Ocular irritation, ophthalmic formulations

Current guidelines for toxicity evaluation of ophthalmic formulations involve both single and multiple applications, dependent on the proposed clinical use [39]. The multiple applications may extend over a 9-month period and incorporate evaluations of ocular irritation and toxicity, systemic toxicity, and determinations of systemic exposure (toxicokinetics). In many cases the systemic exposure from an ocular route is less than by parenteral administration, information that will assist in determining whether additional studies may be needed to establish systemic safety of the ophthalmic preparation. U.S. and international guidance documents are available [71,72], and regulations and tests have been summarized for ophthalmic preparations [39,73,74],... 

Surfactants. The use of surfactants is greatly restricted in formulating ophthalmic solutions. The order of surfactant toxicity is anionic > cationic >> nonionic. Several nonionic surfactants are used in relatively low concentrations to aid in dispersing steroids in suspensions and to achieve or to improve solution clarity. Those principally used are the sorbitan ether esters of oleic acid (Polysorbate or Tween 20 and 80), polymers of oxyethylated octyl phenol (Tyloxapol), and polyoxyl 40 stearate. The lowest concentration possible is used to perform the desired function. Their effect on preservative efficacy and their possible binding by macromolecules must be taken into account, as well as their effect on ocular irritation. The use of surfactants as cosolvents for an ophthalmic solution of chloramphenicol has been described [271]. This com-... 

An ideal ophthalmic formulation should be installed in the ocular area without causing any irritation or blurred vision [29]. The in-situ gel-forming drug delivery system is often considered as suitable ophthalmic formulation because after administration in the ocular area, it immediately undergoes phase transition to form viscoelastic gel, which in turn enhances the residence period of the drug at the target site to yield better drug performance [66]. 

This new type of ophthalmic formulations has to possess well defined properties in order to meet biopharmaceutical requirements such as be capable of delivering the effective ocular drug concentrations along an extended period of time (without inducing systemic side effects), user friendly, and exempt of side effects such as blurring, irritation, or foreign-body sensation. 

Emulsions have been used for centuries for the oral administration of medical oils and vitamins and as dermatological vehicles. Recently, their application has been extended as drug carriers in the delivery and targeting of ophthalmic drags. An indomethacin emulsion has been reported to increase ocular bioavailability and efficacy compared to commercially available formulation in rabbits. 0.4% indomethacin emulsion showed 2.2 fold increase in the area under the anterior aqueous drag concentration/time curve compared to a 1% indomethacin suspension. The emulsion formulation also reduced ocular surface irritation caused by indomethacin Similar advantages have been shown for a pilocarpine emulsion which produced a prolonged therapeutic effect in comparison with pilocarpine hydrochloride eyedrops in man. It can be administered only twice a day, rather than four times daily for conventional formulation. 

The sensitivity of the eye requires that the formulation and sterility of ocular medication are of critical importance. An inappropriate formulation can cause irritation or disruption of the mechanisms responsible for the protection of the eye. Contaminated ophthalmic preparations could, especially in the case of an injured eye, cause infections or exacerbate the infection. 

In conclusion, the fluid dynamics in the precorneal area of the eye have a huge effect on ocular drug absoiption and disposition. When the normal fluid dynamics are altered by e.g., tonicity, pH, or irritant drugs or vehicles, the situation becomes even more complex. The formulation 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. 

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