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A number of gel formulations were developed for bendroflumethiazide (BFTZ). The gels were composed of BFTZ dissolved in an alcohol–polyol–water medium and mixed with polyacrylic acid. Based on preformulation studies it was determined that a transdermal therapeutic system (TTS) could be constructed with 5% BFTZ, 40% ethanol (EtOH), 20% of a 1:1 mixture of 2-pyrrolidone and N-methyl-2-pyrrolidone (pyrol), 2% polyacrylic acid (PA) and 33% purified water, sandwiched between an aluminum foil backing and a porous polypropylene rate-control membrane. The device was tested, with and without the rate-control membrane, by in vitro diffusion across whole thickness SKH-1 hairless mouse skin and by in vivo percutaneous absorption in New Zealand White rabbits. In vitro results indicate that this device will deliver BFTZ at penetration rates of 0.66 and 0.98 μg/cm2 per h across hairless mouse skin, with and without the rate-control membrane, respectively. In vivo results show that blood levels of 50–300 ng/ml could be reached over a 12-h dosing period. Stability studies on the gel formulation and the TTS indicate that elevated storage temperatures will change the viscosity of the gel matrix and the release of BFTZ from the device. |
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