Thiolated Hydroxypropyl-β-cyclodextrin: A Potential Multifunctional Excipient for Ocular Drug Delivery

Abstract

The goal of this study was the design and evaluation of a thiolated cyclodextrin providing high drug solubilizing and mucoadhesive properties for ocular drug delivery. Hydroxypropyl-β-cyclodextrin (HP-β-CD) was thiolated via a microwave-assisted method, resulting in a degree of thiolation of 33%. Mucoadhesive properties of thiolated HP-β-CD (HP-β-CD-SH) were determined via rheological measurements and ex vivo studies on isolated porcine cornea. Due to thiolation of HP-β-CD, a 2-fold increase of mucus viscosity and a 1.4-fold increase in residence time on isolated corneal tissue were achieved. After instillation, the mean precorneal residence time and AUC of dexamethasone (DMS) eye drops were 4-fold and 11.7-fold enhanced by HP-β-CD-SH, respectively. Furthermore, in the presence of HP-β-CD-SH, a constant high level of DMS in aqueous humour between 30 and 150 min after administration was observed. These results suggest that HP-β-CD-SH is an excellent excipient for ocular formulations of poorly soluble drugs in order to prolong their ocular residence time and bioavailability.

Thiolated 2-Methyl-β-Cyclodextrin as a Mucoadhesive Excipient for Poorly Soluble Drugs: Synthesis and Characterization

“…The selection of optimal reaction conditions was set in terms of mass yield (%) and product thiolation degree (TD, % of thiolated sugars). In general, the product loss and the resulting low yields values are due to cyclodextrin degradation through ring-opening and fragmentation [ 14 ]. Initially, the reaction was performed as a single MW reaction step, but notably, a quick 5 min boost to a higher temperature (87 °C) was effective in improving the thiolation degree, without significantly altering the reaction yield.…”

“…In agreement with observations for the HPβCD, the application of milder conditions, in the presence of citrate buffer, was unsuccessful and nearly no thiolation was obtained. However, with respect to HPβCD [ 14 ], the conditions selected for the thiolation of MβCD led to a higher thiolation degree, 67% vs. 33% (for MβCD-SH and HPβCD-SH, respectively), and comparable product yields of about 30%.…”

“…Thiolated methyl-β-cyclodextrin (MβCD-SH) was prepared by optimizing the method reported in Grassiri et al, 2022 [ 14 ] (reaction conditions are reported in Table S1 ). Briefly, 200 mg of MβCD was dissolved in 1 mL of 10% acetic acid, whereas 1.07 g of thiourea were dissolved at 40 °C under stirring in 4 mL of HCl 0.44 M. Once both compounds were solubilized, the dissolved thiourea was added dropwise to the MβCD solutions.…”

“…Therefore, growing interest has been reported in mucoadhesive thiolated cyclodextrins, as they are valuable solubilizing agents as well as mucoadhesive tools for topical drug delivery of poorly soluble or easily degradable drugs [ 10 ]. Adhering to the mucus layer through disulphide bond formation thiolated cyclodextrins efficiently improves drug residence time and permeation when topically administered, as demonstrated in vitro [ 11 , 12 , 13 ] and in vivo [ 14 ]. Previously described thiolation methods are based on organic solvents.…”

“…In addition to the encouraging results obtained on the ocular application of thiolated hydroxypropyl-β-cyclodextrin (HPβCD-SH) [ 14 ], the aim of the present study is to evaluate the potential of thiolated 2-methyl-β-cyclodextrin (MβCD-SH) as a functional mucoadhesive drug complexing agent. Indeed, methyl-β-cyclodextrin is a freely soluble βCD derivative, with pharmaceutical interest and approved in products with ocular and nasal routes of administration, being at present the only cyclodextrin derivative used as an excipient for nasal delivery (EMA 2017).…”