Pillay Viness, Danckwerts Michael P, Fassihi Reza
University of the Witwatersrand, Department of Pharmacy and Pharmacology, Medical School, Johannesburg, Gauteng, South Africa.
Drug Deliv. 2002 Apr-Jun;9(2):77-86. doi: 10.1080/10426500290095593.
This study proposes a novel binary crosslinked ternary multiple-unit system, collectively referred to as calcium-alginate-pectinate-cellulose acetophthalate gelispheres (CAPCA), for the purpose of obtaining linear, controlled drug release. This polymeric system, composed of sodium alginate, pectin, and cellulose acetophthalate, was developed through a binary crosslinking reaction in a composite aqueous system consisting of calcium and acetate ions. The crosslinking reaction was optimized in terms of maximizing drug release suppression and could be obtained by exposing the gelispheres for 24 hours to a combined aqueous solution of 15% w/v acetic acid and 2% w/v calcium chloride. The highly acidic nature of this solution (pH 1.9) was desirable for enhancing the drug entrapment efficiency of the gelispheres. Synchronization of matrix swelling and erosion appeared to be responsible for the attainment of zero-order drug release. However, such perfect synchronization was only achievable through application of the ternary polymeric combination presented in this work. The main advantages of the ternary system shown in this study over the previously presented binary calcium-alginate-pectinate system (CAP) proposed by Pillay and Fassihi (1999a, 1999b), was provision of extended drug release over 18 hours, minimization of late-phase drug release tapering, and provision of superior linearity in drug release profiles. Kinetic modeling of dissolution data using various power law equations highlighted the significance of matrix relaxation and erosion in modulation of drug release rate. In all cases of model fitting excellent correlation (r(2) > 0.98) was obtained between observed and predicted data. Textural profiling of crosslinked gelispheres reflected a significantly lower reduction in matrix resilience as the concentration of cellulose acetophthalate was increased in the gelisphere formulation. This may be attributed to the concentration-dependent matrix plastic-transforming property of cellulose acetophthalate.
本研究提出了一种新型的二元交联三元多单元系统，统称为藻酸钙-果胶-醋酸纤维素凝胶球（CAPCA），目的是实现线性、可控的药物释放。该聚合物系统由海藻酸钠、果胶和醋酸纤维素组成，是在由钙离子和醋酸根离子组成的复合水体系中通过二元交联反应形成的。交联反应在最大程度抑制药物释放方面进行了优化，通过将凝胶球暴露于15% w/v醋酸和2% w/v氯化钙的混合水溶液中24小时可实现。该溶液的高酸性（pH 1.9）有利于提高凝胶球的药物包封效率。基质溶胀和侵蚀的同步似乎是实现零级药物释放的原因。然而，只有通过应用本研究中提出的三元聚合物组合才能实现这种完美的同步。本研究中所示的三元系统相对于Pillay和Fassihi（1999a，1999b）之前提出的二元藻酸钙-果胶系统（CAP）的主要优点是药物释放延长超过18小时，晚期药物释放逐渐减少最小化，以及药物释放曲线具有更好的线性。使用各种幂律方程对溶解数据进行动力学建模突出了基质松弛和侵蚀在调节药物释放速率方面的重要性。在所有模型拟合情况下，观察到的数据与预测数据之间都具有极好的相关性（r(2) > 0.98）。交联凝胶球的质地分析表明，随着凝胶球配方中醋酸纤维素浓度的增加，基质弹性的降低明显减少。这可能归因于醋酸纤维素的浓度依赖性基质塑性转变特性。
