Comparative study on solid self-nanoemulsifying drug delivery and solid dispersion system for enhanced solubility and bioavailability of ezetimibe.
BACKGROUND
The objective of this study was to compare the physicochemical characteristics, solubility, dissolution, and oral bioavailability of an ezetimibe-loaded solid self-nanoemulsifying drug delivery system (SNEDDS), surface modified solid dispersion (SMSD), and solvent evaporated solid dispersion (SESD) to identify the best drug delivery system with the highest oral bioavailability.


METHODS
For the liquid SNEDDS formulation, Capryol 90, Cremophor EL, and Tween 80 were selected as the oil, surfactant, and cosurfactant, respectively. The nanoemulsion-forming region was sketched using a pseudoternary phase diagram on the basis of reduced emulsion size. The optimized liquid SNEDDS was converted to solid SNEDDS by spray drying with silicon dioxide. Furthermore, SMSDs were prepared using the spray drying technique with various amounts of hydroxypropylcellulose and Tween 80, optimized on the basis of their drug solubility. The SESD formulation was prepared with the same composition of optimized SMSD. The aqueous solubility, dissolution, physicochemical properties, and pharmacokinetics of all of the formulations were investigated and compared with the drug powder.


RESULTS
The drug existed in the crystalline form in SMSD, but was changed into an amorphous form in SNEDDS and SESD, giving particle sizes of approximately 24, 6, and 11 µm, respectively. All of these formulations significantly improved the aqueous solubility and dissolution in the order of solid SNEDDS ≥ SESD > SMSD, and showed a total higher plasma concentration than did the drug powder. Moreover, SESD gave a higher area under the drug concentration time curve from zero to infinity than did SNEDDS and SMSD, even if they were not significantly different, suggesting more improved oral bioavailability.


CONCLUSIONS
Among the various formulations tested in this study, the SESD system would be strongly recommended as a drug delivery system for the oral administration of ezetimibe with poor water solubility.
College of Pharmacy and Institute of Pharmaceutical Science and Technology, Hanyang University, Ansan, South Korea.
Rehmana
R
Rashid
College of Pharmacy and Institute of Pharmaceutical Science and Technology, Hanyang University, Ansan, South Korea.
Dong Wuk
DW
Kim
College of Pharmacy and Institute of Pharmaceutical Science and Technology, Hanyang University, Ansan, South Korea.
Abid Mehmood
AM
Yousaf
College of Pharmacy and Institute of Pharmaceutical Science and Technology, Hanyang University, Ansan, South Korea.
Omer
O
Mustapha
College of Pharmacy and Institute of Pharmaceutical Science and Technology, Hanyang University, Ansan, South Korea.
Fakhar Ud Din
College of Pharmacy and Institute of Pharmaceutical Science and Technology, Hanyang University, Ansan, South Korea.
Jong Hyuck
JH
Park
College of Pharmacy, Yeungnam University, Gyeongsan, South Korea.
Chul Soon
CS
Yong
College of Pharmacy, Seoul National University, Seoul, South Korea.
Yu-Kyoung
YK
Oh
School of Pharmacy, Sungkyunkwan University, Suwon, South Korea.
Yu Seok
YS
Youn
College of Pharmacy, Yeungnam University, Gyeongsan, South Korea.
Jong Oh
JO
Kim
College of Pharmacy and Institute of Pharmaceutical Science and Technology, Hanyang University, Ansan, South Korea.
Han-Gon
HG
Choi
D000284:Administration, Oral; D000818:Animals; D000924:Anticholesteremic Agents / Q000737:chemistry / Q000493:pharmacokinetics; D001682:Biological Availability; D002152:Calorimetry, Differential Scanning; D002626:Chemistry, Pharmaceutical / Q000379:methods; D016503:Drug Delivery Systems / Q000379:methods*; D004655:Emulsions / Q000737:chemistry*; D000069438:Ezetimibe / Q000737:chemistry* / Q000493:pharmacokinetics*; D008297:Male; D008855:Microscopy, Electron, Scanning; D053758:Nanoparticles / Q000008:administration & dosage* / Q000737:chemistry; D010316:Particle Size; D051381:Rats; D017207:Rats, Sprague-Dawley; D012822:Silicon Dioxide / Q000737:chemistry; D012995:Solubility; D017550:Spectroscopy, Fourier Transform Infrared; D014018:Tissue Distribution
D000924:Anticholesteremic Agents; D004655:Emulsions; D012822:Silicon Dioxide; D000069438:Ezetimibe
bioavailability; ezetimibe; solid dispersion; solid self-nanoemulsifying drug delivery system; solubility