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Innovations in Topical Ocular Corticosteroid Therapy for the Management of Postoperative Ocular Inflammation and Pain
Clifford L. Salinger, MD; Bruce I. Gaynes, OD, PharmD; and Rajesh K. Rajpal, MD

Innovations in Topical Ocular Corticosteroid Therapy for the Management of Postoperative Ocular Inflammation and Pain

Clifford L. Salinger, MD; Bruce I. Gaynes, OD, PharmD; and Rajesh K. Rajpal, MD
Topical ophthalmic corticosteroids are of clinical benefit in the management of pain and inflammation after ocular surgery; however, their use can be associated with class-associated adverse events (AEs) and limited bioavailability. Selection of an appropriate topical corticosteroid depends on drug-specific variables such as AE profile, efficacy, potency, dosing, patient-specific administration needs, and formulation properties aimed at minimizing precorneal drug loss, increasing ocular surface drug residence time, and maximizing drug delivery to the anterior tissues. Recently, strategies for improving ocular penetration of ophthalmic formulations have included use of mucoadhesive formulations (ie, polycarbophil-containing gels) and drug particle size reduction, enabling faster drug dissolution and therefore increased bioavailability and penetration. Loteprednol etabonate (LE) is a carbon-20 ester corticosteroid developed through retrometabolic drug design with potent anti-inflammatory effects and a reduced propensity for eliciting corticosteroid class AEs. This drug has been formulated for topical ophthalmic use after surgery as 0.5% and 1% suspensions, a 0.5% ointment, and a 0.5% gel. Preclinical and clinical data for a new 0.38% LE gel will be reviewed demonstrating that reducing the drug particle size to the nanometer range in diameter provides effective ocular tissue penetration and resolution of pain and inflammation despite a reduced drug concentration (0.38%) and dosing frequency.

Am J Manag Care. 2019;25:S215-S226
Several common ophthalmic conditions, including cataracts, glaucoma, late-onset Fuchs endothelial dystrophy, and uncorrected refractive errors, can result in visual impairment, including blindness.1 Surgical intervention is a common treatment option for these and other ocular conditions. As the US population ages, these visually impairing ophthalmic conditions are expected to increase in prevalence (Table 1).2-10 Given the substantial burden of ocular disease in the United States and the large number of ocular surgeries performed each year to address the condition, a need exists for therapies that effectively resolve postoperative inflammation with minimal adverse reactions, in addition to supporting patient needs for drop comfort and convenience of administration. Topical corticosteroids are routinely used as part of the postoperative treatment regimen after ocular surgery. Traditional topical ophthalmic corticosteroids are associated with varying degrees of class adverse events (AEs), whereas physiologic barriers to drug penetration (eg, tear clearance, corneal absorption) can result in limited ocular bioavailability.11 Selection of an appropriate topical corticosteroid depends on drug-specific variables such as AE profile, efficacy, potency, dosing, patient-specific administration needs, and formulation properties aimed at minimizing precorneal drug loss, increasing drug residence time on the ocular surface, and maximizing bioavailability and the amount of drug delivered into the ocular tissues.

Loteprednol etabonate (LE) is a unique carbon-20 (C-20) ester corticosteroid designed to have potent anti-inflammatory effects after cataract, refractive, glaucoma, and corneal transplant surgeries, among others, with a lower propensity to elicit corticosteroid class-associated AEs.12-15 Recently, strategies for improving ocular penetration of ophthalmic drug formulations, and LE formulations in particular, have included use of mucoadhesive polymers (ie, polycarbophil-containing gels) and drug particle size reduction, enabling faster drug dissolution and therefore increased penetration.11,14-16 This article reviews the available topical ocular corticosteroids (suspensions, ointments, emulsions, and gels) indicated for the postoperative management of inflammation and pain after ocular surgery, with a brief review of LE drug design and focus on formulation development of available LE products (Table 2).17-21 An overview is provided for the newest ophthalmic formulation to enter the market, Lotemax® SM (loteprednol etabonate ophthalmic gel, 0.38%; Bausch + Lomb, Bridgewater, NJ). Preclinical and clinical data for this new submicron gel formulation are reviewed and demonstrate that reducing the drug particle size to the nanometer range in diameter provides effective ocular tissue penetration and resolution of pain and inflammation despite a reduced drug concentration (0.38%) and dosing frequency (3 times a day).12-14,20

Postoperative Management of Inflammation and Pain After Ocular Surgery
Mechanical trauma during ocular surgery (eg, membrane disruption and tissue injury) induces an inflammatory response. Inadequately controlled inflammation increases the risk of postoperative pain, edema, erythema, anterior chamber cells and flare, secondary glaucoma, posterior synechia, and, potentially, cystoid macular edema (CME).22-26 There are no published consensus guidelines or sufficient evidence from randomized controlled studies to establish a preferred postoperative regimen for control of inflammation and pain after cataract surgery and other intraocular surgeries.22,27 Treatment must be patient specific, and the cause of pain must be carefully identified and treated accordingly. In clinical practice, patients may be treated with combination therapy including both a topical ocular corticosteroid (eg, LE, difluprednate, fluorometholone, dexamethasone, or prednisolone) and a nonsteroidal anti-inflammatory drug (NSAID) (eg, ketorolac, diclofenac, bromfenac, or nepafenac) or with either class individually.22,28 NSAIDs inhibit inflammation primarily through the cyclooxygenase (COX) pathway and are typically initiated 1 to 2 days before cataract surgery and continued for a minimum of 2 weeks after surgery.26 Prolonged postoperative use of NSAIDs for 4 to 6 weeks or longer is often employed to prevent CME, especially in patients at high risk.28,29 Recently, a prospective study in 914 nondiabetic patients demonstrated that a combination of a topical NSAID and a corticosteroid is more effective in the prevention of CME after cataract surgery than NSAID treatment alone.30 Corneal melt—a rare, but serious, and potentially visually compromising AE—has been reported in association with the use of some topical ocular NSAIDs and should be considered when deciding to include a topical ocular NSAID in a patient’s postoperative regimen, especially in patients with pre-existing ocular surface conditions.26,31-35

Topical ocular corticosteroids are a vital component of treatment for postoperative inflammation after ocular surgery to ameliorate inflammation-associated signs and symptoms, including photophobia, swelling, pain, and tenderness.36 Corticosteroids, and more specifically glucocorticoids, are believed to modulate the inflammatory response through several independent mechanisms at cytosolic glucocorticoid receptors (GRs).22,36-38 Corticosteroids bind to and activate GRs, allowing translocation into the nucleus, and directly and indirectly regulate the transcription of genes with anti-inflammatory effects (eg, regulating the expression of genes that encode inflammatory cytokines, chemokines, adhesion molecules, and other inflammatory mediators).37,39-41 By inhibiting phospholipase A2-mediated arachidonic acid conversion from membrane phospholipids, corticosteroids block downstream COX and lipoxygenase pathways of the inflammatory cascade and prevent eicosanoid production (leukotrienes, prostaglandins, and thromboxanes).23-26,36,40,42 At the tissue level, corticosteroids inhibit edema, fibrin deposition, capillary dilation, fibroblast production, leukocyte migration, and deposition of collagen, ultimately preventing scar formation.19,36,43,44

Topical ocular instillation delivers corticosteroids directly to the desired sites in the eye with negligible risk of systemic AEs.16,45 Several ophthalmic formulations of corticosteroids are available (eg, suspension, emulsion, ointment, gel) and, where studied, have demonstrated safety and efficacy in resolving inflammation and pain after cataract, refractive, and corneal transplant surgeries.15,19,38,44,46-50 Topical ocular corticosteroids are typically initiated after surgery, followed by a gradual taper.24,36 The use of topical corticosteroids has been associated with local AEs, including delayed wound healing, exacerbation or reactivation of an existing infection (eg, reactivation of latent herpes simplex virus keratitis), and development of a secondary infection.14,36,45,51 Ophthalmic use of ocular corticosteroids has also been associated with the formation of cataracts and clinically significant elevations in intraocular pressure (IOP) and subsequent potential for glaucoma, especially with longer-term use. 14,36,45,51

Although the precise mechanism is not fully understood, corticosteroid-induced elevations in IOP are believed to be the result of increased aqueous humor outflow resistance; if left untreated, elevations in IOP may lead to progressive optic nerve damage, vision loss, and corticosteroid-induced glaucoma.36 The potential for a specific topical ocular corticosteroid to raise IOP may be influenced by the pharmacokinetics of the drug itself, such as differences between the tissue penetration and half-life of the drug, as well as dosage and treatment duration.36,42 Moreover, an estimated 5% of the population are categorized as high steroid responders, meaning that they will experience clinically significant IOP elevations above 15 mm Hg after topical corticosteroid therapy.42,45 Differences in the potency of particular ocular corticosteroids has also been suggested as a potential reason for differences in IOP-elevating potential, although there are not yet data to support this theory.45 Several factors have made it difficult to quantify differences in the extent to which topical ocular corticosteroids, especially older agents (eg, dexamethasone and prednisolone), may cause elevations in IOP, including inconsistent IOP measures, lack of placebo-controlled trial data, and changes in stringency of regulatory approval requirements over time.36

The formation of cataracts, particularly posterior subcapsular cataracts, is a concerning AE with extended-duration corticosteroid therapy.52 The presence of a C-20 ketone group in certain corticosteroids, including prednisolone, dexamethasone, fluorometholone, and difluprednate, is implicated in the formation of Schiff base intermediates with lens proteins, which is a common first step implicated in cataract formation with ketone steroids.15,16,37,46-50,53 Another possible mechanism in the formation of posterior subcapsular cataracts may include aberrant migration of lens epithelial cells, and there may be additional mechanisms of corticosteroid-induced cataractogenesis.15,52

Minimizing the Risk of Adverse Events Through Retrometabolic Drug Design
To minimize the risk of AEs associated with topical ocular corticosteroid use (eg, increased IOP and cataract formation) while maintaining or improving efficacy, several ocular corticosteroids were designed more than 20 years ago using retrometabolic design, a drug development process that takes into account structure-metabolism relationships and structure-activity relationships.37,54 The goal of this strategy is to synthesize an analog of a reference compound from a known inactive metabolite of that reference compound. The inactive metabolite is converted into an analog of the reference compound with structural changes designed to elicit the targeted therapeutic effect before being metabolized to the original inactive metabolite.15,37,55

The C-20 chloromethyl ester corticosteroid LE was developed by retrometabolic drug design specifically to maintain steroid potency while lowering the risk of AEs.56 LE is derived from the inactive metabolite of prednisolone acetate, Δ1-cortienic acid, with a 17β-chloromethyl ester replacing the ketone group at the C-20 position and a 17α-ethyl carbonate substitution of the 17α-hydroxyl group. This modification allows activity at the GR and subsequent predictable hydrolysis to the inactive carboxylic acid metabolite after eliciting the anticipated pharmacologic activity (Figure 1).15,54,56,57 Studies confirmed that any LE not bound to GRs is quickly metabolized to Δ1-cortienic acid by local circulating esterases.16,37 The cornea is the primary site of metabolism of LE to inactive metabolites, as exhibited by the highest overall concentration of LE and the highest ratio of metabolite (Δ1-cortienic acid) to LE.58 Lower levels of LE were detected in the aqueous humor (100-fold less than levels found in the cornea) and underscore the probability that LE is less likely to cause elevations in IOP.15 Data from preclinical research demonstrated that LE is able to penetrate into the ocular tissues, including the cornea, the aqueous humor, and the iris-ciliary body, with the latter tissue levels considered most relevant in the treatment of postoperative inflammation.58 LE has a lipophilicity 10 times greater than that of dexamethasone, which enhances penetration into ocular tissue. LE has an increased binding affinity for GRs that is up to 4.3 times greater than that of dexamethasone and a therapeutic index (the ratio of drug activity to drug toxicity) that is up to 20-fold greater than other corticosteroids.15,37,42,56 Collectively, these features allow LE to effectively penetrate ocular tissues, bind to GRs, and produce potent anti-inflammatory effects, with minimal potential for AEs.42

Across several head-to-head studies, LE demonstrated potent anti-inflammatory efficacy in reducing anterior chamber cells and flare after cataract surgery,59,60 preventing immunologic transplant rejection episodes,61 and preventing corneal haze after photorefractive keratectomy surgery,62 compared with either prednisolone acetate, difluprednate, or prednisolone acetate tapered to fluorometholone.15,37 In addition, replacement of the ketone at the C-20 position in prednisolone with an ester is hypothesized to contribute to decreased potential for steroid-induced cataract development. The absence of a C-20 ketone precludes formation of Schiff base intermediates with lens proteins, which is a common first step implicated in cataract formation with ketone steroids.15,16,53 Long-term use of LE suspension 0.2% for the treatment of seasonal allergic conjunctivitis did not reveal an increased propensity for cataract formation with follow-up of 12 to 36 months or more.63 In alignment with this finding, review of AEs in association with the use of all marketed LE formulations (ophthalmic suspension [0.5% and 0.2%], gel [0.5%], and ointment [0.5%]) demonstrated a low incidence of cataracts; from launch of LE suspensions in 1998 to 2016, there were just 12 incidences of cataracts reported to the manufacturer’s AE database.64

Pooled clinical evidence also confirmed that incidences of elevated IOP are low with short-term and long-term use of topical LE formulations.15,42,65 Sheppard et al pooled data from studies that defined an IOP increase over baseline of at least 10 mm Hg as clinically significant and determined that 0.8% of patients (14/1725) given short-term LE treatment (less than 28 days) and 1.5% (21/1386) given long-term LE treatment (at least 28 days) experienced clinically relevant elevations in IOP.42 Furthermore, studies have demonstrated that incidences of IOP elevations are lower with LE treatment relative to prednisolone acetate and dexamethasone.42,59,61,66 In the review by Sheppard et al, pooled data indicated that the cumulative incidences of clinically significant IOP elevations were higher in patients given prednisolone acetate 1% (11.3% [33/292]) compared with those given LE (3.4% [10/291]) (P <.001) and in patients given dexamethasone 1%/tobramycin 0.3% (5.2% [25/485]) compared with those given LE/tobramycin 0.3% (1.8% [9/491]) (P = .008).42 In known steroid responders, prednisolone acetate demonstrated greater mean IOP elevations compared with LE.67 A comparison of the pivotal clinical trial data for each agent indicated that difluprednate, a derivative of prednisolone that is difluorinated at the C6 and C9 positions, demonstrated a higher propensity to raise IOP than LE.13,23,68-71

Addressing Drug Delivery Challenges Associated With Topical Ocular Corticosteroids
Delivery of corticosteroids to ocular tissues is challenging. Physiologic barriers may inhibit optimal drug delivery in the eye after topical administration. Local delivery of topical ocular corticosteroids is driven by the speed by which the drug dissolves in tears, or dissolution, which can be limited by a high rate of tear turnover, induced lacrimation (secretion of tears), loss of drug through nasolacrimal drainage, and the blinking process.16,72 Any sensation of irritation causes patients to blink and tear, reducing retention and residence time on the ocular surface and diluting the drop. In addition, when a drug mixes with tear fluid, the physical properties of the combination, including pH and osmolality, may cause irritation or discomfort, leading to reflex tearing and blinking and further drug dilution.16 As a result of these challenges, it is estimated that approximately 5% of a locally administered ophthalmic drug penetrates into and crosses the cornea to reach the intraocular tissues.11,16,72,73 To overcome these barriers, developments in the formulation of topical ocular corticosteroids focus on improving corneal penetration, drug residence time, and bioavailability by the addition of viscosity and permeation enhancers.11

Most currently available topical ocular corticosteroids, including prednisolone, fluorometholone, dexamethasone, and LE, have often been formulated as suspensions because of their poor aqueous solubility.37,46-50,74 Ophthalmic suspensions have poor viscosity; drug particles tend to settle out of solution and interact to form clumps, resulting in poor homogeneity, which may affect both efficacy and safety.16,75-77 Typically, ophthalmic suspensions, including LE suspension 0.5%, require vigorous shaking before administration to resuspend drug particles, which has proven difficult for many patients, especially elderly patients, who are the main patient group eligible for cataract and other ophthalmic surgeries.16,76,78,79 In particular, generic prednisolone suspension preparations may be associated with markedly more particle clumping than branded preparations and this clumping may not be easily remedied by vigorous shaking.76

Because corticosteroids have low aqueous solubility, ophthalmic ointments have been formulated to provide greater homogeneity.80 Ophthalmic ointments create a drug reservoir when the ointment becomes trapped in the fornices of the eye, which may increase drug contact time with the ocular surfaces by up to 8 hours, thereby increasing drug absorption approximately 2-fold in blinking eyes and up to 4-fold in non-blinking eyes.15,80,81 For these reasons, ophthalmic ointments may be ideal for nighttime dosing or for patients who have trouble instilling eye drops, such as those with tremors or arthritis.15,81,82 Fluorometholone and LE are available as ophthalmic ointments.18,49 The LE ointment formulation does not contain a preservative, and as a result, it is associated with better long-term tolerability and the potential for less epithelial toxicity than formulations that contain preservatives.15,18,49,82 Inherent challenges with ophthalmic ointments include blurred vision, which can lead to poor adherence and dosing variability due to difficulty many patients experience when instilling a precise ribbon of ointment (eg, half inch) in the eye.16,81
A more recent development in the formulation of topical ocular corticosteroids is the oil-in-water lipid emulsion, which allows drugs with poor water solubility to be dissolved in an oil phase with surfactants to provide stability.76 Difluprednate ophthalmic emulsion Durezol® (difluprednate ophthalmic emulsion, 0.05%; Alcon Laboratories, Fort Worth, TX) is the sole topical ocular corticosteroid available in this formulation; it received FDA approval in 2008 for the treatment of inflammation and pain associated with ocular surgery.44,76 Compared with topical ocular corticosteroids formulated as suspensions, ophthalmic emulsions provide better dose uniformity without the need for vigorous shaking before administration and have the potential for improved ocular bioavailability.76

For most topical ocular corticosteroid formulations available (prednisolone, fluorometholone, dexamethasone, difluprednate, and most formulations of LE), frequent dosing—4 times per day—is required to achieve therapeutic levels of the active drug.44,46-50 In general, dosing frequency has been identified as a major barrier to adherence, with more frequent dosing being associated with lower adherence.83,84 Medication regimen complexity may further impede adherence, which is especially relevant because postoperative regimens after ocular surgery may include 2 or more drug classes.27,83

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