卡波姆与羟丙甲纤维素硬脂氧醚水凝胶中醋酸曲安奈德的稳定性考察

Investigation on Stability of Triamcinolone Acetonide Acetate in Hydrogels Containing Carbopol or Hydroxypropyl Methylcellulose Stearoxy Ether

本试验考察了酯类药物醋酸曲安奈德(1)在离子型聚合物卡波姆(Carbopol 940,CP)与非离子型聚合物羟丙甲纤维素硬脂氧醚(Sangelose 90L,SGL)水凝胶中的稳定性差异,为凝胶剂的处方选择提供依据。考察并对比了60℃下放置10 d,含1 1 mg/g的CP凝胶(0.5%)和SGL凝胶(0.5%)中药物含量的变化。为解析含量变化的可能原因,另将1(20μg/ml)溶解在含30%甲醇的不同溶媒(水,p H 4.7、5.8、7.4、9.18的磷酸盐缓冲液,0.01、0.1、1 mol/L的氯化钠溶液)中,测定其在25℃放置10 d的含量变化,考察p H值和中性盐对1水解的影响。结果表明,在SGL和CP凝胶中,1分别降为原来的82.0%和74.4%;在不同溶液(水,p H 4.7、5.8、7.4、9.18的磷酸盐缓冲液,0.01、0.1、1 mol/L的氯化钠溶液)中,1含量在d10分别降为原来的92.1%、25.0%、30.5%、33.9%、4.38%、89.5%、85.8%和82.8%。可知酸性或碱性环境会加速1的水解,中性条件下电解质会加速1的水解,因此推测1在非离子型凝胶SGL中比在离子型凝胶CP中稳定。酯类药物宜选用非离子型凝胶基质,并且处方中尽量避免加入电解质。

This paper investigated the stability of the ester drug triamcinolone acetonide acetate（TAA） in ionic Carbopol 940（CP） and in nonionic hydroxypropyl methylcellulose stearoxy ether（Sangelose 90 L, SGL） hydrogels to provide the basic guideline for gelling formulation. The content change of TAA（1 mg/g） dispersed in either CP（0.5%）or in SGL（0.5%） was examined during the storage at 60 ℃ for 10 d. To explore the possible reasons for the changes in content of TAA in CP and SGL gels, the stability of dissolved TAA（20 μg/ml） in respective solvents（water, phosphate buffers of p H 4.7, 5.8, 7.4 and 9.18, sodium chloride solutions of 0.01, 0.1 and 1 mol/L） containing 30% methanol was investigated during the storage at 25 ℃ for 10 d. The effects of p H value and neutral salts on the hydrolysis of TAA were studied. In the SGL and CP hydrogels, TAA decreased to 82.0% and 74.4%, respectively. In respective solutions（water, phosphate buffers of p H 4.7, 5.8, 7.4, and 9.18, sodium chloride solutions of 0.01, 0.1 and 1 mol/L）, TAA reduced to 92.1%, 25.0%, 30.5%, 33.9%, 4.38%, 89.5%, 85.8% and 82.8%. TAA was stable in methanol-water but unstable in acidic, especially in alkalic solutions. The stability of TAA decreased as the ionic strengths（concentrations of sodium chloride） of the solution increased in a neutral solution. By the catalysis of H~＋, OH^-or Lewis acid and salt effect, the ester bond could be induced to polarize and accelerate the hydrolysis. The triethanolammonium cation in CP hydrogel, as a Lewis acid, induced the ester bond of TAA polarizing and nucleophilic（OH^-） attacking to the carbonyl group resulting in promoting the hydrolysis of TAA. We concluded that TAA was more stable in the nonionic SGL hydrogel than in the ionic CP hydrogel. For ester drugs, it was suggested that nonionic polymer should be considered and electrolytes should be avoided in the hydrogel formulations.