| Diabetes is a chronic systemic metabolic disease, often accompanied by some other symptoms, ie. polyuria, polydipsia, polyphagia and weight loss. Recent years, the incidence rate of diabetes is increasing. According to the new version of the world’s "Diabetes Map" issued by the International Diabetes Federation (IDF) in 2013, about 98.4 million people was with diabetes in China, ranking first in the world; and it is estimated that the number of diabetes in China will be 143 million in 2035. Diabetes has become "the third killer" with cardiovascular disease and cancer hazard to human health, which brought a major crisis to human health, and also a huge economic burden to the whole society.In recent years, more and more drugs for diabetes treatment are produced, but insulin is still the most important and most effective one. In clinical treatment, the most common administration for insulin is subcutaneous, but the long-term injection often make patients painful, and usually lead to inflammation, nodules and some other adverse reactions. Transdermal drug delivery is the ideal way of insulin administration, due to its non-invasive and sustained release characteristics, and no adverse reactions caused by the too high drug concentration instantly. Since insulin is a protein macromolecular drug with a molecular weight of approximately 5800Da, it is difficult to penetrate through the dense corneum structure and then into the body circulation naturally. Therefore, studies on searching a suitable carrier and combining it with other penetration enhancers to improve the transdermal absorption of insulin are in hot.In this paper, we chose chitosan as carrier to load the insulin into the nanoparticles. The invitro transdermal behaviors of insulin-loaded quaternized chitosan nanoparticles (IQCNPs), as well as electret joint IQCNPs were explored. The mechanism of the enhancement of electret on insulin transdermal penetration was also studied. This paper is divided into the following four parts:1. Preparation of insulin-loaded quaternized chitosan nanoparticlesWe used insulin as model drug, quaternized chitosan as carrier, tripolyphosphate as crosslinking agent to prepare the insulin-loaded quaternized chitosan nanoparticles by ion crosslinked method. The IQCNPs were characterized and the prescription was optimized by single factor and orthogonal design.The results showed that the IQCNPs prepared under the optimism prescription were with good morphology, small size and good encapsulation efficiency, which satisfied the requirement of experiment.2. In vitro transdermal evaluation of nanoparticles based electret transdermal system for insulinThe in vitro transdermal behaviors of insulin solution, IQCNPs, and electret joint IQCNPs were studied by using the improved Franz diffusion cell.The results showed that the IQCNPs prepared in this study could significantly increase the insulin transdermal delivery as compared with that of the insulin solution. However, positive electrets could significantly increase the transdermal delivery of insulin from IQCNPs as compared with that of single use of IQCNPs. The enhancing effect of positive electrets on insulin transdermal delivery from IQCNPs increased with the surface potential of electret. Therefore, combination of electret and nanoparticles was a good strategy for transdermal delivery of macromolecular drugs.3. The effects of electric field of electrets on preparation of nanoparticlesIn this part, we prepared insulin-loaded quaternized chitosan nanoparticles under the electric field of electrets, and then characterized them. The in vitro transdermal penetration experiment was also carried out. The results showed that not only the IQCNPs prepared under the electric field were also with good morphology and small size, but the encapsulation efficiency was significantly increased. The cumulative penetration amount was higer than that of the normal ones. Therefore, it was possible to use the electric field of electrets to significantly increase the encapsultion efficiency and the transdermal delivery of macromolecular drugs.4. Penetration mechanism of electret insulin transdermal delivery systemIn this part, the microstructure of normal and diabetic rat skin were studied after application of positive electrets on rat skin. The skin sample was prepared and sliced at different time point, and the microstructure was observed by optical microscope. And then the penetration mechanism of the electret insulin transdermal delivery system was elaborated.The results showed that positive electret could make stratum corneum of normal rat skin thinner, stratum corneum and dermis cells arranged orderlessly and the cell gap became larger, which were benefit for drug penetration through the skin. Furthermore, the positive electret could repair the structure of the diabetic rat skin.In summary, combination of electrets and insulin quaternized chitosan nanoparticles showed synergistic enhancing effect on transdermal delivery of insulin. The electrostatic field of electrets could significantly increase the encapsulation efficientcy of insulin in quaternized chitosan nanoparticles. Therefore, electret combining nanoparticles is a good method for transdermal delivery of macromolecular drugs. |
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