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FEATURE ARTICLE – PUBLIC ACCESS

Lipid Analysis on Block Copolymer–containing Packaging Solution and Lens Care Regimens: A Randomized Clinical Trial

Shows, Amanda BS1,∗; Redfern, Rachel L. OD, PhD, FAAO2; Sickenberger, Wolfgang MS Optom3; Fogt, Jennifer S. OD, FAAO4; Schulze, Marc PhD, FAAO5; Lievens, Christopher OD, MS, FAAO6; Szczotka-Flynn, Loretta OD, PhD, FAAO7; Schwarz, Stefan FAAO8; Tichenor, Anna A. OD, PhD, FAAO9; Marx, Sebastian MSc3; Lemp-Hull, Jessie M. MS, DrPH1

Author Information
Optometry and Vision Science: August 2020 - Volume 97 - Issue 8 - p 565-572
doi: 10.1097/OPX.0000000000001553

Abstract

Silicone hydrogel contact lenses are the most widely prescribed contact lens worldwide.1 Compared with conventional hydrogel lenses, silicone hydrogel lenses provide increased oxygen transmissibility.2 However, the addition of the hydrophobic siloxane moieties to the hydrogel lens produces a relatively hydrophobic surface, which enhances the affinity of the lens for tear film lipids.2 As a result, significantly higher amounts of tear film lipids are deposited (sorbed) onto or into silicone hydrogel lenses compared with conventional hydrogel lenses.2–8

The tear film, which contains lipids, proteins, mucins, electrolytes, and other substances, comprises a superficial lipid layer, which serves to slow evaporation by rapidly spreading lipids over the ocular surface; an aqueous layer, which contains proteins, salt, water, and other components; and an underlying mucin layer.3–10 The lipid layer itself comprises an outermost nonpolar phase and an innermost polar (surfactant) phase. The majority of the tear lipid layer consists of nonpolar lipids secreted by the meibomian glands, primarily cholesteryl esters but also cholesterol, wax esters, and fatty acids.11 The polar lipids include phospholipids and saturated and unsaturated fatty acids, which may derive from other ocular sources.3–10

With insertion of the contact lens, tear film stability is disrupted, thinning the tear film,12–14 and increasing dryness symptoms14 and deposition of tear film components, including lipids.3–10 Although the tear film contains many lipids, cholesterol and cholesteryl esters account for 50.8% (mole percent) of the total lipid concentration in the tear film.11 Cholesterol has also been reported to be the major lipid that accumulates on silicone hydrogel contact lenses,10,15,16 accounting for 70 to 80% of the total lipid deposited on silicone hydrogel lenses10 and ranging in quantity from 0 to 37.0 μg/lens.9,16 The type and amount of lipid deposited are influenced by the lens material itself, with certain silicone hydrogel lenses being more prone to lipid deposition than others.2 The type and amount of lipid deposited are also influenced by length of wear and lens care solutions used,17 by lipid structure, and by intersubject variability due to diet, genetics, and/or other factors.12

Lipid deposition may negatively impact contact lens wear.18,19 Tear components are sorbed onto and into the lens rapidly and progressively over time.12,20 The combination of progressively greater deposition of nonpolar lipids (total cholesterol) and increased wear time with reusable lenses may result in nonwettable regions on the surface, impacting comfort.12,20 The presence of lipid deposits disrupts the smooth lens surface and may also contribute to symptoms of dryness and discomfort20–22 and reduced visual performance,22–24 both of which may lead to contact lens discontinuation.2 Among available silicone hydrogel contact lenses, clinical studies have shown that lotrafilcon B (AIR OPTIX AQUA; Alcon Laboratories, Inc., Fort Worth, TX) lenses better resist lipid deposition than other types of silicone hydrogel contact lenses tested.9,25,26

A number of methods have been developed to improve the hydrophilicity, wettability, and therefore comfort of silicone hydrogel contact lenses. These include surface treatments, treatments to the lens chemistry or lens bulk, and the addition of internal and external wetting agents.27 Contact lens packaging solutions and lens care cleaning solutions also incorporate a variety of surfactants and wetting agents to increase overall lens wettability by lowering the surface tension.9,17 One particular additive wetting agent is the block copolymer, polyoxyethylene-polyoxybutylene, in the packaging solution of spherical lotrafilcon B lenses (AIR OPTIX plus HydraGlyde; Alcon Laboratories, Inc.).28 In addition to its inclusion in the packaging solution of lotrafilcon B, polyoxyethylene-polyoxybutylene is also used in two lens care cleaning and disinfecting solution products, OPTI-FREE PUREMOIST Multi-Purpose Disinfecting Solution and CLEAR CARE PLUS with HydraGlyde Moisture Matrix (Alcon Laboratories, Inc.).29,30

Extensive clinical testing of total cholesterol extracted from lotrafilcon B lenses packaged in non–polyoxyethylene-polyoxybutylene packaging solution and cared for with lens care solutions not containing polyoxyethylene-polyoxybutylene has been performed in the past years9,25,26; however, the amount of total cholesterol extracted from lotrafilcon B lenses packaged in solution containing polyoxyethylene-polyoxybutylene and cared for with polyoxyethylene-polyoxybutylene–containing contact lens solutions has not yet been examined. This study assessed the total cholesterol extracted from worn lotrafilcon B lenses packaged in blister solution containing the wetting agent polyoxyethylene-polyoxybutylene (lotrafilcon B +polyoxyethylene-polyoxybutylene) and cared for with polyoxyethylene-polyoxybutylene–containing lens care solutions compared with the total cholesterol extracted from other types of worn silicone hydrogel contact lenses cared for with multipurpose solutions that do not contain polyoxyethylene-polyoxybutylene. The primary efficacy end point was ex vivo total cholesterol extracted after 30 days of wear. Safety outcomes included adverse events, biomicroscopy findings, and device deficiencies.

METHODS

Subjects

Subjects were recruited at eight sites, five in the United States, two in Germany, and one in Canada. The study was conducted in accordance with the ethical principles of the Declaration of Helsinki and Good Clinical Practice. The study protocol was approved by the institutional review board/ethics committee of each site, and all subjects provided written informed consent. The trial was registered at Clinical Trials.gov as NCT03026257.

Subjects were eligible for inclusion if they had vision correctable to 0.1 (logMAR) or better in each eye at distance with habitual lenses and manifest cylinder (at screening) less than or equal to 0.75 D in each eye and spectacle add less than +0.50 D in each eye. Eligible participants had to be current, full-time (habitual) wearers of four reusable silicone hydrogel contact lenses: senofilcon C monthly replacement (ACUVUE VITA; Johnson & Johnson Vision Care, Inc., Jacksonville, FL), senofilcon A 2-week replacement (ACUVUE OASYS; Johnson & Johnson), comfilcon A monthly replacement (Biofinity; CooperVision, Inc., Scottsville, NY), and samfilcon A monthly replacement lenses (ULTRA; Bausch + Lomb Incorporated, Rochester, NY) within the power range of lens powers available and were currently using a multipurpose solution that did not contain polyoxyethylene-polyoxybutylene in the ingredients. Exclusion criteria included habitual lens wear in an extended wear modality (sleeping in lenses overnight for ≥1 d/wk); any anterior segment infection, inflammation, disease, or abnormality that contraindicates contact lens wear; history of herpetic keratitis, corneal surgery, or irregular cornea; prior refractive surgery; or currently using or have not discontinued Restasis (cyclosporine ophthalmic emulsion 0.05%; Allergan, Inc., Dublin, Ireland) or Xiidra (lifitegrast ophthalmic solution 5%; Novartis International AG, Basel, Switzerland) and/or topical steroids within the past 7 days.

Study Design

This was a multicenter, prospective, randomized, observer-masked and quasi–subject-masked (masked to study lenses and test solution brand only), controlled, parallel-group study. At their initial visit, subjects were randomized 1:1 either to lotrafilcon B lenses packed in solution containing polyoxyethylene-polyoxybutylene or to their habitual silicone hydrogel contact lenses packaged in solution not containing polyoxyethylene-polyoxybutylene: senofilcon C, senofilcon A, comfilcon A, and samfilcon A (Fig. 1). Subjects randomized to lotrafilcon B contact lenses were further randomized 1:1 to either of the two lens care solutions that contain polyoxyethylene-polyoxybutylene, OPTI-FREE PUREMOIST, or CLEAR CARE PLUS with HydraGlyde. Subjects randomized to their habitual silicone hydrogel contact lenses continued to use their habitual multipurpose solution not containing polyoxyethylene-polyoxybutylene. Randomization occurred using an electronic capture system and was blocked to ensure a balance of study regimen allocation within investigational sites and strata. Study personnel were masked, except for the study monitor, the lead clinical study manager, the person responsible for the randomization schedule, and the person who analyzed the cholesterol deposited on the contact lenses. Background was eliminated from the lens material by using a set of negative control lenses, consisting of unworn lenses of the same lens type, which were rinsed three times in 1.0 mL phosphate-buffered solution and then extracted alongside the test lenses. The analyst could not be masked because of the use of these negative controls. The masking parameters were maintained throughout the study.

FIGURE 1
FIGURE 1:
Study flowchart. CCP = CLEAR CARE PLUS with HydraGlyde; EOBO = polyoxyethylene-polyoxybutylene; HMPS = habitual multipurpose solution; MPS = multipurpose solution; OFPM = OPTI-FREE PUREMOIST.

After 30 ± 3 days of wear, right contact lenses were collected from all subjects, with the exception of senofilcon A lenses, which were collected after 15 ± 1 days of wear. The collected lenses were frozen at −20°C or lower and sent to the laboratory for analysis. Of these, a subset of approximately 20 to 25 worn right eye lenses from each lens/solution group was analyzed for cholesterol deposition.

Cholesterol Extraction

The subset of lenses for analysis was thawed, and lipids were extracted using a two-step chloroform/methanol (1:1) method similar to that described previously.9,26 Total cholesterol (free cholesterol and cholesteryl esters) concentrations obtained from each contact lens/lens care group were measured using an adapted blood serum fluorometric enzymatic assay (Cholesterol Fluorometric Assay Kit; Cayman Chemical, Ann Arbor, MI). This is a highly specific and sensitive technique for total cholesterol quantification that can determine whether the various silicone hydrogel lenses have comparable cholesterol accumulation. This assay has a dynamic range of 0 to 1.55 μg/lens, with interassay and intra-assay coefficients of variation of 3.4 and 6.4%, respectively, using human plasma samples.26 Test lenses were diluted to a sufficient volume to ensure they fell within the dynamic range of this assay. To compare total cholesterol extracted from groups of lenses, the geometric least squares mean and upper confidence limit were calculated for each contact lens/lens care solution combination based on a general linear model. The geometric least squares mean is defined as the least squares mean resulting from fitting the statistical analysis model on the log-transformed amounts of total cholesterol extracted; this is the recommended statistical method for summarizing log-transformed data because of the nonnormal distribution of lipid deposition. The upper confidence limit is the upper limit of the two-sided confidence interval, which is used to assess the hypothesis of superiority, as well as to provide an upper estimate of the differences between contact lens/lens care solution combinations.

Safety

Safety outcomes included adverse events, biomicroscopy findings (e.g., limbal and bulbar hyperemia, bulbar conjunctival compression, chemosis, corneal infiltrates, anterior segment inflammation, and conjunctival and cornea staining) and device deficiencies.

Sample Size Justification

The primary end point of this study was ex vivo total cholesterol uptake. The minimum sample size required to achieve 97% power for the primary end point using a one-sided α = 0.05 t test was calculated to be 25 subjects per group.

Statistical Analysis

Results of lotrafilcon B lenses and each polyoxyethylene-polyoxybutylene–containing solution were compared with those of habitual silicone hydrogel lens/habitual multipurpose solution regimens using the Dunnett test for multiple comparisons, with all reported P values being one-sided. The amount of total cholesterol extracted was assessed by comparing all four habitual silicone hydrogel lens/habitual multipurpose solution regimens both by individual regimen and as a group versus each group of lotrafilcon B + polyoxyethylene-polyoxybutylene lens cared for with OPTI-FREE PUREMOIST and CLEAR CARE PLUS with HydraGlyde (two analyses) using ANOVA with the Dunnett test. All statistical analyses were performed using SAS version 9.4 software (SAS Corp., Cary, NC).

RESULTS

Subject Characteristics

The study was initiated on February 13, 2017, and was completed on August 18, 2017. A total of 257 subjects were randomized into the study and included in the intention-to-treat population. The safety population included all subjects/eyes exposed to the control or test product evaluated in the study. Of the 257 randomized subjects, 5 were not exposed and were discontinued from the study; the safety analysis therefore included 252 subjects.

Of the 257 subjects in the intention-to-treat population, 129 were randomized to their habitual silicone hydrogel lenses plus their habitual multipurpose solution; this group included 25 subjects using senofilcon C, 46 using senofilcon A, 34 using comfilcon A, and 24 using samfilcon A lenses. The remaining 128 subjects were randomized to lotrafilcon B + polyoxyethylene-polyoxybutylene lenses and further randomized 1:1 to either of the two polyoxyethylene-polyoxybutylene–containing lens care solutions, with 62 to CLEAR CARE PLUS with HydraGlyde and 66 to OPTI-FREE PUREMOIST. A subset of the first 20 to 25 collected evaluable worn right eye lenses from each of the six lens/solution groups was analyzed and included 143 lenses, 95 from the habitual group and 48 from the lotrafilcon B + polyoxyethylene-polyoxybutylene groups. Among the 95 habitual lenses cared for with habitual multipurpose solution, 23 were senofilcon C, 28 were senofilcon A, 24 were comfilcon A, and 20 were samfilcon A lenses. Of the 48 lotrafilcon B lenses, 23 were cared for using CLEAR CARE PLUS with HydraGlyde and 25 with OPTI-FREE PUREMOIST (Fig. 1). The demographic characteristics of the six analyzed subgroups were generally well balanced (Table 1), as were the habitual multipurpose solutions used by study subjects before enrollment in this trial (Appendix Figure A1, available at http://links.lww.com/OPX/A453). The mean age of subjects overall was 28.2 years, 72% of subjects were female, and 74% were White.

TABLE 1
TABLE 1:
Demographic characteristics of the six study subgroups assessed for total cholesterol extraction

Cholesterol Extraction from Contact Lenses

The mean ± standard deviation amount of total cholesterol extracted from the 48 lotrafilcon B + polyoxyethylene-polyoxybutylene contact lenses cared for with either OPTI-FREE PUREMOIST or CLEAR CARE PLUS with HydraGlyde was lower than the amount extracted from all combinations of 95 habitual silicone hydrogel contact lenses cared for with habitual multipurpose solutions (0.28 ± 0.37 versus 2.64 ± 2.51 μg/lens; P < .001; Table 2, Fig. 2). In addition, comparisons of individual combinations showed that the amount of cholesterol extracted was significantly lower for lotrafilcon B + polyoxyethylene-polyoxybutylene contact lenses with both polyoxyethylene-polyoxybutylene–containing lens care solutions than for any other contact lens/multipurpose solution combination (P < .0001; Table 3, Fig. 3). Mean ± standard deviation total cholesterol extracted was significantly lower for the lotrafilcon B/CLEAR CARE PLUS with HydraGlyde (0.28 ± 0.18 μg/lens) and OPTI-FREE PUREMOIST (0.28 ± 0.48 μg/lens) regimens than for any habitual silicone hydrogel lens cared for with habitual multipurpose solutions, including senofilcon C (4.18 ± 3.25 μg/lens), senofilcon A (2.19 ±2.69 μg/lens), comfilcon A (2.17 ± 1.47 μg/lens), and samfilcon A (2.07 ± 1.48 μg/lens) lenses (P < 0001 for all).

TABLE 2
TABLE 2:
Total cholesterol extracted from lotrafilcon B + EOBO lenses cared for with EOBO-containing lens care solutions versus the combination of all habitual contact lenses/habitual lens care solutions
FIGURE 2
FIGURE 2:
Total cholesterol extracted from habitual silicone hydrogel lenses with non-EOBO multipurpose solutions and from lotrafilcon B contact lenses with EOBO-containing solutions. *Lotrafilcon B lenses packaged in blister solution containing the wetting agent EOBO. **CLEAR CARE PLUS with HydraGlyde and OPTI-FREE PUREMOIST lens care solutions formulated with EOBO. †Senofilcon A lenses worn for 2 weeks. EOBO = polyoxyethylene-polyoxybutylene; HMPS = habitual multipurpose solution; SiHy = silicone hydrogel.
TABLE 3
TABLE 3:
Total cholesterol extracted from individual combinations of contact lenses/lens care regimens
FIGURE 3
FIGURE 3:
Total cholesterol extracted from each individual combination of habitual silicone hydrogel and lotrafilcon B contact lenses with solutions. *Lotrafilcon B lenses packaged in blister solution containing the wetting agent EOBO. **CLEAR CARE PLUS with HydraGlyde and OPTI-FREE PUREMOIST lens care solutions formulated with EOBO. †Senofilcon A lenses worn for 2 weeks. CCP = CLEAR CARE PLUS with HydraGlyde; HMPS = habitual multipurpose solution; OFPM = OPTI-FREE PUREMOIST.

Safety Outcomes

The safety analysis set included all 252 subjects/eyes exposed to the control or test product evaluated in the study. Adverse events were analyzed for the comparison of the combined lotrafilcon B + polyoxyethylene-polyoxybutylene groups (n = 124 subjects) and the combined habitual lens/solution groups (n = 128 subjects). Ocular adverse event rates were similarly low in subjects randomized to lotrafilcon B + polyoxyethylene-polyoxybutylene lenses and both polyoxyethylene-polyoxybutylene–containing lens care solutions and those randomized to their habitual contact lenses and habitual multipurpose solutions. All ocular nonserious adverse events were mild or moderate.

Ocular adverse events were experienced by 28 (11.4%) of 248 eyes in the group randomized to lotrafilcon B + polyoxyethylene-polyoxybutylene lenses and both polyoxyethylene-polyoxybutylene–containing lens care solutions and by 22 (8.5%) of 256 eyes in the group randomized to their habitual contact lenses and habitual multipurpose solutions. Only two eyes (0.8%) in the lotrafilcon B/polyoxyethylene-polyoxybutylene group and only seven (2.7%) in the habitual lens/habitual multipurpose solution group experienced ocular events deemed related to the study. All ocular nonserious adverse events were mild or moderate. Three subjects (five eyes) randomized to lotrafilcon B + polyoxyethylene-polyoxybutylene lenses/polyoxyethylene-polyoxybutylene solutions discontinued because of adverse events, two for intolerance to the lenses and one for ocular discomfort unrelated to study products; none of these eyes were included in the lipid analysis. All reported adverse device effects recovered/resolved except for one report of dry eye (ULTRA/habitual multipurpose solution) with unknown status.

DISCUSSION

A major drawback of silicone hydrogel contact lens use is surface dewetting,12 which has been attributed to the hydrophobicity of the siloxane moiety in the lens.2 The incorporation of effective wetting agents, such as polyoxyethylene-polyoxybutylene, into contact lens blister pack solutions and into disinfecting lens care solutions has been found to improve the surface wettability of silicone hydrogel lenses.9,12

Silicone hydrogel lenses have also been found to have higher lipid deposition compared with other hydrogel lenses.2–8 To date, no clinical study has been performed on lotrafilcon B lenses packaged with the added wetting agent, polyoxyethylene-polyoxybutylene, and cared for with polyoxyethylene-polyoxybutylene–containing contact lens solution. This analysis is imperative in understanding if the additional use of polyoxyethylene-polyoxybutylene in the lens care formulation interferes with the lipid deposition resistance of lotrafilcon B lens material. This ex vivo study evaluated the amounts of total cholesterol extracted from worn lotrafilcon B lenses packaged in blister packs containing polyoxyethylene-polyoxybutylene and cared for with polyoxyethylene-polyoxybutylene–containing contact lens solutions compared with those extracted from four types of reusable silicone hydrogel lenses packaged in blister packs and cared for with multipurpose solutions not containing polyoxyethylene-polyoxybutylene. We found that the amount of total cholesterol extracted from the group of lotrafilcon B lenses with polyoxyethylene-polyoxybutylene–containing lens packaging and lens care solutions was significantly lower than that from the habitual silicone hydrogel lenses with lens packaging and lens care solutions not containing polyoxyethylene-polyoxybutylene. There was no significant difference between the amount of cholesterol extracted from lotrafilcon B + polyoxyethylene-polyoxybutylene lenses cared for with the two polyoxyethylene-polyoxybutylene–containing lens care solutions, OPTI-FREE PUREMOIST and CLEAR CARE PLUS with HydraGlyde.

Previous clinical studies have shown that the ex vivo sorption of cholesterol onto lotrafilcon B lenses without polyoxyethylene-polyoxybutylene was significantly lower than that of other lenses tested.9,25,26 In a study that compared the total cholesterol extracted from seven different types of silicone hydrogel contact lenses worn on a daily basis for 2 to 4 weeks, the median total cholesterol ± quartile extracted was significantly lower for lotrafilcon B and lotrafilcon A than for the five other lenses tested (P < .0001).26 All lotrafilcon B contact lenses are manufactured with a smooth, ultrathin (25-nm), continuous, permanent, and hydrophilic plasma surface layer that serves as an effective barrier against the underlying hydrophobic silicone lens.31,32 By contrast, none of the four other silicone hydrogel lenses tested in this study have this type of surface modification, and all had higher extracted cholesterol levels. This study found that, similar to other studies using lotrafilcon B lenses without added polyoxyethylene-polyoxybutylene,9,25,26 a lens with an ultrathin plasma layer with the addition of polyoxyethylene-polyoxybutylene wetting agent in both the lens packaging solution and the lens care solution correlated with reduced extraction of cholesterol and cholesteryl esters when compared with the other contact lenses and lens care solutions tested.

The fluorometric enzymatic assay used in the current study is a simple and efficient means of quantifying the amount of cholesterol and cholesteryl esters extracted from ex vivo contact lenses and has been used in previous studies.25,26 Moreover, the methodology used to extract lipids using the solvents chloroform and methanol is similar to that reported by Jones et al.2 and Zhao et al.,9 in which 1:1 chloroform/methanol had extraction efficiencies ranging from 73 to 95%. Although the efficiency of these solvents across a broad range of contact lens materials has not been determined, the dual-extraction protocol is regarded as optimal for the extraction of cholesterol from contact lenses, increasing the extraction efficiency over a one-step extraction protocol.25 Differences in solvent efficiency may have contributed to differences in the amounts of cholesterol extracted from the different lens types.

One important limitation of this study design is that, although habitual lens wearers used their habitual multipurpose solutions, the study was not designed to ensure that the types of lens care products used were uniform among groups, although variations among groups were minimal (Appendix Figure A1, available at http://links.lww.com/OPX/A453). Although the aim of this study was to compare total cholesterol sorption with lenses and lens care solutions that did and did not contain polyoxyethylene-polyoxybutylene, differences among the various habitual lens care solutions used may have influenced the results. In addition, this study was not designed to determine the differences in total cholesterol sorption between lotrafilcon B lenses and lotrafilcon B lenses packaged in blister solution containing polyoxyethylene-polyoxybutylene and cared for with polyoxyethylene-polyoxybutylene–containing lens care solutions. Further research is needed to determine the direct effect of polyoxyethylene-polyoxybutylene on lipid uptake by lotrafilcon B lenses.

CONCLUSIONS

Previous clinical trials have shown that the surface technology used in lotrafilcon B contact lenses defends against lipid deposits for up to 30 days of wear.9,25,26 Similarly, in this study, lotrafilcon B contact lenses packaged in solution containing polyoxyethylene-polyoxybutylene and used with the polyoxyethylene-polyoxybutylene–containing lens care solutions CLEAR CARE PLUS with HydraGlyde and OPTI-FREE PUREMOIST resulted in lower cholesterol sorption compared with any of the habitual silicone hydrogel and habitual multipurpose solution regimens in this study. The addition of polyoxyethylene-polyoxybutylene to lens packaging and lens care solutions to enhance the sustained wettability of lenses did not have a negative effect on cholesterol uptake by lotrafilcon B lenses. However, further ex vivo research is necessary to understand the direct impact of polyoxyethylene-polyoxybutylene on lipid deposition.

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