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Controlled delivery of pirfenidone through vitamin E-loaded contact lens ameliorates corneal inflammation

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Abstract

Chemical injury by alkali burn is a major cause of corneal blindness in the clinical setting. Current management advocates multiple therapies aimed to prevent inflammation, initiate quick re-epithelialization, arrest the fibrosis, and avoid dry eye and pain by using bandage contact lenses. We hypothesized sustained delivery of the anti-inflammatory, antifibrotic drug pirfenidone through vitamin E-loaded contact lenses as a logical single approach to counter the pathology involved. Vitamin E particles were created in situ in commercial silicon hydrogel contact lenses by soaking the lenses in a vitamin E-ethanol solution. The vitamin E-laden lenses were then placed into pirfenidone-saline solution to load the drug into the lens. The contact lenses were evaluated by both in vitro and in vivo means. For in vitro, lenses were placed into 3 mL of saline solution. The concentration of pirfenidone released was measured by UV-vis spectrophotometry. The contact lenses were implanted in rabbit eyes following the alkali burn; the drug availability in the aqueous humor was evaluated by HPLC at various time points 10 min, 30 min, 2 h, and 3 h; and gene expression of inflammatory cytokines IL-1β, TNF-α, and TGF-β1 was evaluated in the cornea at the end of the study period. In another group of rabbits inflicted with alkali injury, the corneas were graded after 7 days of contact lens implantation with and without pirfenidone. A mathematical model was developed for delivery of the drug to the cornea and aqueous humor after a contact lens is inserted in the eye. The model was validated with experimental data and used to determine the bioavailability both for contact lenses and eye drops. In vitro release of unmodified commercial contact lenses saw a release time of approximately 20 min, with a partition coefficient of 2.68 ± 0.06. The release of pirfenidone from 20% vitamin E-loaded lenses saw a release time of approximately 80 min, with a partition coefficient of 4.20 ± 0.04. In vivo, the drug was available in the aqueous humor for up to 3 h. Gene expression of inflammatory cytokine IL-β1 and profibrotic growth factor TGF-β1 was significantly suppressed in corneas treated with pirfenidone contact lenses. A week after the alkali burn, the eyes with pirfenidone contact lenses showed significant improvement in corneal haze in comparison to the control eyes. About 50% of the drug loaded in the lens reached the aqueous humor compared to 1.3% with eye drops. Vitamin E-loaded contact lenses serve as a suitable platform for delivery of pirfenidone following alkali burn in rabbit eyes; positive pre-clinical outcome identifies it as promising therapy for addressing corneal inflammation and fibrosis. The bioavailability is about 40-fold higher for contact lenses compared to that for eye drops.

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  • 22 September 2018

    In the original article the typesetter made several errors. Figures 7 and 9 are incorrect. Following are the correct figures:

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Acknowledgements

We acknowledge the fund received from the Department of Science and Technology, Govt of India; West Bengal University of Animal & Fishery Sciences; CSIR-IICB; and the Dept of Chemical Engineering, University of Florida, for providing the necessary infrastructure.

Nomenclature

α, aspect ratio of barrier; φ, vitamin E loading in lens; φ∗, absorbed vitamin E in lens; τ, time scales of pirfenidone release of vitamin E loaded; τ0, time scales of pirfenidone release of control lens; Aconjunctiva, area of conjunctiva; As, surface area of contact lens; Caq, concentration of pirfenidone in aqueous humor/cornea system; Cg, concentration of pirfenidone in contact lens; Cg, f, concentration of pirfenidone in contact lens after loading; Cg, i, concentration of pirfenidone in contact lens after loading; Cl, f concentration of pirfenidone in loading solution; C0, concentration at time zero for tear film after the elution of the eye drop; Cr, concentration of pirfenidone in release medium; Cr, f, final concentration of release medium; Ctear, concentration of pirfenidone in tear film; D, diffusion coefficient of gel; f, fraction of drug released from the lens that reaches the cornea; feye drops, bioavailability of eye drops; h, half thickness of contact lens; hc, thickness of cornea; hPOLTF, thickness of tear film; ja, flux of pirfenidone into cornea; jlens, flux of pirfenidone from lens; Kg, partition coefficient of pirfenidone in contact lens; Kconjunctiva, permeability of pirfenidone in conjunctiva; Kcornea, permeability of pirfenidone in cornea; Mo, total mass of pirfenidone in an eye drop; qaq, volumetric drainage rate from aqueous humor/cornea system; qtear, drainage rate of tear film; t, time; td, diffusion time of pirfenidone in contact lens; td, aq, diffusion time of pirfenidone in aqueous humor; td, tear, diffusion time of pirfenidone in tear film; tq, aq, time scale of drainage from aqueous humor; tq, tear, time scale of drainage from tear film; Vaq, volume of aqueous humor and cornea; Vg, volume of contact lens; Vr, volume of release medium; Vtear, volume of tear film; y, axis of thickness

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Authors and Affiliations

  1. Department of Chemical Engineering, University of Florida, 1030 Center Drive, Gainesville, FL, 32611, USA

    Phillip Dixon & Anuj Chauhan

  2. Department of Veterinary Surgery & Radiology, West Bengal University of Animal & Fishery Sciences, 37&68 Khudiram Bose Sarani, Kolkata, India

    Tanushri Ghosh & Sarbani Hazra

  3. CSIR-IICB, Jadavpur, Kolkata, India

    Kalyani Mondal & Aditya Konar

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  1. Phillip Dixon
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Correspondence to Sarbani Hazra.

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Dixon, P., Ghosh, T., Mondal, K. et al. Controlled delivery of pirfenidone through vitamin E-loaded contact lens ameliorates corneal inflammation. Drug Deliv. and Transl. Res. 8, 1114–1126 (2018). https://doi.org/10.1007/s13346-018-0541-5

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