Introduction and Objectives: The use of cyclodextrins in ophthalmic formulations have great potential due to their ability to improve drug solubility by forming inclusion complexes, increasing drug bioavailability and stability. Different safety levels have been described at ophthalmic level for different types of cyclodextrins [1,2]. The aim of this work was to study possible corneal alterations after administration of cyclodextrin aqueous solutions: α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, hydroxypropyl-α-cyclodextrin, hydroxypropyl-β-cyclodextrin, hydroxypropyl-γ-cyclodextrin, partially methylated-β-cyclodextrin and sulfobutylether-β-cyclodextrin. In addition, the in vitro and in vivo bioadhesive behavior of cyclodextrins has also compared.
Methods: BCOP trial was performed with fresh bovine corneas. Corneal transparency and fluorescein permeability were measured before of contact with the cyclodextrin solutions. HET-CAM assay was performed to quantify the irritation potential. Corneal Mucoadhesive Assay was performed by SHIMADZU® texturometer using fresh bovine corneas. Ophthalmic permanence studies by PET were carried out in rats. The formulations labelled with 18F-FDG, were instilled into the eye and static PET frames at different times were acquired.
Results: BCOP: Partially methylated-β-cyclodextrin shows transparency values similar to those of the positive control. The fluorescein permeability has been affected to a greater extent by the solution of α-cyclodextrin and hydroxypropyl-γ-cyclodextrin. HET-CAM: None of the formulations caused damage to the CAM blood vessels except αCD which modified the vessel´s appearance. Corneal Mucoadhesive Assay: All cyclodextrin solutions have similar bioadhesive properties, except for SBECD that presents a significantly lower bioadhesion work-value compared to the other cyclodextrins. PET: Hydroxypropylic cyclodextrins have a better t1/2 on the ocular surface compared to the other tested cyclodextrins.
Conclusion: All cyclodextrins were safe with the exception of partially methylated-β-cyclodextrin. Hydroxypropylic cyclodextrins improve the ocular surface permanence so they could be useful for the preparation of ophthalmic formulations as long as they are the most suitable for the generation of inclusion complexes with the desired drug.
References
[1] EMA, Background Review for Cyclodextrins Used as Excipients, pp. 1–17, 2014.
[2] Marc Francois,1 Eric Snoeckx,1 Peter Putteman,1 Fons Wouters,1 Eddy De Proost,1 Urbain Delaet,1 Jef Peeters,2and Marcus E. Brewster. A mucoadhesive, cyclodextrin-based vaginal cream formulation of itraconazole. AAPS PharmSci. 2003;5(1):E5.
Acknowlwdgements
X.G-O and R.V-F acknowledges the financial support of Health Research Institute Foundation of Santiago de Compostela (FIDIS).
