Serres A, Baudys M, Kim S W
University of Utah, Department of Pharmaceutics and Pharmaceutical Chemistry, Center for Controlled Chemical Delivery, Salt Lake City 84112, USA.
Pharm Res. 1996 Feb;13(2):196-201. doi: 10.1023/a:1016026711364.
Stimuli-sensitive polymers are suitable candidates for oral peptide drug delivery vehicles since they will prevent gastric degradation in the stomach while providing a controlled release of a peptide drug such as calcitonin later. The purpose of this study was to fabricate polymeric beads from pH/temperature sensitive linear terpolymers (poly(N-isopropylacrylamide-co-butylmethacrylate-co-acrylic acid) and load them with a peptide drug, human calcitonin, which was dissolved in aqueous phase.
The polymeric beads were formed by solubilizing a cold, aqueous solution of temperature sensitive polymer with human calcitonin. This solution was added dropwise into an oil bath kept at a temperature above the LCST of a polymer, precipitating polymer and entrapping the peptide. The quantity and the physical state of the peptide were analyzed by reverse-phase HPLC, CD and FTIR and its biological activity after loading was determined in vivo.
The loading efficiency and stability of human calcitonin into the polymeric beads was studied as a function of pH and ionic strength of the loading buffer and temperature of the oil bath. Final optimal loading conditions were 20 mM glycine/HCl buffer, pH 3.0 containing 0.15 M NaCl as a dissolution medium and 23 degrees C as the oil bath temperature. Loading and release of human calcitonin were also studied as a function of acrylic acid content in the terpolymers. As the acrylic acid content increased from 0 to 10 mol %, the loading efficiency and stability of calcitonin improved significantly. The same trend was observed for the quantity of released calcitonin. In vivo biological activity of the released hormone was preserved.
The results showed that the beads made of the polymers with high content of acrylic acid (most hydrophilic) provided better loading, stability and release of human calcitonin. The designed beads represent a new potential system for oral delivery of calcitonin and other peptides.
刺激敏感型聚合物是口服肽类药物递送载体的合适候选物，因为它们能在胃中防止肽类药物降解，同时随后能实现如降钙素等肽类药物的控释。本研究的目的是由pH/温度敏感的线性三元共聚物（聚（N-异丙基丙烯酰胺-共-甲基丙烯酸丁酯-共-丙烯酸））制备聚合物微球，并将其负载溶于水相的肽类药物人降钙素。
通过将温度敏感型聚合物的冷水溶液与人降钙素溶解来形成聚合物微球。将该溶液逐滴加入保持在聚合物最低临界溶液温度以上的油浴中，使聚合物沉淀并包封肽。通过反相高效液相色谱、圆二色光谱和傅里叶变换红外光谱分析肽的量和物理状态，并在体内测定负载后其生物活性。
研究了人降钙素负载到聚合物微球中的负载效率和稳定性与负载缓冲液的pH和离子强度以及油浴温度的关系。最终的最佳负载条件是20 mM甘氨酸/盐酸缓冲液，pH 3.0，含有0.15 M氯化钠作为溶解介质，油浴温度为23℃。还研究了人降钙素的负载和释放与三元共聚物中丙烯酸含量的关系。随着丙烯酸含量从0增加到10 mol%，降钙素的负载效率和稳定性显著提高。降钙素释放量也观察到相同趋势。释放的激素的体内生物活性得以保留。
结果表明，由高含量丙烯酸（最亲水）的聚合物制成的微球能更好地负载、稳定和释放人降钙素。所设计的微球代表了一种用于口服递送降钙素和其他肽的新的潜在系统。
