Discussion
hypoglycemic, peripheral hyperinsulinemia
ADVERSE REACTIONS, ADVERSE EVENTS, -20
This is the first clinical study of N11005, to evaluate its pharmacokinetics, pharmacodynamics, and safety in healthy subjects so as to verify its use as a prandial insulin.Microemulsified human insulin (N11005) is a nanodroplet with a size smaller than 200 nm, which contributes to drug penetration in the gastrointestinal tract and absorption of protein drugs after oral administration. Its solid form overcomes the storage instability of human insulin in a liquid environment. The representation data of multiple batches of N11005 have demonstrated that this microemulsified drug is characterized by uniform size, good stability, and avoidance of a layered character in storage. Compared with insulin injection, oral insulin has the following dominant advantages. Firstly, it can relieve patients from discomfort due to frequent daily injections, hence higher compliance. Secondly, it can avoid the embarrassment caused by injection and is more convenient to administer on a daily basis because there are no restrictions regarding the administration environment. Thirdly, this oral insulin drug is cost friendly as it is easy to store and carry in granular form. There is no need for low-temperature storage by patients and for cold-chain transportation by manufacturers. Fourthly, it is more acceptable because its administration is so simple and convenient that patients can use it without training. They only need add water to emulsify the granule before administration. Fifthly, it can enter the liver through portal vein circulation after it is absorbed by the gastrointestinal tract (The rationale of dose selection for the study drug was based on the preclinical studies of N11005 in pharmacology and toxicology as well as the clinical trial dosing of other similar dosage forms. Considering the bioavailability of N11005 in dogs was 1.83%, 300 IU was determined as a dose of administration in the present study. During the study, the C-peptide levels and blood glucose levels of subjects reflected the stability of the euglycemic clamp platform. After oral administration of N11005 at a dose of 300 IU, C-peptide was remarkably inhibited, and GIRs also indicated excellent absorption of N11005.For healthy people, beta cells in pancreatic islets will secrete insulin within 5 minutes after a meal due to stimulation of glucose, with an onset of action in 10-20 minutes, peak of action in 1-2 hours, and duration of action of 3-5 hours. This kind of rapid- and short-acting insulin is called prandial insulin whose major function is to normalize postprandial blood glucose (The study drug is oral insulin most of which enters the liver through the portal vein after being absorbed in the digestive tract and forms a local high concentration in the liver with only a small amount joining systemic circulation. In this way, it inhibits the decomposition of glycogen in the liver and reduces the occurrence of peripheral hyperinsulinemia, which is identical to normal physiology. The fact that its relative pharmacokinetic bioavailability was lower than relative pharmacodynamic bioavailability might be due to the decrease of serum insulin concentration caused by insulin uptake and utilization by the liver and the first pass effect. In addition, no significant peak of serum insulin concentration was observed after administration in this study. Apart from the reasons above, it might also result from so high an insulin level in the circulation system that direct serum insulin in subjects became less obvious, and from great individual variation because of the small sample size in this study. Further observation will be conducted in the follow-up clinical trial. We did not use somatostatin to inhibit endogenous insulin and glucagon secretion and compared its hypoglycemic effect with oral insulin, which is a limitation of the study.The adverse reactions of the study drug N11005 and the reference drug Novolin R were monitored during this study. No adverse events were discovered in any subjects.