Solid dispersions of itraconazole for inhalation with enhanced dissolution, solubility and dispersion properties
Solid dispersions of itraconazole for inhalation with enhanced dissolution, solubility and dispersion properties
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DOI：
10.1016/j.ijpharm.2012.03.002
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发表时间：
2012-05-30
影响因子：
5.8
通讯作者：
Amighi, Karim
中科院分区：
文献类型：
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作者：
Duret, Christophe;Wauthoz, Nathalie;Amighi, Karim
本研究的目的是生产一种溶解性差的活性成分（伊曲康唑：ITZ）的吸入用干粉（DPI），该干粉将呈现出改善的溶出速率和增强的溶解度以及良好的雾化特性。无定形ITZ、甘露醇和（当适用时）D-α-生育酚聚乙二醇1000琥珀酸酯（TPGS）的固体分散体通过喷雾干燥其中溶解有所有试剂的水-醇溶液来制备。这些干制剂的特征在于它们的气雾剂性能和它们的溶解度、溶解度和物理性质。调制差示扫描量热法和X-射线粉末衍射分析表明，从不同的喷雾干燥的解决方案中回收的ITZ是在一个无定形状态和甘露醇是结晶。喷雾干燥过程中选择的入口干燥温度和间接的出口温度是关键参数。出口温度应低于ITZ玻璃化转变温度，以避免严重的颗粒团聚。无定形ITZ和甘露醇之间的固体分散体的形成允许制备具有改善的溶解速率、比本体ITZ更大的饱和溶解度和良好的气溶胶性质的干粉。聚合物表面活性剂（如TPGS）的使用在溶解速率加速和溶解度增强方面是有益的，但它也降低了气雾剂性能。例如，当引入1%（w/w）TPGS时，获得了显著的溶出速率加速（f（2）< 50）和更大的饱和溶解度（平均溶出时间从50.4分钟下降到36.9分钟，饱和溶解度从20 +/-3 ng/ml增加到46 +/-2 ng/ml）。然而，细颗粒分数从47 +/-2%降至37.2 +/-0.4%。该研究表明，甘露醇固体分散体可以提供用于生产溶解性差的活性成分的DPI的有效制剂类型，如ITZ所例示的。(C)2012爱思唯尔有限公司版权所有。
The purpose of this study was to produce a dry powder for inhalation (DPI) of a poorly soluble active ingredient (itraconazole: ITZ) that would present an improved dissolution rate and enhanced solubility with good aerosolization properties. Solid dispersions of amorphous ITZ, mannitol and, when applicable, D-alpha-tocopherol polyethylene glycol 1000 succinate (TPGS) were produced by spray-drying hydro-alcoholic solutions in which all agents were dissolved. These dry formulations were characterized in terms of their aerosol performances and their dissolution, solubility and physical properties. Modulate differential scanning calorimetry and X-ray powder diffraction analyses showed that ITZ recovered from the different spray-dried solutions was in an amorphous state and that mannitol was crystalline. The inlet drying temperature and, indirectly, the outlet temperature selected during the spray-drying were critical parameters. The outlet temperature should be below the ITZ glass transition temperature to avoid severe particle agglomeration. The formation of a solid dispersion between amorphous ITZ and mannitol allowed the dry powder to be produced with an improved dissolution rate, greater saturation solubility than bulk ITZ and good aerosol properties. The use of a polymeric surfactant (such as TPGS) was beneficial in terms of dissolution rate acceleration and solubility enhancement, but it also reduced aerosol performance. For example, significant dissolution rate acceleration (f(2) < 50) and greater saturation solubility were obtained when introducing 1% (w/w) TPGS (mean dissolution time dropped from 50.4 min to 36.9 min and saturation solubility increased from 20 +/- 3 ng/ml to 46 +/- 2 ng/ml). However, the fine particle fraction dropped from 47 +/- 2% to 37.2 +/- 0.4%. This study showed that mannitol solid dispersions may provide an effective formulation type for producing DPIs of poorly soluble active ingredients, as exemplified by ITZ. (C) 2012 Elsevier B.V. All rights reserved.