A composition

Abstract

The invention relates to a synergistically refined composition, comprising the following components: flavonoids, octacosanol, curcumin, partially hydrolyzed guar gum, solubilizer, promoter, stabilizer, compound shading auxiliary material, functional sugar alcohol, preservative and distilled water; according to the characteristics of each extract, cross-linking and integration are carried out to introduce nano-level ultra-high purity extracts into the composition, while maintaining the physiological activities of octacosanol and curcumin, the water solubility and stability thereof are increased, the absorption rate and bioavailability in the body are increased, and premature elimination by the body is avoided, and the effective dose in the blood is ensured to be maintained; according to actual needs, by adjusting the changes in the components, the composition is used in the fields of weight loss, disease prevention, astronauts and development of military high-energy, special function and new generation sports medicine compositions; the preparation method is adjusted to obtain a liquid or solid composition.

Description

Technical Field

[0001] The invention relates to the technical field of drug processing, and in particular to a synergistically refined composition and a preparation method thereof. Background Art

[0002] Medicine and food have the same origin, which refers to a class of items that can be used as food, directly consumed, and as medicine to treat diseases. The first important medical book in my country, Huangdi Neijing, appeared during the Autumn and Warring States Period. The book first proposed the idea of ​​medicine and food having the same origin, which has a history of more than 2,000 years. The book shows the idea of ​​medicine and food having the same function and the same principle, which is the earliest principle of diet therapy. The earliest existing pharmaceutical monograph in my country, Shennong Bencao Jing, records that coix seeds, lotus leaves, honey, hawthorn, lily, tangerine peel, etc. are all foods with medicinal properties and are often used as raw materials for preparing medicinal diets. It fully reflects the idea that there is no strict distinction between medicine and food, which is the embryonic state of the idea of ​​medicine and food having the same origin. Sun Simiao of the Tang Dynasty said, "Know what he has done wrong, and treat it with food. If diet therapy does not work, then prescribe medicine." He agreed that diet therapy should be superior to drug therapy, and food health care should be the main method of health preservation.

[0003] The harmful effects of obesity are greater than those of smoking and drinking in terms of overall health status and health-related costs; obesity is a prevalent health problem in itself and a risk factor for chronic diseases such as coronary heart disease, type 2 diabetes, hypertension, dyslipidemia, stroke and cancer; modest weight loss, even as little as 5% to 10%, is sufficient to achieve significant health benefits and prevent obesity-related diseases;

[0004] Alzheimer's disease is the most common type of dementia, accounting for about 60-70% of all cases. It is characterized by a progressive decline in memory, thinking, language and learning abilities. In the final stages, patients may even lose their autonomy and need care from others. Therefore, prevention is worthy of attention.

[0005] In the prevention and treatment of chronic diseases, my country's traditional advanced concept of "medicine and food have the same origin" plays an important role; many data show that the occurrence and development of chronic diseases are closely related to dietary nutrition, and can even be used as an important means to prevent and treat certain chronic diseases; the ingredients rich in various coarse grains, whole grains and fruits can improve lipid metabolism and reduce weight through their physiological characteristics, and can also prevent and treat chronic diseases and metabolic syndrome; scientific, healthy and reasonable eating habits play an important role in preventing the occurrence and development of chronic diseases, and are an indispensable part of chronic disease treatment; foods that are both medicine and food have a broad mass base, contain a profound cultural heritage, are easy to promote and develop, and are the development direction and inevitable trend of foods that are both medicine and food have the same origin.

[0006] China's food culture is profound and extensive, and the idea of ​​"food and medicine have the same origin" is deeply rooted. As people have paid more and more attention to health in recent years, their attitude towards diseases has shifted from treatment to prevention, and the concept of health care has been increasingly recognized by people. Due to the side effects and high prices of chemical drugs, people are paying more and more attention to functional Chinese herbal foods made from natural plants on the market.

[0007] However, the current research on herbal food-medicine combinations is mainly focused on combinations with single food-medicine functionality. Some of them make the food-medicine combinations more nutritious and more beautiful in color by mixing several substances together and then processing them. Most of the research on herbal food-medicine combinations is mainly based on technology, and the processing technology is relatively simple, lacking in-depth theoretical research on food-medicine combinations.

[0008] ⒈ Partially hydrolyzed guar gum (PHGG).

[0009] A newly published Japanese single-center retrospective cohort study article in April 2021, The effect of partly hydrolyzed guar gum preventing influenza infection, explored the effect of partially hydrolyzed guar gum (PHGG) in preventing influenza infection; an article published in Nutrients in 2020 used a microbial model to study the effects of partially hydrolyzed guar gum (PHGG), further verifying the role of this soluble dietary fiber in improving intestinal microecology; known public literature studies have shown that in addition to improving intestinal health, partially hydrolyzed guar gum (PHGG) can also improve blood sugar, lower cholesterol and blood lipids, and enhance the absorption of minerals; studies have confirmed that partially hydrolyzed guar gum (PHGG) can increase the abundance of Lactobacillus and Bifidobacterium and the content of SCFAs, and improve abdominal distension, flatulence, constipation and diarrhea. Therefore, partially hydrolyzed guar gum (PHGG) has no toxic side effects, has the effects of enhancing immunity and improving the intestinal environment, and has broad application prospects for development and application in functional foods as auxiliary prevention and treatment of diseases and obesity.

[0010] 2. Bamboo leaf flavonoids are a type of plant flavonoids.

[0011] A study conducted by Dutch experts found that the experiment of 4,807 participants showed that people who drank 375 ml of green tea every day had half the risk of heart disease and only one-third the risk of fatal heart disease. The important reason for this was the flavonoids contained in green tea (American Journal of Clinical Nutrition, 2002.4.25).

[0012] Research on the physiological effects of bamboo leaf flavonoids shows that:

[0013] ⑴ Bamboo leaf flavonoids have good effects in preventing vascular sclerosis, anti-angiogenesis, anti-myocardial ischemia, lowering blood pressure, lowering blood lipids, protecting cardiovascular and cerebrovascular vessels, etc.; it has pharmacological effects such as radiation protection, liver protection, liver detoxification, liver cirrhosis, purgation, cough relief, expectoration, asthma relief, spasm relief, anti-allergy, anti-allergy and anti-virus; it can significantly reduce the content of blood lactate after exercise, and at the same time enhance the activity of lactate dehydrogenase; it can improve the body's immune function and promote the body's health;

[0014] ⑵ Excess nutrition in the human body is converted into fat, and the fat stored in the body will oxidize and degenerate. This is one of the reasons why obese people find it difficult to lose weight. Bioflavonoids can prevent lipid peroxidation and reduce fat accumulation, becoming a new way to lose weight;

[0015] ⑶ Bamboo leaf flavonoids contain phenolic hydroxyl groups in their structure, which are consistent with the acidic environment of human gastric juice and intestinal juice, and can avoid the first-pass effect; they are highly hydrophilic, which is conducive to the development of medicines and foods; they are a natural antioxidant, and their antioxidant properties are comparable to those of VE, which can prevent or delay the oxidation of food, improve the stability of food and prolong its storage period; they have antibacterial functions, and have varying degrees of antibacterial activity against many microorganisms (including Gram-positive bacteria, Gram-negative bacteria and fungi); they can be used in the food industry;

[0016] ④Research reports in recent years have shown that: the acute toxicity test (Horn's method) was applied to bamboo leaf flavonoids. According to the Ames test result judgment standard, the tested bamboo leaf flavonoids had no mutagenic effect; no toxic or harmful ingredients have been found in its active ingredients so far, unlike ginkgo leaves which contain a certain amount of ginkgolic acid, which is harmful to the human body; in 1998, (light) bamboo leaves were approved by the Ministry of Health to be included in the "List of Natural Plants for Both Medical and Edible Uses", which shows that bamboo leaves themselves are safe to use; and the Zhejiang Academy of Medical Sciences conducted a toxicological safety evaluation on bamboo leaf flavonoids powder and bamboo leaf flavonoids between 1998 and 1999, confirming that bamboo leaf flavonoids have no toxic side effects and are very safe.

[0017] 3. Octacosanol is a physiologically active substance.

[0018] The existence and functional properties of octacosanol were proposed by Dr. Cureton of Illinois University in the United States in 1949 after 20 years of testing on 894 people in 42 items. Later, clinical studies by many nutrition experts also reached the same conclusion: it has the effects of anti-fatigue, improving endurance, energy (including improving reaction sensitivity and stress resistance) and physical strength; improving muscle strength (muscle function), improving muscle pain, and reducing muscle friction; shortening muscle nerve reaction time, improving stress resistance, and improving reaction sensitivity; strengthening heart function and improving myocardial function;

[0019] ⑶ Improve stress resistance and metabolic rate of the body; enhance resistance to stress such as high mountains; reduce systolic blood pressure; improve oxygen transport capacity and oxygen utilization rate of the body, reduce necessary oxygen demand; stimulate sex hormones. It can enhance sexual function, stimulate sexual behavior of animals and humans, and has a therapeutic effect on reproductive disorders in the human body. Dr. Cureton is also known as the "Father of World Health" for the above research.

[0020] Octacosanol is extremely safe. Oral tests on mice confirmed that the median L particle size D50 of octacosanol is above 18,000 mg / kg, which is safer than table salt (median L particle size D50 = 3,000 mg / kg). At the same time, the results of mouse sperm aberration test, mouse bone marrow micronucleus test and Ames test were all negative, which was also confirmed by scholars such as CLAleman of the Cuban Natural Products Center. It can completely pass any review by the World Health Organization and the World Sports Organization.

[0021] The U.S. FDA's 1999 DSSI (Dietary Supplement Sales Information) clearly lists octacosanol as a functional food additive derived from natural plants; GB16740-2014 "National Food Safety Standard Health Food" allows octacosanol to be used as an effective ingredient in health (functional) foods.

[0022] 4. Curcumin is extracted from turmeric, a plant of the ginger family, and is also found in other ginger plants.

[0023] The American VITY Vitamin Magazine reported: "The main pharmacological effects of curcumin include anti-oxidation, anti-inflammation, anti-coagulation, lipid-lowering, anti-atherosclerosis, anti-aging, free radical elimination and tumor growth inhibition.

[0024] In November 2006, an article in the American journal Arthritis & Rheumatism pointed out that curcumin can prevent joint swelling and arthritis, and is effective against cardiovascular disease, cancer, etc.

[0025] According to statistics from clinicaltrails.gov, to date, there are a total of 139 clinical trials of curcumin on humans approved by the National Institutes of Health (NIH) (including completed and ongoing trials), mainly involving adenomas, astrocytomas, head and neck tumors, multiple myeloma, breast cancer, colon cancer, pancreatic cancer and other cancers, as well as various types of human diseases caused by dysfunction of the nervous system, digestive system, lymphatic system, etc.; because curcumin can inhibit the growth of various tumor cell lines, prevent the formation of various tumors induced by chemical and radioactive experimental animals, and significantly reduce the number of tumors and reduce the size of tumors, the National Cancer Institute of the United States has listed curcumin as a third-generation cancer chemoprevention drug.

[0026] Researchers from the University of California, Irvine, reported in the latest issue of the journal Anti-Aging Research that they conducted a study on fruit flies. The results showed that if fruit flies regularly eat curcumin, their lifespan can be extended by 20%, and they are more flexible and less likely to get cancer. The head of the study, Mahtab Jafari, said that preliminary experimental results showed that curcumin contains a variety of anti-inflammatory, antioxidant and anti-cancer ingredients, which can affect the genes that cause aging in fruit flies. Therefore, the researchers said that the "longevity" effect of curcumin may also apply to humans, because fruit flies and humans "have many of the same genes and aging mechanisms."

[0027] According to a study published in a well-known American journal (J.Am.Chem.Soc.), the antioxidant capacity of natural curcumin is 2.33 times that of bioflavonoids, 1.6 times that of vitamin E and 2.75 times that of vitamin C, and can help the human body fight many diseases.

[0028] Many studies have shown that curcumin has anti-inflammatory, antioxidant, lipid-lowering, inhibition of type 2 diabetes complications, inhibition of thrombosis and myocardial infarction, inhibition of obesity, anti-aging, anti-cancer, anti-ulcer, liver protection, anti-myocardial ischemia, anti-depression, antibacterial, anti-inflammatory, antiviral and antifungal effects, prevention of Alzheimer's disease and cardiovascular disease, anti-aging and nerve protection, and other wide-ranging biological and pharmacological activities; it has positive effects on exercise-induced muscle damage, periodontitis, recurrent aphthous stomatitis, polycystic ovary syndrome, non-alcoholic fatty liver disease, oral submucosal fibrosis, osteoarthritis, irritable bowel syndrome, ulcerative colitis, auxiliary weight loss, allergic rhinitis, prevention of bone loss, pain relief, improvement of sarcopenia, improvement of premenstrual syndrome, improvement of functional dyspepsia, and anti-oxidative stress; it can be used to treat cancer, diabetes, coronary heart disease, arthritis, Alzheimer's disease (premature dementia) and other chronic diseases.

[0029] Turmeric has been used by humans for more than 4,000 years. It belongs to the ginger family and is the source of the yellow color in curry. In ancient Indian and Chinese medicine, turmeric was used to treat inflammatory diseases, protect the liver, skin diseases and trauma. In the Indian herbal medicine system, ginger is also used to warm the body and enhance the efficacy of drugs. Common uses include improving digestion, improving intestinal motility, relieving flatulence, cleaning and strengthening liver and gallbladder function, regulating menstruation, relieving arthritis and swelling, etc. It can be called herbal aspirin. At the same time, curcumin is one of the highly safe natural edible products recognized by the World Health Organization (WHO) and the Food and Agriculture Organization of the United Nations (FAO), and turmeric and curcumin are listed as food additives.

[0030] 5. Based on public literature, conventional technical knowledge in the field and industry consensus.

[0031] ⑴ Current status and situation of flavonoid and octacosanol extraction technology research at home and abroad:

[0032] The Chinese patent "200610053436.2 Production process of extracting bamboo leaf flavonoid series products from bamboo leaves" shows that the purity of bamboo leaf flavonoids is 60%; the Chinese patent "200810195064.6 Preparation method of bamboo leaf flavonoid extract" shows that the purity of bamboo leaf flavonoids is 40% to 65%;

[0033] The 24-34 carbon higher alkanols contained in Cuban Policosanol account for more than 90% of the weight of the extract, of which the content of octacosanol is 60%-70%; claim (5) of the Chinese patent "CN105237339B-Method for extracting octacosanol using sugar factory mixed juice scum as raw material" shows: Take crystals 3, repeat the above crystallization operation step (4), that is, perform multiple recrystallization operations at 20°C, and obtain crystals 4, the yield of crystals 4 is 1.00%-2.00%, and the content of octacosanol in the obtained crystals 4 is 68.00%-80.00%.

[0034] Based on the common knowledge in the industry, flavonoids and octacosanol of different purities have different effects in different fields. The higher the purity of flavonoids and octacosanol, the stronger their activity and the greater their polarity. Therefore, purity determines the physiological activity of a drug. Currently, the above-mentioned purity can only be used for health care functions such as anti-fatigue and improving human body functions in the market, thus limiting its further development in the fields of medicine, food and pharmaceuticals.

[0035] At the same time, although octacosanol has strong functionality, since octacosanol is a macromolecular fat-soluble substance, once this macromolecular fat-soluble substance enters the body, it will produce a strong hydrophobic effect under the action of water molecules in the body fluid; the experiment of gavage of octacosanol to rats showed that due to its low hydrophilic index, it has poor absorption in the body and is not easy to exert its pharmacological effect; in addition, its dispersibility in the aqueous phase system is poor, which is mainly manifested in that octacosanol is difficult to disperse in compound functional compositions and foods, so its application in products such as compositions is greatly limited; therefore, it is very necessary to increase the solubility of octacosanol in water.

[0036] ⑵ Research progress on bioavailability and formulation of curcumin:

[0037] Curcumin should have broad prospects for drug application due to its rich pharmacological effects and low toxicity; however, curcumin is almost insoluble in water, sensitive to light, and easily degraded in an alkaline environment from pH 7.8, and is easily affected by changes in the gastrointestinal environment; in addition, curcumin is rapidly and extensively metabolized into dihydrocurcumin, tetrahydrocurcumin and hexahydrocurcumin in the body, however, the biological activity of these metabolites is usually much weaker than that of curcumin; therefore, the blood drug concentration is low and the drug half-life is short; these factors lead to extremely low bioavailability of curcumin. When curcumin is orally administered to rats at a dose of 2000 mg / kg, the maximum serum concentration is 1.35±0.23 μg / mL, and the bioavailability in rat plasma is about 1%. Due to the low absorption efficiency of curcumin by the human body, even if 8 g / day of curcumin is taken orally, curcumin in the blood is still difficult to be detected, and the rapid metabolism in the body leads to its low bioavailability in the body, which greatly limits the practical application of curcumin.

[0038] ⑶ Pharmacokinetic studies on curcumin have shown that oral curcumin is poorly absorbed in vivo and has low bioavailability:

[0039] Researchers at the University of Leicester in the UK conducted a clinical trial on the oral dosage of curcumin. The researchers provided curcumin to patients with advanced colorectal cancer orally (180 mg / d). After taking it for 4 consecutive months, they found that this dose of curcumin had almost no adverse reactions on the patients, but the bioavailability was very low. After rats were given a high dose of oral curcumin (2% curcumin in the diet, equivalent to 1.2 g / kg of curcumin orally), only nanomolar levels of curcumin were detected in plasma, liver and colon mucosal tissue. Ravindranath et al. used an in vitro intestinal absorption test to study the absorption process of curcumin. They used labeled [3H] curcumin to conduct experiments and found that curcumin had no adverse reactions in the intestinal absorption process. Biotransformation occurs in the body, and it is found that most of the curcumin taken orally is excreted in the feces, and only one-third of it exists in the original form of curcumin; Shoba et al. gave rats 2g / kg curcumin orally, and used HPLC to measure the blood concentration at 0, 0.25, 0.50, 0.75, 1, 2, 3, 4, 5, and 6 hours, respectively. It was found that the serum curcumin content reached a peak of (1.00±0.26) mg / L at 0.75-1h, and then the blood concentration gradually decreased, reaching zero at 5h. 2g curcumin was given orally to 8 volunteers, and the curcumin content in human serum was very low or undetectable, with a peak concentration of only (0.OO6±0.005) mg / L, and the concentration reached zero at 3h;

[0040] Ireson et al. conducted in vitro treatment studies on curcumin using microsomal suspensions of human hepatocytes, liver tissue or intestines. The results once again proved that curcumin is metabolized extremely rapidly and is completely converted in just a few minutes.

[0041] Judging from the results of clinical trials available so far, although there is a lot of evidence proving the medicinal value and safety of curcumin, it has not been widely used. This is mainly because oral curcumin has a serious first-pass effect when administered through the gastrointestinal tract, and undergoes intestinal-hepatic circulation, most of which is converted and cleared, and has extremely low bioavailability in the body. It has low bioavailability, instability under physiological pH conditions, insolubility in water, slow cell uptake, and rapid metabolism in cells; as well as limitations such as easy clearance by the human body, it still has certain bottlenecks in the prevention and treatment of human diseases.

[0042] Research over the past three decades has shown that curcumin is poorly absorbed, metabolized quickly, its metabolites lose their activity, and the drug is eliminated from the body extremely quickly. This has undoubtedly become a roadblock to research progress, and the academic community's enthusiasm for curcumin research has been dormant for nearly 20 years.

[0043] In summary:

[0044] ⑴ At present, although there have been certain achievements in the extraction methods of bamboo leaf flavonoids, octacosanol and curcumin, based on the common knowledge in the industry, bamboo leaf flavonoids, octacosanol and curcumin of different purities have different effects in different fields; the higher the purity of bamboo leaf flavonoids, octacosanol and curcumin, the stronger their activity and the greater their polarity. Therefore, purity determines the physiological activity of a drug; the purity mentioned above in the market can only be used for health care functions such as anti-fatigue and improving human body functions, and it also brings a lot of trouble to further separation, and the subsequent refining process is relatively cumbersome and time-consuming; thus, its further development in the fields of food and medicine is limited.

[0045] ⑵There are many types of functional compositions with single addition of partially hydrolyzed guar gum (PHGG), bamboo leaf flavonoids, octacosanol, and curcumin on the market, but most of them are just a trade name due to technical limitations of manufacturers. And its single system also limits the scope of application and effect; there are still certain limitations in the industrial application of functional compositions. Summary of the invention

[0046] In the present application, partially hydrolyzed guar gum (PHGG) and flavonoids are hot water-soluble therapeutic substances, while octacosanol and curcumin are poorly water-soluble therapeutic substances; however, both the experience of the ancients and modern scientific research indicate the positive role of octacosanol and curcumin in safeguarding human health;

[0047] At present, the work in this field is still in its infancy. The research on dosage forms is mostly focused on cyclodextrin inclusion compounds, nanoparticles, microspheres, liposomes, etc. However, there are problems such as unsatisfactory drug loading rates and difficulty in achieving effective therapeutic concentrations. Most dosage forms can only be used for external use. At the same time, the research content mostly stays on the research methods of dosage forms. There are few research reports on the effects of dosage forms on effective blood drug concentrations and pharmacological effects. Therefore, the development of ideal new dosage forms has important practical significance and urgent needs. How to improve the shortcomings of bamboo leaf flavonoids, octacosanol, and curcumin, and prepare high-efficiency and potent bamboo leaf flavonoids, octacosanol, and curcumin derivatives and their preparations with high bioavailability and low dosage has become a topic that needs to be urgently solved by food and medicine workers in recent years.

[0048] In order to overcome these limitations and solve the above problems, while maintaining the pharmacological activity of octacosanol and curcumin, increasing the blood concentration of octacosanol and curcumin, prolonging the metabolism time and improving the bioavailability are key factors in improving the application value of curcumin; improving the pharmacological performance of octacosanol and curcumin by changing the dosage form is an important and convenient means.

[0049] It is found through searching the prior art documents that currently, there are certain technical attempts for the single use of partially hydrolyzed guar gum (PHGG), bamboo leaf flavonoids, octacosanol or curcumin in the processing technology of the composition, and the excellent properties of partially hydrolyzed guar gum (PHGG), bamboo leaf flavonoids, octacosanol and curcumin themselves are self-evident, and the methods and means of their combined use have not yet seen a relatively successful case; the present application provides a synergistically refined composition and a preparation method thereof, which can not only improve the solubility and dissolution of octacosanol and curcumin, but also increase the types of preparations, give full play to their excellent physiological activity, expand the application of partially hydrolyzed guar gum (PHGG), bamboo leaf flavonoids, octacosanol and curcumin in the fields of weight loss, disease prevention, astronauts and the military to develop military supplies high energy, special functions and a new generation of sports medicine, and this aspect has not been reported. Therefore, a synergistically refined composition and a preparation method thereof are provided, which have the urgency of technology and application, meet people's expectations, and have strong application value.

[0050] In order to achieve the above purpose, the technical solution adopted in this application is:

[0051] 1. A synergistically refined composition, comprising the following components: 2.5-4 parts of partially hydrolyzed guar gum (PHGG) as a therapeutic ingredient, 0.05-0.1 parts of flavonoids as a therapeutic ingredient, 0.01-0.02 parts of octacosanol as a therapeutic ingredient, 0.2-0.6 parts of curcumin as a therapeutic ingredient, 1.5-3 parts of a solubilizer, 1-2.5 parts of an accelerator, 1.5-3 parts of a stabilizer, 1.5-3 parts of a composite sunscreen auxiliary material, 0.8-2.3 parts of a functional sugar alcohol, 0.015-0.025 parts of a preservative, and 300 parts of distilled water;

[0052] The flavonoids are nano-scale bamboo leaf flavonoid dispersions with a purity of 99.9% and a median particle size of D50=0.084 μm, and the octacosanol is a nano-scale sucrose octacosanol dispersion with a purity of 99.5% and a median particle size of D50=0.07 μm, both of which are provided by Guangzhou Lvhui New Materials Research Institute Co., Ltd.; the detection method is to use a laser particle size analyzer for wet particle size detection, and the purity detection method is to use a high performance liquid chromatography (HPLC) for detection and determination;

[0053] The curcumin is purchased from Sigma Company of the United States with a purity of ≥99.5%, and is ground by Guangzhou Lvhui New Materials Research Institute Co., Ltd. to a nano-scale curcumin dispersion with a median particle size D50 of 0.082 μm. The detection method is to use a laser particle size analyzer for wet particle size detection.

[0054] 2. The solubilizing agent is any one of the following poloxamer binary component mixtures;

[0055] The poloxamer compound is poloxamer 403 / poloxamer 338, poloxamer 403 / poloxamer 288, poloxamer 403 / poloxamer 407, poloxamer 403 / poloxamer 238, poloxamer 403 / poloxamer 188, poloxamer 401 / poloxamer 338, poloxamer 401 / poloxamer 288, poloxamer 401 / poloxamer 407, poloxamer 181 / poloxamer 407, and poloxamer 331 / poloxamer 335, and the ratio between the two is 1:2.

[0056] 3. The accelerator is a mixture of two or more of lemon balm essential oil, Chinese cinnamon essential oil, Ceylon cinnamon essential oil, castor essential oil, ginger essential oil, real lavender essential oil, eye-catching lavender essential oil, spike lavender essential oil, neroli essential oil, sweet orange essential oil, palmarosa essential oil, black pepper essential oil, Damascus rose essential oil, dried leaf rose essential oil, and white rose essential oil.

[0057] 4. The stabilizer is a mixture of two or more of submicron solid organic plant fiber, hydroxypropyl methylcellulose, and carboxymethyl anionic guar gum;

[0058] The submicron solid organic plant fiber is any one of sugarcane fiber with a median particle size of D50 = 0.261 μm, bamboo fiber with a median particle size of D50 = 0.316 μm, and lotus leaf fiber with a median particle size of D50 = 0.230 μm, all of which are provided by Guangzhou Lvhui New Materials Research Institute Co., Ltd.; the detection method is to use a laser particle size analyzer for wet particle size detection.

[0059] 5. The composite shading auxiliary material is a mixture of tea polyphenols and submicron starch, with the ratio of the two being 1:2;

[0060] The submicron starch is any one of soft rice starch, japonica rice starch, indica rice starch, corn starch, high-amylose wheat starch, and high-amylose corn starch with a median particle size D50≦0.320 μm, all of which are provided by Guangzhou Lvhui New Materials Research Institute Co., Ltd.; the detection method is to use a laser particle size analyzer for wet particle size detection.

[0061] 6. The functional sugar alcohol is maltitol, erythritol or a mixture of both.

[0062] 7. The preservative is nisin.

[0063] 8. The preparation method comprises the following steps:

[0064] (1) According to the weight ratio, 0.01-0.02 parts of the therapeutic substance octacosanol, 0.2-0.6 parts of the therapeutic substance curcumin, 1.5-3 parts of the solubilizer, and 1-2.5 parts of the accelerator are weighed and added into a sealed dispersion reactor, and heated to 40-50° C., and stirred at a speed of 300-500 rpm until completely dissolved, and then set aside;

[0065] ⑵ According to the weight ratio, weigh 2.5-4 parts of partially hydrolyzed guar gum (PHGG), 0.06-0.1 parts of flavonoids, 1.5-3 parts of stabilizer, 1.5-3 parts of compound shading auxiliary materials, and 300 parts of distilled water, add them into a sealed grinding emulsification reactor, stir at room temperature at a speed of 300-500rpm until completely dissolved; slowly add them into ⑴, heat to 75℃-80℃, and stir at a speed of 10000-22000rpm. After grinding and emulsification for 5 to 15 minutes, the temperature is lowered to 45 to 50° C., 0.8% to 2.3 parts of functional sugar alcohol and 0.015 to 0.025 parts of preservatives are added, and the mixture is stirred at a speed of 300 to 500 rpm for 30 minutes to obtain colostrum; (3) the colostrum obtained in (2) is placed in a high-pressure homogenizer, treated once at 60° C. and a pressure of 200 bar, and then treated 2 to 4 times at a pressure of 500 to 1000 bar to obtain a liquid composition;

[0066] (4) The liquid composition obtained in (3) is spray-freeze-dried to obtain a solid composition.

[0067] 9. The synergistically refined composition has a pH value of 5.8 to 6.8.

[0068] 10. The synergistically refined composition can be used in the fields of weight loss, disease prevention, and the development of high-energy, special-function and new-generation sports medicine compositions for astronauts and the military by adjusting the changes in components according to actual needs.

[0069] Beneficial effects:

[0070] In order to overcome the limitations caused by the shortcomings of existing technologies at home and abroad, the research of this application focuses on developing new methods and designing multi-combination ultra-high purity extracts and multi-combination synergistic purification methods; the solubility and dissolution of octacosanol and curcumin are improved, and the types of preparations can be increased to give full play to their excellent physiological activity, and the stability and bioavailability, pharmacokinetics and delivery characteristics of octacosanol and curcumin are improved; these efforts can be divided into the following five strategies.

[0071] ⒈ This application uses nanoscale material preparation to improve bioavailability and efficacy.

[0072] ⑴Based on the common knowledge in the industry:

[0073] ① Bamboo leaf flavonoids, octacosanol and curcumin of different purities have different effects in different fields; since the higher the purity, the stronger the activity and the greater the polarity, therefore, purity determines the physiological activity of a drug; currently in the market, the above-mentioned purity can only be used to improve the health care and dietary conditioning of human functions, and it also brings a lot of trouble to further separation, and the subsequent refining process is relatively cumbersome and time-consuming; thus limiting its further development in the fields of medicine, food and medicine.

[0074] ② According to the Noyes-Whitney and Friendly Ostwald equations, from the perspective of pharmacology, the dissolution rate and solubility of a drug are directly proportional to the specific surface area of ​​the drug particles, and the specific surface area is inversely proportional to the particle size.

[0075] (2) This application uses a nano-scale bamboo leaf flavonoid dispersion with a purity of 99.9% and a median particle size of D50 = 0.084 μm, a nano-scale sucrose octacosanol dispersion with a purity of 99.5% and a median particle size of D50 = 0.07 μm, and a nano-scale curcumin dispersion with a purity of ≥99.5% (HPLC) and a median particle size of D50 = 0.082 μm. Experimental studies have found and verified that:

[0076] Its surface area, dispersibility, adsorption capacity, surface activity, etc. have undergone comprehensive changes compared with the original drug; its specific surface area has been greatly increased, thereby significantly increasing its solubility and dissolution rate, making it easy to disperse and dissolve in gastrointestinal fluid, and the contact area with the gastrointestinal mucosa has become larger, and the adhesion has been enhanced, so that the nano-scale material obtained in this application has a longer residence time in the digestive tract, making the absorption of the active ingredients more sufficient and complete, greatly improving the bioavailability and efficacy of the preparation obtained in this application; it can also reduce local irritation.

[0077] ① The effects of bamboo leaf flavonoid samples with different purities on blood lipid levels in mice (x±s), see Table 1:

[0078] Table 1

[0079]

[0080] Note: The conventional bamboo leaf flavonoids group with 50% purity and the nano-grade bamboo leaf flavonoids group with 99.9% purity in this application were both fed with high-fat feed. After 5 weeks of feeding, 3 mice were randomly selected without fasting to draw blood for the determination of serum TC and TG.

[0081] As can be seen from Table 1, the TC and TG levels of the high-fat diet group were significantly higher than those of the ordinary diet group (P<0.01), indicating that the mouse hyperlipidemia model was successfully established, and the high-fat diet can completely cause mice to suffer from hyperlipidemia. Compared with the high-fat diet group and the bamboo leaf flavonoid group with a purity of 70% in the conventional market, the nano-grade bamboo leaf flavonoid group with a purity of 99.9% in this application significantly reduced the TC and TG levels of mice (P<0.01), and blood lipids were significantly reduced. And the sample dosage of the nano-grade bamboo leaf flavonoid group with a purity of 99.9% in this application is only 1 / 4 of the sample of the bamboo leaf flavonoid group with a purity of 70% in the conventional market, and the effect of reducing TC and TG is still better than the latter, which provides a solid theoretical and large-scale market operability basis for adopting high-purity nano-grade flavonoid raw materials, preparing high-efficiency and low-toxic lipid-lowering drugs, and carrying out disease prevention and treatment mechanism preparation.

[0082] ② Effects of octacosanol extract on biochemical parameters of weight-bearing swimming mice (x±s, n=15), see Table 2:

[0083] Table 2

[0084]

[0085] Note: Mice were given the drug by gavage for 30 days. 30 minutes after the last administration, they were placed in 30℃ water to swim for 90 minutes and then taken out to measure blood lactate, liver glycogen content and serum urea nitrogen.

[0086] As can be seen from Table 2, after the mice were gavaged for 30 days and swam with weight, only the blood lactate of the nano-octacosanol group with a purity of ≥99.5% of the present application was significantly lower than that of the control group, indicating that the effect may be related to the purity and dosage of the test substance; the liver glycogen content of the nano-octacosanol group with a purity of 99.5% of the present application was significantly increased compared with the octacosanol with a purity of 80% in the conventional market and the control group, and there was no obvious change in the octacosanol group with a purity of 80% in the conventional market, indicating that the nano-octacosanol with a purity of 99.5% of the present application can improve the glycogen accumulation capacity in animals; the serum urea nitrogen level of the mice that were gavaged for 30 days after swimming was measured, and each administration group was significantly lower than the control group, among which the nano-octacosanol group with a purity of 99.5% of the present application was significantly different from the control group, indicating that the nano-octacosanol with a purity of 99.5% of the present application can reduce serum urea nitrogen and improve the body's endurance and adaptability to exercise load.

[0087] ③ The effects of curcumin samples of different purities on the adjuvant treatment of human osteoarthritis are shown in Table 3:

[0088] Table 3

[0089]

[0090] Note: Treatment method: 500 mg each time, 2 times / day; Experimental period: 8 months.

[0091] Experimental results: The nano-curcumin group with a purity of ≥99.5% in this application significantly improved the level of inflammatory factors / pain without any adverse reactions; in this study, it was further confirmed that supplementing with the nano-curcumin group with a purity of ≥99.5% in this application can help improve bone health and significantly reduce the frequency of use of the anti-inflammatory drug ibuprofen, and oral curcumin may bring positive help.

[0092] The curcumin with a purity of ≥99.5% used in this application meets the pharmaceutical grade standard of curcumin in the United States; however, in China, based on the existing technology, according to the curcumin standard of the "National Food Safety Standard Food Additives GB1886.76-2015", there are no pharmaceutical grade specifications and food grade specifications. Therefore, the application scope of the nano-scale curcumin dispersion with a purity of ≥99.5% and a median particle size D50≦0.082μm used in this application in medicine and food is self-evident.

[0093] Therefore, the nano-scale ultra-high purity bamboo leaf flavonoid dispersion, octacosanol dispersion and curcumin dispersion used in the present application can greatly improve the bioavailability of the drug.

[0094] ⒉ The present application adopts a nano-microemulsion preparation method, a binary component poloxamer block copolymer and a promoter to improve the solubility of the nano-scale octacosanol and curcumin of the present application in the gastrointestinal tract, improve the solubility and dissolution of the poorly soluble octacosanol and curcumin, and then enhance the absorption of octacosanol and curcumin in the gastrointestinal tract, thereby comprehensively improving the oral bioavailability.

[0095] As we all know, drugs must first be dissolved in aqueous solution before they can have a therapeutic effect. Some water-insoluble drugs have very low solubility in water, which limits the diffusion and absorption of drugs. For oral administration, drugs must first be dissolved in gastrointestinal digestive fluid before absorption, so that they can pass through the digestive tract mucosa and enter the blood circulation by absorption mechanisms such as passive diffusion or active transport. The poor dissolution rate of drugs in gastrointestinal fluid directly leads to incomplete drug absorption, which reduces oral bioavailability and seriously affects the clinical efficacy of drugs and the treatment of diseases. Based on the above unfavorable factors, although some water-insoluble compounds have high therapeutic activity, such drugs are difficult to enter clinical application.

[0096] Conventional methods for increasing drug solubility include forming salts, using solubilizers, complexing agents, etc.; however, the use of conventional methods is increasingly restricted by the side effects caused by the formation of salts, the addition of co-solvents, and the large amount of excipients in the preparations; other methods for improving drug bioavailability include microemulsions, cyclodextrin inclusion, hot melt extrusion, emulsions, liposomes, and solid dispersions; these methods have been successfully used to develop drugs with poor water solubility, especially the development of preparations for poorly soluble drugs, but these solutions often have practical problems such as poor physical stability, low drug loading, and difficulty in industrial production.

[0097] As poorly soluble drugs, solubility is an important physical property and one of the important bases for designing formulations. Examining solubility is of great significance. The experimental results show that octacosanol and curcumin have extremely poor water solubility, and no drug concentration was detected in distilled water within 72 hours. Because these drugs have relatively low solubility in water and poor dissolution in the gastrointestinal tract, if traditional formulation methods are used for development, there will be problems such as poor bioavailability, slow onset of action, and poor patient compliance.

[0098] ⑴ This application adopts the principle of poloxamer of binary component amphiphilic molecules and their interaction:

[0099] Poloxamer is a series of block copolymers with dozens of models and HLB values ​​of 1-40. Poloxamers dissolve in monomer form, but when the critical micelle concentration (CMC) and critical micelle temperature (CMT) are exceeded, they can change their structure under the action of temperature, and can aggregate and self-assemble to form micelles. Since these poloxamers have different molecular weights and hydrophobic and hydrophilic properties, they have different behavioral characteristics. The mixture of amphiphilic molecules of suitable components often produces much superior surface activity than a single component. Since the compound is non-toxic and non-irritating, its micelles have a strong solubilizing ability for hydrophobic compounds. The micelles prepared by mixing two poloxamer materials with different molecular weights can make up for the defects of poor stability, low drug loading and dilution instability of single micelles, providing new ideas for the research of polymer drug delivery systems. Therefore, its compounding rules have guiding significance for product formulation research. Secondly, studying the interaction rules and influencing factors of amphiphilic molecules in the binary components of poloxamer will help to deeply understand the mechanism of amphiphilic self-organization, which is of great significance for revealing the essence of natural phenomena.

[0100] However, the aggregation behavior of binary poloxamer mixtures in aqueous solution is quite complex, which means that so far, there have been few studies on the interaction of binary poloxamer copolymers. Currently, there is only one literature reporting the situation when three hydrophilic poloxamer block copolymers 237, F88 and 407 respectively form a binary mixture with a mass ratio of 1:1. They believe that the PPO block length ratio of the two-component poloxamer copolymer molecules determines the interaction between the two. When the PPO block lengths of the two components are similar, mutual mixing and aggregation occurs, while when the PPO block lengths differ greatly, it is difficult for interaction to occur.

[0101] However, the present application used 12 probe solubilization spectrophotometry to investigate the micellization behavior of binary / multi-poloxamer amphiphilic block copolymers in aqueous solution, and the results were found and verified:

[0102] ① For a mixed system using two or more poloxamers of different molecular weights and mixed combinations with different molecular PPO block lengths, when the mass fraction of low molecular weight poloxamer in the aqueous solution phase is <0.5, due to the formation of mixed pre-micelles of the mixed system, the high molecular weight poloxamer only generates single-component micelles at higher concentrations. When the mass fraction of low molecular weight poloxamer is >0.5, mixed micelles of the mixed system are generated in the solution, and the increase in temperature promotes the micellization behavior; ② In the mixed micelles prepared by the combination of hydrophobic poloxamer and hydrophilic poloxamer, after being diluted by body fluids in a simulated physiological environment, the micelles are formed. After release, the remaining drug content of the micelles was greater than 90%. The results showed that the same hydrophobic chain structure was easy to form synergistic micelles, and the mixed micelles had strong thermodynamic stability and were not easy to dissociate. These molecules interacted with each other in the entire concentration ratio range and formed mixed micelles. The total critical micelle concentration was between the critical micelle concentrations of the components constituting the mixed system and each of them existed as a single component. The interaction between the PPO chains of the two changed the aggregation behavior of the single micelles, which was related to the lower CMC value of the mixed micelles, so that the polymer micelles could resist the dilution of solutions and body fluids to a certain extent.

[0103] ③ Compared with poloxamer of the same PPO / PEO ratio, the effective concentration for gel formation is the same and decreases with the increase of polymer molecular weight;

[0104] ④ The CMC value of poloxamer aqueous solution decreases with the increase of temperature and PEO segment number, indicating that polymers with larger hydrophobic (PPO) domains form micelles at lower concentrations and temperatures;

[0105] ⑤ The larger the proportion of ethylene oxide segments, the higher the HLB value; when the proportion of ethylene oxide segments is the same, the smaller the relative molecular mass of the copolymer, the higher the HLB value; choosing a suitable poloxamer for use in combination can easily obtain the HLB value required for the emulsified liquid; ⑥ Poloxamer varieties with smaller ethylene segments, larger polyoxypropylene segments and higher relative molecular mass have stronger wetting ability; 101, 231, 331, 401, 181, etc. containing 10% ethylene oxide segments are almost insoluble in water or have very low solubility (<1%), and all have good wettability; among them, 401 has the largest relative molecular mass and has the best spreading effect on hydrophobic substances;

[0106] ⑦ Copolymers with a polyoxyethylene ratio of more than 30% are easily soluble in water (>10%) regardless of their relative molecular weight, especially poloxamer 338, which is representative of poloxamer. 338 has low toxicity and effective viral transduction ability, especially in difficult-to-transform cells derived from T cells, and is the best choice.

[0107] This application experimental study found and verified:

[0108] ① Polymers with a high proportion of hydrophobic chains, such as poloxamer 401 and 403, have a large hydrophobic core and are easy to dissolve more hydrophobic drugs, but due to the low proportion of hydrophilic chains, they often have a thinner hydrophilic shell, making the particles easy to aggregate in the solution environment and have poor stability. In order to increase stability, they can be mixed with other materials, such as poloxamer 338;

[0109] ② The poloxamer 335 block copolymer has an intermediate hydrophilic-lipophilic balance (HLB) value of 15, and can form spherical micelles with small particle size in aqueous solution; poloxamer 331 is a hydrophobic poloxamer with long polymers (HLBlong1), which can usually form lamellar aggregates with larger size (1000nm) in a-spherical micelles formed with higher solubility in aqueous solution than hydrophilic ones; these results indicate that inserting a small amount of hydrophobic 331 into the 335 micellar system can improve the solubility.

[0110] ③ The polymer was prepared using poloxamer 338 as raw material; its particle size, zeta potential and polydispersity were determined by dynamic light scattering and characterized by transmission electron microscopy (TEM), and it was observed that the polymer regulates drug release according to pH;

[0111] In vivo experiments have shown that the use of this new polymer formulation during radiotherapy has achieved good results in enhancing tumor control, especially for improving the prognosis of patients with advanced and metastatic disease.

[0112] ④ As we all know, the water solubility of octacosanol and curcumin is extremely poor, but the solubility is greatly increased in the composite solution of the solubilizer and promoter used in the present application. The solubility test results show that the solubility of the nano-scale octacosanol and curcumin in water (>10 mg / mL) of the present application is about 1 million times higher than that of the pure curcumin powder (8.02 ng / mL), which provides a possibility for improving bioavailability; the in vitro release results show that the dissolution rate of octacosanol and curcumin can be significantly improved by combining with the composite solution of the solubilizer and promoter used in the present application; this suggests that we can choose the composite solution of the solubilizer and promoter used in the present application as a formulation excipient to promote the solubility, dissolution and bioavailability of the nano-scale octacosanol and curcumin in the present application.

[0113] ⑵The particle size of emulsion droplets can be used as an important evaluation index of microemulsion. The particle size of emulsion droplets determines the speed and extent of drug absorption. The smaller the particle size of emulsion droplets, the larger the specific surface area, the more drug is absorbed, and microemulsions can be transported through lymph, avoiding the first-pass effect of the liver and improving the bioavailability of drugs.

[0114] The speed of the emulsification process is the direct determining factor of the droplet size, which directly affects the final particle size of the microemulsion; the greater the stirring speed, the greater the shear force on the system, the better the dispersion effect of the oil phase as the dispersed phase in the continuous phase, and the smaller the particle size of the microemulsion; the experimental research of this application found and verified that: except for the difference in the properties of the microemulsion caused by the particle size, changing the emulsification speed has no significant effect on other characteristics of the microemulsion. According to the requirements of this application, the speed is set at 10000-22000rpm and the pressure is 500-1000bar to form a nano-scale composition with an average particle size of 30-70nm.

[0115] The pharmacokinetic test results of this application:

[0116] ① Comparison of blood drug concentration after intragastric administration of the therapeutic drug solution prepared by the nano-microemulsion process of the present application and the therapeutic drug solution prepared by the traditional process:

[0117] A. The blood drug concentration of the therapeutic drug solution prepared by the nano-microemulsion process of the present application after intragastric administration is shown in Table 4

[0118] Table 4

[0119]

[0120] B. Blood drug concentration of the powder solution of the therapeutic agent prepared by traditional technology after intragastric administration, see Table 5

[0121] Table 5

[0122]

[0123] It can be seen from Tables 4 and 5 that the blood drug concentrations of the two groups of therapeutic agents after administration are absorbed in the initial stage. When the therapeutic agent powder solution prepared by the traditional process is administered by oral gavage, the blood drug concentration rapidly reaches a peak value at about 1 hour, and then decreases slowly; however, when the therapeutic agent solution prepared by the nano-microemulsion process of the present application is administered by oral gavage, the peak concentration appears at 3 hours, and the peak concentration of the therapeutic agent solution group prepared by the nano-microemulsion process of the present application after administration is significantly higher than that of the therapeutic agent solution group prepared by the traditional process, which is about 7 times the peak concentration of the therapeutic agent solution group prepared by the traditional process, and the blood drug concentration of the therapeutic agent solution group prepared by the nano-microemulsion process of the present application at each time point is higher than that of the therapeutic agent solution group prepared by the traditional process at the same time point; therefore, there are significant differences in both the peak time and the maximum peak concentration.

[0124] After 2.5 hours of administration, the blood drug concentration of the therapeutic substance solution group prepared by the traditional process was lower than the detection limit, while the original therapeutic substance could still be detected 15 hours after administration of the therapeutic substance solution group prepared by the nano-microemulsion process of the present application, indicating that after administration of the therapeutic substance solution group prepared by the nano-microemulsion process of the present application, the absorption amount of the therapeutic substance and the retention time of the therapeutic substance in the body were significantly improved.

[0125] ② Comparison of pharmacokinetic parameters after intragastric administration of the therapeutic substance solution prepared by the nano-microemulsion process of the present application and the therapeutic substance solution prepared by the traditional process:

[0126] A. Pharmacokinetic parameters of the therapeutic substance solution prepared by the nano-microemulsion process of the present application after oral administration, see Table 6

[0127] Table 6

[0128]

[0129] B. Pharmacokinetic parameters of therapeutic substance solution prepared by traditional process after intragastric administration, see Table 7

[0130] surface

[0131]

[0132] ③ Comparison of relative bioavailability of solutions prepared by the nano-microemulsion process of this application, see Table 8

[0133] Table 8

[0134]

[0135] Tables 5-8 show the main kinetic parameters, peak time, peak concentration, elimination rate constant, half-life and area under the blood drug concentration-time curve of the therapeutic drug solution prepared by the nano-microemulsion process of the present application and the therapeutic drug solution prepared by the traditional process.

[0136] The results show that: compared with the therapeutic drug solution prepared by the traditional process, the therapeutic drug solution prepared by the nano-microemulsion process of the present application has a 2h release rate of blood drug concentration that is 7.9 times that of the pure therapeutic drug solution preparation, and the area under the blood drug concentration-time curve is 11.4 times that of the pure therapeutic drug solution preparation;

[0137] The therapeutic substance solution prepared by the traditional process reaches the peak concentration in 1 hour, and then the concentration drops rapidly. It is difficult to be detected after 2.5 hours. The elimination rate constant is 0.42 and the half-life is 1.94, indicating that the therapeutic substance solution prepared by the traditional process is rapidly metabolized in the body; after the therapeutic substance solution preparation is prepared by the nano-microemulsion process of the present application, the therapeutic substance solution reaches the peak concentration in 3 hours, and the peak time is significantly prolonged. It can still be detected at 82ng / mL-1 at 19 hours. The elimination rate constant is 0.15 and the half-life is 4.69. This shows that after the therapeutic substance solution preparation is prepared by the nano-microemulsion process of the present application, the action time can be extended, the elimination rate constant is significantly reduced, and the half-life is significantly prolonged, indicating that it can increase the action time of the therapeutic substance in the body, thereby reducing the elimination rate and improving the bioavailability;

[0138] The therapeutic substance solution prepared by the nano-microemulsion process of the present application has a relative bioavailability increased by 15.44 times, showing the largest peak concentration and the smallest elimination rate constant, indicating that the therapeutic substance solution prepared by the nano-microemulsion process of the present application can enhance drug absorption and sustained release; and significantly improve the in vivo absorption process of the therapeutic substance.

[0139] During the plasma separation process, it was found that after oral administration of the solution prepared by the nano-microemulsion process of the present application, the plasma sample was relatively turbid and contained fat droplets. This indicates that after oral administration of the therapeutic substance solution prepared by the nano-microemulsion process of the present application, the therapeutic substance remains in the blood for a long time, and the therapeutic substance needs to be slowly released into the blood from the promoter of the present application, which slows down the clearance rate, thereby producing a certain sustained-release effect.

[0140] The above results all indicate that the therapeutic substance solution prepared by the nano-microemulsion process of the present application has a slower elimination of the preparation, achieves a certain sustained-release effect, and prolongs the in vivo circulation time to a certain extent.

[0141] 3 The present application adopts two types of stabilizers in combination to improve the stability of the therapeutic agent solution preparation of the present application, so that the composition of the present application has better long-term stability.

[0142] According to the principle of adsorption, stabilizers are mainly divided into ionic stabilizers and spatial stabilizers (polymer type); ionic surfactants mainly rely on electrostatic repulsion to prevent particle aggregation, and the mode of action of spatial stabilizers is mainly that the polymer is adsorbed to the surface of the particles, increasing the spatial distance between the particles, generating stereoscopic repulsion, thereby preventing the particles from approaching each other; in the selection and use of these stabilizers, there are many issues to consider: such as the length and molecular size of the material, which affect its mutual adsorption with the drug particles; higher concentrations of stabilizers may also cause the solubility of nano drugs to decrease, affecting the bioavailability of the drug; the use of certain stabilizers may increase the side effects of the drug; therefore, when the nano-microemulsion process of the present application is used to prepare the therapeutic drug solution, the selection and use of stabilizers has become an important link that must be examined in the experimental process;

[0143] The carboxymethyl anionic guar gum used in the present application is an ionic stabilizer, and hydroxypropyl methylcellulose and submicron solid organic plant fiber are steric stabilizers.

[0144] The present application adopts submicron solid organic plant fibers as the nano-microemulsion process of the present application to prepare the stabilization mechanism of the therapeutic drug solution, which mainly has four types:

[0145] ① Mechanical hindrance mechanism of interfacial film; Submicron solid organic plant fibers are adsorbed on the oil / water interface and closely arranged on the surface of emulsion droplets to form a solid interfacial film. Its steric hindrance hinders the collision and aggregation between emulsion droplets; at the same time, submicron solid organic plant fibers are adsorbed on the surface of droplets, which increases the repulsive force between emulsion droplets and improves the stability of the emulsion; the solid organic plant fiber boundary film adsorbed on the oil-water interface has a certain elasticity. When external force acts or droplets squeeze and collide with each other, the solid organic plant fiber boundary film on the surface of the emulsion droplets will deform to a certain extent, but it will not break the emulsion;

[0146] ② Three-dimensional viscoelastic particle network mechanism: In the emulsion system, the unadsorbed solid particles are interconnected to form a particle-particle three-dimensional network structure, which increases the viscosity of the emulsion, restricts the flow of dispersed phase droplets, reduces the frequency of mutual aggregation and collision between droplets, and effectively improves the stability of the emulsion;

[0147] ③ Three-dimensional droplet bridging network mechanism: The submicron solid organic plant fibers on the droplet surface bridge each other through interaction, connecting adjacent droplets to form a droplet-droplet three-dimensional network structure, allowing the droplets to stably exist in the emulsion system;

[0148] ④ The stability of the emulsion usually increases with the decrease in the size of solid particles. This is because as the size of submicron solid organic plant fibers decreases, more and tighter solid organic plant fibers are arranged at the oil / water interface, and the solid interface film wrapped around the emulsion droplets becomes stronger, thereby improving the stability of the emulsion. Within a certain particle concentration range, the increase in the concentration of submicron solid organic plant fibers will reduce the particle size of the resulting emulsion droplets, thereby improving the stability of the emulsion.

[0149] This application has been found and verified through experimental research:

[0150] (1) In vitro dissolution tests showed that in the case of pure therapeutic drug solution preparations, the release rate quickly increased to 20% within the initial period, but the drug precipitated rapidly within 2 hours, and the release amount was reduced to 1 / 7 of the original amount;

[0151] (2) The therapeutic substance solution prepared by the nano-microemulsion process of the present application, after adding the stabilizer of the present application, forms a new drug release system. The emulsion in a supersaturated state can significantly inhibit the crystallization of the therapeutic substance and prolong the supersaturated state of the therapeutic substance in the gastrointestinal tract, thereby increasing the solubility of the therapeutic substance and reducing the dosage of the solubilizer and promoter used in the present application;

[0152] ⑶ Due to the unique interfacial solid layer and its steric hindrance effect of the solution of the present application, the active substance is difficult to overflow from the interface after being encapsulated, so it has good encapsulation stability and can stabilize the biologically active substance in the composition system;

[0153] ④ A grid is formed or wrapped around the surface of the oil droplets, providing a tight barrier for the oil droplets, which can prevent the aggregation and Oswald ripening of the oil droplets, resulting in the enhancement of the interfacial strength of the solution of the present application and the network structure in the continuous phase, and the rheology and stability of the solution of the present application are significantly improved;

[0154] ⑶ Studies have shown that the combined use of two types of stabilizers can make the therapeutic substance solution preparation prepared by the nano-microemulsion process of the present application have better long-term stability.

[0155] 4. Test of influencing factors.

[0156] Stability studies are helpful in predicting the stability of therapeutic agents in the high-energy composition of this application. Through experimental studies of this application, it has been found and verified that:

[0157] (1) Based on the fact that curcumin is easily decomposed into ferulic acid and vanillin under light conditions, which limits its application, this application proposes to use light-stable compound excipients to solve the light stability solution of curcumin.

[0158] The results of the present application show that for pure curcumin, after 5 minutes of illumination, the stability is reduced to about 60%, and the stability of curcumin decreases linearly with continuous light irradiation; and the nano-microemulsion of the present application is compounded with a compound shading auxiliary material, which is relatively stable under indoor light and a light intensity of 4500 lux, and there is almost no degradation of the therapeutic agent of the present application within 24 hours, showing excellent stability, which can reach 95%; it can also be seen from the results that when the ratio of the compound shading auxiliary material to the nano-microemulsion of the present application is increased, better stability and lower photolysis efficiency can be obtained, and the compound shading auxiliary material can block and absorb most of the light energy; the experimental results show that the more compound shading auxiliary materials are added, the better the photostability, indicating that the compound shading auxiliary materials of the present application play a role in protecting the nano-microemulsion of the present application from light, and the preparation process does not need to be carried out in dark;

[0159] Among food ingredients, some small molecules with biological activity often show instability due to the influence of temperature, oxygen and light; the composite light-shielding auxiliary material of the present application as a carrier is not only a good nutrient itself, but also can improve the stability of the embedded therapeutic agent to temperature and oxygen.

[0160] (2) Studies have shown that the therapeutic drug solution of the present application is stable under conditions of pH 4 to pH 6.8, while the drug is easily degraded in other acidic and alkaline ranges to generate other substances; considering the direct influence of the physical stability and chemical stability of the composition system of the present application, and the fact that the pH of the human intestinal tract is approximately weakly acidic, all raw materials of the composition of the present application are weakly acidic, and the pH value of the composition of the present application is finally determined to be 5.8-6.8, which is within the pH range that the human body can tolerate. Therefore, after preparation, there is no need to adjust the pH of the composition of the present application.

[0161] The solution of the therapeutic agent of the present application alone degrades by 35% within 24 hours under the condition of 80°C water bath, and its degradation process is a first-order kinetic process; while the solution of the therapeutic agent of the present application after adding the promoter can be stable within 48 hours under the high temperature condition of 80°C water bath, indicating that when preparing the composition of the present application, dissolving the therapeutic agent of the present application in the promoter can maintain the stability of the therapeutic agent of the present application.

[0162] 5. The present application adopts the compatibility with functional sugar alcohols, and its advantages in the production of the composition of the present application are comprehensively manifested in:

[0163] ⑴Maltitol will not cause an increase in blood sugar concentration and will not stimulate insulin secretion.

[0164] In 1971, Japanese researchers such as Hosoya conducted an experiment on adult men aged 27 to 56, in which they consumed 0.5 g of maltitol per kilogram of body weight. After one week, they found that there was no significant change in various components in the blood, such as blood sugar, insulin and inorganic substances. Under the same conditions, the results of those who consumed glucose were the opposite. This proves that maltitol does not cause blood sugar to rise or stimulate insulin secretion after consumption, and is therefore a boon for diabetic patients. It also has certain fat properties, namely a certain emulsification and thickening property, which can also promote calcium absorption, and has a significant preventive and therapeutic effect on bone diseases caused by insufficient calcium absorption in children and the elderly.

[0165] ⑵ Erythritol, a new type of pure natural sweetener.

[0166] It has the characteristics of non-hygroscopicity, fast dissolution, no calories, refreshing taste, anti-caries, high tolerance, no increase in blood sugar, stable processing performance, etc. It effectively masks the aftertaste of other auxiliary materials, making it more suitable for the composition.

[0167] In view of the defects and shortcomings in the prior art, the present application proposes a synergistically refined composition and a preparation method thereof, which has the following advantages compared with other known methods.

[0168] ⑴ The nano-scale ultra-high purity bamboo leaf flavonoids, octacosanol and curcumin used in this application greatly improve the bioavailability of the drug.

[0169] Experimental studies have found and verified that the surface area, dispersibility, adsorption capacity, surface activity, etc. of the nano-scale ultra-high purity bamboo leaf flavonoids, octacosanol and curcumin used in this application have undergone comprehensive changes compared with the original drugs; their specific surface area has been greatly increased, thereby significantly increasing their solubility and dissolution rate, making them easy to disperse and dissolve in gastrointestinal fluid, and the contact area with the gastrointestinal mucosa has become larger, and the adhesion has been enhanced, so that the nano-scale material preparation obtained in this application has a longer residence time in the digestive tract, making the absorption of the effective ingredients more sufficient and complete, greatly improving the bioavailability and efficacy of the preparation obtained in this application; it can also reduce local irritation.

[0170] The nano-scale therapeutic agent used in this application is extremely well encapsulated and protected due to its small particle size, thereby improving the antioxidant activity and protecting the biological activity to the maximum extent; it is easily absorbed through the gastrointestinal barrier in the body, has strong surface adsorption and affinity, greatly improves the digestion and absorption rate of the product by the human body, and greatly improves the bioavailability of the product; products based on nano-scale therapeutic agents can improve bioavailability and increase drug exposure in oral and non-oral dosage forms. The appropriate formulation for the most commonly used route of administration can be determined by milligram doses of the drug, providing another way to screen and identify excellent new drugs for the development of innovative drugs.

[0171] The nano-scale therapeutic substances used in this application have special physical and chemical properties that the same village materials made by traditional processing technology do not have, such as very significant dispersibility, adsorption, solubility, chemical reaction activity, etc. This is a major advantage of the nano-scale material technology used in this application! Therefore, this technology will have a very wide range of applications in the fields of medicine and so on.

[0172] (2) The present application uses a binary amphiphilic poloxamer block copolymer, which is spontaneously formed with relatively simple ingredients, solubilizes and delivers hydrophilic and lipophilic therapeutic agents of the present application, improves the solubility of the nano-sized octacosanol and curcumin in the gastrointestinal tract, and then enhances the absorption of octacosanol and curcumin in the gastrointestinal tract, thereby comprehensively improving oral bioavailability.

[0173] Microemulsion is a transparent or translucent, low-viscosity, isotropic and thermodynamically stable oil-water mixed system. Using it as a carrier for poorly soluble drugs is beneficial to the absorption of drugs and can improve the bioavailability of drugs in the body. At present, microemulsions are mainly used as drug carriers, and are rarely used as carriers of food functional factors. There are no reports on loading microemulsions with octacosanol and curcumin. The reason is that the traditional microemulsion system requires a large amount of surfactants, and the amount of emulsifier is about 30% to 60%, and an emulsifier is generally required. However, the emulsifier may irritate the gastrointestinal tract, and the emulsifier and its metabolites in the body The biological changes caused by microemulsions may also cause toxic side effects to the body, including acute toxicity, subacute toxicity, chronic toxicity, etc. At the same time, large doses of emulsifiers can cause membrane damage and cell death. On the other hand, most emulsifiers in traditional microemulsion systems are synthetic emulsifiers, which have the problems of high toxicity and strong irritation. As the concept of sustainable development becomes more and more popular among consumers, the common synthetic emulsifiers in microemulsions are difficult to meet consumers' pursuit of natural green food. Therefore, the edibility and safety of traditional surfactants limit their application in the food industry.

[0174] At present, although there have been many studies on nanoemulsions in China, it is still in its infancy, with only a few products on the market, and there are still many problems that need to be solved: such as the small variety of excipients available, the lack of in-depth understanding of the behavior and effects of nanocarriers or drug particles on the body's biological molecules and cells, the cytotoxicity of nanoparticles and their degradation products, and the side effects caused by long-term accumulation, etc.; At present, traditional microemulsification technology and its use in the food industry are only used in turbidity removal, mold inhibitors, and synergistic determination of trace element extraction in food; At present, reports on the application of microemulsification technology to solve the solubility of additives are only seen in antioxidants.

[0175] The poloxamer used in this application meets the following conditions: ① HLB value 1-28, with efficient emulsification ability; ② has a certain physiological adaptability, is non-toxic and non-irritating to the human body; ③ has good biocompatibility and does not affect the function of the loaded functional components; ④ is less affected by various factors, has stable chemical properties, is not easy to decompose, can withstand hot pressure sterilization and low-temperature freezing without changing its physical stability and does not decompose during long-term storage, etc.

[0176] The poloxamer block copolymer of the poloxamer binary component amphiphilic molecule used in the present application has an HLB value of 1-28. The hydrophilic chain poloxamers arranged alternately increase the inherent hydration layer thickness of the mixture, overcome the disadvantage of the thin hydration layer of the single hydrophobic poloxamer micelle shell, help protect the micelle core from dilution damage, and enhance the spatial stability of the micelle; it can not only give play to the advantages of high drug loading and high encapsulation rate of the hydrophobic poloxamer, but also increase the spatial stability of the micelle by combining with a poloxamer with a higher hydrophilic chain ratio, thereby achieving high drug loading, high stability and slow release; it is spontaneously formed with relatively simple ingredients, solubilizes and delivers hydrophilic and lipophilic therapeutic agents in the present application, and poloxamer has unique physical and chemical properties and good biocompatibility.

[0177] The nano-microemulsion of the present application as the therapeutic substance transport system of the present application has the following advantages:

[0178] ① The therapeutic substance is encapsulated in the inner phase, so that the therapeutic substance is prevented from direct contact with body fluids or tissue fluids. This isolation increases stability, prolongs its degradation time, and increases drug stability; thus, targeted sustained release can be achieved over a long period of time, increasing the therapeutic effect of the therapeutic substance;

[0179] ②Poorly soluble therapeutic substances often have a certain degree of lipophilicity. Dissolving or solubilizing them in a suitable promoter to make nano-microemulsions can improve the solubility of poorly soluble therapeutic substances;

[0180] ③ The HLB value of poloxamer used in this application is 1-28; although lecithin is the preferred surfactant for preparing food-grade microemulsions, it also has disadvantages: because of its small HLB value (hydrophile-lipophile balance), it has poor fluidity in the aqueous phase system and is difficult to form O / W microemulsions, which makes it difficult to prepare food-grade microemulsions.

[0181] In summary, due to the amphiphilic nature of the amphiphilic block copolymer molecular chain and the microscopic phase separation trend of its molecular structure, it has many special properties, which makes it have broad application prospects in many aspects such as emulsification, solubilization, sustained release control, and drug carrier in this application.

[0182] ⑶ The present application uses submicron solid organic plant fibers as the stabilizer system for preparing therapeutic drug emulsions using the nano-microemulsion process of the present application, which has unique advantages over other systems.

[0183] First, since the emulsion is essentially a thermodynamically unstable system, during the storage stage, the droplets in the emulsion system are constantly moving and colliding, which increases the instability of the oil-water interface, deteriorates the dispersion of the droplets, forms larger emulsion droplets, and causes the average particle size to increase and settle and decompose; the present application uses submicron solid organic plant fibers to replace traditional precipitation inhibitors, and the emulsion formed by irreversible adsorption on the oil-water interface shows higher resistance to agglomeration and Ostwald ripening than traditional emulsions, and the particle size increases by less than 1%, which has extremely strong stability; while the emulsion stabilized by traditional precipitation inhibitors has a significantly increased particle size change during the storage period, resulting in sedimentation and decomposition; compared with ordinary suspensions, the present application has higher oral bioavailability.

[0184] Second, in the nano-microemulsion of the present application, submicron solid organic plant fibers are added, and the emulsion is in a supersaturated state, which can significantly inhibit the crystallization of the therapeutic substance of the present application, prolong the supersaturated state of the therapeutic substance in the gastrointestinal tract, thereby increasing the solubility of the therapeutic substance, reducing the amount of solubilizer used, and having a strong emulsification aid.

[0185] Third, submicron solid organic plant fibers are added to the nano-microemulsion of the present application. Due to the irreversible adsorption of the submicron solid organic plant fibers, the interface layer formed is more stable, which can effectively isolate the contact between oxygen and the internal promoter, thereby reducing the oxidation of the promoter; therefore, the nano-microemulsion of the present application has stronger antioxidant stability; compared with the addition of traditional precipitation inhibitor emulsions, the potential risks brought by small molecule surfactants can be reduced; the solution of the present application has excellent stability and safety, excellent biocompatibility, and has great application potential in the controlled release of bioactive substances, oxidation inhibition of oils and fats, etc.

[0186] Fourth, the addition of submicron solid organic plant fibers to the nano-microemulsion of the present application can effectively protect the active substances encapsulated inside; therefore, the system of the present application has the ability to protect the nutritional value and biological activity of the encapsulated substances and can provide the necessary protection for the active ingredients, which is mainly due to its stable structure.

[0187] Fifth, it is expected to be an effective method to improve the physicochemical properties and oral absorption of the therapeutic substances of the present application, and can provide a reference for the selection of stabilizers in the preparation of nanoformulations for other drugs that are relatively unstable to water.

[0188] ⑷ The present application is prepared in a nano-microemulsion manner, which significantly improves the bioavailability of the therapeutic agent of the present application.

[0189] ①Nano-microemulsions significantly increase the solubility of therapeutic agents and improve their dissolution; ②Dispersion forms nano-microemulsions, which have a large interfacial area, low surface tension, and are easy to pass through the hydration layer of the gastrointestinal wall; ③Due to the use of solubilizers and promoters, the rheological properties of the intestinal surface mucus are changed, the viscosity is reduced, the permeability of intestinal epithelial cells is increased, and drug absorption is promoted; ④The adhesion of nano-microemulsions allows the droplets to be in close contact with the gastrointestinal mucosa for a long time, which can promote the transmembrane transport of therapeutic agents in the gastrointestinal mucosa; after intestinal absorption, they are transported through the lymphatic system, avoiding the first-pass effect of the liver, continuing the metabolic process of the therapeutic agent in the body, and improving the bioavailability of the therapeutic agent; ⑤The therapeutic agent is absorbed in the form of nano-droplets like fat. After entering the body, the therapeutic agent is still wrapped in the nano-droplets. The therapeutic agent needs to diffuse out of the nano-droplets to be metabolized, and its metabolic process in the body is delayed, which slows down the elimination process of the prototype therapeutic agent in the body, thereby improving the bioavailability.

[0190] The present application uses a nano-microemulsion drug delivery system made of water-insoluble octacosanol and curcumin to solve the in vitro and in vivo application defects of octacosanol and curcumin themselves, provides a method for solubilizing poorly soluble octacosanol and curcumin, and the prepared water-soluble solution of octacosanol and curcumin is further optimized by taking different measures to further optimize the prescription, greatly improving the stability of octacosanol and curcumin, and evaluating the bioavailability through pharmacokinetic and tissue distribution studies, providing a basis and basis for the extensive industrial application of octacosanol and curcumin in medicine; At present, a large number of drugs with poor water solubility, instability in water, and poor bioavailability are administered orally and by injection, and the dissolution rate in gastrointestinal fluid is poor, which directly leads to incomplete drug absorption, reduces oral bioavailability, and seriously affects the clinical efficacy of drugs and the treatment of diseases; Based on the above unfavorable factors, although some water-insoluble compounds have high therapeutic activity, since such drugs are difficult to enter clinical application, many pharmaceutical companies have excluded them in the early stage of drug screening. The research on the nano-microemulsion drug delivery system of the present application provides a new option and a scientific reference, has strong theoretical and practical application significance for improving the solubility of poorly soluble drugs, and has great development prospects and application value.

[0191] (5) All raw materials of the composition of the present application are weakly acidic. The final pH value of the composition of the present application is determined to be 5.8-6.8, which is within the pH range that can be tolerated by the human body. The release of the therapeutic agent of the present application can be adjusted according to the pH; this behavior is a very useful tool because the change in pH value (pH6.8) at the tumor level will lead to faster drug release than when circulating in the bloodstream.

[0192] ⑹ All raw materials of the composition of the present application have eliminated possible toxic and side effects on the human body, including acute toxicity, subacute toxicity, chronic toxicity, and irritation.

[0193] ⑺ The preparation method of the composition of the present application can be either solid or liquid, and is easy to use, small in size, easy to carry, easy to store, and easy to transport.

[0194] In summary, the therapeutic ingredient composition of the composition of the present application utilizes the synergistic effect of four therapeutic ingredients, namely, partially hydrolyzed guar gum (PHGG), nano-scale ultra-high purity flavonoids, octacosanol and curcumin extract, to provide a new way for health maintenance and disease prevention. Long-term drinking can also regulate body metabolism, promote physical improvement, and promote the development of human health. It has important practical significance and is a promising attempt. The process of the present application is simple, the quality is stable, and it has obvious economic value and broad market prospects. At present, there are few reports in this regard, and there are no products of this formula at home and abroad. The present application fills this gap.

[0195] Since many substances that play an important role in the human body are both medicinal and edible, the application of the composition of this application in drug development can provide technical support for the research and development and application of other herbal plant compositions and provide a basis for industrial production. DETAILED DESCRIPTION

[0196] The present application is further described in detail below through examples. These examples are only used to illustrate the present application and do not limit the scope of the present application.

[0197] Example 1

[0198] A synergistically refined composition, and a preparation method thereof, comprising the following steps:

[0199] (1) Weigh 0.01 parts of the therapeutic ingredient octacosanol, 0.2 parts of the therapeutic ingredient curcumin, 0.5 parts of poloxamer 401, 1 part of poloxamer 288, 0.5 parts of lemon balm essential oil, and 0.5 parts of Chinese cinnamon essential oil according to the weight ratio, add them into a sealed dispersion reactor, heat to 40°C at the same time, stir at a speed of 300 rpm until completely dissolved, and set aside;

[0200] (2) According to the weight ratio, 2.5 parts of partially hydrolyzed guar gum (PHGG), 0.05 parts of flavonoids, 1.2 parts of sugarcane fiber with a median particle size of D50 = 0.261 μm, 0.3 parts of carboxymethyl anionic guar gum, 0.5 parts of tea polyphenols, 1.5 parts of soft rice starch with a median particle size of D50 = 0.320 μm, and 300 parts of distilled water were weighed and added into a sealed grinding and emulsification reactor, and stirred at a speed of 300 rpm at room temperature until completely dissolved; (1) was slowly added, and heated to 75°C at the same time, and after grinding and emulsification treatment at a speed of 10000 rpm for 5 minutes, the temperature was lowered to 45°C, 0.8 parts of maltitol and 0.015 parts of preservatives were added, and the stirring was continued for 30 minutes at a speed of 300 rpm to obtain colostrum;

[0201] (3) placing the colostrum obtained in (2) into a high-pressure homogenizer, treating it once at 60° C. and a pressure of 200 bar, and then treating it twice at a pressure of 500 bar, to obtain a liquid synergistically refined composition;

[0202] (4) spray freeze-drying the liquid synergistically refined composition obtained in (3) to obtain a solid synergistically refined composition;

[0203] The pH value of the synergistically refined composition is 5.8-6.8.

[0204] Example 2

[0205] A synergistically refined composition, and a preparation method thereof, comprising the following steps:

[0206] (1) According to the weight ratio, 0.015 parts of the therapeutic ingredient octacosanol, 0.4 parts of the therapeutic ingredient curcumin, 0.8 parts of poloxamer 331, 1.6 parts of poloxamer 335, 1 part of Ceylon cinnamon essential oil, and 0.5 parts of castor essential oil were weighed and added into a sealed dispersion reactor, and heated to 45° C., stirred at a speed of 300 rpm until completely dissolved, and set aside;

[0207] ⑵ According to the weight ratio, 3.2 parts of partially hydrolyzed guar gum (PHGG), 0.08 parts of flavonoids, 1.8 parts of bamboo fiber with a median particle size of D50 = 0.316 μm, 0.4 parts of carboxymethyl anionic guar gum, 0.6 parts of tea polyphenols, 1.4 parts of indica rice starch with a median particle size of D50 = 0.320 μm, and 300 parts of distilled water were weighed and added into a sealed grinding and emulsification reactor, and stirred at a speed of 400 rpm at room temperature until completely dissolved; ⑴ was slowly added, and heated to 75°C at the same time, and after grinding and emulsification treatment at a speed of 16000 rpm for 10 minutes, the temperature was lowered to 47°C, 1.5 parts of erythritol and 0.02 parts of preservatives were added, and the stirring was continued for 30 minutes at a speed of 400 rpm to obtain colostrum;

[0208] (3) placing the colostrum obtained in (2) into a high-pressure homogenizer, treating it once at 60° C. and a pressure of 200 bar, and then treating it three times at a pressure of 800 bar to obtain a liquid synergistically refined composition;

[0209] (4) spray freeze-drying the liquid synergistically refined composition obtained in (3) to obtain a solid synergistically refined composition;

[0210] The pH value of the synergistically refined composition is 5.8-6.8.

[0211] Example 3

[0212] A synergistically refined composition, and a preparation method thereof, comprising the following steps:

[0213] (1) According to the weight ratio, 0.02 parts of the therapeutic ingredient octacosanol, 0.6 parts of the therapeutic ingredient curcumin, 1 part of poloxamer 403, 2 parts of poloxamer 338, 2 parts of ginger essential oil, and 0.5 parts of real lavender essential oil were weighed and added into a sealed dispersion reactor, and heated to 50° C., stirred at a speed of 500 rpm until completely dissolved, and set aside;

[0214] ⑵ According to the weight ratio, 4 parts of partially hydrolyzed guar gum (PHGG), 0.1 part of flavonoids, 2.5 parts of lotus leaf fiber with a median particle size of D50 = 0.230 μm, 0.5 parts of carboxymethyl anionic guar gum, 1 part of tea polyphenols, 2 parts of high-amylose corn starch with a median particle size of D50 = 0.320 μm, and 300 parts of distilled water were weighed and added into a sealed grinding and emulsification reactor, and stirred at a speed of 500 rpm at room temperature until completely dissolved; ⑴ was slowly added, and heated to 80°C at the same time, and after grinding and emulsification treatment at a speed of 22000 rpm for 15 minutes, the temperature was lowered to 50°C, 2.3 parts of maltitol and 0.025 parts of preservatives were added, and the stirring was continued for 30 minutes at a speed of 500 rpm to obtain colostrum;

[0215] (3) placing the colostrum obtained in (2) into a high-pressure homogenizer, treating it once at 60° C. and a pressure of 200 bar, and then treating it four times at a pressure of 1000 bar to obtain a liquid composition;

[0216] (4) spray freeze-drying the liquid synergistically refined composition obtained in (3) to obtain a solid synergistically refined composition;

[0217] The pH value of the synergistically refined composition is 5.8-6.8.

[0218] Lipid metabolism disorder induced by a high-fat, high-sugar diet is one of the risk factors for aggravating insulin resistance. On the one hand, hypertrophic adipocytes release excessive free fatty acids. On the other hand, adipose tissue can produce chronic inflammation, inhibit the secretion of adiponectin, and thus reduce the insulin sensitivity of target tissues. Therefore, the composition is used for medicinal purposes to prevent and treat diseases and strengthen the body. It can significantly reduce the frequency of use of anti-inflammatory drugs and is an important part of the research on the homology of medicine and food. At present, there are no very effective measures in this regard at home and abroad.

[0219] The present application has found and verified that the following synergistically refined composition obtained according to the above-mentioned examples has an effect on regulating metabolic disorders induced by a high-fat and high-sugar diet in mice:

[0220] ⑴ Experimental methods

[0221] The normal group was fed a low-fat diet, and the remaining mice were fed a high-fat, high-sugar mouse diet until their body weight was 40% overweight compared with the normal group, which was considered a model successfully induced by a high-fat, high-sugar diet; they were respectively a model group, a metformin group, and a combination group of the present application; the oral gavage dose was calculated according to the unit body weight of the mouse, and according to the preliminary experimental results of the present application, the oral gavage dose of the combination group of the present application was set to 3000 mg / (kg·d), and the oral gavage dose of metformin in the metformin group was 150 mg / (kg·d); the normal group and the model group were given an equal volume of normal saline, and the drug was administered continuously by oral gavage for 8 weeks; during the oral gavage period, the normal group was fed a low-fat diet, and the remaining groups of mice continued to be fed a high-fat, high-sugar diet; after the end of the medication period, the mice were fasted overnight and samples were taken for testing.

[0222] (2) The effect of the composition of the present application on the changes in body weight of mice fed a high-fat and high-sugar diet is shown in Table 9

[0223]

[0224] As can be seen from Table 9, after 8 weeks of feeding with a high-fat and high-sugar diet, the body weight of the mice increased significantly; after the start of gavage, the dietary conditions of each group remained unchanged; compared with the normal group, the body weight and growth rate of the mice in the model group continued to increase under high-fat and high-sugar diet, and after gavage with metformin, the body weight of the mice decreased by 4.3% compared with the initial level; after gavage with the composition of the present application for 8 weeks, the body weight of the mice was significantly lower than that of the model group, and the body weight growth rate decreased, indicating that the composition of the present application can control the body weight growth of mice under a high-fat and high-sugar diet.

[0225] ⑶ The effect of the composition of the present application on blood glucose homeostasis in mice fed a high-fat and high-sugar diet is shown in Table 10

[0226]

[0227] As shown in Table 10, after 16 weeks of high-fat and high-sugar diet intake, the fasting serum glucose and insulin levels of the model group mice were significantly higher than those of the normal group mice, the insulin resistance index (4.7 mol / IU) increased by 5.2 times that of the normal group (0.9 mol / IU), and the glycosylated hemoglobin content (999 μg / mL) was 3.3 times that of the normal group mice (299.2 μg / mL); after intervention with metformin and the composition of the present application, the glycosylated hemoglobin content in each group of mice was significantly reduced; the serum glucose content and insulin resistance index of the composition group of the present application decreased significantly, but the serum insulin content did not change significantly; the serum glucose content of the mice in the metformin and composition groups of the present application decreased to 4.5 and 5.2 mmol / L, respectively, and the insulin content decreased to 10.6 and 11.9 mol / L, respectively, and the insulin resistance index decreased by 61% and 48% respectively compared with the model group; the research results show that the composition of the present application can maintain the stability of insulin secretion and glucose homeostasis in the basal state of mice.

[0228] ⑷ The effect of the composition of the present application on lipid metabolism in mice fed a high-fat and high-sugar diet is shown in Table 11

[0229]

[0230] As shown in Table 11, after the intervention of the composition of the present application, the effect of decreasing the triglyceride content in the serum of mice was consistent with that of the metformin group (1.6 mmol / L); compared with the model group, the cholesterol, low-density lipoprotein cholesterol and free fatty acid levels of the composition group of the present application were significantly decreased; in addition, after high-fat and high-sugar induction, the mass concentration of adiponectin in mice (8.5 mg / L) was 28% lower than that of the normal group (11.8 mg / L), while the adiponectin levels of mice in the metformin and composition groups of the present application were not significantly different from those of the normal group;

[0231] The results suggest that the composition of the present application can improve lipid metabolism disorders in mice, and the blood sugar regulating effect of the composition of the present application is related to adipose tissue.

[0232] ⑸ The composition of the present application can not only maintain the normal morphology of adipose tissue of mice fed a high-fat, high-sugar diet and reduce free fatty acids in serum, but more importantly, after the mice fed a high-fat, high-sugar diet were supplemented with the composition of the present application, adiponectin in fat cells can be restored to normal secretion levels, which helps to improve insulin sensitivity, thereby alleviating insulin resistance, and has positive significance for improving body weight and insulin resistance.

[0233] ⑹ The results of regulating the glucose and lipid metabolism homeostasis and intestinal environment of mice induced by a high-fat and high-sugar diet showed that the composition of the present application can control body weight gain, reduce fasting blood sugar, improve glucose tolerance, improve dyslipidemia and protect adipose tissue morphology, and has good blood sugar and lipid-lowering effects; the composition of the present application can improve the metabolic disorders induced by a high-fat and high-sugar diet in mice, and reduce the risk of diabetes, obesity, etc.

[0234] ⑺ The composition of the present application is used as a functional drug for preventing and treating diabetes and obesity, which has broad application prospects.

[0235] All of the above descriptions of specific exemplary embodiments of the present application are for the purpose of explanation and illustration; these descriptions are not intended to limit the present application to the precise form disclosed, and it is obvious that many changes and variations can be made based on the above teachings; the purpose of selecting and describing the exemplary embodiments is to explain the specific principles of the present application and its practical application, so that technical personnel in the field can implement and utilize various different exemplary embodiments of the present application and various different selections and changes; or to make equivalent substitutions for some of the technical features therein; and these modifications or substitutions, and other conceivable alternative means, are all within the scope of protection of the present application, and do not deviate the essence of the corresponding technical solution from the spirit and scope of the technical solution of each embodiment of the present application.

Claims

1. A composition, characterized in that: The method is prepared from the following raw materials: 2.5-4 parts of partially hydrolyzed guar gum PHGG, 0.05-0.1 parts of flavonoids, 0.01-0.02 parts of octacosanol, 0.2-0.6 parts of curcumin, 1.5-3 parts of solubilizer, 1-2.5 parts of accelerator, 1.5-3 parts of stabilizer, 1.5-3 parts of compound shading auxiliary material, 0.8-2.3 parts of functional sugar alcohol, 0.015-0.025 parts of preservative and 300 parts of distilled water; The flavonoids are nano-scale bamboo leaf flavonoid dispersions with a purity of 99.9% and a median particle size D50 of ≤0.084 μm; The octacosanol is a nano-scale sucrose octacosanol dispersion with a purity of 99.5% and a median particle size D50 ≤ 0.07 μm; The curcumin is a nano-scale curcumin dispersion with a purity of ≥99.5% and a median particle size D50 ≤0.082 μm; The solubilizing agent is a poloxamer compound, wherein the poloxamer compound is poloxamer 403 and poloxamer 338; the ratio of the two in the poloxamer compound is 1:2; The stabilizer is a mixture of sugarcane fiber with a median particle size of D50 = 0.261 μm and carboxymethyl anionic guar gum, or bamboo fiber with a median particle size of D50 = 0.316 μm and carboxymethyl anionic guar gum, or lotus leaf fiber with a median particle size of D50 = 0.230 μm and carboxymethyl anionic guar gum; The accelerator is a mixture of two or more of lemon balm essential oil, Chinese cinnamon essential oil, Ceylon cinnamon essential oil, castor essential oil, ginger essential oil, real lavender essential oil, eye-catching lavender essential oil, spike lavender essential oil, orange blossom essential oil, sweet orange essential oil, palmarosa essential oil, black pepper essential oil, Damascus rose essential oil, dried leaf rose essential oil, and white rose essential oil; The compound shading auxiliary material is a mixture of tea polyphenols and submicron starch, with the ratio of the two being 1:2; The submicron starch is any one of soft rice starch, polished rice starch, indica rice starch, corn starch and high-amylose wheat starch with a median particle size D50≤0.320 μm.

2. A composition according to claim 1, characterized in that: The functional sugar alcohol is maltitol, erythritol or a mixture of the two.

3. A composition according to claim 1, characterized in that: The preservative is nisin.

4. A composition according to any one of claims 1 to 3, characterized in that: The preparation method thereof comprises the following steps: (1) According to the weight ratio, 0.01-0.02 parts of octacosanol, 0.2-0.6 parts of curcumin, 1.5-3 parts of solubilizer and 1-2.5 parts of accelerator were weighed and added into a sealed dispersion reactor, and heated to 40-50° C., stirred at a speed of 300-500 rpm until completely dissolved, and set aside; (2) According to the weight ratio, weigh 2.5-4 parts of partially hydrolyzed guar gum PHGG, 0.05-0.1 parts of flavonoids, 1.5-3 parts of stabilizers, 1.5-3 parts of compound shading auxiliary materials and 300 parts of distilled water, add them into a sealed grinding emulsification reactor, stir at a speed of 300-500rpm at room temperature until completely dissolved, and then slowly add them into (1), heat to 75°C-80°C, grind and emulsify at a speed of 10000-22000rpm for 5-15min, cool to 45-50°C, add 0.8-2.3 parts of functional sugar alcohol and 0.015-0.025 parts of preservatives, and continue stirring for 30min at a speed of 300-500rpm to obtain colostrum; (3) placing the colostrum obtained in (2) into a high-pressure homogenizer, treating it once at 60° C. and a pressure of 200 bar, and then treating it 2 to 4 times at a pressure of 500 to 1000 bar to obtain a liquid composition; (4) The liquid composition obtained in (3) was spray-freeze-dried to obtain a solid composition.

5. A composition according to claim 4, characterized in that: The pH value is 5.8~6.8.

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