Ophthalmic Econazole Hydrogels for the Treatment of Fungal Keratitis

Díaz-Tomé, Victoria; Luaces-Rodríguez, Andrea; Silva‐Rodríguez, Jesús; Blanco‐Dorado, Sara; García-Quintanilla, Laura; Llovo-Taboada, José; Blanco-Méndez, J.; García-Otero, Xurxo; Varela-Fernández, Rubén; Herranz, Míchel; Gil-Martínez, María; Lamas, María Jesús; González‐Barcia, Miguel; Otero-Espinar, Francisco J.; Fernández‐Ferreiro, Anxo

doi:10.1016/j.xphs.2017.12.028

Cited by 43 publications

(21 citation statements)

References 34 publications

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“…Previous to the preparation of the poly(pseudo)rotaxanes, the capability of αCD to form an inclusion complex with natamycin, which is more soluble than free natamycin, was verified. The information available on the use of αCD to solubilize ocular antifungal drugs is so far very limited [41]. The apparent solubility of natamycin in aqueous 5% and 10% ( w / v ) αCD solutions was determined to be 103.7 ± 1.4 µg/mL and 143.5 ± 4.6 µg/mL in 0.9% NaCl medium, and 96.4 ± 2.9 µg/mL and 126.6 ± 0.4 µg/mL in pH 6.4 buffer, respectively (Figure S3 in the Supplementary Material).…”

Section: Resultsmentioning

confidence: 99%

Cyclodextrin–Amphiphilic Copolymer Supramolecular Assemblies for the Ocular Delivery of Natamycin

et al. 2019

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Natamycin is the only drug approved for fungal keratitis treatment, but its low water solubility and low ocular penetration limit its efficacy. The purpose of this study was to overcome these limitations by encapsulating the drug in single or mixed micelles and poly(pseudo)rotaxanes. Soluplus and Pluronic P103 dispersions were prepared in 0.9% NaCl and pH 6.4 buffer, with or without α-cyclodextrin (αCD; 10% w/v), and characterized through particle size, zeta potential, solubilization efficiency, rheological properties, ocular tolerance, in vitro drug diffusion, and ex vivo permeation studies. Soluplus micelles (90–103 nm) and mixed micelles (150–110 nm) were larger than Pluronic P103 ones (16–20 nm), but all showed zeta potentials close to zero. Soluplus, Pluronic P103, and their mixed micelles increased natamycin solubility up to 6.00-fold, 3.27-fold, and 2.77-fold, respectively. Soluplus dispersions and poly(pseudo)rotaxanes exhibited in situ gelling capability, and they transformed into weak gels above 30 °C. All the formulations were non-irritant according to Hen’s Egg Test on the Chorioallantoic Membrane (HET-CAM) assay. Poly(pseudo)rotaxanes facilitated drug accumulation into the cornea and sclera, but led to lower natamycin permeability through the sclera than the corresponding micelles. Poly(pseudo)rotaxanes made from mixed micelles showed intermediate natamycin diffusion coefficients and permeability values between those of Pluronic P103-based and Soluplus-based poly(pseudo)rotaxanes. Therefore, the preparation of mixed micelles may be a useful tool to regulate drug release and enhance ocular permeability.

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Section: Resultsmentioning

confidence: 99%

Cyclodextrin–Amphiphilic Copolymer Supramolecular Assemblies for the Ocular Delivery of Natamycin

et al. 2019

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“…Cyclosporine and dexamethasone are topically administered for the treatment of different inflammatory diseases affecting the surface of the eye, but they are also successfully used in the treatment of posterior eye diseases [6,23,24]. Econazole is used primarily for the treatment of mycosis of the surface of the eye [25,26,27]; additionally, some researchers provided the proof of principle of a potential application in reducing vascular loss and progression of age-related macular degeneration (AMD) [28].…”

Section: Introductionmentioning

confidence: 99%

Ex Vivo Conjunctival Retention and Transconjunctival Transport of Poorly Soluble Drugs Using Polymeric Micelles

et al. 2019

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This paper addresses the problem of ocular delivery of lipophilic drugs. The aim of the paper is the evaluation of polymeric micelles, prepared using TPGS (d-α-Tocopheryl polyethylene glycol 1000 succinate), a water-soluble derivative of Vitamin E and/or poloxamer 407, as a vehicle for the ocular delivery of dexamethasone, cyclosporine, and econazole nitrate. The research steps were: (1) characterize polymeric micelles by dynamic light scattering (DLS) and X-ray scattering; (2) evaluate the solubility increase of the three drugs; (3) measure the in vitro transport and conjunctiva retention, in comparison to conventional vehicles; (4) investigate the mechanisms of enhancement, by studying drug release from the micelles and transconjunctival permeation of TPGS; and (5) study the effect of micelles application on the histology of conjunctiva. The data obtained demonstrate the application potential of polymeric micelles in ocular delivery, due to their ability to increase the solubility of lipophilic drugs and enhance transport in and across the conjunctival epithelium. The best-performing formulation was the one made of TPGS alone (micelles size ≈ 12 nm), probably because of the higher mobility of these micelles, an enhanced interaction with the conjunctival epithelium, and, possibly, the penetration of intact micelles.

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“…Formulation for aqueous and oil suspension and preparations for topical and local application of statins are available [41]. Ophthalmic formulation has also been developed to topically administer econazole having poor aqueous solubility [42]. These studies lend support to the potential use of HMGR and CYP51 inhibitors as topical agents in the treatment of AK.…”

Section: Effect Of Combination Of Pitavastatin and Isavuconazolementioning

confidence: 99%

In Vitro Effect of Pitavastatin and Its Synergistic Activity with Isavuconazole against Acanthamoeba castellanii

et al. 2020

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Acanthamoeba keratitis (AK) can occur in healthy individuals wearing contact lenses and it is a painful, blinding infection of the cornea caused by a free-living ameba Acanthamoeba. Current treatment for AK relies on a combination of chlorhexidine, propamidine isethionate, and polyhexamethylene biguanide. However, the current regimen includes an aggressive disinfectant and in 10% of cases recurrent infection ensues. Therefore, development of efficient and safe drugs is a critical unmet need to avert blindness. Acanthamoeba sterol biosynthesis includes two essential enzymes HMG-CoA reductase (HMGR) and sterol 14-demethylase (CYP51), and we earlier identified a CYP51 inhibitor isavuconazole that demonstrated nanomolar potency against A. castellanii trophozoites. In this study, we investigated the effect of well-tolerated HMGR inhibitors and identified pitavastatin that is active against trophozoites of three different clinical strains of A.castellanii. Pitavastatin demonstrated an EC50 of 0.5 to 1.9 µM, depending on strains. Combination of pitavastatin and isavuconazole is synergistic and led to 2- to 9-fold dose reduction for pitavastatin and 11- to 4000-fold dose reduction for isavuconazole to achieve 97% of growth inhibition. Pitavastatin, either alone or in combination with isavuconazole, may lead to repurposing for the treatment of Acanthamoeba keratitis.

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Ophthalmic Econazole Hydrogels for the Treatment of Fungal Keratitis

Cited by 43 publications

References 34 publications

Cyclodextrin–Amphiphilic Copolymer Supramolecular Assemblies for the Ocular Delivery of Natamycin

Cyclodextrin–Amphiphilic Copolymer Supramolecular Assemblies for the Ocular Delivery of Natamycin

Ex Vivo Conjunctival Retention and Transconjunctival Transport of Poorly Soluble Drugs Using Polymeric Micelles

In Vitro Effect of Pitavastatin and Its Synergistic Activity with Isavuconazole against Acanthamoeba castellanii

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