Investigation of Combined Cyclodextrin and Hydrogel Formulation for Ocular Delivery of Dexamethasone Acetate by Means of Experimental Designs

Roseline Mazet,Denis Wouessidjewe,Luc Choisnard,Delphine Levilly,Annabelle Gèze

doi:10.3390/pharmaceutics10040249

Abstract

Dexamethasone acetate (DXMa) has proven its efficiency to treat corneal inflammation, without a great propensity to increase intraocular pressure. Unfortunately, its poor aqueous solubility, associated with a rapid precorneal elimination, results in a low drug bioavailability and a low penetration after topical ocular administration. The main objective of this study was to improve the apparent aqueous solubility of DXMa using cyclodextrins. First, hydroxypropyl-β-CD (HPβCD) and hydroxypropyl-γ-CD (HPγCD) were used to enhance DXMa concentration in aqueous solution. The β and γ HPCD derivatives allowed the increase of the DXMa amount in solution at 25 °C by a factor of 500 and 1500, respectively. Second, with the aim of improving the persistence of the complex solution after instillation in the eye, the formulations of DXMa-based CD solutions with marketed ophthalmic gels (CELLUVISC®, GEL-LARMES®, and VISMED®) were investigated and optimized by means of special cubic mixture designs, allowing the defining of mixed gels loaded with 0.7% (HPβCD) and 2% (HPγCD) DXMa with osmolality within acceptable physiological range. Finally, in vitro drug release assays from the mixed gels were performed and compared with reference eye drops. Similarly to MAXIDEX® and DEXAFREE®, in the case of mixed gel containing HPβCD, more than 90% of the drug was released within 2 h, while in mixed gel containing HPγCD, the release of DXMa was partial, reaching ≈60% in 2 h. This difference will have to be further addressed with ex vivo and in vivo ocular delivery experiments.

Highlights

Ocular inflammation is the consequence of many potential eye disorders among which uveitis is believed to be the cause of about 10% of the cases of severe visual handicap in the United States [1].Topical administration of anti-inflammatory drugs, steroidal (SAID) and non steroidal (NSAID), is the most frequently used method to treat ocular surface and anterior segment inflammation as it presents an easy accessibility, a simplicity of use, a non invasive way, and generally a good tolerance
Dexamethasone acetate (DXMa), a poorly water-insoluble steroid, was selected in this study to be formulated for topical ocular administration
High drug contents in aqueous solution were achieved by using HPβCD or HPγCD at a concentration of 600 mg/mL, allowing the increase by a factor of around 500 and 1500, respectively, of the DXMa amount in water at 25 ◦C

Summary

Introduction

Ocular inflammation is the consequence of many potential eye disorders among which uveitis is believed to be the cause of about 10% of the cases of severe visual handicap in the United States [1].Topical administration of anti-inflammatory drugs, steroidal (SAID) and non steroidal (NSAID), is the most frequently used method to treat ocular surface and anterior segment inflammation as it presents an easy accessibility, a simplicity of use, a non invasive way, and generally a good tolerance. Ocular inflammation is the consequence of many potential eye disorders among which uveitis is believed to be the cause of about 10% of the cases of severe visual handicap in the United States [1]. The ocular drug bioavailability in conventional eye drops is notoriously poor; only 1–5% of drug applied to the surface penetrates the cornea. This is the consequence of various effective. 22ooff1176 pprrootteeccttiivveemmeecchhaanniissmmssaannddmmuullttiipplleebbaarrrriieerrssttooddrruuggeennttrryy,,iinncclluuddiinnggaaffaassttnnaassoo--llaacchhrryymmaallddrraaiinnaaggee dduueettoo hhiigghh tteeaarr fflluuiidd ttuurrnnoovveerr aanndd lliidd bblliinnkkiinngg,, tthhee ccoorrnneeaallssttrruuccttuurreewwiitthhaa hhyyddrroopphhiilliiccssttrroommaa ssaannddwwicichheeddbbeetwtweeeenntthheelliippoopphhiliilciceeppitithheeliluiummaannddeennddooththeeliluiumm, ,eeppitihtheelilaial lddrruuggtrtraannssppoorrttbbaarrrrieierrss, , aannddcclleeaarraanncceeffrroommtthheevvaassccuullaattuurreeiinntthheeccoonnjjuunnccttiivvaa [[22,,33]]. NNuummeerroouussssttrraateteggieiesshhaavveebbeeeennddeevveeloloppeeddtotoininccrreeaasseeththeebbioioaavvaailialabbiliiltiytyooffoopphhththaalmlmicicddruruggs.s. OOnneeoofftthheemmiissttoopprroolloonnggtthheeccoonnttaaccttttiimmeebbeettwweeeenn tthhee ddrruugg aanndd tthhee ccoorrnneeaall//ccoonnjujunncctitvivaalleeppitithheeliluiumm bbyytthheeuussee ooff mmuuccooaaddhheessiivveehhyyddrrooggeellss[[44]]. AAnneennhhaanncceeddrreessidideenncceetitmimeewwililllininccrreeaasseetthheettiimmeeoovveerr wwhhiicchhaabbssoorrppttiioonnccaannooccccuurraannddtthheettoottaallaammoouunnttooffddrruuggaabbssoorrbbeeddaannddhhaassbbeeeennsshhoowwnnttoorreessuullttiinn pprroolloonnggeeddeeffffeeccttaannddiinnccrreeaasseeddbbiiooaavvaaiillaabbiililtityyiinnsseevveerraallssttuuddiieess[[55]]..AAssaanneexxaammpplele,,tthhiissssttrraatteeggyyiiss uusseeddiinnmmaarrkkeetteeddeeyyeeddrrooppssssuucchhaassTTIIMMOOPPTTOOLL LLPP®®aannddGGEELLTTIIMMLLPP®®, ,wwhhicichhaarreeininsstitlilleleddoonncceeddaailiyly vvss..ttwwiciceeddaailiylywwitithhTTIIMMOOCCOOMMOODD®®

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