New Drug Delivery Vehicles

To deliver ophthalmic drugs into contact with the eye surface to permit absorption, detailed formulation requirements have to be satisfied in terms of pH, osmolality, tonicity, and viscosity to achieve chemical and physical stability, solubility, and comfort for the patient. New vehicles are under investigation to further prolong the corneal contact time. Currently, solutions and suspensions remain the most commonly used vehicles for ophthalmic drug delivery.

1.5.1 Emulsions. Emulsions are traditionally defined as two-phase systems in which one liquid is dispersed throughout another liquid in the form of small droplets. The development of the specialized submicrometer emulsion has created new interest in this delivery system. The emulsion is characterized by the droplet size of the oily phase in the range of 0.1-0.3 mm. The nonionic surfactants used in stabilizing this emulsion are nonirritating. Emulsions have the advantage of allowing the delivery of lipid-soluble drugs in an aqueous-like form. By formulation of the drug in an emulsion, the drug can be protected from susceptible oxidation or hydrolysis. Animal studies have demonstrated improved performance of some ophthalmic drugs formulated in a specialized submicrometer emulsion.44 The increased ocular retention time probably explained the improved bioavailability and enhanced effectiveness. Specialized submicrometer emulsions also demonstrated a reduction of ocular irritation, although the mechanism is currently unknown.

1.5.2 Gels. Gels are single continuous or multiphase semisolid systems. Drug release from a gel occurs by diffusion and erosion of the gel surface. Because gels can also be degraded by microorganisms, they require the inclusion of a preservative. There are several in situ gelation systems currently under investigation. Examples of these systems are ion-activated, pH-activated, and temperature-sensitive gelation systems.45-47 They combine the advantages of dispensing an aqueous solution with the increased retention time of a high-viscosity formulation.

In the ion-activated gelation system, Gelrite as a polysaccharide, low-acetyl gellan gum forms clear gels in the presence of monovalent or bivalent ions. The concentration of sodium ions in tears is sufficient to cause gelation in the conjunctival sac.45 The prolonged contact time with the ocular surface increases the bioavailability of the drug.

The pH-activated gelation system is composed of a large amount of an anionic polymer in the form of nanodispersion, which has a very low viscosity at pH <5. On contact with the tear film, which normally has a pH of 7.0-7.4, the particles agglomerate and assume a gel form. The gelation process is due to swelling of the particles from neutralization of the acid groups on the polymer chain and the ab-

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sorption of water.

Different materials are used to achieve gelation at the temperature of the ocular surface. A 25% poloxamer 407 achieved an increase in viscosity with an increase in temperature from an ambient temperature of 25° C to a temperature at the ocular surface of 32°C to 34°C.48 Harsh and Gehrke47 developed a temperature-sensitive hydrogel based on cross-linking cellulose ethers such as hydroxycellulose. Cellulose ethers have been approved by the FDA for food and drug use. They offer an advantage over many synthetic gels based on polymers or monomers, which are carcinogenic or teratogenic.

Another approach to achieve gelation was attempted by a combination of polymers responding simultaneously to two gelating factors, such as pH and temperature. An aqueous solution containing a combination of 0.3% carbopol, a poly-acrylic acid polymer that gelates when the pH is raised over its pKa of 5.5, and a 1.5% methylcellulose that gelates when the temperature is raised above 30°C was reported by Kumar et al.49 to form a gel under simulated physiologic conditions. This approach may reduce the total polymer content of the delivery system.

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