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One of the reasons is that insulin is a hydrophilic compounds and is difficult to cross the mucosa barrier. In this paper, we developed a novel technique to fabricate the insulin\u2013phospholipids complex by a solvent evaporation method with the aim of improving the lipophilicity of insulin. A systematic study on the preparation conditions of the insulin\u2013phospholipids complex is reported in the present work. The formation mechanism and the physicochemical properties of the complex are studied. The associated efficiency of the phospholipids and insulin can be up to 100% when their mass ratio is 7.5\u2009:\u20091 or more, and the solubility of the complex is improved more than 40\u2009000 times compared with that of insulin alone in the <jats:italic>n<\/jats:italic>\u2010octyl alcohol. The results of the insulin content in the complex and hypoglycemic effects in diabetic mice indicated that insulin was able to withstand the preparation procedure. The stability results showed that the complex was stable for 1\u2009year at \u221220\u2009\u00b0C. The interaction mechanism of this formation is that the peptide bonds of insulin interact with the water\u2010soluble head of phospholipids, forming a reverse micelle\u2010like structure. This novel complex will be of great importance in the drug delivery system for insulin via noninvasive routes. This method is cost effective, scalable, and can be used in many other peptide drugs. Copyright \u00a9 2012 European Peptide Society and John Wiley &amp; Sons, Ltd.<\/jats:p>","DOI":"10.1002\/psc.2423","type":"journal-article","created":{"date-parts":[[2012,7,26]],"date-time":"2012-07-26T00:29:41Z","timestamp":1343262581000},"page":"541-548","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["The preparation of a complex of insulin\u2013phospholipids and their interaction mechanism"],"prefix":"10.1002","volume":"18","author":[{"given":"Cuiping","family":"Zhou","sequence":"first","affiliation":[{"name":"Beijing Key Laboratory of Drug Delivery Technology and Novel Formulation, Institute of Materia Medica Chinese Academy of Medical Sciences &amp; Peking Union Medical College  Beijing 100050 People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuejun","family":"Xia","sequence":"additional","affiliation":[{"name":"Beijing Key Laboratory of Drug Delivery Technology and Novel Formulation, Institute of Materia Medica Chinese Academy of Medical Sciences &amp; Peking Union Medical College  Beijing 100050 People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuling","family":"Liu","sequence":"additional","affiliation":[{"name":"Beijing Key Laboratory of Drug Delivery Technology and Novel Formulation, Institute of Materia Medica Chinese Academy of Medical Sciences &amp; Peking Union Medical College  Beijing 100050 People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lin","family":"Li","sequence":"additional","affiliation":[{"name":"Beijing Key Laboratory of Drug Delivery Technology and Novel Formulation, Institute of Materia Medica Chinese Academy of Medical Sciences &amp; Peking Union Medical College  Beijing 100050 People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2012,7,25]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMp068177"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1517\/17425247.2011.615308"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jconrel.2004.03.010"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jconrel.2010.08.004"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.2217\/nnm.11.116"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijpharm.2005.01.018"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1021\/bm0703923"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1021\/bm060065f"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1208\/s12249-010-9561-2"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.addr.2007.08.019"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.2337\/dc08-9025"},{"issue":"6","key":"e_1_2_8_13_1","first-page":"32","article-title":"Development of and advances in insulin delivery","volume":"78","author":"Sindhu A","year":"2011","journal-title":"SA Pharm. 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