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

Abstract

Thiolated cyclodextrins are structurally simple mucoadhesive macromolecules, which are able to host drugs and increase their apparent water solubility, as well as interact with the mucus layer prolonging drug residence time on the site of absorption. The aim of this study was to synthesize through green microwave-assisted process a freely soluble thiolated 2-methyl-β-cyclodextrin (MβCD-SH). Its inclusion complex properties with dexamethasone (Dex), a poor water soluble drug, and mucoadhesive characteristics were also determined. The product was deeply characterized through NMR spectroscopy (2D COSY, 2D HSQC, 1D/2D TOCSY, and 1D ROESY), showing a thiolation degree of 67%, a selective thiolation on the C6 residues and a monomeric structure. The association constant of MβCD and MβCD-SH with Dex resulted in 2514.3 ± 32.3 M−1 and 2147.0 ± 69.3 M−1, respectively, indicating that both CDs were able to host the drug. Microrheological analysis of mucin in the presence of MBCD-SH showed an increase of complex viscosity, G′ and G″, due to disulphide bond formation. The cytotoxicity screening on fibroblast BALB/3T3 clone A31 cells indicated an IC50 of 27.7 mg/mL and 30.0 mg/mL, for MβCD and MβCD-SH, respectively. Finally, MβCD-SH was able to self-assemble in water into nanometric structures, both in the presence and absence of the complexed drug.

Bergamot Essential Oil: A Method for Introducing It in Solid Dosage Forms

“…The DLS analysis of the BEO/QA-Ch-MCD conjugate showed that the conjugation process led to agglomerates with nanometer size, not different from those formed from BEO/MCD. However, the agglomerates obtained from BEO/QA-Ch-MCD had a more inhomogeneous distribution than those from BEO/MCD, as demonstrated by the PdI values, which confirms the ability of CD host/guest complexes to self-assemble in water [ 23 , 24 ]. In both cases, the ζ-potential absolute values indicate that the agglomerates were reasonably stable, leading to a colloidal dispersion of the lipophilic compounds [ 25 ].…”

Enhanced Mucoadhesion of Thiolated β-Cyclodextrin by S-Protection with 2-Mercaptoethanesulfonic Acid

“…The diffusion of coumarin-6, complexed in native β-CD, β-CD-SH, and β-CD-SS-MESNA into purified porcine intestinal mucus, was studied via the rotating tube method, as described previously. , In brief, silicone tubes were cut into 50 mm long pieces and filled with 250 μL of purified porcine intestinal mucus. Afterward, 50 μL of 1% (m/v) complexes in 50 mM phosphate buffer pH 6.8 was added to the mucus-filled tubes.…”

“…The percentage of the polymer diffused into the mucus was calculated based on a calibration curve. 12,15 Statistical Data Analysis. Statistical analyses of all data were implemented using Student's t-test, with a confidence interval (CI) of p < 0.05.…”

“…Mucoadhesion is provided by ionic interactions and hydrogen bonding in combination with the interpenetration of polymeric chains into the mucus gel layer, followed by chain entanglements. − Since CDs are nonionic and too small for chain entanglements, they are not mucoadhesive at all. To trigger prolonged mucosal residence time, modification of CDs with thiol groups is in focus of recent research. − The sulfhydryl groups can form disulfide bonds with cysteine moieties of mucus glycoproteins and immobilize the carrier in the mucus layer . Thiolated CDs are investigated mostly for ocular and oral drug delivery. ,, They can be generated by covalent attachment of thiol-containing ligands − or direct hydroxyl-to-thiol conversions. − ,,, The latter is preferred because it does not alter the CDs’ characteristics, such as its complexation ability or cytotoxicity .…”

“…This poor solubility could be addressed by the use of other, more soluble CD derivatives, such as methylated or hydroxypropylated β-CDs. 13,15 The main limitation of thiolated drug delivery systems, besides the limited aqueous solubility, is that the thiol groups tend to oxidize to disulfides, lowering the available free thiol content. Moreover, mucoadhesion occurs already on the outer, loose mucus layer that is rapidly eliminated by the mucus turnover process, strongly limiting the residence time of the thiolated drug carriers.…”