Pharmaceutical composition for treating hyperlipidemia and preparation method thereof

Abstract

A pharmaceutical composition for treating hyperlipidemia and a preparation method thereof, the pharmaceutical composition comprising chlorogenic acid, vitamins, pharma- ceutical acceptable auxiliary materials and optional trace elements, the pharmaceutical composition for treating hyperlipidemia has excellent effects of lowering serum total cholesterol and serum triglycerides and increasing high-density lipoprotein content, and the pharmaceutical composition has clear ingredients, a simple structure, is safe and has no side effects, and can be widely used in the clinical treatment of hyperlipidemia.

Description

[Technical field]

[0001] The present invention belongs to the field of medicine, specifically to a pharmaceutical composition for treating hyperlipidemia and its preparation method. [Background technology]

[0002] Hyperlipoproteinemia is an increase in the levels of cholesterol and triglycerides in plasma and a decrease in the content of high-density lipoproteins, and is one of the important factors that cause diseases such as atherosclerosis, coronary heart disease, hypertension, diabetes, and stroke. At present, there are no unified diagnostic criteria for hyperlipidemia at home or abroad, and generally, hypercholesterolemia can be diagnosed when the total cholesterol concentration in plasma is >5.17mmol / L (200mg / dl), and hypertriglyceridemia can be diagnosed when the triglyceride concentration in plasma is >2.3mmol / L (200mg / dl).

[0003] Hyperlipidemia can be divided into two categories: primary hyperlipidemia, which is caused by congenital defects in lipid and lipoprotein metabolism, and secondary hyperlipidemia, which often develops secondary to metabolic disorders such as diabetes, hypertension, liver disease, kidney disease, thyroid disease, and alcohol consumption, smoking, and high-fat diets.

[0004] Current methods for treating hyperlipidemia include non-pharmacological therapies, which generally treat hyperlipidemia by methods such as weight control, exercise, smoking cessation, and dietary therapy, and pharmacotherapy, which includes the administration of drugs such as statins to reduce serum total cholesterol and low-density lipoprotein levels, or fibrates and niacin to reduce serum triglyceride levels.

[0005] Chlorogenic acid is a phenylpropanoid substance synthesized by intermediate products of the pentose phosphate pathway during aerobic respiration in plants. Its extraction technology is mature and it is possible to synthesize small amounts. Chlorogenic acid has already been developed and applied in multiple fields such as food, health food, cosmetics and medicine. Current research results show that chlorogenic acid has various pharmacological effects such as cardiovascular protection, antioxidant, anti-ultraviolet rays, anti-radiation, anti-cancer, antibacterial, anti-viral, immune regulation and treatment of metabolic disorders.

[0006] Previous studies have shown that vitamins such as vitamin E and vitamin C, and trace elements such as zinc, copper, manganese, iron, chromium, selenium, calcium, magnesium, etc. are all related to lipid metabolism, and some scholars have proposed that lipid metabolism levels can be adjusted by supplementing trace elements based on this. However, the regulatory effect of vitamins and trace elements on blood lipids is still unclear, and excessive supplementation of vitamins and trace elements can cause various health problems, so there have been no clinical reports on treating hyperlipidemia with vitamin and trace element supplementation.

[0007] An object of the present invention is to provide a pharmaceutical composition having an excellent therapeutic effect against hyperlipidemia. Summary of the Invention

[0008] The object of the present invention is to provide a pharmaceutical composition for treating hyperlipidemia and its preparation method and use.

[0009] In one aspect, the present invention provides a pharmaceutical composition for treating hyperlipidemia, comprising chlorogenic acid, vitamins, pharma- ceutically acceptable auxiliary materials and optional trace elements.

[0010] Preferably, 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.

[0011] Preferably, the trace elements are selected from zinc, manganese, selenium, chromium, copper or a combination thereof, more preferably, the trace elements are selected from zinc gluconate, manganese gluconate, chromium chloride, copper gluconate or a combination thereof, and most preferably, the trace elements are selected from manganese gluconate.

[0012] Preferably, the pharma- ceutically acceptable auxiliary material is selected from fillers, binders, disintegrants, lubricants, solvents, antioxidants, scaffolding agents, etc., and more preferably, the antioxidant is selected from one or a mixture of two or more of sodium bisulfite, sodium metabisulfite, and L-cysteine ​​hydrochloride, and the scaffolding agent is selected from one or a mixture of two or more of sucrose, mannitol, glucose, lactose, trehalose, hydroxyethyl starch, dextran 20, sorbitol, PEG1000, glycerol, glycine, and 1,2-propanediol.

[0013] Preferably, said pharmaceutical composition for treating hyperlipidemia only contains chlorogenic acid, vitamins and optional trace elements as active ingredients.

[0014] Preferably, 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, and most preferably, the weight ratio of the chlorogenic acid, vitamins and optional trace elements is 100:3:0.03.

[0015] The pharmaceutical composition for treating hyperlipidemia described in the present invention can be administered via the digestive tract or a route other than the digestive tract, and more preferably, the pharmaceutical composition for treating hyperlipidemia described in the present invention is administered via a route other than the digestive tract.

[0016] Preferably, the pharmaceutical composition for treating hyperlipidemia according to the present invention includes, in its pharmaceutical dosage form administrable via the digestive tract, tablets, capsules, granules, oral liquids, etc., and in its pharmaceutical dosage form administrable via a route other than the digestive tract, injection solutions, infusion solutions, freeze-dried powder injections, etc.

[0017] In yet another aspect, the present invention provides a method for preparing a pharmaceutical composition for treating hyperlipidemia, the method comprising: A step (1) of weighing each ingredient; and (2) preparing the pharmaceutical formulation for administration via the digestive tract or via a route other than the digestive tract, according to conventional methods in the art.

[0018] Specifically, the present invention provides a method for preparing an injection solution for treating hyperlipidemia, the method comprising: A step (1) of weighing each ingredient; and (2) preparing water for injection, sequentially adding chlorogenic acid, antioxidants, vitamins and optional trace elements, stirring to fully dissolve, adjusting the volume to a constant volume, controlling the pH to 2-5, adding activated carbon, stirring for 20-40 minutes, removing the activated carbon by filtration, and then microfiltrating through a 0.22 um hydrophilic microporous filtration membrane until the filtrate becomes clear, and then aseptically filling the solution to obtain an injection for treating hyperlipidemia.

[0019] The present invention provides a method for preparing a lyophilized powder injection for treating hyperlipidemia, the method comprising: A step (1) of weighing each ingredient; (2) preparing water for injection, sequentially adding chlorogenic acid, antioxidants, scaffolding agents, vitamins and optional trace elements, stirring to dissolve thoroughly, adjusting the volume to a constant volume, controlling the pH to 2-5, adding activated carbon, stirring for 20-40 minutes, removing the activated carbon by filtration, and then microfiltrating through a 0.22um hydrophilic microporous filtration membrane until the filtrate is clear, aseptically filling, and freeze-drying to obtain a freeze-dried powder injection for treating hyperlipidemia.

[0020] The present invention provides a method for preparing a tablet for treating hyperlipidemia, the method comprising: A step (1) of weighing each ingredient; and (2) sifting chlorogenic acid, vitamins, optional trace elements, a filler and a disintegrant through a 60-100 mesh sieve, mixing them uniformly, preparing a soft material with an appropriate amount of binder, granulating the material through a 14 mesh sieve, drying the granulated material, sifting the material through a 12 mesh sieve to size the granules, adding a lubricant, mixing the material uniformly and compressing the mixture into tablets to obtain tablets for treating hyperlipidemia.

[0021] In yet another aspect, 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.

[0022] Preferably, 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.

[0023] Preferably, 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, and most preferably, the trace elements are selected from manganese gluconate.

[0024] Preferably, the pharma- ceutically acceptable auxiliary material is selected from fillers, binders, disintegrants, lubricants, solvents, antioxidants, scaffolding agents, etc., and more preferably, the antioxidant is selected from one or a mixture of two or more of sodium bisulfite, sodium metabisulfite, and L-cysteine ​​hydrochloride, and the scaffolding agent is selected from one or a mixture of two or more of sucrose, mannitol, glucose, lactose, trehalose, hydroxyethyl starch, dextran 20, sorbitol, PEG1000, glycerol, glycine, and 1,2-propanediol.

[0025] Preferably, said pharmaceutical composition for treating hyperlipidemia only contains chlorogenic acid, vitamins and optional trace elements as active ingredients.

[0026] Preferably, 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, and most preferably, the weight ratio of the chlorogenic acid, vitamins and optional trace elements is 100:3:0.03.

[0027] The pharmaceutical composition for treating hyperlipidemia described in the present invention can be administered via the digestive tract or a route other than the digestive tract, and more preferably, the pharmaceutical composition for treating hyperlipidemia described in the present invention is administered via a route other than the digestive tract.

[0028] Preferably, the pharmaceutical composition for treating hyperlipidemia according to the present invention includes, in its pharmaceutical dosage form administrable via the digestive tract, tablets, capsules, granules, oral liquids, etc., and in its pharmaceutical dosage form administrable via a route other than the digestive tract, injection solutions, infusion solutions, freeze-dried powder injections, etc. Effect of the Invention

[0029] The present invention provides an excellent pharmaceutical composition for treating hyperlipidemia by combining chlorogenic acid with vitamins and any trace elements, and the combination of chlorogenic acid, vitamin C and manganese gluconate is particularly effective, significantly reducing serum total cholesterol and serum triglyceride levels and improving high density lipoprotein content. The pharmaceutical composition for treating hyperlipidemia of the present invention has clear ingredients, simple composition, precise blood lipid lowering effect, safe and without side effects, and can be widely used in the clinical treatment of hyperlipidemia. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0030] To aid in the understanding of the present invention, the present invention will now be described in further detail.

[0031] Example 1: Injection for treating hyperlipidemia 100 g of chlorogenic acid, 3 g of vitamin C, 1 g of sodium hydrogen sulfite, 0.03 g of manganese gluconate, and an appropriate amount of water for injection were prepared in the following manner.

[0032] (1) Each ingredient was weighed. (2) Water for injection is prepared, and chlorogenic acid, sodium bisulfite, vitamin C, and manganese gluconate are added in that order. The solution is stirred to dissolve thoroughly, the pH is adjusted to 3.5, the volume is adjusted to 2000 mL, activated charcoal is added, and the solution is stirred for 20 to 40 minutes. The activated charcoal is then removed by filtration, and the solution is then precision-filtered using a 0.22 um hydrophilic microporous filtration membrane until the filtrate becomes clear. 1000 bottles are filled aseptically to obtain an injection for treating hyperlipidemia.

[0033] Example 2: Lyophilized powder injection for treating hyperlipidemia 100 g of chlorogenic acid, 4 g of vitamin C, 2 g of sodium bisulfite, 0.05 g of manganese gluconate, 80 g of mannitol, and an appropriate amount of water for injection were prepared in the following manner.

[0034] (1) Each ingredient was weighed. (2) Water for injection was prepared, and chlorogenic acid, sodium bisulfite, mannitol, vitamin C, and manganese gluconate were added in that order. The mixture was stirred to dissolve thoroughly, the pH was adjusted to 4, the volume was adjusted to 2000 mL, activated charcoal was added, and the mixture was stirred for 20 to 40 minutes. The activated charcoal was then removed by filtration, and the mixture was then microfiltered using a 0.22 um hydrophilic microporous filtration membrane until the filtrate became clear. 1000 bottles were filled aseptically and freeze-dried to obtain a freeze-dried powder injection for treating hyperlipidemia.

[0035] Example 3: Tablets for Treating Hyperlipidemia 100 g of chlorogenic acid, 3 g of vitamin C, 0.03 g of manganese gluconate, 364 g of microcrystalline cellulose, 30 g of croscarmellose sodium, 3 g of magnesium stearate, and an appropriate amount of ethanol were prepared in the following manner.

[0036] (1) Each ingredient was weighed. (2) Chlorogenic acid, manganese gluconate, vitamin C, microcrystalline cellulose, and croscarmellose sodium were sifted through an 80 mesh sieve, then uniformly mixed, and an appropriate amount of ethanol was used to prepare a soft material, which was granulated through a 14 mesh sieve, dried, and sized through a 12 mesh sieve. Magnesium stearate was added, and the mixture was uniformly mixed and compressed into tablets to prepare 1,000 tablets for the treatment of hyperlipidemia.

[0037] Effect Example 1: Lipid-reducing effect of the pharmaceutical composition for treating hyperlipidemia of the present invention 1.1 Experimental drugs TIFF2024518060000001.tif164170 All of the above drugs were prepared according to the method of Example 1 into injection solutions or emulsions, and the total concentration of the active drugs was adjusted to 0.53%, and the emulsions were mixed uniformly before use.

[0038] 1.2 Experimental animals 210 male Kunming mice weighing 18-20g were randomly divided into 21 groups of 10 mice each after 1d of adaptation breeding, and were designated as normal group, model group, blank group, and drug 1-18 groups, respectively, and recorded as the first day of the experiment. The normal group was fed with a general diet, and the model group, blank group, and drug 1-18 groups were fed with a high-fat diet. The general diet was composed of 60% corn flour, 35% bran, 2% wheat flour, 1.5% fish meal, 1% salt, and 0.5% fish liver oil, and the high-fat diet was composed of 2% cholesterol, 0.5% sodium cholate, 7.5% lard, and 90% general diet. All mice were allowed to freely consume water. The mice in each group were injected with the corresponding experimental drug twice a day, 200μL each time, via the tail vein, and the normal group and blank group were injected with an equal amount of water for injection via the tail vein. Feeding was continued for 4 weeks, and on the 6th, 13th, 20th and 27th days, water intake was prohibited and weights were measured 8 hours later. On the 28th day of the experiment, blood was collected from the mice's orbits 2 hours after the final administration, and serum total cholesterol, triglyceride and high density lipoprotein contents were measured using the ELISA method. The mice were sacrificed by cutting the neck, and the entire liver was removed and washed with 0-4°C saline, absorbed with filter paper and dried, then weighed and liver index was calculated. Specific experimental results are shown in Tables 1-2. Here, Liver index = wet liver weight / body weight*100.

[0039] 1.3 Experimental results Data analysis was performed using the multifactorial analysis of variance module of the statistical software SPSS. P<0.05 indicates that the difference is statistically significant, and P<0.01 indicates that the difference is significantly different.

[0040] Table 1. Effect of the pharmaceutical composition of the present invention on the body weight of mice fed a high-fat diet TIFF2024518060000002.tif192170Comparison with blank group: △, P<0.05.

[0041] Table 2. Effects of the pharmaceutical composition of the present invention on liver index and blood lipids in high-fat fed mice TIFF2024518060000003.tif190170Comparison with blank group: △, P<0.05, △△, P<0.01. Comparison with model group: *, P<0.05, **, P<0.01.

[0042] The experimental results in Tables 1 and 2 show that the mice in the model group fed a high-fat diet had significantly higher body weight, wet liver weight, liver index, serum total cholesterol, and triglyceride levels, and the high-density lipoprotein content was significantly lower than those in the blank group fed regular chow, indicating that the hyperlipidemia model was successfully modeled.

[0043] Chlorogenic acid and the combination of chlorogenic acid with vitamins and / or trace elements all show certain effects of suppressing the increase in body weight and liver weight of mice caused by high-fat diet, reducing serum total cholesterol and triglyceride levels, and significantly improving the content of high-density lipoprotein. Chlorogenic acid and the combination of chlorogenic acid with vitamins and / or trace elements all have certain blood lipid lowering effects, and the corresponding effects of the combination of chlorogenic acid with vitamins and / or trace elements are generally better than those of chlorogenic acid alone, which shows that the combination of chlorogenic acid with vitamins and / or trace elements has obviously better blood lipid lowering effect. However, the experimental results also show that the more types of drug active ingredients, the higher the blood lipid lowering effect of the corresponding drug combination, which are due to the influence of the water solubility of active substances, the various effects of the interactions between active substances, and the decrease in the drug concentration of a single active substance with the increase in the types of active substances. Extensive screening experiments have shown that, when the concentrations of administered drugs are the same, the combination of chlorogenic acid with vitamin C or manganese gluconate has a significantly superior blood lipid lowering effect compared to other drug combinations (Note: the above blood lipid lowering effects of chlorogenic acid, and drug combinations of chlorogenic acid and vitamins and / or trace elements are merely shown as examples, and are not a complete experimental process for screening the drug combinations of chlorogenic acid, and chlorogenic acid and vitamins and / or trace elements of the present invention).

[0044] Effect example 2: Effect of the ratio of chlorogenic acid, vitamin C, and manganese gluconate on the lipid-reducing effect of the drug composition 2.1 Experimental drugs TIFF2024518060000004.tif96170

[0045] 2.2.Experimental Method According to the method of Example 1, the effects of various ratios of chlorogenic acid, vitamin C, and manganese gluconate on the body weight, wet liver weight, liver index, serum total cholesterol, triglyceride, and high density lipoprotein contents of mice were measured. Specific experimental results are shown in Tables 3 to 4.

[0046] Table 3. Effect of a combination of chlorogenic acid, vitamin C, and manganese gluconate on the body weight of mice fed a high-fat diet TIFF2024518060000005.tif121170Comparison with blank group: △, P<0.05, △△, P<0.01. Comparison with model group: *, P<0.05.

[0047] Table 4. Effect of a combination of chlorogenic acid, vitamin C, and manganese gluconate on liver index and blood lipids in high-fat fed mice TIFF2024518060000006.tif122170Comparison with blank group: △, P<0.05, △△, P<0.01. Comparison with model group: *, P<0.05, **, P<0.01.

[0048] The experimental results in Tables 3-4 show that the mixing ratio of chlorogenic acid, vitamin C, and manganese gluconate has obvious effect on its blood lipid-reducing effect, and with the decrease in the ratio of vitamin C and manganese gluconate, the blood lipid-reducing effect of the drug combination is gradually strengthened. Here, the combination corresponding to chlorogenic acid: vitamin C: manganese gluconate = 100: 3: 0.03 showed the optimal blood lipid-reducing effect, and with the further decrease in the ratio of vitamin C and manganese gluconate, the blood lipid-reducing effect of the corresponding combination gradually decreased (Note: the above ratios of chlorogenic acid, vitamin C, and manganese gluconate are only shown as examples, and are not a complete experimental process for screening the ratios of chlorogenic acid, vitamin C, and manganese gluconate of the present invention).

[0049] Although the preferred embodiment of the present invention has been described above, the present invention is not limited thereto. Those skilled in the art can make improvements and modifications to the disclosed embodiment without departing from the scope and spirit of the present invention.

Claims

1. A pharmaceutical composition for treating hyperlipidemia, comprising chlorogenic acid, vitamins, pharma-ceutically acceptable auxiliary materials and optional trace elements.

2. The pharmaceutical composition for treating hyperlipidemia according to claim 1, characterized in that the pharmaceutical composition for treating hyperlipidemia contains only chlorogenic acid, vitamins and optional trace elements as active ingredients.

3. The pharmaceutical composition for treating hyperlipidemia according to claim 1 or 2, characterized in that the vitamin is selected from vitamin C, vitamin E, vitamin B6, vitamin B12 or a combination thereof, preferably the vitamin is selected from vitamin C.

4. The pharmaceutical composition for treating hyperlipidemia according to claim 1 or 2, characterized in that the trace elements are selected from zinc, manganese, selenium, chromium, copper or a combination thereof, preferably the trace elements are selected from zinc gluconate, manganese gluconate, chromium chloride, copper gluconate or a combination thereof, more preferably the trace elements are selected from manganese gluconate.

5. The pharmaceutical composition for treating hyperlipidemia according to claim 1 or 2, characterized in that the weight ratio of the chlorogenic acid, vitamins and optional trace elements is 100:1-5:0.01-0.05, preferably, the weight ratio of the chlorogenic acid, vitamins and optional trace elements is 100:2-4:0.02-0.04, and more preferably, the weight ratio of the chlorogenic acid, vitamins and optional trace elements is 100:3:0.

03.

6. The pharmaceutical composition for treating hyperlipidemia according to claim 1 or 2, characterized in that the pharmaceutical composition for treating hyperlipidemia is administered via the digestive tract or a route other than the digestive tract, and preferably, the pharmaceutical dosage form administered via the digestive tract includes tablets, capsules, granules, and oral liquids, and the pharmaceutical dosage form administered via a route other than the digestive tract includes injection solutions, infusion solutions, and freeze-dried powder injections.

7. A step (1) of weighing each ingredient; (2) preparing a pharmaceutical dosage form for administration via the digestive tract or a route other than the digestive tract according to a conventional method in the art; 3. A method for preparing a pharmaceutical composition for treating hyperlipidemia according to claim 1 or 2, comprising:

8. 13. Use of a combination of chlorogenic acid, vitamins and optional trace elements in the preparation of a pharmaceutical composition for treating hyperlipidemia.

9. 9. The use according to claim 8, characterized in that the vitamins are selected from vitamin C, vitamin E, vitamin B6, vitamin B12 or combinations thereof and the trace elements are selected from zinc, manganese, selenium, chromium, copper or combinations thereof.

10. The use according to claim 9, characterized in that the weight ratio of chlorogenic acid, vitamins and optional trace elements is 100:1-5:0.01-0.05.