As with permeability in most other routes of administration, the permeability of drugs into and through the cornea is function of their lipoid and aqueous solubility. The cornea is composed of three distinct layers: the outer epithelium, an inner stroma, and the endothelium. The epithelium and endothelium are much more lipoidal than stroma. Therefore drugs must possess biphasic solubility characteristics in order to be absorbed through this route.
Weakly basic drugs, such as tropicanade, epinephrine, pilocarpine, atropine, homatro-pine, or cyclopentolate, freely penetrate the cornea because of rapid equilibration between their lipid-soluble unionized forms and their water-soluble ionized forms. The penetration of quaternary ammonium compounds, such as carbachol, echothiophate iodide, and demecarium bromide, which are charged and water-soluble at all pH values, is postulated on a binding mechanism which permits a small but sufficient quantity of these potent antiglaucomic agents to reach aqueous humor and evoke a therapeutic response. Tetracycline, gentamicin, carbeni-cillin, and methicillin do not penetrate the cornea because of their low lipid solubility, but chloramphenicol shows good penetration.
Fluorescein is used for diagnostic purposed because of its high-lipid solubility, which prevents its entry into the stroma unless there is abrasion. If there is an abrasion, fluorescein enters the stroma and possibly the aqueous humor, giving a brilliant green color due to its alkaline pH. In the precorneal film fluorescein exists in a yellow or orange form.
A variety of physiologic factors influence corneal drug absorption. Lacrimal drainage of an instilled drug solution competes for drug with corneal penetration and can account for a considerable loss of drug. When a drop of solution is applied to the eye, two processes occur simultaneously: the solution is diluted by reflex tearing and the added volume in excess of the normal lacrimal volume is drained from the eye, which is partly facilitated by reflex blinking. In humans, administration of 25 |iL of solution to the eye at three-minute intervals will minimize volume build-up, dilution, excess drainage, and overflow. Shorter intervals of administration would reduce ophthalmic bioavailability. The normal lacrimal volume in humans is about 7 |iL, and if blinking does not occur the human eye can hold approximately 10 |iL. Since the size of commercial ophthalmic drops is between 50 and 75 |iL, the loss of drug due to spillage out of the eye can be considered a significant factor in the reduction of bioavailability.
Ophthalmic dosage forms include solutions, ointments, suspensions, lyophilized powders, and oily solutions. Several new dosage forms have recently been introduced to the market. One is an ophthalmic insert, an elliptical device consisting of a drug-containing core surrounded by a flexible copolymer membrane through which pilocarpine diffuses while the ocular delivery system remains in contact with conjunctiva (Occusert). A spray device has also been designed for accurate delivery of drugs.
Polymers such as methylcellulose, hydroxypropyl methylcellulose, and polyvinyl alcohol decrease the surface tension and increase the viscosity of solutions, thus enhancing bioavail-ability. Soft contact lenses soaked in pilocarpine have also been used. Biodegradable polymers have been employed for the controlled delivery of hydrocortisone and tetracycline.
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