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Archivos de la Sociedad Española de Oftalmología

versión impresa ISSN 0365-6691

Arch Soc Esp Oftalmol v.78 n.2 Madrid feb. 2003






In spite of active and continued research and of frequent introduction of novel ophthalmic drugs, ocular drug delivery does not seem to progress at the lively pace typical of e.g. oral, transdermal or transmucosal delivery. In recent years, only few advanced ocular delivery systems have been introduced into the market. The vast majority of existing ocular delivery systems are still, as indicated by Lee and Robinson in 1986 (1), «fairly primitive and inefficient». A similar concept was expressed in 1993 by Hughes and Mitra (2), who stated that «…The primitive ophthalmic solutions, suspensions and ointment dosage forms are clearly no longer sufficient to combat some present virulent diseases...».

The pharmacokinetics and constraints of ocular drug absorption are nowadays well understood. It is recognized that the ocular bioavailability of drugs topically applied as eyedrops is very poor, due to efficient protective mechanisms ensuring the proper functioning of the eye, and to other concomitant factors. As a consequence of these mechanisms and factors the rate of loss of drug from the eye can be 500 to 700 times greater than the rate of absorption into the anterior chamber, and 1-5% or less of the drug applied topically as a solution reaches the inner eye.

The main current dosage forms are solutions, suspensions, paraffin ointments and (to a much lesser extent) aqueous gels. Solutions, in spite of their limitations (first of all, a quick elimination from the precorneal area, resulting in poor bioavailability) are still given top priority by formulators, since they are relatively simple to prepare, filter and sterilize, and are cost-effective. While normal saline is an acceptable vehicle for ophthalmic drugs, slightly viscous solutions are generally recognized more satisfying to use by the patients. To an augmented viscosity also corresponds an increased time of residence of the medication in the eye. However, there appears to be only a narrow band of acceptable viscosity (15-18 Cps), since the products must have negligible visual effects, should not obstruct the puncti and canaliculi, and should be filterable and sterilizable.

Suspensions, while not as common as solutions, are widely used for formulations involving poorly soluble drugs as e.g. anti-inflammatory steroids. A novel concept in ocular suspension design is the Betoptic®S ophthalmic suspension (Alcon Laboratories, Inc.), containing a soluble drug (betaxolol hydrochloride) adsorbed on an insoluble ion-exchange resin, providing sustained release. Poorly soluble ophthalmic drugs can now be solubilized by the use of cyclodextrins (CDs), a group of cyclic oligosaccharides capable of forming water-soluble inclusion complexes with many drugs (3).

Semisolid, petrolatum-based occupy a position of minor importance. They are ill-accepted on account of their greasiness, vision-blurring effect, etc., and are generally used as night-time medications. They are, when possible, being superseded by aqueous gels, better tolerated by patients. Pilopine® HS gel (4% pilocarpine, Alcon Canada, Inc) can be mentioned as example.

Novel approaches to ocular drug delivery, commercialized in recent times or still under evaluation, aim at enhancing the drug bioavailability by ensuring a prolonged retention of the medication in the eye, and/or by facilitating transcorneal penetration. New, more efficient medications for dry eye conditions are also actively investigated. Some of these approaches will briefly be considered:

  1. In-situ activated gel-forming systems;

  2. mucoadhesive polymers;

  3. absorption promoters;

  4. vesicular/colloidal systems;

  5. inserts and collagen shields.

1) In-situ activated gel-forming systems are liquid formulations which undergo a viscosity increase upon instillation in the eye, thus ensuring a prolonged precorneal retention. A typical example is Gelrite®, a polysaccharide (low-acetyl gellan gum) which forms clear gels at low concentration in the presence of mono or divalent cations typically found in tear fluid (4). It is marketed as a once-a day dosing vehicle for timolol maleate (Timoptic® XE, Merck & Co., Inc.).

2) Mucoadhesive polymers, i.e., macromolecules capable of retaining the medication in the precorneal area by establishing physico-chemical interactions with the mucin layer covering the corneal epithelium, are a relatively recent discovery (5). The following synthetic, semi-synthetic and naturally occurring polymers have been found to possess mucoadhesive properties: carboxymethylcellulose, hydroxypropylcellulose, polyvinyl alcohol, polyacrylic acid (Carbomer), high molecular weight (>200,000) polyethylene glycols, chitosans, hyaluronic acid, polygalacturonic acid, xyloglucan, etc.

Some of these polymers have found their way in lachrymal substitutes for treatment of dry eye conditions, as e.g. Cellufresh®, Celluvisc® monodose, Dacriosol® Refresh® (cellulose derivatives); Liquifilm® Tears, Lacrilux®, Hypotears® (polyvinyl alcohol); Dropstar® TG, Vismed®, Hy-drop® (hyaluronic acid); Dacriogel®, Viscotirs® (polyacrylic acid); TSP® 0,5 (xyloglucan).

Examples of medicated formulations containing polyacrylic acid (Carbopol®) are Fucithalmic® viscous eye drops (1% fusidic acid, Leo Pharma Inc.) and the previously mentioned Pilopine® HS gel. All of these formulations presumably owe their improved ocular retention to the presence of a mucoadhesive polymer.

3) The use of absorption promoters, i.e. of substances facilitating drug penetration through the corneal tissues is a potentially interesting, still little-exploited approach to improving ophthalmic bioavailability (6). The effect of these substances (surface active agents, calcium chelators) on the cornea is to enhance the permeability of corneal epithelium by altering the cell membranes and loosening the tight junctions between superficial cells. Among the promoters that have been investigated, sometimes with positive results, the following can be mentioned: benzalkonium chloride, polyoxyethylene glycol lauryl ether (Brij® 35), polyoxyethylene glycol stearyl ether (Brij® 78), polyoxyethylene glycol oleyl ether (Brij® 98), ethylenediaminetetraacetic acid, Na salt (EDTA), digitonin, sodium taurocholate, saponins, Cremophor-EL, etc. Some of the previously mucoadhesive polymers (e.g., chitosans) have been found active also as ocular absorption promoters. Unfortunately some agents, while effective, cause transient irritation or produce irreversible damages to corneal tissues. A typical example is benzalkonium chloride, a preservative present in a myriad of ophthalmic formulations. This agent, although proved effective as corneal absorption promoter for different ophthalmic drugs, is now viewed with suspect on account of potential eye irritation, and preservative-free, single-use eyedrops are gradually substituting the preserved multi-dose ones. A multi-dose container fitted with a sterilizing filter, allowing to dispense sterile, preservative-free solutions (Abak®) has been recently patented by Théa Laboratories (France) and is used for an artificial tear formulation (FilmAbak® PVP artificial tears).

4) As main examples of vesicular/colloidal systems, liposomes, micro/nanoparticles and microemulsions will be mentioned. Liposomes are microscopic vesicles composed of membrane-like phospholipid bilayers enclosing aqueous compartments. According to their size and structure they are known as small unilamellar vesicles (SUV, 10-100 nm), large unilamellar vesicles (LUV, 100-3000 nm) and multilamellar vesicles (7). Micro/nanoparticles are polymeric colloidal systems, ranging in size from 10 nm to micrometers, in which the drug is dissolved, entrapped, encapsulated or adsorbed. Some of these systems appear promising for vitreoretinal drug delivery (8). The attention of some researchers has also been focused on the potentiality of microemulsions as carriers for ophthalmic drugs. These consist of large, or «swollen» micelles containing the internal phase, and, unlike emulsions, appear as clear transparent dispersions. Ocular delivery of various drugs (antibiotics, antivirals, antiinflammatories, etc.) by all of these formulations is being successfully explored in a number of laboratories.

5) Ophthalmic inserts are solid devices, intended to be placed in the conjunctival sac and to deliver the drug at a comparatively slow rate (9). An interesting insert, developed by Alza Corp., Palo Alto, California, was the Ocusert®, a diffusion unit consisting of a drug reservoir (e.g., pilocarpine HCl in an alginate gel) enclosed by two release-controlling membranes made of ethylene-vinyl acetate copolymer. Clinical studies with the pilocarpine Ocusert® demonstrated that slow release of the drug can effectively control the increased intraocular pressure in glaucoma, with a minor incidence of side-effects, such as miosis, myopia, browache, etc.

Other inserts, both erodible and nonerodible (as e.g. medicated contact lenses, collagen shields, the Minidisc® etc.) have also been shown capable to diminish the systemic absorption of ocularly applied drugs, as a result of a decreased drainage into the nasal cavity, which is one of the major systemic absorption sites of topical ocular medications. Another potential advantage of insert therapy is the possibility of promoting non-corneal drug penetration, thus increasing the efficacy of some hydrophilic drugs which are poorly absorbed through the cornea. However, in spite of great expectations, attention on inserts has gradually waned in recent years.

In conclusion, constant progress in the understanding of principles and processes governing ocular drug absorption and disposition, and continuing technological advances have surely brought improvements in the efficacy of ophthalmic delivery systems.

Even if the introduction of novel of ocular dosage forms appears to proceed at a very slow pace, both on consideration of industrial costs and of the many restraints of the site of application, some drugs already in use have been recently revived in new, longer-acting liquid presentations advertised for once-daily application. Some of these dosage forms have been developed in the light of the vast body of knowledge derived from studies on bio/mucoadhesion. The time appears ripe, therefore, for introduction of advanced, more efficient ocular delivery systems.

1 Department of Bioorganic Chemistry and Biopharmaceutics Faculty of Pharmacy, University of Pisa, Italy. 



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