Constraints To Ocular Drug Delivery

Ocular tissues are protected from exogenous toxic substances in the environment or bloodstream by a variety of mechanisms, notably, tear secretion continuously flushing its surface, an impermeable surface epithelium, and a

Figure 4 Miosis-time profiles: Plots of the average observed changes in pupillary diameter (APD) as a function of time following the instillation of 25.0 mL of the isotonic 1% pilocarpine nitrate solutions, which contained the different concentrations of citrate buffer. The vertical lines through the data points are ±SD (data points with standard deviation lines omitted is for clarity of the figure). (From Ref. 20.)

Figure 4 Miosis-time profiles: Plots of the average observed changes in pupillary diameter (APD) as a function of time following the instillation of 25.0 mL of the isotonic 1% pilocarpine nitrate solutions, which contained the different concentrations of citrate buffer. The vertical lines through the data points are ±SD (data points with standard deviation lines omitted is for clarity of the figure). (From Ref. 20.)

transport system actively clearing the retina of agents potentially able to disturb the visual process. However, the same protective mechanisms may cause subtherapeutic drug levels at the intended site. The difficulties can be compounded by the structure of the globe itself, where many of its internal structures are isolated from the blood and the outside surface of the eye. A major goal in ocular therapeutics is to circumvent these structural obstacles and protective mechanisms to elicit desired pharmacological response.

Physiological barriers to the diffusion and productive absorption of topically applied ophthalmic drugs exist in the precorneal and corneal spaces. Anterior chamber factor also greatly influence the disposition of topically applied drugs. Precorneal constraints include solution drainage, lacrimation and tear dilution, tear turnover, and conjunctival absorption. For acceptable bioavailability, a proper duration of contact with the cornea must be maintained. Instilled solution drainage away from the precorneal area has been shown to be the most significant factor reducing this contact time and ocular bioavailability of topical solution dosage forms (21,22). Instilled dose leaves the precorneal area within 5 minutes of instillation in humans (21,23). The natural tendency of the cul-de-sac is to reduce its fluid volume to 7-10 mL (24-26). A typical ophthalmic dropper delivers 30 mL, most of which is rapidly lost through nasolacrimal drainage immediately following dosage. This drainage mechanism may then cause the drug to be systemically absorbed across the nasal mucosa or the gastrointestinal tract (27). Systemic loss from topically applied drugs also occurs from conjunctival absorption into the local circulation. The conjunctiva possesses a relatively large surface area, making this loss significant.

Simple dilution of instilled drug solution in the tears acts to reduce the transcorneal flux of drug remaining in the cul-de-sac. Lacrimation can be induced by many factors, including the drug entity, the pH, and the tonicity of the dosage from (28-30). Formulation adjuvants can also stimulate tear production (20).

Tear turnover acts to remove drug solution from the conjunctival cul-de-sac. Normal human tear turnover is approximately 16% per minute, which can also be stimulated by various factors, as described elsewhere (21,25). These factors render topical application of ophthalmic solutions to the cul-de-sac extremely inefficient. Typically, less than 1% of the instilled dose reaches the aqueous humor (27,31). The low fraction of applied dose (1%) of drug solution reaching the anterior chamber further undergoes rapid elimination from the intraocular tissues and fluids. Absorbed drug may exit the eye through the canal of Schlemm or via absorption through the ciliary body of suprachoroid into the episcleral space (27). Enzymatic metabolism may account for further loss, which can occur in the precorneal space and/or in the cornea (32,33). Age and genetics have been determined to be two important factors in ocular metabolism (34,35).

Clearly, the physiological barriers to topical corneal absorption are formidable. The result is that the clinician is forced to recommend frequent high doses of drugs to achieve therapeutic effect. This pulsatile dosing not only results in extreme fluctuations in ocular drug concentrations but may cause many local and/or systemic side effects. Approaches taken to circumvent this pulsatile dosing and their ramifications on ocular therapies are the subject matter of this text.

For the effective treatment of diseases involving the retina, drugs must cross the blood-ocular barrier in significant amounts to demonstrate therapeutic effect. The blood-ocular barrier is a combination of microscopic structures within the eye, which physiologically separate it from the rest of the body. It is comprised of two systems: (a) blood-aqueous barrier, which regulates solute exchange between blood and the intraocular fluid, and (b) blood-retinal barrier, which separates the blood from the neural retina. Both barriers contain epithelial and endothelial components whose tight junctions limit transport.

A transient increase in the blood-retinal barrier permeability can be achieved by modification of the barrier properties. For instance, opening of the blood-retinal barrier can be achieved by intracarotid infusion of a hyper-osmotic solution, such as mannitol or arabinose. Perfusion with such a solution for about 30 seconds is shown to open the blood-retinal barrier reversibly. Osmotically induced shrinkage of the retinal and brain capillary endothelial cells causes opening of the tight junctions. Other methods include perfusion with oleic acid or protamine. These methods, however, produce a nonspecific opening of the blood-retinal barrier, possibly with associated retinal and central nervous system toxicity.

Chemical modification is more commonly employed to enhance drug transport across biological barriers. Lipophilic analogs of the parent drug increase lipid solubility and thereby their blood-retinal barrier permeability. Another approach to enhance transport across the blood-retinal barrier could involve utilizing specific carrier systems on the epithelial membrane. Drugs may be modified in such a way that their structures resemble endogenous ligands for a specific carrier system on the blood-retinal barrier.

Drug delivery through nutrient transport systems has been reported previously with intestinal absorption (36-38). ^-Lactam antibiotics and other compounds that share the structural features of the endogenous pep-tides are recognized by the peptide transporters. Recently valacyclovir (valyl ester of acyclovir) (39,40) and valganciclovir (valyl ester of ganciclovir) (41) were shown to be the substrates for peptide transporters. These prodrugs increased the oral bioavailability of acylclovir and ganciclovir significantly (42,43), thus reducing the daily oral dose requirement.

Various transporters/receptors are reported to be present on the retina and/or the blood-ocular barriers. The reader is referred to specific chapters in this volume for detailed description. However, very few studies have been carried out to explore the transporters present on the retina or the blood-ocular barrier. The transporters/receptors present on the retina or the blood-ocular barrier may be exploited to increase ocular bioavailability of drugs with poor intrinsic permeability.

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