Application of butyrate or amino acid eutectic crystal thereof in preventing or treating metabolic diseases

Abstract

The invention discloses an application of butyrate or its amino acid eutectic crystal in prevention or treatment of metabolic diseases, and belongs to the technical field of medicines. The butyric acid or the derivative thereof and the compound of the butyric acid and the amino acid or the derivative thereof are disclosed for the first time, can greatly promote GLP-1 secretion of intestinal cells and have a weight-losing effect, so that the variety of drugs for preventing or treating metabolic diseases is enriched, and the compound can be used for preparing the drugs for preventing or treating metabolic diseases and has wide application prospects. The important clinical application value is realized.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of pharmaceutical technology, in particular to the use of butyrate or its amino acid co-crystal in the prevention or treatment of metabolic diseases. BACKGROUND

[0002] Overweight and obesity not only causes changes in body shape, but also increases the incidence of chronic diseases such as diabetes, coronary heart disease, hypertension, complications of hypertension, chronic kidney disease, and respiratory diseases, and induces the incidence of cancer.

[0003] Sodium butyrate, as one of the metabolic products of intestinal microorganisms, not only serves as an energy source for epithelial cells, but also affects various cellular functions related to colon health. Numerous studies have reported that butyrate may have potential anti-cancer and anti-inflammatory effects, affect the intestinal barrier, maintain intestinal epithelial permeability, and play a role in satiety and oxidative stress. It has the effects of regulating intestinal flora, inhibiting inflammatory factors, protecting the intestinal mucosal barrier, and maintaining intestinal immune balance.

[0004] Clinical studies have shown that sodium butyrate intervention can significantly improve ischemic stroke, accompanied by a decrease in the levels of lipopolysaccharide, serum pro-inflammatory cytokines, and improvement of the blood-brain barrier, mainly manifested as a decrease in neuronal apoptosis, and promotion of the release of anti-inflammatory factors such as IL-10, while down-regulating pro-inflammatory factors such as IL-17 and TNF-α, and up-regulating short-chain fatty acid levels.

[0005] However, there has been no in-depth study on the improvement of the therapeutic effect of structural changes of butyrate in the treatment of metabolic diseases. SUMMARY

[0006] To solve at least one of the above technical problems, the technical solutions adopted by the present application are as follows: The present application provides the use of a compound selected from at least one of the following groups in the preparation of a drug for preventing and / or treating metabolic diseases: (1) butyric acid; (2) a butyric acid derivative; (3) a complex of (1) or (2) and an amino acid; (4) a complex of (1) or (2) and an amino acid derivative; (5) a derivative of (3) or (4).

[0007] The inventors have unexpectedly found that butyric acid or its derivatives, and their complexes with amino acids or their derivatives, can stimulate GLP-1 secretion, produce good weight loss effects, and thus prevent or treat metabolic diseases.

[0008] In some embodiments of the present application, the butyric acid derivative includes butyrate, including but not limited to metal salts of butyric acid.

[0009] In some embodiments of the present application, the amino acid is selected from one of the group comprising natural amino acids or artificially synthesized amino acids including proline, valine, lysine, arginine, taurine, homo taurine.

[0010] In some embodiments of the present application, the amino acid derivative is an amino acid with a functional group carboxyl and / or imino site chemically modified.

[0011] In some specific embodiments of the present application, the butyric acid derivative is sodium butyrate and the amino acid is proline.

[0012] In some embodiments of the present application, the metabolic disease is a lipid metabolic disease, a purine metabolic disease and / or an insulin metabolic disease.

[0013] Further, the metabolic disease is selected from at least one of obesity, diabetes, an atherosclerosis-related disease, a cardiovascular disease, hyperuricemia.

[0014] Further, the atherosclerosis-related disease is selected from at least one of coronary heart disease, coronary artery disease, atherosclerotic heart disease, atherosclerotic cardiovascular disease, ischemic heart disease.

[0015] Further, the cardiovascular disease is selected from at least one of acute coronary syndrome, angina pectoris, arteriosclerosis, atherosclerosis, carotid atherosclerosis, cerebrovascular disease, cerebral infarction, congestive heart failure, congenital heart disease, coronary heart disease, coronary artery disease, coronary plaque stabilization, dyslipidemia, dyslipoproteinemia, endothelial dysfunction, familial hypercholesterolemia, familial combined hyperlipidemia, hypoalphalipoproteinemia, hypertriglyceridemia, hyperbetalipoproteinemia, hypercholesterolemia, hypertension, hyperlipidemia, intermittent claudication, ischemia, ischemia-reperfusion injury, ischemic heart disease, myocardial ischemia, metabolic syndrome, multi-infarct dementia, myocardial infarction, obesity, peripheral vascular disease, reperfusion injury, restenosis, renal atherosclerosis, rheumatic heart disease, stroke, thrombotic disorders, transient ischemic attack, and lipoprotein abnormalities associated with Alzheimer's disease, obesity, diabetes, syndrome X, impotence, multiple sclerosis, Parkinson's disease, inflammatory diseases.

[0016] In some embodiments of the present application, the drug prevents or treats the metabolic disease by controlling, regulating, improving or reducing one or more of blood sugar, blood lipids, blood pressure, inflammation, overweight.

[0017] In some embodiments of the present application, the drug prevents or treats the metabolic disease by regulating or improving one or more of gastrointestinal dysfunction, including gastric acid, stomach pain, gastrointestinal dysfunction, indigestion, constipation, and diarrhea, and controlling appetite.

[0018] In some embodiments of the present application, the drug prevents or treats the metabolic disease by stimulating GLP-1 secretion.

[0019] Glucagon-like peptide-1 (GLP-1) is a peptide hormone that is secreted by L cells in the jejunum, ileum, and colon in response to elevated blood glucose levels after carbohydrate ingestion, stimulating insulin and reducing glucagon secretion to help control blood glucose levels in the body. In addition to this, the hormone can also inhibit gastric acid secretion, slow down gastrointestinal motility, increase satiety, and reduce appetite, thereby achieving the purpose of weight loss. Therefore, GLP-1 receptor agonists can reduce the incidence of cardiovascular disease by lowering blood glucose, blood pressure, and blood lipids, improving inflammation, and reducing body weight. In addition, GLP-1 receptor agonists can also reduce the risk of non-fatal myocardial infarction, non-fatal stroke, and cardiovascular death.

[0020] In some embodiments of the present application, the complex is a co-crystal or a salt, preferably a co-crystal. According to the FDA's "Guidance for Industry: Regulatory Classification of Pharmaceutical Co-crystals", a co-crystal is a crystalline material that contains two or more different molecules in the same crystal lattice; while a salt is a crystalline compound formed by the replacement of some or all of the acidic hydrogens with metal or metalloid groups, resulting in ionic or polar bonds.

[0021] In some embodiments of the present application, the co-crystal is prepared by one of solvent evaporation crystallization, cooling crystallization, grinding crystallization, reaction crystallization, hot melt extrusion crystallization, melt crystallization, and acoustic wave crystallization.

[0022] Butyrate has a fast metabolism in vitro and is not strongly targeted to GLP-1 receptor agonists, resulting in low in vivo drug efficacy or target effectiveness. Therefore, to improve the structural efficacy of butyrate, its structure is optimized, and through the form of a co-crystal, the metabolic stability, bioavailability, and target effectiveness of butyrate can be greatly improved without changing the efficacy structure of butyrate. Further, in the present application, it is unexpectedly found that by co-crystallizing butyrate with an amino acid such as proline, GLP-1 secretion by intestinal cells can be greatly promoted, which has obvious advantages over butyrate alone. Butyrate amino acid co-crystal products can effectively control energy intake and metabolism in the body by stimulating GLP-1 secretion, producing good weight loss effects.

[0023] The second aspect of the present application provides a medicine for preventing and / or treating metabolic diseases, comprising at least one compound selected from the following group or a combination thereof with at least one pharmaceutically acceptable excipient and / or diluent: (1) butyric acid; (2) butyric acid derivative; (3) a complex of (1) or (2) with an amino acid; (4) a complex of (1) or (2) with an amino acid derivative; (5) a derivative of (3) or (4).

[0024] In some embodiments of the present application, the dosage form of the medicine is selected from one of the group comprising oral preparations, injections, aerosols, suppositories, drops and transdermal patches.

[0025] In some embodiments of the present application, the medicine is administered through the respiratory system or the digestive system; or subcutaneously; or through the nasal mucosa or submucosa; or through the eye or ear; or rectally; or vaginally.

[0026] The third aspect of the present application provides a method for predicting and / or treating metabolic diseases, comprising the step of administering to a subject a therapeutically effective amount of the medicine of any one of the second aspect of the present application.

[0027] The fourth aspect of the present application provides a preparation method of butyrate amino acid co-crystal, comprising the following steps: Equal chemical equivalent of butyrate and amino acid are added into 20-30 times volume of solvent, dissolved under heating reflux, concentrated under reduced pressure to obtain solid, 3-10 times volume of tetrahydrofuran is added, stirred at 0-5℃ for 0.5-2h, and the solid is extracted by filtration, dried to obtain butyrate amino acid co-crystal.

[0028] In some embodiments of the present application, the solvent is selected from one or more of water, methanol and ethanol.

[0029] Advantages of the present application Compared with the prior art, the present application has the following advantages: The present application discloses for the first time that butyric acid or its derivative, and its complex with amino acid or its derivative can greatly promote the GLP-1 secretion of intestinal cells, especially the butyrate amino acid co-crystal product, by stimulating GLP-1 secretion, can effectively control the energy intake and metabolism of the body, produce good weight loss effect, and further prevent or treat metabolic diseases. BRIEF DESCRIPTION OF DRAWINGS

[0030] Figure 1 Figure 1 shows the hydrogen spectrum of sodium butyrate L-proline co-crystal.

[0031] Figure 2Sodium butyrate L-proline salt co-crystal Form-2 HNMR is shown.

[0032] Figure 3 Sodium butyrate L-proline salt co-crystal Form-2 CNMR is shown.

[0033] Figure 4 Sodium butyrate L-proline salt co-crystal XRD pattern is shown.

[0034] Figure 5 L-proline XRD pattern is shown.

[0035] Figure 6 Sodium butyrate L-proline salt co-crystal DSC pattern is shown.

[0036] Figure 7 Sodium butyrate L-proline salt co-crystal promotes GLP-1 secretion in NCI-H716 cell line is shown.

[0037] Figure 8 Sodium butyrate L-proline salt co-crystal concentration gradient promotes GLP-1 secretion in NCI-H716 cell line is shown.

[0038] Figure 9 Sodium butyrate L-proline salt co-crystal concentration oral administration in mice is shown.

[0039] Figure 10 Sodium butyrate L-proline salt co-crystal concentration oral administration in mice is shown.

[0040] Figure 11 Sodium butyrate L-proline salt co-crystal concentration oral administration in mice is shown.

[0041] Figure 12 Sodium butyrate L-proline salt co-crystal concentration oral administration in mice is shown. DETAILED DESCRIPTION

[0042] Unless otherwise indicated, all parts and percentages expressed herein are based upon weight and all tests and measurements are made at the date of filing of this application. To the extent that any patent, patent application, or publication is cited in this application, the contents of all such citations are incorporated herein by reference in their entirety, and their equivalents, as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. If a definition set forth in the art is inconsistent with any definition provided in this application, the definition provided in this application shall control.

[0043] The numerical ranges used in this application are approximate values ​​and therefore may include values ​​outside the range unless otherwise stated. The numerical range includes all values ​​from the lower limit to the upper limit, increasing by one unit, provided there is an interval of at least two units between any lower and any higher value. For ranges containing values ​​less than 1 or fractions greater than 1 (e.g., 1.1, 1.5, etc.), one unit is appropriately considered as 0.0001, 0.001, 0.01, or 0.1. For ranges containing single digits less than 10 (e.g., 1 to 5), one unit is generally considered as 0.1. These are merely specific examples of what is intended to be expressed, and all possible combinations of values ​​between the listed minimum and maximum values ​​are considered to be clearly described in this application.

[0044] The terms “comprising,” “including,” “having,” and their derivatives do not exclude the presence of any other components, steps, or processes, regardless of whether such other components, steps, or processes are disclosed in this application. To eliminate any doubt, unless expressly stated otherwise, all compositions using the terms “comprising,” “including,” or “having” in this application may contain any additional additives, excipients, or compounds. Conversely, except for those necessary for operational performance, the term “substantially constitutes…” excludes any other components, steps, or processes described below with respect to that term. The term “consisting of…” does not include any components, steps, or processes not specifically described or listed. Unless expressly stated otherwise, the term “or” refers to the individual members listed or any combination thereof.

[0045] To make the technical problems solved by the present invention, the technical solutions and the beneficial effects of the present invention clearer, the present invention will be further described in detail below with reference to the embodiments.

[0046] The following examples are used to illustrate preferred embodiments of the invention. Those skilled in the art will understand that the techniques disclosed in the examples represent techniques discovered by the inventors that can be used to implement the invention, and therefore can be considered preferred embodiments for implementing the invention. However, those skilled in the art should understand from this specification that many modifications can be made to the specific embodiments disclosed herein, still yielding the same or similar results, without departing from the spirit or scope of the invention.

[0047] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains, and all materials publicly cited herein and referenced by them are incorporated herein by reference.

[0048] Those skilled in the art will recognize, or can learn through routine experimentation, many equivalents of the specific embodiments of the invention described herein. These equivalents will be included in the claims.

[0049] Unless otherwise specified, the experimental methods used in the following examples are conventional methods. Unless otherwise specified, the instruments and equipment used in the following examples are all conventional laboratory instruments and equipment; unless otherwise specified, the experimental materials used in the following examples were all purchased from conventional biochemical reagent stores.

[0050] Example 1: Synthesis of Sodium Butyrate L-Proline Salt by Single Solvent Crystallization Under normal pressure and with the temperature controlled at around 60°C, 90g of 99% n-butyric acid (1.02mol) was added dropwise to 41.6g of NaOH (1.04mol) aqueous solution (the molar ratio of n-butyric acid to NaOH was 1:1), wherein the mass percentage of NaOH in the NaOH aqueous solution was 35%. After the addition was complete, the system was kept at 60°C for 3 hours. After the reaction was completed, the solid obtained by concentrating the reaction solution under reduced pressure was dried at 55°C for 15 hours to obtain 110g of sodium n-butyrate.

[0051] An equimolar amount of sodium butyrate and L-proline was added to 25 times its volume of anhydrous ethanol and heated under reflux until just dissolved. The mixture was stirred for approximately 3 hours, allowed to cool naturally to crystallize, and no crystals precipitated. The solution was concentrated under reduced pressure to obtain a solid, which was then slurried with 5 times its volume of tetrahydrofuran at 0–5°C for 1 hour. The solid was filtered and analyzed by XRD, 1H NMR, and DSC. After vacuum drying to constant weight, 90 g of a white solid was obtained, with a yield of 55.90%. XRD, 1H NMR, 1C NMR, and DSC analyses were performed.

[0052] Structural characterization results show that: (1) Proton spectrum The proton spectrum of the product is as follows Figure 1 and Figure 2 As shown.

[0053] Graphical integral: 1 H-NMR (400 MHz, D2O) δ 3.98-3.92 (m, 1H), 3.28-3.22 (m, 1H), 3.19-3.13 (m, 1H), 2.23-2.12 (m, 1H), 2.00-1.94 (m, 2H), 1.93-1.78 (m, 3H),1.43-1.34 (m, 2H), 0.73 (t, J=7.5Hz, 3H).

[0054] Spectral analysis: δ2.00-1.94 (m, 2H), 1.43-1.34 (m, 2H), 0.73 (t, J=7.5Hz, 3H) can be attributed to hydrogen atoms on butyric acid; δ3.98-3.92 (m, 1H), 3.28-3.22 (m, 1H), 3.19-3.13 (m, 1H), 2.23-2.12 (m, 1H), 1.93-1.78 (m, 3H) are attributed to hydrogen atoms on L-proline. The 1H NMR spectrum shows a butyric acid:L-proline ratio of 1:1.

[0055] (2) Carbon spectrum The carbon spectrum of the product is as follows Figure 3 As shown.

[0056] Graphical integral: 13 C-NMR (10 MHz, D2O) δ 184.2, 174.7, 61.2, 46.1, 39.6, 29.0, 23.8, 19.4, 13.3.

[0057] Spectral analysis: δ 184.2, 39.6, 19.4, and 13.3 are assigned to carbons on butyric acid; δ 174.7, 61.2, 46.1, 29.0, and 23.8 are assigned to carbons on L-proline. The spectrum indicates that the sample contains both butyric acid and L-proline.

[0058] (3) XRD pattern The XRD pattern of the product is as follows Figure 4 As shown.

[0059] The results showed that there were no characteristic peaks of L-proline in the sample. The characteristic peaks of the sample at 2θ were: 6.134°, 15.091°, 17.995°, 19.514°, 24.786°, 24.882°, 31.304°, and 37.792°.

[0060] The characteristic peaks of L-proline 2θ are: 15.110°, 18.001°, 19.518°, 24.770°, 30.528°, and 32.120°. Figure 5 As shown.

[0061] (4) DSC spectrum The DSC spectrum of the product is as follows Figure 6 As shown.

[0062] Depend on Figure 6 Analysis shows that the sample has a melting point of 131.61℃, while L-proline has a melting point of 228℃. Therefore, it can be determined that sodium butyrate L-proline salt is a eutectic salt compound, not a physical mixture.

[0063] pass 1 H-NMR, 13 Analysis of the sample by C-NMR, XRD and DSC showed that the sample was a cocrystal of sodium butyrate and L-proline (1:1).

[0064] Example 2: Sodium butyrate L-proline cocrystal salt promotes GLP-1 secretion in NCI-H716 cell line (1) Materials: NCI-H716 cells (Pronosai, #CL-0405), NCI-H716 cell culture medium (Pronosai, #CM-0405), PSCeasy® human pluripotent stem cell seeding solution (Saibe Biotech, #CA3003100), benzyl sulfonyl fluoride (Solarbio, #R0010), L-proline (Feiyu Biotech, #FY21B0316), sodium butyrate (Aladdin, #J2215430), lithium chloride (Maclean, #C1432198), fetal bovine serum (BI, #04-001-1ACS), KREBS-RINGER buffer (Solarbio, #G0430), human GLP-1 ELISA kit (Abcam, #ab277395).

[0065] (2) Method: GLP-1 secretion: 1×10⁻⁶ two days before the experiment. 6 Cells were seeded in 12-well plates pre-coated with matrix gel and incubated overnight, then the medium was replaced with fresh medium. On the day of the experiment, the medium was replaced with KRB containing 0.2% (w / v) BSA, and the cells were incubated for 2 hours with or without the test drug. Then, 50 μg / mL of benzyl sulfonyl fluoride (PMSF) was added, the supernatant was collected, and the cells were frozen at -80°C for later analysis. GLP-1 levels were measured according to the Abcam, ab277395 human GLP-1 ELISA kit method.

[0066] Drug treatment grouping: BuNaPro: Sodium butyrate L-proline cocrystal salt NaB: Sodium butyrate L-Proline: L-proline 1x10 6 A number of NCI-H716 cells were seeded in 12-well plates and treated with different concentrations of drugs at 10 mM for 2 h. The secreted GLP-1 content in the supernatant was detected by ELISA.

[0067] The results are as follows Figure 7 As shown, BunaPro has a significant stimulatory effect on GLP-1 secretion, and is significantly stronger than sodium butyrate (…). P=0.05) or L-proline ( P <0.001).

[0068] The results are as follows Figure 8 As shown, BuNaPro can significantly promote GLP-1 secretion, and this promoting effect is concentration-dependent. P <0.001).

[0069] Example 3: Oral administration of sodium butyrate L-proline cocrystal salt to an obese mouse model (1) Materials: Four-month-old obese mice (DIO) fed a 60% high-fat diet for 2 months, four-month-old C57BL / 6 mice, sodium butyrate (Aladdin, #J2215430, BN), sodium butyrate L-proline cocrystal salt (BN) P ).

[0070] (2) Method The experiment was divided into C57BL / 6 mouse group (Normol group), obese mouse group treated with 1020 mg / kg sodium butyrate-L-proline (BNP+HFD group), obese mouse group treated with 500 mg / kg sodium butyrate (BN+HFD group), and obese mouse group treated with ddH2O by gavage according to the sodium butyrate group administration volume (HFD group).

[0071] Mice were given the drug by gavage after 5 days of acclimatization, once a day, and the weight of the mice was recorded daily for a total of 23 days. On the 24th day, the mice were anesthetized and blood was collected from the orbital vein to obtain mouse serum. Subsequently, the liver, epididymal adipose tissue, and groin adipose tissue of the mice were taken, and their weight was measured. They were then placed in tissue fixative for tissue section staining.

[0072] The results are as follows Figure 9 , Figure 10 , Figure 11 and Figure 12 As shown, long-term recording of mouse weight revealed that, compared with the Normal group, the HFD mice had a significantly increased body weight. P <0.05), and morphologically, the HFD group mice had increased volume. Compared with the HFD group, the BN group mice had significantly decreased body weight ( P <0.05; compared with the BN group, the body weight of mice in the BNP group was also significantly reduced ( P <0.05. Further data analysis revealed that the weight gain in the HFD group was significantly greater than that in the Normal group ( P <0.05), followed by the BN group and BNP group. This is basically consistent with the detection of epididymal adipose tissue and inguinal adipose tissue in mice.

[0073] The results are as follows Figure 9As shown, compared with the Normal group mice, the HFD mice had a significantly increased body weight ( P <0.001), BNP administration significantly reduced the body weight of mice on a high-fat diet ( P <0.001), and significantly stronger than mice treated with BN ( P <0.001).

[0074] result Figure 10 As shown, compared with the Normal group mice, the HFD group mice showed a significantly greater increase in body weight ( P <0.01%, BNP administration significantly reduced the increase in body weight in the HFD group mice ( P <0.01%, and significantly stronger than mice treated with sodium butyrate ( P <0.05).

[0075] The results are as follows Figure 11 As shown, compared with the Normal group mice, the epididymal adipose tissue volume of HFD mice was significantly increased ( P <0.001, BNP administration significantly reduced the accumulation of epididymal adipose tissue in HFD group mice ( P <0.05%, and significantly stronger than mice treated with sodium butyrate ( P <0.05).

[0076] The results are as follows Figure 12 As shown, compared with the Normal group mice, the volume of inguinal subcutaneous adipose tissue in HFD mice was significantly increased ( P <0.001), BNP administration significantly reduced the increase in body weight in the HFD group mice ( P <0.01), and significantly stronger than mice treated with sodium butyrate ( P <0.01).

[0077] All documents mentioned in this invention are incorporated herein by reference as if each document were individually incorporated by reference. Furthermore, it should be understood that after reading the foregoing teachings of this invention, those skilled in the art can make various alterations or modifications to this invention, and these equivalent forms also fall within the scope defined by the appended claims.

Claims

1. The use of at least one compound selected from the group consisting of: (1) Butyric acid; (2) Butyric acid derivatives; (3) Complexes of (1) or (2) with amino acids; (4) Complexes of (1) or (2) with amino acid derivatives; (5) (3) or (4) derivatives.

2. The application according to claim 1, characterized in that, The butyric acid derivatives include butyrate.

3. The application according to claim 1 or 2, characterized in that, The amino acid is selected from one of the following groups: natural amino acids or artificially synthesized amino acids, including proline, valine, lysine, arginine, taurine, and high-taurine.

4. The application according to any one of claims 1-3, characterized in that, The amino acid derivative is an amino acid whose functional group carboxyl group and / or imine site have been chemically modified.

5. The application according to any one of claims 1 to 4, characterized in that, The butyric acid derivative is sodium butyrate, and the amino acid is proline.

6. The application according to any one of claims 1 to 5, characterized in that, The metabolic diseases mentioned are lipid metabolism diseases, purine metabolism diseases and / or insulin metabolism diseases.

7. The application according to claim 6, characterized in that, The metabolic disease is selected from at least one of obesity, diabetes, atherosclerosis-related diseases, cardiovascular diseases, and hyperuricemia.

8. The application according to claim 7, characterized in that, The atherosclerosis-related diseases mentioned are selected from at least one of coronary heart disease, coronary artery disease, atherosclerotic heart disease, atherosclerotic cardiovascular disease, and ischemic heart disease.

9. The application according to claim 7, characterized in that, The cardiovascular diseases mentioned are selected from acute coronary syndrome, angina pectoris, arteriosclerosis, atherosclerosis, carotid atherosclerosis, cerebrovascular diseases, cerebral infarction, congestive heart failure, congenital heart disease, coronary heart disease, coronary artery disease, stable coronary plaques, dyslipidemia, dyslipoproteinemia, endothelial dysfunction, familial hypercholesterolemia, familial complex hyperlipidemia, hypoalpha-lipoproteinemia, hypertriglyceridemia, hyperbeta-lipoproteinemia, hypercholesterolemia, hypertension, and hyperlipidemia. Intermittent claudication, ischemia, ischemia-reperfusion injury, ischemic heart disease, myocardial ischemia, metabolic syndrome, multiple cerebral infarction dementia, myocardial infarction, obesity, peripheral vascular disease, reperfusion injury, restenosis, renal artery atherosclerosis, rheumatic heart disease, stroke, thrombotic disorders, transient ischemic attacks, and at least one of the following lipoprotein abnormalities associated with Alzheimer's disease, obesity, diabetes, syndrome X, impotence, multiple sclerosis, Parkinson's disease, and inflammatory diseases.

10. The application according to any one of claims 1-9, characterized in that, The drug prevents or treats the metabolic diseases by controlling, regulating, improving, or reducing one or more of blood sugar, blood lipids, blood pressure, inflammation, and overweight.

11. The application according to any one of claims 1-10, characterized in that, The drug prevents or treats the metabolic disease by regulating or improving one or more of the following: gastrointestinal dysfunction, including stomach acid, stomach pain, gastrointestinal disorders, indigestion, constipation, and diarrhea.

12. The application according to any one of claims 1-11, characterized in that, The drug prevents or treats the metabolic disease by stimulating the secretion of GLP-1.

13. The application according to any one of claims 1-12, characterized in that, The complex is a eutectic.

14. The application according to claim 13, characterized in that, The eutectic is prepared using one of the following methods: solvent evaporation crystallization, cooling crystallization, grinding crystallization, reaction crystallization, hot melt extrusion crystallization, melt crystallization, and acoustic crystallization.

15. A medicament for the prevention and / or treatment of metabolic diseases, characterized in that, Includes compounds selected from at least one of the following groups, or compounds thereof with at least one pharmaceutically acceptable excipient and / or diluent: (1) Butyric acid; (2) Butyric acid derivatives; (3) Complexes of (1) or (2) with amino acids; (4) Complexes of (1) or (2) with amino acid derivatives; (5) (3) or (4) derivatives.

16. The medicament according to claim 15, characterized in that, The dosage form of the drug is selected from one of the group consisting of oral preparations, injections, aerosols, suppositories, drops, and transdermal patches.

17. The medicament according to claim 15, characterized in that, The drug is administered via the respiratory or digestive system; or subcutaneously; or via the nasal mucosa or submucosa; or via the eye or ear; or via the rectum; or via the vagina.

18. A method for predicting and / or treating metabolic diseases, characterized in that, The step includes administering a therapeutically effective amount of the drug according to any one of claims 15-17 to a subject.

19. A method for preparing a butyrate amino acid eutectic, characterized in that, Includes the following steps: Equivalent amounts of butyrate and amino acids are added to 20-30 times their volume of solvent, dissolved under reflux, concentrated under reduced pressure to obtain a solid, 3-10 times their volume of tetrahydrofuran are added, stirred at 0-5°C for 0.5-2 hours, filtered to obtain a solid, and dried to obtain butyrate-amino acid eutectic.

20. The preparation method according to claim 19, characterized in that, The solvent is selected from one or more of water, methanol, and ethanol.

Images