Biological Barriers and Fundamentals of Passive Transport

Membranes as Barriers

In a very general sense, biological membranes serve an extremely useful function, effectively walling off the body from invasive and destructive pathological microorganisms as well as noxious influences of the environment. They allow tissues to customize their environments. Dosage forms are therefore devised so that either the therapeutic agent is introduced by a physical or chemical means that penetrates the barrier and introduces the drug behind the impediment or the drug design or dosage form itself enables the therapeutic agent to penetrate the barrier. If the latter is the preferred means, both the drug and the vehicle need to avoid producing a significant toxic insult to the barrier, lest that barrier be compromised in its ability to prevent intrusion of foreign chemical or biological agents or be rendered sufficiently uncomfortable that neither the delivery is effective nor the patient compliant.

The significance of the barrier function of membranes has been the topic of considerable research. The blood-brain barrier and the blood-retinal barrier are well understood, and the microscopic structures imparting and controlling barrier properties have been quite thoroughly investigated and the science reviewed (11,188,189). The structures and functions of ocular membranes specific to transport associated with ophthalmic drug administration also have been topics of extensive research (11,190,191).

The most common means of administering drugs to the eye is by topical administration of agents capable of penetrating the cornea and targeting the appropriate tissue for either physiological or medicinal effect (192,193). The trilaminar structure of the transparent avascular cornea has been described previously. The corneal epithelium exposes a hydrophobic barrier to hydrophilic therapeutic agents and a hydrophilic corneal stromal barrier to hydrophobic agents. Nonetheless, as the models considered below rationalize, low-molecular-weight therapeutic agents of modest hydrophobicity and high water solubility are often capable of penetrating the eye and may be effective ocular therapeutic agents if their potency, or receptor affinity if that is appropriate, can be maintained in the accommodation to these requirements.

More recently alternative routes of drug administration have been sought and utilized. Scientists are developing technologies to circumvent the constraints imposed on molecular weight, water solubility, and modest hydrophobicity by the conventional transcorneal route. Patents exist for ophthalmically acceptable penetration enhancers. More water-soluble therapeutic agents now in use for glaucoma appear to achieve approximately equal access by both scleral-limbal and transcorneal routes of administration (194,195). Research is ongoing to understand and utilize scleral administration of therapeutic agents; the role of hydrostatic pressure on the transport of both water and drug has been investigated to determine the classes of therapeutic agent for which this mode of delivery may be utilized (196-199). One consequence will be the determination of the diminished transport constraints imposed by a barrier from which the hydrophobic layer is absent. Both academic and industrial investigations have led to technologies for scleral implants and sustained release.

Role of Hydrodynamics

Basic hydrodynamic phenomena govern the duration of exposure of corneal and conjunctival membranes to the therapeutic agents. Rapid clearance provides a temporal barrier to drug delivery.

Drainage of the drop through the nasolacrimal system into the gastrointestinal tract begins immediately on instillation. This takes place when either reflex tearing or the dosage form causes the volume of fluid in the cul-de-sac and precorneal tears to exceed the normal lacrimal volume of 7 to 10 |iL. Reference to Figure 7 indicates the pathway for this drainage. The excess fluid volume enters the superior and inferior lacrimal puncta, moves

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