compounds, their dissolution in vitreous is very slow and dissolved free drugs readily migrate into ocular tissues because of their lipophilicity. 12 Therefore, pharmacokinetic studies from vitreous taps or whole vitreous often underestimate the in vivo therapeutic duration.…”

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confidence: 99%

“…However, pretreatment with HDP-cCDV demonstrated 100% protection of retina from HSV infection 68 days after a single intravitreal injection. 9 In that study, a detailed pharmacokinetic study of the drug in retina and choroid was not performed because the compound was not radiolabeled. We hypothesized that HDP-cCDV was incorporated into retina and choroid to serve as a second drug depot, which further extended the duration of efficacy.…”

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Intraocular Pharmacokinetics of a Crystalline Lipid Prodrug, Octadecyloxyethyl-Cyclic-Cidofovir, for Cytomegalovirus Retinitis

Cheng

Beadle

Tammewar

et al. 2011

Journal of Ocular Pharmacology and Therapeutics

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Purpose: To evaluate the intraocular pharmacokinetics of octadecyloxyethyl-cyclic-cidofovir (ODE-cCDV) after intravitreal injection into rabbit eyes. Methods: Twenty-seven New Zealand red rabbits (27 eyes) received intravitreal injections of 14 C-labeled ODEcCDV (100 mg drug suspended in 5% dextrose), and ocular tissues were collected from 3 rabbits at each predetermined time point (1 h, 1 day, 3 days, 1 week, 2 weeks, 3 weeks, 5 weeks, and 9 weeks) after the injection. The eye globes were enucleated, and the vitreous, retina, and choroids were separated and harvested into preweighed scintillation vials. Levels of ODE-cCDV were measured by counting in a liquid scintillation counter, and pharmacokinetic (PK) parameters were determined. In addition, 3 eyes of 3 animals were used for autoradiography study at day 1, week 3, and week 6. Results: ODE-cCDV in vitreous as a whole followed a 2-phase first-order elimination, whereas ODE-cCDV in retina and choroid manifested a nearly steady state during the first 3 weeks and then followed a first-order elimination with the apparent elimination half-life of 10.1 and 7.2 days. For vitreous, apparent elimination halflife was 25 days. However, the drug mean residence time was much longer in retina (17.6 days) and choroid (19.6 days) than that in the vitreous (11.6 days). The drug exposure to the retina [area under the curve (AUC) ¼ 1120837.1 ng Á day/mL] was greater than the exposure to the vitreous (AUC ¼ 958645.8 ng Á day/mL) and the choroid (AUC ¼ 415407.47). Conclusion: A crystalline lipid prodrug, ODE-cCDV, has longer vitreous half-life than that in other ocular tissues due to its solid drug depot formation in vitreous. Over time, dissolved free ODE-cCDV from drug depot feeds and accumulates in the retina.

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Alkoxyalkyl Ester Prodrugs of Antiviral Nucleoside Phosphates and Phosphonates

Beadle

Hostetler

2011

Antiviral Drug Strategies

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Characterization of a Novel Intraocular Drug-Delivery System Using Crystalline Lipid Antiviral Prodrugs of Ganciclovir and Cyclic Cidofovir

Abstract: 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.

Cited by 39 publications

References 10 publications

The Effect of Ocular Pigmentation on Transscleral Delivery of Triamcinolone Acetonide

The Effect of Ocular Pigmentation on Transscleral Delivery of Triamcinolone Acetonide

Intraocular Pharmacokinetics of a Crystalline Lipid Prodrug, Octadecyloxyethyl-Cyclic-Cidofovir, for Cytomegalovirus Retinitis

Alkoxyalkyl Ester Prodrugs of Antiviral Nucleoside Phosphates and Phosphonates

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