Division of Pharmaceutics, The University of Texas at Austin, Austin, TX, USA.
Drug Dev Ind Pharm. 2010 Sep;36(9):1064-78. doi: 10.3109/03639041003652973.
To investigate the ability of KinetiSol Dispersing to prepare amorphous solid dispersions of itraconazole using concentration-enhancing polymers.
Concentration-enhancing nature of several cellulosic polymers (HPMC, hypromellose acetate succinate) was studied using a modified in vitro dissolution test. Solid dispersions were prepared by KinetiSol Dispersing and characterized for solid-state properties using X-ray diffraction and differential scanning calorimetry. Potency and release characteristics were also assessed by high-performance liquid chromatography. Oral bioavailability of lead formulations was also assessed in animal models.
Screening studies demonstrated superior concentration-enhancing performance from the hypromellose acetate succinate polymer class. Data showed that stabilization was related to molecular weight and the degree of hydrophobic substitution on the polymer such that HF > MF approximately LF, indicating that stabilization was achieved through a combination of steric hindrance and hydrophobic interaction, supplemented by the amphiphilic nature and ionization state of the polymer. Solid dispersions exhibited amorphous solid-state behavior and provided neutral media supersaturation using a surfactant-free pH change method. Rank-order behavior was such that LF > MF > HF. Addition of Carbopol 974P increased acidic media dissolution, while providing a lower magnitude of supersaturation in neutral media because of swelling of the high viscosity gel. In vivo results for both lead compositions displayed erratic absorption was attributed to the variability of gastrointestinal pH in the animals.
These results showed that production of amorphous solid dispersions containing concentration-enhancing polymers through KinetiSol Dispersing can provide improved oral bioavailability; however, additional formulation techniques must be developed to minimize variability associated with natural variations in subject gastrointestinal physiology.
研究 KinetiSol 分散法用增溶聚合物制备伊曲康唑无定形固体分散体的能力。
使用改良的体外溶解试验研究了几种纤维素聚合物（HPMC、醋酸琥珀酸羟丙甲纤维素）的增溶性质。通过 KinetiSol 分散法制备固体分散体，并通过 X 射线衍射和差示扫描量热法对其固态特性进行表征。还通过高效液相色谱法评估了效力和释放特性。还在动物模型中评估了铅制剂的口服生物利用度。
筛选研究表明，醋酸琥珀酸羟丙甲纤维素聚合物类具有优越的增溶性能。数据表明，稳定性与聚合物的分子量和疏水性取代程度有关，即 HF > MF ≈ LF，表明稳定性是通过空间位阻和疏水相互作用的结合以及聚合物的两亲性和电离状态来实现的。固体分散体表现出无定形的固态行为，并通过无表面活性剂的 pH 变化法提供中性介质过饱和度。按等级顺序，LF > MF > HF。添加 Carbopol 974P 增加了酸性介质的溶解度，同时由于高粘度凝胶的溶胀，在中性介质中提供了较低的过饱和度。两种铅制剂的体内结果均显示不规则的吸收归因于动物胃肠道 pH 值的可变性。
这些结果表明，通过 KinetiSol 分散法生产含有增溶聚合物的无定形固体分散体可以提高口服生物利用度；然而，必须开发额外的制剂技术来最小化与受试者胃肠道生理学自然变化相关的变异性。
