Improvement of physicochemical properties of N-4472 part I formulation design by using self-microemulsifying system.
The optimization of oral dosage form formulation has been developed for 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 having a lipid-lowering effect. Formulations that contained various surfactants and water-soluble polymers were prepared and the solubility of N-4472 was evaluated in JP XIV first fluid (pH 1.2), JP XIV second fluid (pH 6.8), and distilled water. The highest solubility of N-4472 was achieved when L-ascorbic acid (VC), Gelucire 44/14, and HCO-60 were used as additives. It was confirmed that this formulation could create microemulsion droplets with a mean droplet size of approximately 20 nm and a sharp droplet distribution pattern in JP XIV first fluid, JP XIV second fluid, and distilled water. When JP XIV second fluid was used as a dissolution medium, however, an eventual decrease of solubility was observed, that is, the fluid became white and cloudy as time passed. It was found that the addition of sodium dodecyl sulfate (SDS) was effective to prevent the lowering of solubility, and that a weight ratio of 1.0/1.5/11.4/4.9/3.8 for N-4472/VC/Gelucire 44/14/HCO-60/SDS was optimum for the self-microemulsifying formulation. It was assumed that electrostatic repulsion of microemulsion droplets and an increase of the cloud point by the addition of SDS were responsible for the successful formation of a stable microemulsion.
Itoh
K
K
Graduate School of Pharmaceutical Sciences, Chiba University, 1-33 Yayoicho, Inage-ku, Chiba 263-8522, Japan. itoh028@attglobal.net
Tozuka
Y
Y
Oguchi
T
T
Yamamoto
K
K
D055598:Chemical Phenomena; D002626:Chemistry, Pharmaceutical; D002627:Chemistry, Physical; D002851:Chromatography, High Pressure Liquid; D004655:Emulsions; D005079:Excipients; D000960:Hypolipidemic Agents / Q000737:chemistry*; D010316:Particle Size; D010880:Piperidines / Q000737:chemistry*; D012995:Solubility; D012997:Solvents; D013056:Spectrophotometry, Ultraviolet; D013696:Temperature; D014508:Urea / Q000031:analogs & derivatives / Q000737:chemistry*
D004655:Emulsions; D005079:Excipients; D000960:Hypolipidemic Agents; C457839:N-(2-(3,5-di-tert-butyl-4-hydroxyphenethyl)-4,6-difluorophenyl)-N'-(4-(N-benzylpiperidyl)) urea; D010880:Piperidines; D012997:Solvents; D014508:Urea