A water-soluble, mucoadhesive quaternary ammonium chitosan-methyl-β-cyclodextrin conjugate forming inclusion complexes with dexamethasone

Abstract

The ocular bioavailability of lipophilic drugs, such as dexamethasone, depends on both drug water solubility and mucoadhesion/permeation. Cyclodextrins and chitosan are frequently employed to either improve drug solubility or prolong drug contact onto mucosae, respectively. Although the covalent conjugation of cyclodextrin and chitosan brings to mucoadhesive drug complexes, their water solubility is restricted to acidic pHs. This paper describes a straightforward grafting of methyl-β-cyclodextrin (MCD) on quaternary ammonium chitosan (QA-Ch60), mediated by hexamethylene diisocyanate. The resulting product is a water-soluble chitosan derivative, having a 10-atom long spacer between the quaternized chitosan and the cyclodextrin. The derivative is capable of complexing the model drug dexamethasone and stable complexes were also observed for the lyophilized products. Furthermore, the conjugate preserves the mucoadhesive properties typical of quaternized chitosan and its safety as solubilizing excipient for ophthalmic applications was preliminary assessed by in vitro cytotoxicity evaluations. Taken as a whole, the observed features appear promising for future processing of the developed product into 3D solid forms, such as controlled drug delivery systems, films or drug eluting medical devices.

Antibacterial, Antibiofilm, and Antiadhesive Properties of Different Quaternized Chitosan Derivatives

“…Additionally, it is known that Ch containing cationic or hydrophobic residues can exhibit an enhanced antibacterial/antibiofilm potential [17,18]. Therefore, quaternized Ch grafted with methyl--cyclodextrin (coded QAH-CD and QAL-CD, respectively) [19] were also tested, seeing that the cyclic oligosaccharide has a hydrophilic external surface and a hydrophobic internal cavity. All these Ch-derivatives have water solubility irrespective of pH as they all have pendant ammonium quaternary chains.…”

“…High and low MW multifunctional quaternary ammonium-Ch conjugates substituted with protected thiol groups (QAH-Pro and QAL-Pro, respectively) were obtained as previously described [55]. The preparation of multifunctional quaternary ammonium-Ch derivatives of high or low MW, conjugated with methyl-β-cyclodextrin (QAH-CD or QAL-CD) followed a reported protocol [19,20]. The main features of the polymers assayed in the study are reported in Table 1, details of the characterization techniques, including spectroscopy analysis, are reported in Supplementary Figures S7-S10.…”

Improvement of Peptide Affinity and Stability by Complexing to Cyclodextrin-Grafted Ammonium Chitosan

“…Briefly, 5 g of Ch were dissolved in 2% acetic acid solution and reacted with NaNO 2 (0.1 M, 12.5 mL) at 30 • C for 4 h. Afterwards, the solution pH was adjusted to pH 7.8 by using NaOH 10 M, and the obtained reduced molecular weight chitosan (rCh) was recovered by filtration, washed with water, and vacuum dried. The rCh was alkylated on -NH 2 groups via a reaction of quaternarization optimized by Zambito et al [2,11]: 2-methyl-β-cyclodextrin (MCD) was grafted on N + -rCh, following a procedure [21] articulated into several steps: 350 mg of N + -rCh were solubilized in 7 mL of DMSO under inert atmosphere (N 2 ) overnight. Sequentially, N + -rCh (350 mg) and TEA (0.056 mL, 0.40 mol) were added to a solution of HMDI (0.7 mL, 4.4 mmol) in DMSO (8 mL), and the mixture was placed in an oil bath at 70 • C, under inert atmosphere.…”

“…Aliphatic groups make the internal surface of the toroidal cavity more water-repellent, favoring the inclusion of lipophilic molecules. Methyl-cyclodextrins grafted on chitosan are hence responsible for a considerable acceleration of dissolution processes of poorly water-soluble drugs [21].…”

Carbohydrate‐based nanomaterials for biomedical applications

“…O ‐Alkyl TMCS nanomicelles, encapsulating peptide nucleic acid showed hemocompatability and a dramatic increase in cellular uptake (C. Liu, Wang, et al, ). Other types of QCS served as pH responsive nanocarriers (de Oliveira Pedro, Hoffmann, et al, ; Piras et al, ).…”