Pose-Vilarnovo Beatriz, Rodríguez-Tenreiro Carmen, Rosa dos Santos José Fernando, Vázquez-Doval Juan, Concheiro Angel, Alvarez-Lorenzo Carmen, Torres-Labandeira Juan J
Departamento de Farmacia e Tecnoloxía Farmacéutica, Facultade de Farmacia, Universidade de Santiago de Compostela, Campus Sur, E-15782, Santiago de Compostela, Spain.
J Control Release. 2004 Feb 10;94(2-3):351-63. doi: 10.1016/j.jconrel.2003.10.002.
This paper reports on the effect of beta-cyclodextrin (beta-CD) and hydroxypropyl-beta-cyclodextrin (HP-beta-CD) on the diffusion and the release behavior of diclofenac sodium and sulphamethizole from HPMC K4M gels and matrix tablets. The gels were prepared with 0.5-2.0% polymer and different drug/CD mole ratios, and their viscosity, cloud point and drug diffusion coefficients were estimated. No differences in cloud point were observed. The viscosity of the gels strongly depended on HPMC proportions (from 0.7 to 100 mPa.s), which affected to a lesser extent the resistance to the diffusion of the drugs (D values from 60 x 10(-6) to 5 x 10(-6) cm(2)/s). The influence of CD on diffusion was particularly evident in gels prepared with polymer proportions above its entanglement concentration, 2.0% HPMC K4M. In these systems, while high drug/CD proportions enhanced the diffusivity preventing polymer/drug hydrophobic interactions, low drug/CD ratios hindered it. An excess of free CD, especially the bulky HP-beta-CD, made the diffusion of the complexes in the relatively low mesh size 2% polymer network more difficult. In the case of tablets, CD plays an additional role as dissolution rate promoter. To evaluate to what extent the balance between the increase in dissolution rate and the decrease in diffusion rate induced by CD determines drug release, matrix tablets were prepared by direct compression of 100 mg drug and 400 mg polymer/CD/lactose blends, whose composition was chosen following a simplex centroid design. A higher CD/lactose ratio significantly increased the release rate of hydrophobic drugs (sulphamethizole), but decreased the release rate of hydrophilic drugs (diclofenac sodium), indicating the predominance of a different contribution depending on the hydrophilicity of the drug. Therefore, the use of CD derivatives may be particularly useful to modulate drug release from HPMC gels and matrix tablets; the influence of these additives being dependent on the nature of the drug and on the molecular size and hydrophilic character of the CD used.
本文报道了β-环糊精（β-CD）和羟丙基-β-环糊精（HP-β-CD）对双氯芬酸钠和磺胺甲噻二唑从羟丙甲纤维素K4M凝胶和骨架片中的扩散及释放行为的影响。凝胶由0.5 - 2.0%的聚合物及不同的药物/环糊精摩尔比制备而成，并对其粘度、浊点和药物扩散系数进行了评估。未观察到浊点有差异。凝胶的粘度强烈依赖于羟丙甲纤维素的比例（从0.7到100 mPa·s），而这对药物扩散阻力的影响较小（扩散系数D值从60×10⁻⁶到5×10⁻⁶ cm²/s）。环糊精对扩散的影响在聚合物比例高于其缠结浓度（2.0%羟丙甲纤维素K4M）制备的凝胶中尤为明显。在这些体系中，高药物/环糊精比例增强了扩散性，防止聚合物/药物疏水相互作用，而低药物/环糊精比例则阻碍了扩散。过量的游离环糊精，尤其是体积较大的HP-β-CD，使复合物在相对低网孔尺寸的2%聚合物网络中的扩散更加困难。对于片剂，环糊精还起到了溶出速率促进剂的额外作用。为了评估环糊精引起的溶出速率增加和扩散速率降低之间的平衡在多大程度上决定药物释放，通过直接压片制备了骨架片，该片剂由100 mg药物和400 mg聚合物/环糊精/乳糖混合物组成，其组成按照单纯形重心设计选择。较高的环糊精/乳糖比例显著提高了疏水性药物（磺胺甲噻二唑）的释放速率，但降低了亲水性药物（双氯芬酸钠）的释放速率，这表明取决于药物亲水性的不同作用占主导地位。因此，使用环糊精衍生物可能对调节药物从羟丙甲纤维素凝胶和骨架片中的释放特别有用；这些添加剂的影响取决于药物的性质以及所用环糊精的分子大小和亲水特性。
