Cyclodextrins are excellent excipients for various routes of administration, the ophthalmic delivery is potentially one of the most useful applications of cyclodextrins as the adminiestered volumes are very low and the dose needs to be high. For eye drops there are several cyclodextrins accepted by the European Medicines Agency, however there are still only a handful of ophthalmic products on the market containing cyclodextrins. Practically all 4 common cyclodextrin derivatives can be used in eye drops, even hydroxypropyl gamma-cyclodextrin (HPGCD), and the randomly methylated beta-cyclodextrin (RAMEB), which do not have USP or Ph.Eur. monographs, yet there have been marketed eye drops on the market containing these cyclodextrins. The safest hydroxyproyl beta-cyclodextrin (HPBCD) and sulfobutylether beta-cyclodextrin (SBECD) are of course viable candidates as ophthalmic excipients as well. The native cyclodextrins are slightly less useful in ocular delivery, but gamma cyclodextrin (GCD) is also an excellent and safe candidate for eye drops.
Even though sometimes eye drop formulations containing cyclodextrins are aimed to replace therapies with intravitreal injections as a non-invasive option, it can be useful to explore intravitreal routes with cyclodextrins. Recently, as we also reported, SBECD was accepted as an orphan drug for Stargardt disease as it has the potential to reduce the lipofuscin levels in the retina. Cyclodextrins themselves cannot penetrate biological surfaces in most cases, so in the case of ReVision’s therapy, REV-0100 is planned to be delivered via intravitreal injection to the patients.
As the intravitreal application of cyclodextrins is quite new, there are not a lot of information on the safety and toxicity of cyclodextrins via this route. This hole is slowly being filled. In the spring of 2021, the group of Professor Thorsteinn Loftsson’s team published an article together with the Institute for Ophthalmic Research at the University of Tübingen first-authored by by Manisha Prajapati (Prajapati et al 2021). In this article they examine the cytotoxicity of HPBCD and RAMEB in retinal explants, and they try to explain the results regarding to what we can learn about the intravitreal toxicity via these in vitro / ex vivo studies.
They used wild-type mouse retinal explants, the cytotoxicity was assessed in the inner and in the outer retinal surfaces by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) and they determined the retinal uptake of fluorescently-labelled RAMEB and HPBCD derivatives via fluorescence microscopy. Cyclodextrin concentrations of 10 mM and 100 mM were tested, which is roughly equal to 1.3-1.4% and 13-14% (w/v) concentrations of RAMEB and HPBCD. It was shown that RAMEB was more toxic than HPBCD, and that the retina can safely tolerate HPBCD at levels as high as 10 mM. The difference between the 2 cyclodextrins may be explained by the fact that RAMEB is about 5x better in solubilizing cholesterol than HPBCD. The fluorescence studies showed that both CDs can penetrate deep into the inner nuclear layer of the retina. According to the results HPBCD seems to be a safer option than RAMEB for intravitreal drug delivery and I can just agree with the authors, that these results “may advance the use of CDs in the development of drugs designed for intravitreal administration”.
Reference: Prajapati, M.; Christensen, G.; Paquet-Durand, F.; Loftsson, T. Cytotoxicity of β-Cyclodextrins in Retinal Explants for Intravitreal Drug Formulations. Molecules 2021, 26, https://doi.org/10.3390/molecules26051492
Photo credit: https://iris-photo.com.au/
SBECD-enabled melphalan (Evomela) was administered intravitreally in clinics (Memorial Sloan Kettering Cancer Center): https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7329086/
Thanks for the comment, István, you are of course absolutely right! 🙂