van Drooge D J, Hinrichs W L J, Frijlink H W
Department of Pharmaceutical Technology and Biopharmacy, Groningen University Institute of Drug Exploration (GUIDE), Antonius Deusinglaan 1, 9713AV, Groningen, The Netherlands.
J Control Release. 2004 Jul 7;97(3):441-52. doi: 10.1016/j.jconrel.2004.03.018.
In this study, anomalous dissolution behaviour of tablets consisting of sugar glass dispersions was investigated. The poorly aqueous soluble diazepam was used as a lipophilic model drug. The release of diazepam and sugar carrier was determined to study the mechanisms governing dissolution behaviour. The effect of carrier dissolution rate and drug load was tested with four different sugars, in the order of decreasing dissolution rates: sucrose, trehalose and two oligo-fructoses; inulinDP11 and inulinDP23 having a number average degree of polymerization (DP) of 11 and 23, respectively. Diazepam was incorporated in these sugar glasses in the amorphous state by means of freeze drying using water and tertiary butyl alcohol (TBA) as solvents. None of the tablets disintegrated during dissolution. Dissolution of 80% of the lipophilic drug within 20 min was found when diazepam and sugar dissolution profiles coincided. The sugar carrier and diazepam dissolved at the same rate, which was constant in time and fast. This condition was met for relatively slow dissolving carriers like the inulins or for low drug loads. For relatively fast dissolving carriers like sucrose or trehalose with high drug loads, release profiles of diazepam and sugar did not coincide: diazepam dissolved much more slowly than the sugars. In case of non-coinciding release profiles, diazepam release was split into three phases. During the first phase non-steady-state dissolution was observed: diazepam release accelerated and a drug rich layer consisting of crystalline diazepam was gradually formed. This first phase determined the further release of diazepam. During the second phase a steady-state release rate was reached: zero-order release was observed for both drug and carrier. During this phase, the remaining (non-crystallised) solid dispersion is dissolved without the further occurrence of crystallisation. The third phase, starting when all carrier is dissolved, involved the very slow dissolution of crystallised diazepam, which was present either as the skeleton of a tablet resulting in a zero-order release profile or as separate particles dispersed in the dissolution medium resulting in a first-order release. To understand the anomalous dissolution behaviour, a model is proposed. It describes the phenomena during dissolution of amorphous solid dispersion tablets and explains that fast dissolution is observed for low drug loads or slow dissolving carriers like inulin.
在本研究中，对由糖玻璃分散体组成的片剂的异常溶解行为进行了研究。水溶性差的地西泮被用作亲脂性模型药物。测定地西泮和糖载体的释放情况，以研究控制溶解行为的机制。用四种不同的糖测试了载体溶解速率和药物负载量的影响，按照溶解速率降低的顺序排列：蔗糖、海藻糖和两种低聚果糖；菊粉DP11和菊粉DP23的数均聚合度（DP）分别为11和23。通过使用水和叔丁醇（TBA）作为溶剂进行冷冻干燥，将地西泮以无定形状态掺入这些糖玻璃中。在溶解过程中，没有片剂崩解。当地西泮和糖的溶解曲线一致时，发现亲脂性药物在20分钟内溶解了80%。糖载体和地西泮以相同的速率溶解，该速率在时间上是恒定的且很快。对于像菊粉这样溶解较慢的载体或低药物负载量，满足该条件。对于像蔗糖或海藻糖这样溶解较快且药物负载量高的载体，地西泮和糖的释放曲线不一致：地西泮的溶解比糖慢得多。在释放曲线不一致的情况下，地西泮的释放分为三个阶段。在第一阶段观察到非稳态溶解：地西泮的释放加速，由结晶地西泮组成的富药层逐渐形成。第一阶段决定了地西泮的进一步释放。在第二阶段达到稳态释放速率：药物和载体均观察到零级释放。在该阶段，剩余的（未结晶的）固体分散体溶解，不再发生结晶。第三阶段，当所有载体溶解时开始，涉及结晶地西泮的非常缓慢的溶解，其要么作为片剂的骨架存在，导致零级释放曲线，要么作为分散在溶解介质中的单独颗粒存在，导致一级释放。为了解释这种异常溶解行为，提出了一个模型。它描述了无定形固体分散体片剂溶解过程中的现象，并解释了对于低药物负载量或像菊粉这样溶解较慢的载体观察到快速溶解的原因。
