Intravitreal systems

Vitrasert (ganciclovir) a nondegradable intravitreal system for localized delivery of ganciclovir over 6 months for patients with cytomegalovirus retinitis. 

The therapeutic utility of systemically administered ASON had been limited by their short plasma half life (sometimes even less than 3 min). This is due to their sensitivity to nuclease digestion. When the first-generation ASON were chemically modified, e.g., by replacing the oxygen in the phosphodiester bond with sulfur (phosphorothiorate) they obtained an increased stability in biological fluids while their antisense effect has been maintained. First-generation agents can be delivered via intravitreal injection, parenterally, by topical cream, enema, and inhaled aerosol. These antisense... 

Pharmacokinetics Minimal systemic absorption following intravitreal injection. 

Pharmacokinetics Human pharmacokinetics data are limited. Based on preclinical data, it is slowly absorbed into systemic circulation from the eye after intravitreous administration. Metabolized by endo- and exonucleases. Excreted in urine. Half-life 10 days (plasma). 

Pharmacokinetics No information on human pharmacokinetics is available. In the rabbit model, half-life in the vitreous humor was 62 hours and 79 hours in the retina, while the retinal half-life in monkeys was 78 hours. Systemic exposure to fomivirsen following single or repeated intravitreal injection in monkeys was not quantifiable. 

The drug is slowly cleared from vitreous with a half-life of approximately 55 hours in humans and is subsequently cleared from the retina. Measurable concentrations of drug are not detected in the systemic circulation following intravitreal administration. Immediate therapy of CMV retinitis with fomivirsen was more effective in delaying progression than deferred treatment in a recent clinical trial. Concurrent systemic anti-CMV therapy is recommended to protect against extraocular and contralateral retinal CMV disease. Potential side effects include iritis and vitreitis as well as increased intraocular pressure and changes in vision. An interval of at least 2-4 weeks is recommended between cidofovir administration and use of fomivirsen because of the risk of ocular inflammation. 

To explore the utility of this approach, plasma samples obtained after injection of TACA into the posterior segment of the eye in pigs were analyzed [8], The objective of this therapeutic strategy was to achieve a local, sustained, pharmacologically active concentration in the eye, with minimal systemic concentrations. In this application, the low water solubility of TACA contributes to its prolonged duration of action at the injection site a previous human study showed that intraocular TACA maintained concentrations >100 ng/mL in the eye for at least 700 h after a single 4-mg intravitreal TACA treatment [9], However, TACA concentrations in plasma... 

The main drawbacks associated with liposomes are their short shelf life and difficulty in storage, limited drag-loading capacity and instability on sterilization and finally, transient blurring of vision after an intravitreal injection. Despite these disadvantages, they have a potential as drag delivery systems as they are composed of substances that are non-toxic and totally biodegradable. 

Sustained delivery of ophthalmic medications is a novel approach in treating chronic intraocular infections in conditions where systemic administration is accompanied by undesirable side-effects and repeated intravitreal injections carry the risk of infection. The administration of medications by implants or depot devices is a very rapidly developing technology in ocular therapeutics. The various types of implant and mechanisms of drug release have been discussed in general in Chapter 4. 

Hydrophilic drugs, such as gentamicin, do not cross the blood-retinal barrier readily after systemic administration. After intravitreal administration they have a prolonged half-life of 24 hours or more in the vitreous humor.Their major route of exit is across the lens zonules and into the aqueous humor and then through the aqueous outflow pathways. For the vitreous to act as a depot for these drugs, the agents must be injected, introduced by iontophoresis, or slowly released by a surgically implanted intraocular device. 

Various colloidal systems have been studied for use as potential ophthalmic delivery systems, including liposomes and nanoparticles. Liposomes are bioerodible and biocompatible systems consisting of microscopic vesicles composed of lipid bilayers surrounding aqueous compartments. Liposomes have demonstrated prolonged drug effect at the site of action but with reduced toxicity. Ophthalmic studies have included topical, subconjunctival, and intravitreal administration, but no commercial preparations are currently available for ophthalmic use. 

Corticosteroids administered intravitreally bypass the blood-ocular barrier to achieve therapeutic levels in the eye while minimizing systemic side effects. Initial studies of intravitreal corticosteroids combined dexamethasone and gentamicin in the treatment of inflammation associated with experimentally reduced endophthalmitis.As of late, interest has shifted to triamcinolone acetonide because of the longer half-life in the vitreous and its use in treatment of proliferative vitreoretinopathies. 

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