Clinical Benefits of Preservative-Free Treatment for Glaucoma with a Focus on Preservative-Free Latanoprost

Abstract

Purpose

To highlight the clinical benefits of preservative-free topical therapies in the management of glaucoma, with a focus on preservative-free latanoprost, and their role in improving ocular surface health and long-term treatment outcomes.

Methods

A targeted literature search was conducted through May 30, 2024, to identify studies evaluating the efficacy, safety, and patient outcomes associated with preservative-free latanoprost (Monoprost^®/Iyuzeh™, Laboratoires Théa, France).

Results

Glaucoma is a chronic, progressive disease and the leading cause of irreversible blindness globally, with prevalence expected to rise as the US population ages. Most patients begin with topical eye drops—primarily prostaglandin analogs—to reduce intraocular pressure, often requiring lifelong treatment. However, chronic use of preserved formulations, especially those containing benzalkonium chloride, is associated with ocular surface disease, discomfort, and reduced adherence. Preservative-free topical therapies offer equivalent intraocular pressure-lowering efficacy to preserved alternatives, while significantly improving tolerability, reducing ocular surface disease symptoms, and minimizing conjunctival inflammation that may complicate future surgical interventions. In Europe, preservative-free therapies are well established in treatment guidelines. In the US, preservative-free latanoprost 0.005% (Iyuzeh) was approved in 2022, providing a new option for patients sensitive to preservatives or with coexisting ocular surface conditions. Advancements in multidose preservative-free packaging and sustained-release delivery systems further enhance the potential for improved adherence and long-term disease control.

Conclusions

This review highlights the benefits of preservative-free topical glaucoma therapies and includes a targeted review of preservative-free latanoprost 0.005%. Recent technologic advancements including multidose preservative-free delivery systems and sustained-release drug delivery approaches are also discussed.

Plain Language Summary

Glaucoma is a chronic eye disease that can lead to permanent vision loss if left untreated. It is one of the leading causes of irreversible blindness worldwide. Most people with glaucoma use daily eye drops to reduce intraocular pressure (IOP), which helps protect the optic nerve and preserve vision. However, many of these drops contain preservatives, especially benzalkonium chloride (BAK), which can irritate the eyes and damage the eye’s surface over time. Long-term use of BAK-preserved eye drops is linked to a condition called ocular surface disease (OSD). Symptoms of OSD include eye dryness, burning, redness, and blurred vision. These side effects can reduce a person’s comfort and make it harder for them to consistently use their medication, leading to worse disease outcomes. Preservative-free (PF) eye drops offer an effective alternative, providing the same IOP-lowering benefits without the harmful effects of preservatives. PF drops have been widely adopted in Europe for many years, with evidence showing improved quality of life for patients and reduced complications related to eye surgery. PF therapies have only recently come to attention in the US, likely because of restricted access due to high costs and limited insurance coverage. This review highlights the advantages of PF eye drops, which include better eye health, fewer side effects, and improved adherence to treatment. It also discusses the recent US approval of PF latanoprost (Iyuzeh) and new technologies for PF drug delivery. PF therapies represent an important shift toward safer, more comfortable long-term glaucoma care.

Key Summary Points

Preservative-free (PF) glaucoma therapies provide comparable intraocular pressure (IOP) control to preserved treatments while significantly reducing ocular surface disease symptoms and improving patient quality of life

Benzalkonium chloride, the most common preservative in topical glaucoma medications, is associated with ocular toxicity, including tear film instability, inflammation, and long-term structural damage to ocular tissues

The widespread use of PF therapies in Europe contrasts with limited adoption in the US; this is primarily due to cost barriers and payer-related access challenges, though recent approvals like PF latanoprost (Iyuzeh) signal shifting treatment paradigms

Reducing preservative exposure with PF formulations both enhances patient adherence and comfort and decreases the risk of surgical complications from preoperative ocular inflammation

Introduction

Glaucoma is a chronic, progressive disease of optic neuropathy [1] and the leading cause of irreversible blindness worldwide [2, 3]. In the USA, the estimated number of glaucoma cases in adults > 40 years of age is 2.6% [4]. Older age is an intrinsic risk factor [5, 6], and the prevalence of glaucoma increases to 7.8% in adults aged 65–84 years and to 13.5% in adults aged ≥ 85 years [7]. Due to the aging of the US baby boomer generation [6, 8], by 2050 the number of US adults aged ≥ 65 years is projected to grow by 30% [8], and glaucoma prevalence is expected to reach 6.3 million [9].

Patients with glaucoma typically require lifelong treatment to prevent progression to blindness [1, 10]. Topical eye drops are the most common initial and enduring glaucoma treatment, received as first-line therapy by approximately 70% of patients [11]. Typical first-line topical therapy may include a prostaglandin analog (PGA), such as latanoprost, tafluprost, or bimatoprost [1, 11]. Switching or adding additional topical therapies is common throughout the disease course [1, 11, 12], with many patients needing to administer more than one type of eye drop daily. A retrospective US commercial healthcare claims analysis (2015–2017) found that immediately after diagnosis, 29.7% of patients with open-angle glaucoma (OAG) had prescription fills for ≥ 2 unique topical glaucoma medication classes. In the 12 months following diagnosis, 25–45% of patients intensified treatment, most commonly with the addition of a topical therapy [13]. Although reliance on topical medication is reduced for patients who undergo interventional treatment like selective laser trabeculoplasty (SLT), these procedures do not definitively eliminate the need for eye drops [11, 14–16], and SLT is not fully successful for approximately 35% of patients [15, 16]. In addition, the intraocular pressure (IOP)-lowering benefits of the procedure wane over time, leading to eye drop reinitiation [17] and repeat procedures with IOP-lowering effects that may diminish [18].

A number of well-documented limitations exist to the long-term utility and sustainability of topical treatment for patients with glaucoma [19], and the potential for IOP increases because patient treatment noncompliance is a primary concern for physicians [20, 21]. Barriers include medication burden, side effects, and nonadherence, all of which are interrelated and negatively impact patient quality of life (QoL) [19, 21, 22]. A primary and avoidable shortcoming of topical glaucoma therapies is the toxic effect of preservatives used in the majority of eye drop formulations [19]. These preservatives, most commonly benzalkonium chloride (BAK), are a principal cause of numerous ocular disorders known as preservative-induced ocular surface disease (OSD) [23–31]. Characterized by damage or malfunction of the cornea, conjunctiva, and/or meibomian glands (i.e., the ocular surface) [32], OSD affects as many as 70% of patients with glaucoma [23, 24, 30], with incidence increasing with age [33, 34]. The presence of OSD increases the odds of patient treatment dissatisfaction by four- to seven-fold [35–37], and adverse events (AEs) due to concomitant OSD negatively impact treatment compliance [38]. OSD signs and symptoms also contribute to impaired QoL [39–47] and poorer functional status [47]. These factors can intensify noncompliance and ultimately disease progression [41, 48].

In anticipation of the longevity and needs of the aging US population, a paradigm shift is underway in glaucoma treatment that is focused on both preserving long-term vision and eye health-related QoL [1, 19, 25, 49]. New treatment strategies are addressing the shortcomings of conventional topical therapies [19, 50, 51], and novel interventional technologies are being used earlier in the treatment cascade to reduce reliance on topical therapies [19]. In particular, there is growing interest in topical therapies that improve IOP without causing ocular damage, including preservative-free (PF) and non–BAK-preserved formulations [26, 50].

PF ophthalmic solutions have been available for decades in the US and Europe [52, 53], with PF timolol maleate (a beta blocker) dating back to 1986 [54]. However, PF topical therapy use only became widespread in Europe after 2008, when PF tafluprost (Taflotan; Santen Oy, Tampere, Finland) became the first nonpreserved PGA to receive marketing authorization in Germany and Denmark [55]. This was followed by the 2012 European Union (EU) approval of PF latanoprost 0.005% (Monoprost^®; Laboratoires Théa, France) [56]. In contrast, in the US the first BAK-free PGA, PF tafluprost (Zioptan^®; Théa Pharma Inc., Waltham, MA; but first marketed by Merck & Co., Rahway, NJ), was approved in 2012 [57]. Most recently, Monoprost entered the US market as Iyuzeh™ (Théa Pharma Inc) in 2022 [58]. PF formulations of dorzolamide, both alone (EU only) and in combination with timolol (EU and US), are also available [59, 60]. Until recently, however, PF formulations have not been typically considered for routine use in the US [1, 61]. A number of reasons exist for this discrepancy, including higher costs for PF formulations [62] and substantial cost increases for branded drugs over the past decade, leading to the increased use of generic treatments [63]. Furthermore, the US payer system often poses significant challenges to accessing PF formulations (e.g., patients may be ineligible for PF treatment unless they have failed preserved treatment). All these factors can contribute to US clinicians having less prescribing control than their EU colleagues.

This review summarizes the history, efficacy, and safety of PF topical glaucoma therapies in general and provides a literature review of clinical evidence for the PF latanoprost formulation recently approved in the US.

Methods

A literature search was conducted through May 30, 2024, using PubMed and Google Scholar to identify clinical data relevant to the clinical efficacy and safety of PF latanoprost (Monoprost^®/Iyuzeh™). Keywords used for the literature search included “glaucoma,” “ocular hypertension,” “benzalkonium chloride,” “preservative-free,” and “latanoprost.” Articles were limited to human studies, with no limits on publication dates or the geographic study location. The search results were reviewed to limit selection to the targeted drug product, and additional sources were identified using related references within already-identified articles. This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.

Results

History of Preservative Use in Glaucoma Drugs

Preservatives are used in topical glaucoma formulations to prolong shelf life and prevent microbial growth [24]. Ophthalmic solutions housed within classical (i.e., without novel technology) multidose containers may become contaminated with bacteria within 1–2 weeks after first use [64], and patients typically use individual bottles for months [64]. Microbial contamination can result in serious consequences, including vision loss and blindness [27, 65], with such events recorded from the 1960s to the present day [27, 66]. In the 1970s, to avoid ocular infections arising from contaminated solutions, regulatory agencies, including the U.S. Food and Drug Administration (FDA), U.S. Pharmacopeia, and European Pharmacopoeia, began mandating the use of preservatives in multidose ophthalmic preparations [26, 27, 67–69].

Today, most (70%) glaucoma medications contain BAK, a detergent and quaternary ammonium compound with broad-spectrum antimicrobial properties [19, 26, 27, 70]. Used widely in ophthalmic products since the 1940s, initially to preserve contact lens solutions [70], BAK became the most commonly used preservative because of its comparative safety and efficacy as an antimicrobial product relative to other preservatives available at the time [69].

Starting in the 2000s, it was theorized that BAK-preserved ocular medications could yield improved drug activity at target tissues and therefore achieve greater clinical efficacy, albeit at the expense of ocular tissues [27, 71–73]. This hypothesis was based on the demonstrated ability of BAK to disrupt the tight junctions of the corneal epithelium (the hydrophobic, semipermeable barrier that regulates fluid and solute exchange between the avascular corneal stroma and aqueous humor) [27, 74–78]. It was posited that BAK could facilitate the penetration of active drug to reach higher concentrations in the cornea and anterior chamber [27, 74, 75]. This hypothesis has been subsequently disputed and disproved [56, 79–90], and the toxic effects of BAK have been confirmed in numerous experimental, laboratory, and clinical studies [24, 26, 27, 67, 91]. Altogether, evidence now suggests that an intact corneal epithelial barrier acts as a defense against biologic, chemical, and physical threats from the environment and that the loss of this barrier is associated with ocular surface disorders [92].

The Detrimental Effects of BAK on the Ocular Surface and Deeper Ocular Tissues

Exposure to BAK in topical glaucoma therapies has a documented detrimental ocular impact, inducing or exacerbating existing OSD [24, 26–28]. Certain effects of BAK on the ocular surface can be observed after only short-term exposure (e.g., within 30 min to 24 h of use), including tear film instability, apoptosis of healthy cells, and disruption of corneal barrier function [27, 28, 91, 93–95]. Over time, topical BAK exerts persistent proinflammatory effects and leads to cytotoxic damage to both the ocular surface and deeper ocular structures, including the tear film, conjunctiva, cornea, and trabecular meshwork (TM) (Table 1) [19, 24, 26–28, 91, 96–100]. It has been proposed that deeper ocular structures are impacted via preservative-induced inflammatory mediators from the ocular surface penetrating into deeper ocular tissues [96, 101, 102], including via noncorneal routes (i.e., the sclera and conjunctiva) [103]. This theory is reinforced by in vivo research confirming BAK accumulation in the sclera, TM, and choroid [67]; evidence of trabecular cell loss and inflammation in the excised TM of patients treated with preservative-containing eye drops [97]; and in vitro evidence showing the induction of apoptosis and inflammation in trabecular cells exposed to BAK [97].

Table 1.

BAK-induced ocular cytotoxic effects and damage [24, 27, 28, 91, 97–100]

Ocular surface
Eyelid and tear film: Blepharitis, increased pro-inflammatory cytokines and tear film instability, which, combined with conjunctival goblet cell loss, lead to DED
Cornea and corneal nerve: Epithelial and limbal stem cell injury and death; disrupted barrier function; delayed wound healing; neurotoxicity and corneal hypoesthesia (i.e., reduced corneal sensitivity and eventual neurotrophic keratopathy)
Conjunctiva: Lymphocyte infiltration of epithelium and stroma; goblet cell loss (resulting in decreased mucin production and tear film instability); epithelial cell death

Deeper ocular structures
Lens: Increased epithelial stress and inflammation, which may induce cataract and increased rates of cataract and glaucoma surgery
Trabecular meshwork: Long-term BAK instillation may lead to increased BAK retention with potential toxicity to trabecular structures; oxidative damage and DNA fragmentation causing altered gene expression; decreased survival of epithelial cells; damage may lead to worsening IOP
Optic nerve: May cause gradual loss of retinal ganglion cells

BAK benzalkonium chloride, DED dry eye disease, DNA deoxyribonucleic acid, IOP intraocular pressure

BAK-related AEs are dose-dependent, which worsen with increased exposure [19, 70, 104]. With prolonged use, preservative-induced OSD develops, wherein ocular surface damage accrues and induces OSD-related pathologies [31]. The most common preservative-induced OSD arises from tear film destabilization and manifests as dry eye disease (DED) [19, 27, 37, 91, 104]. DED is a multifactorial OSD [104] characterized by loss of tear film homeostasis, resulting in ocular discomfort and visual disturbance [105]. DED is prevalent in 30% to 70% of patients using topical glaucoma medications [19]; its symptoms include burning, dryness, fluctuating visual acuity, foreign body sensation, hyperemia, itching, photophobia, and tearing [41, 91, 105]. DED presence and severity are associated with the use of preserved topical glaucoma therapies, with preservative load playing a key pathogenic role [91]. The condition’s etiologic mechanisms include hyperosmolarity and tear film instability, ocular surface inflammation and damage, and neurosensory abnormalities. Each of these effects can worsen the others, cascading into a cycle of worsening DED [105].

Finally, prolonged exposure to BAK may also lead to the failure of subsequent glaucoma filtering surgery because of BAK-induced preoperative conjunctival inflammation and delayed wound healing [106–109]. A retrospective chart review of patients with glaucoma and a history of trabeculectomy (N = 128) found that each additional preoperative daily BAK-preserved eye drop increased the risk of early surgical failure by 21% [107].

Innovations and Challenges in PF Topical Glaucoma Therapies

In 2009, the European Medicines Agency (EMA) called on pharmaceutical companies to develop PF glaucoma formulations for patients who could not tolerate eye drops with preservatives [110]. PF topical glaucoma therapies, initially packaged in single-unit-dose containers, have emerged as a solution to protect ocular tissues from preservative-induced damage while still maintaining sterility [24]. However, there have been barriers to the uptake of unit-dose PF formulas, due to cost, handling, and regulatory requirements [24, 62, 67]. Differences in global regulatory requirements for preservatives in multidose containers can make formulation decisions challenging for companies seeking to market ophthalmic products [67]. Unit-dose packaging can be more costly to produce than multidose packaging and can also be more difficult for patients to properly use (due to the mechanics of tearing opening each vial vs traditional screw-top multidose containers) [24, 62, 67]. Handling issues can be particularly challenging for elderly patients with dexterity issues [62]. Concern has also been expressed that patients will fail to discard the remaining solution in a single-unit dose, keeping it for later use, thus potentially exposing themselves to infection [62]. However, this can be mitigated with proper patient education.

In recent years, new delivery technologies have been developed to overcome the limitations of unit-dose containers and optimize ease of use [24, 111]. For example, certain multidose PF artificial tear formulations are available in containers that employ dual-channel systems to release eye drops. These include sterilizing, porous, and/or bidirectional membrane filters, as well as mechanical pathways and exit valves, to block fluid return. These technologies help maintain sterility while allowing for multiple dosing [62, 111]. The artificial tear industry provides an example of successfully transitioning away from preservatives as well as moving to multidose formulations. In the 2017 Tear Film and Ocular Surface Society’s Dry Eye Workshop (DEWS) II report, nonpreserved ocular lubricants are a second-step treatment option if eliminating the offending systemic/topical medications proves inadequate to control DED [112]. Due to the growing appreciation of how preservatives exacerbate OSD, most topical DED monotherapies are now PF [113].

The key to the successful and safe use of unit-dose PF topical formulations is proper handling and storage. For example, patients should be counseled to wash their hands prior to handling the eye drop container or touching their eyes [114]. In addition, patients should not touch the dropper tip with their hands, nor should they touch the bottle to their eye or eyelid when instilling drops [114]. Last, patients should take care to follow instructions regarding medication storage regarding temperature and discard the container based on the number of days indicated by the manufacturer [115].

Benefits of PF Topical Glaucoma Therapies

Clinical trials and meta-analyses of randomized clinical trials (RCTs) show equivalent IOP-lowering efficacy with BAK-preserved vs PF glaucoma formulations in patients with OAG or ocular hypertension (OHT) [56, 79–90]. Specifically, equivalent IOP-lowering efficacy has been established between multiple PF and BAK-containing formulations, including latanoprost [80–83], bimatoprost [85, 86], tafluprost [116–118], and the fixed-combinations dorzolamide/timolol [89] and latanoprost/timolol [87]. Additionally, research evaluating patients switched from BAK-preserved medications to PF formulations show equivalent or similar IOP-lowering efficacy [88, 90, 96, 119].

Not surprisingly, because preservative-induced OSD commonly occurs with therapies containing BAK [23–30], PF formulations consistently demonstrate better tolerability profiles than BAK-preserved topical drugs [56, 79–81, 83, 84, 91, 117, 119–127], confirmed by reductions in OSD signs and symptoms [80, 87, 96, 119, 125, 128–131] and decreased anterior chamber flare (a sign of inflammation) [102].

Efficacy, Safety, and Tolerability of PF Latanoprost

Latanoprost was the first marketed topical PGA (1996) and continues to be the most commonly prescribed topical ocular hypotensive [58, 132]. Of available PGAs, latanoprost is considered to have the best efficacy and tolerability [132], and patient persistence is higher with latanoprost than with other PGAs or beta-blockers [133]. PF latanoprost 0.005% is commercially available in 46 countries (branded as Monoprost^®; Laboratoires Théa), including the EU (approved 2012) and Canada (2016) [56]. In December 2022, this formulation of PF latanoprost received FDA approval in the US (branded as Iyuzeh^®, Thea Pharma, Inc.) [56]. Prior to this approval, US patients requiring PF latanoprost could only obtain this treatment via compounding pharmacies.

Multiple evaluations, including RCTs, cohort and registry studies, various real-world analyses, and meta-analyses, have compared the use of PF latanoprost with BAK latanoprost. Research shows that patients treated with PF latanoprost experience similar IOP lowering compared to those treated with BAK latanoprost [56, 79–81, 83, 84, 91, 120–124]. PF latanoprost treatment is also consistently associated with significant improvements in ocular symptoms, including better tolerability, treatment comfort, and reduced AEs [56, 80, 83, 119, 120, 123, 125, 126]. This includes reduced burning and use of dry-eye lubricating drops [123, 125] and greater patient adherence [134] and satisfaction [123, 125, 126, 135]. These features are all associated with improved patient QoL [79, 119, 123].

Definitive improvements in certain ocular surface parameters have also been observed in patients treated with PF latanoprost. A pooled analysis of five published studies found that, after 84 days, composite OSD scores (comprising ocular signs and symptoms, including eyelid redness, eyelid swelling, corneal staining, conjunctival staining, and tear breakup time [TBUT]), improved by 32.2% in patients switched from preserved to PF latanoprost (n = 504) vs a decrease of 14.1% (P < 0.001) in patients switched from PF latanoprost to BAK latanoprost (n = 176) [79]. Research also showed significant reductions in conjunctival hyperemia with PF latanoprost [79, 80, 83, 84, 119, 120, 122, 124, 125] as well as decreased ocular inflammation, including anterior chamber flare [102], and reduced inflammatory tear cytokines [136]. The outcome of switching to PF latanoprost on other ocular parameters (e.g., corneal fluorescein staining, TBUT, tear meniscus height) are less clear. While one study showed improvements in TBUT in patients switched from BAK latanoprost to PF latanoprost [119], another showed no differential effect in TBUT or tear meniscus height [122]. Likewise, a small, prospective, observational study (N = 40) found no significant between-group differences in TBUT, corneal fluorescein staining, OSD index, tear meniscus height, or conjunctival hyperemia between patients treated with PF latanoprost vs BAK latanoprost. However, researchers noted that the wide variation in treatment duration (6 to 120 months) among study patients could have confounded the results [136].

Other Preservatives Used in Topical Glaucoma Therapies

Due to concerns over the deleterious effects of BAK, topical glaucoma therapies with alternative preservatives have also become available [26, 70]. As opposed to the cell-lysing effects of BAK, these preservatives cause oxidative damage to exert antimicrobial activity [26, 62]. Table 2 describes preservatives used in currently available US glaucoma medications, along with their mechanism of action and data regarding their toxicity compared to BAK. Although these preservatives may be gentler on the ocular surface than BAK, more studies are needed regarding ocular toxicity over long-term use [70]. In addition, these preservative formulations are proprietary, limiting their use outside of manufacturer formulations [24, 104].

Table 2.

Topical glaucoma medications available in the US with alternative preservatives

Preservative and class	Mechanism of action	Toxicity vs BAK	Glaucoma product(s)
Stabilized oxychloro complex (Purite®) Oxidizing agent	Penetrates cell membranes to disrupt normal cellular function by oxidizing unsaturated lipids and glutathione; less toxic to human cells than microbes due to antioxidant properties of mammalian cells [62, 68]	Better tolerability, including reduced allergic conjunctivitis [147, 148]	Alphagan® P (brimonidine tartrate ophthalmic solution; Allergan, Inc., Irvine, CA)
Borate, sorbitol, propylene glycol, and zinc (SofZia®) Ionic buffer, oxidizing agent	Disrupts cell membranes, causes oxidative damage to microbes and subsequent death; less toxic to human cells due to degradation upon contact with ocular surface cations (i.e., positively charged) [62, 68, 149]	Improved OSDI score, TBUT, and conjunctival hyperemia and decreased corneal staining [150–152]	Travatan Z® (travoprost; Novartis, East Hanover, NJ)
Potassium sorbate/sorbic acid	Interferes with microbial cellular membranes, disrupting key cellular processes, including carbohydrate metabolism and the citric acid cycle (i.e., energy production), hindering microbes’ ability to grow and reproduce [31, 149]	More conjunctival hyperemia, eye pain, and eye pruritis vs BAK; also, more severe adverse events vs BAK [153]	Xelpros® (latanoprost ophthalmic emulsion; Sun Pharmaceutical Industries, Inc., Cranbury, NJ)

Polyquarternium-1 has been omitted from this table; while this preservative is used in a travoprost preparation in Europe, it is no longer commercially available in the US [68]

BAK benzalkonium chloride, OSDI Ocular Surface Disease Index, TBUT tear break-up time

US and EU Glaucoma Treatment Guidelines

European clinical treatment guidelines show the region’s attention to PF topical glaucoma formulations [110] relative to US guidelines, which only recently (2024) provided recommendations related to preservative-induced OSD and the use of PF medications [61]. Table 3 summarizes clinical guideline recommendations from both regions related to the use of glaucoma therapies containing preservatives. European regulators have supported the use of PF topical therapies since 2009, with the EMA being the earliest regulatory body calling for PF formulations for patients who could not tolerate preserved eye drops as well as for those requiring long-term treatment [110]. Subsequent European guidelines, including those from the European Glaucoma Society (EGS), have made explicit the role of preservatives in inducing and/or exacerbating OSD and have positioned PF products in treatment sequencing (Fig. 1) [25, 49, 137]. In addition to the use of PF formulations, EGS discusses the utility of low-preservative-load treatment to reduce preservative-induced OSD [25].

Table 3.

Guideline and expert recommendations for treatment with preservative-free and/or non-BAK-preserved glaucoma topical therapies [1, 25, 49, 61, 110, 137]

European Union, guidelines and expert statements
EMA (2009)	Recommend PF topical formulations for patients who:   Cannot tolerate preserved eye drops   Require long-term treatment When preserved therapies are used, use minimum concentration needed for adequate antimicrobial function
EGS (2021)	Recommend PF or non-BAK topical formulations for patients with:   Preexisting OSD or dry eye   OSD, dry eye, or ocular irritation due to topical therapy Use fixed combinations to reduce the number of eye drops The success rate of filtering surgery may be compromised by long-term BAK use
NICE (2022)	Recommend PF topical formulations for patients who, after initial treatment:   Show an allergic response to preservatives   Develop clinically significant, symptomatic OSD
Swedish National Program (2024)	Recommend PF topical formulations for patients who, after initial treatment:   Develop allergies, eye irritation, OSD, or other issues

US, guidelines
AAO (2021)	No specific recommendations for the use of PF topical formulations
AOA (2024)	Recommend evaluating patients treated with topical IOP-lowering therapies for OSD Consider treatment change for patients who exhibit clinical signs or symptoms of OSD PF formulations may be clinical beneficial for patients who:   Are highly sensitive to preservatives due to preexisting or concomitant OSD   Receive combination therapy with ≥ 2 topical drugs   Are at risk for surgery   Will need treatment for several decades

AAO American Academy of Ophthalmology, AOA American Optometric Association, BAK benzalkonium chloride, EGS European Glaucoma Society, EMA European Medicines Agency, NICE National Institute for Health and Care Excellence, OSD ocular surface disease, PF preservative free

Fig. 1.

European Glaucoma Society: Medical Management, Choosing Therapy

Conversely, as recently as 2021, US guidelines provided no explicit recommendations for the use of topical PF formulations in glaucoma treatment [1]. However, in 2024, the American Optometric Association (AOA) published guidelines recommending that all patients prescribed IOP-lowering topical medications be evaluated for OSD [61]. For patients with clinical signs or symptoms of OSD, treatment changes such as the use of PF formulations, less toxic (non-BAK) preservatives, and/or fewer eye drop instillations per day should be considered. The AOA notes that, compared to preserved therapies, PF formulations are associated with fewer symptoms of ocular irritation. According to the AOA, the recognition and treatment of OSD may reduce AEs and improve tolerability, ocular surface health, patient QoL, and patient treatment satisfaction. Importantly, PF formulations may offer “clinically relevant benefits” for patients with OSD as well as for those who receive combination therapy with ≥ 2 drugs, for those who are at risk for requiring surgery, or for those who will require treatment for several decades.

Sustained-Release Drug Delivery with PF Formulations

Sustained-release drug delivery (SRDD), including conjunctival fornix inserts, contact lenses, intracameral implants, intraocular lens implants, and punctal plugs, have emerged as a potential solution to the shortcomings of topical medications [19, 138]. In the US, available FDA-approved PF-SRDD systems include the PF-bimatoprost intracameral implant (Durysta^®; AbbVie Inc., Chicago, IL) [139] and the PF-travoprost intracameral implant (iDose^® TR; Glaukos Corp., San Clemente, CA) [140]. Once these SRDD systems have been implanted, drug is released continuously, eliminating some barriers to adherence, including ocular surface issues caused by preservatives (SRDD medications do not require preservatives), medication handling, the burden of multiple daily drops, and forgetfulness [19, 138]. Other SRDD systems are in various stages of development and may ultimately offer PF alternatives to topical eye drops [19, 138]. However, SRDD systems are not without shortcomings; for example, the PF-travoprost intracameral implant requires a small surgical incision in the eye and therefore requires a trip to the operating room for implantation, extraction, and replacement [141], and the PF-bimatoprost intracameral implant is approved for a single administration per eye without retreatment and is designed to release drug for only up to 4 months [139, 142].

Discussion

Glaucoma is a chronic condition, with ongoing and lifelong therapy required for patients to maintain their vision [1, 10]. In the US, most patients with glaucoma use preservative-containing topical eye drops on a daily basis [11, 70]. Until recently, the irritant properties of BAK, the most commonly used preservative in topical glaucoma medications, were largely considered a justifiable tradeoff for BAK’s antimicrobial utility. However, a change in treatment patterns is underway owing to evidence indicating pervasive toxicity with BAK, leading to OSD [23–30], and the availability of topical PF formulations that provide comparable efficacy but show better tolerability profiles than BAK-preserved drugs [56, 79–81, 83, 84, 91, 119–126]. These data are bolstered by studies showing improved adherence, treatment satisfaction, and QoL in patients switched from preserved to PF formulations [79, 123, 125, 126, 134, 135].

As the availability of PF topical therapies increases, it is important that more eye care professionals become aware of the role of these formulations in protecting the integrity of the ocular surface and deeper ocular structures in patients with glaucoma. In all cases, the effective management of chronic ocular disease must balance the benefits and affordability of preserved formulations against the long-term adverse effects of use. When feasible, PF medications should be provided as a first-line option. Consistent with recent recommendations, any patient with ocular surface issues should be transitioned to PF medications or low preservative load regimens [25]. In all cases, global strategies should be considered to improve patient satisfaction and treatment adherence, and physicians should work with patients to implement reminder systems and simpler dosing regimens [21, 25]. The overprescribing of topical glaucoma medications may also be common and presents an additional barrier to patient adherence [143] because of challenges with regimen complexity and cost burden [63, 143–146]. In all situations, streamlining topical glaucoma medication regimens should be a priority [1, 25] to ensure that patients are receiving treatment that is effective, safe, and delivered in a manner that maximizes patient willingness and ability to adhere to their treatment plan.

The 2008 EU approval of BAK-free PGA formulations [55] led to the earlier and more widespread use of PF topical glaucoma medications in Europe and generated a strong literature base documenting the efficacy and safety of these products. In the US, it can be anticipated that physician and patient awareness of the potential benefits of PF treatment will increase. This will lead to an improved understanding of the ocular damage associated with preservatives and an increased interest in using PF topical medications.

Author Contributions

Aakrita G. Shukla: Methodology, Review & editing outline and draft. Darrell E. White: Methodology, Review & editing, Writing – original outline draft. Zeba A. Syed: Methodology, Review & editing outline and draft. Paul Singh: Methodology, Review & editing, Writing – original outline and draft. Deepinder K. Dhaliwal: Methodology, Review & editing, Writing – original outline and draft.

Funding

This manuscript and the journal’s Rapid Service Fee were funded by Thea Pharma.

Data Availability

Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.

Declarations

Conflict of Interest

Deepinder K. Dhaliwal: Consultant/Advisor: Thea, Bausch + Lomb, Johnson & Johnson, Staar Surgical, Aurion Biotech, Scope Eyecare, Tarsus, CSI Dry Eye Software, Epion Therapeutics, Lenz Therapeutics, and EyeYon Medical. Research grants: Bausch + Lomb, Epion Therapeutics, Kala. Aakrita G. Shukla: Consultant/Speaker: Alcon; Consultant: Thea; Consultant: AbbVie. Paul Singh: Consultant: Allergan, Alcon, Bausch + Lomb, Glaukos, iSTAR Medical, New World Medical, Nova Eye Medical, and Sight Sciences; Lecture fees: Allergan, Alcon, Bausch + Lomb, Glaukos, iSTAR Medical, New World Medical, Nova Eye Medical, Sight Sciences, Thea, and Viatris. Zeba A. Syed: nothing to disclose. Darrell E. White: Consultant: Aldeyra Therapeutics; Speaker/Consultant: Allergan/AbbVie; Speaker/Consultant: Bausch + Lomb; Consultant: Bruder; Speaker/Consultant: Viatris/Oyster Point Pharma; Speaker/Consultant: Sun Ophthalmics; Consultant: Tarsus; Speaker/Consultant/ Investor: Orasis Pharmaceuticals: Speaker/Consultant: Nordic Pharma; Consultant/Investor: SpyGlass Pharma.

Ethical Approval

This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.