Division of Pharmaceutics, The University of Texas at Austin, 1 University Station A1920, Austin, TX 78712, United States.
Eur J Pharm Sci. 2013 Mar 12;48(4-5):758-66. doi: 10.1016/j.ejps.2013.01.004. Epub 2013 Jan 21.
The dissolution enhancement advantages inherent to amorphous solid dispersions systems are often not fully realized once they are formulated into a solid dosage form. The objective of this study was to investigate the ability of inorganic salts to improve the dissolution rate of carbamazepine (CBZ) from tablets containing a high loading of a Soluplus®-based solid dispersion. Cloud point and viscometric studies were conducted on Soluplus® solutions to understand the effect of temperature, salt type and salt concentration on the aqueous solubility and gelling tendencies of Soluplus®, properties that can significantly impact dissolution performance. Studies indicated that Soluplus® exhibited a cloud point that was strongly dependent on the salt type and salt concentration present in the dissolving medium. The presence of kosmotropic salts dehydrated the polymer, effectively lowering the cloud point and facilitating formation of a thermoreversible hydrogel. The ability of ions to impact the cloud point and gel strength generally followed the rank order of the Hofmeister series. Solid dispersions of CBZ and Soluplus® were prepared by KinetiSol® Dispersing, characterized to confirm an amorphous composition was formed and incorporated into tablets at very high levels (70% w/w). Dissolution studies demonstrated the utility of including salts in tablets to improve dissolution properties. Tablets that did not contain a salt or those that included a chaotropic salt hydrated at the tablet surface and did not allow for sufficient moisture ingress into the tablet. Conversely, the inclusion of kosmotropic salts allowed for rapid hydration of the entire tablet and the formation of a gel structure with strength dependent on the type of salt utilized. Studies also showed that, in addition to allowing tablet hydration, potassium bicarbonate and potassium carbonate provided effervescence which effectively destroyed the gel network and allowed for rapid dissolution of CBZ. Subsequent dissolution studies in 0.1 N HCl showed that potassium bicarbonate was an effective tablet disintegrant at levels as low as 1% and provided for tablets that rapidly disintegrated over a wide range of applied compression forces, presumably due to synergy between the ability to form a weak hydrogel structure and carbon dioxide liberation. Similar dissolution performance was measured in pH 4.5 acetate buffer, despite reduced polymer solubility caused by kosmotropic salts in solution, demonstrating robustness. With the use of inorganic salts such as potassium bicarbonate, it may be possible to substantially improve disintegration and dissolution characteristics of tablets containing Soluplus®.
无定形固体分散体系统固有的溶解增强优势，在将其制成固体制剂后，往往无法完全实现。本研究的目的是考察无机盐提高高载量基于 Soluplus®的固体分散体的卡马西平（CBZ）片剂溶出度的能力。通过浊点和黏度研究对 Soluplus®溶液进行了研究，以了解温度、盐类型和盐浓度对 Soluplus®的水溶性和胶凝趋势的影响，这些性质会显著影响溶解性能。研究表明，Soluplus®表现出强烈依赖于溶解介质中盐类型和盐浓度的浊点。反离子盐使聚合物脱水，有效地降低浊点并促进热可逆水凝胶的形成。离子影响浊点和凝胶强度的能力通常遵循豪夫迈斯特序列的等级顺序。通过 KinetiSol®分散法制备 CBZ 和 Soluplus®的固体分散体，对其进行了表征以确认形成了无定形组成并以非常高的水平（70%w/w）掺入片剂中。溶解研究表明，在片剂中包含盐以改善溶解性能是有用的。不包含盐的片剂或包含亲水性盐的片剂在片剂表面水合，并且不允许足够的水分进入片剂。相反，包含反离子盐允许整个片剂快速水合，并形成具有强度取决于所使用盐类型的凝胶结构。研究还表明，除了允许片剂水合外，碳酸氢钾和碳酸钾还提供了泡腾作用，有效地破坏了凝胶网络，并允许 CBZ 快速溶解。随后在 0.1 N HCl 中的溶解研究表明，碳酸氢钾在低至 1%的水平下是有效的片剂崩解剂，并提供了在广泛的施加压缩力下快速崩解的片剂，这可能是由于形成弱水凝胶结构的能力和二氧化碳释放之间的协同作用。在 pH4.5 醋酸盐缓冲液中测量到相似的溶解性能，尽管由于溶液中的反离子盐导致聚合物溶解度降低，但仍具有稳健性。使用碳酸氢钾等无机盐，可能会大大改善含有 Soluplus®的片剂的崩解和溶解特性。
