Retention of topical agents

Some features of topical ocular therapy limit treatment effectiveness. Very little of an administered drop is retained by the eye. When a 50-μL drop is delivered from a conventional commercial dispenser, the volume of the tear lake rises from 7 μL to only 10 μL in the blinking eye of an upright patient. Thus, at most, 20% of the administered drug is retained (10 μL/50 μL). A rapid turnover of fluid also occurs in the tear lake—16% per minute in the undisturbed eye—with even faster turnover if the drop elicits reflex tearing. Consequently, for slowly absorbed drugs, at most only 50% of the drug that was initially retained in the tear reservoir, or 10% of the original dose (50% of the 20% of the delivered medication), remains 4 minutes after instillation, and only 17%, or 3.4% of the original dose, remains after 10 minutes.

Figure 15-1 Diagram of the eye with common drug delivery routes and elimination pathways. Delivery routes: (1) Transcorneal route from the tear film across the cornea into the anterior chamber; (2) transconjunctival route across the conjunctiva, sclera, and anterior uvea into the posterior chamber; (3) intrastromal route directly into corneal stroma; (4) intracameral route directly into anterior chamber; (5) subconjunctival route from the anterior subconjunctival space across the sclera and anterior uvea into the posterior chamber or across the sclera, choroid, retinal pigment epithelium (RPE), and retina into the anterior vitreous; (6) intravitreal drug injection directly into the vitreous; (7) sub-Tenon route from the posterior sub-Tenon space across the sclera, choroid, RPE, and retina into the posterior vitreous; absorption pathways: (8) elimination of drug in the aqueous humor across the trabecular meshwork and Schlemm canal into the systemic vascular circulation; (9) elimination of drug in the aqueous humor across the uvea into the systemic vascular circulation; (10) elimination of drug in the vitreous humor across the blood–retina barrier to the systemic vascular circulation; (11) drug elimination from the vitreous across the anterior hyaloid to the posterior chamber or vice versa; (12) drug elimination from subconjunctival and/or episcleral space to systemic lymphatic or vascular circulation.

(Modified with permission from Levin LA, Nilsson SFE, Ver Hoeve J, Wu SM. Adler’s Physiology of the Eye. 11th ed. Philadelphia: Elsevier/Saunders; 2011:113.)

Some simple measures have been shown to improve ocular absorption of materials that do not traverse the cornea rapidly:

• Patients using more than 1 topical ocular medication should be instructed to allow 5 minutes between instillation of drops; otherwise, the second drop may simply wash out the first.

• Blinking also diminishes a drug’s effect by activating the nasolacrimal pump mechanism, forcing fluid from the lacrimal sac into the nasopharynx, and creating a negative sac pressure that empties the tear lake (see BCSC Section 7, Oculofacial Plastic and Orbital Surgery). Patients can circumvent this loss of drug reservoir either by compressing the nasolacrimal duct through application of digital pressure at the medial canthus or by closing their eyes for 5 minutes after instillation of each drop. These 2 measures will prevent emptying of the tear lake and will reduce systemic toxicity by decreasing absorption through the nasal mucosa. Nasolacrimal occlusion will increase the absorption of topically applied materials and decrease systemic absorption and potential toxicity (Fig 15-2).

• Tear reservoir retention and drug contact time can also be extended either by increasing the viscosity of the vehicle or by using drug delivery objects such as contact lenses, collagen shields, and inserts.

Topical medications that are absorbed by the nasal mucosa can attain significant levels in the blood. One or 2 drops of a topical medication may provide a significant systemic dose of that drug. For example, a 1% solution of atropine has 1 g/100 mL, or 10 mg/1 mL. A simpler way of remembering this conversion is to add a 0 to the drug percentage to change the value to milligrams per milliliter. As there are 20 drops per milliliter (up to 40 in some newer, small-tip dispensers), there is ¼–½ mg of 1% atropine per drop. If this drop is given bilaterally, up to 1 mg of active agent is available for systemic absorption, although the actual amount absorbed is limited by dilution and the washout effect of tears (Fig 15-3).

Figure 15-2 Relative fluorescence in the anterior chamber at various times after application: with nasolacrimal occlusion (NLO), with 5 minutes of eyelid closure, or with no intervention (no NLO).

Figure 15-3 Pharmacokinetics of topical eyedrop drug delivery. GI tract = gastrointestinal tract.

(Modified with permission from Levin LA, Nilsson SFE, Ver Hoeve J, Wu SM. Adler’s Physiology of the Eye. 11th ed. Philadelphia: Elsevier/Saunders; 2011:113.)

Absorption of topical agents

Because the contact time of topical medication is short, the rate of transfer from the tear fluid into the cornea is crucial. The corneal epithelium and endothelium have tight junctions that limit paracellular passage of molecules. To enter the anterior segment, topically applied medication must first pass through hydrophobic/lipophilic cell membranes in the corneal epithelium, then through the hydrophilic/lipophobic stroma, and finally through the hydrophobic/lipophilic cell membranes in the endothelium. Thus, topical ophthalmic drug formulations must be both lipophilic and hydrophilic. As nonionic particles are more lipophilic than ionic particles are, they pass through the cellular phospholipid membranes more readily. The pH of the medication can be manipulated to adjust the percentage of the drug that is in the ionized form and the nonionized form to optimize the rate of drug penetration. Mechanical disruption of the epithelial barrier in corneal abrasion or infection also increases the rate of intraocular drug penetration.

Similar considerations apply to the conjunctiva. However, the permeability of the conjunctiva to small water-soluble molecules is thought to be 20 times that of the cornea. Perilimbal conjunctiva thus offers an effective transscleral route for delivery of drugs to anterior segment structures.

The factors determining the amount of medication that can penetrate the cornea are

• concentration and solubility in the delivery vehicle

• viscosity

• lipid solubility

• pH

• ionic and steric forms

• molecular size

• chemical structure and configuration

• vehicle

• surfactants (also called surface-active agents)

In addition, reflex tearing and the binding of the active medication to proteins in tears and tissue affect drug bioavailability. Many preservatives used in topical drops are surfactants that can alter the barrier effect of the corneal epithelium and increase drug permeability.

Drug concentration and solubility

In order for a sufficient amount of a drug to pass through the corneal barriers, it may be necessary to load the tear reservoir with concentrated solutions (eg, by selecting pilocarpine, 4%, instead of pilocarpine, 1%). A practical limit to exploiting these high concentrations is reached when the high tonicity of the resulting solutions elicits reflex tearing or when drugs that are poorly water-soluble reach their solubility limits and precipitate. A drug with adequate solubility in an aqueous solution can be formulated as a solution, whereas a drug with poor solubility may need to be provided in a suspension.

A suspension is a mixture of a substance with poor solubility and a dispersion medium in which the substance is evenly distributed. A suspension requires agitation so that the active medication is redistributed before administration. Suspensions may be more irritating to the ocular surface than solutions are, a factor that may affect the choice of drug formulation. Prednisolone acetate and brinzolamide are 2 examples of a topical suspension.

An emulsion is similar to a suspension in that it is also a mixture of 2 components; however, the components are immiscible (not susceptible to being mixed) liquids. External force or an emulsifying agent is required to maintain the stability of the emulsion. Compared with solutions, emulsions have the advantages of increased contact time (because of the adsorption of nanodroplets on the corneal surface) and greater bioavailability. An emulsion typically has a cloudy appearance, but in contrast with a suspension, shaking the container before instillation is not necessary. Since emulsions are more viscous than solutions, patients may experience a foreign-body sensation after instillation. Difluprednate and cyclosporine are examples of a topical emulsion.

Viscosity

The addition of high-viscosity substances such as methylcellulose and polyvinyl alcohol (PVA) to a drug increases drug retention in the inferior cul-de-sac, aiding drug penetration. An example is timolol maleate formulated in gellan gum or xanthan gum, both of which are a high-molecular-weight, water-soluble, anionic polysaccharide that thickens on contact with the tear film, maintaining therapeutic levels and allowing the dosing to be decreased to once daily.

Improvement in ocular drug delivery is observed when drug viscosity is in the range of 1–15 cP (1 cP = 1 millipascal-second [mPas]); the optimal viscosity is 12–15 cP. Increases in viscosity above this level do not appear to proportionally increase the drug concentration in aqueous. In fact, formulations with higher levels of viscosity cause ocular surface irritation, resulting in reflex blinking, lacrimation, and increased drainage of the applied formulation. They may also inhibit product–tear mixing and distort the ocular surface. Products with viscosity levels that are too high may impart a sticky feeling, cause blurring of vision, and be uncomfortable for patients to use.

Lipid solubility

Studies of the permeability of isolated corneas to families of chemical compounds show that lipid solubility is more important than water solubility in promoting penetration. To determine the solubility of a drug or group of drugs, researchers ascertain the ratio of lipid solubility to water solubility for each compound in the series by (1) measuring the phase separation of a drug between 2 solvents—1 lipid-soluble and 1 water-soluble (eg, octanol and water); and (2) calculating the ratio of the drug concentration in the 2 compartments (partition coefficient). Drugs with greater relative lipid solubility have a higher partition coefficient. For example, the permeability coefficient is 70 times higher for substituted ethoxzolamides with high lipid solubility than for those of low lipid solubility. Drugs with higher levels of lipid solubility and higher partition coefficients have increased penetration of cell membranes. Compared with the parent molecules, prodrugs, such as various prostaglandin analogues, with ester or amide moieties achieve lipophilicity that is 2-fold to 3-fold higher and in vitro corneal permeability that is enhanced 25- to 40-fold. However, compounds with excessively high partition coefficients are often poorly soluble in tears. Experimental studies of substituted compounds must account for the effects of the substituents on potency, solubility, and the permeability coefficient.

pH and ionic charge

Many eye medications are alkaloids, or weak bases, and are most stable at an acidic pH. The buffer system used should have a capacity adequate to maintain pH within the stability range for the duration of the product shelf life. The pH range that a patient can tolerate is narrow. A large difference between the pH of a topical solution and that of tears may result in ocular irritation and stimulate reflex tearing that dilutes or washes away the topical drops. Thus, the buffer capacity should be adequate for stability but minimized to allow the overall pH of the tear fluid to be disrupted only momentarily upon instillation. Drugs such as tropicamide, cyclopentolate, atropine, and epinephrine exist in both charged and uncharged forms at the slightly alkaline pH of tears (pH 7.4). The partition coefficients, and therefore drug penetration, can be increased by raising the pH of the water phase, thereby increasing the proportion of drug molecules in the more lipid-soluble, uncharged form.

Surfactants

Many preservatives used in topical drops to prevent bacterial contamination are surfactants (also called surface-active agents) that alter cell membranes in the cornea as well as in bacteria, reducing the barrier effect of the corneal epithelium and increasing drug penetration. For example, a 0.1% carbachol solution containing 0.03% benzalkonium chloride can elicit the same miotic response as a 2% solution without this preservative.

Reflex tearing

Ocular irritation and secondary tearing wash out the drug reservoir in the tear lake and reduce the contact time of the drug with the cornea. Reflex tearing occurs when topical medications are not isotonic and when they have a nonphysiologic pH or contain irritants.

Binding of medication

Tear and ocular surface proteins, as well as ocular melanin, may bind topical or systemic medication, making the drug unavailable or creating a slow-release reservoir. This binding may alter the lag time, or onset, of a medication as well as the peak effect and duration of action, and it can cause local toxicity that occurs after discontinuation of the medication. One example of this effect is the retinal toxicity that progresses even after discontinuation of the aminoquinoline antimalarial drugs chloroquine and hydroxychloroquine. The latter is also often used in the management of autoimmune diseases such as lupus and rheumatoid arthritis.

Excerpted from BCSC 2020-2021 series: Section 2 - Fundamentals and Principles of Ophthalmology. For more information and to purchase the entire series, please visit https://www.aao.org/bcsc.