Ординатура / Офтальмология / Английские материалы / Clinical Ocular Pharmacology 5th edition_Bartlett, Jaanus_2008

Table 2-5

Marketed Drugs or Drugs Under Development for Intravitreal Delivery

AMD = age-related macular degeneration; DME = diabetic macular edema;VEGF = vascular endothelial growth factor;VEGFR = VEGF receptor. From Duvvuri S, et al.Advanced Drug Delivery Reviews 57 (2005) 2080–2091;Table 1, p 2082.

Formulations Drug Ophthalmic 2 CHAPTER

36 CHAPTER 2 Ophthalmic Drug Formulations

cavity. Fluocinolone acetonide intravitreal implant 0.59 mg (Retisert) has been approved for treatment of chronic noninfectious uveitis affecting the posterior segment of the eye. It is surgically implanted into the posterior segment of eye and delivers initially 0.6 mcg/day, decreasing to 0.3 to 0.4 mcg/day over about 30 months.

An intraocular drug delivery system that has been developed consists of a biodegradable polymer matrix and may be able to incorporate various medications. A dexamethasone drug delivery system (Surodex) is under investigation for use in preventing postoperative inflammation after cataract surgery. Inserts may also increase the noncorneal route of drug absorption across the sclera. To date, the expense of the slowrelease inserts compared with the economy of eyedrops has hindered their acceptance. However, both theory and clinical experience support the rationality of this approach to ocular dosing. Future improvements in technology and reduced cost would allow increased use of these dosage forms. A posterior segment delivery system (Posurdex) may also allow for similar intraocular administration of a biodegradable matrix for corticosteroid and potentially other medications. Intraocular implants that provide for an extended period of drug delivery are being studied to allow for the treatment of many posterior segment diseases such as cytomegalovirus retinitis, macular degeneration, and macular edema.

OCULAR DRUG DEVELOPMENT

AND THE PATIENT

Many steps are involved in the successful design of an ocular drug formulation.The first is selection of an appropriate drug molecule that maximizes therapeutic benefit and bioavailability while minimizing toxicity. A formulation must then be developed to include a vehicle, a preservative, and a buffer.

Combinations of the aforementioned delivery systems may offer the potential for increased ocular bioavailability and reduced toxicity. Stability, toxicity, and efficacy must then be evaluated for the complete formulation.An effective dosing regimen must also be developed before beginning clinical trials on a wide scale. The U.S. Food and Drug Administration is involved in evaluating these steps to provide formulations that are efficacious and safe.

Of the numerous factors that influence ocular drug efficacy and safety, one of the most important remains that of patient compliance. Determining the proper dosage regimen and getting patients to administer the medication is a primary responsibility of the practitioner. These factors are considered in Chapters 1 and 4.

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The pharmacotherapy of eye disease generally requires high local concentrations of drug at the ocular tissues. Treatment of ocular surface infections or inflammations necessitates effective drug delivery to the eyelids, conjunctiva, or cornea. In contrast, treatment of uveitis, glaucoma, or retinitis involves therapeutic drug levels at appropriate target sites deep within the globe. Although many systems have been developed specifically for drug delivery to the eye, most of them suffer from lack of precision, and those associated with intraocular drug delivery can lead to toxicity.This chapter discusses the most clinically useful drug delivery systems developed for ocular pharmacotherapy, with emphasis on those used in primary eye care.

TOPICAL ADMINISTRATION

Topical application, the most common route of administration for ophthalmic drugs, is convenient, simple, and noninvasive, and patients can self-administer the medication. Topically applied anesthetics are even used as the primary anesthetic for contemporary cataract surgery. The primary source of drug loss in topical administration is diffusion into the circulating blood. Diffusion into the blood takes place through blood vessels of the conjunctiva, episclera, intraocular vessels, and vessels of the nasal mucosa and oral pharynx after drainage through the nasolacrimal system. Because of these losses of drug through the systemic circulation, topically administered medications do not typically penetrate in useful concentrations to the posterior ocular structures and therefore are often of no therapeutic benefit for diseases of the posterior segment.

Solutions and Suspensions

Solutions are the most commonly used mode of delivery for topical ocular medications. Solutions or suspensions are usually preferred over ointments, because the former are more easily instilled, interfere less with vision, and have fewer potential complications. Disadvantages of topically applied solutions include short ocular contact

time, imprecise and inconsistent delivery of drug, frequent contamination, and the possibility of ocular injury with the dropper tip.

Suspensions must be resuspended by shaking to provide an accurate dosage of drug, and the degree of resuspension varies considerably among preparations and among patients. Corticosteroid formulations, for example, are not always adequately resuspended even by the most compliant and carefully instructed patients. Some generic steroid suspensions, moreover, have been found to suspend poorly, and some generic products may develop a clogged dropper tip.These problems have been described primarily in association with 1% prednisolone acetate suspension.

Packaging

Most eyedrop containers consist of two parts,an eyedropper tip and a bottle containing the solution or suspension. Because it is advantageous to administer small volumes of medication to minimize systemic absorption of topically applied solutions or suspensions, some manufacturers have attempted to reduce eyedrop volume by modifying or redesigning dropper tips. Traditionally, commercial eyedrops have ranged in size from 50 to 70 mcl.The typical volumes now delivered by commercial glaucoma medications are in the range of 25 to 56 mcl.

To help reduce confusion in labeling and identification among various topical ocular medications, drug packaging standards are in use. The standard colors for drug labeling and bottle caps are yellow, blue, or both for beta blockers; red for mydriatics and cycloplegics; green for miotics; orange for carbonic anhydrase inhibitors; gray for nonsteroidal anti-inflammatory drugs; pink for steroids; brown or tan for anti-infective agents; and teal for prostaglandin analogues.

Storage

Solutions of drugs should be stored in the examination room in a manner allowing easy identification of labels (Figure 3-1). Containers of solutions often differ little in size, shape, or labeling. The drug name should be

confirmed by inspection each and every time a medication is used.

Although refrigeration of solutions may help to prolong shelf life,there appears to be little difference in local ocular irritation caused by eyedrops stored in the refrigerator or at room temperature. Cold drops, however, often can serve to reinforce proper eyedrop self-administration technique for patients who have difficulty ascertaining when the drops have been properly instilled.

Expiration dates of solutions should be respected. Office staff should periodically survey ophthalmic preparations in the office and discard solutions that have reached the expiration date.The use of old solutions can increase liability as well as introduce the risk of potential drug toxicity or iatrogenic infection. Some commonly used ophthalmic solutions, such as proparacaine, may change color, which indicates oxidation (Figure 3-2), whereas others show no visible signs of deterioration.

Techniques of Instillation

Two methods are commonly used to instill topical ocular solutions:

1.With the patient looking down and the upper lid retracted, a drop of solution is applied to the superiorly exposed bulbar conjunctiva.

2.With the patient’s head inclined backward so that the optical axis is as nearly vertical as possible, the lower lid is retracted and the upper lid stabilized.The patient should be instructed to elevate the globe to move the cornea away from the instillation site to minimize the blink reflex. The solution is instilled, and the dropper tip is kept at least 2 cm from the globe to avoid contact contamination (Figure 3-3). After the lids are gently closed, the patient should be cautioned to avoid lid

squeezing. Pressure should be applied with the fingertips over the puncta and canaliculi to minimize nasolacrimal drainage (Figure 3-4).This position, known as nasolacrimal occlusion, should be maintained for 2 to 3 minutes.

Several investigators have shown that simple eyelid closure alone significantly retards medication drainage and thereby minimizes potential side effects associated

Figure 3-2 Change in color of proparacaine solution (left) indicates deterioration of the formulation.

Figure 3-3 Traditional technique for instillation of topical ocular solutions.The patient’s head is inclined backward, the lower lid is retracted, the globe is elevated, and the dropper tip is kept at least 2 cm from the globe.

with systemic drug absorption. However, when nasolacrimal occlusion is used in conjunction with eyelid closure, intraocular drug absorption may be enhanced. The same maximal drug effect can be achieved with many ocular hypotensive drugs at lower concentrations and with lower dosage frequencies than those generally recommended. This is true at least for use of pilocarpine and timolol. In the long-term treatment of glaucoma with topical drugs, silicone punctal plugs may be used as a

Figure 3-4 Nasolacrimal drainage of solutions may be minimized by applying pressure with fingertips over the puncta and canaliculi.

Box 3-1 Recommended Procedure for Instilling Topical Ocular Solutions

1.Tilt patient’s head backward.

2.Instruct patient to direct gaze toward ceiling.

3.Gently grasp lower outer eyelid below lashes and pull eyelid away from globe.

4.Without touching lashes or eyelids, instill one drop of solution into conjunctival sac.

5.Continue to hold eyelid in this position for a few seconds to allow solution to gravitate into deepest portion of lower fornix.

6.Instruct patient to gaze downward while lifting the eyelid upward until it contacts the globe.

7.Instruct patient to gently close eyes.

8.Patient should keep eyes closed for 2 to 3 minutes.

substitute for manual nasolacrimal occlusion. It is unclear, however, whether these devices actually achieve better intraocular pressure control compared with no occlusion. Boxes 3-1 and 3-2 summarize the recommended procedures for drop instillation.

Administering topical solutions to uncooperative children is often difficult. Several techniques may be used to facilitate drug administration to these patients.The child’s hand can be placed on the forehead, which proprioceptively reinforces upward gaze. In addition, the palpebral aperture can be widened for drop instillation by telling the child to open his or her mouth. A spread of the neural impulse from the mesencephalic root of the fifth cranial nerve to the nucleus of the levator may explain the effectiveness of this maneuver. Another useful method of administering drops to uncooperative pediatric patients is to instruct them to close their eyes.They usually do not resist and are unable to see the approach of the dropper bottle.Through gentle retraction of the lower lid, a small opening through the lashes into the conjunctival sac is

Box 3-2 Instructions to Patients for SelfAdministration of Solutions or Suspensions

1.Tilt head backward.

2.With clean hands, gently grasp lower outer eyelid below lashes and pull eyelid away from the eye.

3.Place dropper over eye by looking directly at it.

4.Just before applying a drop, look upward.

5.After applying the drop, look downward for a few seconds.

6.Lift eyelid upward until it contacts the eye.

7.Gently close eyes for 2 to 3 minutes.

42 CHAPTER 3 Ophthalmic Drug Delivery

created, and the drop can be instilled. The simple placement of the drop on the eyelashes of the closed eyelids has also been shown to achieve effective mydriasis and cycloplegia in the pediatric population.

The self-administration of topical solutions by elderly patients can sometimes be difficult because of arthritis, tremors, or other physically debilitating diseases. It has been shown that most patients older than age 75 have difficulty applying their eyedrops. Although some patients recognize the problem, many are observed to have difficulty but to not acknowledge their inadequacies at eyedrop instillation.Thus, simply asking patients about their eyedrop technique is not likely to reveal which patients are in need of instruction. A better approach is to actually observe the eyedrop instillation technique and to make sure that it is taught to all patients or their caregivers before patients leave the office.The instillation of ocular drugs may be facilitated in these patients by using a pair of spectacle lenses into which a hole has been drilled through the center of each lens.The patient inserts the dropper tip into the hole, gazes superiorly, and squeezes the bottle (Figure 3-5). Only polycarbonate lenses should be used because of the risk associated with drilling into a conventional glass or plastic lens. Various commercial devices are also available (Figure 3-6).

Solutions characterized by significant local toxicity or staining potential (e.g., silver nitrate) can be instilled using a cotton swab as an applicator.This technique minimizes drop size and subsequent overflow onto the patient’s cheek or clothing.

Unit-Dose Dispensers

Recognizing that long-term therapy with frequently applied preserved solutions can be toxic to the ocular surface, manufacturers have formulated some ophthalmic solutions in unit-dose dispensers without preservatives (Figure 3-7).

Figure 3-5 Modification of polycarbonate spectacle lenses to facilitate drop instillation. After a hole is drilled through the center of each lens, the patient inserts the dropper tip into the hole, gazes superiorly, and squeezes the bottle.

A

B

Figure 3-6 Commercial eyedrop assistance device. (A) Insertion of dropper bottle into device. (B) Device in use.

Unpreserved artificial tears are available in this form, as are timolol, cyclosporine, and ketorolac.

Most unit-dose dispensers accommodate solution volumes ranging from 0.1 to 0.6 ml. Because these solutions are unpreserved, they are designed for short-term use (not exceeding 12 hours), after which the unit is discarded.

Sprays

The topical administration of solutions to the eye is often an unpleasant procedure associated with significant burning, stinging, lacrimation, and emotional trepidation,

Figure 3-7 Unit-dose dispensers.

especially in children.Topical sprays represent an alternative method of administering ophthalmic solutions that may be less irritating and less objectionable. Combinations of mydriatics and cycloplegics, such as phenylephrine–tropicamide or phenylephrine–tro- picamide–cyclopentolate, can be used as sprays for routine mydriasis in adults or for cycloplegia in children. Ophthalmic sprays can be prepared by a compounding pharmacy (Figure 3-8) for application of appropriate mydriatic or cycloplegic combinations (see Chapter 21). The unit is held 5 to 10 cm from the eye before activating the spray. Several artificial tears are commercially available as sprays.

One advantage of a mydriatic or cycloplegic spray is that the drug can be applied to closed eyelids.After drug application, patients should be instructed to blink. If the medication reaches the precorneal tear film, mild stinging is expected. After blinking several times (for 10 to 15 seconds), patients should wipe off the excess solution. If no mild burning or stinging occurs after the eye has been sprayed, it is likely that none of the drug reached the precorneal tear film from the lid margin, and another application is necessary. This may occur in patients who have tightly closed lids in which redundancy of the skin shields the lid margins from the spray.

When the efficacy of sprays is compared with that of topically applied eyedrops, sprays provide both mydriasis

Figure 3-8 Ophthalmic sprays can be extemporaneously prepared for delivery of suitable mydriatics or cycloplegics. (Available from Lee Pharmacy, Inc., Fort Smith,Arkansas.)

and cycloplegia comparable with those obtained with eyedrops (Figure 3-9).This occurs even when the spray is applied to the closed eyelid.

Ointments

Although solutions are the most commonly used vehicles for topical ocular medications, ointments are also frequently used for application to the eye. When applied to the inferior conjunctival sac, ophthalmic ointments melt quickly, and the excess spreads out onto the lid margins, lashes, and skin of the lids, depending on the amount instilled and on the extent of lacrimation induced by any irritation.The ointment at the lid margins acts as a reservoir and enhances drug contact time.

TIME (min)

Figure 3-9 Mydriatic effect of ophthalmic spray applied to closed eyes is comparable with that of eyedrops applied to open eyes. (Reprinted with permission from Wesson MD, Bartlett JD, Swiatocha J, et al. Mydriatic efficacy of a cycloplegic spray in the pediatric population. J Am Optom Assoc 1993;64:637–640.)

44 CHAPTER 3 Ophthalmic Drug Delivery

Techniques of Application

Patients are instructed to elevate the gaze, and with the lower lid retracted, the ointment is instilled into the inferior conjunctival sac (Figure 3-10). A pressure patch can then be applied.The daytime use of ointments frequently leads to complaints of blurred vision. For bedtime use, at least 1 cm of ointment is generally applied. If the ointment is not to be applied at bedtime or used under a pressure patch, smaller volumes of ointment should be instilled.

An alternative method of application involves placing the ointment on a cotton-tipped applicator and applying it to the upper lid margin and lashes as well as the medial and lateral canthi. In this way blurring of vision and drug irritation are minimized. In addition, the ointment acts as a drug reservoir and has a therapeutic effect for approximately 6 hours. This method of application may be of practical value in the treatment of ocular infections in all patients, but especially those in the pediatric and geriatric age groups.

A

B

Figure 3-10 Technique of ointment instillation. With the globe elevated and the lower lid retracted, ointment is instilled into the inferior conjunctival sac in a sweeping fashion from lateral canthus (A) to medial canthus (B).

Once the ointment has been instilled, the bioavailability of subsequently instilled solutions may be altered because the solution is blocked from contact with the ocular surface. Whenever both solution and ointment formulations are used in therapy, the solution should be instilled before the ointment is applied.

Complications

Contact dermatitis of the lids sometimes occurs during use of ointments containing sensitizing agents such as atropine or neomycin, because ointments are characterized by prolonged ocular contact time. Hypersensitivity to the incorporated preservatives may also occur.

Blurred vision is one of the most frequent adverse effects from ophthalmic ointments. This problem can often be alleviated or minimized by simply reducing the volume of ointment instilled during the daytime.Another option involves instructing patients to apply the ointment to each eye on an alternating schedule. This allows patients to have acceptable vision with at least one eye at all times during the waking hours.

The effect of ophthalmic ointments on the healing of corneal wounds has been studied. Early formulations of ophthalmic ointments contained waxy grades of petrolatum or unwashed lanolin, which interfered with corneal wound healing. Contemporary ophthalmic ointments, however, are nonemulsive and do not contain the coarse grade of white petrolatum. These ointments cause no significant inhibition of corneal wound healing.

The following guidelines are suggested for the clinical use of ophthalmic ointments:

•Ointments may be used immediately after intraocular surgery under a conjunctival flap or in corneal incisions with excellent wound approximation, because the risk of entrapment of ointment is minimal. Ointments should not be used, however, in any surgical wound in which there is a question of wound integrity, such as when difficulty is experienced maintaining the anterior chamber at surgery. In such cases ointment application should be delayed for several days.

•Ointments should be used with caution in jagged or flap-like corneal lacerations, in eyes with impending corneal perforation, and in open conjunctival lacerations.

•Ointments can be used routinely for superficial corneal abrasions. However, any abrasion involving corneal tissues deeper than the epithelium should be managed on an individual basis depending on the configuration of the wound edges.

•Ointments may be applied to corneal ulcers with little risk of entrapment or inhibition of wound healing. However, they should be used with caution in ulcers with an impending perforation or large overhanging margins because there is a risk of ointment entrapment under a flap.

•Ointments may be preferred in patients undergoing macular hole surgery with postoperative face-down positioning. Ointment administration

permits less frequent dosing of antibiotics and steroids, reducing the number of times patients must look upward during instillation.

Lid Scrubs

Application of solutions or ointments directly to the lid margin is especially helpful in treating seborrheic or infectious blepharitis.After several drops of the antibiotic solution or detergent, such as baby shampoo, are placed on the end of a cotton-tipped applicator, the solution is applied to the lid margin with the eyelids either opened or closed (Figure 3-11). Antibiotic ointments are applied in the same way.

Although baby shampoo is frequently used for cleaning the eyelid margin, commercially available eyelid cleansers are effective, with potentially less ocular stinging, burning, or toxicity. Commercial lid scrub products are designed to aid in removal of oils, debris, or desquamated skin from the inflamed eyelid. The lid scrubs can

A

B

also be used for hygienic eyelid cleansing in contact lens wearers.Although these solutions are designed to be used full strength on eyelid tissues, they must not be instilled directly into the eyes. Some of the products (Table 3-1) are packaged with presoaked gauze or cotton pads, which provide an abrasive action to augment the cleansing properties of the detergent. Patients generally express a preference for the commercially available lid scrub products because they are convenient and easy to use.

Gels

Pilocarpine is commercially available in a carbomer gel vehicle.The 4% pilocarpine gel is packaged in a 3.5-g tube similar to ophthalmic ointments.A practical advantage of this sustained delivery system is the once-daily dosage regimen, with the drug usually administered at bedtime. Minor side effects include superficial corneal haze, which may occur after long-term use (>8 weeks), and superficial punctate keratitis, which can affect almost one-half the treated patients but usually resolves spontaneously.

Several artificial tear preparations are formulated as ophthalmic gels. Tears Again (Cynacon OCuSoft, Richmond, TX) is a sterile lubricant gel consisting of carboxymethylcellulose sodium 2% and povidone 0.1%. GenTeal Lubricant Eye Gel (Novartis Ophthalmics, East Hanover, NJ) contains carbopol 980, a gelling agent with high water-binding affinity that transforms from gel to liquid on contact with ocular tissue. These gel systems tend to minimize the blurred vision that can accompany daytime instillation of ophthalmic ointments.

In situ–activated gel-forming systems are delivered to the ocular surface as eyedrops.These are then converted by temperature changes and ionic movement into a gellike viscosity that permits prolonged contact with the eye. Gellan gum (Gelrite) and a heteropolysaccharide (xanthan gum) are currently used to deliver timolol in the treatment of glaucoma. Studies have confirmed that treatment with 0.5% timolol in gel-forming solution once daily in the morning achieves intraocular pressure levels equal to twice-daily application of 0.5% timolol solution. The gel-forming solution is well tolerated and does not cause blurred vision or ocular discomfort.

Solid Delivery Devices

One of the significant problems with the delivery of drugs in solution is that drug administration is pulsed, with an initial period of overdosage followed by a period of relative underdosage. The development of solid drug delivery devices has been an attempt to overcome this disadvantage.

Soft Contact Lenses

Figure 3-11 Technique of lid scrub. Drug application to the lid margin is accomplished with a cotton-tipped applicator applied to the opened (A) or closed (B) eyelids.

Drugs penetrate soft contact lenses at a rate that depends on the pore size between the cross-linkages of the threedimensional lattice structure of the lens, the concentration