Design and in vitro evaluation of slow-release dosage form of piretanide: utility of beta-cyclodextrin:cellulose derivative combination as a modified-release drug carrier.
To modify the release rate of piretanide, a potent loop diuretic, a double-layer tablet was designed, and in vitro release was evaluated. For a rapidly releasing portion, hydrophilic beta-cyclodextrin derivatives were employed to form a water-soluble complex with piretanide. For a sustained-release portion, cellulose derivatives were used to provide appropriate hydrophobicity. The release rate of piretanide in the pH range 1.2-6.8 was automatically monitored by a pH-changeable dissolution testing apparatus. The low solubility of piretanide in acidic medium was significantly improved by complexations with dimethyl-beta-cyclodextrin (DM-beta-CyD) and hydroxypropyl-beta-cyclodextrin (HP-beta-CyD). The pH-independent slow release was attained by use of hydroxypropylcellulose (HPC):ethylcellulose (EC) matrices. Then, an optimal formulation of a double-layer tablet was obtained by the combination of each fraction. For example, the tablet consisting of the [DM-beta-CyD/(HPC:EC)] system in the weight ratio [1/3(1:3)] provided a sufficiently slow release of the drug over a period of 8 h in a wide pH region following an initial rapid dissolution.
Uekama
K
K
Faculty of Pharmaceutical Sciences, Kumamoto University, Japan.
Matsubara
K
K
Abe
K
K
Horiuchi
Y
Y
Hirayama
F
F
Suzuki
N
N
D002482:Cellulose / Q000031:analogs & derivatives; D002626:Chemistry, Pharmaceutical; D003460:Crystallization; D003505:Cyclodextrins; D003692:Delayed-Action Preparations; D004337:Drug Carriers; D006863:Hydrogen-Ion Concentration; D065347:Hypromellose Derivatives; D008747:Methylcellulose / Q000031:analogs & derivatives; D012995:Solubility; D013449:Sulfonamides / Q000008:administration & dosage*; D013607:Tablets; D014961:X-Ray Diffraction; D047392:beta-Cyclodextrins
D003505:Cyclodextrins; D003692:Delayed-Action Preparations; D004337:Drug Carriers; D013449:Sulfonamides; D013607:Tablets; D047392:beta-Cyclodextrins; D065347:Hypromellose Derivatives; C013517:ethyl cellulose; D002482:Cellulose; D008747:Methylcellulose; C008079:hydroxypropylcellulose; C015451:piretanide; C031215:betadex