Tonicity ophthalmic formulations

It has been also observed that hypertonic and hypotonic salt solutions tend to irritate sensitive tissue and cause pain when applied to mucous membranes of the eye, ear, and nose, etc., whereas isotonic solution causes no tissue irritation when it comes in contact with the tissue. Obviously, the tonicity of formulations that come in to direct contact with blood, muscle, eye, nose, and delicate tissues is critical. Therefore, the issue of tonicity is important in small- and large-volume injectables, ophthalmic products, and products intended for tissue irrigation. The degree of tissue irritation or hemolysis or crenation observed depends on the degree of deviation from isotonicity, the volume injected, the speed of injection, the concentration of the solutes in the injection, and the nature of the membrane. The parenteral and ophthalmic formulations are therefore adjusted to isotonicity if possible. 

The combination of active drug, preservative, and vehicle usually results in a hypotonic formulation (< 290 mOsm). Simple or complex salts, buffering agents, or certain sugars are often added to adjust osmolarity of the solution to the desired value. An osmolarity of 290 mOsm is equivalent to 0.9% saline, and this is the value sought for most ophthalmic and intravenous medications.The ocular tear film has a wide tolerance for variation in osmotic pressure. However, increasing tonicity above that of the tears causes immediate dilution by osmotic water movement from the eyelids and eye. Hypotonic solutions are sometimes used to treat dry eye conditions and to reduce tear osmolarity from abnormally high values. 

Hypotonic ophthalmic solutions or suspensions can be rendered isotonic by the addition of tonicity agents such as sodium chloride, potassium chloride, dextrose, glycerol and buffering salts. As with other adjuvants, the formulator should give due consideration to possible interactions between the tonicity agent and other components of the formulation, including the drug itself. 

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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