Moxifloxacin-loaded acrylic intraocular lenses: In vitro and in vivo performance

doi:10.1016/j.jcrs.2019.07.016

Journal of Cataract & Refractive Surgery

Volume 45, Issue 12, December 2019, Pages 1808-1817

$Journal of Cataract & Refractive Surgery$

https://doi.org/10.1016/j.jcrs.2019.07.016 Get rights and content

Purpose

To assess the possibility of using acrylic intraocular lenses (IOLs) to ensure controlled and sustained release of moxifloxacin, an antibiotic commonly used for endophthalmitis prophylaxis after cataract surgery.

Setting

Academic, industrial, and clinical partners from Portugal, Belgium, Iceland, and the United States.

Design

Experimental study.

Methods

The physical properties of IOLs loaded with moxifloxacin by soaking were characterized. In vitro drug-release studies were performed under hydrodynamic conditions similar to those of the eye, and the activity of the released drug was tested. In vitro cytotoxicity was evaluated, and the in vivo efficacy of the devices was assessed through rabbit experiments in which the effects of topical moxifloxacin drops (control) and moxifloxacin-loaded IOLs were compared.

Results

The presence of moxifloxacin in the IOLs had little effect on the evaluated physical properties and did not induce cytotoxicity. In vitro drug release experiments showed that the IOLs provided controlled release of moxifloxacin for approximately 2 weeks. The drug remained active against the tested microorganisms during that period. Moxifloxacin-loaded IOLs and the control treatment induced similar in vivo behavior in terms of inflammatory reactions, capsular bag opacification scores, and uveal and capsule biocompatibility. The drug concentration in the aqueous humor after 1 week was similar in both groups; however, the concentration with the loaded IOLs was less variable.

Conclusion

The moxifloxacin-loaded IOLs released the drug in a controlled manner, providing therapeutic levels.

Section snippets

Sample Preparation

The raw material used for the study was a chemically crosslinked copolymer of HEMA (80% to 90%) and methyl methacrylate (10% to 20%). The material incorporates an ultraviolet (UV)-light filter and a blue-light filter²⁵ and absorbs 26 wt% of water in the equilibrium state. Disks of 1.0  mm thickness, 5.0 mm diameter, and approximately 20 mg of dry mass were used for the physical characterization studies. Prototype IOLs (+20.0 diopter power) with an average thickness of 0.6 mm and optical zone

Characterization of the Drug-Loaded Samples

Table 1 shows the swelling capacity, optical properties, wettability, and roughness of the disks. The swelling capacity in water was not affected by temperature (P = .701). When moxifloxacin was present in the immersion medium, the swelling capacity of the material increased from 30.0% to 32.5% at 60°C (P = .004).

The refractive index did not change with drug loading (P = .191). The mean transmittance in the wavelength range of 500 to 700 nm of the unloaded material and loaded material was not

Discussion

We assessed the potential of acrylic IOLs to serve as drug vehicles, in particular of moxifloxacin, to prevent endophthalmitis after cataract surgery. The samples (disks and IOLs) were loaded with moxifloxacin by soaking, sterilized, and stored using predefined conditions, which were selected taking into to account that these IOLs might be used clinically in the future. The type of IOL in the study must be packaged in a sterile and hydrated state. Drug loading, sterilization, and storage were

First author:

Helena P. Filipe, MD

Forças Armadas, Polo de Lisboa-EMGFA, Lisbon, Portugal

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This model relies on the partition and the effective diffusivity coefficients of the drug that can be calculated from in vitro drug release experiments. The model was validated using hydrophilic CI26Y IOLs loaded with MXF, through the comparison of the predicted concentration of MXF in the aqueous humor with in vivo results from other works (Kleinmann et al., 2006; Filipe et al., 2019) that tested similar hydrophilic IOLs loaded with MXF. After model validation, the drug concentration in the aqueous humor was estimated for two types of hydrophilic disks (besides the hydrophilic acrylic based material CI26Y, also DEF50, a silicone hydrogel) and other drugs: one antibiotic (LVF), and two NSAIDs (KTL and DFN).
Cataract surgery is one of the most common and safe surgical procedures nowadays. However, it is not free of risks as endophthalmitis, ocular inflammation and posterior capsule opacification (PCO) can appear as post-surgery complications. The usual eye drop therapy used as prophylaxis for the former two complications has limited bioavailability. In turn, the prevention of PCO involves an adequate surgical technique and a careful choice of intraocular lens (IOL) design and material. Also, different drugs have been tested to reduce incidence of PCO, but no prophylaxis demonstrated to be completely effective. In the past few years, IOLs have been proposed as drug delivery devices to replace or/assist the usual eye drop therapy in the post-operatory period. The great advantage of drug loaded IOLs would be to ensure a continuous drug delivery, independent of patient’s compliance without requiring any further action besides IOL implantation. The biggest challenge of drug loaded IOLs production is to achieve a controlled and extended release that meet therapeutic needs without inducing toxicity to the surrounding ocular tissues or affecting the physical properties of the lens.
This review starts by addressing the possible complications after cataract surgery, as well as the most commonly adopted prophylaxis for each of them. The various types of IOLs are described and their main advantages/disadvantages are discussed. The different strategies pursued to incorporate drugs into the IOLs and control their release, which include soaking the IOL in the drugs solution, supercritical impregnation, surface modifications, and attachment of drug reservoirs to the IOL, among others, are reported. For each strategy, a summary of the publications is presented, which includes the target complication, the types and amounts of released drugs and the IOL materials. A brief description of each individual study is given afterwards. Optimization of drug loaded IOLs through mathematical modelling and possible issues raised by their sterilization are also tackled. At the end, the future commercialization of drug loaded IOLs is commented.
Multi-region finite element modelling of drug release from hydrogel based ophthalmic lenses
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Hydrogels have long been considered for biomedical applications [1], notably as carriers for the delivery of drugs [2]. Recent publications have shown the potential of a controlled release of drugs from hydrogel based ophthalmic lenses to sustain therapeutic levels for ophthalmic afflictions [3–6]. The suitability of a hydrogel as a drug delivery device depends largely on network structure [7,8].
Understanding the way in which drug is released from drug carrying hydrogel based ophthalmic lenses aids in the development of efficient ophthalmic drug delivery. Various solute–polymer interactions affect solute diffusion within hydrogels as well as hydrogel–bulk partitioning. Additionally, surface modifications or coatings may add to resistance of mass transfer across the hydrogel interface. It is necessary to consider both interfacial resistances as well as the appropriate driving force when characterizing interface flux. Such a driving force is induced by a difference in concentration which deviates from equilibrium conditions. We present a Galerkin finite element approach for solute transport in hydrogels which accounts for diffusion within the gel, storage effects due to polymer–solute interaction, as well as partitioning and mass transfer resistance effects at the interface. The approach is formulated using a rotational symmetric model to account for realistic geometry. We show that although the resulting global system is not symmetric in the case of partitioning, it is similar to a symmetric negative semidefinite system. Thus, it has non-positive real eigenvalues and is coercive, ensuring the validity of the finite element formulation as well as the numerical stability of the implicit backward Euler time integration method employed. Two models demonstrating this approach are presented and verified with release experimental data. The first is the release of moxifloxacin from intraocular lenses (IOLs) plasma grafted with different polyacrylates. The second accounts for both loading as well as the release of diclofenac from disc shaped IOL material loaded for varied time periods and temperature.
Dual drug delivery from hydrophobic and hydrophilic intraocular lenses: in-vitro and in-vivo studies
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Some of these works were carried out by our group. We have been working on the optimisation of in vitro release profiles of moxifloxacin (MXF) and ketorolac (KTL) from CI26Y, a commercial hydrophilic IOL material [31–33]. Simultaneous release of both drugs complying with the therapeutic needs was achieved: the loaded lenses were effective against S. aureus and S. epidermidis up to 15 days, and the amount of released ketorolac was enough to prevent inflammation for a minimum of 16 days [34].
Posterior capsule opacification (PCO) still remains the most frequent long term complication after cataract surgery, while endophthalmitis is rare but severe and should be prevented at all cost. Intraocular lenses (IOLs) with different designs (eg. edge and body-haptics angle) and materials (acrylic hydrophobic and acrylic hydrophilic surfaces) have been studied to reduce PCO. For the prevention of endophthalmitis, intracameral injection followed or not by topical treatment with antibiotics and anti-inflammatories are usually prescribed. The objective of this work was to investigate the use of IOLs as controlled release platforms of two drugs, the antibiotic moxifloxacin (MXF) and the anti-inflammatory ketorolac (KTL) that could advantageously substitute the usual treatment. Two types of IOLs were chosen, hydrophobic and hydrophilic. Hydrophobic IOLs have shown better results in the prevention of PCO because they adhere better to the posterior capsular bag, while hydrophilic IOLs are advised in the case of patients with uveitis, glaucoma or diabetes. The IOLs were loaded with MXF + KTL and sterilized by high hydrostatic pressure. Both IOLs reduced the tendency for adhesion of LECs. In vivo tests were done to compare the concentration of the drugs in the aqueous humor obtained after eye drops administration and drug-loaded IOLs implantation. The developed IOLs were able to release MXF and KTL at therapeutic levels, in a sustained way, which contrasts with the eye drops prophylaxis. No PCO signs were detected and histological analyses demonstrated biocompatibility of these devices.
Utilization of TBDMS chitosan for synthesis of photoactive chitosan derivatives and application in photografting on ophthalmic lens material
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We have also previously reported the surface modification of IOLs and materials for IOLs to create controlled antibiotic-releasing systems for postoperative endophthalmitis prophylaxis employing plasma-assisted grafting of methacrylic monomers [35,36]. We have also performed an in vivo validation of the suitability of MFX-loaded IOLs for postoperative endophthalmitis prophylaxis [37]. Photografting of IOLs employing a methacrylic monomer has also been recently reported [38], although no drugs were included in the IOL.
Three photoactive chitosan derivatives were synthesized using TBDMS chitosan as the starting material. In this study, we also report an optimized method for producing relatively high average molecular weight chitosan precursors for the synthesis of the three N-modified chitosan derivatives having a N-azidobenzoyl group, a N-methacryloyl group and a N-azidobenzoyl-N′,N′,N′-(acetyl-trimethyl ammoniumyl) group. The methacryloyl and azidobenzoyl derivatives synthesized were photografted onto discs of a crosslinked polymethacrylate copolymer used in the industrial production of intraocular lenses (IOLs), with dimensions comparable to those of IOLs. The photografted polymethacrylate was loaded with the antibiotic moxifloxacin, allowing the creation of an antibiotic releasing system that may be further developed for an application in postoperative endophthalmitis prophylaxis.
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First author:

Helena P. Filipe, MD

Forças Armadas, Polo de Lisboa-EMGFA, Lisbon, Portugal

: Supported by Fundação para a Ciência e a Tecnologia (FCT), Portugal, through research projects M-ERA.NET/0005/2012, M-ERA.NET/0006/2012, and M-ERA.NET/0007/2012; FCT funding from unit projects UID/QUI/00100/2013 (for CQE), UID/BIM/04585/2016 (for CIIEM), UID/EMS/50022/2019 (for LAETA–IDMEC) and UID/EQU/00102/2013 (for CIEPQPF); FCT funding through personal grants SFRH/BD/52334/2013 for doctoral studies (Dr. Pimenta), SFRH/BPD/69410/2010 for postdoctoral studies (Dr. Alves), and SFRH/BPD/73367/2010 for postdoctoral studies (Dr. Coimbra). Co-funded by the European Union through QREN, POFC-COMPETE, and FEDER programs and through research project PTDC/CTM-BIO/3640/2014 (through national funds). The cost of in vivo experiments were supported by research projects 1317939 from Belgian funding agency DGO6 Wallonia, 13-1309 from the Technical Development Fund of Iceland, and an unrestricted grant from Research to Prevent Blindness, Inc., New York, USA, to the Department of Ophthalmology and Visual Sciences, University of Utah.

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Laboratory scienceMoxifloxacin-loaded acrylic intraocular lenses: In vitro and in vivo performance

Purpose

Setting

Design

Methods

Results

Conclusion

Section snippets

Sample Preparation

Characterization of the Drug-Loaded Samples

Discussion

Ophthalmology

Prog Retin Eye Res

J Control Release

J Cataract Refract Surg

J Cataract Refract Surg

J Cataract Refract Surg

Int J Pharm

Colloids Surf B Biointerfaces

Eur J Pharm Biopharm

Eur J Pharm Sci

J Cataract Refract Surg

Ophthalmology

J Cataract Refract Surg

J Cataract Refract Surg

Ophthalmic Physiol Opt

Ophthalmology

Eur J Pharm Biopharm

Global estimates of visual impairment: 2010

Br J Ophthalmol

Prophylaxis of postoperative endophthalmitis following cataract surgery: results of the ESCRS multicenter study and identification of risk factors

J Cataract Refract Surg

Laboratory science
Moxifloxacin-loaded acrylic intraocular lenses: In vitro and in vivo performance