Synthesis of uniform cyclodextrin thioethers to transport hydrophobic drugs.

Methyl and ethyl thioether groups were introduced at all primary positions of α-, ß-, and γ-cyclodextrin by nucleophilic displacement reactions starting from the corresponding per-(6-deoxy-6-bromo)cyclodextrins. Further modification of all 2-OH positions by etherification with iodo terminated triethylene glycol monomethyl ether (and tetraethylene glycol monomethyl ether, respectively) furnished water-soluble hosts. Especially the ß-cyclodextrin derivatives exhibit very high binding potentials towards the anaesthetic drugs sevoflurane and halothane. Since the resulting inclusion compounds are highly soluble in water at temperatures ≤37 °C they are good candidates for new aqueous dosage forms which would avoid inhalation anaesthesia.

Synthesis and in vitro evaluation of cyclodextrin hyaluronic acid conjugates as a new candidate for intestinal drug carrier for steroid hormones.

Steroid hormones became increasingly interesting as active pharmaceutical ingredients for the treatment of endocrine disorders. However, medical applications of many steroidal drugs are inhibited by their very low aqueous solubilities giving rise to low bioavailabilities. Therefore, the prioritized oral administration of steroidal drugs remains problematic. Cyclodextrins are promising candidates for the development of drug delivery systems for oral route applications, since they solubilize hydrophobic steroids and increase their rate of transport in aqueous environments. In this study, the synthesis and characterization of polymeric ß-cyclodextrin derivates is described, which result from the attachment of a hydrophilic ß-CD-thioether to hyaluronic acid. Host-guest complexes of the synthesized ß-cyclodextrin hyaluronic acid conjugates were formed with two poorly soluble model steroids (ß-estradiol, dexamethasone) and compared to monomeric ß-cyclodextrin derivates regarding solubilization and complexation efficiency. The ß-cyclodextrin-drug (host-guest) complexes were evaluated in vitro for their suitability (cytotoxicity and transport rate) as intestinal drug carriers for steroid hormones. In case of ß-estradiol, higher solubilities could be achieved by complexation with both synthesized ß-cyclodextrin derivates, leading to significantly higher intestinal transport rates in vitro. However, this success could not be shown for dexamethasone, which namely solubilized better, but could not enhance the transport rate significantly. Thus, this study demonstrates the biocompatibility of the synthesized and characterized ß-cyclodextrin derivates and shows their potential as new candidate for intestinal drug carrier for steroid hormones like ß-estradiol.

Reversible immobilization of a protein to a gold surface through multiple host-guest interactions.

Monolayers were formed by specific interactions between adamantylated proteins (transferrin, lysozyme) and a ß-cyclodextrin (ß-CD) monolayer on a gold surface. Very high stabilities could be reached by multiple interactions of 3-6 adamantyl moieties linked through triethylene glycol spacers to the protein with ß-CD rings attached to the surface. Furthermore, bound proteins could be completely removed from the surface through competitive binding of an excess of free adamantane. Regenerable protein sensor chips can be constructed by using this supramolecular toolbox. Attached proteins are still recognized by specific antibodies, which was attributed to a loose packing of the protein molecules at the ß-CD monolayer.

Solubilizing steroidal drugs by ß-cyclodextrin derivatives.

Administration of steroidal drugs is hampered by their very low solubilities in water. ß-Cyclodextrin and ß-cyclodextrin derivatives can solubilize steroids and improve bio-availability of these hydrophobic APIs. A systematic overview of the achievable solubility enhancements of various steroids, testosterone, estradiol, progesterone, hydrocortisone, prednisone, dexamethasone, and finasteride, is provided. Beside the spatial fit of the steroid within the cyclodextrin cavity also hydrophilic substituents at the cyclodextrin framework play an important role in the extent of solubilization observed. Uniformly substituted anionic heptakis-6-sulfoethylsulfanyl-6-deoxy-ß-cyclodextrin (HSES) performed best, reaching complexation efficiencies of 60-90mol% for most steroids. Two neutral ß-cyclodextrin thioethers, heptakis-6-methylsulfanyl-6-deoxy-2-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)]-ß-CD (HTMT) and heptakis-6-thioglyceryl-6-deoxy-ß-CD (HTG) showed gender selectivity in binding of hormons: HTMT was selective for testosterone, while HTG was selective for estradiol. Solubilization is mainly due to complexation of the A and B rings as well as C and D rings of the steroid framework as demonstrated by ROESY NMR spectroscopy.