Drug Formulation

Ophthalmic drugs are formulated to bring the active drugs into contact with the eye surface to allow for absorption. Extension of corneal contact time may result in increased drug penetration and a higher intraocular drug level. The most common formulations for ophthalmic drug delivery are solutions and suspensions. In addition to the active drug, ophthalmic solutions or suspensions contain other ingredients to control various characteristics of the formulation, such as the buffering and pH, osmolality and tonicity, viscosity, and antimicrobial preservation. Although these ingredients are listed as inactive, they can affect the permeability of the drug across the ocular surface barrier and alter the therapeutic effectiveness of the drug.

1.4.1 Solution Versus Suspension. Ophthalmic solutions are the most commonly used ocular drug delivery systems and are the least expensive to formulate.7 All of the ingredients are completely dissolved, so there is only minimal interference with vision. Drugs in solution are immediately available for absorption. However, the aqueous solution dosage form can be considered only for drugs with sufficient aqueous solubility to prevent them from precipitating under adverse storage conditions. In some cases, one or more cosolvents may be added to the formulation to facilitate dissolution or maintain the drug in solution.

Ophthalmic suspensions are sterile preparations of drug with low water solubility dispersed in a liquid vehicle. They are formulations mainly for certain salts of corti-costeroids, for example, prednisolone acetate and fluorometholone acetate. The drug is present in a micronized form, generally <10 mm in diameter.30 The aqueous phase of the suspension is saturated with the drug. Different salts of the same drug can vary in water solubility, so a salt may be obtained that renders an otherwise-soluble drug insoluble. The small drug particles of a suspension presumably remain in the cul-de-sac longer than an aqueous solution and can prolong the drug's availability, although there are no reported data to prove this phenomenon.30 The drug delivery from a suspension is characterized by two consecutive phases. The first phase is a rapid delivery of the dissolved drug. The second is a slower but more prolonged delivery from the dissolution of the retained particles.31

The surface area accessible for drug dissolution and the ocular bioavailability from topically applied suspensions are correlated with particle size.32 As particle size decreases, the more rapid dissolution rate of the drug particle in the tear film may result in higher bioavailability. However, a suspension of very small particle sizes can drain from the cul-de-sac without prolonging the availability of the drug. Owing to the particle sedimentation property, adequate shaking of the suspension is required before use to obtain accurate dosing. Particle size influences the rate of settling of the suspension of the drug particles upon shaking the container. Generally, suspensions of larger particle sizes have a faster rate of settling and a lower rate of resuspension upon shaking. In addition, larger particles can lead to increased ocular irritation, with enhanced tearing and drug loss by drainage. To minimize potential irritation, particle size should be <10 mm.33 However, the 10-mm limit may not be clear-cut, because other factors, such as concentration, density, and shape, may contribute to the comfort threshold and retention in the cul-de-sac.30

1.4.2 Buffering and pH. The pH of an ophthalmic formulation is important to achieve the optimal condition of chemical and physical stability for the formulation, the solubility of the active ingredient as well as the adjuvant ingredients (e.g., preservatives and any viscosity-improving polymers), and the comfort of the ophthalmic formulation.34

Most ophthalmic drugs, being weak acids or bases, are present in solutions as both the nonionized (nondissociated) and the ionized (dissociated) species. The drug may by itself provide the necessary buffering action if its pKa is in the appropriate range. The degree of ionization of a drug in solution is determined by the pKa of the drug and the pH of the solution. A pH that favors a higher proportion of the nonionized species could result in a higher transcorneal permeability.35 The normal tear pH given in the literature ranges from 7.0 to 7.4, depending on different methods of measurement.36 The in vivo pH of the formulation depends on the solution pH and the tear pH. The pH of the tears may modify the final in vivo pH of the drug and, subsequently, the drug's effectiveness.37 On the other hand, the pH of the tears, which have their own buffer system, may be temporarily altered by the ophthalmic drops and subsequently elicit reflex tearing. This can cause excessive washout of the drug, which interferes with absorption.

1.4.3 Osmolality and Tonicity. Tear osmolality varies between 302 and 318mOsm/kg with the eyelids open, increasing by 1.43mOsm/kg during the day, and varies between 288 and 293mOsm/kg after prolonged eyelid closure.34 There are significant individual variations in the tonicity of normal human tears. To avoid irritation, ophthalmic formulations intended for topical instillation should be approximately isotonic with the tears. The eye can tolerate a considerable range of tonicity between 266 and 445 mOsm/kg before any pain or discomfort is detected.38 Also, the tears can adjust the tonicity of the topically applied solutions by osmosis. Increased tonicity of topical drops is immediately diluted by the tears. Because ophthalmic drugs listed in the Physicians' Desk Reference do not exceed 5% of an active compound, they are within the acceptable range of tonicity between 220 and 640 mOsm/kg. Excessive ranges of tonicity can elicit reflex tearing. Examples are a few ophthalmic solutions, such as pilocarpine 8% and 10%, phenylephrine 10%, and sulfacetamide 10%, that cause a strong burning and stinging sensation upon instillation.39

The tonicity of ophthalmic products is generally adjusted to physiologically compatible values by using sodium chloride. In cases where a precipitating effect of sodium chloride may reduce the solubility of the drug or other ingredients, the nonionizing substance mannitol may be used.

1.4.4 Viscosity. Increasing the viscosity of a topically applied ocular formulation is expected to reduce drainage, increase the residence time in the conjunctival sac, and thus lead to enhanced intraocular penetration and therapeutic effect. Improvement in ocular drug delivery is observed over the viscosity range from 1 to 15 cp (cen-tipoise), and it is suggested that the optimal viscosity should be 12-15 cp.40 Further increases in viscosity above this level do not appear to proportionally increase the drug concentration in aqueous. Formulations with higher viscosity cause ocular surface irritation, resulting in reflex blinking, lacrimation, and increased drainage of the applied formulation. Higher viscosity may also have the effect of inhibiting product-tear mixing accompanied by optical surface distortion, which produces visual disturbance for the patient. Formulations with viscosity of 30 cp or higher impart a sticky feel to the formulation, making it uncomfortable to use.

The most commonly used agents for increasing viscosity include polyvinyl alcohol (PVA) and derivatives of methylcellulose. The viscosities of solutions containing 1.4% PVA and 0.5% hydroxypropyl methylcellulose, which are the concentrations usually used in ophthalmic products, are about 10 and 20 cp or less, respectively.34

1.4.5 Preservatives. Ophthalmic drug delivery systems packaged in a multiple-dose container must contain a suitable mixture of substances to prevent the growth of microorganisms or to destroy any that are accidentally introduced when the container is open during use. Common preservatives in ophthalmic preparations are quaternary cationic surfactants such as benzalkonium chloride and benzododecium bromide; mercurials such as thimerosal, chlorobutanol, and parahydroxy benzo-ates; and aromatic alcohols. It has been shown that preservatives used in ophthalmic solutions can be toxic to the ocular surface following topical administration and can enhance the corneal permeability of various drugs.41

Benzalkonium chloride is the most commonly used preservative in ophthalmic preparations. As a surfactant, benzalkonium chloride can increase the solubility of drugs that are hydrophilic and exert their bactericidal effect by emulsification of the bacterial cell walls. Ocular damage from these agents is most likely due to emul-sification of the cell membrane lipids.42 Adverse reactions are not uncommon with this preservative. Although most of the side effects are reversible, irreversible cyto-pathologies can also be seen. The compound is known to cause edema, desquamation, punctate keratitis, and papillary conjunctivitis.43 Benzalkonium chloride binds to soft contact lenses and tends to concentrate in the contact lens. Parallel use of soft contact lens and vehicles containing benzalkonium chloride can result in severe but reversible and temporary epithelial keratitis without significant endo-thelial damage.

Another preservative used only with brimonidine tartrate is Purite, which is a stabilized oxychloro complex that has oxidative properties and is different from benzalkonium chloride. Purite may be better tolerated in eyes sensitive to benzal-konium chloride.

Adverse ocular side effects attributed to the organomercurials are less common. Hypersensitivity to the organomercurials appears to be the most dramatic side effect incurred with these agents and is estimated to occur in about 10% to 50% of patients. Hyperemia, edema, and blepharoconjunctivitis may result.43

1.4.6 Drug Delivery by Prodrugs. The main route of entry of topically applied drugs into the anterior chamber is through the cornea. One way to increase the penetration of the corneal epithelium is by increasing the lipophilicity of the drug. Dipivefrin (Propine), latanoprost (Xalatan), travoprost (Travatan), and nepafenac (Nevanac) are examples of prodrugs developed for this purpose. The ester group in these compounds increases their lipophilicity and enhances corneal permeability. These prodrugs are then converted into the active drugs, the acidic forms, by the esterase enzymes in the cornea. Prodrugs allow increased penetration into the anterior chamber and may reduce local and systemic side effects by decreasing the concentration of drug required.

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