Barreiro-Iglesias Rafael, Bromberg Lev, Temchenko Marina, Hatton T Alan, Alvarez-Lorenzo Carmen, Concheiro Angel
Departamento de Farmacia y Tecnología Farmacéutica, Facultad de Farmacia, Universidad de Santiago de Compostela, 15782 Santiago de Compostela, Spain.
Eur J Pharm Sci. 2005 Dec;26(5):374-85. doi: 10.1016/j.ejps.2005.07.014. Epub 2005 Sep 13.
Potential utility of copolymers comprising Pluronic (PEO-PPO-PEO) surfactants covalently conjugated with poly(acrylic acid) (PAA) as excipients for sustained-release tablets was explored. Apparent particle density, particle size distribution, Carr index, thermal stability, and compression behavior of the Pluronic-PAA copolymers were characterized. Tablets prepared by direct compression of blends of Pluronic-PAA copolymers were evaluated on the basis of their thermomechanical profile, crushing strength, friability, and drug release properties. Small molecular weight drugs of aqueous solubility decreasing in the order theophylline>hydrochlorothiazide>nitrofurantoin were incorporated to the tablets. For comparison purposes, tablets were also prepared from PAA of Carbopol 71G (C71G), and mixtures of C71G and Pluronic F127, with each of the above three drugs. The Pluronic-PAA aggregates are stabilized by hydrophobic associations between poly(propylene oxide) (PPO) segments in aqueous solutions, and thus require higher ionization of the carboxylic groups to overcome the associations and swell. The swelling pattern of the Pluronic-PAA copolymers is more dramatically pH-dependent than that of Carbopol lacking any hydrophobic associations. The drug retention in and release from the Pluronic-PAA based tablets is profoundly pH-dependent and hence specific to the pH exceeding that of the pK(a)>5 of these copolymers. Theophylline- and hydrochlorotiazide-containing tablets made with Pluronic-PAA copolymers showed a reduced release rate under acidic conditions compared to the neutral or alkaline conditions, while the opposite pattern was observed with the Carbopol-based tablets due to the different pH-dependent swelling behavior of the polymers. Nitrofurantoin-containing tablets showed a remarkably low drug release rate owing to the strong hydrophobic character of nitrofurantoin and of its complexes with the copolymers. Integrity of the nitrofurantoin-containing tablets was maintained during the 24h release test. Zero-order kinetics of the cumulative release profile of all drugs under study was observed with the Pluronic-PAA as a tablet excipient. Adequate mechanical properties, the self-assembling behavior, and the pH-sensitiveness of the Pluronic-PAA copolymers make them promising excipients for tablets with preferential delivery into a neutral to alkaline pH environment.
探索了包含与聚丙烯酸（PAA）共价共轭的普朗尼克（PEO-PPO-PEO）表面活性剂的共聚物作为缓释片辅料的潜在用途。对普朗尼克-PAA共聚物的表观颗粒密度、粒度分布、卡尔指数、热稳定性和压缩行为进行了表征。基于其热机械曲线、抗压强度、脆碎度和药物释放特性，对通过直接压片法制备的普朗尼克-PAA共聚物混合物片剂进行了评估。将水溶性按氨茶碱>氢氯噻嗪>呋喃妥因顺序降低的小分子药物加入片剂中。为作比较，还分别用卡波姆71G（C71G）的PAA以及C71G与普朗尼克F127的混合物，与上述三种药物中的每一种制备片剂。普朗尼克-PAA聚集体在水溶液中通过聚环氧丙烷（PPO）链段之间的疏水缔合作用得以稳定，因此需要更高程度的羧基离子化来克服缔合并发生溶胀。与缺乏任何疏水缔合作用的卡波姆相比，普朗尼克-PAA共聚物的溶胀模式对pH的依赖性更强。基于普朗尼克-PAA的片剂中药物的保留和释放对pH有很强的依赖性，因此特定于pH超过这些共聚物pK(a)>5的情况。与中性或碱性条件相比，用普朗尼克-PAA共聚物制成的含氨茶碱和氢氯噻嗪的片剂在酸性条件下显示出较低的释放速率，而由于聚合物不同的pH依赖性溶胀行为，基于卡波姆的片剂则呈现相反的模式。含呋喃妥因的片剂显示出极低的药物释放速率，这是由于呋喃妥因及其与共聚物的络合物具有很强的疏水性。在24小时释放试验期间，含呋喃妥因片剂的完整性得以保持。以普朗尼克-PAA作为片剂辅料时，观察到所有研究药物的累积释放曲线均符合零级动力学。普朗尼克-PAA共聚物具有足够的机械性能、自组装行为和pH敏感性，使其成为有望用于优先递送至中性至碱性pH环境的片剂的辅料。
