Inclusion complexes of noscapine in beta-cyclodextrin offer better solubility and improved pharmacokinetics.
OBJECTIVE
Noscapine (NOS) is a unique class of tubulin-binding anticancer agents. Their potential usefulness as anticancer drugs is however limited by the poor bioavailability, thus necessitating administration of a higher dose regime in the range of 300-600 mg/kg for tumor growth inhibition. To augment bioavailability, we prepared an inclusion complex of NOS in beta-cyclodextrin (beta-CD) and evaluated its physico-chemical characteristics.


RESULTS
Our phase-solubility analysis shows a 1:1-complexation (Kc approximately 0.454 mM(-1)) of NOS with beta-CD that offers better dissolution properties. We confirmed complex formation in solid state by differential scanning calorimetry, powder X-ray diffractometry, Fourier-transform infrared spectroscopy, 1H nuclear magnetic resonance spectroscopy, rotating frame Overhauser enhancement spectroscopy and by molecular modeling methods. Based upon theoretical calculations in gas phase, we propose O-CH2-O- in orientation of NOS in the beta-CD cavity. The thermal behavior data also provides complementary evidences of complex formation. The pharmacokinetic studies showed a 1.87-fold increase in bioavailability of NOS upon complexation in the beta-CD inclusion complex state as compared to free NOS. Furthermore, the complex retains the anticancer attributes of NOS.


CONCLUSIONS
Our studies propose for the first time a stable NOS-beta-CD inclusion complex as an effective approach to enhance the solubility and bioavailability of NOS for anticancer therapy.
Madan
Jitender
J
Department of Pharmaceutics, Hindu College of Pharmacy, Sonepat, Haryana, India.
Dhiman
Neerupma
N
Parmar
Vinod K
VK
Sardana
Satish
S
Bharatam
Prasad V
PV
Aneja
Ritu
R
Chandra
Ramesh
R
Katyal
Anju
A
D000284:Administration, Oral; D000818:Animals; D019540:Area Under Curve; D001682:Biological Availability; D002152:Calorimetry, Differential Scanning; D045744:Cell Line, Tumor; D002851:Chromatography, High Pressure Liquid; D004339:Drug Compounding; D004355:Drug Stability; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008657:Metabolic Clearance Rate; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D009665:Noscapine / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics*; D012995:Solubility; D017550:Spectroscopy, Fourier Transform Infrared; D013696:Temperature; D014961:X-Ray Diffraction; D047392:beta-Cyclodextrins / Q000737:chemistry*
D047392:beta-Cyclodextrins; D009665:Noscapine; C031215:betadex