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KR-20260067216-A - PEPTIDE-BASED POLYPROPYLENE OXIDE-CONTAINING BLOCK POLYMER CONJUGATES FOR ENHANCING THE THERAPEUTIC EFFICACY OF METABOLIC DISEASE THERAPEUTICS

KR20260067216AKR 20260067216 AKR20260067216 AKR 20260067216AKR-20260067216-A

Abstract

The present invention relates to a peptide-polypropylene oxide containing block polymer conjugate, wherein the conjugate can be usefully used for the improvement and treatment of obesity and diabetes with peptide drugs.

Inventors

  • 나건
  • 안민지
  • 나유현

Assignees

  • 주식회사 엔비알
  • 가톨릭대학교 산학협력단

Dates

Publication Date
20260512
Application Date
20241105

Claims (7)

  1. A pharmaceutical composition for the prevention or treatment of obesity comprising, as active ingredients, exenatide and a conjugate in which a poloxamer is linked to one end of exenatide.
  2. A pharmaceutical composition for the prevention or treatment of obesity, wherein the poloxamer is poloxamer 188, in accordance with claim 1.
  3. A pharmaceutical composition for the prevention or treatment of obesity according to claim 1, wherein the poloxamer is bonded to exenatide via 4-nitrophenyl chloroformate.
  4. A pharmaceutical composition for the prevention or treatment of obesity comprising, as active ingredients, exenatide, a poloxamer bound to one end of exenatide, and a conjugate in which a fatty acid is linked to the end of the poloxamer.
  5. A pharmaceutical composition for the prevention or treatment of obesity, wherein the poloxamer is poloxamer 188.
  6. A pharmaceutical composition for the prevention or treatment of obesity, wherein the poloxamer is bonded to exenatide via 4-nitrophenyl chloroformate.
  7. A pharmaceutical composition for the prevention or treatment of obesity, wherein, in paragraph 4, the fatty acid is oleylamine.

Description

Peptide-based polypropylene oxide-containing block polymer conjugates for enhancing the therapeutic effect of metabolic disease therapies The present invention relates to a peptide-polypropylene oxide containing block polymer conjugate, wherein the conjugate can be usefully used for the improvement and treatment of obesity and diabetes with peptide drugs. Peptides are substances consisting of 2 to 50 amino acids linked together, which are the building blocks of proteins, and are defined as the 'minimal unit with protein function.' Peptide drug candidates are selected from the smallest units of proteins that possess outstanding physiological activity to regulate biological signal transduction and function. As new drug candidates, they are distinguished by being 'biocompatible' and 'in vivo specific,' allowing them to exhibit powerful pharmacological effects and activity with minimal side effects and even in small amounts. Currently, seven out of the 100 peptide drugs sold worldwide have achieved blockbuster status, generating over 1 trillion won in sales in the global market. Furthermore, the peptide drug market is expanding, showing an annual growth rate of 18% as of 2005, which is three times that of the overall pharmaceutical market. The biggest problem with peptide drugs is their bioavailability; they degrade before entering the body, reaching their targets, and exhibiting their therapeutic effects, thus failing to produce sufficient physiological effects. Currently, representative peptide drugs include exenatide and Lupron. Glucagon-like peptide-1 (GLP-1) is a hormone primarily produced by enterocrine L cells in the intestine and secreted into the bloodstream when food containing fats, proteins, and carbohydrates enters the duodenum. GLP-1 is derived from cell-specific post-translational processing of the pro-proglucagon gene. Initially, GLP-1 was identified from this processing, but it was later discovered that the two N-terminus cleaved products, GLP-1 (7-37) and GLP-1 (7-36), recognize pancreatic receptors. These two products were determined to be the in vivo active forms. GLP-1 has been shown to stimulate insulin secretion, thereby inducing glucose uptake by cells and reducing serum glucose levels. GLP-1 agonists are available for the treatment of Type 2 Diabetes Mellitus as preferred drugs because they do not cause hypoglycemia and have positive benefits for weight loss. Endogenous substances GLP-1 (7-37) and GLP-1 (7-36) are cleaved by peptidases, resulting in very short half-lives. Therefore, efforts are being made to improve performance by developing GLP-1 analogs with improved half-lives. The first GLP-1 analog drug approved in 2005 was exenatide, administered twice daily at a dose of 10 mcg, which was found to demonstrate a significant improvement in HbA1c, a control marker for glucose. Additionally, Novo Nordisk developed liraglutide, administered subcutaneously at a dose of 1.8 mg once daily, which was approved in 2010. Recently, semaglutide, a GLP-1 analog, was approved by the U.S. FDA and is sold under the brand name Ozempic. It is administered as a once-weekly subcutaneous injection. Although many attempts to create GLP-1 analogs with improved efficacy and duration of action have been reported in the literature, there is still a need to develop GLP-1 analogs with optimal desirable characteristics in terms of duration of action, efficacy, and safety. Figure 1 shows the structure of a polypropylene oxide block-containing polymer used in the present invention. FIG. 2 shows the structure of a polymer conjugate containing a linker-polypropylene oxide block prepared according to an example of the present invention. FIG. 3 shows the structure of a polymer-fatty acid conjugate containing an excendin-polypropylene oxide block prepared according to one example of the present invention. Figure 4 shows the result of confirming the molecular weight of the excendine-polypropylene oxide-containing polymer conjugate. Figure 5 shows the results of measuring the circular dichroism of an excendine-polypropylene oxide-containing polymer conjugate. Figure 6 shows the results of measuring body weight after administering exenatide (EX only), liraglutide, and an exenatide-polypropylene oxide block-containing polymer conjugate (EX-PX) to mice, respectively. Figure 7 shows the result of Figure 6 displayed as a change in body weight. Figure 8 shows the results of confirming changes in body weight after administering exenatide (EX only), liraglutide, exenatide-polypropylene oxide block-containing polymer conjugate (EX-PX), and exenatide-polypropylene oxide block-containing polymer-oleylamine conjugate (EX-PX-OA) to mice, respectively. Figure 9 shows the results of checking the food intake after administering exenatide (EX only), liraglutide, exenatide-polypropylene oxide block-containing polymer conjugate (EX-PX), and exenatide-polypropylene oxide block-containing polymer-oleylamine conjugate (EX-PX-OA) to mice, res