Improvement of the Ocular Bioavailability of Econazole Nitrate upon Complexation with Cyclodextrins

El-Gawad, A. Abd; Soliman, Osama A.; El-Dahan, Marwa Salah; Al-Zuhairy, Saeed A S

doi:10.1208/s12249-016-0609-9

Cited by 26 publications

(19 citation statements)

References 49 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…As such, Larsen and colleagues showed that different CD based formulations of prednisolone are able to improve the drug solubility, increase drug concentration and in turn, ameliorate bioavailability [ 32 ]. Further, an in vivo study in rabbits by El-Gawad and colleagues reported that eye drop formulations containing CD/econazole complexes showed higher ocular bioavailability than econazole alone, indicated by higher AUC, C max , and relative bioavailability values [ 33 ]. Comparable observations have been reported by Abdelkader et al, where a diclofenac complex with CD has been reported to feature a higher transfer rate through the cornea compared to free drug administration [ 34 ].…”

Section: Discussionmentioning

confidence: 99%

Bio-Distribution and Pharmacokinetics of Topically Administered γ-Cyclodextrin Based Eye Drops in Rabbits

et al. 2021

View full text Add to dashboard Cite

The purpose of this study was to evaluate the ocular pharmacokinetics, bio-distribution and local tolerability of γ-cyclodextrin (γCD) based irbesartan 1.5% eye drops and candesartan 0.15% eye drops after single and multiple topical administration in rabbit eyes. In this randomized, controlled study, a total number of 59 New Zealand White albino rabbits were consecutively assigned to two study groups. Group 1 (n = 31) received irbesartan 1.5% and group 2 (n = 28) candesartan 0.15% eye drops. In both groups, single dose and multiple administration pharmacokinetic studies were performed. Rabbits were euthanized at five predefined time points after single-dose administration, whereas multiple-dose animals were dosed for 5 days twice-daily and then euthanized 1 h after the last dose administration. Drug concentration was measured by using liquid chromatography-tandem mass spectrometry (LC-MS/MS) in the retinal tissue, vitreous humor, aqueous humor, corneal tissue and in venous blood samples. Pharmacokinetic parameters including maximal drug concentration (Cmax), time of maximal drug concentration (Tmax), half-life and AUC were calculated. To assess local tolerability, six additional rabbits received 1.5% irbesartan eye drops twice daily in one eye for 28 days. Tolerability was assessed using a modified Draize test and corneal sensibility by Cochet Bonnet esthesiometry. Both γCD based eye drops were rapidly absorbed and distributed in the anterior and posterior ocular tissues. Within 0.5 h after single administration, the Cmax of irbesartan and candesartan in retinal tissue was 251 ± 142 ng/g and 63 ± 39 ng/g, respectively. In the vitreous humor, a Cmax of 14 ± 16 ng/g for irbesartan was reached 0.5 h after instillation while Cmax was below 2 ng/g for candesartan. For multiple dosing, the observed Cmean in retinal tissue was 338 ± 124 ng/g for irbesartan and 36 ± 10 ng/g for candesartan, whereas mean vitreous humor concentrations were 13 ± 5 ng/g and <2 ng/g, respectively. The highest plasma concentrations of both irbesartan (Cmax 5.64 ± 4.08 ng/mL) and candesartan (Cmax 4.32 ± 1.04 ng/mL) were reached 0.5 h (Tmax) after single administration. Local tolerability was favorable with no remarkable differences between the treated and the control eyes. These results indicate that irbesartan and candesartan in γCD based nanoparticle eye drops can be delivered to the retinal tissue of the rabbit’s eye in pharmacologically relevant concentrations. Moreover, safety and tolerability profiles appear to be favorable in the rabbit animal model.

show abstract

Section: Discussionmentioning

confidence: 99%

Bio-Distribution and Pharmacokinetics of Topically Administered γ-Cyclodextrin Based Eye Drops in Rabbits

et al. 2021

View full text Add to dashboard Cite

show abstract

“…Econazole and miconazole are imidazole compounds with potent antifungal properties, and that differ from each other by one chlorine atom 21 . Both drugs are commonly employed antifungals that are delivered topically for dermal or vaginal fungal infections as an ointment or cream, but both can also be applied orally, and econazole is well tolerated in an eyedrop formulation with cyclodextrin 22 . Moreover, intravitreal injection of other miconazole and ketoconazole at substantially higher doses do not result in retinal toxicity 23 , 24 .…”

Section: Discussionmentioning

confidence: 99%

Imidazole Compounds for Protecting Choroidal Endothelial Cells from Complement Injury

Zeng

Wen

Workalemahu

et al. 2018

Sci Rep

View full text Add to dashboard Cite

Age-related macular degeneration (AMD) is a common, blinding disease associated with increased complement system activity. Eyes with AMD show elevated accumulation of the membrane attack complex (MAC) in the choriocapillaris and degeneration of macular choriocapillaris endothelial cells (ECs). Thus, one could reasonably conclude that the endothelial cell death that occurs in AMD is due to injury by the MAC. We therefore sought to identify strategies for protecting ECs against MAC lysis. RF/6A endothelial cells were pre-incubated with a library of FDA-approved small molecules, followed by incubation with complement intact human serum quantification of cell death. Two closely related molecules identified in the screen, econazole nitrate and miconazole nitrate, were followed in validation and mechanistic studies. Both compounds reduced lysis of choroidal ECs treated with complement-intact serum, across a range of doses from 1 to 100 µM. Cell rescue was confirmed in mouse primary choroidal ECs. Both exosome release and cell surface roughness (assessed using a Holomonitor system) were reduced by drug pretreatment in RF/6A cells, whereas endosome formation increased with both drugs, consistent with imidazole-mediated alterations of cell surface dynamics. The results in the current study provide further proof of principle that small molecules can protect choroidal ECs from MAC-induced cell death and suggest that FDA approved compounds may be beneficial in reducing vascular loss and progression of AMD.

show abstract

“…These molecules are the β-CD [7], the γ-CD [8], its CD derivatives (hydroxypropyl-beta-cyclodextrin (HP-β-CD)), and the randomly methylated beta-cyclodextrin (RM-β-CD) [118]. Econazole nitrate (EC) and CD/ HP-β-CD were complexed to form different EC-CD inclusion complexes through coprecipitation in order to improve ocular bioavailability [119].…”

Section: Cyclodextrin Nanoparticlesmentioning

confidence: 99%

Breaking down the Barrier: Topical Liposomes as Nanocarriers for Drug Delivery into the Posterior Segment of the Eyeball

Santos¹,

Altamirano-Vallejo²,

Navarro-Partida³

et al. 2020

Role of Novel Drug Delivery Vehicles in Nanobiomedicine

View full text Add to dashboard Cite

Topical instillation is the most widely preferred noninvasive route of drug administration to treat diseases affecting the anterior segment of the eye. Nonetheless, the ocular bioavailability for deeper ocular tissues is very low. Different routes of administration, such as intravitreal injections, periocular injections, and systemic administration, have been used to deliver drugs into the posterior segment ocular tissues. However, the presence of blood-retinal barriers (BRBs) makes systemic administration an impractical approach, whereas the drug delivery with the periocular administration route is compromised by ocular static and dynamic barriers. On the other hand, intravitreal injection, the most common and widely recommended route for drug administration to treat posterior ocular diseases, is related to several side effects such as endophthalmitis, hemorrhage, retinal detachment, and poor patient tolerance. Diverse strategies to overcome ocular barriers have been explored for topical drop formulations in order to deliver drugs into the posterior segment ocular tissues. In this chapter, we will review the promising topical nanocarriers for drug delivery into the posterior segment of the eye, emphasizing the use of liposomes for topical ophthalmic formulations targeting the vitreous cavity and the retina.

show abstract

Improvement of the Ocular Bioavailability of Econazole Nitrate upon Complexation with Cyclodextrins

Cited by 26 publications

References 49 publications

Bio-Distribution and Pharmacokinetics of Topically Administered γ-Cyclodextrin Based Eye Drops in Rabbits

Bio-Distribution and Pharmacokinetics of Topically Administered γ-Cyclodextrin Based Eye Drops in Rabbits

Imidazole Compounds for Protecting Choroidal Endothelial Cells from Complement Injury

Breaking down the Barrier: Topical Liposomes as Nanocarriers for Drug Delivery into the Posterior Segment of the Eyeball

Contact Info

Product

Resources

About