Department of Pharmaceutics, Manipal College of Pharmaceutical Sciences, Manipal University, Manipal, Karnataka 576104, India.
J Mater Sci Mater Med. 2011 Apr;22(4):865-78. doi: 10.1007/s10856-011-4274-y. Epub 2011 Mar 23.
The purpose of this study was to develop sustained release formulation of anastrozole-loaded chitosan microspheres for treatment of breast cancer. Chitosan microspheres cross-linked with two different cross-linking agents viz, tripolyphosphate (TPP) and glutaraldehyde (GA) were prepared using single emulsion (w/o) method. A reverse phase HPLC method was developed and used for quantification of drug in microspheres and rat plasma. Influence of cross-linking agents on the properties of chitosan microspheres was extensively investigated. Formulations were characterized for encapsulation efficiency (EE), compatibility of drug with excipients, particle size, surface morphology, swelling capacity, erosion and drug release profile in phosphate buffer pH 7.4. EE varied from 30.4 ± 1.2 to 69.2 ± 3.2% and mean particle size distribution ranged from 72.5 ± 0.5 to 157.9 ± 1.5 μm. SEM analysis revealed smooth and spherical nature of microspheres. TPP microspheres exhibited higher swelling capacity, percentage erosion and drug release compared to GA microspheres. Release of anastrozole (ANS) was rapid up to 4 h followed by slow release status. FTIR analysis revealed no chemical interaction between drug and polymer. DSC analysis indicated ANS trapped in the microspheres existed in amorphous form in polymer matrix. The highest correlation coefficients (R (2)) were obtained for Higuchi model, suggesting a diffusion controlled mechanism. There was significant difference in the pharmacokinetic parameters (AUC(0-∞), Kel and t(1/2)) when ANS was formulated in the form of microspheres compared to pure drug. This may be attributed to slow release rate of ANS from chitosan microspheres and was detectable in rat plasma up to 48 h which correlates well with the in vitro release data.
本研究旨在开发阿那曲唑载壳聚糖微球的缓释制剂，用于治疗乳腺癌。采用单乳液（w/o）法制备了两种不同交联剂（三聚磷酸钠（TPP）和戊二醛（GA））交联的壳聚糖微球。建立了反相高效液相色谱法，并用于微球和大鼠血浆中药物的定量分析。广泛研究了交联剂对壳聚糖微球性质的影响。对制剂的包封效率（EE）、药物与赋形剂的相容性、粒径、表面形态、溶胀能力、侵蚀和在磷酸盐缓冲液 pH 7.4 中的药物释放情况进行了表征。EE 从 30.4±1.2%到 69.2±3.2%变化，平均粒径分布从 72.5±0.5μm到 157.9±1.5μm变化。SEM 分析表明微球具有光滑和球形的性质。与 GA 微球相比，TPP 微球表现出更高的溶胀能力、百分比侵蚀和药物释放。阿那曲唑（ANS）的释放在前 4 小时迅速，随后是缓慢释放状态。FTIR 分析表明药物与聚合物之间没有化学相互作用。DSC 分析表明，聚合物基质中 ANS 以无定形形式存在于微球中。Higuchi 模型获得了最高的相关系数（R（2）），表明释放机制为扩散控制。与纯药物相比，当 ANS 以微球的形式配制时，药代动力学参数（AUC（0-∞）、Kel 和 t（1/2））有显著差异。这可能归因于 ANS 从壳聚糖微球中的缓慢释放速率，并且在大鼠血浆中可检测到长达 48 小时，这与体外释放数据吻合良好。
