Pharmaceutical composition and application thereof

Abstract

The invention discloses a pharmaceutical composition and application thereof. The composition comprises a basic component and a synergistic component, wherein the basic component comprises 0.1-9.4 wt.% of 1, 4-polyisoprene; the synergistic component comprises a first synergistic component and a second synergistic component, and the content of the first synergistic component and the second synergistic component is 90.0-99.9 wt.%. The first synergistic component comprises fatty acid and / or non-sterol fatty acid ester, and the second synergistic component comprises sterol and / or sterol ester. On the basis of the total mass of the synergistic components, the first synergistic component is prepared from 64.0 to 99.9 weight percent of unsaturated fatty acid and / or non-sterol unsaturated fatty acid ester and 0 to 24.0 weight percent of saturated fatty acid and / or non-sterol saturated fatty acid ester; and the second synergistic component comprises 0.1 to 2.0 weight percent of sterol and / or sterol ester. According to the composition disclosed by the invention, the pharmaceutical activity of the 1, 4-polyisoprene is improved, and a better drug effect can be obtained under the condition of the same dosage.

Description

Technical Field

[0001] The present invention belongs to the field of medicine, and in particular relates to a pharmaceutical composition and application thereof. Background Art

[0002] Chronic metabolic diseases are a group of metabolic clinical syndromes primarily characterized by atherosclerotic cardiovascular and cerebrovascular diseases (including coronary heart disease, stroke, coronary atherosclerosis, carotid atherosclerosis, cerebral atherosclerosis, renal atherosclerosis, intestinal atherosclerosis, and limb atherosclerosis), type 2 diabetes, hypercholesterolemia, hypertriglyceridemia, fatty liver, colitis, polycystic ovary syndrome, and obesity. These diseases are closely associated with chronic inflammation. Neurodegenerative diseases, including Alzheimer's disease and Parkinson's disease, are also closely related to chronic inflammation and metabolic abnormalities.

[0003] CN119112780A discloses a drug for treating chronic metabolic diseases, including atherosclerotic cardiovascular and cerebrovascular diseases, type II diabetes, hypercholesterolemia, hypertriglyceridemia, fatty liver, colitis, polycystic ovary syndrome, and obesity. Its active ingredient is 1,4-polyisoprene (PI). CN117752677A further expands the drug's indications to include Alzheimer's disease.

[0004] Because PI is a solid at room temperature, it must be dissolved in a solvent to exert its pharmaceutical activity. Suitable solvents include fatty acids, fatty alcohols, ester compounds, and lipid compounds. In CN119112780A and CN117752677A, the solvent serves only to dissolve and disperse 1,4-polyisoprene. The solvent's selection is primarily based on safety, good solubility in PI, and low viscosity, without considering any synergistic effects. Summary of the Invention

[0005] In a first aspect, the present invention provides a pharmaceutical composition comprising a base component and a synergistic component, wherein the base component comprises 1,4-polyisoprene, the synergistic component comprises a first synergistic component and a second synergistic component, the first synergistic component comprises fatty acids and / or non-sterol fatty acid esters; the second synergistic component comprises sterols and / or sterol esters;

[0006] Wherein, based on the total mass of the pharmaceutical composition, the content of the basic component is 0.1wt.%-9.4wt.%; the content of the synergistic component is 90.0wt.%-99.9wt.%;

[0007] Wherein, based on the total mass of the synergistic components, the first synergistic component comprises:

[0008] Unsaturated fatty acids and / or non-sterol unsaturated fatty acid esters 64.0wt.%-99.9wt.%;

[0009] Saturated fatty acids and / or non-sterol saturated fatty acid esters 0wt.% -24.0wt.%;

[0010] Based on the total mass of the synergistic components, the second synergistic component comprises:

[0011] Sterol and / or sterol ester 0.1wt.%-2.0wt.%.

[0012] In a second aspect, the present invention also provides a pharmaceutical composition for use in preparing drugs for treating atherosclerotic cardiovascular and cerebrovascular diseases, metabolic diseases and neurodegenerative diseases.

[0013] Advantages and features of the present invention:

[0014] 1. The present invention utilizes the synergistic effect of the synergistic components in the pharmaceutical composition to enhance the pharmaceutical activity of the PI, thereby achieving a better pharmaceutical effect at the same PI dosage.

[0015] 2. On the contrary, when the drug effect is the same, the amount of PI used can be reduced, the drug production cost can be reduced, the safety of the drug can be increased, and the patient's compliance with the drug can be improved.

[0016] 3. The synergistic component can be prepared from refined animal and vegetable oils that meet the national food safety standards (GB-2716), with lower production costs. BRIEF DESCRIPTION OF THE DRAWINGS

[0017] Figure 1 This is the fatty acid gas chromatogram of composition 1 provided in Example 1. From left to right, the chromatographic peaks are 1 palmitic acid, 2 stearic acid, 3 oleic acid, 4 linoleic acid, and 5 linolenic acid.

[0018] Figure 2 This is the fatty acid gas chromatogram of composition 2 provided in Example 2. The chromatographic peaks from left to right are: 1. palmitic acid, 2. stearic acid, 3. oleic acid, 4. linoleic acid, 5. linolenic acid;

[0019] Figure 3 This is the fatty acid gas chromatogram of PI solution 1 provided in Comparative Example 1. The chromatographic peaks from left to right are: 1. caprylic acid, 2. capric acid, 3. lauric acid, 4. myristic acid, 5. palmitic acid, 6. stearic acid, 7. oleic acid, 8. linoleic acid;

[0020] Figure 4This is the fatty acid gas chromatogram of PI solution 2 provided in Comparative Example 2. The chromatographic peaks from left to right are: 1. palmitic acid, 2. stearic acid, 3. oleic acid, 4. linoleic acid, 5. linolenic acid;

[0021] Figure 5 This is a common optical microscope photograph of foamy macrophages in 10 test groups provided in Application Example 1;

[0022] Figure 6 This is a bar graph showing the proportion of foamy macrophages to the total cells in the 10 experimental groups provided in Application Example 1;

[0023] Figure 7 This is a bar graph showing the test results of the expression level of IL-6, a marker gene of the macrophage M1 type, in the 10 experimental groups provided in Application Example 2 after LPS treatment;

[0024] Figure 8 This is a bar graph showing the test results of the expression level of the macrophage M1 marker gene IL-1β after LPS treatment in the 10 test groups provided in Application Example 2;

[0025] Figure 9 This is a bar graph showing the test results of the expression level of TNF-α, a marker gene of macrophage M1, in the 10 experimental groups provided in Application Example 2 after LPS treatment;

[0026] Figure 10 This is a bar graph showing the test results of the expression level of IL-4, a marker gene of the macrophage M2 type, after LPS treatment in the 10 experimental groups provided in Application Example 2;

[0027] Figure 11 This is a bar graph showing the test results of the expression level of IL-10, a marker gene of macrophage M2, in the 10 experimental groups provided in Application Example 2 after LPS treatment;

[0028] Figure 12 This is an optical photograph of the mouse aorta in the six experimental groups provided in Application Example 3, taken under a dissecting microscope after staining with Oil Red O;

[0029] Figure 13 This is a bar graph showing the percentage of the mouse aortic plaque area to the mouse aortic area in the six experimental groups provided in Application Example 3;

[0030] Figure 14 These are optical microscope photographs of aortic root sections of mice in the six experimental groups provided in Application Example 3, stained with Oil Red O;

[0031] Figure 15 This is a bar graph showing the results of aortic root plaque detection in mice in the six experimental groups provided in Application Example 3;

[0032] Figure 16 This is a bar graph showing the blood glucose test results for mice in the six test groups provided in Application Example 4;

[0033] Figure 17 This is a bar graph showing the test results of serum glucose levels in mice in the six test groups provided in Application Example 4;

[0034] Figure 18 This is a bar graph showing the test results of sera glycated serum protein levels in mice in the six test groups provided in Application Example 4;

[0035] Figure 19 These are photos of mouse livers in the six experimental groups provided in Application Example 5;

[0036] Figure 20 is a bar graph showing the percentage of mouse liver mass to total mouse mass in the six experimental groups provided in Application Example 5;

[0037] Figure 21 This is a bar graph showing the test results of triglyceride content in mouse liver tissues in the six test groups provided in Application Example 5;

[0038] Figure 22 is a line graph of the DAI quantitative scoring test results of mouse colon lesions in the six test groups provided in Application Example 6;

[0039] Figure 23 is a line graph of the weight loss rates of mice in the six experimental groups provided in Application Example 6;

[0040] Figure 24 are photos of the mouse colons in the six experimental groups provided in Application Example 6;

[0041] Figure 25 is a bar graph of the colon length measurement results of mice in the six experimental groups provided in Application Example 6;

[0042] Figure 26 is a bar graph of the colon weight measurement results of mice in the six experimental groups provided in Application Example 6;

[0043] Figure 27 is a bar graph of the escape latency of mice in the six experimental groups provided in Application Example 7;

[0044] Figure 28 is a bar graph showing the number of times mice in the six experimental groups crossed the target platform provided in Application Example 7;

[0045] Figure 29 is a bar graph showing the number of times mice in the six experimental groups passed through the target quadrant provided in Application Example 7;

[0046] Figure 30This is a bar graph showing the proportion of foamy macrophages in the total cells in the 11 experimental groups provided in Application Example 8;

[0047] Figure 31 This is a graph showing the mean difference of the proportion of foamy macrophages in the total cells in the 11 experimental groups provided in Application Example 8, with the PI solution group as the comparison object, 95% confidence interval, and Dunnett test;

[0048] Figure 32 This is a graph showing the mean difference of the proportion of foamy macrophages in the total cells in the 11 experimental groups provided in Application Example 8, with the composition 8-5 group as the comparison object, and a 95% confidence interval, as tested by Dunnett's test;

[0049] Figure 33 This is a bar graph showing the proportion of foamy macrophages to the total cells in the 10 experimental groups provided in Application Example 9;

[0050] Figure 34 This is a graph showing the mean difference of the proportion of foamy macrophages in the total cells in the 10 experimental groups provided in Application Example 9, using the PI solution group as the comparison object, with a 95% confidence interval, and a Dunnett test;

[0051] Figure 35 This is a bar graph showing the proportion of foamy macrophages to total cells in the 10 experimental groups provided in Application Example 10;

[0052] Figure 36 This is a graph showing the mean difference of the proportion of foamy macrophages in the total cells in the 10 experimental groups provided in Application Example 10, using the PI solution group as the comparison object, with a 95% confidence interval, as tested by Dunnett's test;

[0053] Figure 37 This is a bar graph showing the proportion of foamy macrophages to the total cells in the 10 experimental groups provided in Application Example 11;

[0054] Figure 38 This is a graph showing the mean difference of the proportion of foamy macrophages in the total cells in the 10 experimental groups provided in Application Example 11, with the PI solution group as the comparison object, 95% confidence interval, and Dunnett test;

[0055] Figure 39 This is a bar graph showing the proportion of foamy macrophages in the total cells in the eight experimental groups provided in Application Example 12;

[0056] Figure 40 This is a graph showing the mean difference of the proportion of foamy macrophages in the total cells in the eight experimental groups provided in Application Example 12, with the PI solution group as the comparison object, 95% confidence interval, and Dunnett's test;

[0057] Figure 41 This is a bar graph showing the proportion of foamy macrophages in the total cells in the eight experimental groups provided in Application Example 13;

[0058] Figure 42 This is a graph showing the mean difference of the proportion of foamy macrophages in the total cells in the eight experimental groups provided in Application Example 13, with the PI solution group as the comparison object, 95% confidence interval, and Dunnett's test. DETAILED DESCRIPTION

[0059] The pharmaceutical composition according to the present invention comprises a base component and a synergistic component, wherein the base component comprises 1,4-polyisoprene, the synergistic component comprises a first synergistic component and a second synergistic component, the first synergistic component comprises fatty acids and / or non-sterol fatty acid esters; the second synergistic component comprises sterols and / or sterol esters;

[0060] Wherein, based on the total mass of the pharmaceutical composition, the content of the basic component is 0.1wt.%-9.4wt.%; the content of the synergistic component is 90.0 wt.%-99.9 wt.%;

[0061] Wherein, based on the total mass of the synergistic components, the first synergistic component comprises:

[0062] Unsaturated fatty acids and / or non-sterol unsaturated fatty acid esters 64.0wt.%-99.9wt.%;

[0063] Saturated fatty acids and / or non-sterol saturated fatty acid esters 0wt.% -24.0wt.%;

[0064] Based on the total mass of the synergistic components, the second synergistic component comprises:

[0065] Sterol and / or sterol ester 0.1wt.%-2.0wt.%.

[0066] According to the pharmaceutical composition of the present invention, preferably, based on the total mass of the composition, the total content of the basic component and the synergistic component is ≥95.0 wt.%, preferably 98.0 wt.%-100 wt.%.

[0067] According to the pharmaceutical composition of the present invention, preferably, based on the total mass of the pharmaceutical composition, the mass percentage of the basic component is 0.1wt.%-9.4wt.%, preferably 0.24wt.%-3.8wt.%, and further preferably 0.4wt.%-2.0wt.%.

[0068] In a specific embodiment, based on the total weight of the composition, the pharmaceutical composition comprises or consists of the following components: basic component 0.49wt.%-0.69wt.%; ethyl palmitate 6wt.%-10wt.%; ethyl stearate 5wt.%-9wt.%; ethyl oleate 20wt.%-30wt.%; ethyl linoleate 35wt.%-40wt.%; ethyl linolenate 16wt.%-24wt.%; β-sitosterol 0.2wt.%-0.32wt.%; and stigmasterol 0.15wt.%-0.19wt.%.

[0069] According to the pharmaceutical composition of the present invention, the basic component PI is derived from artificial synthesis or plant extraction.

[0070] Plant extraction is the extraction of PI from natural rubber-producing plants. According to current human knowledge, there are about 2,500 rubber-producing plants that can synthesize PI, belonging to the Euphorbiaceae, Asteraceae, Moraceae, Apocynaceae, Sapotaceae, Eucommiaceae, Akebiaceae, etc. Common rubber-producing plants include Hevea brasiliensis ( Hevea brasiliensis ), Russian dandelion ( Taraxacum koksaghy z)、Guayule( Parthenium argentatum ),Fig( Ficus carica ), Ficus microcarpa ( Ficus elastica )、Parabellaria officinalis( Periploca sepium )、Sapodilla tree( Manilkara zapota )、 Mimusops balata 、 Palaquium gutta (HK. F.) Baill, Cat Shit Melon ( Decaisnea insignis )、Eucommia ulmoides( Eucommia ulmoides Oliv., etc. PI can be extracted from the rubber-containing parts of these rubber-producing plants. For example, the bark (including the latex that oozes out when the bark is cut), roots, leaves, flowers, fruits, and seeds of the Hevea brasiliensis tree all contain PI and can be used as raw materials for PI extraction.

[0071] PI extraction methods include tapping, squeezing, and solvent extraction. Tapping involves cutting the tissue of rubber plants with a rubber knife and collecting the PI-containing latex that flows out. Squeezing involves mechanically destroying and squeezing the plant tissue to extract the PI-containing latex or oils in which the PI has been dissolved. Extraction involves soaking the plant tissue in a solvent that dissolves the PI, transferring the PI from the plant tissue into the solvent for extraction.

[0072] As a preferred technical solution of the present application, the degree of polymerization n of the 1,4-polyisoprene is ≥6. For example, the numerical range of the degree of polymerization n of the 1,4-polyisoprene is: 6≤n≤100000. Specifically, n can be 6, 10, 20, 50, 100, 200, 500, 1000, 2000, 5000, 8000, 10000 or 100000, etc.

[0073] Since 1,4-polyisoprene with a degree of polymerization less than 6 has certain volatility and pungent odor and has an inhibitory effect on the growth of cells cultured in vitro, 1,4-polyisoprene with a degree of polymerization ≥ 6 is selected as the basic component.

[0074] It should be noted that in this application, there are no special restrictions on the cis- and trans-structures and sources of 1,4-polyisoprene. It can be prepared from natural rubber or synthesized artificially. Synthetic 1,4-polyisoprene contains both cis and trans structures, with the cis structure being the predominant one. In natural rubber, the vast majority of plant or fungal sources, including Hevea brasiliensis, have a cis structure. It is now clearly known that natural rubber produced from Eucommia ulmoides has a trans structure, i.e., trans-1,4-polyisoprene.

[0075] Artificial synthesis uses isoprene monomer as raw material, polymerizes it under specific conditions, and then separates and purifies it to obtain PI.

[0076] According to the pharmaceutical composition of the present invention, preferably, based on the total mass of the synergistic components, the unsaturated fatty acid and / or non-sterol unsaturated fatty acid ester comprises:

[0077] ω-3 polyunsaturated fatty acids and / or ω-3 polyunsaturated fatty acid esters 14.0 wt.%-26.0 wt.%;

[0078] ω-6 polyunsaturated fatty acids and / or ω-6 polyunsaturated fatty acid esters 31.0 wt.%-44.0 wt.%;

[0079] Monounsaturated fatty acids and / or monounsaturated fatty acid esters 15.0 wt.%-31.0 wt.%.

[0080] According to the pharmaceutical composition of the present invention, "ω-3" fatty acids are polyunsaturated fatty acids characterized by the first double bond being located at the third carbon atom (ω-3 position) from the methyl end of the carbon chain. This refers to oils containing any or all of the polyunsaturated fatty acids of this chemical name and their derivatives, including those derived from: animals (e.g., fish); plants (e.g., evening primrose oil, borage); other living sources, such as algae, bacteria, yeast, and their "bioengineered" derivatives; purified, modified, or synthetic products; and "ω-3" precursors, including water-soluble derivatives. Preferably, the ω-3 polyunsaturated fatty acids and / or ω-3 polyunsaturated fatty acid esters are selected from α-linolenic acid (ALA), α-linolenic acid, eicosapentaenoic acid (EPA), eicosapentaenoic acid, docosahexaenoic acid (DHA), docosahexaenoic acid, docosapentaenoic acid (DPA), docosapentaenoic acid, stearidonic acid (SDA), stearidonic acid, hexadecatrienoic acid (HTA), hexadecatrienoic acid, eicosatetraenoic acid (Eicosatetraenoic acid, ETA) and at least one of eicosatetraenoic acid, preferably at least one of α-linolenic acid, α-linolenic acid ester, eicosapentaenoic acid, eicosapentaenoic acid ester, docosahexaenoic acid or docosahexaenoic acid ester, more preferably α-linolenic acid and / or α-linolenic acid ester;

[0081] According to the pharmaceutical composition of the present invention, the "ω-6" fatty acid is a polyunsaturated fatty acid in which the first double bond is located at the sixth carbon atom (ω-6 position) from the methyl end of the carbon chain. This refers to oils containing any or all of the polyunsaturated fatty acids of this chemical name and their derivatives, such as those described for ω-3. The ω-6 polyunsaturated fatty acids and / or ω-6 polyunsaturated fatty acid esters are selected from at least one of linoleic acid (LA), linoleic acid esters, gamma-linolenic acid (GLA), gamma-linolenic acid esters, arachidonic acid (ARA), and arachidonic acid esters, preferably at least one of linoleic acid, linoleic acid esters, gamma-linolenic acid, or gamma-linolenic acid esters, and more preferably linoleic acid and / or linoleic acid esters.

[0082] According to the pharmaceutical composition of the present invention, the monounsaturated fatty acid and / or monounsaturated fatty acid ester is selected from at least one of palmitoleic acid, palmitoleate, oleic acid, oleate, elaidic acid, elaidic acid, gadoleic acid, gadoleic acid, eicosenoic acid, nervonic acid, nervonic acid, tetracosenoic acid or tetracosenoic acid, preferably at least one of palmitoleic acid, palmitoleate, oleic acid, oleate, eicosenoic acid, eicosenoic acid, nervonic acid or nervonic acid, further preferably oleic acid and / or oleate.

[0083] According to the pharmaceutical composition of the present invention, the saturated fatty acid and / or non-steroidal saturated fatty acid ester is selected from at least one of butyric acid, butyrate, caproic acid, caproate, caprylic acid, caprylate, capric acid, capric ester, lauric acid, laurate, myristic acid, myristate, palmitic acid, palmitate, stearic acid, stearate, arachidic acid, arachidic acid, behenic acid, behenic acid, lignoceric acid, lignoceric acid, ceric acid or ceric acid ester, preferably at least one of caprylic acid, caprylate, capric acid, capric ester, lauric acid, laurate, myristic acid, myristate, palmitic acid, palmitate, stearic acid, stearate, arachidic acid, arachidic acid, behenic acid or behenic acid ester, further preferably at least one of palmitic acid, palmitate, stearic acid or stearate.

[0084] According to the pharmaceutical composition of the present invention, the non-sterol fatty acid ester is selected from at least one of glycerol esters, ethanol esters, C16-C30 monohydric alcohol esters, inositol esters or sphingosine esters of fatty acids, preferably glycerol esters and / or ethanol esters.

[0085] According to the pharmaceutical composition of the present invention, the second synergistic component is a phytosterol and / or a phytosterol ester, preferably selected from β-sitosterol, β-sitosterol ester, stigmasterol, stigmasterol ester, campesterol, campesterol ester, rapeseed sterol, rapeseed sterol ester, cycloartenol, cycloartenol ester, fuccasterol, fuccasterol ester, lanosterol, lanosterol ester, spinachsterol, spinachsterol ester, brassicasterol, brassicasterol ester, sitostanol, sitostanol ester, ergosterol, ergosterol ester, Δ 5 -Avenasterol, Δ 5 -Avenasterol esters, Δ 7 -Stigmasterol, Δ 7 -Stigmasterol ester, Δ 7 -Avenasterol or Δ 7 - at least one of avenasterol esters, more preferably at least one of β-sitosterol, β-sitosterol esters, stigmasterol or stigmasterol esters.

[0086] According to the pharmaceutical composition of the present invention, the sterol ester is selected from at least one of sterol fatty acid esters, sterol sulfates, sterol glycoside esters or sterol phosphates, and is preferably a sterol fatty acid ester. Sterol fatty acid esters are esters formed by esterification of sterols and fatty acids. In principle, any fatty acid is possible as the fatty acid. Fatty acids obtained from natural sources, in particular fatty acids obtained from plants and marine sources, or fatty acids corresponding to these fatty acids but produced by artificial synthesis are preferred. Fatty acids of plant or marine origin are particularly preferred.

[0087] The fatty acids can be used as pure substances or as substances containing mainly one or more fatty acids in small amounts, or as mixtures of a number of different fatty acids. Fatty acids having health benefits are preferably used. Such fatty acids having additional health benefits are particularly monounsaturated fatty acids and polyunsaturated fatty acids, such as ω-3 polyunsaturated fatty acids; all of these fatty acids, their preparation, recovery and purification are well known to those skilled in the art.

[0088] In the pharmaceutical composition of the present invention, the synergistic component, i.e., a mixture of fatty acids and / or non-sterol fatty acid esters with sterols and / or sterol esters, can be prepared using either highly purified individual components, mixed according to the synergistic component formula ratio, or one or more safe, edible, refined natural animal or vegetable oils (i.e., meeting the national food safety standard GB-2716). Natural animal or vegetable oils can be used directly based on the measured fatty acid and sterol composition if the formula ratio is met; otherwise, they are compounded to meet the formula ratio.

[0089] According to the pharmaceutical composition of the present invention, in a specific embodiment, the synergistic component is obtained by extracting and refining animal raw materials and / or plant raw materials; wherein the plant raw materials are selected from at least one of eucommia seeds, peony seeds, palm fruits, palm kernels, rice bran, sunflower seeds, high oleic sunflower seeds, peanuts, rapeseeds, soybeans, cotton seeds, safflower seeds, perilla seeds, tea seeds, olive fruits, cocoa beans, almonds, apricot kernels, rubber seeds, corn germ, wheat germ, sesame seeds, evening primrose seeds, hazelnuts, pumpkin seeds, walnuts, grape seeds or seaweed; the animal raw materials are selected from terrestrial animal oils and aquatic animal oils, and the terrestrial animal oils are selected from at least one of lard, beef tallow, mutton fat, chicken fat, duck fat, goose fat or butter; and the marine animal oils are selected from at least one of fish oil, krill oil, whale oil or seal oil.

[0090] In particular, the pharmaceutical compositions of this invention must meet the basic safety requirements for drugs or pharmaceutical raw materials. If the ingredients are derived from natural animal or vegetable oils, the most basic safety requirement is that they be refined and safe for consumption, i.e., comply with the national food safety standard (GB-2716). Unrefined crude oils should not be used directly.

[0091] Some special plant seeds may contain both PI and vegetable oil. If, after specific extraction and refining methods, the ratio of PI to the fatty acids and sterols in the refined vegetable oil precisely meets the requirements of the composition formulation of the present invention, this can also be used as a method for preparing the composition of the present invention. For example, literature reports indicate that the seeds of Eucommia ulmoides contain both PI (eucommia gum, a type of natural rubber, namely 1,4-polyisoprene) and oil (eucommia seed oil, whose fatty acids include the ω-3 polyunsaturated fatty acid linolenic acid, the ω-6 polyunsaturated fatty acid linoleic acid, the monounsaturated fatty acid oleic acid, saturated fatty acids, and phytosterols). It is just that people generally believe that PI is an impurity that will be removed intentionally or unintentionally during the extraction and refining of oils and fats (Wu Tao, Zhao Yu, Bai Yunai, et al. Research on the processing technology of Eucommia ulmoides seed oil [J]. China Oils and Fats, 2006, 31 (8): 2. DOI: 10.3321 / j.issn: 1003-7969.2006.08.023; Li Yonghui. Research on the separation technology of Eucommia ulmoides seed oil [J]. Grain and Food Industry, 2010 (2): 2. DOI: 10.3969 / j.issn.1672-5026.2010.02.005 9-2; Wu Tao. Research on the extraction technology of Eucommia ulmoides resin and Eucommia ulmoides seed oil [J]. China Oils and Fats, 2016, (12): 19-21.). The present invention does not provide a specific method for preparing refined Eucommia ulmoides seed oil containing PI, but only illustrates this possibility.

[0092] The pharmaceutical composition of the present invention is used in preparing medicines for treating atherosclerotic cardiovascular and cerebrovascular diseases, metabolic diseases and neurodegenerative diseases.

[0093] According to the application of the present invention, the atherosclerotic cardiovascular and cerebrovascular diseases include coronary atherosclerosis, carotid atherosclerosis, cerebral atherosclerosis, renal atherosclerosis, intestinal atherosclerosis, and limb atherosclerosis; the metabolic diseases include type II diabetes, non-alcoholic fatty liver disease, colitis, hypertriglyceridemia, hypercholesterolemia, chronic kidney disease, polycystic ovary syndrome, and hyperuricemia; and the neurodegenerative diseases include Alzheimer's disease and Parkinson's disease.

[0094] The raw materials used in the following examples and comparative examples are all commercially available, among which:

[0095] PI (1,4-polyisoprene) reagent was purchased from Sigma-Aldrich, product number 431257;

[0096] Ethyl palmitate, purity ≥98.0 wt.%, purchased from Shanghai Macklin Company;

[0097] Ethyl stearate, purity ≥97.0 wt.%, purchased from Shanghai Macklin Company;

[0098] Ethyl oleate, purity ≥95.0 wt.%, purchased from Shanghai Macklin Company;

[0099] Ethyl oleate, purity ≥85.0 wt.%, purchased from Wuhan Lanabai Company;

[0100] Ethyl linoleate, purity ≥97.0 wt.%, purchased from Shanghai Macklin Company;

[0101] Ethyl linolenate, purity ≥98.0 wt.%, purchased from Shanghai Macklin Company;

[0102] Ethyl linolenate, purity ≥80.0 wt.%, purchased from Shanghai Macklin Company;

[0103] β-Sitosterol, purity ≥75.0 wt.%, total phytosterols ≥95.0 wt.%, purchased from Shanghai Macklin Company;

[0104] Stigmasterol, purity ≥95.0 wt.%, purchased from Shanghai Macklin Company;

[0105] Refined linseed oil was purchased from Yihai Kerry Golden Dragon Fish Company;

[0106] Refined soybean oil was purchased from COFCO Fortune Company;

[0107] Refined coconut oil was purchased from Hainan Chunguang Food Company;

[0108] The cells used in the experiment were purchased from Nanjing Foxai Company;

[0109] All experimental animals were purchased from Jiangsu Jicui Pharmaceutical Co., Ltd.

[0110] Example 1, Preparation of Composition 1 of the Present Invention

[0111] Basic component: PI (1,4-polyisoprene) reagent, weigh 6.0 g.

[0112] Preparation of synergistic component 1: Weigh 180.0 g of ethyl palmitate, 140.0 g of ethyl stearate, 500.0 g of ethyl oleate (purity ≥95.0 wt.%), 760.0 g of ethyl linoleate, 410.0 g of ethyl linolenate (purity ≥80.0 wt.%), 6.0 g of β-sitosterol, and 4.0 g of stigmasterol, mix them together, dissolve all the solid substances, and mix evenly to obtain 2000.0 g of synergistic component 1.

[0113] Preparation of Composition 1: Add 6.0 g of the base component to 994.0 g of the synergistic component 1, and heat with stirring at 50°C overnight until all solids are dissolved, to obtain 1000.0 g of Composition 1. During heating and stirring, the container was filled with nitrogen as a protective gas to prevent oxidation.

[0114] After testing, the acid value of the composition is 0, the PI content in the composition is 0.59wt.%, and the detection method is thermal pyrolysis gas chromatography-mass spectrometry; the sterol content is 0.44wt.% (β-sitosterol 0.27wt.%, stigmasterol 0.17wt.%); the unsaponifiable matter content is 1.03wt.%, and the total fatty acid ester content is 98.97wt.%.

[0115] The sample of composition 1 was methyl esterified and its fatty acid composition was determined. The normalized fatty acid content of the composition was as follows: 16.2 wt.% of total saturated fatty acids (8.8 wt.% of palmitic acid and 7.4 wt.% of stearic acid), 83.8 wt.% of total unsaturated fatty acids, including 26.1 wt.% of oleic acid (a monounsaturated fatty acid), 37.5 wt.% of linoleic acid (an ω-6 polyunsaturated fatty acid), and 20.2 wt.% of linolenic acid (an ω-3 polyunsaturated fatty acid). The gas chromatogram of the fatty acid methyl ester is shown in FIG. Figure 1 .

[0116] According to actual measurements, the ingredients and proportions of the synergistic component 1 meet the requirements of the synergistic component of the present invention, and the ingredients and proportions of the composition 1 also meet the requirements of the composition of the present invention.

[0117] Example 2, Preparation of Composition 2 of the Present Invention

[0118] Preparation of Base Component 2: Approximately 1000 ml of latex from Hevea brasiliensis trees was harvested and adjusted to a pH of approximately 5 with formic acid. The resulting rubber mass was then repeatedly rinsed with water until the effluent was clear. The mass was then repeatedly extruded into sheets and dried to yield 298.2 g of natural rubber. Testing revealed a PI content of ≥97 wt.%.

[0119] Take 8.0 g of natural rubber block, immerse it in liquid nitrogen and freeze it for 30 minutes, then crush it with a high-speed crusher, and pass the crushed particles through a 20-mesh sieve. Weigh 6.0 g of the crushed particles to obtain base component 2.

[0120] Preparation of synergistic component 2: 600.0 g of refined linseed oil and 1400.0 g of refined soybean oil were mixed to obtain 2000.0 g of synergistic component 2.

[0121] Preparation of Composition 2: 6.0 g of the base component was added to 994.0 g of the synergistic component 2. The mixture was heated and stirred at 50°C overnight until all solids were dissolved, yielding a crude solution of Composition 2. During heating and stirring, the container was filled with nitrogen as a protective gas to prevent oxidation. The crude solution of Composition 2 was then centrifuged at 4000 g for 10 minutes at room temperature. The undissolved trace precipitate and impurities at the bottom of the centrifuge tube were discarded to yield 992.0 g of Composition 2 of the present invention.

[0122] After testing, the acid value of composition 2 was 0.2 mgKOH / g, the PI content in the composition was 0.59 wt.%, and the detection method was pyrolysis gas chromatography-mass spectrometry; the sterol and sterol ester content was 0.42 wt.% (β-sitosterol and β-sitosterol fatty acid esters totaled 0.33 wt.%, stigmasterol and stigmasterol fatty acid esters totaled 0.09 wt.%); the unsaponifiable matter content was 1.44 wt.%, and the total content of fatty acid esters was 98.56 wt.%.

[0123] The sample of composition 2 was methyl esterified and its fatty acid composition was determined. The gas chromatogram of fatty acid methyl ester of the composition is shown in FIG. Figure 2 The normalized fatty acid content test results are as follows: the total content of saturated fatty acids is 15.1wt.% (palmitic acid 9.4wt.%, stearic acid 5.7wt.%), the total content of unsaturated fatty acids is 84.3wt.%, of which the monounsaturated fatty acid - oleic acid is 24.2wt.% ( Figure 2 Peak 3 includes two adjacent peaks, which are two isomers of oleic acid. The main peak is C18:1n-9cis, with a content of 22.2wt.%, and the small peak on the right is C18:1n-7 cis, with a content of 2.0wt.%), ω-6 polyunsaturated fatty acid - linoleic acid 39.4wt.%, ω-3 polyunsaturated fatty acid - linolenic acid 20.7wt.%.

[0124] According to actual measurements, the ingredients and proportions of the synergistic component 2 meet the requirements of the synergistic component of the present invention; the ingredients and proportions of the composition 2 also meet the requirements of the composition of the present invention.

[0125] Comparative Example 1, Preparation of PI Solution 1

[0126] Solute: about 1.0 g of the natural rubber block prepared in Example 2, produced from Hevea brasiliensis, with a purity of ≥97 wt.%.

[0127] Solvent 1: about 200.0 g refined natural coconut oil.

[0128] Preparation of PI Solution 1: Freeze 1.0 g of natural rubber block in liquid nitrogen, then pulverize using a high-speed grinder. Pass the pulverized particles through a 20-mesh sieve, and weigh 0.6 g of the pulverized particles. Mix this with 99.4 g of refined coconut oil and heat at 50°C with stirring overnight until all solids are dissolved, yielding a crude PI Solution 1 solution. During heating and stirring, the container is filled with nitrogen as a protective gas to prevent oxidation. Centrifuge the hot crude PI Solution 1 solution at 4000 g for 10 minutes. Discard any undissolved precipitate and impurities at the bottom of the centrifuge tube to yield 98.2 g of PI Solution 1.

[0129] After testing, the content of PI in PI solution 1 was 0.59wt.%, and the detection method was pyrolysis gas chromatography-mass spectrometry. No phytosterols were detected in the solution, and the content of unsaponifiable matter was 0.76wt.%. The sample of PI solution 1 was methylated to determine its fatty acid composition. The content detection results after fatty acid normalization are as follows: the total content of saturated fatty acids is 92.5% (7.4wt.% caprylic acid, 6.0wt.% capric acid, 48.6wt.% lauric acid, 18.2wt.% myristic acid, 9.3wt.% palmitic acid, 3.0wt.% stearic acid), and the total content of unsaturated fatty acids is 6.6wt.%, including: monounsaturated fatty acid - oleic acid 5.6wt.%, ω-6 polyunsaturated fatty acid - linoleic acid 1.0wt.%, and no ω-3 polyunsaturated fatty acids were detected. The gas chromatogram of its fatty acid methyl ester is shown in Figure 3 .

[0130] The solvent in PI Solution 1 was measured to contain no second synergistic component, and the composition and ratio of fatty acids and / or fatty acid esters did not meet the requirements for the first synergistic component. This indicates that the solvent is not a synergistic component and PI Solution 1 is not a composition of the present invention.

[0131] Comparative Example 2, Preparation of PI Solution 2

[0132] Solute: Take about 8.0 g of the natural rubber block prepared in Example 2, produced from Hevea brasiliensis, with a purity of ≥97 wt.%.

[0133] Solvent 2: Take about 2000.0 g of ethyl oleate, purity ≥85.0 wt.%.

[0134] Preparation of PI Solution 2: Freeze 8.0 g of natural rubber block in liquid nitrogen, then pulverize using a high-speed grinder. Pass the pulverized particles through a 20-mesh sieve, and weigh 6.0 g of the pulverized particles. Mix this with 994.0 g of ethyl oleate and heat with stirring at 50°C overnight until all solids are dissolved, yielding a crude solution of PI Solution 2. During heating and stirring, the container is filled with nitrogen as a protective gas to prevent oxidation. Centrifuge the crude PI Solution 2 at 4000 g for 10 minutes at room temperature. Discard any undissolved precipitate and impurities at the bottom of the centrifuge tube to yield 993.6 g of PI Solution 2.

[0135] After testing, the content of PI in PI solution 2 was 0.59wt.%, and the detection method was pyrolysis gas chromatography-mass spectrometry. No phytosterols were detected in the solution, and the unsaponifiable matter content was 0.60wt.%. The sample of PI solution 2 was methylated to determine its fatty acid composition. The content detection results after fatty acid normalization are as follows: the total content of saturated fatty acids is 3.1wt.% (palmitic acid 2.1wt.%, stearic acid 1.0wt.%), and the total content of unsaturated fatty acids is 96.3wt.%, including: monounsaturated fatty acid - oleic acid 86.6wt.%, ω-6 polyunsaturated fatty acid - linoleic acid 7.2wt.%, ω-3 polyunsaturated fatty acid - linolenic acid 2.5wt.%. The gas chromatogram of fatty acid methyl ester is shown in Fig. Figure 4 .

[0136] Measurements revealed that Solvent 2 of PI Solution 2 did not contain the second synergistic component, and the composition and ratio of the fatty acid and / or fatty acid ester did not meet the requirements for the first synergistic component. This indicates that Solvent 2 is not a synergistic component, and PI Solution 2 does not constitute a composition of the present invention.

[0137] Application Example 1: Comparison of the inhibitory effects of the compositions prepared in Examples 1 and 2 and the PI solutions prepared in Comparative Examples 1 and 2 on macrophage foaming

[0138] Experimental Methods: Oxidized low-density lipoprotein (oxLDL) was used as a stimulus to induce foaming cell formation in the mouse monocytic cell line RAW264.7. Simultaneously, various test substances were added for 24 hours. The cells were then stained with Oil Red O to assess the level of foaming cell formation. Experimental groupings are shown in Table 1.

[0139] Table 1

[0140]

[0141] The morphology of the macrophages provided by the above-mentioned groups of experiments was examined using an optical microscope. The test results are as follows: Figure 5 At the same time, the percentage of foamy macrophages in the total number of cells in each of the above groups was statistically analyzed to obtain a bar graph of the percentage of foamy macrophages, as shown in Figure 6 shown. Figure 6 The numbers 1-10 on the horizontal axis correspond to groups 1-10 in Table 1, respectively. ns indicates no statistically significant difference, and asterisks (*) indicate significant differences. The same applies below.

[0142] The test results showed that in terms of the effect of inhibiting macrophage foaming: simple solvents 1 and 2 had no effect, simple synergistic components 1 and 2 had no effect, and there was no significant difference between them compared with the stimulant model; PI solutions 1 and 2 and compositions 1 and 2 had significant effects compared with the stimulant model; at the same PI dose, the effects of compositions 1 and 2 were significantly higher than those of PI solutions 1 and 2, indicating that compositions 1 and 2 had a synergistic effect.

[0143] Application Example 2: Comparison of the effects of the compositions prepared in Examples 1 and 2 and the PI solutions prepared in Comparative Examples 1 and 2 on macrophage polarization

[0144] Experimental Methods: Mouse RAW264.7 monocytes were treated with various test substances for 24 hours. Lipopolysaccharide (LPS) was then added as a stimulus to induce polarization of the RAW264.7 cells for 10 hours. RNA was extracted from the cells and reverse-transcribed into cDNA. The expression of macrophage M1 polarization-associated factors (IL-6, IL-1β, TNF-α) and M2 polarization-associated factors (IL-4, IL-10) was then measured by qPCR. Experimental groupings are shown in Table 2.

[0145] Table 2

[0146]

[0147] Fluorescence quantitative PCR instrument was used to detect the mRNA content of each test group. The expression levels of macrophage M1 marker genes IL-6, IL-1β, and TNF-α after LPS treatment were respectively Figure 7 、 Figure 8 、 Figure 9 ; The expression levels of IL-4 and IL-10, the marker genes of M2 macrophages, were shown in Figure 10 、 Figure 11 .

[0148] The experimental results showed that in terms of the effect on the polarization direction of macrophages: simple solvents 1 and 2 and simple synergistic components 1 and 2 did not show the ability to inhibit the polarization of macrophages to M1 and promote polarization to M2, and there was no significant difference between them compared with the stimulant model group; PI solutions 1 and 2 and compositions 1 and 2 significantly inhibited the polarization of macrophages to M1 and promoted polarization to M2 compared with the stimulant model; at the same PI dose, the ability of compositions 1 and 2 to inhibit the polarization of macrophages to M1 and promote polarization to M2 was significantly higher than that of PI solutions 1 and 2, indicating that compositions 1 and 2 have a synergistic effect.

[0149] Application Examples 1 and 2 also show that no matter what the sources of the synergistic components 1 and 2 are, as long as the formula ratio of the present invention is met, when they are combined with the same content of PI to form compositions 1 and 2, there is no difference in the pharmaceutical activity between them.

[0150] Application Examples 1 and 2 also demonstrate that PI Solutions 1 and 2 prepared using Solvents 1 and 2 that do not meet the present invention's formulation ratios exhibit no difference in drug activity at the same PI concentration, regardless of solvent source. In subsequent animal testing, PI Solution 2 prepared in Comparative Example 2 will be selected for comparison. This is because PI Solution 2 prepared in Comparative Example 2 is liquid at room temperature, making it convenient for gavage administration to animals. In contrast, PI Solution 1 prepared in Comparative Example 1 is solid at room temperature due to the higher freezing point of coconut oil, making it inconvenient for gavage administration to animals.

[0151] Application Example 3: Comparison of the Anti-atherosclerotic Effects of the Substances Prepared in Examples 1, 2, and Comparative Example 2 on Model Mice

[0152] Experimental method: 36 8-week-old male apoE - / - Mice were randomly divided into 6 groups, with 6 mice in each group. The control group was fed a normal diet for 16 weeks, and the other 5 groups were fed a high-fat diet (21 wt.% fat, 0.5 wt.% cholesterol) for 16 weeks and gavaged daily according to the experimental grouping table 3.

[0153] Table 3

[0154]

[0155] After 16 weeks, the mice were euthanized and the aorta and root were collected. The aorta root and aorta were then stained with Oil Red O. The Oil Red O positive areas were counted using the ImageJ program to detect the size of atherosclerotic plaques in the above groups of experimental mice. The results of the mouse aortic plaque size test are shown in Figure 2. Figure 12 The positive area, i.e. the percentage of plaque area to the area of mouse aorta is shown in Figure 13 shown.

[0156] The aortic root of mice was frozen and then stained with Oil Red O. The results of the aortic root plaque size test were as follows: Figure 14 As shown, the statistical graph of the positive area, i.e. the plaque area, is shown in Figure 15 shown.

[0157] The test results showed that both the composition and the PI solution were effective in combating atherosclerosis. At the same PI dose, the composition was more effective than the PI solution, demonstrating a synergistic effect. The synergistic components alone had no therapeutic effect compared to the model group. At the same PI concentration and dose, synergistic components from different sources, as long as they met the composition and ratios specified in the present invention, showed no difference in synergistic effect on the PI. This means that there was no difference in the pharmacological activity between Composition 1 and Composition 2.

[0158] Application Example 4: Comparison of therapeutic effects of the substances prepared in Examples 1, 2 and Comparative Example 2 on type II diabetes model mice

[0159] Test method: 25 7-week-old SPF males db / db Mice were randomly divided into 5 groups, 5 mice in each group, and 5 7-week-old SPF male m / m Mice served as the control group. Specific experimental groups and gavage and feeding conditions are shown in Table 4.

[0160] Table 4

[0161]

[0162] For blood glucose (FBG) content determination, mice were fasted for more than 12 hours but not water. The tails of mice were disinfected with alcohol during the test. Blood was collected from the tail tip vein. A second drop of blood was collected using a Roche blood glucose meter to measure blood glucose. Figure 16 .

[0163] Determination of serum glucose (GLU) and glycosylated serum protein (GSP) content in serum: Mouse serum was collected and the GLU and GSP in the serum were detected using a biochemical detector. The test results are shown in Figure 17 and Figure 18 .

[0164] The test results showed that both the composition and the PI solution were effective in treating type 2 diabetes model mice. At the same PI dose, the composition was more effective than the PI solution, demonstrating a synergistic effect. The synergistic components alone had no therapeutic effect compared to the model group. At the same PI concentration and dose, synergistic components from different sources, as long as they met the composition and ratios specified in the present invention, showed no difference in synergistic effect on PI, indicating no difference in the pharmacological activity between Compositions 1 and 2.

[0165] Application Example 5: Comparison of therapeutic effects of the substances prepared in Examples 1, 2 and Comparative Example 2 on fatty liver model mice

[0166] Experimental Methods: Thirty six-week-old male C57BL / 6J mice were divided equally into six groups of five mice each and fed for 14 weeks. Specific experimental groupings, gavage administration, and feeding conditions are shown in Table 5.

[0167] Table 5

[0168]

[0169] After 14 weeks, the mice were euthanized, and the livers and tissues were collected for photographing and weighing. The morphological photos of the livers of the mice in each group and the statistical graphs of the percentage of the liver weight to the total weight of the mice are shown in the figure below. Figure 19 、 Figure 20 As shown in the figure, the model group was compared with the control group, and the fatty liver model was successfully established. The triglyceride content in fatty liver tissue is a quantitative indicator of the degree of fatty liver disease. The triglyceride (TG) content in the liver tissue of each group of mice was detected using a tissue triglyceride (TG) enzymatic assay kit to quantify the degree of fatty liver disease. The test results are shown in the figure. Figure 21 shown.

[0170] The test results showed that both the composition and the PI solution were effective in inhibiting the development of fatty liver disease induced by a high-sugar, high-fat diet. At the same PI dose, the composition was more effective than the PI solution, demonstrating a synergistic effect. The synergistic component alone had no therapeutic effect compared to the model group. At the same PI concentration and dose, synergistic components from different sources, as long as they met the composition and ratios specified in the present invention, showed no difference in synergistic effect on PI, indicating no difference in the pharmacological activity between Compositions 1 and 2.

[0171] Application Example 6: Comparison of therapeutic effects of the substances prepared in Examples 1, 2 and Comparative Example 2 on enteritis model mice

[0172] Experimental Methods: Thirty 8-week-old male C57BL / 6J mice were randomly divided into six groups of five mice each and fed for seven days. Specific experimental groupings, gavage, and feeding conditions are shown in Table 6.

[0173] Table 6

[0174]

[0175] The experimental feeding period lasted for 7 days, with mice weighed and recorded daily. Feces were also collected daily to observe fecal status and the presence of occult blood or hematochezia. This data was used to quantify the disease activity index (DAI). The DAI (Disease Activity Index) is a comprehensive score based on the percentage of weight loss, stool consistency, and stool hemorrhage. The DAI scoring criteria are shown in Table 7.

[0176] Table 7

[0177]

[0178] *In the table above, normal stool refers to formed stool; loose stool refers to mushy, semi-formed stool that does not adhere to the anus; and loose stool refers to watery, loose stool that adheres to the anus. A "+" indicates a more pronounced characteristic.

[0179] The DAI score quantifies the extent of colitis in mice. The higher the DAI score, the more severe the colitis. Figure 22 The change of mouse body weight is also a quantitative indicator of colon lesions, because colon lesions can affect nutrient absorption, leading to weight loss. Figure 23 .

[0180] The length and weight of the mouse colon are also quantitative indicators of the severity of colitis. The more severe the colitis, the shorter the length and lighter the weight of the colon. After 7 days of feeding, the mice were euthanized and the colon was taken. Figure 24 The colon length and weight of each group of mice were measured, and the test results are shown in Figure 25 、 Figure 26 .

[0181] The test results showed that both the composition and the PI solution were effective in inhibiting and alleviating colitis caused by dextran sulfate sodium (DSS). At the same PI dose, the composition was more effective than the PI solution, demonstrating a synergistic effect. The synergistic components alone had no therapeutic effect compared to the model group. At the same PI concentration and dose, synergistic components from different sources, as long as they met the composition and ratios specified in this invention, showed no difference in PI synergistic effect, indicating no difference in the pharmacological activity of Compositions 1 and 2.

[0182] Application Example 7: Comparison of therapeutic effects of the substances prepared in Examples 1, 2 and Comparative Example 2 on Alzheimer's disease model mice

[0183] Experimental Methods: Thirty 8-week-old male APP / PS1 mice of the C57BL / 6J background were randomly divided into five groups, with six mice per group. These mice are double-transgenic AD models. Six wild-type (WT) C57BL / 6J mice served as controls. The groups, feeding schedule, and oral gavage treatment of the mice are shown in Table 8.

[0184] Table 8

[0185]

[0186] One week after the end of the feeding period, spatial learning and memory abilities of mice were assessed using a Morris Water Maze (MWM) video tracking analysis system. A circular pool was divided into four quadrants and filled with water. A target platform was immersed and fixed in the middle of the first quadrant, 2 cm below the water surface. Titanium dioxide pigment was added to the pool to render the platform invisible. Over the next six days, the water maze test consisted of a spatial probe test and a hidden platform test. During the training phase, mice were placed in the water facing the pool wall and allowed to swim freely. The time it took to find the target platform was recorded. Within 60 seconds, if the mouse found the target platform, it remained on the platform for 5 seconds before being removed. If the mouse did not find the platform within 60 seconds, the operator guided it to the platform and allowed it to remain there for 5 seconds. Each mouse was trained four times daily for five consecutive days, entering the water from a different quadrant each time. On the day after the final training session (day 6), the platform was removed and a 60-second probe test was conducted. The mouse enters the water in the quadrant opposite to the original platform and swims freely for 60 seconds. The mouse's movement trajectory is recorded, and the time (escape latency) and number of times the mouse passes through the target quadrant or target platform are counted. Figure 27 Escape latency of mice Figure 28 Statistics of the number of times mice crossed the target platform, Figure 29 Statistics of the number of times mice crossed the target quadrant.

[0187] from Figure 27 、 28 , 29 It can be seen that after treatment with PI solution or composition, the escape latency of mice was significantly shortened relative to the model group, and the number of times they crossed the target platform and the number of times they crossed the target quadrant increased significantly, which means that both increased the cognitive ability of AD mice. And at the same PI dose, the therapeutic effect of the composition was higher than that of the PI solution, suggesting that there was a synergistic effect between the PI and the synergistic component in the composition; the synergistic component alone did not show an improvement effect compared to the model group. When the PI concentration and dose are the same, as long as the synergistic components from different sources meet the composition and ratio of the present invention, there is no difference in the synergistic effect on PI, that is, there is no difference in the drug activity of composition 1 and composition 2.

[0188] Application Example 8: Exploration of the preferred concentration range of the basic component PI in the composition

[0189] Using the synergistic component 1 prepared in Example 1 as a solvent, it was mixed with the base component PI (1,4-polyisoprene) reagent according to Table 8-1. The mixture was mixed and dissolved on a shaker to prepare a series of compositions with varying PI concentrations. Compositions 8-1 and 8-2 were prepared directly, while the remaining PI compositions were prepared by serial dilution using the previous compositions as stock solutions. During the preparation process, composition 8-1 was found to be relatively viscous and exhibited poor fluidity. However, the preparation of the remaining compositions proceeded smoothly, with normal fluidity.

[0190] Table 8-1

[0191]

[0192] The pharmaceutical activity of a series of compositions formulated in this application example was evaluated using a macrophage foam cell model. Test methods: Oxidized low-density lipoprotein (oxLDL) was used as a stimulus to induce foam cell formation in the mouse monocytic cell line RAW264.7. Simultaneously, different test substances were added to quantitatively measure their inhibitory effects on macrophage foam cell formation. The experimental groups are shown in Table 8-2.

[0193] Table 8-2

[0194]

[0195] After adding the stimulant and test substance, the cells were incubated for 24 hours. Then, they were stained with Oil Red O and the percentage of foamy macrophages in the total cell number in each group was counted under an optical microscope to quantify the level of foamy macrophages. Figure 30 shown.

[0196] The PI solution group was used as the control. The differences in the mean values between the groups using the Dunnett test with 95% confidence intervals were shown in Table 2. Figure 31 This indicates that compared with the PI solution group, compositions 8-2, 8-3, 8-4, 8-5, 8-6, and 8-7 had stronger effects in inhibiting macrophage foaming, showing a synergistic effect; whereas compositions 8-1 and 8-8 had no significant differences compared with the PI solution group, showing no synergistic effect.

[0197] Taking the composition 8-5 with the lowest mean (i.e., good effect) as the control, the difference in means between the groups by Dunnett test with 95% confidence interval is shown in Figure 32 This indicates that in terms of the effect of inhibiting macrophage foaming, compositions 8-2, 8-3, 8-4, 8-6, and 8-7 have no significant difference compared with composition 8-5, indicating that their synergistic effects are relatively strong; the effects of compositions 8-1 and 8-8 are significantly inferior to those of composition 8-5.

[0198] Statistical analysis of the test results showed that in the composition composed of the synergistic component, the preferred range of the concentration of the basic component PI is 0.10wt.%-9.4wt.%, within this range, it has better biological activity and shows a significant synergistic effect with the synergistic component.

[0199] Application Example 9: Exploration of the optimal concentration range of ω-3 polyunsaturated fatty acids in the synergistic component

[0200] Using the formulation of Composition 1 prepared in Example 1 as a benchmark, a series of compositions with varying ω-3 polyunsaturated fatty acid (linolenic acid) contents were prepared by increasing or decreasing the proportion of ω-3 polyunsaturated fatty acid (ethyl linolenate) in the unsaturated fatty acids. The preparation method is as follows.

[0201] Preparation of mother solution 9-1: Take 4.8 mg of PI (1,4-polyisoprene) reagent and 795.2 mg of ethyl linolenate (purity ≥98.0 wt.%), heat to 40°C, and mix well on an oscillator to obtain 800 mg of mother solution 9-1.

[0202] Preparation of mother liquor 9-2: Take 22.5 mg of PI (1,4-polyisoprene) reagent, 337 mg of ethyl palmitate, 262 mg of ethyl stearate, 936 mg of ethyl oleate (purity ≥95.0 wt.%), 1423 mg of ethyl linoleate, 11.2 mg of β-sitosterol, and 7.5 mg of stigmasterol, mix them together, heat to 40°C, and shake on an oscillator to dissolve all solid substances and mix evenly to obtain 3000 mg of mother liquor 9-2.

[0203] Then, according to Table 9-1, compositions 9-1, 9-2, 9-3, 9-4, 9-5, 9-6, 9-7, and 9-8 were prepared. The ingredients of the prepared compositions are shown in Table 9-2.

[0204] Table 9-1

[0205]

[0206] Table 9-2

[0207]

[0208] The pharmaceutical activity of a series of compositions formulated in this application example was evaluated using a macrophage foam cell model. Experimental methods: Oxidized low-density lipoprotein (oxLDL) was used as a stimulus to induce foam cell formation in the mouse monocytic cell line RAW264.7. Simultaneously, different test substances were added to quantitatively measure their inhibitory effects on macrophage foam cell formation. Experimental groupings are shown in Table 9-3.

[0209] Table 9-3

[0210]

[0211] After adding the stimulant and test substance, the cells were incubated for 24 hours. Then, they were stained with Oil Red O and the percentage of foamy macrophages in the total cell number in each group was counted under an optical microscope to quantify the level of foamy macrophages. Figure 33 shown.

[0212] The differences in the mean values between the groups were compared with the PI solution group using the Dunnett test with 95% confidence intervals. Figure 34 This indicates that compared with the effect of PI solution in inhibiting macrophage foaming, the effects of compositions 9-2, 9-3, 9-4, 9-5, and 9-6 were better, showing a significant synergistic effect; while the effects of compositions 9-1 and 9-7 in inhibiting macrophage foaming were not significantly different from those of PI solution, and no synergistic effect was shown.

[0213] Statistical analysis of the test results showed that when the content of ω-3 polyunsaturated fatty acids (linolenic acid) in the synergistic component was 14.0wt.%-26.0wt.%, the synergistic component could exert a significant synergistic effect on PI; when it was lower than 14.0wt.% or higher than 26.0wt.%, the synergistic effect was not significant.

[0214] Application Example 10: Exploration of the optimal concentration range of ω-6 polyunsaturated fatty acids in the synergistic component

[0215] Using the formulation of Composition 1 prepared in Example 1 as a benchmark, a series of compositions with varying ω-6 polyunsaturated fatty acid (linoleic acid) contents were prepared by increasing or decreasing the proportion of ω-6 polyunsaturated fatty acid (linoleic acid ethyl ester) in the unsaturated fatty acids. The preparation methods are as follows.

[0216] Preparation of mother solution 10-1: Take 9.0 mg of PI (1,4-polyisoprene) reagent and 1491.0 mg of ethyl linoleate, heat to 40°C, and mix well on an oscillator to obtain 1500 mg of mother solution 10-1.

[0217] Preparation of mother liquor 10-2: Take 14.4 mg of PI (1,4-polyisoprene) reagent, 349.1 mg of ethyl palmitate, 271.5 mg of ethyl stearate, 969.8 mg of ethyl oleate (purity ≥95.0 wt.%), 775.8 mg of ethyl linolenate (purity ≥98.0 wt.%), 11.6 mg of β-sitosterol, and 7.8 mg of stigmasterol, mix them together, heat to 40°C, and shake on an oscillator to dissolve all solid substances and mix evenly to obtain 2400 mg of mother liquor 10-2.

[0218] Then, a series of compositions were prepared according to Table 10-1. The ingredients of each composition are shown in Table 10-2.

[0219] Table 10-1

[0220]

[0221] Table 10-2

[0222]

[0223] The pharmaceutical activity of a series of compositions formulated in this application example was evaluated using a macrophage foaming cell model. Test methods: Oxidized low-density lipoprotein (oxLDL) was used as a stimulus to induce foaming cell formation in the mouse monocytic cell line RAW264.7. Simultaneously, different test substances were added to quantitatively measure their inhibitory effects on macrophage foaming cell formation. The experimental groups are shown in Table 10-3.

[0224] Table 10-3

[0225]

[0226] After adding the stimulant and test substance, the cells were incubated for 24 hours. Then, they were stained with Oil Red O and the percentage of foamy macrophages in the total cell number in each group was counted under an optical microscope to quantify the level of foamy macrophages. Figure 35 shown.

[0227] The differences in the mean values between the groups were compared with the PI solution group using the Dunnett test with 95% confidence intervals. Figure 36 This indicates that compared with the effect of PI solution in inhibiting macrophage foaming, the effects of compositions 10-2, 10-3, 10-4, 10-5, and 10-6 were superior, showing a significant synergistic effect; whereas the effects of compositions 10-1 and 10-7 in inhibiting macrophage foaming showed no significant difference compared with PI solution, and no synergistic effect was shown.

[0228] Statistical analysis of the test results showed that when the content of ω-6 polyunsaturated fatty acid (linoleic acid) in the synergistic component was 31.0wt.%-44.0wt.%, the synergistic component could exert a significant synergistic effect on PI; when it was lower than 31.0wt.% or higher than 44.0wt.%, the synergistic effect was not significant.

[0229] Application Example 11: Exploration of the optimal concentration range of monounsaturated fatty acids in the synergistic component

[0230] Using the formulation of Composition 1 prepared in Example 1 as a benchmark, a series of compositions with varying monounsaturated fatty acid (oleic acid) contents were prepared by increasing or decreasing the ratio of monounsaturated fatty acid (ethyl oleate) in the unsaturated fatty acid. The preparation method is as follows.

[0231] Preparation of mother solution 11-1: 6.0 mg of PI (1,4-polyisoprene) reagent and 994.0 mg of ethyl oleate (purity ≥ 95.0 wt.%) were heated to 40°C and mixed on an oscillator to obtain 1000 mg of mother solution 11-1.

[0232] Preparation of mother liquor 11-2: 18.0 mg of PI (1,4-polyisoprene) reagent, 360.2 mg of ethyl palmitate, 280.2 mg of ethyl stearate, 1521.0 mg of ethyl linoleate, 800.5 mg of ethyl linolenate (purity ≥98.0 wt.%), 12.0 mg of β-sitosterol, and 8.0 mg of stigmasterol were mixed together, heated to 40°C, and shaken on an oscillator to dissolve all solid substances and mix evenly to obtain 3000 mg of mother liquor 11-2.

[0233] Then, a series of compositions were prepared according to Table 11-1. The ingredients of each composition prepared are shown in Table 11-2.

[0234] Table 11-1

[0235]

[0236] Table 11-2

[0237]

[0238] The pharmaceutical activity of a series of compositions formulated in this application example was evaluated using a macrophage foam cell model. Experimental methods: Oxidized low-density lipoprotein (oxLDL) was used as a stimulus to induce foam cell formation in the mouse monocytic cell line RAW264.7. Simultaneously, various test substances were added to quantitatively measure their inhibitory effects on macrophage foam cell formation. Experimental groupings are shown in Table 11-3.

[0239] Table 11-3

[0240]

[0241] After adding the stimulant and test substance, the cells were incubated for 24 hours. Then, they were stained with Oil Red O and the percentage of foamy macrophages in the total cell number in each group was counted under an optical microscope to quantify the level of foamy macrophages. Figure 37 shown.

[0242] The differences in the mean values between the groups were compared with the PI solution group using the Dunnett test with 95% confidence intervals. Figure 38 This indicates that compared with the effect of PI solution in inhibiting macrophage foaming, the effects of compositions 11-2, 11-3, 11-4, 11-5, and 11-6 were better, showing a significant synergistic effect; while the effects of compositions 11-1 and 11-7 in inhibiting macrophage foaming were not significantly different from those of PI solution, and no synergistic effect was shown.

[0243] Statistical analysis of the test results showed that when the content of monounsaturated fatty acid (oleic acid) among unsaturated fatty acids in the synergistic component was 15.0wt.%-31.0wt.%, the synergistic component could exert a significant synergistic effect on PI; when it was lower than 15.0wt.% or higher than 31.0wt.%, the synergistic effect was not significant.

[0244] Application Example 12: Exploration of the optimal concentration range of saturated fatty acids in the synergistic component

[0245] Based on the formulation of Composition 1 prepared in Example 1, a series of compositions with different saturated fatty acid contents were prepared by increasing or decreasing the ratio of saturated fatty acids (ethyl palmitate and ethyl stearate). The preparation method is as follows.

[0246] Preparation of mother solution 12-1: Take 3.0 mg of PI (1,4-polyisoprene) reagent, 279.6 mg of ethyl palmitate, and 217.4 mg of ethyl stearate, heat to 40°C, and mix well on an oscillator to obtain 500 mg of mother solution 12-1.

[0247] Preparation of mother liquor 12-2: Mix 15.0 mg of PI (1,4-polyisoprene) reagent, 744.0 mg of ethyl oleate (purity ≥95.0 wt.%), 1130.9 mg of ethyl linoleate, 595.2 mg of ethyl linolenate (purity ≥98.0 wt.%), 8.9 mg of β-sitosterol, and 6.0 mg of stigmasterol. Heat to 40°C and shake on an oscillator to dissolve all solid substances and mix evenly to obtain 2500 mg of mother liquor 12-2.

[0248] Then, a series of compositions were prepared according to Table 12-1. The ingredients of each composition are shown in Table 12-2.

[0249] Table 12-1

[0250]

[0251] Table 12-2

[0252]

[0253] The pharmaceutical activity of a series of compositions formulated in this application example was evaluated using a macrophage foaming cell model. Test methods: Oxidized low-density lipoprotein (oxLDL) was used as a stimulus to induce foaming cell formation in the mouse monocytic cell line RAW264.7. Simultaneously, various test substances were added to quantitatively measure their inhibitory effects on macrophage foaming cell formation. The experimental groups are shown in Table 12-3.

[0254] Table 12-3

[0255]

[0256] After adding the stimulant and test substance, the cells were incubated for 24 hours. Then, they were stained with Oil Red O and the percentage of foamy macrophages in the total cell number in each group was counted under an optical microscope to quantify the level of foamy macrophages. Figure 39 shown.

[0257] The differences in the mean values between the groups were compared with the PI solution group using the Dunnett test with 95% confidence intervals. Figure 40 This indicates that compared with the effect of PI solution in inhibiting macrophage foaming, the effects of compositions 12-1, 12-2, 12-3, and 12-4 were superior, showing a significant synergistic effect; whereas the effect of composition 12-5 in inhibiting macrophage foaming was not significantly different from that of PI solution, and no synergistic effect was shown.

[0258] Statistical analysis of the test results showed that when the content of saturated fatty acids (ethyl palmitate, ethyl stearate) in the synergistic component was less than or equal to 24wt.%, the synergistic component could exert a significant synergistic effect on PI, and the content of saturated fatty acids could be as low as 0; when the content of saturated fatty acids (ethyl palmitate, ethyl stearate) was higher than 24.0wt.%, the synergistic effect was not significant.

[0259] Application Example 13: Exploration of the preferred concentration range of the second synergistic component sterol in the synergistic component

[0260] Based on the formulation of Composition 1 prepared in Example 1, the proportion of the second synergistic component, sterol (β-sitosterol, stigmasterol), was increased or decreased to prepare a series of compositions with different sterol contents. The preparation method is as follows.

[0261] Preparation of mother liquor 13: Take 6.0 mg of PI (1,4-polyisoprene) reagent, 85.8 mg of ethyl palmitate, 66.7 mg of ethyl stearate, 283.4 mg of ethyl oleate (purity ≥95.0 wt.%), 362.3 mg of ethyl linoleate, 190.7 mg of ethyl linolenate (purity ≥98.0 wt.%), 30.0 mg of β-sitosterol, and 20.0 mg of stigmasterol, mix them together, dissolve all solid substances and mix evenly to obtain 1000 mg of mother liquor 13.

[0262] Prepare diluent 13: Take 12.0 mg of PI (1,4-polyisoprene) reagent, 180.7 mg of ethyl palmitate, 140.6 mg of ethyl stearate, 502.0 mg of ethyl oleate (purity ≥95.0 wt.%), 763.1 mg of ethyl linoleate, and 401.6 mg of ethyl linolenate (purity ≥98.0 wt.%), mix them together, and allow all solid substances to dissolve and mix evenly to obtain 2000 mg of diluent 13.

[0263] Then, according to Table 13-1, a series of compositions were prepared by serial dilution method. The ingredients of each prepared composition are shown in Table 13-2.

[0264] Table 13-1

[0265]

[0266] Table 13-2

[0267]

[0268] The pharmaceutical activity of a series of compositions formulated in this application example was evaluated using a macrophage foam cell model. Experimental methods: Oxidized low-density lipoprotein (oxLDL) was used as a stimulus to induce foam cell formation in the mouse monocytic cell line RAW264.7. Simultaneously, different test substances were added to quantitatively measure their inhibitory effects on macrophage foam cell formation. Experimental groupings are shown in Table 13-3.

[0269] Table 13-3

[0270]

[0271] After adding the stimulant and test substance, the cells were incubated for 24 hours. Then, they were stained with Oil Red O and the percentage of foamy macrophages in the total cell number in each group was counted under an optical microscope to quantify the level of foamy macrophages. Figure 41 shown.

[0272] The differences in the mean values between the groups were compared with the PI solution group using the Dunnett test with 95% confidence intervals. Figure 42This indicates that compared with the effect of PI solution in inhibiting macrophage foaming, the effects of compositions 13-2, 13-3, and 13-4 were superior, showing a significant synergistic effect; whereas the effects of compositions 13-1 and 13-5 in inhibiting macrophage foaming showed no significant difference compared with PI solution, and did not show a synergistic effect.

[0273] Statistical analysis of the test results showed that when the content of the second synergistic component, sterol (β-sitosterol, stigmasterol) in the synergistic component was between 0.10-2.0wt.%, the synergistic component could exert a significant synergistic effect on PI; when the sterol (β-sitosterol, stigmasterol) content was higher than 2.0wt.% or lower than 0.1wt.%, the synergistic effect was not significant.

Claims

1. A pharmaceutical composition comprising a base component and a synergistic component, wherein the base component comprises 1,4-polyisoprene, the synergistic component comprises a first synergistic component and a second synergistic component, the first synergistic component comprises fatty acids and / or non-sterol fatty acid esters; the second synergistic component comprises sterols and / or sterol esters; in, Based on the total mass of the pharmaceutical composition, the content of the basic component is 0.1 wt.%-9.4 wt.%; the content of the synergistic component is 90.0 wt.%-99.9 wt.%; Wherein, based on the total mass of the synergistic components, the first synergistic component comprises: Unsaturated fatty acids and / or non-sterol unsaturated fatty acid esters 64.0wt.%-99.9wt.%; Saturated fatty acids and / or non-sterol saturated fatty acid esters 0wt.% -24.0wt.%; Wherein, based on the total mass of the synergistic components, the second synergistic component comprises: Sterol and / or sterol ester 0.1wt.%-2.0wt.%.

2. The pharmaceutical composition according to claim 1, characterized in that Based on the total mass of the pharmaceutical composition, the total content of the basic component and the synergistic component is ≥95.0wt.%.

3. The pharmaceutical composition according to claim 1 or 2, characterized in that Based on the total mass of the pharmaceutical composition, the content of the basic component is 0.1wt.%-9.4wt.%.

4. The pharmaceutical composition according to claim 1 or 2, characterized in that Based on the total mass of the pharmaceutical composition, the content of the basic component is 0.24wt.%-3.8wt.%.

5. The pharmaceutical composition according to claim 1 or 2, characterized in that Based on the total mass of the pharmaceutical composition, the content of the basic component is 0.4wt.%-2.0wt.%.

6. The pharmaceutical composition according to claim 1 or 2, characterized in that Based on the total weight of the composition, the pharmaceutical composition comprises or consists of the following components: basic component 0.49wt.%-0.69wt.%; ethyl palmitate 6wt.%-10wt.%; ethyl stearate 5wt.%-9wt.%; ethyl oleate 20wt.%-30wt.%; ethyl linoleate 35wt.%-40wt.%; ethyl linolenate 16wt.%-24wt.%; β-sitosterol 0.2wt.%-0.32wt.%; and stigmasterol 0.15wt.%-0.19wt.%.

7. The pharmaceutical composition according to claim 1 or 2, characterized in that The numerical range of the polymerization degree n of the 1,4-polyisoprene is: 6≤n≤100000.

8. The pharmaceutical composition according to claim 1 or 2, characterized in that Based on the total mass of the synergistic components, the unsaturated fatty acids and / or non-sterol unsaturated fatty acid esters comprise: ω-3 polyunsaturated fatty acids and / or ω-3 polyunsaturated fatty acid esters 14.0 wt.%-26.0 wt.%; ω-6 polyunsaturated fatty acids and / or ω-6 polyunsaturated fatty acid esters 31.0 wt.% -44.0 wt.%; Monounsaturated fatty acids and / or monounsaturated fatty acid esters 15.0 wt.%-31.0 wt.%.

9. The pharmaceutical composition according to claim 8, characterized in that The ω-3 polyunsaturated fatty acid and / or ω-3 polyunsaturated fatty acid ester is selected from at least one of α-linolenic acid, α-linolenic acid ester, eicosapentaenoic acid, eicosapentaenoic acid ester, docosahexaenoic acid, docosahexaenoic acid ester, docosapentaenoic acid, docosapentaenoic acid ester, octadecatetraenoic acid, octadecatetraenoic acid ester, hexadecatrienoic acid, hexadecatrienoic acid ester, eicosatetraenoic acid, and eicosatetraenoic acid ester; and / or, The ω-6 polyunsaturated fatty acid and / or ω-6 polyunsaturated fatty acid ester is selected from at least one of linoleic acid, linoleic acid ester, γ-linolenic acid, γ-linolenic acid ester, arachidonic acid, and arachidonic acid ester; and / or, The monounsaturated fatty acid and / or monounsaturated fatty acid ester is selected from at least one of palmitoleic acid, palmitoleate, oleic acid, oleate, vaccenic acid, vaccenic acid, gadoleic acid, gadoleate, eicosenoic acid, eicosenoate, nervonic acid, nervonic acid ester, tetracosenoic acid or tetracosenoate.

10. The pharmaceutical composition according to claim 1 or 2, characterized in that The saturated fatty acids and / or non-sterol saturated fatty acid esters are selected from at least one of butyric acid, butyrate, caproic acid, caproate, caprylic acid, caprylate, capric acid, caprate, lauric acid, laurate, myristic acid, myristic acid ester, palmitic acid, palmitate, stearic acid, stearate, arachidic acid, arachidic acid ester, behenic acid, behenate, lignoceric acid, lignoceric acid ester, cerotic acid or cerotic acid ester.

11. The pharmaceutical composition according to claim 1 or 2, characterized in that The non-sterol fatty acid ester is selected from at least one of glycerol ester, ethanol ester, C16-C30 monohydric alcohol ester, inositol ester or sphingosine ester of fatty acid.

12. The pharmaceutical composition according to claim 1 or 2, characterized in that The second synergistic component is phytosterol and / or phytosterol ester.

13. The pharmaceutical composition according to claim 1 or 2, characterized in that The sterol ester is selected from at least one of sterol fatty acid esters, sterol sulfates, sterol glycoside esters or sterol phosphates.

14. The pharmaceutical composition according to claim 1 or 2, characterized in that The synergistic component is obtained by extracting and refining animal raw materials and / or plant raw materials, wherein the plant raw materials are selected from at least one of eucommia seeds, peony seeds, palm fruit, palm kernel, rice bran, sunflower seeds, high oleic sunflower seeds, peanuts, rapeseed, soybeans, cotton seeds, safflower seeds, perilla seeds, tea seeds, olives, cocoa beans, almonds, apricot kernels, rubber seeds, corn germ, wheat germ, sesame seeds, evening primrose seeds, hazelnuts, pumpkin seeds, walnuts, grape seeds or seaweed; The animal raw material is selected from terrestrial animal oil and aquatic animal oil.

15. The pharmaceutical composition according to claim 1 or 2, characterized in that The synergistic component is obtained by mixing linseed oil and soybean oil; the weight ratio of linseed oil to soybean oil is 1:2.2-2.

5.

16. Use of the pharmaceutical composition according to any one of claims 1 to 15 in the preparation of medicaments for treating atherosclerotic cardiovascular and cerebrovascular diseases, metabolic diseases and neurodegenerative diseases.

17. The use according to claim 16, wherein the atherosclerotic cardiovascular and cerebrovascular diseases include coronary atherosclerosis, carotid atherosclerosis, cerebral atherosclerosis, renal atherosclerosis, intestinal atherosclerosis, and limb atherosclerosis; the metabolic diseases include type II diabetes, non-alcoholic fatty liver disease, colitis, hypertriglyceridemia, hypercholesterolemia, chronic kidney disease, polycystic ovary syndrome, or hyperuricemia; and the neurodegenerative disease is Alzheimer's disease or Parkinson's disease.

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