Drug Absorption and Disposition in the Eye
The pharmacokinetics and constraints of ocular drug absorption have been examined thoroughly in the literature. [49-58] A pharmacokinetic scheme illustrating the precorneal fluid dynamics and the distribution/ disposition of pilocarpine in rabbits is presented in Figure 5.

Figure 5: Pharmacokinetic Scheme Illustrating the Distribution of Pilocarpine from the Tear Fluid into the Aqueous Humour (modified from reference 59)

It is common knowledge that the ocular bioavailability of drugs applied topically as eye-drops is very poor. The absorption of drugs in the eye is severely limited by some protective mechanisms that ensure the proper functioning of the eye, and by other concomitant factors, for example:
• Drainage of the instilled solutions;
• Lacrimation and tear turnover;
• Metabolism;
• Tear evaporation;
• Non-productive absorption/adsorption;
• Limited corneal area and poor corneal permeability; and
• Binding by the lacrimal proteins.
The drainage of the administered dose via the nasolacrimal system into the nasopharynx and the gastrointestinal tract takes place when the volume of fluid in the eye exceeds the normal lacrimal volume of 7–10 microlitres. Thus, the portion of the instilled dose (one to two drops, corresponding to 50–100 microlitres) that is not eliminated by spillage from the palpebral fissure is quickly drained and the contact time of the dose with the absorbing surfaces (cornea and sclera) is reduced to a maximum of two minutes. The lacrimation and the physiological tear turnover (16% per minute in humans in normal conditions) can be stimulated and increased by the instillation even of mildly irritating solutions. The net result is a dilution of the applied medication and an acceleration of drug loss. It is now definitively established that the rate at which instilled solutions are removed from the eye varies linearly with instilled volume. In other words, the larger the instilled volume, the more rapidly the instilled solution is drained from the precorneal area. Ideally, a high concentration of drug in a minimum drop volume would be desirable. However, there is a practical limit to the concept of minimum dosage volume. Droppers delivering small volumes are difficult to design and to produce. In addition, their practical usefulness could be reduced by the fact that most patients cannot detect the administration of small volumes.
The conjunctival absorption, which occurs via the vessels of the palpebral and scleral conjunctiva, concurs in reducing the drug available for absorption into the eye. Any instilled drug that has not been swept away from the precorneal area by the drainage apparatus is subject to protein binding and to metabolic degradation in the tear film. All of these factors may result in transcorneal absorption of 1% or less of the drug applied topically as a solution. In summary, 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.
Drugs applied topically are potentially available for absorption by the scleral and palpebral conjunctiva (the so-called ‘non-productive’ absorption). Although direct transscleral access to some intraocular tissues cannot be excluded, it is well documented that drugs that penetrate the conjunctiva are rapidly removed from the eye by local circulation and undergo systemic absorption. This may range, for example, from 65% for dipivalylepinephrine to 74% for flurbiprofen and 80% for timolol. [60] These effects are frequently not anticipated, recognised or treated appropriately.
In conclusion, the fluid dynamics in the precorneal area of the eye have a huge effect on ocular drug absorption and disposition. When the normal fluid dynamics are altered by, for example, tonicity, pH or irritant drugs or vehicles, the situation becomes more complex. The formulations of ophthalmic drug products must take into account not only the stability and compatibility of a drug in a given formulation, but also the influence of that formulation on precorneal fluid dynamics. The concepts exposed in this section are summarised in Figure 6, which illustrates the various factors and pathways involved in the ocular disposition of formulations applied topically to the eye.

Figure 6: Schematic Illustration of the Ocular Disposition of Topically Applied Formulations

Recent advances and challenges in ocular drug delivery system
Recent advances in topical drug delivery have been made that improve ocular drug contact time and drug delivery, including the development of ointments, gels, liposome formulations and various sustained and controlled-release substrates, such as the Ocusert, collagen shields and hydrogel lenses. The development of newer topical delivery systems using polymeric gels, colloidal systems and cyclodextrins will provide exciting new topical drug therapeutics.[61, 62] The delivery of therapeutic doses of drugs to the tissues in the posterior segment of the eye, however, remains a significant challenge.[63]

Early approaches
A considerable amount of effort has been made in ophthalmic drug delivery since the 1970s. The various approaches attempted in the early stages can be divided into two main categories: bioavailability improvement and controlled release drug delivery. The latter was attempted by various types of inserts and nanoparticles. After initial investigations, some approaches were dropped quickly, whereas others were highly successful and led to marketed products.

Table 1:

Developments and challenges
Solutions and suspensions
Solutions are the pharmaceutical forms most widely used to administer drugs that must be active on the eye surface or in the eye after passage through the cornea or the conjunctiva. Solutions also have disadvantages: the very short time the solution stays at the eye surface, its poor bioavailability (a major portion, i.e., 75% is lost via nasolacrimal drainage), the instability of the dissolved drug and the necessity of using preservatives. A considerable disadvantage of using eye drops is the rapid elimination of the solution and their poor bioavailability. The retention of a solution in the eye is influenced by viscosity, hydrogen ion concentration, the osmolality and the instilled volume. Extensive work has been done to prolong ocular retention of drugs in the solution state by enhancing the viscosity or altering the pH of the solution. [64-70]

Figure 7: Ophthalmic solution.

Sol to gel systems
The new concept of producing a gel in situ (e.g., in the cul-de-sac of the eye) was suggested for the first time in the early 1980s. It is widely accepted that increasing the viscosity of a drug formulation in the precorneal region leads to an increased bioavailability, due to slower drainage from the cornea. Several concepts for the in situ gelling systems have been investigated. These systems can be triggered by pH, temperature or by ion activation. Middleton and Robinson prepared a sol to gel system with mucoadhesive property to deliver the steroid fluorometholone to the eye. The formulation gave better release of drug over a long period of time in the rabbit’s eye as compared to conventional eye drops. [71]

Figure 8: Ophthalmic gel applied to eye.

Although not commonly used, some practitioners use mydriatics or cycloplegics alone or in combination in the form of eye spray. These sprays are used in the eye for dilating the pupil or for cycloplegics examination.

Figure 8: ophthalmic sprays are applied always on closed eyes.



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