Abstract
We previously developed two optimized formulations of dexamethasone acetate (DXMa) hydrogels by means of special cubic mixture designs for topical ocular administration. These gels were elaborated with hydroxypropyl-β-CD (HPβCD) and hydroxypropyl-γ-CD (HPγCD) and commercial hydrogels in order to enhance DXMa water solubility and finally DXMa’s ocular bioavailability and transcorneal penetration. The main objective of this study was to characterize them and to evaluate in vitro, ex vivo, and in vivo their safety, biopermanence, and transcorneal permeation. Gels A and B are Newtonian fluids and display a viscosity of 13.2 mPa.s and 18.6 mPa.s, respectively, which increases their ocular retention, according to the in vivo biopermanence study by PET/CT. These hydrogels could act as corneal absorption promoters as they allow a higher transcorneal permeation of DXMa through porcine excised cornea, compared to DEXAFREE® and MAXIDEX®. Cytotoxicity assays showed no cytotoxic effects on human primary corneal epithelial cells (HCE). Furthermore, Gel B is clearly safe for the eye, but the effect of Gel A on the human eye cannot be predicted. Both gels were also stable 12 months at 25 °C after sterilization by filtration. These results demonstrate that the developed formulations present a high potential for the topical ocular administration of dexamethasone acetate.
Highlights
Dexamethasone (DXM) is one of the most prescribed anti-inflammatory drug in the treatment of acute and chronic eye inflammation due to its high potency and effectiveness [1]
This is due to the presence of various anatomical and physiological barriers, which leads to a poor bioavailability of the ophthalmic drugs; only 1–5% of drug instilled reaches in aqueous humor [4]
Pure DXM acetate (DXMa) and DXMa formulated in Gels A and B presented a retention time of 3.2 ± 0.2 min and their chromatograms are presented in Supplementary Materials (Figure S1)
Summary
Dexamethasone (DXM) is one of the most prescribed anti-inflammatory drug in the treatment of acute and chronic eye inflammation due to its high potency and effectiveness [1]. Despite the many advantages offered by this route of administration, these marketed formulations present a major disadvantage by requiring frequent administrations (up to six times/day) [2] This is due to the presence of various anatomical and physiological barriers, which leads to a poor bioavailability of the ophthalmic drugs; only 1–5% of drug instilled reaches in aqueous humor [4]. Leibowitz et al demonstrated that the acetate form was more effective compared to the phosphate derivative in suppressing inflammation in the cornea. This therapeutic effect was not associated with a greater propensity to increase intraocular pressure, one of the most frequent side effects of glucocorticoids [6]
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