Determination of permeability coefficients of ophthalmic drugs through different layers of porcine, rabbit and bovine eyes

Loch, Christian; Žakelj, Simon; Kristl, Albin; Nagel, Stefan; Guthoff, Rudolf; Weitschies, Werner; Seidlitz, Anne

doi:10.1016/j.ejps.2012.05.007

Cited by 76 publications

(64 citation statements)

References 30 publications

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“…Although there is no scientific evidence of which is best animal model for the study of corneal permeability, the thickness seems to play an important role. When considering the treatment of thin human corneas, as in keratoconus, the rabbit model may be suitable [42]. To limit corneal edema and the resulting increase in corneal thickness, only fresh eyes less than 6 h after euthanization were used for measurements.…”

Section: Discussionmentioning

confidence: 99%

Corneal Absorption of a New Riboflavin-Nanostructured System for Transepithelial Collagen Cross-Linking

et al. 2013

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Corneal collagen cross-linking (CXL) has been described as a promising therapy for keratoconus. According to standard CXL protocol, epithelium should be debrided before treatment to allow penetration of riboflavin into the corneal stroma. However, removal of the epithelium can increase procedure risks. In this study we aim to evaluate stromal penetration of a biocompatible riboflavin-based nanoemulsion system (riboflavin-5-phosphate and riboflavin-base) in rabbit corneas with intact epithelium. Two riboflavin nanoemulsions were developed. Transmittance and absorption coefficient were measured on corneas with intact epithelia after 30, 60, 120, 180, and 240 minutes following exposure to either the nanoemulsions or standard 0.1% or 1% riboflavin-dextran solutions. For the nanoemulsions, the epithelium was removed after measurements to assure that the riboflavin had passed through the hydrophobic epithelium and retained within the stroma. Results were compared to de-epithelialized corneas exposed to 0.1% riboflavin solution and to the same riboflavin nanoemulsions for 30 minutes (standard protocol). Mean transmittance and absorption measured in epithelialized corneas receiving the standard 0.1% riboflavin solution did not reach the levels found on the debrided corneas using the standard technique. Neither increasing the time of exposure nor the concentration of the riboflavin solution from 0.1% to 1% improved riboflavin penetration through the epithelium. When using riboflavin-5-phosphate nanoemulsion for 240 minutes, we found no difference between the mean absorption coefficients to the standard cross-linking protocol (p = 0.54). Riboflavin nanoemulsion was able to penetrate the corneal epithelium, achieving, after 240 minutes, greater stromal concentration when compared to debrided corneas with the standard protocol (p = 0.002). The riboflavin-5-phosphate nanoemulsion diffused better into the stroma than the riboflavin-base nanoemulsion.

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Section: Discussionmentioning

confidence: 99%

Corneal Absorption of a New Riboflavin-Nanostructured System for Transepithelial Collagen Cross-Linking

et al. 2013

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“…The baseline P app of LC, BA and FD-4 used as model permeants in present study was close to the values reported in previous studies, and the IP permeation experiment considered as suitable. [29][30][31][32] Both LC and BA fluxes across the cornea and conjunctiva were increased by the current application and returned to baseline after stopping the current application. LC and BA fluxes in the cornea were increased 2.27-and 2.45-fold compared with baseline by a current application up to 5.0 and 2.0 mA/cm 2 in a current-dependent manner, respectively (Table 1A).…”

Section: Effect Of Electric Current On the Permeation Of Lc Ba And Fmentioning

confidence: 93%

Characterization of Ocular Iontophoretic Drug Transport of Ionic and Non-ionic Compounds in Isolated Rabbit Cornea and Conjunctiva

Sekijima

Ehara

Hanabata

et al. 2016

Biological & Pharmaceutical Bulletin

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Ocular iontophoresis (IP) in isolated rabbit cornea and conjunctiva was examined in terms of transport enhancement, tissue viability and integrity using electrophysiological parameters by the Ussing-type chamber technique. Lidocaine hydrochloride (LC, a cationic compound), sodium benzoate (BA, anionic compound), and fluorescein isothiocyanate labeled dextran (molecular weight 4400 Da, FD-4, hydrophilic large compound) were used as model permeants. Direct electric current was applied at 0.5-5.0 mA/cm 2 for the cornea and 0.5-20 mA/cm 2 for the conjunctiva for 30 min. LC and BA fluxes across the cornea and conjunctiva were significantly increased by the application of electric current up to 2.3-and 2.5-fold and 4.0-and 3.4-fold, respectively, and returned to their baseline level on stopping the current. Furthermore, a much higher increase by IP application was obtained for the FD-4 transport. The increased FD-4 flux in the conjunctiva returned to baseline on stopping the current, whereas the flux in the cornea was sustained at a higher level after stopping the current. The transepithelial electric resistance of the cornea and conjunctiva was lowered by electric current application but fully recovered after stopping the current up to 2.0 mA/cm 2 for the cornea and 10 mA/cm 2 for the conjunctiva, suggesting that the corneal and conjunctival viability and integrity are maintained even after application of these current densities. These results indicate that ocular IP may be a useful non-invasive technique to achieve drug delivery of hydrophilic large molecules into the eyes.Key words ocular drug delivery; physical enhancement; iontophoresis; electric current; cornea; conjunctiva Eye drops are used for treatment of ocular diseases and the drugs applied by the eye drops distribute onto the ocular surface, then penetrate into the eye through the ocular surface tissues such as cornea and conjunctiva.1) In spite of the simple and convenient dosage form of eye drops, elimination and dilution of drugs by turn-over of tear fluid and the low permeability of the surface ocular tissues are major challenges that limit the absorption of an effective amount of drugs into the eyes.2) Thus, approaches to increase drug absorption into the eyes have attracted much attention. One includes chemical approaches such as the use of prodrugs, liposomes, cyclodextrins, and chemical enhancers, while others include physical approaches such as iontophoresis (IP) and sonophoresis. 3,4)IP is known as an useful technique to increase the penetration of ionic and non-ionic compounds into the body across surface epithelial tissues including skin and the ocular surface. 5,6)This technique has a potential to regulate the drug delivery depending upon the applied current density and application time and, thus, provides an ON/OFF control. A number of in vivo ocular IP studies have shown that application of IP increases the drug concentration in the aqueous and vitreous humors compared to instillation with gentamicin, 7-9) vancomycin, 10) tobramycin, 11,12)...

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“…7,49 In fact, less than 5% of drug applied topically reaches its target tissue within the eye, which necessitates the frequent dosing (up to 3 times daily) required for most topical ocular drugs. 50,[59][60][61] Many factors, including ocular anatomy, blinking, and tear film, limit the bioavailability of topical ocular drugs. 50,51,62,63 Additionally, a significant portion of drug (~80%) may be absorbed by blood vessels in the conjunctiva, passing into systemic circulation to cause adverse off-target effects.…”

Section: Discussionmentioning

confidence: 99%

Nanosponge-Mediated Drug Delivery Lowers Intraocular Pressure

Lambert

Carlson

Ende

et al. 2015

Trans. Vis. Sci. Tech.

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Purpose: We examined the efficacy of an extended-release drug delivery system, nanosponge (NS) encapsulated compounds, administered intravitreally to lower intraocular pressure (IOP) in mice.Methods: Bilateral ocular hypertension was induced in mice by injecting microbeads into the anterior chamber. Hypertensive mice received NS loaded with ocular hypotensive drugs via intravitreal injection and IOP was monitored. Retinal deposition and retinal ganglion cell (RGC) uptake of Neuro-DiO were examined following intravitreal injection of Neuro-DiO-NS using confocal microscopy.Results: Brimonidine-loaded NS lowered IOP 12% to 30% for up to 6 days (P , 0.02), whereas travoprost-NS lowered IOP 19% to 29% for up to 4 days (P , 0.02) compared to saline injection. Three bimatoprost NS were tested: a 400-nm NS and two 700-nm NS with amorphous (A-NS) or amorphous/crystalline (AC-NS) crosslinkers. A single injection of 400 nm NS lowered IOP 24% to 33% for up to 17 days compared to saline, while A-NS and AC-NS lowered IOP 22% to 32% and 18% to 26%, respectively, for up to 32 days (P , 0.046). Over time retinal deposition of Neuro-DiO increased from 19% to 71%; Neuro-DiO released from NS was internalized by RGCs.Conclusions: A single injection of NS can effectively deliver ocular hypotensive drugs in a linear and continuous manner for up to 32 days. Also, NS may be effective at targeting RGCs, the neurons that degenerate in glaucoma.Translational Relevance: Patient compliance is a major issue in glaucoma. The use of NS to deliver a controlled, sustained release of therapeutics could drastically reduce the number of patients that progress to vision loss in this disease.

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Determination of permeability coefficients of ophthalmic drugs through different layers of porcine, rabbit and bovine eyes

Cited by 76 publications

References 30 publications

Corneal Absorption of a New Riboflavin-Nanostructured System for Transepithelial Collagen Cross-Linking

Corneal Absorption of a New Riboflavin-Nanostructured System for Transepithelial Collagen Cross-Linking

Characterization of Ocular Iontophoretic Drug Transport of Ionic and Non-ionic Compounds in Isolated Rabbit Cornea and Conjunctiva

Nanosponge-Mediated Drug Delivery Lowers Intraocular Pressure

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