Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
  • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
  • A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
  • A61K31/19—Carboxylic acids, e.g. valproic acid
  • A61K31/191—Carboxylic acids, e.g. valproic acid having two or more hydroxy groups, e.g. gluconic acid
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
  • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
  • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
  • A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
  • A61K31/355—Tocopherols, e.g. vitamin E
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
  • A61K31/365—Lactones
  • A61K31/375—Ascorbic acid, i.e. vitamin C; Salts thereof
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/4415—Pyridoxine, i.e. Vitamin B6
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
  • A61K31/7135—Compounds containing heavy metals
  • A61K31/714—Cobalamins, e.g. cyanocobalamin, i.e. vitamin B12
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K33/00—Medicinal preparations containing inorganic active ingredients
  • A61K33/04—Sulfur, selenium or tellurium; Compounds thereof
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K33/00—Medicinal preparations containing inorganic active ingredients
  • A61K33/24—Heavy metals; Compounds thereof
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K33/00—Medicinal preparations containing inorganic active ingredients
  • A61K33/24—Heavy metals; Compounds thereof
  • A61K33/30—Zinc; Compounds thereof
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K33/00—Medicinal preparations containing inorganic active ingredients
  • A61K33/24—Heavy metals; Compounds thereof
  • A61K33/32—Manganese; Compounds thereof
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K33/00—Medicinal preparations containing inorganic active ingredients
  • A61K33/24—Heavy metals; Compounds thereof
  • A61K33/34—Copper; Compounds thereof
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/06—Antihyperlipidemics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

• the invention belongs to the field of medicines, and in particular relates to a pharmaceutical composition for treating hyperlipidemia and a preparation method thereof.
• Hyperlipidemia refers to the increase of plasma cholesterol and triglyceride levels and the decrease of high-density lipoprotein content, which is an important factor causing atherosclerosis, coronary heart disease, hypertension, diabetes, stroke and other diseases one. At present, there is no uniform diagnostic standard for hyperlipidemia at home and abroad. Generally, hypercholesterolemia can be diagnosed when the plasma total cholesterol concentration> 5.17mmol/L (200mg/dl), and hypercholesterolemia can be diagnosed when the plasma triglyceride concentration> 2.3mmol/L (200mg/dl) can be diagnosed as hypertriglyceridemia.
• Hyperlipidemia can be divided into primary hyperlipidemia and secondary hyperlipidemia.
• Primary hyperlipidemia is caused by congenital defects in lipid and lipoprotein metabolism, while secondary hyperlipidemia is mostly secondary to metabolic disorders such as diabetes, hypertension, liver disease, kidney disease, thyroid disease Diseases and drinking, smoking, high-fat diet, etc.
• the current treatment methods for hyperlipidemia include non-drug treatment and drug treatment, wherein non-drug treatment generally treats hyperlipidemia through methods such as weight control, exercise, smoking cessation, and diet therapy, while drug treatment includes administration that can reduce serum total cholesterol and Statins for low-density lipoprotein levels or drugs such as fibrates and niacin that lower serum triglyceride levels.
• Chlorogenic acid is a phenylpropanoid compound synthesized through the intermediate product of the pentose phosphate pathway during the process of plant aerobic respiration. Its extraction technology is mature and it can also be synthesized in a small amount. Chlorogenic acid has been developed and used in many fields such as food, health care products, cosmetics and pharmaceuticals. The current research results show that chlorogenic acid has various pharmacological effects such as cardiovascular protection, anti-oxidation, anti-ultraviolet, anti-radiation, anti-cancer, anti-bacterial, anti-virus, immune regulation and treatment of metabolic disorders.
• the present invention is committed to providing a pharmaceutical composition with excellent therapeutic effect on hyperlipidemia.
• the object of the present invention is to provide a pharmaceutical composition for treating hyperlipidemia and its preparation method and application.
• the present invention provides a pharmaceutical composition for treating hyperlipidemia, including chlorogenic acid, vitamins, pharmaceutically acceptable auxiliary materials and optional trace elements.
• the vitamin is selected from: vitamin C, vitamin E, vitamin B6, vitamin B12 or a combination thereof; more preferably, the vitamin is selected from vitamin C;
• the trace element is selected from: zinc, manganese, selenium, chromium, copper or a combination thereof; more preferably, the trace element is selected from zinc gluconate, manganese gluconate, chromium chloride, copper gluconate or its combination combination; most preferably, the trace element is selected from manganese gluconate;
• the pharmaceutically acceptable auxiliary materials are selected from: fillers, binders, disintegrants, lubricants, solvents, antioxidants, scaffolding agents, etc.; more preferably, the antioxidants are selected from: Sodium bisulfate, sodium metabisulfite, L-cysteine hydrochloride, or a mixture of two or more, the scaffolding agent is selected from: sucrose, mannitol, glucose, lactose, trehalose, hydroxyethyl starch , dextran 20, sorbitol, PEG1000, glycerin, glycine, 1,2-propanediol or a mixture of two or more;
• the pharmaceutical composition for treating hyperlipidemia uses chlorogenic acid, vitamins and optional trace elements as the only active ingredients;
• the weight ratio of the chlorogenic acid, vitamins and optional trace elements is 100:1-5:0.01-0.05; more preferably, the weight ratio of the chlorogenic acid, vitamins and optional trace elements is 100:2-4:0.02-0.04; most preferably, the weight ratio of the chlorogenic acid, vitamins and optional trace elements is 100:3:0.03;
• the pharmaceutical composition for treating hyperlipidemia of the present invention can be administered via gastrointestinal tract or parenteral route, more preferably, the pharmaceutical composition for treating hyperlipidemia of the present invention is administered via parenteral route.
• the pharmaceutical composition for treating hyperlipidemia according to the present invention can be administered through the gastrointestinal tract in pharmaceutical dosage forms including: tablets, capsules, granules, oral liquids, etc., and the pharmaceutical dosage forms that can be administered through parenteral routes include: : Injection, large infusion, freeze-dried powder injection, etc.;
• the present invention provides a kind of preparation method of the pharmaceutical composition for the treatment of hyperlipidemia, it comprises the following steps:
• the present invention provides a kind of preparation method of the injection for the treatment of hyperlipidemia, it may further comprise the steps:
• the present invention provides a kind of preparation method of freeze-dried powder injection for treating hyperlipidemia, it comprises the following steps:
• the invention provides a kind of preparation method of the tablet for treating hyperlipidemia, it comprises the following steps:
• the present invention provides the use of a combination of chlorogenic acid, vitamins and optional trace elements in the preparation of a pharmaceutical composition for treating hyperlipidemia;
• the vitamin is selected from: vitamin C, vitamin E, vitamin B6, vitamin B12 or a combination thereof; more preferably, the vitamin is selected from vitamin C;
• the trace elements are selected from: zinc, manganese, selenium, chromium, copper, etc.; more preferably, the trace elements are selected from zinc gluconate, manganese gluconate, chromium chloride, copper gluconate or combinations thereof; Most preferably, the trace elements are selected from manganese gluconate;
• the pharmaceutically acceptable auxiliary materials are selected from: fillers, binders, disintegrants, lubricants, solvents, antioxidants, scaffolding agents, etc.; more preferably, the antioxidants are selected from: Sodium bisulfate, sodium metabisulfite, L-cysteine hydrochloride, or a mixture of two or more, the scaffolding agent is selected from: sucrose, mannitol, glucose, lactose, trehalose, hydroxyethyl starch , dextran 20, sorbitol, PEG1000, glycerin, glycine, 1,2-propanediol or a mixture of two or more;
• the pharmaceutical composition for treating hyperlipidemia uses chlorogenic acid, vitamins and optional trace elements as the only active ingredients;
• the weight ratio of the chlorogenic acid, vitamins and optional trace elements is 100:1-5:0.01-0.05; more preferably, the weight ratio of the chlorogenic acid, vitamins and optional trace elements is 100:2-4:0.02-0.04; most preferably, the weight ratio of the chlorogenic acid, vitamins and optional trace elements is 100:3:0.03;
• the pharmaceutical composition for treating hyperlipidemia of the present invention can be administered via gastrointestinal tract or parenteral route, more preferably, the pharmaceutical composition for treating hyperlipidemia of the present invention is administered via parenteral route.
• the pharmaceutical composition for treating hyperlipidemia according to the present invention can be administered through the gastrointestinal tract in pharmaceutical dosage forms including: tablets, capsules, granules, oral liquids, etc., and the pharmaceutical dosage forms that can be administered through parenteral routes include: : Injection, large infusion, freeze-dried powder injection, etc.
• an excellent pharmaceutical composition for treating hyperlipidemia is obtained by combining chlorogenic acid with vitamins and optional trace elements, especially the combination of chlorogenic acid, vitamin C and manganese gluconate has the best effect, It can significantly reduce serum total cholesterol and serum triglyceride levels, and increase high-density lipoprotein levels.
• the pharmaceutical composition for treating hyperlipidemia of the present invention has clear ingredients, simple composition, definite blood lipid lowering effect, safety and no side effects, and can be widely used in clinical treatment of hyperlipidemia.
• Embodiment 1 a kind of injection for the treatment of hyperlipidemia
• Embodiment 2 A kind of freeze-dried powder injection for treating hyperlipidemia
• Embodiment 3 a kind of tablet for treating hyperlipidemia
• Effect example 1 the lipid-lowering effect of the pharmaceutical composition for treating hyperlipidemia in the present invention
• the above drugs were all prepared into injections or emulsions according to the method of Example 1, wherein the total concentration of active drugs was adjusted to 0.53%, and the emulsions were mixed evenly before use.
• mice 210 male Kunming mice with a body weight of 18-20 g were randomly divided into 21 groups after 1 day of adaptive feeding, with 10 mice in each group, which were respectively normal group, model group, blank group and drug 1-18 group, and recorded as experimental On the 1st day, the mice in the model group, the blank group and the drug 1-18 group were all given a high-fat feed.
• the formula of the common feed was: 60% cornmeal, 35% bran, 2% flour, 1.5% fish meal, 1% salt, 0.5% cod liver oil
• the formula of the high-fat feed is: cholesterol 2%, sodium cholate 0.5%, lard 7.5%, common feed 90%, all mice are free to drink water.
• mice in each group were injected with the corresponding experimental drug into the tail vein, twice a day, 200 ⁇ L each time, and the normal group and the blank group were injected with the same amount of water for injection through the tail vein. They were fed continuously for 4 weeks, and the rats were weighed after drinking water for 8 hours on the 6th day, the 13th day, the 20th day and the 27th day. On the 28th day of the experiment, blood was taken from the orbit of the mice 2 hours after the last administration, and the serum total cholesterol, triglyceride and high-density lipoprotein contents were measured by ELISA method. Wash the liver with saline, dry it with filter paper, weigh it, and calculate the liver index. For specific experimental results, see Table 1-2, in which:
• liver index liver wet weight/body weight*100.
• the multi-factor analysis of variance module of the statistical software SPSS was used for data analysis. P ⁇ 0.05 indicated that the difference was statistically significant, and P ⁇ 0.01 indicated that the difference was significant.
• mice in the model group were significantly higher than those in the blank group eating ordinary feed, and the levels of high-density lipid The protein content was significantly reduced, indicating that the hyperlipidemia model was successfully established.
• Chlorogenic acid and its drug combination with vitamins and/or trace elements have shown certain effects of inhibiting the increase of mouse body weight and liver weight caused by high-fat diet, and reducing serum total cholesterol and triglyceride levels, and showed The obvious effect of increasing the content of high-density lipoprotein shows that chlorogenic acid and its combination with vitamins and/or trace elements have a certain effect of lowering blood lipids, and the corresponding combination of chlorogenic acid and vitamins and/or trace elements The effect is generally better than that of chlorogenic acid alone, which shows that the combination of chlorogenic acid and vitamins and/or trace elements has a significantly better effect of lowering blood lipids.
• the stronger the lipid-lowering effect of the combination the reasons include the influence of the water solubility of the active substances, the influence of different interactions between the active substances, and the decrease in the drug concentration of a single active substance as the number of active substances increases.
• a large number of screening experiments have shown that the combination of chlorogenic acid, vitamin C, and manganese gluconate has significantly better blood lipid-lowering effects than other drug combinations (Note: the above chlorogenic acid and its combination with The blood lipid-lowering effect of the drug combination of vitamins and/or trace elements is only an exemplary display, and it is not a complete experimental process for screening chlorogenic acid and its combination with vitamins and/or trace elements in the present invention).
• Effect example 2 Effect of the ratio of chlorogenic acid, vitamin C and manganese gluconate on the lipid-lowering effect of the pharmaceutical composition
• Example 1 According to the method of Example 1, the effects of different ratios of chlorogenic acid, vitamin C, and manganese gluconate combined on mouse body weight, liver wet weight, liver index, serum total cholesterol, triglyceride and high-density lipoprotein content were determined, specifically See Table 3-4 for the experimental results.

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