Solubilization of vorinostat by cyclodextrins.
BACKGROUND
Vorinostat (suberoylanilide hydroxamic acid) is the first histone deacetylase inhibitor approved by US FDA for use in oncology. However, as a hydrophobic acid, its limited aqueous solubility poses a problem for parenteral delivery. Such limited solubility may also affect its oral bioavailability.


OBJECTIVE
The aim of this study was to evaluate whether cyclodextrins (CDs), common excipients used in pharmaceutical industry, could increase the aqueous solubility of vorinostat.


METHODS
The actual aqueous solubility of vorinostat was investigated by phase-solubility method. Molecular simulation was employed to predict the interaction energy and preferred orientation of vorinostat in CD cavities.


RESULTS
Phase-solubility studies indicated that the solubility of vorinostat (7·24×10(-1) mm) was substantially increased when complexed with various CDs, in the following order: randomly methylated-β-cyclodextrin (RM-β-CD)>hydroxypropyl-β-cyclodextrin (HP-β-CD)>α-cyclodextrin>hydroxypropyl-α-cyclodextrin>Hydroxypropyl-γ-cyclodextrin>γ-cyclodextrin. RM-β-CD 300 mm increased vorinostat solubility to 70·8 mm, almost two orders of magnitude higher than the baseline solubility. Such findings were in good agreement with the results obtained from molecular simulation.


CONCLUSIONS
CDs, particularly RM-β-CD and HP-β-CD, increased vorinostat's solubility. Future studies could be focused on the application of HP-β-CD in parenteral delivery of vorinostat or using RM-β-CD as an oral absorption enhancer. Molecular simulation appeared to be a useful tool for the selection of appropriate CD as excipient for drug delivery.
Cai
Y Y
YY
Department of Pharmacy, Faculty of Science, National University of Singapore, Singapore.
Yap
C W
CW
Wang
Z
Z
Ho
P C
PC
Chan
S Y
SY
Ng
K Y
KY
Ge
Z G
ZG
Lin
H S
HS
D000073738:2-Hydroxypropyl-beta-cyclodextrin; D000042:Absorption; D000284:Administration, Oral; D001682:Biological Availability; D055598:Chemical Phenomena; D003505:Cyclodextrins / Q000737:chemistry*; D005079:Excipients / Q000737:chemistry; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage* / Q000737:chemistry; D006877:Hydroxamic Acids / Q000008:administration & dosage* / Q000737:chemistry*; D007262:Infusions, Intravenous; D008958:Models, Molecular; D012995:Solubility / Q000187:drug effects; D000077337:Vorinostat; D047392:beta-Cyclodextrins / Q000737:chemistry*
D003505:Cyclodextrins; D005079:Excipients; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D047392:beta-Cyclodextrins; D000073738:2-Hydroxypropyl-beta-cyclodextrin; D000077337:Vorinostat