1, 4-polyisoprene dispersion system, active pharmaceutical ingredient and application of 1, 4-polyisoprene dispersion system and active pharmaceutical ingredient

Abstract

The invention provides a 1, 4-polyisoprene dispersion system, a pharmaceutical active component and application of the 1, 4-polyisoprene dispersion system and the pharmaceutical active component. The dispersion system keeps stable in a gastric acid environment of mammals, does not separate out 1, 4-polyisoprene clots, has no oral toxicity to mammals, and does not contain sensitizers; and the 1, 4-polyisoprene dispersion system comprises a 1, 4-polyisoprene solution dispersion system and a 1, 4-polyisoprene emulsion dispersion system. The 1, 4-polyisoprene dispersion system provided by the invention can be used as an active pharmaceutical ingredient for preparing drugs for treating chronic metabolic diseases including atherosclerotic cardiovascular and cerebrovascular diseases, type 2 diabetes, hypercholesteremia, hypertriglyceridemia, fatty liver, colitis, obesity and polycystic ovarian syndrome.

Description

[0001] This application claims the priority of patent application No. 2023102432456 (the filing date of the prior application is March 14, 2023, and the name of the invention is A 1,4-polyisoprene dispersion system and pharmaceutical active ingredients and their applications). Technical Field

[0002] The invention belongs to the technical field of pharmaceutical materials, and specifically relates to a 1,4-polyisoprene dispersion system and a pharmaceutical active ingredient and applications thereof. Background Art

[0003] Chronic metabolic diseases are a group of metabolic clinical syndromes mainly characterized by atherosclerotic cardiovascular and cerebrovascular diseases (coronary heart disease, stroke), type 2 diabetes, hypercholesterolemia, hypertriglyceridemia, fatty liver, chronic enteritis, polycystic ovary syndrome, obesity and other diseases.

[0004] Among the top ten causes of death in the world in 2016 announced by the World Health Organization, except for road traffic injuries, which ranked eighth, the other nine were all different types of diseases, of which three were chronic metabolic diseases, namely ischemic heart disease, which ranked first, stroke, which ranked second, and diabetes, which ranked seventh. The situation in China is similar. Although the mortality rate of diseases such as obesity, hyperlipidemia, fatty liver, polycystic ovary syndrome, and chronic enteritis is not as high as that of cardiovascular and cerebrovascular diseases and diabetes, they have a high incidence rate among adults, a large number of patients, and cause huge health hazards.

[0005] In the existing technology for treating chronic metabolic diseases, people have developed many drugs for different diseases. Taking atherosclerotic heart disease as an example, the existing drugs include lipid-lowering and stabilizing atherosclerotic plaque drugs statins, PCSK9 inhibitors, antiplatelet drugs aspirin, clopidogrel, antihypertensive drugs beta-blockers, RAS inhibitors, etc.

[0006] In the prior art, there are also drug research and development for various symptoms of chronic metabolic diseases. CN101505594A discloses a drug that can be used to treat various metabolic disorders such as insulin resistance syndrome, diabetes, polycystic ovary syndrome, hyperlipidemia, fatty liver disease, cachexia, obesity, atherosclerosis and arteriosclerosis.

[0007] Despite this, chronic metabolic diseases are still a type of disease that causes high mortality, a large number of patients, and serious harm to humans. Humans need to develop more and better drugs to meet the challenges of such diseases. Summary of the invention

[0008] In view of the deficiencies of the prior art, the present invention aims to provide a 1,4-polyisoprene dispersion system and a pharmaceutical active ingredient and their application. The present invention uses a 1,4-polyisoprene dispersion system as a pharmaceutical active ingredient, and utilizes the characteristics of being stable in the gastric acid environment of mammals, having no 1,4-polyisoprene clots, having no oral toxicity to mammals, and containing no allergens, so that the dispersion system can be used to prepare drugs for treating chronic metabolic diseases including atherosclerotic cardiovascular and cerebrovascular diseases, type 2 diabetes, hypercholesterolemia, hypertriglyceridemia, fatty liver, colitis, obesity, and polycystic ovary syndrome.

[0009] To achieve this object, the present invention adopts the following technical solutions:

[0010] In a first aspect, the present invention provides a 1,4-polyisoprene dispersion system, which remains stable in the gastric acid environment of mammals, has no 1,4-polyisoprene clots, has no oral toxicity to mammals, and does not contain allergens.

[0011] In the present invention, 1,4-polyisoprene exists in a dispersed state in the 1,4-polyisoprene dispersion system. The present invention uses the 1,4-polyisoprene dispersion system as a pharmaceutical active ingredient, and utilizes its characteristics of being stable in the gastric acid environment of mammals, having no 1,4-polyisoprene clots, having no oral toxicity to mammals, and containing no allergens, so that it is used to prepare drugs for treating chronic metabolic diseases including atherosclerotic cardiovascular and cerebrovascular diseases, type 2 diabetes, hypercholesterolemia, hypertriglyceridemia, fatty liver, colitis, obesity, and polycystic ovary syndrome.

[0012] The following are preferred technical solutions of the present invention, but are not intended to limit the technical solutions provided by the present invention. Through the following preferred technical solutions, the objectives and beneficial effects of the present invention can be better achieved and realized.

[0013] As a preferred technical solution of the present invention, the 1,4-polyisoprene dispersion system includes a 1,4-polyisoprene solution dispersion system and a 1,4-polyisoprene emulsion dispersion system;

[0014] The components of the 1,4-polyisoprene solution dispersion system include: 1,4-polyisoprene and a solvent;

[0015] The components of the 1,4-polyisoprene emulsion dispersion system include: 1,4-polyisoprene, an emulsifier and water.

[0016] As a preferred technical solution of the present invention, the polymerization degree of the 1,4-polyisoprene is ≥6, with no upper limit, for example, it can be 6, 10, 20, 50, 100, 200, 500, 1000, 2000, 5000, 8000, 10000 or 100000, etc.

[0017] 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 to prepare a 1,4-polyisoprene dispersion system.

[0018] It should be noted that in the present invention, there is no special restriction on the cis-trans structure and source of 1,4-polyisoprene, which can be prepared from natural latex or obtained by artificial synthesis. Artificially synthesized 1,4-polyisoprene contains both cis and trans structures, with the cis structure being the main one. In natural rubber, most plants or fungi, including Hevea brasiliensis, are of cis structure. It is now clearly known that natural rubber produced from Eucommia ulmoides is of trans structure, i.e., trans-1,4-polyisoprene.

[0019] As a preferred technical solution of the present invention, the solvent is selected from any one or a combination of at least two of fatty acids, fatty alcohols, ester compounds or lipid compounds.

[0020] Preferably, the ester compound includes any one of monohydric alcohol ester, dihydric alcohol ester or polyhydric alcohol ester, or a combination of at least two thereof.

[0021] In the present invention, the monohydric alcohol ester is obtained by reacting a fatty acid with a monohydric alcohol, the dihydric alcohol ester is obtained by reacting a fatty acid with a monohydric alcohol, and the polyhydric alcohol ester is obtained by reacting a fatty acid with a polyhydric alcohol.

[0022] Preferably, the monohydric alcohol ester comprises fatty acid ethyl ester.

[0023] Preferably, the fatty acid ethyl ester includes any one of lauric acid ethyl ester, palmitic acid ethyl ester, stearic acid ethyl ester, oleic acid ethyl ester, linoleic acid ethyl ester, linolenic acid ethyl ester, eicosapentaenoic acid (EPA) ethyl ester, and docosahexaenoic acid (DHA) ethyl ester, or a combination of at least two thereof.

[0024] Preferably, the polyol esters include glycerol esters.

[0025] Preferably, the glycerol ester includes any one of monoglyceride, diglyceride or triglyceride, or a combination of at least two of them.

[0026] Preferably, the monoglyceride and diglyceride are obtained by reacting lauric acid, palmitic acid, stearic acid, oleic acid, linoleic acid, linolenic acid and glycerol.

[0027] Preferably, the triglyceride comprises synthetic C6-C12 medium chain fatty acid triglyceride and / or coconut oil among natural triglycerides.

[0028] Preferably, the lipid compound comprises any one of squalene, phospholipids, glycolipids, sphingolipids or steroids, or a combination of at least two of them.

[0029] Preferably, the lipid compound comprises squalene.

[0030] It should be noted that the selection of the solvent in the 1,4-polyisoprene solution dispersion system of the present invention mainly considers the safety of the solvent, good solubility in 1,4-polyisoprene, and low viscosity.

[0031] Among monoalcohol esters, ethanol esters are safer than methanol esters, so monoalcohols are preferably ethanol esters. Among ethanol esters, if the number of carbon atoms in the carbon chain of the fatty acid is less than 12, the solubility in 1,4-polyisoprene decreases, so fatty acids with carbon atoms ≥ 12 are selected; among fatty acids with carbon atoms ≥ 18, the higher the degree of unsaturation, the better the fluidity at room temperature. Therefore, monoalcohol esters are preferably any one of lauric acid ethyl ester, palmitic acid ethyl ester, stearic acid ethyl ester, oleic acid ethyl ester, linoleic acid ethyl ester, linolenic acid ethyl ester, eicosapentaenoic acid (EPA) ethyl ester, and docosahexaenoic acid (DHA) ethyl ester, or a combination of at least two thereof.

[0032] Among polyol esters, glycerol esters (glycerol esters) are safest, and glycerol alcohol esters include monoglycerides, diglycerides, and triglycerides. The monoglycerides and diglycerides generated by C12-C18 fatty acids and glycerol have small molecular weights, low viscosities, and good solubility in 1,4-polyisoprene. Therefore, it is preferred that any one of lauric acid, palmitic acid, stearic acid, oleic acid, linoleic acid, and linolenic acid react with glycerol to obtain monoglycerides or diglycerides. Triglycerides have three ester bonds and contain three fatty acids. If the fatty acid is a long-chain fatty acid with more than 12 carbon atoms, the overall molecular weight of the triglyceride is large, the viscosity is high, and the solubility in 1,4-polyisoprene is poor; on the contrary, if the fatty acid is a short-chain fatty acid with less than 6 carbon atoms, the overall molecule of the triglyceride is more non-polar and the solubility in 1,4-polyisoprene is also poor. Therefore, medium-chain fatty acid triglycerides with 6-12 carbon atoms (e.g., 6, 8, 10 or 12) have moderate molecular weight, moderate viscosity, and good solubility in 1,4-polyisoprene. Medium-chain fatty acid triglycerides with 6-12 carbon atoms include synthetic medium-chain fatty acid glycerides and coconut oil in natural oils and fats.

[0033] Preferably, the lipid compounds include phospholipids, glycolipids, sphingolipids, steroids, squalene, etc., which are mostly solid at room temperature and have poor solubility in 1,4-polyisoprene. Therefore, squalene, which is liquid at room temperature and is a non-polar molecule like 1,4-polyisoprene, is preferably used as a solvent.

[0034] As a preferred technical solution of the present invention, the mass percentage of 1,4-polyisoprene in the 1,4-polyisoprene solution dispersion system is ≤60% and is not 0 (for example, it can be 0.05%, 0.1%, 0.5%, 1%, 2%, 5%, 7%, 10%, 12%, 15%, 18%, 20%, 30%, 40%, 50% or 60%, etc.), preferably 0.2% to 20%.

[0035] In a 1,4-polyisoprene solution dispersion system, as the mass percentage of 1,4-polyisoprene increases, the solution becomes more and more viscous, making it difficult to prepare and use. Selecting a solvent with a small molecular weight and high fluidity can reduce the viscosity of the solution to a certain extent. Studies have found that it is difficult to prepare a 1,4-polyisoprene solution dispersion system with a content of more than 60% using existing technical means, while a content of less than 20% has better preparation efficiency and fluidity, so the upper limit is selected as 60%, and 20% is further preferred. There is no lower limit to the content of 1,4-polyisoprene, but as the content of 1,4-polyisoprene decreases, in order to obtain therapeutic drug activity, mammals or cells must use a larger volume of solution, and the convenience of use decreases.

[0036] It should be noted that the preparation method of the 1,4-polyisoprene solution dispersion system in the present invention is not particularly limited. It is only necessary to finally obtain a system in which the 1,4-polyisoprene molecules are completely dispersed in the solvent. Examples include but are not limited to:

[0037] The blocky 1,4-polyisoprene produced from the Hevea brasiliensis tree is placed in liquid nitrogen to be frozen into a brittle solid, and then crushed by a high-speed crusher. After the crushed particles pass through a 20-mesh sieve, they are placed in a solvent and stirred continuously until the 1,4-polyisoprene is completely dissolved in the solvent, thereby obtaining the 1,4-polyisoprene solution dispersion system.

[0038] The 1,4-polyisoprene was pulverized by a high-speed pulverizer, and the pulverized particles were passed through a 20-mesh sieve in order to accelerate the dissolution of the 1,4-polyisoprene.

[0039] As a preferred technical solution of the present invention, the emulsifier is selected from any one or at least two components selected from cationic surfactants, anionic surfactants, zwitterionic surfactants, and nonionic surfactants.

[0040] Preferably, the nonionic surfactant comprises any one of polyoxyethylene (20) sorbitan monolaurate (Tween-20), polyoxyethylene (20) sorbitan monopalmitate (Tween-40), polyoxyethylene (20) sorbitan monostearate (Tween-60), polyoxyethylene (20) sorbitan monooleate (Tween-80), decaglycerol monolaurate (Q-12S), decaglycerol monomyristate (Q-14S), decaglycerol monopalmitate (Q-16S), decaglycerol monooleate (Q-17S), decaglycerol monostearate (Q-18S), and C12-C18 monofatty acid sucrose esters, or a combination of at least two thereof.

[0041] It should be noted that in the existing human technology, there are millions of known surfactants, with many varieties and properties that vary greatly. The preferred surfactants are only selected from common low-toxic or non-toxic surfactants in the present invention, and have been experimentally confirmed to be able to maintain the stability of 1,4-polyisoprene emulsion dispersion systems in a strong acid environment of pH = 1. There is still the possibility that other available emulsifiers (including two or more compound emulsifiers) have not been tested and optimized, and they can be discovered and optimized by simple repeated testing. The emulsion dispersion system composed of these potentially available emulsifiers and 1,4-polyisoprene is also within the scope of protection of this patent.

[0042] As a preferred technical solution of the present invention, the mass percentage of 1,4-polyisoprene in the 1,4-polyisoprene emulsion system is ≤80% and is not 0 (for example, it can be 0.05%, 0.1%, 0.5%, 1%, 2%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70% or 80%, etc.), and is more preferably 0.5% to 70%.

[0043] The higher the mass percentage of 1,4-polyisoprene in the 1,4-polyisoprene emulsion dispersion system, the worse the fluidity and stability of the emulsion. A mass percentage of 80% 1,4-polyisoprene is the highest content of the emulsion that can be stably prepared under the existing technical conditions of the present invention, but the fluidity is relatively poor. When the content drops to 70%, the stability and fluidity of the emulsion can reach a good level. Therefore, the upper limit of the content of 1,4-polyisoprene in the emulsion is 80%, preferably 70%. There is no lower limit to the content of 1,4-polyisoprene, but as the content of 1,4-polyisoprene decreases, in order to obtain therapeutic drug activity, mammals or cells must use a larger volume of emulsion, and the convenience of use decreases. Studies have found that a content of 0.5% is the lower limit of acceptable convenience of use, so 0.5% is preferably the lower limit of the mass percentage of 1,4-polyisoprene.

[0044] As a preferred technical solution of the present invention, the average particle size of the emulsion droplets in the 1,4-polyisoprene emulsion system is ≤10 μm, for example, it can be 0.1 μm, 0.5 μm, 1 μm, 2 μm, 3 μm, 4 μm, 5 μm, 6 μm, 7 μm, 8 μm, 9 μm or 10 μm, etc.

[0045] The smaller the particle size of the 1,4-polyisoprene emulsion dispersion system, the better its dispersion effect. Studies have found that when the average particle size of the emulsion droplets in the 1,4-polyisoprene emulsion system is ≤10 μm, a significant drug effect can be obtained.

[0046] It should be noted that the 1,4-polyisoprene emulsion dispersion system that can be used as a pharmaceutical active ingredient in the present invention is a different substance from the natural latex collected from the Brazilian Hevea brasiliensis tree, the industrial concentrated latex prepared with natural latex as raw material, and the artificially synthesized 1,4-polyisoprene latex in the prior art. The composition and properties are very different, and they cannot be mixed or replaced.

[0047] The components and characteristics of the 1,4-polyisoprene emulsion dispersion system of the present invention are as follows:

[0048] 1. The ingredients are few and clear, consisting of 1,4-polyisoprene, water and emulsifier;

[0049] 2. It can remain stable in a strong acidic environment with a pH value of 1, thereby ensuring that it remains dispersed in the gastric acid environment of mammals without the precipitation of 1,4-polyisoprene clots;

[0050] 3. No allergens, will not cause allergies in humans and other mammals;

[0051] 4. All ingredients are safe for mammals and have no oral toxicity.

[0052] The composition and characteristics of natural latex are as follows:

[0053] 1. The composition is complex and unclear. In addition to 1,4-polyisoprene and water, it also contains five major substances: protein, lipids, water-soluble substances, acetone-soluble substances, and inorganic salts. The protein content accounts for 1%-2% of the mass of fresh latex, of which about one-fifth of the protein is distributed on the surface of rubber particles, forming a protective layer of rubber particles, and about three-fifths are dispersed in whey, while the rest are present in the bottom layer of latex. In addition to the main proteins such as rubber protein and α-globulin, the protein component also contains a large number of enzymes, including coagulase, oxidase, peroxidase, reductase, protease, phospholipase and many other known ones. The lipid content is about 1%, which is composed of complex compounds such as triglycerides, fatty acids, waxes, sterols, sterol esters and phospholipids. The content of acetone-soluble substances is about 1%, mainly composed of oleic acid, linoleic acid, stearic acid, sterols and sterol esters. The content of water-soluble matter is 1%-2%, and the main components are quebracho alcohol and cyclohexane hexol isomers, sucrose, glucose, galactose, fructose and pentose. Inorganic salts mainly include potassium, calcium, magnesium, copper, iron, phosphate, sodium and a small amount of sulfate, hydrochloride, aluminum, manganese, nickel, rubidium and other ions, accounting for 0.3-0.7% of the latex mass.

[0054] 2. It is alkaline and relatively stable in an alkaline environment. When it encounters a weak acid, 1,4-polyisoprene will precipitate and solidify.

[0055] 3. It contains rubber protein hev1, whose amino acid sequence is highly homologous to Urtica dioica agglutinin (UDA) of the genus Urtica. It is highly allergenic and is the main allergen of rubber products.

[0056] Aside from the obvious allergenicity, the biggest problem with natural rubber latex is that it coagulates when exposed to acid, so it cannot be used as an active ingredient in medicines.

[0057] The composition and characteristics of concentrated natural latex and synthetic latex are as follows:

[0058] 1. The ingredients are complex and unclear. In addition to the complex ingredients of natural latex, concentrated latex also needs to add various chemical-grade stabilizers, such as ammonia, TMTD (tetramethylthiuram disulfide) / ZnO, and some also add formaldehyde, sodium sulfite, hydroxylamine, hydrogen peroxide, sodium carbonate, urea, organic amines (such as methylamine), sodium pentachlorophenol, etc. Some low-ammonia or low-protein concentrated latex also needs to add 2,2'-thiobis (4,6-dichlorophenol), 1,4-dioxacyclohexanone and its derivatives, Stmktol LB219, dodecanoic acid dihydroxypropyl salt (BeKa100), polyethylene glycol monohexadecene sodium sulfate (trade name Levenol WX), ethoxylated fatty alcohols, ethoxylated alkylphenols, ethoxylated long-chain alkylamines, N-(2-hydroxy)propyl-3-trimethylamine chloride chitosan, triazine derivatives, etc. Artificial synthetic latex is a polyisoprene latex made by polymerizing chemical-grade polyisoprene monomers in the presence of catalysts and initiators. In addition to the addition of various stabilizers, there will also be catalysts (neodymium trioxide, tri-n-butyl phosphate, methylaluminoxane, etc.), solvents (usually toxic, such as toluene and n-hexane), monomers and oligomers (polyisoprene with a very low degree of polymerization), and approximately 5-10% of non-1,4-polyisoprene products (non-target products).

[0059] 2. 1,4-polyisoprene precipitates and solidifies in an acidic environment. Concentrated natural latex is the product of natural latex concentrated by centrifugation. It inherits the property of natural latex to solidify in acid, and this property has become an essential attribute in the subsequent production and processing of latex products and has been strengthened. Whether it is the production of film-forming products such as latex gloves, condoms, balloons, or the production of sponge products such as latex mattresses and pillow cores, concentrated latex has a process of solidification from the flowing latex state, and this process requires the addition of a coagulant. The coagulant is mainly organic acid, and sometimes divalent metal salts are added. For example, in the production of medical latex products, the coagulant of concentrated latex is organic acids such as formic acid, acetic acid, lactic acid, cyclohexyl acetate, and boric acid; in the Dunlop process of latex mattress production, the coagulant of concentrated latex is hydrofluoric acid produced by the hydrolysis of sodium silicofluoride; in the Talley process, the coagulant of concentrated latex is carbon dioxide filled in after vacuum foaming and freezing, and the acidity of carbonic acid is used to gradually solidify the concentrated latex. Artificial synthetic latex is used to replace natural concentrated latex in the production of various latex products. In order to meet the production process, it must also have the same acid coagulation property as natural latex.

[0060] 3. Natural concentrated latex still contains rubber protein hev1 allergen.

[0061] 4. Both concentrated natural latex and synthetic latex contain a large amount of substances that are orally toxic to mammals. Whether it is concentrated natural latex or synthetic latex, various stabilizers with oral toxicity must be added. Synthetic latex also contains residual catalysts, solvents, raw material monomers, raw material oligomers, N-nitrosamines and their precursors (strong carcinogens), which are more toxic orally.

[0062] Therefore, in addition to containing a large amount of oral toxic substances, the biggest problem of natural concentrated latex and synthetic latex is still the property of coagulation when exposed to acid. However, the 1,4-polyisoprene emulsion dispersion system provided by the present invention will remain dispersed in mammalian gastric juice, thereby exerting pharmaceutical activity.

[0063] It should be noted that in the present invention, there is no special limitation on the preparation method of the 1,4-polyisoprene emulsion dispersion system, and the preparation method thereof exemplarily includes but is not limited to:

[0064] The natural rubber latex collected from Hevea brasiliensis is centrifuged at high speed at room temperature, the upper emulsion is taken (other substances except rubber particles in the natural rubber latex, including some allergenic protein components are removed), an emulsifier is added, and then water is added and stirred evenly, alkaline protease isoenzymes are added (to decompose the protein allergenic components remaining in the rubber particles to obtain purified 1,4-polyisoprene), and then incubated, and then centrifuged at high speed again, the upper emulsion (emulsifier-coated 1,4-polyisoprene) is taken, and a specific mass concentration is diluted with water to obtain the 1,4-polyisoprene emulsion dispersion system.

[0065] In a second aspect, the present invention provides a pharmaceutically active ingredient, wherein the pharmaceutically active ingredient comprises the 1,4-polyisoprene dispersion system as described in the first aspect.

[0066] In a third aspect, the present invention provides a drug comprising the active pharmaceutical ingredient as described in the second aspect.

[0067] Preferably, the drug includes a drug for treating chronic metabolic diseases;

[0068] Preferably, the chronic metabolic diseases include atherosclerotic cardiovascular and cerebrovascular diseases, type 2 diabetes, hypercholesterolemia, hypertriglyceridemia, fatty liver, colitis, polycystic ovary syndrome, and obesity.

[0069] Chronic metabolic diseases caused by long-term excess nutrition and energy, including atherosclerotic cardiovascular and cerebrovascular diseases, type 2 diabetes, hypercholesterolemia, hypertriglyceridemia, obesity, polycystic ovary syndrome, and chronic enteritis, are all chronic inflammatory diseases. Scientific research shows that excess nutrition leads to reprogramming of cell metabolism, and these metabolites in turn cause macrophages resident in tissues to transform into the pro-inflammatory M1 type, thereby recruiting more inflammatory cells to aggregate in tissues, ultimately causing chronic inflammatory lesions in tissues and organs, causing the occurrence and progression of the disease. Therefore, developing drugs that target macrophage polarization, inhibiting macrophage foaming, inhibiting their polarization to the M1 type, and promoting their transformation to the M2 type is an important strategy for developing drugs to treat chronic metabolic diseases.

[0070] The active pharmaceutical ingredients provided by the present invention can effectively inhibit macrophage foaming, inhibit its transformation to M1 type, and promote its transformation to M2 type. The research results are shown in Application Examples 1 and 2. Through the experimental animal model research of the disease, it was found that the active pharmaceutical ingredients provided by the present invention can prevent and treat atherosclerotic cardiovascular and cerebrovascular diseases (Application Examples 3 and 4), type 2 diabetes (Application Example 5), hypercholesterolemia and hypertriglyceridemia (Application Example 6), fatty liver (Application Example 7), colitis (Application Example 8), polycystic ovary syndrome (Application Example 9), and obesity (Application Example 10).

[0071] Compared with the prior art, the present invention has the following beneficial effects:

[0072] (1) The 1,4-polyisoprene dispersion system provided by the present invention can be used as a pharmaceutical active ingredient, and it remains stable in the gastric acid environment of mammals, no 1,4-polyisoprene clots are precipitated, and it has no oral toxicity to mammals and does not contain allergens.

[0073] (2) The use of the 1,4-polyisoprene dispersion system provided by the present invention as a pharmaceutical active ingredient in the preparation of drugs for treating chronic metabolic diseases including atherosclerotic cardiovascular and cerebrovascular diseases, type 2 diabetes, hypercholesterolemia, hypertriglyceridemia, fatty liver, colitis, polycystic ovary syndrome, and obesity. The 1,4-polyisoprene dispersion system can significantly inhibit macrophage foaming, inhibit macrophage polarization to M1 type, promote its polarization to M2 type, and improve inflammatory response; it has a significant effect on the prevention and treatment of atherosclerotic cardiovascular and cerebrovascular diseases; at the same time, it has a significant therapeutic effect on type 2 diabetes, hypercholesterolemia, hypertriglyceridemia, fatty liver, colitis, obesity, and polycystic ovary syndrome. BRIEF DESCRIPTION OF THE DRAWINGS

[0074] Figure 1 is an optical microscope photograph of the 1,4-polyisoprene emulsion dispersion system provided in Example 2;

[0075] Figure 2 These are ordinary optical microscope photos of foamy macrophages in the seven experimental groups provided in Application Example 1;

[0076] Figure 3 It is a bar graph of the test results of the foamy macrophage content in the whole cells of the 7 experimental groups provided in Application Example 1;

[0077] Figure 4 This is a graph showing the test results of the expression level of the macrophage M1 marker gene IL-1β in the seven experimental groups after LPS treatment provided in Application Example 2;

[0078] Figure 5 This is a graph showing the test results of the expression level of iNOS, a marker gene of the M1 type of macrophages, in the seven experimental groups provided in Application Example 2 after being treated with LPS;

[0079] Figure 6 This is a graph showing the test results of the expression level of IL-10 mRNA, a marker gene of the M2 type of macrophages, in the seven experimental groups provided in Application Example 2 after LPS treatment;

[0080] Figure 7 This is a graph showing the test results of the expression level of the macrophage M2 marker gene CD206 in the seven experimental groups after LPS treatment provided in Application Example 2;

[0081] Figure 8 This is a graph showing the detection results of the aortic plaque sizes of mice in the four experimental groups provided in Application Example 3;

[0082] Fig. 9 It is a bar graph showing the percentage of the aortic plaque area of ​​mice to the aortic area of ​​mice in the four experimental groups provided in Application Example 3;

[0083] Fig.10 This is a graph showing the detection results of the plaque size at the aortic root of mice in the four experimental groups provided in Application Example 3;

[0084] Fig.11 It is a histogram of plaque area of ​​aortic root of mice in 4 experimental groups provided in Application Example 3;

[0085] Fig.12 This is a graph showing the detection results of the aortic plaque sizes of mice in the four experimental groups provided in Application Example 4;

[0086] Fig.13 is a bar graph showing the percentage of the aortic plaque area of ​​mice to the aortic area of ​​mice in the four experimental groups provided in Application Example 4;

[0087] Fig.14 is a graph showing the detection results of the plaque size at the aortic root of mice in the four experimental groups provided in Application Example 4;

[0088] Fig.15 is a histogram of plaque areas at the aortic root of mice in the four experimental groups provided in Application Example 4;

[0089] Fig.16 This is a graph showing the test results of blood glucose levels in mice in four experimental groups provided in Application Example 5;

[0090] Fig.17 This is a graph showing the test results of serum glucose content in mice in four experimental groups provided in Application Example 5;

[0091] Fig.18 This is a graph showing the test results of the glycosylated serum protein content of mice in the four experimental groups provided in Application Example 5;

[0092] Fig.19 This is a graph showing the test results of high-density lipoprotein cholesterol content in mice in four experimental groups provided in Application Example 6;

[0093] Fig. 20 This is a graph showing the test results of low-density lipoprotein cholesterol content in mice in four experimental groups provided in Application Example 6;

[0094] Fig.21 This is a graph showing the test results of total cholesterol content in mice in four experimental groups provided in Application Example 6;

[0095] Fig. 22 This is a graph showing the test results of triglyceride content in mice in four experimental groups provided in Application Example 6;

[0096] Fig.23 This is a graph showing the test results of mouse lipoprotein lipase content in four experimental groups provided in Application Example 6;

[0097] Fig.24 This is a graph showing the test results of mouse liver esterase content in four experimental groups provided in Application Example 6;

[0098] Fig.25 This is a graph showing the test results of the mouse fat triglyceride hydrolase content in the four experimental groups provided in Application Example 6;

[0099] Fig.26 This is a graph showing the test results of the hormone-sensitive triglyceride lipase content in mice in the four experimental groups provided in Application Example 6;

[0100] Fig. 27 These are photos of mouse livers in four experimental groups provided in Application Example 7;

[0101] Fig.28 It is the test result of the percentage of the liver mass of mice to the total mass of mice in the four experimental groups provided in Application Example 7;

[0102] Fig.29It is a microscope photo of the liver sections of mice in the four experimental groups provided in Application Example 7 after H&E staining;

[0103] Fig.30 It is a microscope photo of the liver sections of mice in the four experimental groups provided in Application Example 7 after H&E staining;

[0104] Fig.31 This is a graph showing the test results of triglyceride content in mouse liver tissues in four experimental groups provided in Application Example 7;

[0105] Fig.32 It is the DAI quantitative scoring test result in the four experimental groups provided in Application Example 8;

[0106] Fig.33 This is a graph showing the test results of the weight loss rate of mice in the four experimental groups provided in Application Example 8;

[0107] Fig.34 This is an optical photograph of the mouse colon after the mice in the four experimental groups provided in Application Example 8 were euthanized;

[0108] Fig.35 This is a graph showing the test results of the length of the mouse colon after the mice in the four experimental groups provided in Application Example 8 were euthanized;

[0109] Fig.36 This is a graph showing the weight test results of the mouse colon after the mice in the four experimental groups provided in Application Example 8 were euthanized;

[0110] Fig.37 This is a graph showing the test results of rat weight in four experimental groups provided in Application Example 9;

[0111] Fig.38 is a graph showing the test results of serum testosterone content of rats in four experimental groups provided in Application Example 9;

[0112] Fig.39 This is a graph showing the fasting blood glucose test results of rats in the four experimental groups provided in Application Example 9;

[0113] Fig.40 This is a graph showing the test results of blood glucose levels of rats in four experimental groups at different times provided in Application Example 9;

[0114] Fig.41 is a graph of the area under the curve test results of the glucose tolerance test of rats in the four experimental groups provided in Application Example 9;

[0115] Fig.42 This is a graph showing the test results of the anti-Müllerian hormone AMH / GAPDH (mRNA) level in the blood of rats in the four experimental groups provided in Application Example 9;

[0116] Fig.43This is a graph showing the test results of IL-1β expression levels of rats in four experimental groups provided in Application Example 9;

[0117] Fig.44 This is a graph showing the test results of TNF-α expression levels of rats in four experimental groups provided in Application Example 9;

[0118] Fig.45 It is the test result of the weight of mice in the 4 experimental groups provided in Application Example 10;

[0119] Fig.46 It is the test result of fat mass of mice in 4 experimental groups provided in Application Example 10;

[0120] Fig.47 is a graph showing the test results of the adipose tissue morphology of mice in the four experimental groups provided in Application Example 10;

[0121] Fig.48 It is the test result of the average area of ​​mouse fat cells in the four experimental groups provided in Application Example 10;

[0122] Fig.49 This is a photograph of the stomach contents of mice in the natural rubber latex group provided in Application Example 11;

[0123] Fig.50 This is a photo of the stomach contents of mice in the rubber solution group provided in Application Example 11;

[0124] Fig.51 This is a photo of the stomach contents of mice in the rubber latex group provided in Application Example 11;

[0125] Fig.52 These are photographs of the existence states of 15 groups of 1,4-polyisoprene emulsion dispersion systems provided in Application Example 12 under acidic conditions. DETAILED DESCRIPTION

[0126] The technical solution of the present invention is further described below in conjunction with the accompanying drawings and through specific implementation methods. It should be understood by those skilled in the art that the embodiments are only to help understand the present invention and should not be regarded as specific limitations of the present invention.

[0127] The sources of some components in the following examples and comparative examples are as follows:

[0128] Block cis-1,4-polyisoprene (referred to as block 1,4-polyisoprene): Take fresh natural rubber latex produced from Hevea brasiliensis, add 0.1 mol / L hydrochloric acid dropwise to obtain a solidified natural rubber block, then rinse with water, squeeze to remove water, and dry to obtain block 1,4-polyisoprene.

[0129] Block trans-1,4-polyisoprene: Take dry bark and leaves of Eucommia ulmoides, crush them mechanically, soak them with n-hexane, concentrate the extract by rotary evaporation, add excess 75% ethanol to precipitate a gel, dissolve the gel again with n-hexane, add 75% ethanol again to precipitate, evaporate the solvent, and obtain block trans-1,4-polyisoprene.

[0130] Example 1

[0131] This embodiment provides a cis-1,4-polyisoprene solution dispersion system (hereinafter referred to as rubber solution) with a mass percentage of 2%. The preparation method of the 1,4-polyisoprene solution dispersion system is as follows:

[0132] The block of 1,4-polyisoprene is immersed in liquid nitrogen and frozen, and then crushed by a high-speed crusher. The crushed particles are passed through a 20-mesh sieve, 2.0 grams of the crushed particles are weighed, 98.0 grams of ethyl oleate are added, and the mixture is stirred continuously at 40° C. until the 1,4-polyisoprene particles are completely dissolved to obtain the 1,4-polyisoprene solution dispersion system, that is, the rubber solution.

[0133] Example 2

[0134] This embodiment provides a 1,4-polyisoprene emulsion dispersion system (hereinafter referred to as rubber emulsion) with a mass percentage of 10%. The preparation method of the 1,4-polyisoprene emulsion dispersion system is as follows:

[0135] Take fresh natural rubber latex produced from Hevea brasiliensis, centrifuge at high speed at room temperature, take the upper layer of emulsion, add 1% by weight of emulsifier polyoxyethylene (20) sorbitan monooleate (purchased from MercK Company), then add water and stir evenly, add alkaline protease isozymes (to decompose the protein emulsifier in natural latex that causes human allergies), incubate at 37°C for 4 hours, then centrifuge at high speed again, take the upper layer of emulsion, dilute with water to a mass percentage of 1,4-polyisoprene of 10% and a content of emulsifier polyoxyethylene (20) sorbitan monooleate of 0.2%, and obtain the 1,4-polyisoprene emulsion dispersion system, i.e., rubber latex.

[0136] The 1,4-polyisoprene emulsion dispersion system provided in this embodiment was characterized using an optical microscope. The test results are as follows: Figure 1 As shown. Figure 1 It can be seen that the average particle size of the 1,4-polyisoprene emulsion dispersion system provided in this embodiment is ≤10 μm.

[0137] Example 3

[0138] This embodiment provides a trans-1,4-polyisoprene solution dispersion system (hereinafter referred to as trans rubber solution) with a mass percentage of 2%. The preparation method is the same as that of Example 1, except that the blocky 1,4-polyisoprene is replaced by blocky trans-1,4-polyisoprene, and the other conditions are the same as those of Example 1.

[0139] Comparative Example 1

[0140] This comparative example provides a rat feed containing 1,4-polyisoprene particles (hereinafter referred to as rubber particles), and the preparation method of the rat feed containing 1,4-polyisoprene particles is as follows:

[0141] Block 1,4-polyisoprene was immersed in liquid nitrogen and frozen, crushed with a high-speed crusher, and the crushed particles were passed through a 20-mesh sieve. It was added to the powdered mouse feed (purchased from Jiangsu Collaborative Pharmaceutical Bioengineering Co., Ltd.) at a ratio of 5 / 10,000 and mixed evenly. At this ratio, the amount of 1,4-polyisoprene ingested by mice through feed per day was equivalent to the amount of 1,4-polyisoprene ingested by the experimental group through oral gavage. The mixed feed was granulated by a feed granulator to make a mouse feed containing rubber particles, referred to as rubber particles.

[0142] Application Example 1 Inhibitory effect on macrophage foaming

[0143] Oxidized low-density lipoprotein (oxLDL) was used to induce foaming of human macrophage cell line RAW264.7. The macrophages were treated with rubber solution (dissolved in ethyl oleate, with a 1,4-polyisoprene content of 2% by mass), trans-rubber solution (dissolved in ethyl oleate, with a trans-1,4-polyisoprene content of 2% by mass), or rubber latex (1,4-polyisoprene content of 10% by mass, emulsifier polyoxyethylene (20) sorbitan monooleate content of 0.2% by mass) for 24 hours, and then stained with Oil Red O to detect the level of macrophage foaming.

[0144] The experiment was divided into 7 groups, as shown in Table 1 below:

[0145] Table 1

[0146] Serial number Group Name Additives and their final concentrations in the culture medium 1 Control group / 2 Oxidized low-density lipoprotein group oxLDL, 40ug / mL 3 Oxidized low-density lipoprotein + rubber solution group oxLDL, 40ug / mL + rubber solution, 100ug / mL 4 Oxidized low-density lipoprotein + trans-rubber solution group oxLDL, 40ug / mL + trans-rubber solution, 100ug / mL 5 Oxidized low-density lipoprotein + solvent group oxLDL, 40ug / mL + ethyl oleate, 98ug / mL 6 Oxidized low-density lipoprotein + rubber latex group oxLDL, 40ug / mL + rubber latex, 100ug / mL 7 Oxidized low-density lipoprotein + emulsifier group oxLDL, 40ug / mL + emulsifier, 0.2ug / mL

[0147] The morphology of macrophages provided by the above 7 groups of experiments was detected using an optical microscope. The test results are as follows: Figure 2 As shown ( Figure 2 (A) Photographs of macrophages provided for the control group. Figure 2 (B) Photographs of macrophages provided for the oxLDL group. Figure 2 (C) Photograph of macrophages provided for the oxLDL+ rubber solution group. Figure 2 (D) Photograph of macrophages provided for the oxLDL+trans-rubber solution group, Figure 2 (E) Photographs of macrophages provided for the oxLDL+solvent group. Figure 2 (F) is a photo of macrophages provided by the oxLDL+ rubber latex group. Figure 2 (G) is a photo of macrophages provided by the oxLDL+emulsifier group). Meanwhile, the percentage of foamy macrophages in the total cells in the above 7 groups was counted. The histogram of foamy macrophage content is shown in FIG. Figure 3 As shown, it should be noted that Figure 3 In the table, ns means there is no statistically significant difference, and asterisk (*) means there is a significant difference (the same below).

[0148] Depend on Figure 2-3 It can be seen that compared with the oxLDL group, the rubber solution group and rubber latex group including cis and trans structures significantly inhibited the foaming of macrophages, and the degree of foaming was lower; while the solvent group and emulsifier group had no significant effect on the foaming of macrophages, and the degree of foaming was higher.

[0149] At the same time, by Figure 2-3 It can be seen that the cis-trans structure of 1,4-polyisoprene has no significant effect on drug activity.

[0150] Application Example 2 Effect on Macrophage Polarization

[0151] The human macrophage cell line RAW264.7 was treated with the rubber solution provided in Example 1, the rubber latex provided in Example 2, or the trans-rubber solution provided in Example 3 for 24 hours, and then RAW264.7 was polarized by lipopolysaccharide (LPS) for 10 hours. The expression of marker genes related to macrophage polarization was detected by real-time fluorescence quantitative PCR.

[0152] The experiment was divided into 7 groups, as shown in Table 2 below:

[0153] Table 2

[0154] Serial number Group Name Additives and final concentrations in the culture medium 1 Control group / 2 LPS group LPS, 1ug / mL 3 LPS+rubber solution group LPS, 1ug / mL + rubber solution, 100ug / mL 4 LPS+trans-rubber solution group LPS, 1ug / mL + trans-rubber solution, 100ug / mL 5 LPS+solvent group LPS, 1ug / mL + ethyl oleate, 98ug / mL 6 LPS+rubber latex group LPS, 1ug / mL + rubber latex, 100ug / mL 7 LPS+emulsifier group LPS, 1ug / mL + emulsifier, 0.2ug / mL

[0155] The mRNA content of the above 7 experimental groups was detected using a fluorescence quantitative PCR instrument. The expression of IL-1β and iNOS, the marker genes of M1 type macrophages, after LPS treatment were as follows: Figure 4-5 As shown in Figure 2, the expression of CD206 and IL-10 mRNA marker genes of M2 macrophages after LPS treatment were Figure 6-7 shown.

[0156] Depend on Figure 4-7It can be seen that after LPS treatment, the expression of macrophage M1 marker genes IL-1β and iNOS was upregulated, while the expression of M2 phenotype marker genes IL-10 and CD206 was downregulated. Compared with the LPS group, rubber solution and rubber latex significantly reduced the expression levels of IL-1β and iNOS mRNA, increased the expression levels of CD206 and IL-10 mRNA, and both the rubber solution group and the trans rubber solution group showed activity, with no statistical difference. This shows that both cis- and trans-structured rubber solutions and rubber latex can inhibit the polarization of macrophages to M1 type, promote their polarization to M2 type, and improve the inflammatory response, while solvents and emulsifiers have no significant effect on macrophage polarization.

[0157] At the same time, by Figure 4-7 It can be seen that the cis-trans structure of 1,4-polyisoprene has no significant effect on drug activity.

[0158] Application Example 3: Study on the Prevention of Atherosclerosis

[0159] This application example is a preventive study, that is, the drug is started to intervene when the experimental mice have not yet formed atherosclerotic plaques, in order to study the preventive effect of the drug on atherosclerosis.

[0160] Twenty-eight 8-week-old male apoE- / - mice were randomly divided into 4 groups, with 7 mice in each group, namely: control group, atherosclerosis model group (referred to as model group), model + rubber solution group, and model + rubber particle group.

[0161] The control group was fed with a normal diet for 16 weeks, and the other three groups were fed with a high-fat diet (21% fat, 0.5% cholesterol) for 16 weeks. The atherosclerosis model group, model + rubber solution group, and model + rubber particle group were gavaged with ethyl oleate, rubber solution, and ethyl oleate at a dose of 3g / kg body weight every day. At the same time, rubber particles were added to the mouse feed of the model + rubber particle group. The experimental mice were grouped as shown in Table 3 below:

[0162] Table 3

[0163] Serial number Group Name Diet 1 Control group Normal diet 2 Atherosclerosis model group (model group) High-fat diet + ethyl oleate 3 Model + rubber solution set High-fat diet + rubber solution 4 Model + Rubber Particles Group High-fat diet + ethyl oleate + rubber particles

[0164] After the experiment, the aorta and root of the mice were collected, and then the aorta root of the mice was stained with Oil Red O. The positive area was counted using the ImageJ program to detect the size of atherosclerotic plaques in the above four groups of experimental mice. The whole aorta of the mice was stained with Oil Red O. The detection results of the aortic plaque size of the mice are shown in Figure 2. Figure 8 As shown ( Figure 8 (A) is the detection result of aortic plaque size in mice of the control group. Figure 8 (B) is the detection result of aortic plaque size in mice in atherosclerosis model group. Figure 8(C) is the detection result of aortic plaque size in mice in the model + rubber solution group. Figure 8 (D) is the detection result of aortic plaque size in mice in the model + rubber particle group), and the percentage of the positive area (plaque area) to the area of ​​the mouse aorta is shown in Fig. 9 shown.

[0165] Depend on Figure 8-9 It can be seen that the rubber solution significantly inhibited the growth of plaques in atherosclerotic mice, while the plaque content of the group fed with rubber particles did not change significantly.

[0166] The whole aortic root of mice was stained with Oil Red O, and the results of the detection of mouse aortic plaque size were as follows Fig.10 As shown ( Fig.10 (A) is the detection result of aortic root plaque size in mice of the control group. Fig.10 (B) is the detection result of aortic root plaque size in mice in atherosclerosis model group. Fig.10 (C) is the detection result of aortic root plaque size in mice in the model + rubber solution group. Fig.10 (D) is the detection result of the plaque size of the aorta root of mice in the model + rubber particle group), and the positive area (plaque area) bar graph is shown in Fig.11 shown.

[0167] Depend on Figure 10-11 It can be seen that the rubber solution significantly inhibited the increase of plaques in atherosclerotic mice, while the plaque content in the group fed with rubber particles was not significant.

[0168] The occurrence and development of atherosclerotic plaques are the key to cardiovascular and cerebrovascular diseases. This experiment confirmed that the rubber solution has a preventive effect on mice that have not yet formed atherosclerotic plaques, reducing the speed of atherosclerosis formation and the volume of plaques. Rubber particles did not show a preventive effect.

[0169] Application Example 4: Study on the Treatment of Atherosclerosis

[0170] This application example is a treatment study, that is, the drug is introduced only after atherosclerotic plaques have formed in the experimental mice, in order to study the therapeutic effect of the drug on atherosclerosis.

[0171] Twenty-eight 8-week-old male apoE- / - mice were randomly divided into 4 groups, with 7 mice in each group, namely: control group, atherosclerosis model group, model + rubber solution group, and model + rubber particle group.

[0172] The control group was fed a normal diet for 16 weeks, and the other three groups were fed a high-fat diet (21% fat, 0.5% cholesterol) for 16 weeks. From the 12th week, the atherosclerosis model group, model + rubber solution group, and model + rubber particle group were gavaged with ethyl oleate, rubber solution, and ethyl oleate at a dose of 3g / kg body weight every day, and the high-fat diet of mice in the model + rubber particle group was supplemented with rubber particles from the 12th week. The grouping of experimental mice is shown in Table 4 below.

[0173] Table 4

[0174] Serial number Group Name Diet 1 Control group Normal diet 2 Atherosclerosis model group (model group) High-fat diet, followed by ethyl oleate after 12 weeks 3 Model + rubber solution set High-fat diet, with rubber solution added after 12 weeks 4 Model + Rubber Particles Group High-fat diet, with ethyl oleate and rubber particles added after 12 weeks

[0175] After the experiment, the aorta and root of the mice were collected, and then the aortic root of the mice was stained with Oil Red O. The ImageJ program was used to count the positive areas to detect the size of atherosclerotic plaques in the above four groups of experimental mice.

[0176] The whole aorta of mice was stained with Oil Red O, and the results of the detection of the plaque size of the mouse aorta were as follows: Fig.12 As shown ( Fig.12 (A) is the detection result of aortic plaque size in mice of the control group. Fig.12 (B) is the detection result of aortic plaque size in mice in atherosclerosis model group. Fig.12 (C) is the detection result of aortic plaque size in mice in the model + rubber solution group. Fig.12 (D) is the detection result of aortic plaque size in mice in the model + rubber particle group), and the percentage of the positive area (plaque area) to the area of ​​the mouse aorta is shown in Fig.13 shown.

[0177] Depend on Figure 12-13 It can be seen that the rubber solution significantly inhibited the growth of plaques in atherosclerotic mice, while the plaque content of the group fed with rubber particles did not change significantly.

[0178] The whole aortic root of mice was stained with Oil Red O, and the results of the detection of mouse aortic plaque size were as follows Fig.14 As shown ( Fig.14 (A) is the detection result of aortic root plaque size in mice of the control group. Fig.14 (B) is the detection result of aortic root plaque size in mice in atherosclerosis model group. Fig.14 (C) is the detection result of aortic root plaque size in mice in the model + rubber solution group. Fig.14 (D) is the detection result of the plaque size of the aorta root of mice in the model + rubber particle group), and the positive area (plaque area) bar graph is shown in Fig.15 shown.

[0179] Depend on Figure 14-15It can be seen that the rubber solution significantly inhibited the increase of plaques in atherosclerotic mice, while the plaque content in the group fed with rubber particles was not significant.

[0180] The occurrence and development of atherosclerotic plaques are the key to cardiovascular and cerebrovascular diseases. This experiment confirmed that the rubber solution has a therapeutic effect on mice that have already formed atherosclerotic plaques, reducing the speed of atherosclerosis formation and the volume of plaques. Rubber particles did not show any therapeutic effect.

[0181] Application Example 5: Study on the treatment of type 2 diabetes

[0182] Five 7-week-old SPF male m / m mice were used as the control group, and 15 7-week-old SPF male db / db mice were randomly divided into three groups, with 5 mice in each group, namely: type 2 diabetes group, type 2 diabetes + rubber solution group, type 2 diabetes + rubber particles group. Random blood glucose was taken on two different days. If the blood glucose on both days was ≥16.7mmol / L, the model was successfully established.

[0183] After the model was successfully established, the type 2 diabetes + rubber solution group was gavaged with rubber solution at a dose of 3g / kg body weight once a day for 12 consecutive weeks; the type 2 diabetes + rubber particles group was gavaged with ethyl oleate at a dose of 3g / kg body weight once a day, and their feed was replaced with feed containing rubber particles for 12 consecutive weeks.

[0184] The following tests were performed on mice in the control group, type 2 diabetes group, type 2 diabetes + rubber solution group, and type 2 diabetes + rubber particles group:

[0185] (1) Determination of blood glucose (FBG) content: Mice were fasted but not watered for more than 12 h. The tails of mice were disinfected with alcohol and blood was collected from the tail tip vein. The second drop of blood was collected using a Roche blood glucose meter to measure blood glucose.

[0186] (2) Determination of serum glucose (GLU) and glycosylated serum protein (GSP) content in serum: Whole blood was collected from mice to prepare serum, and the serum glucose and glycosylated serum protein content in mouse serum was detected using an automatic biochemical analyzer.

[0187] Test results such as Figure 16-18 As shown by Figure 16-18 It can be seen that the rubber solution reduces the blood sugar, serum glucose, and serum glycosylated serum protein content of diabetic model mice, and has a therapeutic effect on diabetes, while the rubber particles have no therapeutic effect on diabetes.

[0188] Application Example 6: Study on the Treatment of Hypertriglyceridemia and Hypercholesterolemia

[0189] Twenty seven-week-old apoe- / - mice were evenly divided into four groups, 5 mice in each group, namely the control group, model group, model + rubber solution group and model + rubber particles group. The entire experimental period was 8 weeks. The hyperlipidemia mouse model was established in the first 4 weeks, and the drug was used for treatment in the last 4 weeks.

[0190] During the entire 8-week feeding period, the control group was fed with a basic diet, and the other three groups were fed with a high-sugar and high-fat diet. The high-sugar and high-fat diet was purchased from Research Diets.

[0191] During the 5th to 8th week, the control group, model group, model + rubber solution group, and model + rubber particles group were gavaged with pure water, ethyl oleate, rubber solution, and ethyl oleate at a dose of 3 g / kg body weight once a day for 4 consecutive weeks. During the 5th to 8th week, the feed of the model + rubber particles group was replaced with feed containing rubber particles.

[0192] The levels of total cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C) in the serum of each group of mice were detected by an automatic biochemical analyzer.

[0193] The enzyme-linked immunosorbent assay (ELISA) method was used to determine the levels of triglyceride-related hydrolases in the serum of each group of mice, including adipose triglyceride hydrolase (ATGL), lipoprotein lipase (LPL), liver esterase (HL), and hormone-sensitive triglyceride lipase (HSL).

[0194] Triglyceride hydrolase (ATGL) and hormone-sensitive triglyceride lipase (HSL) are the most important lipases in mammals, accounting for more than 95% of triglyceride hydrolase activity in white adipose tissue. The catabolism of triglycerides (TG) is mainly carried out under the action of ATGL and HSL, which are the key rate-limiting enzymes for fat hydrolysis. Hepatic esterase (HL) is mainly synthesized and secreted by liver parenchymal cells and participates in lipid metabolism.

[0195] Depend on Figure 19-22 It can be seen that the rubber solution reduced the content of total cholesterol, triglycerides, and low-density lipoprotein cholesterol in blood lipids, and increased the content of high-density lipoprotein cholesterol, while the rubber particles had no significant effect on blood lipids. This shows that the rubber solution has a significant therapeutic effect on hypercholesterolemia and hypertriglyceridemia, while the rubber particles have no therapeutic effect on hypercholesterolemia and hypertriglyceridemia.

[0196] Depend on Figure 23-26It can be seen that the rubber solution significantly increased the levels of enzymes related to triglyceride metabolism: adipose triglyceride hydrolase (ATGL), lipoprotein lipase (LPL), and liver esterase (HL), and significantly reduced the content of hormone-sensitive triglyceride lipase (HSL). Rubber particles had no significant effect on enzymes related to triglyceride metabolism. This shows that rubber solution can promote TG hydrolysis. In other words, rubber solution has a significant therapeutic effect on hypertriglyceridemia, while rubber particles have no therapeutic effect on hypertriglyceridemia.

[0197] Application Example 7: Study on the Treatment of Fatty Liver

[0198] Twenty 6-week-old male C57BL / 6 mice were randomly divided into 4 groups, 5 mice in each group, namely, control group, fatty liver model group (referred to as model group), model + rubber solution group, and model + rubber particle group.

[0199] The control group was fed with a basic diet for 14 weeks, and the other three groups were fed with a high-fat diet (21% fat, 0.15% cholesterol) for 14 weeks. Rubber particles were also added to the feed of the model + rubber particle group. At the same time, the mice in the control group, fatty liver model group, model + rubber solution group, and model + rubber particle group were gavaged with pure water, ethyl oleate, rubber solution, and ethyl oleate once a day at a dose of 3g / kg body weight for 14 weeks.

[0200] After the experiment, the mouse liver and tissues were collected for photographing and weighing.

[0201] The morphological photos of the livers of mice in each group and the statistical graphs of the percentage of the liver mass to the total mass of mice are shown in the figure below. Figure 27-28 As shown ( Fig. 27 (A) is a photo of the liver of mice in the control group. Fig. 27 (B) is a picture of the liver in the model group. Fig. 27 (C) is a photo of the liver in the model + rubber solution group. Fig. 27 (D) is a photo of the liver in the model + rubber particles group. Fig. 27 It can be seen that the model group successfully established fatty liver compared with the control group; the liver fat accumulation of mice in the rubber solution group was significantly inhibited; the liver fat of the rubber particle group did not change significantly compared with the model group. Fig.28 It can be seen that the weight of the model group was significantly increased compared with the control group, while the rubber solution group significantly reversed the increase in fatty liver weight caused by lipid accumulation, and the weight of the rubber particle group did not change significantly relative to the model group.

[0202] The liver tissues of mice in each group were further sliced ​​and stained with H&E and oil red, respectively. The liver slices stained with H&E and oil red were examined using an optical microscope. The test results were as follows: Figure 29-30 shown. Fig.29 (A) and Fig.30 (A) Photos of liver sections of mice in the control group after H&E staining and oil red staining. Fig.29 (B) and Fig.30 (B) The photos of liver sections of mice in the model group after H&E staining and oil red staining. Fig.29 (C) and Fig.30 (C) The photos of liver sections of mice in the model + rubber solution group after H&E staining and oil red staining. Fig.29 (D) and Fig.30 (D) Photos of liver sections of mice in the model + rubber particle group after H&E staining and oil red staining.

[0203] Depend on Fig.29 It can be seen that H&E staining shows the morphology of liver cells. Compared with the control group, the liver cells in the fatty liver model group had a large number of necrotic cells forming necrotic cores. Compared with the model group, the liver cells in the rubber solution group had a complete structure and were tightly arranged, with no obvious cell necrosis and no necrotic cores. The fatty liver lesions were significantly reversed; the rubber particle group also had a large number of necrotic cells forming necrotic cores, which was similar to the degree of lesions in the model group.

[0204] Depend on Fig.30 Oil red staining showed the distribution of fat in hepatocytes. Compared with the model group, the rubber solution significantly inhibited the increase of fat in mice with fatty liver induced by a high-fat diet, and there was no significant change in the fat content of the group fed with rubber particles.

[0205] The content of triglycerides in 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 tested using a tissue triglyceride (TG) enzymatic assay kit to quantify the degree of fatty liver disease. The test results are as follows: Fig.31 As shown. Fig.31 It can be seen that compared with the model group, intragastric administration of rubber solution significantly reduced the triglyceride content in liver tissue, while the triglyceride content in the rubber particle feeding group did not change significantly.

[0206] From the above content, it can be seen that the rubber solution can significantly inhibit the development of fatty liver caused by a high-fat diet and has the effect of treating fatty liver, while the rubber particles have no such effect.

[0207] Application Example 8: Study on the Treatment of Colitis

[0208] Thirty-two 8-week-old male mice were randomly divided into 4 groups, 8 mice in each group, namely, control group, colitis model group (referred to as model group), model + rubber solution group, and model + rubber particle group.

[0209] The entire experimental feeding lasted for 7 days. The control group was fed with normal feed, and the other three groups were fed with 4% dextran sulfate sodium (DSS) to induce enteritis symptoms. Rubber particles were also added to the feed of the model + rubber particle group. At the same time, the mice in the control group, colitis model group, model + rubber solution group, and model + rubber particle group were gavaged with pure water, ethyl oleate, rubber solution, and ethyl oleate at a dose of 3g / kg body weight once a day for 7 days.

[0210] During the experimental period, the mice were weighed and recorded every day. At the same time, the feces of the mice were collected every day to observe the fecal status and whether there was occult blood or blood in the stool, and the DAI quantitative score was calculated based on these data.

[0211] DAI (Disease activity index) is a comprehensive score based on the percentage of weight loss, stool viscosity and stool bleeding of mice. The DAI scoring standard is shown in Table 5.

[0212] Table 5

[0213]

[0214]

[0215] In the above table, normal stool refers to formed stool; loose stool refers to mushy, semi-formed stool that does not stick to the anus; and loose stool refers to watery stool that can stick to the anus.

[0216] The DAI score quantifies the extent of colitis in mice. The higher the DAI score, the more severe the colitis. Fig.32 As shown. Fig.32 It can be seen that compared with the colitis model group, the DAI score of the model + rubber solution group was lower, while the model + rubber particle group had no significant difference from the colitis model group. This shows that the rubber solution has the effect of alleviating the symptoms of colitis in mice, while the rubber particles have no such effect.

[0217] When other conditions remain unchanged, the weight loss of mice is also an indicator of the severity of colitis in mice. The statistical chart of the weight loss rate of mice in the four experimental groups is as follows: Fig.33 As shown by Fig.33 It can be seen that the weight of mice in the colitis model group gradually decreased with the number of experimental days; the weight of mice in the model + rubber solution group decreased more slowly than that in the colitis model group; the weight loss degree of the model + rubber particles group was not significantly different from that of the colitis model group. This also shows that the rubber solution has the effect of alleviating the symptoms of colitis in mice, while the rubber particles have no such effect.

[0218] 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 of the colon and the lighter the weight. The mice were euthanized after 7 days and the colon was taken. Fig.34 As shown, the colon length and weight of each group of mice were measured, and the test results are shown in Figures 35-36. Figure 34-36 It can be seen that compared with the control group, the colon length of the colitis model group was shortened and the weight was lighter, but the colon of the model + rubber solution group was less affected than that of the colitis model group, while the colon length and weight of the model + rubber particles group were not significantly different from those of the colitis group. This shows that the rubber solution has the effect of treating colitis in mice, while the rubber particles do not have this effect.

[0219] Application Example 9: Study on the Treatment of Polycystic Ovary Syndrome

[0220] Twenty 4-week-old female SD rats were randomly divided into 4 groups, 5 rats in each group, namely: control group, polycystic ovary syndrome model group (referred to as model group), model + rubber solution group, and model + rubber particles group.

[0221] The whole experiment lasted for 3 weeks. During the experiment, except for the control group, the other 3 groups of rats were given letrozole by gavage once a day for 3 weeks to establish the PCOS model. At the same time, the control group, PCOS model group, model + rubber solution group, and model + rubber particle group were gavaged with pure water, ethyl oleate, rubber solution, and ethyl oleate at a dose of 3g / kg body weight once a day for 3 weeks, and the feed of the model + rubber particle group was replaced with feed containing rubber particles.

[0222] After the intragastric administration, the rats were weighed, blood was collected from the tail vein, and serum was prepared to measure the serum testosterone content. The rats were fasted for 12 hours, blood was collected from the tail vein, and the fasting blood glucose of the rats was detected using a blood glucose meter. The rats were fasted for 12 hours, blood was collected from the tail vein, and the blood glucose value was detected using a blood glucose meter, which was the fasting blood glucose of the rats; then the rats were intraperitoneally injected with glucose (10g / 100mL) at a dose of 2g / kg, and blood was collected from the tail vein at 15min, 30min, 60min, 90min, and 120min after injection, and the blood glucose value was detected using a blood glucose meter. The rats were euthanized, the ovarian tissues of the rats were taken, tissue RNA was extracted, and the mRNA expression levels of anti-Müllerian hormone (AMH), IL-1β, and TNF-α were detected using a real-time fluorescence quantitative PCR instrument.

[0223] As the rat polycystic ovary syndrome model was established, the weight of the rats gradually increased. The extent of weight gain can reflect the severity of polycystic ovary syndrome. The weight of the four groups of rats was tested, and the test results are as follows: Fig.37 As shown. Fig.37It can be seen that intragastric administration of rubber solution significantly reduced the weight gain caused by PCOS, while feeding rubber particles had no significant effect on the body weight of rats.

[0224] An important phenomenon of PCOS is the increase in androgen levels. The level of testosterone, a male hormone, can reflect the severity of PCOS. The serum testosterone levels of the four groups of rats were tested. The test results are as follows: Fig.38 It can be seen that intragastric administration of rubber solution significantly inhibited the increase of serum testosterone in rats with polycystic ovary syndrome model, and the serum testosterone content of the group fed with rubber particles did not change significantly compared with the model group.

[0225] Impaired glucose tolerance is one of the common metabolic abnormalities in PCOS. The degree of impaired glucose tolerance can reflect the degree of PCOS pathology. The fasting blood glucose, blood glucose levels at different times, and glucose tolerance of the four groups of rats were tested. The test results are as follows: Figure 39-41 As shown. Figure 39-41 It can be seen that rats in the PCOS model group showed increased fasting blood glucose and abnormal glucose tolerance, but oral administration of rubber solution significantly improved fasting blood glucose and abnormal glucose tolerance, while feeding rubber particles had no obvious effect.

[0226] Increased levels of anti-Müllerian hormone (AMH) are a sign of impaired follicular development in patients with PCOS. The levels of anti-Müllerian hormone (AMH) / GAPDH (mRNA) in the blood of the four groups of rats were tested (normalized with the GAPDH internal reference gene). The test results are as follows: Fig.42 As shown. Fig.42 It can be seen that the AMH mRNA level in the ovarian tissue of rats in the PCOS model group was significantly increased, and oral administration of rubber solution instead of feeding rubber particles reduced the AMH mRNA level.

[0227] The ovarian tissue of patients with PCOS has a persistent chronic inflammatory response. The expression of chronic inflammatory factors IL-1β and TNF-α increases, which can be used as indicators of the severity of the disease. The expression levels of inflammatory factors IL-1β and TNF-α in the blood of the above four groups of rats were tested, and the test results were as follows: Figure 43-44 As shown. Figure 43-44 It can be seen that compared with the control group, the expression of IL-1β and TNF-α in the ovarian tissue of rats in the PCOS model group was significantly increased; after oral gavage with rubber solution, the expression of inflammatory factors in the rat ovaries was significantly downregulated, while the expression of inflammatory factors in the group fed with rubber particles did not change significantly.

[0228] From the above content, it can be seen that a comprehensive comparison of multiple indicators of PCOS rats, including body weight, serum testosterone level, fasting blood glucose, glucose tolerance, anti-Müllerian hormone AMH level in ovarian tissue, and expression levels of inflammatory factors IL-1β and TNF-α, proves that rubber solution has the efficacy of treating PCOS, while rubber particles have no such effect.

[0229] Application Example 10: Study on the treatment of obesity

[0230] Twenty-four 6-week-old male C57BL / 6 mice were randomly divided into four groups, 6 mice in each group, namely: control group, high-fat model group, high-fat + rubber solution group, and high-fat + rubber particle group. The average weight of the four groups of mice was 20±2g.

[0231] The experiment lasted for 18 weeks. The control group was fed with basic feed, and the other three groups were fed with high-fat feed (fat content 35%). Rubber particles were added to the feed of the high-fat + rubber particle group. The control group, high-fat model group, high-fat + rubber solution group, and high-fat + rubber particle group were gavaged with pure water, ethyl oleate, rubber solution, and ethyl oleate at a dose of 3g / kg body weight once a day for 18 weeks.

[0232] The body weight of mice was recorded every week, and at the end of the experiment, the fat mass of mice was recorded and analyzed using a body fat meter. The mice were euthanized, and the adipose tissue around the epididymis was sliced ​​and stained with H&E to calculate the average area of ​​each fat cell.

[0233] The body weight and fat mass test results of mice in the above four experimental groups are as follows: Figures 45-46 As shown. Fig.45 It can be seen that compared with the control group, the weight of mice in the high-fat model group increased significantly. Oral administration of rubber solution significantly inhibited the weight gain induced by the high-fat diet, while feeding rubber particles had no such inhibitory effect. Fig.46 It can be seen that the data on fat mass are consistent with the data on body weight. The rubber solution significantly inhibited the increase in fat mass of high-fat-induced mice, while feeding rubber particles had no such inhibitory effect.

[0234] The adipose tissue morphology of mice was tested using an optical microscope. The test results are as follows: Fig.47 As shown ( Fig.47 (A) is a photo of the adipose tissue morphology of the control group. Fig.47 (B) is a photo of the adipose tissue morphology of the high-fat model group. Fig.47 (C) is a photo of the adipose tissue morphology of the model + rubber solution group. Fig.47 (D) is a photo of the adipose tissue morphology of the model + rubber particles group. Fig.47It can be seen that the fat cells of the control group mice were smaller and arranged neatly; the fat cells of the obese mice in the high-fat group became larger and were partially infiltrated by inflammatory cells; the rubber solution significantly inhibited the enlargement of fat cells induced by the high-fat diet; the cell morphology of the rubber particle group was similar to that of the high-fat group.

[0235] Using an optical microscope, the average area of ​​fat cells in mice was tested. The test results are as follows: Fig.48 As shown. Fig.48 It can be seen that through statistical calculation of the area of ​​each fat cell, it was found that the average area of ​​a single fat cell in the high-fat group was 2.8 times that of the control group; the rubber solution significantly inhibited the trend of fat cell area growth, and its average area of ​​a single fat cell was only 1.2 times that of the control group; the rubber particle group had no significant change compared with the high-fat group.

[0236] A comprehensive comparison of data including body weight, fat weight, adipose tissue pathological staining, and average area of ​​single fat cells of the four groups of mice proved that the rubber solution can significantly inhibit obesity induced by a high-fat diet and has the effect of treating obesity, while rubber particles have no such effect.

[0237] Application Example 11 Study on the existence state of natural rubber latex, rubber emulsion and rubber solution in mouse stomach

[0238] Fifteen 6-week-old male C57BL / 6 mice were randomly divided into three groups, 5 mice in each group, namely natural rubber latex group, rubber latex group, and rubber solution group. The experiment lasted for 7 days and the mice were fed with basic feed.

[0239] The natural latex group, rubber emulsion group, and rubber solution group mice were gavaged with natural latex, rubber emulsion, and rubber solution from Hevea brasiliensis, respectively, at a dose of 3 g / kg body weight once a day for 7 days. The feces of mice were collected every day and examined with a dissecting microscope. The last gavage dose was increased to 15 g / kg body weight. Within 30 minutes after the gavage, the mice were euthanized, and the stomach contents in the mouse stomach were taken out and examined with a dissecting microscope.

[0240] The stomach contents of mice in the natural rubber latex group, the rubber solution group, and the rubber latex group were tested respectively. The test results are as follows: Figure 49-51 As shown. Figure 49-51 It can be seen that rubber clots were observed in the stomach contents of mice in the natural rubber latex group, while no rubber clots were observed in the stomach contents of mice in the rubber latex group and the rubber solution group.

[0241] It can be seen from this that natural rubber latex will directly aggregate and coagulate into large rubber lumps when entering the mouse stomach, cannot remain in a dispersed state, has no pharmaceutical activity, and is then excreted from the body through the digestive tract; while the rubber latex and rubber solution provided by the present invention will not coagulate into large rubber lumps when entering the mouse gastrointestinal tract, but will remain in a dispersed state and have pharmaceutical activity.

[0242] Application Example 12 Study on the stability of rubber latex prepared with different emulsifiers in strong acid and weak acid environments

[0243] In order to test the stability of natural latex collected from Hevea brasiliensis in the prior art, industrial concentrated latex prepared with natural latex as raw material (including high ammonia concentrated latex, low ammonia concentrated latex, low protein concentrated latex) and artificially synthesized 1,4-polyisoprene latex under acidic conditions, and to compare with the 1,4-polyisoprene emulsion system prepared by the preferred emulsifier of the present invention, the inventors used hydrochloric acid solutions with pH=1 and pH=3 to simulate the gastric acid environment of mammals in vitro to test the stability of rubber latex prepared by different emulsifiers. The former represents the strong acid environment of gastric juice, and the latter represents the weak acid environment of gastric juice.

[0244] The method for preparing the 1,4-polyisoprene emulsion system with the preferred emulsifier of the present invention can refer to the method provided in Example 2, the only difference being that the emulsifier is different.

[0245] Whether it is stable under weak acid conditions of pH = 3: Add 5 ml of hydrochloric acid solution (1.0 mmol / L) with pH = 3 into a glass dish, and use a pipette to drop 0.1 ml of 1,4-polyisoprene emulsion, stir evenly, and observe whether solids are precipitated. If solids are precipitated, the 1,4-polyisoprene emulsion system is unstable under weak acid conditions of pH = 3; otherwise, it is stable;

[0246] Whether it is stable under strong acid conditions at pH = 1: Add 5 ml of hydrochloric acid solution (0.1 mol / L) at pH = 1 into a glass dish, and use a pipette to drop 0.1 ml of 1,4-polyisoprene emulsion, stir evenly, and observe whether there is solid precipitation. If solid precipitation is present, the 1,4-polyisoprene emulsion system is unstable under strong acid conditions at pH = 1; otherwise, it is stable.

[0247] The description and test results of different 1,4-polyisoprene emulsion dispersion systems are detailed in Table 6 below:

[0248] Table 6

[0249]

[0250]

[0251] Fig.52 Here are some test results, including:

[0252] A is a photo of the natural latex of Hevea brasiliensis being dropped into hydrochloric acid at pH=3;

[0253] B is a photo of high ammonia concentrated natural rubber latex being dropped into hydrochloric acid at pH = 3;

[0254] C is a photograph of low-ammonia concentrated natural rubber latex being dropped into hydrochloric acid at pH = 3;

[0255] D is a photo of low-protein concentrated natural rubber latex being dropped into hydrochloric acid at pH = 3;

[0256] E is a photograph of artificial synthetic isoprene latex added dropwise into hydrochloric acid at pH = 3;

[0257] F is a photograph of a rubber latex prepared by using polyoxyethylene (20) sorbitan monolaurate (Tween-20) as an emulsifier and added dropwise to hydrochloric acid at pH=1;

[0258] G is a photograph of a rubber latex prepared by using polyoxyethylene (20) sorbitan monopalmitate (Tween-40) as an emulsifier and added dropwise to hydrochloric acid at pH=1;

[0259] H is a photograph of a rubber latex prepared by using polyoxyethylene (20) sorbitan monostearate (Tween-60) as an emulsifier and added dropwise to hydrochloric acid at pH=1;

[0260] I is a photograph of a rubber latex prepared by using polyoxyethylene (20) sorbitan monooleate (Tween-80) as an emulsifier in Example 2 of the present invention, which is added dropwise to hydrochloric acid at pH=1;

[0261] J is a photograph of a rubber latex prepared by using polyglycerol monolaurate (Q-12S) as an emulsifier in the present invention and added dropwise to hydrochloric acid at pH=1;

[0262] K is a photograph of a rubber latex prepared by using decaglycerol monomyristate (Q-14S) as an emulsifier and added dropwise to hydrochloric acid at pH=1;

[0263] L is a photograph of a rubber latex prepared by using decaglycerol monopalmitate (Q-16S) as an emulsifier and added dropwise to hydrochloric acid at pH=1;

[0264] M is the result of adding the rubber latex prepared by using decaglycerol monooleate (Q-17S) as an emulsifier to hydrochloric acid at pH=1;

[0265] N is a photograph of the rubber latex prepared by using decaglycerol monostearate (Q-18S) as an emulsifier in the present invention and added dropwise to hydrochloric acid at pH=1;

[0266] O is a photograph of the rubber latex prepared by using sucrose monostearate as an emulsifier in the present invention being added dropwise into hydrochloric acid at pH=1.

[0267] From Table 6 and Fig.50 It can be seen that the natural latex collected from the Brazilian Hevea brasiliensis tree, the industrial concentrated latex prepared from the natural latex as raw material (including high ammonia concentrated latex, low ammonia concentrated latex, low protein concentrated latex) and the artificially synthesized 1,4-polyisoprene latex in the prior art are all unstable under the acidic conditions of pH = 1 and pH = 3, and 1,4-polyisoprene will coagulate and precipitate. It can be seen that it will also coagulate and precipitate in the gastric juice of mammals, and cannot maintain a dispersed state, and will not produce pharmaceutical activity.

[0268] The present invention preferably uses polyoxyethylene (20) sorbitan monolaurate (Tween-20), polyoxyethylene (20) sorbitan monopalmitate (Tween-40), polyoxyethylene (20) sorbitan monostearate (Tween-60), polyoxyethylene (20) sorbitan monooleate (Tween-80), decaglycerol monolaurate (Q-12S), decaglycerol monomyristate (Q-14S), decaglycerol monopalmitate (Q-16S), decaglycerol monooleate (Q-17S), decaglycerol monostearate (Q-18S), and sucrose monostearate as emulsifiers to prepare the emulsion system, which remains stable under acidic conditions of pH=1.0 and pH=3.0. It can be seen that the rubber latex prepared in this way will also remain dispersed in mammalian gastric juice, thereby exerting pharmaceutical activity.

[0269] From the above content, it can be known that in the present invention, by dispersing 1,4-polyisoprene in a solution dispersion system and an emulsion dispersion system, it can remain stable in the gastric acid environment of mammals, no 1,4-polyisoprene clots are precipitated, and it has no oral toxicity to mammals and does not contain allergens. Dispersed 1,4-polyisoprene can significantly inhibit macrophage foaming, inhibit macrophage polarization to M1 type, promote its polarization to M2 type, and improve inflammatory response; it has a significant effect on the prevention and treatment of atherosclerotic cardiovascular and cerebrovascular diseases; and it also has a significant therapeutic effect on type 2 diabetes, hypercholesterolemia, hypertriglyceridemia, fatty liver, colitis, polycystic ovary syndrome, and obesity.

[0270] The applicant declares that the present invention illustrates the detailed process flow of the present invention through the above-mentioned embodiments, but the present invention is not limited to the above-mentioned detailed process flow, that is, it does not mean that the present invention must rely on the above-mentioned detailed process flow to be implemented. Those skilled in the art should understand that any improvement of the present invention, equivalent replacement of the raw materials of the product of the present invention, especially the solvent and emulsifier, the addition of auxiliary components, the selection of specific methods, etc., all fall within the protection scope and disclosure scope of the present invention.

Claims

1. A 1,4-polyisoprene dispersion system, characterized in that: The dispersion system remains stable in the gastric acid environment of mammals, has no 1,4-polyisoprene clots precipitated, has no oral toxicity to mammals, and does not contain allergens.

2. The 1,4-polyisoprene dispersion system according to claim 1, characterized in that: The 1,4-polyisoprene dispersion system includes a 1,4-polyisoprene solution dispersion system and a 1,4-polyisoprene emulsion dispersion system; The components of the 1,4-polyisoprene solution dispersion system include: 1,4-polyisoprene and a solvent; The components of the 1,4-polyisoprene emulsion dispersion system include: 1,4-polyisoprene, an emulsifier and water.

3. The 1,4-polyisoprene dispersion system according to claim 1 or 2, characterized in that: The polymerization degree of the 1,4-polyisoprene is ≥6.

4. The 1,4-polyisoprene dispersion system according to claim 2 or 3, characterized in that: The solvent is selected from any one or a combination of at least two of fatty acids, fatty alcohols, ester compounds or lipid compounds; Preferably, the ester compound includes any one of monohydric alcohol ester, dihydric alcohol ester or polyhydric alcohol ester, or a combination of at least two thereof; Preferably, the lipid compound comprises any one of phospholipids, glycolipids, sphingolipids, steroids, and squalene, or a combination of at least two of them.

5. The 1,4-polyisoprene dispersion system according to any one of claims 2 to 4, characterized in that: The mass percentage of 1,4-polyisoprene in the 1,4-polyisoprene solution dispersion system is ≤60% and is not 0, preferably 0.2% to 20%.

6. The 1,4-polyisoprene dispersion system according to any one of claims 2 to 5, characterized in that: The emulsifier is selected from any one or at least two components selected from cationic surfactants, anionic surfactants, zwitterionic surfactants, and nonionic surfactants; Preferably, the nonionic surfactant comprises any one of polyoxyethylene (20) sorbitan monolaurate, polyoxyethylene (20) sorbitan monopalmitate, polyoxyethylene (20) sorbitan monostearate, polyoxyethylene (20) sorbitan monooleate, decaglycerol monolaurate, decaglycerol monomyristate, decaglycerol monopalmitate, decaglycerol monooleate, decaglycerol monostearate, and C12-C18 monofatty acid sucrose esters, or a combination of at least two thereof.

7. The 1,4-polyisoprene dispersion system according to any one of claims 2 to 6, characterized in that: The mass percentage of 1,4-polyisoprene in the 1,4-polyisoprene emulsion dispersion system is ≤80% and is not 0, preferably 0.5% to 70%.

8. The 1,4-polyisoprene dispersion system according to any one of claims 2 to 7, characterized in that: The average particle size of the emulsion droplets in the 1,4-polyisoprene emulsion dispersion system is ≤10 μm.

9. A pharmaceutical active ingredient, characterized in that The pharmaceutical active ingredient comprises the 1,4-polyisoprene dispersion system according to any one of claims 1 to 8.

10. A drug, characterized in that The drug comprises the active pharmaceutical ingredient as claimed in claim 9; Preferably, the drug includes a drug for treating chronic metabolic diseases; Preferably, the chronic metabolic diseases include atherosclerotic cardiovascular and cerebrovascular diseases, type 2 diabetes, hypercholesterolemia, hypertriglyceridemia, fatty liver, colitis, polycystic ovary syndrome, and obesity.

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