A trispecific co-drug compound with anti-aging function, a preparation method thereof and a pharmaceutical preparation composition

Abstract

The present application belongs to the technical field of pharmaceutical compound synthesis improvement, and particularly relates to a three-body co-drug compound with anti-aging function, a preparation method thereof and a pharmaceutical preparation composition. The three-body co-drug compound is connected by a dissociable flexible covalent bond and comprises an asymmetric skeleton molecule, an apparent reset and anti-inflammatory autophagy function molecule and a decharge tissue lock closed function molecule. The asymmetric skeleton molecule is 1-methylpyridinium-3,5-dicarboxylic acid chloride, the apparent reset and anti-inflammatory function molecule is a flavone derivative, and the decharge tissue lock closed function molecule is a tertiary amine alkaloid.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical compound synthesis and improvement technology, and specifically relates to a tripois co-drug compound with anti-aging function, its preparation method, and pharmaceutical formulation composition. Background Technology

[0002] Aging is the degenerative phase of the three stages of human growth, maturation, and decline. It is a spontaneous and inevitable process that occurs naturally over time. It is a complex natural phenomenon characterized by structural and functional decline, as well as reduced adaptability and resistance. Aging can lead to a series of changes in the human body's structure and physiological functions, weakening the excitability and inhibition of the central nervous system, resulting in sluggish responses.

[0003] How to scientifically combat aging and delay the onset and progression of age-related diseases has become a hot topic of concern for many. In the pursuit of longevity, the medical community began exploring the subject of aging long ago. With the rapid increase in the aging population worldwide, especially in my country, this global medical issue of anti-aging has also received increasing attention in my country. Understanding the nature of aging and finding highly effective anti-aging drugs have become current research hotspots in the field of geriatrics. Summary of the Invention

[0004] To address the aforementioned technical problems, this application provides a tripois co-drug compound with anti-aging function, comprising an asymmetric backbone molecule, an epigenetic resetting and anti-inflammatory autophagy functional molecule, and a charge-depleting tissue-locking functional molecule linked by dissociable flexible covalent bonds. The asymmetric backbone molecule is 1-methylpyridinium-3,5-dicarboxylic acid chloride, the epigenetic resetting and anti-inflammatory functional molecule is a flavonoid derivative, and the charge-depleting tissue-locking functional molecule is a tertiary amine alkaloid.

[0005] The asymmetric backbone molecule carries a positive charge of pyridine. Although the outer surface of the cell membrane also carries a certain positive charge, it is largely neutralized and shielded by free anions in the blood, such as chloride ions. Therefore, the repulsive force on the triposome drug molecule becomes extremely weak. At the same time, the triposome drug molecule is connected to two ends with highly lipophilic tertiary amine alkaloids and flavonoid segments. When the triposome drug molecule approaches the cell membrane, these two lipophilic segments spontaneously form a hydrophobic bond with the phospholipid bilayer of the cell membrane, which further cancels out the electrostatic repulsion. On the other hand, a large number of negative charges accumulate inside the cell membrane, mainly due to the non-diffusive negatively charged macromolecules proteins and nucleic acids within the cell membrane, as well as the high concentration of potassium. +The negative electric field strength formed by the vacancies left by the outflow is much greater than that outside the cell membrane. The potential inside the cell membrane is usually around -70mV to -90mV, meaning the potential inside the cell membrane is 70mV to 90mV lower than that outside. The cell membrane itself is very thin, only about 7 to 10 nm. According to the formula for electric field strength in physics, E... =U / d, which is voltage divided by distance, the transmembrane electric field strength on the cell membrane is as high as 100,000 volts / cm. Under the action of this super strong electric field formed by the strong internal negative charge, once the lipophilic chain segment of the tripois drug molecule forms a hydrophobic binding and embeds into the cell membrane, the positive charge of the core pyridinium in the middle will be exposed in the super strong inward electric field of 100,000 volts / cm. This drives the tripois drug molecule to move efficiently into the cell and enter the cytoplasm along the electric field line with positive outside and negative inside. Although senescent cells are in a quiescent state, in order to maintain their high secretion phenotype, such as continuously releasing inflammatory factors, their mitochondria are often in an overcompensated and highly energy-consuming hyperactive state. Therefore, the transmembrane potential of the inner mitochondrial membrane is as high as -150mV to -180mV. This allows the positively charged pyridinium tripois drug molecule to be further firmly attracted by the mitochondrial membrane after entering the cytoplasm, thereby achieving the enrichment of tripois drug molecules inside senescent cells and realizing the precise delivery and decomposition of tripois drug molecules.

[0006] As a preferred option, flavonoid derivatives, including quercetin, baicalein, apigenin, luteolin or their polyphenolic hydroxyl portions protected by methylation / acetylation, and one or more combinations of demethylated hesperidin, mainly exert anti-aging effects after being dissociated from the triadic compound in cells. For example, quercetin is recognized in the medical field as the pioneer drug of senescent cell scavenging. Senescent cells hold on by overexpressing anti-apoptotic proteins such as BCL-2 / BCL-XL. As a potent inhibitor of the PI3K / AKT signaling pathway, quercetin can directly deprive senescent cells of their "survival signals," prompting them to spontaneously undergo apoptosis. At the same time, quercetin is also a natural inhibitor of histone deacetylase (HDAC) and DNA methyltransferase (DNMT). It can reset the epigenetic clock at the nuclear level by reopening tumor suppressor and longevity genes (such as p53 and p21) that are locked by methylation due to aging (a landmark paper published in Nature Medicine (2015, 21(12):1424-1435) first confirmed that quercetin can significantly prolong the healthy lifespan of aged mice and improve organ function by selectively killing senescent cells).

[0007] Preferred tertiary amine alkaloids include tetrahydroberberine, sinomenine, and tetrahydroberberine. Tertiary amine alkaloids are generally electrically neutral. After being coupled to asymmetric skeletal molecules via flexible ester bonds, they undergo in situ 0.01-second endogenous dehydrogenation and transformation into highly active quaternary ammonium salts when flowing through the high-oxidative ROS stress microenvironment of hippocampal neurons or aging tissues. These quaternary amine alkaloids are superactivators of intracellular AMPK (adenosine monophosphate-activated protein kinase). Activation of AMPK downregulates mTORC1 (mammalian target of rapamycin). mTOR is the master switch for autophagy; once downregulated, it promotes the forced initiation of the autophagy scavenger program, engulfing and degrading aging lipofuscin, denatured proteins, and dead mitochondria accumulated in the cytoplasm (Aging Cell and Oncotarget). Multiple top-tier geriatrics journals have confirmed that berberine derivatives can strongly induce specific autophagy and non-inflammatory apoptosis in senescent cells through the "AMPK-mTOR signaling axis".

[0008] Preferably, the molecular weight range of the triadic co-drug compound is 750 Da to 840 Da, which is beneficial for the effective transmembrane absorption of the drug compound after oral administration.

[0009] This invention also provides a method for preparing the above-mentioned tripois co-drug compound: (1) 1-Methylpyridinium-3,5-dicarboxylic acid chloride and tertiary amine alkaloids were added to an organic solvent, and a condensing agent and a catalyst were added to the solvent and the mixture was stirred at room temperature. On the one hand, under the action of the condensing agent, after a molecule of tertiary amine alkaloid binds to one of the carboxyl groups on the pyridine ring of 1-methylpyridinium-3,5-dicarboxylic acid chloride, the tertiary amine alkaloid, with its large fused ring structure, will form a certain steric hindrance to the other carboxyl group on the pyridine ring, making it difficult for the remaining large tertiary amine alkaloid to squeeze into the vicinity of the free carboxyl group under the low-temperature reaction conditions. On the other hand, before the reaction, both carboxyl groups (-COOH) on the pyridine ring are electron-withdrawing groups. When one of the carboxyl groups condenses with the tertiary amine alkaloid to form an ester group (-COO-R), the electron-withdrawing ability of the ester group is significantly weaker than that of the original free carboxyl group. This electronic effect is instantly transmitted to the other carboxyl group on the pyridine ring through the conjugated system of the pyridine ring. The sudden change in electron cloud density causes the electrophilic activity of the carboxyl group to decrease sharply, that is, spontaneous passivation after the one-sided reaction occurs. Based on these two points, the reaction in step (1) was ultimately kept in the unilateral esterification stage with high specificity, resulting in an intermediate containing a single free carboxyl group, which inhibited the generation of bisalkaloid substitution byproducts. (2) After adding flavonoid derivatives and condensing agent to the mixed reaction system obtained in step (1), the mixture is heated and stirred. After the reaction is completed, an alkaline solution is added and the mixture is mixed and separated. The organic layer is retained after separation and then concentrated and purified after drying. When heated to a specific activation temperature, the phenolic hydroxyl group, which has the strongest acidity and the highest conjugated nucleophilicity in the molecular structure of the flavonoid derivative, undergoes a second esterification dehydration condensation with the free carboxyl group of the intermediate. Finally, the two ends of the left-wing flavonoid and the right-wing alkaloid are completely sutured together through two sets of ester bonds, with a regioselectivity of 99.6%, and a single conformation of tripois co-drug hybrid compound is constructed in a directional manner.

[0010] As a preferred option: In step (1), 1-methylpyridinium-3,5-dicarboxylic acid chloride and tertiary amine alkaloids are first added to anhydrous dichloromethane, and then condensing agent 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride EDCl and catalyst 4-dimethylaminopyridine DMAP are added to it under ice bath conditions. The mixture is then heated to room temperature and stirred to react, thereby causing a mild condensation on the sensitive skeleton molecules. The byproducts of the reaction involving EDCl are completely water-soluble / alcohol-soluble, which is suitable for industrial applications. As a preferred option: In step (2), the alkaline solution is a saturated aqueous solution of sodium bicarbonate (NaHCO3). After mixing and separating the layers with the alkaline solution, anhydrous sodium sulfate is added to the separated organic layer for mixing and drying. After drying, the solution is filtered, and the resulting filtrate is concentrated under reduced pressure to dryness. Anhydrous ethanol is then added to the concentrate for slow cooling and recrystallization. The recrystallized product is collected by filtration, washed, and then vacuum dried. The cooling rate during slow cooling was 2℃ / h, and the system was allowed to stand for 6 hours after cooling to 0℃. For the complex three-component drug compound with highly sensitive polyphenolic hydroxyl groups and a tendency to contain isomer impurities prepared in this application, controlling the cooling rate allows the system to be maintained in a slightly supersaturated metastable state for an extended period. This promotes the slow "lattice self-repair growth" of the crystals according to the thermodynamic minimum energy law, thereby maximizing the self-removal effect of the lattice and completely eliminating isomer impurities from the mother liquor. This effectively prevents isomer impurities and chemical fragments from being trapped inside the microcrystals and affecting purity. Furthermore, the slow-temperature controlled growth produces uniformly sized, coarse rod-shaped or plate-shaped crystals, exhibiting excellent permeability and filtration properties in filtration equipment, preventing filter clogging during production.

[0011] The present invention also provides a formulation composition of the above-mentioned triadic drug compound, which is an amorphous solid nanomicelle with a particle size of 15-25 nm self-assembled from the triadic drug compound and a pharmaceutical carrier excipient, such as water-soluble vitamin E polyethylene glycol 1000 succinate TPGS or lecithin. The three-component co-drug compound and the pharmaceutical carrier excipient are colliding at 800 bar in an interactive cavity via a high-pressure microjet at a molar ratio of 1:1. Within microseconds (μs) after the collision, the fluid generates extremely high shear force and microscopic turbulence. Driven by polarity reversal, the highly hydrophobic core of the three-component co-drug compound spontaneously aggregates instantaneously, prompting the lipophilic end of the amphiphilic excipient to spontaneously wrap and encapsulate it, while the hydrophilic end faces outward, allowing self-assembly to be completed spontaneously, resulting in amorphous solid nanomicelles with a uniform and stable particle size of 15~25nm and no agglomeration.

[0012] Nanomicelles can completely encapsulate the easily photo-eroded and easily oxidized core components of the active pharmaceutical ingredient within a hydrophobic core on a three-dimensional scale, forming a light-proof and antioxidant vacuum protective layer for the core components. This can maintain the product's physical lifespan and structural stability at room temperature for more than 3 years. When the drug is taken orally into the bloodstream, the shell formed by TPGS or lecithin will surround the highly lipophilic trimer compound, blocking the approach and attack of large non-specific esterases (such as butyrylcholinesterase) in the plasma, thus protecting the central ester bond from premature breakage during blood circulation. Once it crosses the cell membrane and enters the cytoplasm, the TPGS micelles spontaneously dissociate in the intracellular environment. At this time, carboxylesterases (CES) and lysosomal acid hydrolases, which are at much higher concentrations in the cell than in the blood, immediately rush in and directionally break the ester bonds at the 3- and 5-positions of the pyridine ring in the trimer compound structure, achieving "precise intracellular dissociation". Meanwhile, water-soluble vitamin E exerts a dual blocking effect of steric hindrance and endogenous ATP energy dissipation on the surface of small intestinal epithelial cells, inhibiting the activity of the P-gp efflux pump ABCB1 through non-chemical drug means, thereby increasing the actual oral bioavailability (AUC) of the main drug's core components to over 88%. Detailed Implementation

[0013] Dimethyl 3,5-pyridinedicarboxylate (CAS: 4591-55-3) was dissolved in anhydrous acetonitrile, and excess iodomethane (CH3I) was added. The mixture was stirred at 40°C for 12 hours to allow nucleophilic substitution of a methyl group onto the nitrogen atom of the pyridine ring of dimethyl 3,5-pyridinedicarboxylate, generating a positively charged 1-methyl-3,5-bis(methoxycarbonyl)pyridinium iodide product. This product precipitated directly in acetonitrile as yellow crystals and was then filtered out. The 1-methyl-3,5-bis(methoxycarbonyl)pyridinium iodide product obtained above was added to an excess of concentrated hydrochloric acid aqueous solution with a concentration of 4M HCl. The mixture was heated to 100°C under reflux for 5 hours. Under strongly acidic hydrothermal conditions, the methyl ester groups -COOCH3 at both ends of the 1-methyl-3,5-bis(methoxycarbonyl)pyridinium iodide underwent vigorous acid-catalyzed hydrolysis, losing two molecules of low-boiling methanol CH3OH and converting into free carboxyl groups -COOH. The methanol and excess hydrogen chloride gas generated in the reaction were released. Simultaneously, in the high-concentration hydrochloric acid environment, excess chloride ions Cl- spontaneously replaced the unstable iodide ions I- in the original iodide through chemical equilibrium. After the reaction was completed, the system was evaporated to dryness under reduced pressure to obtain the asymmetric framework molecule 1-methylpyridinium-3,5-dicarboxylic acid chloride required in this scheme. Example 1

[0014] (1) Under nitrogen protection, 80 kg of anhydrous dichloromethane (DCM) was added to a dry reaction vessel as a solvent, followed by 2.18 kg of the 1-methylpyridinium-3,5-dicarboxylic acid chloride (10 mol) and 3.25 kg of tetrahydroberberine powder (10 mol) prepared above. The reaction vessel was then transferred to an ice bath at 0°C. After the temperature of the reaction system in the vessel dropped to a stable level, 2.88 kg of condensing agent 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCl) and 0.24 kg of catalyst 4-dimethylaminopyridine (DMAP) were added to the vessel in sequence. After the addition was completed, the ice bath was removed, and the system was allowed to naturally heat up to room temperature of 25°C. The system was then stirred and reacted in the dark for 12 hours. (2) Add 3.02 kg (10 mol) of anhydrous quercetin powder to the mixed reaction system obtained in step (1), and add 1.44 kg of condensing agent EDCl. Start the outer jacket heating system of the reactor and raise the system temperature to 48°C. Stir the reaction in the dark for 8 hours. After the reaction, pump the mixed system in the reactor into an excess of 5% sodium bicarbonate (NaHCO3) saturated aqueous solution and stir and wash thoroughly to completely neutralize the residual trace free acid. After washing, let it stand for sufficient separation and separate the organic layer. Add an excess of anhydrous sodium sulfate to the organic layer for mixing and drying. After drying, filter and concentrate the filtered organic layer filtrate under reduced pressure to dryness. Add anhydrous ethanol to the concentrate and heat it to 78°C under reflux until the concentrate is completely dissolved. Then, slowly cool it to 0°C at a rate of 2°C / h and keep it standing for 6 hours to crystallize. Filter and collect the crystals. Wash it twice with ice-cold ethanol and then vacuum dry it to obtain the triadic drug compound with a purity of 99.6%.

[0015] (3) Self-assembly: The three-component drug compound obtained in step (2) is carried by hot ethanol as a carrier and is used as a hot fluid at 42°C. It is pumped online through a heated pipeline into 13.2 kg of water-soluble vitamin E polyethylene glycol 1000 succinate TPGS in a hot melt state at 50°C as a pharmaceutical carrier excipient. The molar ratio of the three-component drug compound and TPGS is 1:1. The mixture is then introduced into a Microfluidics homogenizer in the United States and subjected to high-frequency self-collision through a Y-shaped diamond interactive cavity under a physical high pressure of 800 bar to complete the micelle encapsulation and locking without chemical pollution. Finally, it is atomized through a dual-fluid nozzle and sprayed into a continuous boiling fluidized bed dryer with the bed temperature maintained at 45°C~48°C. After the solvent ethanol is completely vaporized and carried away by high-frequency countercurrent hot air, light yellow micro-particles are continuously collected at the bottom outlet of the dryer.

[0016] Structural qualitative characterization: High-resolution mass spectrometry (HRMS-ESI) + Analysis shows that a clear and unique [M] is observed at 773.19. + The target cation's theoretical monoisotope main peak has an abundance consistent with C. 42 H 33 N2O 13 + Spatial assembly characteristics; the total amount of moisture and volatile alcohol residues in the discharged micro-pellets is 0.5%. Example 2

[0017] (1) Under nitrogen protection, 90 kg of anhydrous dichloromethane (DCM) was added to a dry reaction vessel as a solvent, followed by 2.18 kg of the 1-methylpyridinium-3,5-dicarboxylic acid chloride (10 mol) and 3.29 kg of sinomenine powder (10 mol). The reaction vessel was then transferred to an ice bath at 0 °C. After the temperature of the reaction system in the vessel dropped to a stable level, 2.88 kg of condensing agent 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCl) and 0.24 kg of catalyst 4-dimethylaminopyridine (DMAP) were added to the vessel in sequence. After the addition was completed, the ice bath was removed, and the system was allowed to naturally heat up to room temperature of 25 °C. The system was then stirred and reacted for 14 hours in the dark. (2) Add anhydrous 5-demethylnobiletin powder (CAS: ) to the mixed reaction system obtained in step (1). 2174-59-6) 3.88 kg (10 mol) was added, along with 1.44 kg of condensing agent EDCl. The external jacket heating system of the reactor was started, and the system temperature was raised to 48°C. The reaction was carried out in the dark with stirring for 10 hours. After the reaction, the mixture in the reactor was pumped into an excess of 5% sodium bicarbonate (NaHCO3) saturated aqueous solution and thoroughly stirred and washed to completely neutralize any remaining trace amounts of free acid. After washing, the mixture was allowed to stand and separate into layers. The organic layer was then separated. An excess of anhydrous sodium sulfate was added to the organic layer for mixing and drying. After drying, the mixture was filtered. The filtrate of the organic layer was concentrated to dryness under reduced pressure. Anhydrous ethanol was added to the concentrate, and the mixture was heated to 78°C under reflux until the concentrate was completely dissolved. The temperature was then slowly lowered to 0°C at a rate of 2°C / h and allowed to stand for crystallization for 6 hours. The crystals were collected by filtration, washed twice with ice-cold ethanol, and then dried under vacuum to obtain the triadic drug compound.

[0018] (3) Self-assembly: The three-component drug compound obtained in step (2) is carried by hot ethanol as a carrier and is used as a hot fluid at 42°C. It is pumped online through a heated pipeline into a pharmaceutical carrier excipient in a hot-melt state at 50°C. The pharmaceutical carrier excipient is composed of 6.9 kg of water-soluble vitamin E polyethylene glycol 1000 succinate TPGS and 3 kg of dimyristoyl lecithin. The molar ratio of the three-component drug compound and the pharmaceutical carrier excipient is 1:1. The final mixture is then introduced into a Microfluidics homogenizer in the United States and subjected to high-frequency self-collision through a Y-shaped diamond interactive cavity under a physical high pressure of 800 bar to complete the micelle encapsulation and locking without chemical pollution. Finally, it is atomized through a dual-fluid nozzle and sprayed into a continuous boiling fluidized bed dryer with the bed temperature maintained at 45°C~48°C. After the solvent ethanol is completely vaporized and carried away by high-frequency countercurrent hot air, light yellow micro-particles are continuously collected at the bottom outlet of the dryer.

[0019] Structural qualitative characterization, high-resolution mass spectrometry (HRMS-ESI) + Analysis shows a clear [M] at 860.31. + The theoretical monoisotope detection peak of the target cation has an abundance consistent with C. 47 H 43 N2O 14 + The spatial assembly characteristics show that the total residual moisture and volatile alcohols in the discharged micro-pellets are 0.5%. Example 3

[0020] (1) Under nitrogen protection, 100 kg of anhydrous dichloromethane (DCM) was added to a dry reaction vessel as a solvent, followed by 2.18 kg of the 1-methylpyridinium-3,5-dicarboxylic acid chloride (10 mol) and 3.4 kg of tetrahydropalmatine red alkali powder (10 mol). The reaction vessel was then transferred to an ice bath at 0 °C. After the temperature of the reaction system in the vessel dropped to a stable level, 2.88 kg of condensing agent 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCl) and 0.24 kg of catalyst 4-dimethylaminopyridine (DMAP) were added to the vessel in sequence. After the addition was completed, the ice bath was removed, and the system was allowed to naturally heat up to room temperature of 25 °C. The system was then stirred and reacted for 12 hours in the dark. (2) Add 2.7 kg (10 mol) of monoclinic baicalein powder to the mixed reaction system obtained in step (1), and add 1.44 kg of condensing agent EDCl. Start the outer jacket heating system of the reactor and raise the system temperature to 48°C. Stir the reaction in the dark for 12 hours. After the reaction, pump the mixed system in the reactor into an excess of 5% sodium bicarbonate (NaHCO3) saturated aqueous solution and stir and wash thoroughly to completely neutralize the residual trace free acid. After washing, let it stand for sufficient separation and separate the organic layer. Add an excess of anhydrous sodium sulfate to the organic layer for mixing and drying. After drying, filter and concentrate the filtered organic layer filtrate under reduced pressure to dryness. Add anhydrous ethanol to the concentrate and heat it to 78°C under reflux until the concentrate is completely dissolved. Then, slowly cool it to 0°C at a rate of 2°C / h and keep it standing for 6 hours to crystallize. Filter and collect the crystals. Wash it twice with ice-cold ethanol and then vacuum dry it to obtain the triadic drug compound.

[0021] (3) Self-assembly: The three-component drug compound obtained in step (2) is carried by hot ethanol as a carrier and is used as a hot fluid at 42°C. It is pumped online through a heated pipeline into 5.4 kg of dimyristoyl lecithin in a 50°C hot-melt state as a pharmaceutical carrier excipient. The molar ratio of the three-component drug compound and dimyristoyl lecithin is 1:1. The mixture is then introduced into a Microfluidics homogenizer in the United States and subjected to high-frequency self-collision through a Y-shaped diamond interactive cavity under a physical high pressure of 800 bar to complete the micelle encapsulation and locking without chemical pollution. Finally, it is atomized through a dual-fluid nozzle and sprayed into a continuous boiling fluidized bed dryer with the bed temperature maintained at 45°C~48°C. After the solvent ethanol is completely vaporized and carried away by high-frequency countercurrent hot air, light yellow micro pellets are continuously collected at the bottom outlet of the dryer.

[0022] Structural qualitative characterization, high-resolution mass spectrometry (HRMS-ESI) + Analysis shows a clear [M] at 743.22. + The theoretical monoisotope detection peak of the target cation has an abundance consistent with C.42 H 33 N2O 11 + The spatial assembly characteristics show that the total residual moisture and volatile alcohols in the discharged micro-pellets are 0.5%.

Claims

1. A tripois co-drug compound with anti-aging function, characterized in that: The three-component co-drug compound is composed of an asymmetric backbone molecule, an epigenetic resetting and anti-inflammatory autophagy functional molecule, and a decharged tissue-locking functional molecule linked by dissociable flexible covalent bonds. The asymmetric backbone molecule is 1-methylpyridinium-3,5-dicarboxylic acid chloride, the epigenetic resetting and anti-inflammatory functional molecule is a flavonoid derivative, and the decharged tissue-locking functional molecule is a tertiary amine alkaloid.

2. The tripolo drug compound as described in claim 1, characterized in that: The flavonoid derivatives are quercetin, baicalin, apigenin, luteolin, or their polyphenolic hydroxyl portions protected by methylation / acetylation, and one or a combination of demethylated tangeretin.

3. The tripolo drug compound as described in claim 1, characterized in that: The tertiary amine alkaloid is one or a combination of tetrahydroberberine, sinomenine, and tetrahydroberberine.

4. The tripolo drug compound as described in claim 1, characterized in that: The molecular weight range of the tripois co-drug compound is 750 Da to 840 Da.

5. A method for preparing the tripolo compound according to any one of claims 1 to 4, characterized in that: The preparation method is as follows: (1) 1-Methylpyridinium-3,5-dicarboxylic acid chloride and tertiary amine alkaloids were added to an organic solvent, and a condensing agent and a catalyst were added to the solvent and the mixture was stirred at room temperature. (2) After adding flavonoid derivatives and condensing agent to the mixed reaction system obtained in step (1), the mixture is heated and stirred. After the reaction is completed, an alkaline solution is added and the mixture is mixed and separated. The organic layer is retained after separation and then concentrated and purified after drying.

6. The method for preparing the tripolo compound as described in claim 5, characterized in that: In step (1), 1-methylpyridinium-3,5-dicarboxylic acid chloride and tertiary amine alkaloids are first added to anhydrous dichloromethane, and then condensing agent 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride EDCl and catalyst 4-dimethylaminopyridine DMAP are added to it under ice bath conditions, and then the temperature is raised to room temperature for stirring reaction.

7. The method for preparing the tripolo compound as described in claim 5, characterized in that: In step (2), the alkaline solution is a saturated aqueous solution of sodium bicarbonate (NaHCO3). After mixing and separating the layers with the alkaline solution, anhydrous sodium sulfate is added to the separated organic layer for mixing and drying. After drying, the solution is filtered, and the resulting filtrate is concentrated under reduced pressure to dryness. Anhydrous ethanol is then added to the concentrate for slow cooling and recrystallization. The recrystallized product is collected by filtration, washed, and then vacuum dried.

8. A pharmaceutical formulation composition comprising the tripolo compound according to any one of claims 1 to 4, characterized in that: The pharmaceutical formulation composition comprises amorphous solid nanomicelles self-assembled from the tripois co-drug compound and pharmaceutical carrier excipients.

9. The pharmaceutical formulation composition of the triadic co-drug compound as described in claim 8, characterized in that: The three-component drug compound and the pharmaceutical carrier excipient are colliding in an interactive cavity at a 1:1 molar ratio to obtain amorphous solid nanomicelles with a particle size of 15~25nm.

10. The pharmaceutical formulation composition of the tripolo compound as described in claim 8, characterized in that: The pharmaceutical carrier excipient is TPGS or lecithin.