Shuanghuang nano-particles as well as preparation and application thereof

Abstract

The invention provides a Shuanghuang nano-particle as well as preparation and application of the Shuanghuang nano-particle. The main medicinal components of the Shuanghuang nano-particles comprise the rhein compounds and the curcumin compounds, and the solubility of the two slightly soluble or insoluble compounds in water can be remarkably improved in a nanocrystallization mode, so that the bioavailability of the Shuanghuang nano-particles is enhanced. The nanocrystallization combined application of the two compounds helps the compounds to exert greater medicinal values clinically, such as antibiosis, anti-inflammation, antioxidation and tissue damage protection. In addition, the preparation method of the Shuanghuang nanoparticles is simple, convenient, rapid in preparation and convenient for industrial production.

Description

[0001] This application is a divisional application of the invention patent application with application number: 202111251352.0, invention name: A kind of double yellow nanoparticles and their preparation and application, and application date: October 26, 2021. Technical Field

[0002] The invention belongs to the field of medical technology, and specifically relates to a double yellow nanoparticle and its preparation and application. Background Art

[0003] Ruyi Jinhuang Powder originated from the second volume of "Surgery Authentic" written by Chen Shigong in the Ming Dynasty. It is a traditional Chinese medicine compound preparation. Its drug composition includes Radix Trichosanthis, Cortex Phellodendri, Rhubarb, Curcuma Longa, Angelica Dahuricae, Magnolia Bark, Tangerine Peel, Atractylodes Macrocephalae, Arisaema Cone and Licorice. Among them, Radix Trichosanthis, Cortex Phellodendri and Rhubarb are all monarch drugs, which have the effects of clearing away heat and detoxifying, cooling blood and purging fire, and reducing swelling and pus. Curcuma Longa, which has the effect of promoting blood circulation and reducing swelling, and Angelica Dahuricae, which has the effect of relieving symptoms and relieving pain, are both minister drugs. When used together with the monarch drug, they can eliminate heat and toxicity from inside and outside. The traditional method of making Ruyi Jinhuang Powder is to crush the above ten drugs into fine powder, and then sieve and mix them. When used, it can be prepared with tea, vinegar, scallion wine, vegetable oil or honey for external application, and exert its medicinal effect through transdermal absorption. Ruyi Jinhuang Powder has the effects of clearing heat and detoxifying, removing dampness and dispersing blood stasis, and reducing swelling and relieving pain.

[0004] Rhubarb, as one of the main ingredients of Ruyi Jinhuang Powder, has anthraquinone compounds of the rhein class as its main active ingredients. Like many natural small molecule compounds, rhein also exhibits multi-target characteristics in pharmacological actions. Modern medical research shows that rhein can reverse non-alcoholic fatty liver disease to a certain extent and prevent liver fibrosis, showing liver protection effects. Rhein is also used to delay the development of type II diabetes and osteoarthritis. In addition, rhein can also be used to prevent and treat different types of cancers, such as breast cancer, cervical cancer, colon cancer, and liver cancer. The inherent multiple pharmacological activities of rhein lay the foundation for its use in the prevention and treatment of various diseases.

[0005] Turmeric, as one of the main ingredients of Ruyi Jinhuang Powder, includes small molecule compounds of curcuminoids. Curcuminoids have a natural polyphenol structure and also show multi-target characteristics in pharmacological activity. A large number of in vivo and in vitro studies have confirmed that curcuminoids have different pharmacological effects such as gastrointestinal protection, cardiac tissue protection, anti-tumor, anti-inflammatory, antibacterial, and antioxidant.

[0006] However, rhein compounds and curcumin compounds are very slightly soluble or poorly soluble in water, with a solubility of no more than 1 mg / mL. The extremely low solubility of the two compounds in aqueous solutions severely limits the performance of their numerous pharmacological effects and their clinical transformation and application, and has also become one of the stumbling blocks to the modernization of traditional Chinese medicine.

[0007] Compared with traditional drug systems, modern drugs based on nanotechnology have more obvious advantages in diagnosis and treatment. For example, the natural passive targeting ability of nanomedicines when used in the diagnosis and treatment of solid tumors can make the active drug ingredients more concentrated at the site of action, while reducing their distribution in normal tissues and organs. Therefore, the nano-sizing of active drug ingredients is an ideal measure to enhance efficacy and reduce toxicity. The simultaneous nano-sizing of multiple active drug ingredients can not only enable the synergistic administration of multiple active ingredients, but also be used for clinical anti-multidrug resistance. In addition, the nano-sizing of active drug ingredients changes the cellular uptake pathway of active drug ingredients. Active drugs are more often taken up by cells in the form of active transport. Compared with traditional drug systems, nano-sized drugs can significantly improve the bioavailability and efficacy of active drug ingredients. Summary of the invention

[0008] In order to overcome the shortcomings of the prior art and give full play to the advantages of nanomedicine in the field of medicine, the present invention provides a double yellow nanoparticle and its preparation and application.

[0009] The present invention provides the following technical solutions:

[0010] A double yellow nanoparticle, comprising at least one compound having a chemical structure shown in general formula I and at least one compound having a chemical structure shown in general formula II, wherein the compounds directly interact with each other to form crystalline nanoparticles that can be uniformly dispersed in an aqueous solution:

[0011]

[0012] Wherein, R is any atom, ion or group.

[0013] A further technical solution is that the compound having the chemical structure shown in general formula I is selected from at least one of the rhein compounds.

[0014] A further technical solution is that the compound having the chemical structure shown in general formula I is selected from at least one of the following numbered compounds:

[0015]

[0016] A further technical solution is that the compound having the chemical structure shown in general formula II is selected from at least one of curcumin compounds.

[0017] A further technical solution is that the compound having the chemical structure shown in general formula II is selected from at least one of the following numbered compounds:

[0018]

[0019] The numbers of the above numbered compounds correspond to the numbers of the compounds in Table 1.

[0020] A further technical solution is that the direct interaction between the compounds includes ππ stacking, hydrophobic interaction, electrostatic interaction and / or hydrogen bonding.

[0021] A further technical solution is that the double yellow nanoparticles are crystalline particles with a diameter between 30nm and 1000nm, and a Zeta potential of no more than 20mV under the preparation conditions.

[0022] A further technical solution is that the amount ratio of the compound having the chemical structure shown in general formula I to the compound having the chemical structure shown in general formula II is 20:1 to 1:20.

[0023] Preferably, the molar ratio of the compound having the chemical structure shown in general formula I to the compound having the chemical structure shown in general formula II is 10:1 to 1:10.

[0024] Preferably, the molar ratio of the compound having the chemical structure shown in general formula I to the compound having the chemical structure shown in general formula II is 2:1 to 1:2.

[0025] The present invention also provides a method for preparing double yellow nanoparticles, which comprises the following steps:

[0026] (1) mixing the compound with an organic solvent to obtain an organic mixed solution;

[0027] (2) mixing the obtained organic mixed solution with the aqueous phase solution to obtain a double yellow nanoparticle dispersion containing the compound;

[0028] (3) removing the organic solvent in the double yellow nanoparticle dispersion to obtain the double yellow nanoparticle aqueous dispersion containing the compound; optionally, removing the aqueous phase in the double yellow nanoparticle aqueous dispersion to obtain the double yellow nanoparticles containing the compound; further optionally, making the double yellow nanoparticles into different pharmaceutically acceptable preparation forms, including injections, capsules, tablets, patches or sprays.

[0029] The ratio of the amount of the compound having the chemical structure shown in the general formula I to the amount of the compound having the chemical structure shown in the general formula II is 20:1 to 1:20, preferably 10:1 to 1:10, and more preferably 1:2 to 2:1. In addition, the ratio of the amount of the compound of the double yellow nanoparticles obtained by the preparation method of the present application is the same as the above ratio.

[0030] The organic solvent is selected from pharmaceutically acceptable organic solvents, including methylpyrrolidone, pyridine, tetrahydrofuran, acetone, acetonitrile, dimethylformamide, dimethyl sulfoxide, dimethylimidazolidinone, hexamethylphosphoramide, formic acid, acetic acid, propionic acid, butyric acid, methanol, ethanol, ethylene glycol, propanol, propylene glycol, glycerol, butylene glycol, pentanediol, triethylene glycol, furfuryl alcohol, methyldiethanolamine, methyl isonitrile, ethylamine, diethanolamine, diethylenetriamine, acetaldehyde, ethylene glycol dimethyl ether, ethylene glycol monobutyl ether, dioxane or any combination thereof.

[0031] The aqueous phase solution is selected from an aqueous phase solution with a pH value of 0 to 14 at room temperature and pressure, including deionized water, a buffer solution with different pH buffering capacity, or an aqueous phase solution without buffering capacity configured by different acids and bases. Specifically, the buffer solution with different pH buffering capacity is selected from sodium acetate buffer, dimethyl arsenate buffer, citrate buffer, phosphate buffer, barbiturate buffer, glycine sodium hydroxide buffer or phosphate-citrate buffer. The aqueous phase solution without buffering capacity is selected from hydrochloric acid aqueous solution, sulfuric acid aqueous solution or sodium hydroxide aqueous solution. Among them, the pH value of the aqueous phase solution is preferably 2 to 14.

[0032] The double yellow nanoparticles formed by direct interaction of the compound having the chemical structure shown in the general formula I and the compound having the chemical structure shown in the general formula II in an aqueous solution with a pH value of 0 to 14 at normal temperature and pressure are all crystals. The diameter thereof is between 30nm and 1000nm, and the Zeta potential under the preparation conditions is not greater than 20mV.

[0033] The present invention also provides a use of double yellow nanoparticles in preparing antibacterial, anti-inflammatory, antioxidant and tissue damage protection drugs.

[0034] Compared with the prior art, the present invention has the following beneficial effects:

[0035] (1) To give the compound nano properties. The compounds with the chemical structures shown in general formula I and general formula II form nano-scale particles through direct interaction between the compounds, so that the compounds have nano properties in medical applications. For example, the natural targeting of nanoparticles in the diagnosis and treatment of solid tumors can make the compounds play a role in enhancing synergy and reducing toxicity in the process of medicine; (2) To improve the solubility of the compound in the aqueous solution. The compounds with the chemical structures shown in general formula I and general formula II form double yellow nanoparticles that can be uniformly dispersed in the aqueous solution through the present invention, thereby significantly improving the solubility of such slightly soluble or insoluble compounds in the aqueous solution; (3) Combined action of multiple compounds. Through the present invention, the compounds with the chemical structures shown in general formula I and general formula II can be combined to construct a variety of double yellow nanoparticles with combined action effects, so as to play a role in enhancing synergy, reducing toxicity and resisting drug resistance in the medical field; (4) Crystal morphology. The double yellow nanoparticles constructed by the present invention are all in the form of crystals. Therefore, the advantage of higher stability of the compound compared with its amorphous form is retained; (5) High compound ratio. Through the present invention, the compounds with the chemical structures shown in Formula I and Formula II directly interact with each other to form nanoparticles that can be uniformly dispersed in water, and the proportion of the compounds is as high as 100%; (6) More clinical applications are achieved. The double yellow nanoparticles constructed by the present invention achieve the development of more dosage forms and wider pharmacological effects of the compounds with the chemical structures shown in Formula I and Formula II, and then develop more clinical applications. (7) The double yellow nanoparticles constructed by the present invention are taken from ancient Chinese medicine prescriptions, and modern technology is used to dissolve in water and nano-size them, which promotes the modernization of ancient Chinese medicine prescriptions. The process is simple, the preparation is rapid, it is convenient for industrial production, and it is suitable for clinical transformation. BRIEF DESCRIPTION OF THE DRAWINGS

[0036] In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings required for use in the embodiments or the description of the prior art will be briefly introduced below. Obviously, the drawings described below are only one embodiment of the present invention, and for ordinary technicians in this field, other embodiments can also be obtained based on these drawings.

[0037] Figure 1 The dynamic light scattering and particle morphology of the double yellow nanoparticles under scanning electron microscopy shown in Example 1;

[0038] Figure 2 X-ray powder diffraction patterns of the compound shown in number 1 (a), the compound shown in number 3 (b), the physical mixture of the compounds shown in numbers 1 and 3 (c), the double yellow nanoparticles containing the compounds shown in numbers 1 and 3 (d), and mannitol (e);

[0039] Figure 3 The myocardial cross-sectional images and quantitative analysis of infarct area in different drug-treated or non-drug-treated groups in the mouse myocardial ischemia-reperfusion model;

[0040] Figure 4 To analyze the concentration of tumor necrosis factor, glutathione peroxidase activity, malondialdehyde concentration, superoxide dismutase activity and interleukin-6 concentration in the serum of mice in different drug-treated or non-drug-treated groups in the myocardial ischemia-reperfusion model in mice;

[0041] Figure 5 These are cross-sectional staining images of the kidneys of mice in different drug-treated or non-drug-treated groups in the mouse myocardial ischemia-reperfusion model, as well as analysis of serum creatinine and urea nitrogen levels. DETAILED DESCRIPTION

[0042] The present invention provides the following specific implementation cases, which are intended to illustrate the present invention, but the present invention is not limited to the following implementation cases.

[0043] Implementation Case 1 The compound shown in No. 1 (5.4 mg) and the compound shown in No. 3 (7.0 mg) (the ratio of the amount of substance is about 1:1) are mixed with 100 μL of dimethyl sulfoxide, and the resulting mixture is added dropwise to 10 mL of phosphate buffer (pH 7.4) under magnetic stirring, and stirred for 10 minutes to obtain a double yellow nanoparticle dispersion containing the compounds shown in Nos. 1 and 3; the dimethyl sulfoxide in the double yellow nanoparticle dispersion is removed by dialysis to obtain a double yellow nanoparticle aqueous dispersion containing the compounds shown in Nos. 1 and 3; about 1.0% by weight of mannitol is added and freeze-dried to obtain double yellow nanoparticles containing the compounds shown in Nos. 1 and 3, and the particle size, potential and particle size distribution are shown in Table 2 for Case 1 and Figure 1 As shown, the particle size of the double yellow nanoparticles is about 120nm, the zeta potential under the preparation conditions is about -53mV, the particles are evenly distributed, the surface is smooth, and they are spherical. In addition, X-ray powder diffraction shows that the double yellow nanoparticles are in a crystalline form. Figure 2 Figure a is the crystal diffraction pattern of the compound shown in No. 1. Figure 2 Figure b is the crystal diffraction pattern of the compound shown in No. 3. Figure 2 Figure c is a crystal diffraction pattern of a physical mixture of the compounds shown in numbers 1 and 3, which shows a cumulative superposition of the crystal diffraction peak of the compound shown in number 1 and the crystal diffraction peak of the compound shown in number 3. Figure 2 Figure d is the crystal diffraction pattern of the double yellow nanoparticles containing the compounds shown in numbers 1 and 3. The new diffraction peaks at 11.26°, 23.74° and 36.94° indicate that the double yellow nanoparticles containing the compounds shown in numbers 1 and 3 exist in a new crystal form different from their components.

[0044] Implementation Case 2 The compound shown in No. 1 (7.5 mg) and the compound shown in No. 4 (6.0 mg) (the ratio of the amount of substance is about 3:2) are mixed with 150 μL of dimethylformamide, and the resulting mixture is quickly injected into 10 mL of phosphate buffer (pH 7.4) through a syringe, and stirred for 5 minutes to obtain a double yellow nanoparticle dispersion containing the compounds shown in No. 1 and 4; the dimethylformamide in the double yellow nanoparticle dispersion is removed by dialysis to obtain a double yellow nanoparticle aqueous dispersion containing the compounds shown in No. 1 and 4; about 0.8% by weight of mannitol is added and freeze-dried to obtain double yellow nanoparticles containing the compounds shown in No. 1 and 4, and the particle size, potential and particle size distribution are shown in Table 2 Case 2.

[0045] Implementation Case 3: The compound shown in No. 1 (3.7 mg) and the compound shown in No. 5 (6.0 mg) (the ratio of the amount of substance is about 2:3) are mixed with 80 μL of dimethyl sulfoxide, and then 10 mL of phosphate-citrate buffer (pH 6.4) is added dropwise to the obtained organic mixture, and stirring is continued for 12 minutes to obtain a double yellow nanoparticle dispersion containing the compounds shown in No. 1 and 5; the dimethyl sulfoxide in the double yellow nanoparticle dispersion is removed by dialysis to obtain a double yellow nanoparticle aqueous dispersion containing the compounds shown in No. 1 and 5; about 1.0% by weight of mannitol is added and freeze-dried to obtain double yellow nanoparticles containing the compounds shown in No. 1 and 5, and the particle size, potential and particle size distribution are shown in Table 2 Case 3.

[0046] Implementation Case 4: The compound shown in No. 2 (7.0 mg) and the compound shown in No. 3 (7.0 mg) (the ratio of the amount of substance is about 1:1) are mixed with 100 μL of dimethyl sulfoxide, and then 12 mL of phosphate buffer (pH 7.4) is quickly injected into the resulting organic mixture through a syringe, and stirring is continued for 8 minutes to obtain a double yellow nanoparticle dispersion containing the compounds shown in No. 2 and 3; the dimethyl sulfoxide in the double yellow nanoparticle dispersion is removed by dialysis to obtain a double yellow nanoparticle aqueous dispersion containing the compounds shown in No. 2 and 3; about 2.5% by weight of mannitol is added and freeze-dried to obtain double yellow nanoparticles containing the compounds shown in No. 2 and 3, and the particle size, potential and particle size distribution are shown in Table 2 Case 4.

[0047] Implementation Case 5: The compound shown in No. 2 (4.4 mg) and the compound shown in No. 4 (8.0 mg) (the ratio of the amount of substance is about 1:2) are mixed with 80 μL of dimethyl sulfoxide, and the resulting organic mixture is quickly injected into 14 mL of deionized water (pH 7.0) through a syringe, and stirred for 8 minutes to obtain a double yellow nanoparticle dispersion containing the compounds shown in No. 2 and 4; the dimethyl sulfoxide in the double yellow nanoparticle dispersion is removed by dialysis to obtain a double yellow nanoparticle aqueous dispersion containing the compounds shown in No. 2 and 4; about 2.0% by weight of mannitol is added and freeze-dried to obtain double yellow nanoparticles containing the compounds shown in No. 2 and 4, and the particle size, potential and particle size distribution are shown in Table 2, Case 5.

[0048] Implementation Case 6: The compound shown in No. 2 (6.4 mg) and the compound shown in No. 5 (8.0 mg) (the ratio of the amount of substance is about 2:3) are mixed with 80 μL of dimethyl sulfoxide, and the resulting organic mixture is quickly injected into 12 mL of glycine sodium hydroxide buffer (pH 8.6) through a syringe, and stirring is continued for 6 minutes to obtain a double yellow nanoparticle dispersion containing the compounds shown in No. 2 and 5; the dimethyl sulfoxide in the double yellow nanoparticle dispersion is removed by dialysis to obtain a double yellow nanoparticle aqueous dispersion containing the compounds shown in No. 2 and 5; about 1.5% by weight of mannitol is added and freeze-dried to obtain double yellow nanoparticles containing the compounds shown in No. 2 and 5, and the particle size, potential and particle size distribution are shown in Table 2 Case 6.

[0049] Implementation Case 7: The compound shown in No. 1 (9.0 mg), the compound shown in No. 3 (3.7 mg), the compound shown in No. 4 (3.4 mg), and the compound shown in No. 5 (3.1 mg) (the ratio of the amount of substance is about 3:1:1:1) are mixed with 200 μL of dimethylformamide, and the resulting organic mixture is quickly injected into 30 mL of phosphate buffer (pH 7.4) through a syringe, and stirred for 5 minutes to obtain a double yellow nanoparticle dispersion containing the compounds shown in No. 1, 3, 4 and 5; the dimethylformamide in the double yellow nanoparticle dispersion is removed by dialysis to obtain a double yellow nanoparticle aqueous dispersion containing the compounds shown in No. 1, 3, 4 and 5; about 1.0% by weight of mannitol is added and freeze-dried to obtain double yellow nanoparticles containing the compounds shown in No. 1, 3, 4 and 5, and the particle size, potential and particle size distribution are shown in Table 2 Case 7.

[0050] Implementation Case 8: The compound shown in No. 2 (7.4 mg), the compound shown in No. 3 (3.7 mg), and the compound shown in No. 4 (3.4 mg) (the ratio of the amount of substance is about 2:1:1) are mixed with 150 μL of dimethyl sulfoxide, and the resulting organic mixture is quickly injected into 20 mL of phosphate buffer (pH 7.4) through a syringe, and stirred for 10 minutes to obtain a double yellow nanoparticle dispersion containing the compounds shown in No. 2, 3, and 4; the dimethyl sulfoxide in the double yellow nanoparticle dispersion is removed by dialysis to obtain a double yellow nanoparticle aqueous dispersion containing the compounds shown in No. 2, 3, and 4; about 1.0% by weight of mannitol is added and freeze-dried to obtain double yellow nanoparticles containing the compounds shown in No. 2, 3, and 4, and the particle size, potential and particle size distribution are shown in Table 2 Case 8.

[0051] Implementation Case 9: The compound shown in No. 1 (2.8 mg), the compound shown in No. 2 (3.7 mg), and the compound shown in No. 3 (11.1 mg) (the ratio of the amount of substance is about 1:1:3) are mixed with 300 μL of dimethyl sulfoxide, and the resulting organic mixture is injected into 30 mL of phosphate buffer (pH 7.4) through a syringe, and stirred for 8 minutes to obtain a double yellow nanoparticle dispersion containing the compounds shown in No. 1, 2, and 3; the dimethyl sulfoxide in the double yellow nanoparticle dispersion is removed by dialysis to obtain a double yellow nanoparticle aqueous dispersion containing the compounds shown in No. 1, 2, and 3; about 1.0% by weight of mannitol is added and freeze-dried to obtain double yellow nanoparticles containing the compounds shown in No. 1, 2, and 3, and the particle size, potential and particle size distribution are shown in Table 2 Case 9.

[0052] Animal model C57BL / 6 male mice (68 weeks old, 1822g) were randomly divided into 4 groups, 8 mice in each group. Different groups were given or not given myocardial ischemia reperfusion surgery, and then different groups of mice were given normal saline, physical mixture of compounds or double yellow nanoparticles by tail vein injection. One hour later, the left anterior descending branch of the mouse coronary artery was knotted and blocked to cause ischemia, and the ischemia lasted for half an hour. Then the blood supply was restored by reperfusion, and the blood supply continued for 6 hours. After the reperfusion was completed, blood samples were taken from the abdominal aorta, heart and kidneys for further experiments.

[0053] Application Case 1: The protective effect of double yellow nanoparticles on myocardial ischemia-reperfusion injury in mice. Some tissues and organs restore blood supply under ischemic conditions. After a period of time, their functional and structural damage is not repaired. On the contrary, the damage is further aggravated, and even irreversible damage is caused. This phenomenon is called ischemia-reperfusion injury. After 6 hours of myocardial ischemia and reperfusion in mice, Evans blue dye (1 ml, 2.0% solution) was injected into the jugular vein of the heart. The heart was cut open to take 1 mm thick slices, which were incubated in triphenyltetrazolium for 15 minutes and maintained at 37°C. The myocardial infarction area is white, the non-infarction area or risk area is red, and the non-ischemic tissue is blue. The infarction area and the area of ​​the non-ischemic left ventricle were then measured by computer planimetry. The transverse cross-sections of the myocardium of different groups and the quantitative analysis of their infarction area are shown in the figure. Figure 3 Compared with the blank group, myocardial ischemia-reperfusion can cause myocardial infarction in a large area without any drug administration. Compared with the physical mixture of compounds shown in Nos. 1 and 3, the double yellow nanoparticles containing compounds shown in Nos. 1 and 3 can reduce the damage of myocardial ischemia-reperfusion to a level equivalent to that of the blank group, which shows that the double yellow nanoparticles can effectively prevent tissue damage caused by myocardial ischemia-reperfusion.

[0054] Application Case 2 Antioxidant and anti-inflammatory effects of double yellow nanoparticles. The ischemic myocardium will immediately produce a large number of oxidative free radicals after the blood supply is restored. The highly active oxidative free radicals will quickly overwhelm the endogenous free radical scavenging system of the cell, eventually leading to myocardial cell death and aggravating myocardial damage. Among them, the activity of glutathione peroxidase and superoxide dismutase are two important indicators of the ability to scavenge reactive free radicals, while the concentration of malondialdehyde is a biomarker for evaluating oxidative stress response. Blood was collected from mice before they were killed, and the levels of glutathione peroxidase, superoxide dismutase, tumor necrosis factor, interleukin-6 and malondialdehyde in the serum were determined. In the myocardial ischemia-reperfusion model of mice, compared with the blank group, the glutathione peroxidase activity in the myocardial ischemia-reperfusion group ( Figure 4 Figure A) and superoxide dismutase activity ( Figure 4 The physical mixture of compounds No. 1 and No. 3 can partially reduce the reduction of the corresponding enzyme activity. The double yellow nanoparticles containing compounds No. 1 and No. 3 can basically completely prevent the reduction of the corresponding enzyme activity, and there is no significant difference compared with the blank group. In addition, the double yellow nanoparticles can significantly block the inflammatory factor marker tumor necrosis factor ( Figure 4 Figure C) and interleukin-6 ( Figure 4 Figure D) released in serum to the level of the blank group, the concentration of malondialdehyde ( Figure 4 The corresponding experiments showed that Shuanghuang nanoparticles have excellent antioxidant and anti-inflammatory effects, and their myocardial ischemia protection is also related to the reduction of oxidative stress.

[0055] Application Case 3: The protective effect of double yellow nanoparticles on acute kidney injury in mice. A large number of studies have confirmed that in some tissues and organs, ischemia-reperfusion may not only aggravate the necrosis of the corresponding tissues and expand the infarct area, but also lead to the occurrence of serious complications, such as acute kidney injury after myocardial ischemia-reperfusion. Serum creatinine and urea nitrogen are commonly used indicators for evaluating renal function. Blood was collected from mice before they were killed, and the levels of creatinine and urea nitrogen in the serum were measured. After the mice were killed, the kidney tissues were collected, fixed with 10% formaldehyde, then embedded in paraffin, dehydrated in gradient concentrations of alcohol, and sliced. The slices were stained with hematoxylin and eosin according to the instructions, and imaged with an optical microscope. Figure 5 As shown in the figure, compared with the blank group, myocardial ischemia-reperfusion surgery caused a significant increase in the concentration of creatinine and urea nitrogen in the serum of mice, and the physical mixture of the compounds shown in numbers 1 and 3 failed to reduce the release of the above two substances in the serum. The double yellow nanoparticles containing the compounds shown in numbers 1 and 3 can reduce the creatinine and urea nitrogen in the serum to the level of the blank group. In addition, hematoxylin-eosin staining was used to observe the damage of the renal tubules. Compared with the normal renal tubules, the myocardial ischemia-reperfusion group showed obvious glomerular atrophy and cavitation, while the renal tubules of the mice in the double yellow nanoparticle administration group were almost the same as those in the normal group. It can be seen that the double yellow nanoparticles can significantly eliminate the renal tubular damage caused by myocardial ischemia-reperfusion.

[0056] Table 1. Compound numbers and their physicochemical properties

[0057]

[0058] 1 LogP>0, the compound is hydrophobic;

[0059] 2 The solubility is less than 1 mg / mL, and the compound is very slightly soluble or insoluble in water;

[0060] Table 2. Double yellow nanoparticles formula and its particle size, potential and distribution

[0061]

[0062] Note: The numbers of the compounds in the table correspond to those in Table 1;

[0063] 1 The molar ratio of a compound; 2 Organic solvents 3 Organic solvent volume (uL); 4 pH of aqueous solution; 5 Volume of aqueous solution (mL).

[0064] Although the present invention is described herein with reference to an illustrative embodiment of the present invention, the above embodiment is only a specific implementation of the present invention, and the implementation of the present invention is not limited to the above embodiment. It should be understood that those skilled in the art can design more other modifications and implementations, which will fall within the scope and spirit of the principles disclosed in this application.

Claims

1. A double yellow nanoparticle, It is characterized in that The double yellow nanoparticles include at least one compound having a chemical structure shown in general formula I and at least one compound having a chemical structure shown in general formula II, and the compounds directly interact with each other to form nanoparticles with a diameter between 30 nm and 1000 nm that can be uniformly dispersed in an aqueous solution: Wherein, R is any atom, ion or group; and the Zeta potential of the double yellow nanoparticles under the preparation conditions is negative, and the absolute value of the Zeta potential is greater than 20 mV.

2. The double yellow nanoparticles according to claim 1, It is characterized in that The compound having the chemical structure shown in general formula I is selected from at least one of rhein compounds.

3. The double yellow nanoparticles according to claim 2, It is characterized in that The compound having the chemical structure shown in general formula I is selected from at least one of the following numbered compounds:

4. The double yellow nanoparticles according to claim 1, It is characterized in that The compound having the chemical structure shown in general formula II is selected from at least one of curcumin compounds.

5. The double yellow nanoparticles according to claim 4, It is characterized in that The compound having the chemical structure shown in general formula II is selected from at least one of the following numbered compounds:

6. The double yellow nanoparticles according to claim 1, It is characterized in that The direct interactions between the compounds include π-π stacking, hydrophobic interaction, electrostatic interaction and / or hydrogen bonding.

7. The double yellow nanoparticles according to claim 1, It is characterized in that The amount ratio of the compound having the chemical structure shown in general formula I to the compound having the chemical structure shown in general formula II is 20:1 to 1:

20.

8. The method for preparing the double yellow nanoparticles according to any one of claims 1 to 7, comprising the following steps: (1) mixing the compound with an organic solvent to obtain an organic mixed solution; (2) mixing the obtained organic mixed solution with the aqueous phase solution to obtain a double yellow nanoparticle dispersion containing the compound; (3) removing the organic solvent in the Shuanghuang nanoparticle dispersion to obtain the Shuanghuang nanoparticle aqueous dispersion containing the compound; removing the aqueous phase in the Shuanghuang nanoparticle aqueous dispersion to obtain the Shuanghuang nanoparticles containing the compound; making the Shuanghuang nanoparticles into different pharmaceutically acceptable preparations, including injections, capsules, tablets, patches or sprays.

9. Use of the double yellow nanoparticles according to any one of claims 1 to 7 in the preparation of antibacterial, anti-inflammatory, antioxidant and tissue damage protection drugs.

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