Inner Canthus

Nasolacrimal Duct

Figure 11.11 Combined photographic and scintigraphic image of the eye (left); illustration of contact area (right)

accommodative spasms in younger patients and better patient compliance. However, 20% of all patients treated with the Ocusert® lose the device without being aware of the loss. For this reason, patients fitted with the device should be checked regularly.

Collagen shields have proven useful as the basis of a drug delivery device. The shield is made from porcine scleral collagen that is moulded into a contact lens-like shape. This is hardened and crosslinked by exposure to ultraviolet light. The shield conforms to the shape of the eye and lubricates the cornea as it dissolves. The dissolution time depends on the degree of crosslinking which can be controlled to release drug over a period from approximately 12 to 72 hours. Drugs can be incorporated into the collagen matrix during manufacture, adsorbed into the shield during rehydration, or topically applied over the shield in the eye. As the shield dissolves, the drug is released gradually into the tear film, maintaining high concentrations on the corneal surface and increasing drug permeation through the cornea25. Studies suggest that drug delivery by collagen shields may be helpful in the early management of bacterial keratitis, in preference to frequent administration of topical antibiotics, subconjunctival injection, or topical administration over a soft contact lens bandage.

A PVA gel which hydrates on contact with the eye clears with a mean half-life of 8 minutes in normal subjects26 but it increases the bioavailability of pilocarpine by 16 times compared to conventional formulations. This is due to presentation of the drug in the nonionised form; and to sustained high concentration in the lower marginal tear film. Presentation of drug was confined to the sclera with little spread to cornea (Figure 11.11). As the diffusion path from sclera to ciliary body is relatively short, this should result in high concentrations of drug in the lower hemisphere interior with much lower concentrations in the upper segment.

Intraocular drug delivery

Over the last two decades, treatment of intraocular conditions and diseases, such as endophthalmitis, has been attempted mainly by intravenous, topical or subconjunctival administration of suitable drugs. Sub-therapeutic intravitreal concentrations of the drugs following each of these routes frequently resulted in poor recovery of vision. Topical application of drugs for the treatment of posterior segment disorders is severely limited by the highly efficient clearance mechanisms. Improving the precorneal residence time of topically applied drugs by viscosity enhancing agents, gelling agents, or mucoadhesive polymers has failed to provide sufficient concentrations in the vitreous humor. Similarly, subconjunctival injection of antibiotics and antivirals is also unsuccessful in achieving therapeutic concentrations in the vitreous humor. The intraocular penetration of drugs following intravenous administration is hampered by the presence of tight junctional complexes of the retinal pigment epithelium and the retinal blood vessels forming the blood-retinal barrier.

Most diseases affecting the posterior segment are chronic in nature and require prolonged drug administration. Intravitreal injections remain the main route of delivery in order to avoid the concomitant side effects seen with systemic administration. An intravitreal injection provides therapeutic concentrations of the drug adjacent to the intended site of activity and only a small dose of drug is required. However, possible retinal toxicity of the injected dose must be taken into account. Usually an intravitreal injection is restricted to a volume of 0.1-0.2 ml administered following both anterior chamber and vitreal taps. Following injection, the drug diffuses through the vitreous gel with little restriction. For most drugs the diffusion coefficient through the vitreous humor is close to that through water

Once distributed throughout the vitreous humor, rapid elimination of the drug is observed via two routes:

1. anteriorly by simple diffusion to the posterior chamber, followed by removal to the systemic circulation along with the aqueous humor drainage

2. posteriorly across the retina where it is removed by active secretion.

Drugs lost primarily by anterior chamber diffusion have a half life in the vitreous humor of 20-30 hours, while drugs lost via the trans-retinal route, such as the penicillins, have typically much shorter half lives of 5-10 hours. Unfortunately,these time scales are still shorter than required and depot device which deliver over days to weeks are being developed. Ocular inflammation results in the breakdown of the blood-retinal barrier and increases the elimination of non-transported drugs from the vitreous humor. In contrast, drugs that are removed by the active transport systems reside longer in the vitreous following ocular inflammation due the failure in the transport mechanism. Rate of drug loss is also enhanced in vitrectomised and lensectomised eyes.

Liposomes

Liposomal encapsulation has the potential not only to increase the activity and prolong the residence of the drug in the eye, but also to reduce the intraocular toxicity of certain drugs. For example, liposome-encapsulated amphotericin B produces less toxicity than the commercial solubilized amphotericin B formulation when injected intravitreally. The main drawbacks associated with liposomes are their short shelf life and difficulty in storage, limited drug loading capacity and instability on sterilization and finally, transient blurring of vision after an intravitreal injection. Despite these disadvantages, they have potential as drug delivery systems as they are composed of substances that are non-toxic and totally biodegradable.

Microparticulates and nanoparticles

Microspheres and nanoparticles are retained for extended periods within the eye and can provide slow, sustained release of drugs. The delivery systems are especially attractive because of the ease of manufacturing and improved stability compared to liposomes. The polymers used in the manufacture can be erodible, in which case the drug release is due to the polymer degradation, or non-erodible, where the drug is released is by diffusion through the polymer.

Intraocular devices

The administration of medications by implants or depot devices is a very rapidly developing technology in ocular therapeutics. These overcome the potential hazards associated with repeated intravitreal injection such as clouding of the vitreous humor, retinal detachment and endophthalmitis.

Implantable devices have been developed that serve two major purposes. First, to release of drug at zero order rates, thus improving the predictability of drug action, and second, to release of the drug over several months, reducing dramatically the frequency of administration.

Depot devices, have been developed to treat proliferative vitreoretinopathy and retinitis associated with cytomegalovirus. Various implantable devices, such as a gentamicin osmotic minipump, a polyvinyl alcohol/ethylene vinyl acetate cup containing ganciclovir, a polysulfone capillary fibre with daunomycin in tristearin and ganciclovir intraocular implant have been suggested.

Vitrasert® is a commercially available sustained release intraocular device for ganciclovir approved for use in-patients suffering from cytomegalovirus. Apart from the anticipated problems of endophthalmitis and retinal detachment, dislocation of implant and poor intravitreal drug levels due to its placement into the suprachoroidal space has been observed.

Iontophoresis

Iontophoresis (see transdermal chapter) facilitates drug penetration through the intact corneal epithelium. The solution of the drug is kept in contact with the cornea in an eye-cup bearing an electrode. A potential difference is applied with the electrode in the cup having the same charge as the ionized drug, so that the drug flux is into the tissue. This method of administration is very rarely used, except under carefully controlled conditions. Iontophoresis allows penetration of antibiotics that are ionised and therefore do not penetrate by other methods, for example, polymyxin B used in the local treatment of infections. Although the technique is found to be suitable for a range of compounds like NSAIDS, antivirals, antibiotics, anaesthetics and glucocorticoids, its acceptability as a routine drug delivery system is limited by the lack of information on side effects from repeated or multiple applications on the same or different site.

Commonly reported toxic effects include slight retinal and choroidal burns and retinal pigment epithelial and choroidal necrosis, corneal epithelial oedema, persistent corneal opacities and polymorphonuclear cell infiltration. Other disadvantages of iontophoresis include side effects such as itching, erythema and general irritation.

Systemic administration

Drugs are usually administered systemically for the treatment of diseases involving the optic nerve, retina and uveal tract. The blood/aqueous barrier only allows drugs to pass into the anterior chamber of the eye by one of two processes, both of which are very slow:

(1)secretion from the ciliary body

(2)diffusion from the capillaries of the iris.

Most drugs are unable to reach the anterior chamber in therapeutically active concentrations because they are either not sufficiently lipid soluble or they are bound to plasma proteins and hence cannot pass through the blood vessel wall,

Some drugs such as acetazolamide are ineffective when given topically and although it can be administered parenterally this is impractical for chronic administration. A

sustained-release oral preparation of acetazolamide is valuable for patients with glaucoma since it produces consistent and sustained levels of drug. Better carbonic anhydrase inhibitors such as dorzolamide may decrease enthusiasm for acetazolamide. Recently, the sublingual route has been explored for the delivery of timolol to decrease intraocular pressure in patients with ocular hypotension.

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