Enhancement of corneal permeation of riboflavin-5′-phosphate through vitamin E TPGS: A promising approach in corneal trans-epithelial cross linking treatment

Ostacolo, Carmine; Caruso, Ciro; Tronino, Diana; Troisi, Salvatore; Laneri, Sonia; Pacente, Luigi; Prete, Antonio; Sacchi, Antonia

doi:10.1016/j.ijpharm.2012.09.051

Cited by 61 publications

(47 citation statements)

References 30 publications

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“…Furthermore, unless this riboflavin-rich epithelium is specifically removed prior to dissolving the sample, the concentration result will be inappropriately increased. This may have contributed to the observations described by Ostacolo et al 11 in a study in which Ribocross TE was tested using modified Franz-type diffusion cells with freshly excised porcine corneas (both with and without epithelium). After 40 minutes, riboflavin accumulation through an intact epithelium (0.394 6 0.02 nmol/mg) matched that achieved epithelium-off (0.396 6 0.03 nmol/mg).…”

Section: Discussionmentioning

confidence: 82%

“…Dissolving a full-thickness specimen, including a riboflavin-loaded epithelium and precorneal film, will lead to overestimation of corneal stromal riboflavin concentrations by HPLC. This may explain why Ostacolo et al 11 recorded only a 4-fold reduction in stromal concentration when their control riboflavin solution (i.e., no vitamin E) was applied to an intact epithelium, compared with epithelium-off application (0.098 6 0.04 nmol/mg epithelium-on; 0.396 6 0.03 nmol/mg epithelium-off). Cassagne et al 12 also used HPLC in an in vivo rabbit eye study of iontophoresis, testing both the dissolved cornea and aqueous sample.…”

Section: Discussionmentioning

confidence: 99%

“…Another method involves iontophoresis, in which negatively charged riboflavin is driven through the epithelium down an electrical gradient. [7][8][9] Previous studies to quantify riboflavin penetration through an intact epithelium have used high-performance liquid chromatography (HPLC) [10][11][12] and fluorescence microscopy. [13][14][15][16][17] High-performance liquid chromatography, in which the sample is dissolved in a solvent for analysis, can accurately quantify the concentration of riboflavin in a whole block of tissue, but is unable to provide information about the concentration at different depths within the corneal stroma (unless lamella sections are prepared and separately dissolved).…”

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confidence: 99%

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Transepithelial Riboflavin Absorption in an Ex Vivo Rabbit Corneal Model

Gore

O’Brart

French

et al. 2015

Invest. Ophthalmol. Vis. Sci.

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Citation: Gore DM, O'Brart D, French P, Dunsby C, Allan BD. Transepithelial riboflavin absorption in an ex vivo rabbit corneal model. Invest Ophthalmol Vis Sci. 2015;56:5006-5011. DOI:10.1167/iovs.15-16903 PURPOSE. To measure depth-specific riboflavin concentrations in corneal stroma using twophoton fluorescence microscopy and compare commercially available transepithelial corneal collagen cross-linking (CXL) protocols. METHODS.Transepithelial CXL riboflavin preparations-MedioCross TE, Ribocross TE, Paracel plus VibeX Xtra, and iontophoresis with Ricrolinþ-were applied to the corneal surface of fresh postmortem rabbit eyes in accordance with manufacturers' recommendations for clinical use. Riboflavin 0.1% (VibeX Rapid) was applied after corneal epithelial debridement as a positive control. After riboflavin application, eyes were snap frozen in liquid nitrogen. Corneal cross sections 35-lm thick were cut on a cryostat, mounted on a slide, and imaged by two-photon fluorescence microscopy. Mean (SD) concentrations were calculated from five globes tested for each protocol.RESULTS. Peak riboflavin concentration of 0.09% (60.01) was observed within the most superficial stroma (stromal depth 0-10 lm) in positive controls (epithelium-off). At the same depth, peak stromal riboflavin concentrations for MedioCross TE, Ricrolinþ, Paracel/Xtra, and Ribocross TE were 0.054% (60.01), 0.031% (0.003), 0.021% (60.001), and 0.015% (60.004), respectively. At a depth of 300 lm (within the demarcation zone commonly seen after corneal cross-linking), the stromal concentration in epithelium-off positive controls was 0.075% (60.006), while at the same depth MedioCross TE and Ricrolinþ achieved 0.018% (60.006) and 0.016% (0.002), respectively. None of the remaining transepithelial protocols achieved concentrations above 0.005% at this same 300-lm depth. Overall, MedioCross TE was the best-performing transepithelial formulation.CONCLUSIONS. Corneal epithelium is a significant barrier to riboflavin absorption into the stroma. Existing commercial transepithelial CXL protocols achieve relatively low riboflavin concentrations in the anterior corneal stroma when compared to gold standard epithelium-off absorption. Reduced stromal riboflavin concentration may compromise the efficacy of riboflavin/ultraviolet corneal CXL.

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Section: Discussionmentioning

confidence: 82%

Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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Transepithelial Riboflavin Absorption in an Ex Vivo Rabbit Corneal Model

Gore

O’Brart

French

et al. 2015

Invest. Ophthalmol. Vis. Sci.

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“…In addition, overexpression of this protein has also long been known to play a central role in the development of multi-drug resistant cancer ( 54 ). Inhibitors of P-gp are well-documented to improve drug delivery across biological barriers ( 55,56 ), enhance bioavailability of orally administered therapeutics ( 57 ), and overcome multi-drug resistant cancers ( 58 ). For these reasons there has been considerable interest in the development of well-tolerated P-gp inhibitors ( 49 ).…”

Section: Modulation Of the Mdp By ␣ -Tocopherol And ␣ -Tocopherol Sucmentioning

confidence: 99%

α-Tocopherols modify the membrane dipole potential leading to modulation of ligand binding by P-glycoprotein

Davis

Richens

et al. 2015

Journal of Lipid Research

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“…Along with that stiffening cross-linking causes actual keratocyte destruction, swelling and corneal stromal remodeling in living corneas. 19,20 Ribofl avin presently is critical to the cross-linking process and ribofl avin penetrates poorly 21 through an intact corneal epithelium, however much work is occurring to increase the epithelial permeability including recently the addition on an experimental basis of vitamin E TPGS to the ribofl avin solution 22 .…”

mentioning

confidence: 99%

Abbreviated UVA-riboflavin corneal collagen cross-linking for keratoconus and post-LASIK ectasia

Epstein¹,

Epstein²

2013

Scripta Medica

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Introduction. To determine the effect of corneal collagen cross-linking treatment on keratoconus and post-LASIK ectasia particularly after an abbreviated exposure to ultraviolet light exposure. Materials and methods. Fifty-one eyes of 34 patients were treated with epithelium-off UVA-ribofl avin corneal collagen cross-linking for either 20 minutes or 30 minutes as part of a US.FDA clinical study. The study involved eyes with keratoconus but with no prior operation (virginal), patients who had undergone prior intracorneal ring segments, those with keratoconus regression after keratoplasty, and those with post-LASIK ectasia. We report follow up results from three months to one year. Results. In the virginal keratoconus group all 83% of eyes having 20-minute UVA exposure and 75% of those having 30-minute of UVA exposure experienced corneal fl attening or stabilization at 6 months post-operatively with visual improvement in both groups. The average patient age in the virginal keratoconus group was 34.5 years. Seventy fi ve percent of virginal keratoconus eyes of patients under age 40 but only 33% of eyes of patients over age 40 experienced statistically signifi cant corneal fl attening at six months postoperatively. Average vision improved at six months post-operatively over pre-operative levels by-0.0744 logMAR units in the 20 minute group, and by-0.0869 logMAR units in the 30 minute group. Post-LASIK ectasia patients, with an average age of 58.2 years, had slight overall curvature fl attening of-0.75D but without visual improvement one year post-operatively. No one experienced peri-operative complications. Topographic subtraction mapping revealed variations in the power of the cross-linking effect on different portions of the cornea Conclusion. Cross-linking appears safe. It is effective in most young patients causing corneal fl attening and can stabilize eyes with post LASIK ectasia but acts more slowly in older patients. The cross-linking effect may be more pronounced in individuals with darker pigmentation. Cross-linking can produce occasional very signifi cant corneal fl attening. The cross-linking effect increases with time.

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Enhancement of corneal permeation of riboflavin-5′-phosphate through vitamin E TPGS: A promising approach in corneal trans-epithelial cross linking treatment

Cited by 61 publications

References 30 publications

Transepithelial Riboflavin Absorption in an Ex Vivo Rabbit Corneal Model

Transepithelial Riboflavin Absorption in an Ex Vivo Rabbit Corneal Model

α-Tocopherols modify the membrane dipole potential leading to modulation of ligand binding by P-glycoprotein

Abbreviated UVA-riboflavin corneal collagen cross-linking for keratoconus and post-LASIK ectasia

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