A novel pH-dependent gradient-release delivery system for nitrendipine: I. Manufacturing, evaluation in vitro and bioavailability in healthy dogs

TY - JOUR

T1 - A novel pH-dependent gradient-release delivery system for nitrendipine

T2 - I. Manufacturing, evaluation in vitro and bioavailability in healthy dogs

AU - Yang, Mingshi

AU - Cui, Fude

AU - You, Bengang

AU - You, Jian

AU - Wang, Liang

AU - Zhang, Liqiang

AU - Kawashima, Yoshiaki

PY - 2004

Y1 - 2004

N2 - A novel pH-dependent gradient-release delivery system was developed by mixing three kinds of pH-dependent microspheres. Nitrendipine, a dihydropyridine calcium antagonist, was selected as the poorly water-soluble model drug. To obtain gradient-release of the active drug in the stomach, duodenum and lower segment of the small intestine, respectively, three kinds of pH-dependent polymers, i.e. Acrylic resins Eudragit E-100, Hydroxypropylmethylcellulose phthalate and Hydroxypropylmethylcellulose acetate succinate, were formulated to produce the microspheres, which dissolve at an acid condition, the pH of > or = 5.5 and > or = 6.5, respectively. The quasi-emulsion solvent diffusion method was employed in the manufacturing process for the microspheres. All three kinds of microspheres had a highly spherical shape and high incorporation efficiency (>91.0%). The particle sizes were mainly affected by the agitation speed and temperature of the manufacturing process. The results of X-ray diffraction suggested that nitrendipine in the microspheres was molecularly dispersed in an amorphous state. The drug dissolution behavior of the system under the simulated gastrointestinal pH conditions revealed obvious gradient-release characteristics. The dissolution profiles and content of the systems stored at a temperature of 40 degrees C and a relative humidity of 75% were unchanged during a 3-month period of accelerating storage conditions. The results of the bioavailability testing in six healthy dogs suggested that the pH-dependent gradient-release delivery system could improve efficiently the uptake of the poorly water-soluble drug and prolong the Tmax value in vivo.

AB - A novel pH-dependent gradient-release delivery system was developed by mixing three kinds of pH-dependent microspheres. Nitrendipine, a dihydropyridine calcium antagonist, was selected as the poorly water-soluble model drug. To obtain gradient-release of the active drug in the stomach, duodenum and lower segment of the small intestine, respectively, three kinds of pH-dependent polymers, i.e. Acrylic resins Eudragit E-100, Hydroxypropylmethylcellulose phthalate and Hydroxypropylmethylcellulose acetate succinate, were formulated to produce the microspheres, which dissolve at an acid condition, the pH of > or = 5.5 and > or = 6.5, respectively. The quasi-emulsion solvent diffusion method was employed in the manufacturing process for the microspheres. All three kinds of microspheres had a highly spherical shape and high incorporation efficiency (>91.0%). The particle sizes were mainly affected by the agitation speed and temperature of the manufacturing process. The results of X-ray diffraction suggested that nitrendipine in the microspheres was molecularly dispersed in an amorphous state. The drug dissolution behavior of the system under the simulated gastrointestinal pH conditions revealed obvious gradient-release characteristics. The dissolution profiles and content of the systems stored at a temperature of 40 degrees C and a relative humidity of 75% were unchanged during a 3-month period of accelerating storage conditions. The results of the bioavailability testing in six healthy dogs suggested that the pH-dependent gradient-release delivery system could improve efficiently the uptake of the poorly water-soluble drug and prolong the Tmax value in vivo.

KW - Acrylates

KW - Administration, Oral

KW - Animals

KW - Biological Availability

KW - Delayed-Action Preparations

KW - Dogs

KW - Drug Carriers

KW - Drug Stability

KW - Hydrogen-Ion Concentration

KW - Male

KW - Methylcellulose

KW - Microscopy, Electron, Scanning

KW - Microspheres

KW - Nitrendipine

KW - Particle Size

KW - Polymers

KW - X-Ray Diffraction

U2 - 10.1016/j.jconrel.2004.04.022

DO - 10.1016/j.jconrel.2004.04.022

M3 - Journal article

C2 - 15262414

SN - 0168-3659

VL - 98

SP - 219

EP - 229

JO - Journal of Controlled Release

JF - Journal of Controlled Release

IS - 2

ER -