Preparation Of Calcium Carbonate-containing Carriers For Oral Or Transdermal Drugs Delivery On Hypoglycemic Applications

Diabetes is a very common disease nowadays among the people of all age groups and has become a major health problem.More than 425 million people have been affected by diabetes in2017,which makes up around 8.8%of the adults population around the world,according to the report from International Diabetes Federation?IDF?.The traditional medical care for diabetics requires continuous glucose monitoring and subcutaneous injection of insulin to maintain the normoglycemia.However,it can be painful and result in poor compliance.In the past decades,a variety of sustained release systems have been developed for insulin delivery.Among them,the composite drug carrier has received extensive attention due to its multifunctional features.In this thesis,three kinds of calcium carbonate-containing composite drug carriers were prepared by using calcium carbonate compounded with organic polymers.Their hypoglycemic applications of oral administration or transdermal administration were studied,respectively.Specifically,this thesis mainly includes the following three parts:1.In order to overcome the malabsorption disorder of oral delivery of insulin,folic acid which can target with intestinal epithelial cells was modified to hyaluronic acid by animation reaction,and the synthesized products were characterized by Fourier transform infrared?FTIR?and nuclear magnetic resonance?¹H NMR?.The insulin-loaded calcium carbonates?INS-CaCO₃?were prepared by micro emulsion precipitation and folic acid modified hyaluronic acid as shell has been covered on CaCO₃ carriers.The morphology and particle size of obtained composite drug carriers were characterized by transmission electron microscopy?TEM?and dynamic light scattering?DLS?.The obtained composite drug carriers have lower cytotoxicity and well anti-protein degradation ability on HT-29 cells.In addition,the endocytosis of composite drug carriers by HT-29 cells was investigated by laser scanning confocal microscopy?CLSM?.Further study of oral administration by diabetic rats,the results show that oral hypoglycemic effect on a longer time compared with subcutaneous injection2.The insulin was immobilized in CaCO₃ by the precipitation reaction between calcium ion and carbonate ion under the regulation of polyvinylpyrrolidone?PVP?surfactant.Then,the microneedles were prepared from the gel which mixed INS-CaCO₃ microparticles and PVP matrix by using microneedle template method.Compared with pure PVP microneedles,the introduction of CaCO₃ can significantly enhance the compressive strength of microneedles and reduce the rate of dissolution after penetration into the skin.In addition,the prepared CaCO₃/PVP microneedles exhibited relatively lower cytotoxicity.The transdermal delivery of insulin was observed by laser confocal microscopy.The hypoglycemic effect of transdermal administration was also investigated.3.Bismuth?Bi?nanodots which possess near-infrared photothermal property were firstly prepared by rapid reduction method and characterized by transmission electron microscopy?TEM?,Energy-dispersive X-ray?EDX?,Fourier transform infrared spectroscopy?FTIR?and X-ray Diffraction?XRD?.The microneedles were also prepared by using the gel which mixed Bi nanodots,metformin,CaCO₃ and PVP.Then,the lauric acid was coated to the surface of the microneedles.Compared with the CaCO₃/PVP microneedles,the introduction of Bi nanodots allows the microneedles to heat up when irradiated with near-infrared light.In particular,when the mass fraction of Bi nanodots in the gel is 0.044%,the temperature of microneedles can be stabilized at about 47? under the irradiation of near-infrared light.Further,the dissolution process of microneedles and drug permeation process of metformin were measured when triggered by the near-infrared light.The hypoglycemic effect of the microneedles triggered by near-infrared light was also studied,and the results showed that the microneedles has longer hypoglycemic effect and higher drug utilization rate.