Improvement of some pharmaceutical properties of DY-9760e by sulfobutyl ether beta-cyclodextrin.
The interaction of DY-9760e, a novel cytoprotective agent, with sulfobutyl ether beta-cyclodextrin (SBE-beta-CyD) in phosphate buffered saline (PBS) at various pH and ionic-strengths was studied by spectroscopic methods and the solubility method, and the results were compared with that of 2-hydroxypropyl-beta-cyclodextrin (HP-beta-CyD). The circular dichroism (CD) spectroscopic studies suggested that both beta-CyDs form the inclusion complexes with DY-9760e in a molar ratio of 1:1, and the interaction of DY-9760e with SBE-beta-CyD is much stronger than that with HP-beta-CyD at any pH studied, in terms of a synergetic effect of hydrophobic and electrostatic interactions. The different intermolecular interaction between the SBE-and HP-beta-CyD complexes was clearly reflected in the stability constant (K'), e.g. the different dependence of K' value on pH and ionic strength of solutions. 1H- and 13C-NMR studies suggested that HP-beta-CyD interacts preferably with the benzene ring of DY-9760e, whereas SBE-beta-CyD interacts not only with the benzene ring via hydrophobic interaction but also with the piperazine ring of the drug via electrostatic interaction. The solubilizing ability of SBE-beta-CyD against DY-9760e was much greater than that of HP-beta-CyD at any pH studied. Furthermore, SBE-beta-CyD markedly suppressed the photo-degradation of DY-9760e in aqueous solution and reduced the adsorption of DY-9760e from PBS to polyvinyl chloride (PVC) tubes after incubation. The results suggest that SBE-beta-CyD is useful in preparing parenteral solutions of poorly water-soluble drugs with positive charge such as DY-9760e.
Nagase
Y
Y
Tokyo Pharmaceutical Research Center, Daiichi Pharmaceutical Co. Ltd., 1-16-13, Kitakasai, Edogawa-ku, 134-8630, Tokyo, Japan.
Hirata
M
M
Wada
K
K
Arima
H
H
Hirayama
F
F
Irie
T
T
Kikuchi
M
M
Uekama
K
K
D000327:Adsorption; D002942:Circular Dichroism; D003505:Cyclodextrins / Q000737:chemistry*; D004987:Ethers / Q000737:chemistry*; D005079:Excipients; D006863:Hydrogen-Ion Concentration; D007191:Indazoles / Q000008:administration & dosage / Q000737:chemistry*; D007408:Intestinal Absorption; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000737:chemistry*; D010777:Photochemistry; D011143:Polyvinyl Chloride; D012995:Solubility; D047392:beta-Cyclodextrins
C109602:3-(2-(4-(3-chloro-2-methylphenyl)1-piperazinyl)ethyl)5,6-dimethoxy-1-(4-imidazolylmethyl)-1H-indazol dihydrochloride 3.5 hydrate; D003505:Cyclodextrins; D004987:Ethers; D005079:Excipients; D007191:Indazoles; D018696:Neuroprotective Agents; D047392:beta-Cyclodextrins; C093196:SBE4-beta-cyclodextrin; D011143:Polyvinyl Chloride