CN-122005565-A - Pharmaceutical composition for improving glycolipid metabolic disorder by combining N-coumaroyl octopamine and rotundine and application thereof

CN122005565ACN 122005565 ACN122005565 ACN 122005565ACN-122005565-A

Abstract

The invention discloses a pharmaceutical composition for improving glycolipid metabolic disorder by combining N-coumaroyl octopamine and rotundine and application thereof, belonging to the field of biological medicine and metabolic disease treatment. In the db/db diabetic mice model, the invention discovers that NTPC (10 mg/kg) or ROT (10 mg/kg) can improve hyperglycemia, improve insulin resistance and reduce blood fat, and the combination of low dosage (NTPC 5 mg/kg+ROT5 mg/kg) shows the most remarkable metabolism improvement effect, which is obviously superior to that of a single drug group. In an in vitro fatty acid stimulation model, the combination of the two medicaments can remarkably reduce the accumulation of intracellular lipid and inhibit fatty acid synthesis genes.

Inventors

SUN HAIJIAN
ZHANG AOYUAN
YANG LE
XU ANJING
CHEN GUO
LU QIANQIAN
ZHU XUEXUE
LU QINGBO

Assignees

江南大学

Dates

Publication Date: 20260512
Application Date: 20260123

Claims (10)

1. A pharmaceutical composition comprises a therapeutically effective amount of N-paracoumaroyl octopamine and a therapeutically effective amount of rotundine, wherein the combination of the N-paracoumaroyl octopamine and the rotundine has obvious synergistic effect, and the mass ratio of the N-paracoumaroyl octopamine to the rotundine is (1-2); the N-p-coumaroyl octopamine is a compound with a structure shown in the following formula, and a stereoisomer or solvate thereof; , the rotundine is a compound having a structure shown in the following formula, a stereoisomer or a solvate thereof: 。
2. the use of the pharmaceutical composition of claim 1 in any one of the following (a) - (e): (a) Preparing a medicament for improving type 2 diabetes and related metabolic disorders or improving glycolipid metabolic disorders; (b) Preparing a medicament for improving fasting blood glucose, serum insulin levels, HOMA-IR index, and glycogenesis; (c) Preparing a medicament for regulating blood lipid, or preparing a medicament for reducing serum Total Cholesterol (TC), triglyceride (TG), liver triglyceride (liver TG) and liver total cholesterol (liver TC); (d) Preparing a medicament for improving liver lipid deposition, or preparing a medicament for reducing liver TG and liver TC and improving liver steatosis shown by oil red O staining; (e) Preparing a medicament for reducing the expression level of genes related to fatty acid synthesis, or reducing the expression level of FASN, srebp-1, dgat1 and Scd1, and regulating the expression of genes related to fatty acid oxidation and lipid homeostasis PPARgamma and Cpt 1; The combination of the N-coumarone amide and the rotundine has obvious synergistic effect.
3. The use according to claim 2, wherein the N-p-coumarone amide and rotundine are contained as active ingredients in different formulations and are administered simultaneously or at different times; Preferably, the single administration dosage of the N-coumaroyl octopamine is 5-10 mg/kg, the administration frequency is once every three days, and the single administration dosage of the rotundine is 5-10 mg/kg, and the administration frequency is once every three days.
4. The use according to claim 3, wherein the medicament further comprises pharmaceutically acceptable pharmaceutical excipients; Optionally, the auxiliary materials comprise one or more of a binding agent, a pre-gelatinized starch, dextrin, sucrose, lactose and mannitol, a filler, a wetting agent, glycerin, a disintegrating agent, a quaternary ammonium compound, a surfactant, a polysorbate, a sorbitan fatty acid and a glyceride fatty acid, a coloring agent, titanium dioxide, sunset yellow, methylene blue and medicinal ferric oxide red, a lubricant, hydrogenated vegetable oil, talcum powder and polyethylene glycol, a coating material, acrylic resin, hydroxypropyl methylcellulose, povidone and fiber vinegar, and other auxiliary materials, such as a flavoring agent and a sweetener, can be added into the composition; Alternatively, the combined route of administration is selected from the group consisting of oral administration, parenteral administration, transdermal administration, and alternatively, the parenteral administration includes, but is not limited to, intravenous injection, subcutaneous injection, intramuscular injection.
Use of n-p-coumaroyl octopamine for the preparation of a medicament for enhancing rotundine for ameliorating type 2 diabetes and associated metabolic disorders or ameliorating glycolipid metabolic disorders.
6. The use according to claim 5, wherein the medicament comprises N-p-coumaroyl octopamine and pharmaceutically acceptable excipients; Optionally, the auxiliary materials comprise one or more of a binding agent, a pre-gelatinized starch, dextrin, sucrose, lactose and mannitol, a filler, a wetting agent, glycerin, a disintegrating agent, a quaternary ammonium compound, a surfactant, a polysorbate, a sorbitan fatty acid and a glyceride fatty acid, a coloring agent, titanium dioxide, sunset yellow, methylene blue and medicinal ferric oxide red, a lubricant, hydrogenated vegetable oil, talcum powder and polyethylene glycol, a coating material, acrylic resin, hydroxypropyl methylcellulose, povidone and fiber vinegar, and other auxiliary materials, such as a flavoring agent and a sweetener, can be added into the composition; Optionally, the dosage form of the medicine comprises any one of drops, oral liquid, tablets, capsules, granules, films, gels, powder, emulsion, dripping pills or solution; alternatively, the route of administration of the drug includes oral administration, sublingual administration, rectal administration, dermal mucosal administration, inhalation administration or injection administration.
The application of the N-p-coumaroyl octopamine combined with rotundine in preparing the medicines for improving type 2 diabetes and related metabolic disorders or improving glycolipid metabolic disorders has obvious synergistic effect.
8. The use according to claim 7, wherein the N-p-coumarone amide and rotundine can be administered simultaneously, independently formulated and co-administered or independently formulated and administered sequentially.
9. The use according to claim 7, wherein the single dose of N-coumarone is 5-10 mg/kg, the frequency of administration is once every three days, and the single dose of rotundine is 5-10 mg/kg, the frequency of administration is once every three days.
10. Application of rotundine in preparing medicines for enhancing N-p-coumaroyl octopamine for improving type 2 diabetes and related metabolic disorder or improving glycolipid metabolic disorder is provided.

Description

Pharmaceutical composition for improving glycolipid metabolic disorder by combining N-coumaroyl octopamine and rotundine and application thereof Technical Field The invention belongs to the field of biological medicine and metabolic disease treatment, and in particular relates to a pharmaceutical composition for improving glycolipid metabolic disorder by combining N-coumaroyl octopamine and rotundine and application thereof. Background Type 2 diabetes mellitus is a type of chronic metabolic disease caused by insulin secretion deficiency and insulin resistance together, and is accompanied by hyperglycemia, insulin resistance, lipid metabolism disorder, liver fat deposition and other typical characteristics. At present, the main clinical treatment medicaments comprise metformin, GLP-1 receptor agonists, SGLT2 inhibitors and the like, and although the partial metabolic indexes can be improved, the problems of obvious side effects, reduced long-term curative effect, inapplicability to partial patients and the like still exist. Small molecule compounds of vegetable origin are of great interest as potential drugs for the treatment of metabolic diseases. NTPC is a natural phenolic amine compound with a certain anti-inflammatory and metabolic regulatory potential. ROT is an alkaloid derived from rhizoma corydalis (Corydalis yanhusuo), and has been reported to have anti-inflammatory, antioxidant and neuromodulation effects. However, there is no report on the use of NTPC in combination with ROT for the treatment of diabetes and metabolic disorders, nor is there any systematic study of their synergistic improvement of blood glucose, lipid and liver lipid deposition. Therefore, the development of safe, efficient and multi-target drug combinations with metabolism improving capability is of great significance. Disclosure of Invention The invention provides a pharmaceutical composition composed of NTPC and ROT, which is used for preventing or treating type 2 diabetes, insulin resistance, lipid metabolism disorder, hepatic fat deposition and related metabolic syndrome. In the db/db diabetic mice model, the invention discovers that NTPC (10 mg/kg) or ROT (10 mg/kg) can improve hyperglycemia, improve insulin resistance and reduce blood fat, and the combination of low dosage (NTPC 5 mg/kg+ROT5 mg/kg) shows the most remarkable metabolism improvement effect, which is obviously superior to that of a single drug group. In an in vitro fatty acid stimulation model, the combination of the two medicaments can remarkably reduce the accumulation of intracellular lipid and inhibit fatty acid synthesis genes. Therefore, the invention discovers and proves the synergistic effect of NTPC+ROT in sugar metabolism and lipid metabolism regulation for the first time, and provides a new strategy for developing novel metabolic disease treatment medicines. The invention provides a pharmaceutical composition comprising a therapeutically effective amount of N-paracoumaroyl octopamine and a therapeutically effective amount of rotundine, wherein the combination of the N-paracoumaroyl octopamine and the rotundine has obvious synergistic effect. In the pharmaceutical composition, the molecular weight of N-paracoumaroyl octopamine is 355.43 of 299.32 rotundine; The mass ratio of the N-coumaroyl octopamine to the rotundine is (1-2) and (1-2); preferably, the mass ratio is (0.8421): 1.1875; the N-p-coumaroyl octopamine is a compound with a structure shown in the following formula, and a stereoisomer or solvate thereof; the rotundine is a compound having a structure shown in the following formula, a stereoisomer or a solvate thereof: In one embodiment of the invention, the medicament further comprises pharmaceutically acceptable pharmaceutical excipients; In one embodiment of the invention, the auxiliary materials comprise one or more of a binding agent, a diluent, a filler, a wetting agent, a disintegrating agent, an absorption enhancer, a surfactant, a colorant, a lubricant, a hydrogenated vegetable oil, talcum powder and polyethylene glycol, a coating material, an acrylic resin, hydroxypropyl methylcellulose, povidone and fiber acetate, and other auxiliary materials, a flavoring agent and a sweetener, wherein the binding agent comprises cellulose derivatives, alginate, gelatin and polyvinylpyrrolidone, the diluent comprises pregelatinized starch, dextrin, sucrose, lactose, mannitol, the filler comprises starch, sucrose, the wetting agent comprises glycerin, the disintegrating agent comprises sodium carboxymethyl starch, crosslinked polyvinylpyrrolidone and dry starch, the absorption enhancer comprises a quaternary ammonium compound, the surfactant comprises polysorbate, sorbitan fatty acid and glyceride, the colorant comprises titanium dioxide, sunset yellow, methylene blue and medicinal ferric oxide red, the lubricant comprises hydrogenated vegetable oil, talcum powder and polyethylene glycol, and the coating material comprises acrylic acid resin, hydrox