Double-chain polyethylene glycol-insulin compound and preparation method thereof

Abstract

The invention relates to the field of biomedicine. A double-chain polyethylene glycol-insulin compound has a structural formula D-X-R2, wherein in the formula, R is CH3O-(CH2CH2O)n CH2CH2NH, and n is 50 to 250; X is L-glutamic acid residue or L-aspartic acid residue; and D is a product obtained by removing alanine residue of B30 site from natural porcine insulin or removing B30 threonine residue from human insulin. In PEG modification, the amino modification is changed into carboxyl modification, two polyethylene glycol chains are connected to two carboxyls of the B30 amino acid residue of the insulin, and the connection is high-yield and stable due to an amide bond. The synthesized double-chain polyethylene glycol-insulin compound with great application prospect in the long-acting effect is intrinsically chemical modified insulin. The double-chain polyethylene glycol-insulin compound has potential long-acting function.

Description

1. Technical field: [0001] The invention relates to the field of biomedicine, in particular to an insulin compound for diabetes, and also provides a preparation method thereof. 2. Background technology: [0002] Diabetes mellitus is a common multiple metabolic disease, and its incidence is on the rise both at home and abroad. According to incomplete statistics, there are more than 30 million people with diabetes in my country, and the incidence of diabetes is as high as 3.2%. Although many diseases can kill people, diabetes is the third leading cause of death. [0003] Before the discovery of insulin, many unfortunate patients with type 1 diabetes were very tragic, and the vast majority of patients died of ketoacidosis at an early stage. After the discovery of insulin in 1921, a breakthrough has been made in the treatment of diabetes. In the past 80 years, the development of insulin has saved the lives of countless diabetic patients from the early animal insulin to human ...

AI Technical Summary

Problems solved by technology

However, with the use of short-acting insulin analogues, the weakness of NPH's short action time is clearly exposed.

[0011] (2) The peak effect is obvious, and the risk of hypoglycemia at night is high

The peak is reached 5-7 hours after subcutaneous injection. For example, NPH is injected at 10:00pm, and the maximum hypoglycemic effect is achieved at 3:00-5:00am in the morning, but at this time the body's demand for insulin is very low, so the incidence of hypoglycemia at night is quite high , accounting for about 50% of all hypoglycemia events in type 1 diabetes; reducing the amount of NPH at night can improve hypoglycemia at night, but at 5:00-8:00am, insulin sensitivity decreases, which aggravates the relative lack of insulin, resulting in morning hyperglycemia

[0012] (3) Absorption instability

Some people use chemical methods to protect the N-terminal of the A chain, and modify the N-terminal of the B chain and the ε-amino group of the lysine of B29. Although most of the activity of insulin can be retained, the separation of the single-site modified product causes It is very difficult, and it also increases the cost of industrial production; there are also some people who can selectively modify the activity of the reagent by changing the activity of the reagent. For example, the aldehyde derivatives of PEG can selectively modify the N-terminal amino group at low pH. This still needs to protect the N-terminus of the A chain; in short, the current modification method cannot completely avoid the influence of the above four factors, and cannot obtain satisfactory modification results

Images