Insulin is the main drug to treat 1 type (insulin-dependent) and advanced type 2 diabetes (insulin-independent). It is a polypeptide with large molecular weight and poor fat solubility, and it is not easy to penetrate biofilm. Therefore, it has been mainly administered by injection, which is not only inconvenient to use, but also has side effects such as inflammation and induration at the injection site. Therefore, scholars at home and abroad have been committed to the research and development of insulin non-injection preparations. Such as oral administration, transmucosal preparation, transdermal preparation, rectal administration, etc., and has made progress in some aspects. Oral administration: there are many research reports, but there is no practical application, because insulin is easily inactivated by enzyme hydrolysis in gastrointestinal tract and destroyed by the first-pass effect of liver (oral drugs pass through the liver, and the drug concentration decreases under the action of liver drug enzymes); Because of its large molecular weight, it is difficult to penetrate gastrointestinal epithelial cells, so it cannot be administered directly orally. Protecting insulin and promoting its absorption may achieve the purpose of oral insulin. Specifically, it is made into microcapsules, granules, liposomes, emulsions, microemulsions and other dosage forms by adding enzyme inhibitors or other protective agents and absorption promoters. There are many research reports at home and abroad, but no practical application has been seen so far. The main reason is the low bioavailability of insulin, and the quality control and stability of the preparation need to be solved. However, it is reported that insulin enteric-coated pills and insulin enteric-coated capsules have applied to the State Administration of Pharmaceutical Products for clinical application, and the clinical registration of enteric-coated pills was approved in July 2003. In addition, someone applied for the national patent of "Preparation and Application of Oral Insulin Dry Powder by Microencapsulation Technology", saying that it may be put into practice, and it has also been clinically registered in the Food and Drug Administration. I hope these projects can be successful. Mucosal administration: Long-term safety needs to be tested. Mucosa is rich in blood vessels, and the protease content in mucosa is less than that in gastrointestinal tract, so the chance of insulin being destroyed is reduced. Nasal mucosa administration also needs to add absorption enhancers, and of course it cannot be irritating. The Nazlin project of Johnson & Johnson Company in the United States once entered the clinical trial and was terminated. Domestic units have developed similar preparations, and submitted clinical and production notes in 1999 and 200 1 respectively, but no approval information was found. The quick-acting liquid insulin absorbed by buccal mucosa developed by Generex Company of Canada with its patented technology of "RapidMist" was successfully marketed last year, which is suitable for patients with 1 and type 2 diabetes. It is reported that the company has been registered in China drug administration, and the drug administration believes that the safety of its long-term use remains to be seen. There is also a similar product "insulin oral spray" submitted for clinical and production registration in China. Pulmonary Administration: Clinical trials have been approved in China. The total area of alveoli is large, the alveolar wall is thin, the permeability is good, the protease activity is lower than that of gastrointestinal tract, and there is no first-pass effect. Therefore, lung absorption may become a way for macromolecular drugs to be absorbed into systemic circulation. But at the same time, there are some problems in pulmonary administration, such as the need for special administration devices, inaccurate administration dose and actual inhalation dose, and the safety of lung after long-term use remains to be seen. NektarTherapeutics of the United States has made a breakthrough in this field. After it was launched in Ireland in May last year, it was officially listed in Germany, Britain and the United States, and registered in other EU countries. Used in adult patients with type 2 diabetes, 1 type diabetes patients need to combine long-acting or medium-acting insulin. As for the research projects such as rectal administration and transdermal preparation, there is no practical application so far, so I will not repeat them here.