Improvement of physicochemical properties of N-4472. Part II: characterization of N-4472 microemulsion and the enhanced oral absorption.
The optimized formulation of N-4472, N-[2-(3,5-di-tert-butyl-4-hydroxyphenethyl)-4,6-difluorophenyl]-N'-[4-(N-benzylpiperidyl)] urea, which was a poorly water-soluble drug, was developed by utilizing the complexation between N-4472 and L-ascorbic acid (VC). It was found that the formulation with Gelucire((R)) 44/14, HCO-60((R)) and sodium dodecyl sulfate provided a self-microemulsifying system consisting of fine droplets in approximately 18 nm size with a narrow distribution. 1H-NMR spectroscopic study indicated that the N-4472/VC complex was molecularly incorporated into surfactant molecular assembly in the microemulsion droplets. It was found that the N-4472 microemulsion was stable at the pH range from 2.0 to 7.0, suggesting the stability in the gastrointestinal tract. When the microemulsion containing N-4472/VC complex was orally administrated in rats, high AUC value of N-4472 (2 to 4-fold) was observed in comparison with the aqueous solution containing N-4472/VC complex.
Itoh
K
K
Graduate School of Pharmaceutical Sciences, Chiba University, 1-33 Yayoicho, Inage-ku, Japan. itoh028@attglobal.net
Matsui
S
S
Tozuka
Y
Y
Oguchi
T
T
Yamamoto
K
K
D000284:Administration, Oral; D000818:Animals; D001205:Ascorbic Acid; D002368:Castor Oil / Q000031:analogs & derivatives*; D004355:Drug Stability; D004655:Emulsions; D005079:Excipients; D006863:Hydrogen-Ion Concentration; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D010316:Particle Size; D010880:Piperidines / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics; D011092:Polyethylene Glycols; D051381:Rats; D017207:Rats, Sprague-Dawley; D012967:Sodium Dodecyl Sulfate; D012995:Solubility; D014508:Urea / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry* / Q000493:pharmacokinetics; D014867:Water
D004655:Emulsions; D005079:Excipients; C457839:N-(2-(3,5-di-tert-butyl-4-hydroxyphenethyl)-4,6-difluorophenyl)-N'-(4-(N-benzylpiperidyl)) urea; D010880:Piperidines; D014867:Water; C104509:gelucire 44-14; D012967:Sodium Dodecyl Sulfate; D011092:Polyethylene Glycols; C023040:polyethoxylated castor oil; D002368:Castor Oil; D014508:Urea; D001205:Ascorbic Acid