Besifloxacin-Eluting Contact Lens Review: Sustained Delivery

JOURNAL CLUB PRESENTATION

Besifloxacin-Eluting Contact Lens

with Sustained Drug Delivery and Enhanced Bioavailability

Kuang L, Boychev N, Chen L, Ross AE, Kanu LN, et al.

International Journal of Pharmaceutics: X, 11 (2026) 100511

Presenter 1

Presenter 2

Presenter 3

Presenter 4

Presenter 5

Harvard Medical School / Mass Eye and Ear

Presentation Overview

Introduction & Background

Problem Statement

Besifloxacin: The Drug

Drug-Eluting Contact Lens Concept

Materials & Methods — Fabrication

Physicochemical Characterization

In Vitro Drug Release

Stability Studies

Antimicrobial Efficacy & Cytotoxicity

Pharmacokinetics & Biocompatibility

Comprehensive Journal Club Review | Masters Level Evaluation

Introduction: Bacterial Keratitis

What is Bacterial Keratitis?

A rapidly progressive ocular infection caused by bacterial pathogens. Leading cause of corneal blindness worldwide.

Prevalence & Impact

Significant global burden; affects vision and quality of life. Requires urgent and effective treatment.

Current Standard of Care

Intensive topical antibiotics (eye drops or ointments) administered hourly, even at night.

Key Clinical Limitation

Ocular bioavailability typically <7%. Poor corneal penetration + patient non-compliance.

McDonald et al., 2014 | Ung et al., 2019

Barriers to Ocular Drug Delivery

Corneal Layers

Hydrophobic epithelium + endothelium flank the hydrophilic stroma — impedes both hydrophobic & hydrophilic molecules

Tear Turnover

0.5–2.2 μL/min tear turnover dramatically reduces drug concentration

Nasolacrimal Drainage

Drug washed away via nasolacrimal duct

Blinking & Reflex Lacrimation

Further reduces residence time

Drug Half-Life in Tear Film

Only 2–5 minutes for most conventional eye drops!

Result: Intensive hourly dosing regimens required → poor compliance → compromised efficacy

Ross et al., 2019 | Peng et al., 2022 | Jumelle et al., 2020

Besifloxacin (BXF): Drug Profile

Drug Class

Pharmacochemical Properties

Why is BXF Challenging to Deliver?

Tótoli & Salgado, 2018 | Comstock et al., 2010

Existing Formulation Strategies & Their Limitations

Strategy

Examples

Improvement

Limitation

Viscosity enhancers / mucoadhesives

DuraSite® (Besivance®)

Extended ocular residence

Impaired corneal penetration, blurred vision, stickiness

Lipid-based nanocarriers

Liposomes, NLC, NLCs

Improved drug loading & penetration

Sustaining therapeutic levels remains challenging

In situ forming gels

Chitosan-gelrite systems

Better retention

Short-term release, discomfort

Polymeric microneedles

PLGA microneedle arrays

Direct corneal drug delivery

Requires professional administration

Nanofibrous ocular inserts

BXF-loaded nanofibers

Extended release

Sub-therapeutic concentrations

Drug-eluting Contact Lenses

Present Study (BXF-CL)

Sustained 24h+ release, 21.6x higher Cmax

— (This study addresses prior gaps!)

Gap: No besifloxacin-eluting contact lens system had been reported prior to this study

dos Santos et al., 2020 | Polat et al., 2022 | Bhatnagar et al., 2018 | Peng et al., 2022

Study Objectives & Hypothesis

A besifloxacin-eluting contact lens (BXF-CL) incorporating an EC/RSPO polymer film reservoir can overcome the physicochemical limitations of besifloxacin to provide sustained therapeutic ocular drug delivery exceeding conventional eye drops.

Fabricate BXF-CL

Develop and optimize drug-loaded polymer film embedded within contact lens periphery

Physicochemical Characterization

Assess morphology, water content, light transmittance

In Vitro Drug Release

Evaluate sustained-release kinetics vs commercial contact lenses

Stability Assessment

Evaluate drug integrity after UV curing, sterilization (autoclave & gamma irradiation), and 2-year storage

Antimicrobial Efficacy

Test against S. aureus and E. coli using agar disk diffusion

In Vivo Pharmacokinetics

Compare aqueous humor drug levels vs hourly Besivance® eye drops in rabbits

First-ever besifloxacin-eluting contact lens system reported in literature

Materials & Methods: Overview

Key Materials

Methods Overview

All in vivo protocols approved by IACUC — Schepens Eye Research Institute

BXF-CL Fabrication Process

Drug-Polymer Solution

BXF + EC + RSPO dissolved in HFIP

Low-dose: 1:5 (BXF:Polymer)

High-dose: 2:5 (BXF:Polymer)

EC/RSPO blend ratio = 1:1

Spin Coating

50 μL pipetted onto concave blank

Spun at 100 rpm for 6 min

Vacuum dried in desiccator x 7 days

Central Aperture

4-mm dermal biopsy punch used

Creates crisp central aperture

Maintains optimal optical clarity

UV Polymerization

350 μL liquid methafilcon added

Fully covers the dried polymer film

UV cured at ~110 mW/cm² for 5 min

Lathing

Solid methafilcon cylinder is lathed

Machined into final contact lens shape

Final BXF-CL

Hydrated lens OD: 14.7 mm

Polymer film OD: 12.0 mm

Central aperture: 5.2 mm

Film thickness: 51–60 μm

Polymer Matrix Rationale

hydrophobic, diffusion-limiting matrix → controls release rate

flexible, tunable permeability → prevents cracking

optimal film integrity + encapsulation performance

Why peripheral film placement?

Preserves clear central optical zone during drug delivery.

Mimics structural aperture design of cosmetic tinted contact lenses.

Physicochemical Characterization

Morphology (OCT)

Light Transmittance

Water Content

✅

BXF-CLs are physically and optically comparable to commercial contact lenses

Source: Section 3.1 | Chen et al., 2022 | Nguyen et al., 2021

In Vitro Drug Release Kinetics

* p = 0.015–0.029 (Mann-Whitney U) vs Commercial CL | Source: Section 3.2

Commercial CL: Burst Release

29.7 ± 1.3 μg (83%) within 1st hour

No drug detected after 4h

Total: only 35.8 ± 2.3 μg/lens

BXF-CLs: Sustained Release

Sustained and steady release over 24h

Low-dose: 276.7 μg (96.6% of drug load)

High-dose: 521.7 μg (97.7% of drug load)

Key Achievement

Up to 15.4× greater total drug delivery vs commercial CLs

Assay conditions: PBS (pH 7.4), 37°C, 5 mL sink conditions, HPLC quantification

Stability Studies:

UV Irradiation & Sterilization

UV Irradiation Stability

Drug-polymer film exposed to same UV conditions as encapsulation (~110 mW/cm², 5 min)

Interpretation: Polymer matrix PROTECTS besifloxacin from UV damage during fabrication

BXF within polymer film

Identical UV-Vis peaks (245, 288, 338 nm) + identical HPLC retention time (10.1 min)

→ NO DEGRADATION

Free BXF solution (control)

Loss of characteristic peaks

→ Significant degradation

Autoclaving (121°C, 220 kPa, 20 min)

Drug itself: stable (no degradation) ✅

BUT: 58% (low) & 49% (high) cumulative release DECREASED ❌

Drug leached into autoclave buffer during sterilization

Release duration shortened from 48h to 12h

~41% drug released within 1st hour

Conclusion: AUTOCLAVING NOT SUITABLE for BXF-CLs ❌

Gamma Irradiation (25 kGy, Cobalt-60)

Cumulative release: PRESERVED (p = 0.40 low, p = 0.90 high) ✅

Similarity factor f₂ = 91.7 (low) & 81.8 (high) — both ≥50 = SIMILAR ✅

LC-MS/MS: drug integrity confirmed ✅

Morphology, transmittance, water content: all unchanged ✅

✅ GAMMA IRRADIATION SELECTED as terminal sterilization method

Source: Section 3.3 | Galante et al., 2018 | Shah et al., 1997

Long-Term Stability: 2-Year Storage Study

Study Design

Storage conditions: Dry state, 4°C, amber glass vials, preservative-free

Duration: 2 years

n = 5 lenses per formulation per time point

Evaluated: Drug release kinetics, morphology, light transmittance, water content

Drug Chemical Integrity

HPLC: drug released from stored lenses identical to pristine besifloxacin. No degradation detected.

Cumulative Release Amount

Low-dose: p = 0.27 → NOT significantly different from baseline (f₂ = 80.3)

High-dose: p = 0.54 → NOT significantly different from baseline (f₂ = 83.0)

Both f₂ values ≥50 → Release profiles are SIMILAR ✅

Lens Morphology & Transmittance

All lenses maintained normal morphology

Light transmittance: p = 0.27 (low) / p = 0.48 (high) → unchanged

Water content: p = 0.45 (low) / p = 0.78 (high) → unchanged

Clinical & Commercial Implication

Extended 2-year shelf life enables commercial viability and clinical practicality

Dry storage at 4°C is feasible for medical-grade preservation

BXF-CLs maintain drug integrity, release kinetics, and lens properties for at least 2 years — supporting strong translational potential

Source: Section 3.3.3 | Kamaly et al., 2016

In Vitro Antimicrobial Efficacy

Methods & Principle

Agar diffusion & HPLC concentrations are CONSISTENT (p=0.17–0.43, Kruskal-Wallis) — confirming bioactive drug integrity

High-dose > Low-dose

Drug Bioactivity Confirmed

Besifloxacin retained full antimicrobial potency after fabrication, sterilization, and release

Gram+ & Gram− Coverage

Effective broad-spectrum antibacterial activity preserved in BXF-CL system

Clinical Significance

BXF-CLs release therapeutically active drug concentrations throughout 8h wear — sufficient for keratitis treatment

Section 3.4 | Comstock et al., 2010 | Kuang et al., 2021

In Vitro Cytotoxicity on Human Corneal Epithelial Cells

Section 3.5 | ISO 10993-5:2009 | Baig et al., 2020

Ocular Pharmacokinetics: Study Design

Section 2.13 | Ross et al., 2019 | Kuang et al., 2021

6 NZW Rabbits (non-terminal crossover)

Permanent lateral tarsorrhaphy

7-day healing period

ARM A: BXF-CL GROUP

Fresh lens applied at each timepoint

ARM B: EYE DROP

Besivance® 0.6% 5 drops over 4h

Aqueous Humor Collection 1h, 2h, 4h, 8h, 12h, 24h (30G needle, 100 μL)

3-day washout between arms

HPLC drug quantification

Rationale for Aqueous Humor Sampling

Located immediately posterior to cornea

Topical drugs enter predominately via cornea (~90% penetration — Doane et al., 1978)

Provides a conservative estimate of actual corneal drug levels

Allows non-terminal crossover design → reduces animal use (3Rs principles)

Rabbits: Ocular dimensions closely approximate human eyes

Eye Drop Dosing Protocol

5 drops administered hourly (doses at 0, 1, 2, 3, 4h)

Dosing stopped after 5th drop — concentrations plateau after 3–4 doses

Simulates a robust 24-drop daily regimen (AUC estimated)

Note: Each drop = one standard clinical dose of Besivance® 0.6%

Pharmacokinetic Results: BXF-CLs vs Hourly Eye Drops

Source: Table 2 | Section 3.6 | Kuang et al., 2021 | Mah & Sanfilippo, 2016

Bioavailability Enhancement & Drug Utilization Efficiency

AUC Comparison — Bioavailability Marker

Drug Dose Efficiency

Why Better Bioavailability?

Clinical & Stewardship Implications

Source: Section 4 | Ciolino et al., 2014 | Lanier et al., 2020

In Vivo Biocompatibility & Ocular Safety

Draize Test (Ocular Irritation Study)

Study Design

Draize Test Results

BXF-CLs show NO ocular irritation potential — non-irritative material classification

In Vivo Lens Wear Safety (48h Clinical Monitoring)

Assessment Parameters

Fluorescein Staining

BXF-CLs confirmed safe and biocompatible in both chemical safety (Draize) and in vivo wear assessments

Source: Section 3.7 | Wilhelmus, 2001 | Bengani et al., 2020

Discussion

: Mechanism & Clinical Significance

Why BXF-CL Works: Mechanistic Insights

Overcoming BXF's Dual Challenge

Post-Lens Tear Film Effect

Dose Efficiency

Clinical Advantages vs Alternatives

BXF-CL combines the convenience of self-administration with sustained, preservative-free release — a clinically adaptable platform

Source: Section 4 | Stone et al., 2009 | Polat et al., 2022

Limitations & Future Directions

Dry Storage Requirement

Current BXF-CL must be stored dehydrated → requires pre-application hydration step

Implication: Best suited for supervised clinical/in-office use, not home use

Solution needed: Evaluate stability in hydrated packaging for future iterations

E. coli as Gram− Model (Not P. aeruginosa)

P. aeruginosa is the most prevalent Gram− in bacterial keratitis

E. coli was chosen for: wider ZOI dynamic range + better quantitative precision

P. aeruginosa has higher intrinsic resistance + restricted agar diffusion → less precise calibration

Limitation: Efficacy against P. aeruginosa not yet demonstrated

Animal Model Only — No Human Clinical Data

Pharmacokinetics validated only in rabbit model (ocular dimensions similar to humans)

Phase I/II/III clinical trials needed for regulatory approval

Translation studies required

In Vitro Efficacy Only — No In Vivo Infection Model

No bacterial keratitis animal model used in this study

Proof-of-concept antimicrobial efficacy shown; in vivo efficacy studies needed

Hydrated Packaging Studies

Evaluate BXF-CL stability and drug retention during long-term storage in hydrated state

Enables consumer convenience and at-home use

P. aeruginosa Efficacy Testing

In vitro and in vivo testing against the primary Gram− pathogen in bacterial keratitis

In Vivo Infection Efficacy

Rabbit model of bacterial keratitis (MRSA-keratitis model as established precedent)

Validate therapeutic efficacy against eye infection in animal models

Clinical Translation

Phase I safety trials → Phase II efficacy studies

Regulatory pathway (FDA, CE Mark)

Manufacturing scale-up and commercialization studies

These limitations are acknowledged transparently

future studies are clearly defined and clinically motivated

Source: Section 4 Discussion | Sanders et al., 2009

Conclusion & Key Takeaways

SUMMARY

BXF-CLs represent a clinically adaptable platform for sustained ocular antibiotic delivery with strong potential to improve outcomes in bacterial keratitis — particularly in deep stromal infections where conventional eye drops often fail.

First-of-its-Kind

First-ever besifloxacin-eluting contact lens reported in scientific literature. Novel EC/RSPO polymer blend for besifloxacin delivery.

Comparable Physical Properties

Light transmittance and water content equivalent to commercial CLs. Safe, comfortable to wear.

Sustained 24h+ Drug Release

Up to 15.4× more total drug delivered vs conventional soaked lenses. Clinically relevant drug levels maintained throughout wear.

21.6× Higher Cmax

Peak besifloxacin concentration in aqueous humor 21.6-fold greater than hourly eye drops. 18.3× enhanced AUC — dramatically improved bioavailability.

Proven Stability

Maintains drug integrity and lens properties after gamma irradiation sterilization and 2 years of dry storage at 4°C.

Safe & Biocompatible

No cytotoxicity (ISO 10993-5), no ocular irritation (Draize test), no corneal damage (fluorescein staining) — confirmed in human cells and rabbit model.

Funded by NIH R01EY026640 & P30EY003790 | International Journal of Pharmaceutics: X, 11 (2026) 100511

Critical Appraisal of the Study

📋 JOURNAL CLUB

STRENGTHS

LIMITATIONS / WEAKNESSES

Novelty

First BXF-eluting CL; first EC/RSPO combination for BXF delivery

Rigorous characterization

OCT, HPLC, spectrophotometry, gravimetry, LC-MS/MS extensively used

Comparative design

Head-to-head vs clinical standard (hourly eye drops) AND soaked commercial CLs

Clinically relevant PK outcomes

Aqueous humor as surrogate for corneal levels, 3Rs-compliant non-terminal design

Comprehensive stability

UV, autoclaving, gamma irradiation, and 2-year functional storage tested

Validated safety protocols

ISO 10993-5 cytotoxicity, Draize test (OECD), in vivo fluorescein staining

Quantitative antimicrobial confirmation

ZOI directly correlated to concentration via standard curve to validate bioactivity

Clear therapeutic thresholds cited

MIC₉₀ for S. aureus, Gram−, MRSA included to establish clinical translatability

Small animal model constraint

n = 3–6 per timepoint; forced non-parametric statistics due to limited sample size

No in vivo infection model

Efficacy in an actual bacterial keratitis infection model was not demonstrated

No hydrated storage testing

Current form requires pre-use hydration posing a clinical logistics challenge

E. coli vs P. aeruginosa evaluated

A more relevant contact lens-related keratitis pathogen was not directly tested

No long-term in vivo wear study

In vivo evaluation was stringently limited to a ≤48h wear time envelope

Rabbit vs human pharmacokinetics

Translational gap remains; robust human PK data needed to map clinical reality

AUC for eye drops overestimated

Acknowledged by authors: makes BXF-CL comparative outcome overly conservative

Single formulation design

Only methafilcon hydrogel explored; parallel alternative lens materials not compared

OVERALL: Well-designed translational proof-of-concept study with honest discussion of limitations. Strong foundation for clinical translation.

Source: Critical analysis of Sections 3–4 | ISO standards | OECD guidelines

References

Full reference list available in Kuang et al., 2026 — Int. J. Pharmaceutics: X 11, 100511

Kuang L et al. (2026). Besifloxacin-eluting contact lens with sustained drug delivery. Int J Pharm X, 11, 100511.

McDonald EM et al. (2014). Topical antibiotics for bacterial keratitis. Br J Ophthalmol, 98, 1470–1477.

Ung L et al. (2019). Microbial keratitis: global burden & antimicrobial resistance. Surv Ophthalmol, 64, 255–271.

Ross AE et al. (2019). Topical sustained drug delivery to retina with drug-eluting CL. Biomaterials, 217, 119285.

Peng C et al. (2022). Bibliometric analysis of ocular drug delivery 2001–2020. J Control Release, 345, 625–645.

Jumelle C et al. (2020). Advances & limitations of eye drop delivery systems. J Control Release, 321, 1–22.

Comstock TL et al. (2010). Besifloxacin: novel anti-infective for bacterial conjunctivitis. Clin Ophthalmol, 4, 215–225.

dos Santos GA et al. (2020). Besifloxacin liposomes for improved ocular delivery. Sci Rep, 10, 1–18.

Proksch JW et al. (2009). Ocular pharmacokinetics of besifloxacin. J Ocul Pharmacol Ther, 25, 335–344.

Bengani LC et al. (2020). Steroid-eluting contact lenses for ocular inflammation. Acta Biomater, 116, 149–161.

Galante R et al. (2018). Drug-eluting silicone hydrogel: impact of sterilization. Colloids Surf B, 161, 537–546.

Shah VP et al. (1997). FDA guidance: dissolution testing of immediate release solid dosage forms. Dissolution Technol, 4, 15–22.

Mah FS & Sanfilippo CM (2016). Besifloxacin: efficacy and safety. Ophthalmol Ther, 5, 1–20.

Stone JL et al. (2009). Objective evaluation of eyedrop instillation in glaucoma patients. Arch Ophthalmol, 127, 732–736.

Wilhelmus KR (2001). The Draize eye test. Surv Ophthalmol, 45, 493–515.

Ciolino JB et al. (2014). In vivo drug-eluting CL for glaucoma treatment. Biomaterials, 35, 432–439.

Lanier OL et al. (2020). Commercialization challenges for drug eluting contact lenses. Expert Opin Drug Deliv, 17, 1133–1149.

Polat HK et al. (2022). Novel drug delivery systems to improve keratitis treatment. J Ocul Pharmacol Ther, 38, 376–395.

Thank You

Questions & Discussion

For evaluators and audience:

How does the EC/RSPO polymer blend mechanistically contribute to controlled release — and what are the pharmacokinetic implications of the 8h Tmax compared to conventional eye drops?

The study compares BXF-CL to hourly eye drops — is this a clinically fair comparison? What are the statistical limitations of the small sample size?

How might the transition from rabbit to human pharmacokinetics change the observed 21.6-fold Cmax enhancement?

21.6×

Higher Peak Drug Level vs. Hourly Eye Drops

2 Years

Proven Shelf Life

24h

Sustained Therapeutic Release

Kuang L, Boychev N, Chen L et al. Besifloxacin-Eluting Contact Lens with Sustained Drug Delivery and Enhanced Bioavailability. Int. J. Pharmaceutics: X, 11 (2026) 100511. DOI: 10.1016/j.ijpx.2026.100511

NIH Funded: R01EY026640 | P30EY003790