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Chapter 9

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Ophthalmic andOtic Drug Delivery

Abstract This chapter introduces special considerations and formulation tech-

niques for ophthalmic and otic drug delivery. Types of ophthalmic dosage forms are reviewed and placed in a clinically relevant context. Commonly used excipients and their functions are also reviewed.

Keywords Ophthalmic drug delivery · Otic drug delivery · Ophthalmic dosage forms · Ocular bioavailability

Learning Objectives

1. Explain the sterility and preservation considerations as they apply to ophthal-

mic products. List examples of preservatives used in these products and their typical range.

2. Explain isotonicity as it relates to ophthalmic products.

3. Explain the use of buffers as related to ophthalmic products. List examples of

these excipients.

4. Explain the use of viscosity and thickening agents as related to ophthalmic

products. List examples of these excipients.

5. Describe the concept of ocular bioavailability and factors that can affect a

drug’s ocular bioavailability.

6. Compare and contrast ophthalmic solutions, gels, suspensions, ointments, and

emulsions.

7. Explain the proper administration technique for ophthalmic liquid products.

8. Describe the advantages of nonionic surfactants used in ophthalmic delivery

systems based on their compatibility, stability, and toxicity.

9. Describe the concept of otic drug delivery.

10. Explain the barriers to otic drug delivery.

11. Describe formulation considerations of otic dosage forms.

Key Concepts

Students should know and be able to describe each of the following concepts as they review this chapter:

A. D. Brunaugh et al., Essential Pharmaceutics, AAPS Introductions in the Pharmaceutical Sciences 12, https://doi.org/10.1007/978-3-031-52520-9_9

141© The Author(s), under exclusive license to Springer Nature Switzerland AG 2024

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1. Intravitreal injection

2. Ophthalmic delivery

3. Ophthalmic emulsions

4. Ophthalmic gels

5. Ophthalmic ointments

6. Ophthalmic solutions

7. Ophthalmic suspensions

8. Otic delivery

9. Periocular administration

10. Suprachoroidal administration

11. Subconjunctival administration

9 Ophthalmic andOtic Drug Delivery

9.1 Introduction

This chapter focuses on the essentials of ophthalmic and otic delivery systems.

Ophthalmic delivery is dened as the delivery of drugs topically or intraocularly to the eye. This dosage form is primarily used to treat local conditions of the eye such as infections, allergies, inammation, glaucoma, macular degeneration, diabetic macular edema, and dryness, with the benet of having limited risk of systemic side effects. Ophthalmic preparations can be delivered in a number of ways, including via solutions, suspensions, gels, ointments, or emulsions. For example, in an intravitreal injection, the drug in a formulation is directly injected into the vitreous humor, which is the gel-like substance in the center of the eye. Drug administration by an intravitreal injection is used to treat eye conditions affecting the retina and back of the eye. For subconjunctival administration, the drug in a formulation is administered typically by injection directly into the space between the conjunctiva, which is thin membrane covering the white of the eye, and the sclera, which is the outer layer of the eye. For suprachoroidal administration, the drug in formula- tion is delivered to the suprachoroidal space, which is located between the choroid, a vascular layer of the eye, and the sclera. Suprachoroidal injections are typically performed by inserting a specialized cannula (a thin tube) or microcatheter into the suprachoroidal space through a small incision. For periocular administration, the drug in formulation is applied directly to the tissues surrounding the eye, instead of directly onto the eye’s surface or inside the eye (e.g., eyelid margin application, subcutaneous injection beneath the skin around the eye).

Otic delivery is concerned with the local administration to the ear. Similar to the eye, the ear is a delicate and anatomically/physiologically protected organ that requires special formulation approaches to achieve therapeutic delivery. There are several biological barriers to be overcome to allow drug delivery to the target site within the ear.

9.2 Special Considerations inOphthalmic Dosage Forms

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9.2 Special Considerations inOphthalmic Dosage Forms

The volume capacity of the front of the eye is limited. The average tear volume is about 7 microliters (μL), while the maximum volume that can be held in the conjunctival cul-de-sac of the lower lid is about 30μL.The drainage rate from the culde-sac (Fig. 9.1) adjusts with increased volume; therefore, a higher drug concentration in a smaller volume is ideal, as a low volume dose will reduce the amount of drainage and medication wastage. This also leads to an important patient counseling point: administration of two separate eye drops should be separated by a period of time, as the administration of the second drug can dilute the rst. Commercial eye drops typically range from 25 to 70μL.

In addition to considerations regarding dosage volume, ophthalmic products have similar formulation design requirements to injectable and nasal formulations regarding sterility, tonicity, and pH.

Fig. 9.1 Anatomy of the eye

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9 Ophthalmic andOtic Drug Delivery

Table 9.1 Exemplary preservatives for ophthalmic dosage forms

Preservative Concentration

Benzalkonium chloride 0.004%–0.01% Benzethonium chloride 0.01% Chlorobutanol 0.5% Phenylmercuric acetate 0.004% Phenylmercuric nitrite 0.004% Thimerosal 0.005–0.01%

9.2.1 Sterility

Sterility is a compendial requirement for ophthalmic dosage forms, and maintaining sterility of ophthalmic drugs is paramount for patient safety. Preparations can be sterilized through autoclaving or ltration. Often, preservatives are also included in the formulation to prevent microbial growth, particularly for multi-dose products. Some preservatives (e.g., benzalkonium chloride) can cause irritation and toxicity when applied to the ocular surface. If no preservative is present, then the product is typically dispensed in a single-use container. Recently, preservative-free multi-dose bottle packaging has been commercialized. Examples of preservatives and their ranges are listed in Table9.1.

Of note, mixtures of benzalkonium chloride and polymyxin B or disodium ethylenediaminetetraacetate (EDTA) (0.01–0.1%), a chelating agent, are effective against most strains of Pseudomonas aeruginosa, a bacterium that can cause ulceration of the eye and blindness.

9.2.2 Tonicity

Tonicity of ophthalmic products generally should be adjusted to match physiological conditions. Ophthalmic products with an osmotic pressure equivalent to that of

0.6–2% sodium chloride solution have been reported to avoid causing discomfort to the eye.

9.2.3 pH

The pH of an ophthalmic formulation can be buffered to enhance patient comfort and increase stability, solubility, and bioavailability of the drug. Ideally, the pH should be similar to that of tears; however, the eye does have buffering capacity and can typically neutralize administered products, except in cases of large deviation or when the formulation itself is strongly buffered.

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9.2.4 Ocular Bioavailability

Bioavailability of drugs administered via the topical ophthalmic route is generally low and can be affected by a multitude of factors, including ocular barriers (e.g., cornea, conjunctiva, and blood-retinal barrier), tear dilution and drainage, rapid clearance, limited residence time on the eye’s surface, precorneal losses, and poor corneal penetration. Absorption of drugs often occurs primarily through the cornea (Fig.9.1). The cornea features a multilayer barrier to absorption. The most anterior layer, the hydrophobic squamous epithelium, acts as a barrier to hydrophilic molecules, while the stroma, the thickest layer of the cornea, is hydrophilic and acts as a barrier to hydrophobic molecules. Therefore, molecules that have both hydrophilic and lipophilic properties will typically be able to penetrate most readily. Binding of the drug by proteins found in the tears can also reduce bioavailability, as proteinbound drugs are too large to penetrate the corneal epithelium.

The retention time of the medication on the eye is another absorption-limiting factor. A longer retention time on the eye is desirable, as it leads to increased opportunity for the drug to diffuse and be absorbed before being cleared. Viscosity and thickening agents can be used in ophthalmic preparations to increase the time the drug is in contact with the ocular tissue. It has been reported that the optimal viscosity range for an ophthalmic product is between 15 and 25cP.Commonly used thickening agents in ophthalmic preparations are provided in Table9.2.

9.2.5 Packaging

The preferred packaging for a topical ophthalmic preparation is a soft plastic container with a built-in dropper, which protects the product from outside contamination and makes it easier for the patient to use. The patient must be counseled to not touch the tip of the dropper directly on the eye in order to reduce the risk of infection and corneal damage. If the container is single-use, it must be disposed of immediately after administration regardless if there is medication remaining in the packaging, because there is no preservative in the formulation.

Table 9.2 Exemplary thickening agents for ophthalmic dosage forms

Thickening agent Exemplary concentration (% w/v)

Methylcellulose 4000cP 0.25 Methylcellulose 25cP 1 Hydroxypropyl

methylcellulose (hypromellose) 3cP

Polyvinyl alcohol 1.4

0.5

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Table 9.3 Example patient counseling steps for administration of ophthalmic products

Step 1 Wash your hands: Prior to administration, the patient’s or caregiver’s hands should be

washed thoroughly

Step 2 Medication: Determine how to prepare the medication by reviewing patient instructions

in approved package label (e.g., is shaking required for a suspension liquid?)

Step 3 Administration to the eye: To instill eye drops, the patient’s head should be tilted back.

Often it is recommended to pull the lower eyelid of the eye down to create a pocket to which the drop is administered. In the case of an ointment or a gel, a thin ribbon can be applied.

Step 4 Following administration: Close eyes for a few seconds, blink a few times. Application

of gentle pressure applied to the inner corner of the eye near the nose can also be recommended as this prevents a signicant proportion of lacrimal drainage. Excess product around the eyes can be wiped/blotted away with tissue.

Step 5 Complete the task: The cap must be replaced on the container immediately after

administration to reduce the risk of contamination. Take care to not touch the tip of the container.

9 Ophthalmic andOtic Drug Delivery

9.2.6 Administration

It is important to counsel patients on the correct administration of ophthalmic products both to ensure that therapeutic effect is achieved and to prevent infection. Table9.3 outlines patient counseling steps for ophthalmic products.

9.3 Types ofOphthalmic Dosage Forms

Ophthalmic solutions contain active ingredients that are completely soluble in the liquid vehicle. The benet of this type of dosage form is that dose uniformity is ensured, and the application of the drug typically does not cause blurry vision. The disadvantage is that there is very little contact time between the drug and the cornea before the solution is drained away, which can lead to low levels of absorption.

Ophthalmic suspensions consist of particles of insoluble drug in an aqueous vehicle that also contains suspending agents. To be absorbed, the particles must dissolve sufciently during the residence time on the eye, which makes the intrinsic solubility of the drug an important factor to consider. In order to ensure dose uniformity, patients should be counseled to shake the formulation each time before administration, as settling of the drug particles can occur. Particle size of the suspended drug particles is of critical importance due to potential for irritation and drug dissolution.

Ophthalmic ointments consist of the drug incorporated into mineral oil and white petrolatum base. Since the ointment base is anhydrous, it can be used to carry moisture- sensitive medication. The ointment stays in place after application, and this longer contact time results in greater bioavailability. The disadvantage, however, is that the time to onset of action can be slower. The application of the

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ointment will cause blurry vision, and an important patient counseling point is to administer the ophthalmic ointment at bedtime when possible.

Ophthalmic gels contain polymers, including polyvinyl alcohol (PVA), hydroxypropyl methyl cellulose (HPMC; Hypromellose), carbomer, gellan gum, pluronic F127, and hyaluronic acid, that form an aqueous semi-solid dosage form that is applied to the eye in a similar manner to an ointment. In some cases, ophthalmic gels are formulated as a solution in which included polymers form a gel upon contact with tear uid. This transition can occur due to a change in temperature, pH, or the presence of proteins within the tear uid.

The advantage of ophthalmic gels is that they provide increased contact time with the eye tissue before clearance and thus increased drug absorbance and prolonged duration of therapeutic effect. Similar to ointments, the disadvantage of gels is that they can cause blurring of vision.

Ophthalmic emulsions consist of a drug dissolved in a non-aqueous vehicle that is then emulsied with water using a surfactant. This allows for the delivery of poorly water-soluble drugs in an aqueous form. The key component of the emulsion is the inclusion of a surface-active agent (surfactant). Surfactants are molecules that contain both hydrophobic and hydrophilic components. When placed in a system containing hydrophilic and hydrophobic phases, the surfactant accumulates at the interphase of the phases and slows aggregation and coalescence of the two materials. This ensures that the phases do not separate out.

Surfactants are generally classied based upon the polar subgroups in their chemical structures. Categories include amphoteric, cationic, anionic, and nonionic. Compared to the other types of surfactants, nonionic surfactants are preferred in ophthalmic delivery systems because they are generally less toxic, less hemolytic, and less irritating to the surface of the eye. They also tend to maintain near physiological pH in solution. Polyoxyethylated nonionic surfactants are widely used in ophthalmic preparations. These surfactants are amphiphilic in that they have a hydrophilic polyethylene oxide or polyethylene glycol side chain, while the remainder of the molecule possesses lipophilic properties. The extent of the water solubility of these molecules is determined by the length of the alkyl side chain and the number of ethylene oxide units in the molecule. An alkyl side chain of 12 or less carbons with ve or more ethylene oxide units is indicative of solubility in water at room temperature. The higher the percentage weight of polyethylene oxide in the molecule, the higher the hydrophile-lipophile balance (HLB), meaning that the surfactant molecule will have greater solubility in the aqueous solution. Examples of commonly used polyoxyethylated nonionic surfactants are outlined in Table9.4.

Table 9.4 Exemplary polyoxyethylated nonionic surfactants for ophthalmic products

Polysorbates Poloxamers Tyloxapol

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9 Ophthalmic andOtic Drug Delivery

9.4 Special Considerations inOtic Dosage Forms

Anatomically, the ear consists of three major regions: the outer ear, the middle ear, and the inner ear. As shown in Fig. 9.2, the outer ear (known also as the auris externa) extends from the pinna along the ear canal and ends with the tympanic membrane (ear drum). The pH in this region of the ear is slightly acidic (pH5–5.7) to inhibit bacterial growth. The middle ear (known also as the auris media) includes the delicate ossicular chain, which consists of the malleus, incus, and stapes. The Eustachian tube provides a conduit between the middle ear and upper airway that equalizes pressure in the middle ear. The inner ear (known also as the auris interna) consists of the cochlea, organs of balance, vestibule, and semicircular canals. The cochlea is further separated into three uid-lled compartments.

The most common diseases relating to the ear include acute external otitis (e.g., swimmer’s ear) that occurs in the outer ear; otitis media that occurs in the middle ear; and hearing loss, Meniere’s disease, and tinnitus that all occur in the inner ear. Antimicrobials, local anesthetic agents, corticosteroids, and even gene therapy and stem cell therapies are being developed for these diseases.

Depending upon the location of the disease and drug target, several anatomical barriers must be crossed by the drug molecule. The rst major anatomical barrier to administration of therapeutic agents is the tympanic membrane, which separates the outer and middle ear. The tympanic membrane is around 100μm thick and is structurally similar to the skin barrier (see Chap. 10). It is impermeable to most drugs except small molecular weight, lipophilic molecules.

Fig. 9.2 Anatomy of the ear