Paul Willi, Sharma Chandra P
Division of Biosurface Technology, Biomedical Technology Wing, Sree Chitra Tirunal Institute for Medical Sciences & Technology, Thiruvananthapuram 695 012, India.
J Pharm Sci. 2008 Feb;97(2):875-82. doi: 10.1002/jps.21012.
Several attempts have been made for delivering insulin orally utilizing several polymers with varying degrees of effectiveness. A major obstacle associated with polymeric delivery system for protein or polypeptide drugs is the poor retention of the structure and its biological activity of encapsulated proteins particularly for the unstable insulin. Calcium phosphate ceramic is considered highly compatible to protein or peptide drugs, particularly insulin. Therefore, an attempt has been made to load insulin in tricalcium phosphate (TCP) microspheres and coat with pH sensitive polymer of methacrylate derivative, and to study the stability and conformational variations of loaded insulin, and finally the biological activity of the formulation in diabetic rats. TCP microspheres were prepared by a standard procedure. Human insulin was loaded in to these porous microspheres by diffusion filling and coated with Eudragit S100. This was subjected to in vitro release studies in simulated fluids and the stability and conformational variations of the released insulin were studied using photon correlation spectroscopy and circular dichroism (CD). Biological activity of the formulation was studied on induced diabetic rats. Insulin released in the intestinal fluid (SIF) maintained the native conformation without showing any aggregation. A dose dependent reduction of blood glucose level (BGL) was achieved in streptozotocin induced diabetic Wistar rats, demonstrating its biological activity. It has been established from this preliminary study that insulin loaded in to TCP microspheres is highly compatible with no degradation or loss of biological activity of loaded insulin. The TCP microsphere based delayed release formulation of insulin has effected a decrease in elevated glucose level in induced diabetic rats, establishing its feasibility towards the development of a noninvasive delivery device.
人们已经进行了多次尝试，利用多种聚合物口服递送胰岛素，效果各不相同。蛋白质或多肽药物聚合物递送系统的一个主要障碍是，包封蛋白质的结构及其生物活性保留不佳，尤其是对于不稳定的胰岛素而言。磷酸钙陶瓷被认为与蛋白质或肽类药物，特别是胰岛素具有高度相容性。因此，人们尝试将胰岛素负载于磷酸三钙（TCP）微球中，并用甲基丙烯酸酯衍生物的pH敏感聚合物进行包衣，研究负载胰岛素的稳定性和构象变化，最后研究该制剂在糖尿病大鼠中的生物活性。TCP微球通过标准程序制备。通过扩散填充将人胰岛素负载到这些多孔微球中，并用Eudragit S100进行包衣。将其在模拟流体中进行体外释放研究，并使用光子相关光谱和圆二色性（CD）研究释放的胰岛素的稳定性和构象变化。在诱导糖尿病大鼠上研究该制剂的生物活性。在肠液（SIF）中释放的胰岛素保持天然构象，未显示任何聚集。在链脲佐菌素诱导的糖尿病Wistar大鼠中实现了血糖水平（BGL）的剂量依赖性降低，证明了其生物活性。从这项初步研究可以确定，负载于TCP微球中的胰岛素具有高度相容性，负载的胰岛素没有降解或生物活性丧失。基于TCP微球的胰岛素延迟释放制剂使诱导糖尿病大鼠的升高血糖水平降低，确立了其用于开发非侵入性递送装置的可行性。
