Heptakis(2,6-di-O-methyl-3-O-acetyl)-beta-cyclodextrin: A water-soluble cyclodextrin derivative with low hemolytic activity.

Abstract

Acetyl groups were introduced to the hydroxyl groups of heptakis(2, 6-di-O-methyl)-beta-cyclodextrin (DM-beta-CyD), and the resulting heptakis(2,6-di-O-methyl-3-O-acetyl)-beta-CyD (DMA-beta-CyD) was evaluated for the inclusion property and hemolytic activity. It was confirmed by means of NMR and mass spectroscopies that in the DMA-beta-CyD molecule, all seven hydroxyl groups at the 3-position were substituted by acetyl groups. Thus, it has the degree of substitution (DS) of 7, whereas DMA4-beta-CyD with the lower substitution (DS 3.8) was a mixture of components with different DS. The aqueous solubility of DMA-beta-CyD was higher than those of beta-CyD, DM-beta-CyD, and heptakis(2,3,6-tri-O-methyl)-beta-CyD (TM-beta-CyD). The hydrophobicity of the whole molecule, assessed from measurements of surface tension, increased in the order of DM-beta-CyD < DMA-beta-CyD < TM-beta-CyD. The half-life of DMA-beta-CyD for hydrolysis in pH 9.5 and 60 degrees C was about 19 h, and there was only slight liberation of acetic acid in rabbit plasma and carboxylesterase (EC 3.1.1.1) at 37 degrees C. DMA-beta-CyD had an inclusion ability similar to that of TM-beta-CyD for p-hydroxybenzoic acid esters with different alkyl chain lengths and an antiinflammatory drug, flurbiprofen, although it was inferior to that of DM-beta-CyD. The hemolytic activity and rabbit muscular irritation of DMA-beta-CyDs were much weaker than those of DM-beta-CyD: no hemolysis was observed even in the presence of 0.1 M DMA-beta-CyD with DS 7. The results suggest that the water-soluble CyD derivative with superior bioadaptability and inclusion ability can be prepared by properly designing substituents at the 3-position and by optimally controlling their degree of substitution.

• Authors: F Hirayama, S Mieda, Y Miyamoto, H Arima, K Uekama
• Journal: Journal of pharmaceutical sciences (J Pharm Sci) Vol. 88 Issue 10 Pg. 970-5 (Oct 1999) ISSN: 0022-3549 [Print] United States
• PMID: 10514341 (Publication Type: Journal Article)

Chemical References

• Cyclodextrins
• Excipients
• Irritants
• beta-Cyclodextrins
• heptakis(2,6-di-O-methyl-3-O-acetyl)-beta-cyclodextrin
• Cholesterol

Topics

• Animals
• Chemical Phenomena
• Chemistry, Physical
• Cholesterol (blood)
• Cyclodextrins (chemical synthesis, toxicity)
• Erythrocytes (drug effects)
• Excipients (chemical synthesis, toxicity)
• Hemolysis (drug effects)
• Hydrolysis
• In Vitro Techniques
• Irritants (toxicity)
• Muscular Diseases (chemically induced, pathology)
• Rabbits
• Solubility
• Spectrometry, Fluorescence
• beta-Cyclodextrins