Insulin analogue having quick response and stability under acidic condition and preparation thereof

Abstract

The invention relates to an isulin analogue having quick response and stability under acidic condition, and a medicinal composition and a medicinal preparation thereof. Asparagine (Asn) at the A 21 position of the chain A of the isulin analogue is mutated into glycine (Gly), the isulin analogue can be mixed with a long-acting isulin analogue such as insulin glargine to form a premixed preparationwith two functions of quick-acting sugar reduction and stable long-acting sugar reduction, and the problems that the conventional natural insulin (of pigs, cows and human) and quick-acting isulin analogues are unstable in the acidic environment, and the conventional isulin premixed preparation is not clarified and needed to be introduced with a foreign protein (such as protamine) serving as a slow release preparation so as to easily cause immune reaction, and is needed to be injected twice each day, namely in the morning and evening are solved, so that the safety of the preparation is higher.

Description

technical field [0001] The present invention relates to human insulin analogues, in particular to an insulin analogue capable of rapid onset of action and stable under acidic conditions, as well as pharmaceutical compositions and preparations comprising the insulin analogue. Background technique [0002] Diabetes is a common endocrine and metabolic disease. In recent years, the prevalence of diabetes has been increasing rapidly all over the world. In China, with the changes in people's lifestyles and the acceleration of the aging process, the prevalence of diabetes is on the rise. In 2010, the total number of diabetic patients in China has exceeded 90 million, making it the second largest disease after cardiovascular and cerebrovascular diseases and tumors. Another important chronic non-communicable disease that seriously endangers people's health. The acute and chronic complications of diabetes, especially the complications of chronic diseases, involve multiple organs, ca...

AI Technical Summary

Problems solved by technology

However, these premixed insulin preparations still have the following problems: 1. The preparations contain foreign protein-protamine, which is prone to immune reactions; 2. The drug effect lasts less than 24 hours after injection, and patients still need to inject twice a day 3. The drug effect still has a peak, and the drug effect peak is superimposed twice a day, which may easily cause hypoglycemia before lunch and before going to bed; 4. The existing premixed insulin preparations are all suspensions. If the patient mixes unevenly before injection, It is easy to cause continuous differences in the ratio of soluble phase and crystalline phase in the liquid medicine, affecting blood sugar control

However, insulin glargine also has some problems in clinical application: 1. The onset of action is slow (the onset time is about 1.5 hours), and patients with hyperglycemia during meals, or patients who occasionally eat more meals, cannot effectively reduce their mealtimes. 2. It cannot be mixed with other insulins, because the isoelectric points of various insulins are different. Insulin glargine is stable under acidic conditions, while natural insulin and existing fast-acting insulin analogs are stable under neutral conditions. If insulin glargine is directly mixed with other insulins, insulin glargine will precipitate before injection and cannot be administered, and other insulins will also be affected by the pH change of the mixture after mixing, resulting in reduced stability and reduced safety.

However, on the one hand, this method needs to add additional auxiliary materials such as organic acids and chelating agents in the preparation; on the other hand, under the condition of low pH, the Asn at the 21-position of the insulin A chain is very easy to be deaminated and degraded (see "The Stability of Insulin") (Stability of insulin, Jens Brange, 1994), which made the product extremely unstable, and this patent application did not conduct systematic research on the stability of human insulin under low pH conditions and the stability of the combined preparation. The safety of the product incomplete sex data

In addition, the patent application did not solve the problem of product stability and maintaining the clinical characteristics of the product from the molecular structure of insulin

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