Composite micelle composition as well as preparation method and application thereof

Abstract

The invention discloses a composite micelle composition which comprises nitrate ester or nitrite ester, phospholipid and cholate, the molar ratio of the nitrate ester or nitrite ester to the phospholipid is at least 1: 0.1, the molar ratio of the nitrate ester or nitrite ester to the cholate is at least 1: 0.1, and the molar ratio of the phospholipid to the cholate is at least 1: 0.5. The composite micelle composition can improve the solubility, bioavailability and / or stability of nitrate or nitrite.

Description

Technical Field

[0001] The present application relates to the field of medical technology, and in particular to a bile salt / phospholipid complex micelle drug delivery system that does not contain an organic solvent and a preparation method thereof. Background Art

[0002] Generally, poorly soluble drugs are poorly absorbed orally and have low bioavailability. Under injection conditions, they have low drug loading and poor stability, which limits their formulation development and clinical application.

[0003] The conventional solubilization method is to add a solubilizer or cosolvent, such as polyoxyethylene castor oil, Tween-80, propylene glycol or ethanol. Although the solubility problem can be solved, the solubilizer or cosolvent itself is often toxic and easily causes adverse reactions in clinical practice. In addition, the irritation during injection is generally relatively large, which can easily cause poor tolerance in patients.

[0004] Bile salt / phospholipid complex micelles are prepared by coprecipitation and other methods using phospholipids and bile salts with good physiological compatibility and safety to encapsulate or load drugs. Bile salt / phospholipid complex micelles are biocompatible drug delivery systems that have been successfully used to solubilize organic compound drugs such as docetaxel, teniposide, and diazepam.

[0005] Bile salt / phospholipid complex micelles are considered to be "mixed disc structures", in which the bilayer of phosphatidylcholine forms a flat micelle structure, and its hydrophobic hydrocarbon chains form a hydrophobic core, which has a strong affinity for drugs and plays a dissolving role. The hydrophobic part of bile salts is embedded in the bilayer of phosphatidylcholine and surrounds the outer layer of phospholipid bimolecules, solubilizing the hydrocarbon chains of phosphatidylcholine. Hydrophilic and slightly soluble drugs stay in the hydrophilic bonds and fence layers of the micelles, respectively, while completely hydrophobic drugs enter the interior of the micelles. Both phospholipids and bile salts are biocompatible and have the title of "physiological excipients", which further guarantees the safety of the preparation.

[0006] As a poorly soluble drug, nitroglycerin is urgently needed to be prepared into an injection with lower toxicity, higher solubility and greater stability. Summary of the invention

[0007] One or more embodiments of the present application provide a composite micelle composition, which comprises nitrate or nitrite, phospholipid, and bile salt, wherein the molar ratio of the nitrate or nitrite to the phospholipid is at least 1:0.1, the molar ratio of the nitrate or nitrite to the bile salt is at least 1:0.1, and the molar ratio of the phospholipid to the bile salt is at least 1:0.5.

[0008] In one or more embodiments, the molar ratio of the nitrate or nitrite to the phospholipid is 1:0.1-50, for example 1:0.5, 1:1, 1:1.5, 1:2, 1:5, 1:10, 1:11, 1:15, 1:20, 1:30, 1:40.

[0009] In one or more embodiments, the molar ratio of the nitrate or nitrite to the phospholipid is 1:1-20.

[0010] In one or more embodiments, the molar ratio of the nitrate or nitrite to the phospholipid is 1:1-10.

[0011] In one or more embodiments, the molar ratio of the nitrate or nitrite to the bile salt is 1:0.1-50, for example 1:0.5, 1:1, 1:1.5, 1:2, 1:5, 1:10, 1:11, 1:15, 1:20, 1:25, 1:30, 1:40.

[0012] In one or more embodiments, the molar ratio of the nitrate or nitrite to the bile salt is 1:1-25.

[0013] In one or more embodiments, the molar ratio of the nitrate or nitrite to the bile salt is 1:1-10.

[0014] In one or more embodiments, the molar ratio of phospholipid to bile salt is 1:0.5-5, for example, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.8, 1:2, 1:2.5, 1:3, 1:4.

[0015] In one or more embodiments, the molar ratio of the phospholipid to the bile salt is 1:1-3.

[0016] In one or more embodiments, the molar ratio of the phospholipid to the bile salt is 1:1-2.

[0017] In one or more embodiments, the nitrate or nitrite comprises one or more -O-NO2 or -O-NO.

[0018] In one or more embodiments, the nitrate or nitrite comprises RO-NO2 or RO-NO, and R is selected from C2-C8 hydrocarbon group, C2-C8 aldehyde group, C2-C8 ether group, C2-C8 ketone group, C2-C8 carboxyl group, C2-C8 ester group, hydroxyl group, phenyl group, naphthyl group, phenol group, 5-10 membered heteroaryl group and 5-10 membered heterocyclic group.

[0019] In one or more embodiments, the nitrate or nitrite is a polynitrate or a polynitrite.

[0020] In one or more embodiments, the polybasic nitrate or polybasic nitrite is a tribasic nitrate or tribasic nitrite.

[0021] In one or more embodiments, the tribasic nitrate or tribasic nitrite is nitroglycerin or nitroglycerin.

[0022] In one or more embodiments, the C2-C8 hydrocarbon group is a C2-C8 alkyl group, a C2-C8 alkenyl group or a C2-C8 alkynyl group.

[0023] In one or more embodiments, the hydrocarbon group is a linear hydrocarbon group or a branched hydrocarbon group.

[0024] In one or more embodiments, the 5-10 membered heteroaryl or 5-10 membered heterocyclyl contains 1, 2, 3 or 4 heteroatoms selected from oxygen, nitrogen and sulfur.

[0025] In one or more embodiments, the 5- to 10-membered heteroaryl or 5- to 10-membered heterocyclic group is a monocyclic, condensed, spirocyclic or bridged ring structure.

[0026] In one or more embodiments, the 5-10 membered heteroaryl or 5-10 membered heterocyclic group is a 5-membered heterocyclic ring and a 5-membered heterocyclic ring or a 5-membered heterocyclic ring and a 6-membered heterocyclic ring.

[0027] In one or more embodiments, the bile salts include natural bile, cholate, and deoxycholate.

[0028] In one or more embodiments, the bile salt is deoxycholate, glycocholate, taurocholate, chenodeoxycholate.

[0029] In one or more embodiments, the bile salt is a sodium salt or a potassium salt.

[0030] In one or more embodiments, the bile salt is a sodium salt or potassium salt of deoxycholate, glycocholate, taurocholate, or chenodeoxycholate.

[0031] In one or more embodiments, the bile salt is selected from sodium cholate, potassium cholate, sodium deoxycholate, potassium deoxycholate, sodium chenodeoxycholate, potassium chenodeoxycholate, sodium glycocholate, potassium glycocholate, sodium taurocholate, and potassium taurocholate.

[0032] In one or more embodiments, the phospholipids include natural phospholipids, semi-synthetic phospholipids, fully synthetic phospholipids and derivatives thereof.

[0033] In one or more embodiments, the phospholipid is selected from soybean lecithin, egg yolk lecithin, egg phosphatidylglycerol, polyene phosphatidylcholine, phosphatidic acid, myocardial phospholipids, sphingomyelin, phosphatidyl serine, phosphatidylinositol, hydrogenated soybean lecithin (HSPC), hydrogenated egg yolk lecithin (HEPC), distearoylphosphatidylcholine (DSPC), dioleoylphosphatidylcholine (DOPC), dipalmitoylphosphatidylcholine (DPPC), dimyristoylphosphatidylcholine (DMPC), distearoylphosphatidylcholine (DSPE), dipalmitoylphosphatidylethanolamine (DPPE), dioleoylphosphatidylethanolamine (DOPE), dimyristoylphosphatidylethanolamine (DMPE).

[0034] One or more embodiments of the present application provide a method 1 for preparing the composite micelle composition described in the present application, which comprises:

[0035] (1) Dissolve bile salt in water, add phospholipids, and stir to disperse;

[0036] (2) adding nitrate or nitrite, stirring until fully dissolved, and adjusting the pH value to 2.0-8.0;

[0037] (3) Filter to obtain.

[0038] In one or more embodiments, the phospholipid is added at 50°C-60°C.

[0039] In one or more embodiments, the pH is adjusted to 3.0-6.5.

[0040] One or more embodiments of the present application provide a second method for preparing the composite micelle composition described in the present application, which comprises:

[0041] (1) dissolving bile salt in water as the aqueous phase and dissolving phospholipid in an organic solvent as the organic phase;

[0042] (2) adding the organic phase to the aqueous phase, stirring, and adjusting the pH value to 2.0-8.0;

[0043] (3) removing the organic solvent;

[0044] (3) Filter to obtain;

[0045] Wherein, in the step (1), the nitrate ester or nitrite ester is dissolved in the organic phase, or in the step (2), the nitrate ester or nitrite ester is added after stirring.

[0046] In one or more embodiments, the organic solvent is one or more of methanol, ethanol, dichloromethane, chloroform, ethyl acetate, acetonitrile, acetone, propylene glycol, dimethyl sulfoxide, and tetrahydrofuran.

[0047] In one or more embodiments, the pH is adjusted to 3.0-6.5.

[0048] In one or more embodiments, the organic solvent is removed by nitrogen blowing or reduced pressure evaporation.

[0049] One or more embodiments of the present application provide a third method for preparing the composite micelle composition described in the present application, which comprises:

[0050] (1) dissolving bile salt and phospholipid in an organic solvent and stirring to dissolve;

[0051] (2) removing the organic solvent until it reaches a viscous or dry state;

[0052] (3) adding hydrating medium to dissolve, make up to volume, and adjust the pH value to 2.0-8.0;

[0053] (4) Filter to obtain;

[0054] Wherein, in the step (1), the nitrate or nitrite is dissolved in the organic phase, or in the step (3), the nitrate or nitrite is added before the volume is constant.

[0055] In one or more embodiments, the organic solvent is one or more of methanol, ethanol, dichloromethane, chloroform, ethyl acetate, acetonitrile, acetone, propylene glycol, dimethyl sulfoxide, and tetrahydrofuran.

[0056] In one or more embodiments, the organic solvent is removed by nitrogen volatilization, reduced pressure evaporation, freeze drying or spray drying.

[0057] In one or more embodiments, the pH is adjusted to 3.0-6.5.

[0058] In one or more embodiments, the hydration medium is distilled water, physiological saline, isotonic glucose solution or buffer solution.

[0059] In one or more embodiments, in the method 1, method 2, and method 3, the nitrate or nitrite, phospholipid and bile salt and their molar ratios are as described above.

[0060] In one or more embodiments, in the method 1, method 2, and method 3, the aqueous solution obtained after filtering is freeze-dried to obtain a freeze-dried powder.

[0061] In one or more embodiments, the filtration is followed by packaging and / or sterilization.

[0062] In one or more embodiments, in the method one, the method two, and the method three, the stirring is magnetic stirring, high-speed shearing, or high-pressure homogenization.

[0063] One or more embodiments of the present application provide a liquid preparation comprising the composite micelle composition of the present application, water, and a pharmaceutically acceptable auxiliary material or excipient.

[0064] In one or more embodiments, the auxiliary material or excipient is one or more of a pH adjuster, a flavoring agent, a preservative, and an antioxidant.

[0065] In one or more embodiments, the pH adjuster is one or more of hydrochloric acid, malic acid, formic acid and formates, phosphoric acid and phosphates, acetic acid and acetates, boric acid and borates, citric acid and citrates, ammonia water, and sodium hydroxide.

[0066] In one or more embodiments, the liquid preparation is an injection or an oral solution.

[0067] In one or more embodiments, the water is water for injection.

[0068] One or more embodiments of the present application provide a solid preparation comprising the composite micelle composition of the present application and a pharmaceutically acceptable adjuvant or excipient.

[0069] In one or more embodiments, the auxiliary material or excipient is one or more of a pH adjuster, a flavoring agent, a preservative, and an antioxidant.

[0070] In one or more embodiments, the pH adjuster is one or more of hydrochloric acid, malic acid, formic acid and formates, phosphoric acid and phosphates, acetic acid and acetates, boric acid and borates, citric acid and citrates, ammonia water, and sodium hydroxide.

[0071] In one or more embodiments, the solid dosage form is a tablet or a capsule.

[0072] One or more embodiments of the present application provide a lyophilized preparation comprising the composite micelle composition of the present application and a pharmaceutically acceptable auxiliary material or excipient.

[0073] In one or more embodiments, the auxiliary material or excipient is one or more of a lyoprotectant, a pH adjuster, a flavoring agent, a preservative, and an antioxidant.

[0074] In one or more embodiments, the lyoprotectant is one or more of glucose, sucrose, lactose, trehalose, glycine, mannitol, low molecular weight dextran, cyclodextrin, and soluble starch.

[0075] In one or more embodiments, the pH adjuster is one or more of hydrochloric acid, malic acid, formic acid and formates, phosphoric acid and phosphates, acetic acid and acetates, boric acid and borates, citric acid and citrates, ammonia water, and sodium hydroxide.

[0076] One or more embodiments of the present application provide the use of phospholipids and / or bile salts in improving the solubility, bioavailability and / or stability of nitrates or nitrites.

[0077] In one or more embodiments, the nitrate or nitrite is nitroglycerin or nitroglycerin.

[0078] In one or more embodiments, the nitrate or nitrite, phospholipid and bile salt and their molar ratios are as described above.

[0079] One or more embodiments of the present application provide the use of the composite micelle composition, liquid preparation, solid preparation or lyophilized preparation of the present application in the preparation of drugs for treating and / or preventing myocardial infarction, myocardial infarction, angina pectoris, heart failure, coronary heart disease, cor pulmonale, gastrointestinal bleeding caused by liver disease, hypertension, and cardiogenic shock.

[0080] In one or more embodiments, the myocardial infarction, myocardial infarction, angina pectoris, heart failure, coronary heart disease, cor pulmonale, gastrointestinal bleeding caused by liver disease, hypertension, cardiogenic shock are acute.

[0081] In one or more embodiments, the bile salt / phospholipid complex micelle composition of the present application can improve the solubility of the active pharmaceutical ingredient nitrate or nitrite, and does not contain an organic solvent, has low irritation, high safety, and good stability.

[0082] In one or more embodiments, the composite micelle composition of the present application is prepared as an injection preparation or a lyophilized preparation.

[0083] In one or more embodiments, in the composite micellar composition of the present application, the water solubility (concentration in water at 25° C.) of the nitrate or nitrite may be at least 2 mg / mL, for example, 3 mg / mL, 5 mg / mL, 6 mg / mL, 7 mg / mL, 10 mg / mL, 15 mg / mL, 19 mg / mL, 26 mg / mL or 34 mg / mL.

[0084] In one or more embodiments, in the composite micellar composition of the present application, the water solubility of nitroglycerin (concentration in water at 25° C.) may be at least 2 mg / mL, for example, 3 mg / mL, 5 mg / mL, 6 mg / mL, 7 mg / mL, 10 mg / mL, 15 mg / mL, 19 mg / mL, 26 mg / mL or 34 mg / mL. DETAILED DESCRIPTION

[0085] To facilitate the understanding of the technical solution of the present invention, the present invention is further described below in conjunction with specific embodiments.

[0086] Example 1: Preparation of nitroglycerin composite micelle composition using method 1

[0087] Weigh 5.7 g of sodium deoxycholate and add it to 30 mL of water, stir and dissolve, add 6.2 g of soybean lecithin at 60° C., stir and disperse until transparent, then add 0.3 g of nitroglycerin, stir well, make the volume to 100 mL, adjust the pH to 5.5, filter through a 0.22 μm microporous filter membrane, dispense, and sterilize by autoclave at 121° C. for 30 min. In the composite micelle composition, the concentration of nitroglycerin at room temperature is 3 mg / mL.

[0088] Example 2: Preparation of isosorbide dinitrate composite micelle composition using method 1

[0089] Weigh 6.4 g of sodium glycocholate and add it to 30 mL of water, stir and dissolve, add 5.6 g of egg yolk lecithin at 60°C, disperse it by high-speed shearing until it is transparent, then add 0.5 g of isosorbide dinitrate, stir it thoroughly, make the volume to 100 mL, adjust the pH to 5.0, filter it through a 0.22 μm microporous filter membrane, package it, and sterilize it by autoclave at 121°C for 30 min. In the composite micelle composition, the concentration of isosorbide dinitrate at room temperature is 5 mg / mL.

[0090] Example 3: Preparation of nitroglycerin composite micelle composition using method 2

[0091] Weigh 2.1g of sodium deoxycholate and add it to 30mL of water, stir and dissolve it as the water phase; weigh 0.6g of nitroglycerin and 2.2g of soybean lecithin and add it to 5mL of chloroform, stir and dissolve it as the organic phase; add the organic phase to the water phase, high-speed shear, remove the chloroform by rotary evaporation at 40°C, adjust the volume to 100mL, adjust the pH to 6.0; filter with a 0.22μm microporous filter membrane, divide it into portions, and sterilize it by hot pressure steam at 121°C for 30min. In the composite micelle composition, the concentration of nitroglycerin at room temperature is 6mg / mL.

[0092] Example 4: Preparation of nitroglycerin composite micelle composition using method 2

[0093] Weigh 7.6g of sodium taurocholate and add it to 30mL of water, stir and dissolve it as the water phase; weigh 8.5g of HSPC and add it to 5mL of ethanol, stir and dissolve it as the organic phase; add the organic phase to the water phase, stir it thoroughly, add 1.0g of nitroglycerin, homogenize it under high pressure for 2-4 times, blow nitrogen at 40℃ to evaporate the ethanol, make the volume to 100mL, adjust the pH to 5.5; filter it through a 0.22μm microporous membrane, package it, and sterilize it by hot pressure steam at 121℃ for 30min. In the composite micelle composition, the concentration of nitroglycerin at room temperature is 10mg / mL.

[0094] Example 5: Preparation of isosorbide dinitrate composite micelle composition using method 2

[0095] Weigh 14.0g of sodium deoxycholate and add it to 60mL of water, stir and dissolve it as the aqueous phase; weigh 3.0g of isosorbide dinitrate and 12.5g of egg yolk lecithin and add 5mL of ethyl acetate, stir and dissolve it as the organic phase; add the organic phase to the aqueous phase, stir it thoroughly, remove the ethyl acetate by rotary evaporation at 40°C, adjust the volume to 200mL, adjust the pH to 5.3; filter with a 0.22μm microporous filter membrane, divide it into portions, and sterilize it by hot pressure steam at 121°C for 30min. In the composite micelle composition, the concentration of isosorbide dinitrate at room temperature is 15mg / mL.

[0096] Example 6: Preparation of nitroglycerin composite micelle composition using method 3

[0097] Weigh 11.0 g sodium chenodeoxycholate, 10.0 g soybean lecithin, and 1.0 g nitroglycerin, add them to 20 mL ethyl acetate, stir and dissolve; evaporate under reduced pressure on a rotary evaporator at 40°C until a thin film is produced, add physiological saline to elute and adjust the volume to 200 mL, adjust the pH to 5.4; filter with a 0.22 μm microporous filter membrane, dispense, and sterilize with autoclave at 121°C for 30 min. In the composite micelle composition, the concentration of nitroglycerin at room temperature is 5 mg / mL.

[0098] Example 7: Preparation of nitroglycerin composite micelle composition using method 3

[0099] Weigh 12.0 g of sodium glycocholate, 14.5 g of HEPC, and 1.5 g of nitroglycerin, add them to 30 mL of methanol, stir and dissolve; spray dry them to a powder state using a spray dryer, add distilled water to elute and adjust the volume to 300 mL, adjust the pH to 5.0; filter with a 0.22 μm microporous filter membrane, divide and sterilize with autoclave steam at 121° C. for 30 min. In the composite micelle composition, the concentration of nitroglycerin at room temperature is 5 mg / mL.

[0100] Example 8: Preparation of nitroglycerin composite micelle composition using method 3

[0101] Weigh 8.0 g sodium chenodeoxycholate, 7.0 g egg yolk lecithin, and 1.5 g nitroglycerin, add them to 10 mL ethanol, stir and dissolve; transfer to a freeze dryer to dry and remove the solvent, add physiological saline to dissolve, adjust the volume to 100 mL, adjust the pH to 6.0; filter with a 0.22 μm microporous membrane, dispense, and sterilize with autoclave at 121° C. for 30 min. In the composite micelle composition, the concentration of nitroglycerin at room temperature is 15 mg / mL.

[0102] Example 9: Preparation of 5-isosorbide mononitrate composite micelle composition using method three

[0103] Weigh 14.0 g of sodium deoxycholate, 15.0 g of soybean lecithin, and 2.0 g of 5-isosorbide mononitrate, add them to 20 mL of chloroform, stir and dissolve; evaporate at 40°C until a thin film is formed, add distilled water to elute and adjust the volume to 200 mL, adjust the pH to 6.0; filter with a 0.22 μm microporous filter membrane, dispense, and sterilize with autoclave at 121°C for 30 min. In the composite micelle composition, the concentration of 5-isosorbide mononitrate at room temperature is 10 mg / mL.

[0104] Example 10: Preparation of nitroglycerin composite micelle composition using method 3

[0105] Weigh 6.1g of sodium glycocholate, 5.0g of egg yolk lecithin, and 1.0g of nitroglycerin, add them to 40mL of ethanol, and stir to dissolve; evaporate at 40°C until a thin film is produced, add physiological saline to elute and adjust the volume to 200mL, add 20.0g of sucrose, stir to dissolve, adjust the pH to 5.0; filter with a 0.22μm microporous filter membrane, and package. In the composite micelle composition, the concentration of nitroglycerin at room temperature is 5mg / mL. The obtained composite micelle composition is freeze-dried for 48h to obtain a freeze-dried preparation of the nitroglycerin composite micelle composition.

[0106] Example 11: Preparation of nitroglycerin composite micelle composition using method 1

[0107] Weigh 6.4 g of sodium glycocholate and add it to 30 mL of water, stir and dissolve, add 5.6 g of soybean lecithin at 60° C., disperse it by high-speed shearing until it is transparent, then add 0.5 g of nitroglycerin, stir it thoroughly, make the volume to 100 mL, adjust the pH to 5.0, filter it through a 0.22 μm microporous filter membrane, package it, and sterilize it by autoclave at 121° C. for 30 min. In the composite micelle composition, the concentration of nitroglycerin at room temperature is 5 mg / mL.

[0108] Example 12: Stability test of nitroglycerin composite micelle composition

[0109] Several vials of the nitroglycerin composite micelle composition injection (concentration of 5 mg / mL) prepared in Example 11 and a commercially available nitroglycerin injection (dissolved in anhydrous ethanol, concentration of 5 mg / mL) were taken and placed at 40°C and 20°C, respectively, and an accelerated test and a long-term stability test were performed to determine the nitroglycerin content and compare the stability results. The experimental results are as follows:

[0110]

[0111] The experimental results show that in a 6-month accelerated experiment and a long-term experiment, the nitrate or nitrite composite micelle composition of the present application has better stability than the commercially available nitroglycerin injection.

Claims

1. A composite micelle composition comprising nitrate or nitrite, phospholipid, and bile salt, wherein the molar ratio of the nitrate or nitrite to the phospholipid is at least 1:0.1, the molar ratio of the nitrate or nitrite to the bile salt is at least 1:0.1, and the molar ratio of the phospholipid to the bile salt is at least 1:0.

5.

2. The composite micelle composition according to claim 1, wherein the molar ratio of the nitrate or nitrite to the phospholipid is 1:0.1-50, for example 1:0.5, 1:1, 1:1.5, 1:2, 1:5, 1:10, 1:11, 1:15, 1:20, 1:30, 1:40, preferably 1:1-20, more preferably 1:1-10; Preferably, the molar ratio of the nitrate or nitrite to the bile salt is 1:0.1-50, such as 1:0.5, 1:1, 1:1.5, 1:2, 1:5, 1:10, 1:11, 1:15, 1:20, 1:25, 1:30, 1:40, preferably 1:1-25, more preferably 1:1-10; Preferably, the molar ratio of the phospholipid to the bile salt is 1:0.5-5, for example 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.8, 1:2, 1:2.5, 1:3, 1:4, preferably 1:1-3, more preferably 1:1-2.

3. The composite micelle composition of claim 1, wherein the nitrate or nitrite comprises one or more -O-NO2 or -O-NO; preferably, the nitrate or nitrite comprises RO-NO2 or RO-NO, and the R is selected from a C2-C8 hydrocarbon group, a C2-C8 aldehyde group, a C2-C8 ether group, a C2-C8 ketone group, a C2-C8 carboxyl group, a C2-C8 ester group, a hydroxyl group, a phenyl group, a naphthyl group, a phenol group, a 5-10 membered heteroaryl group, and a 5-10 membered heterocyclic group; preferably, the nitrate or nitrite is a polybasic nitrate or a polybasic nitrite; preferably, the polybasic nitrate or a polybasic nitrite is a tribasic nitrate or a tribasic nitrite; preferably, the tribasic nitrate or a tribasic nitrite is nitroglycerin or nitroglycerin; Preferably, the C2-C8 hydrocarbon group is a C2-C8 alkyl, a C2-C8 alkenyl or a C2-C8 alkynyl; preferably, the hydrocarbon group is a straight-chain hydrocarbon group or a branched hydrocarbon group; preferably, the 5-10 membered heteroaryl group or the 5-10 membered heterocyclic group contains 1, 2, 3 or 4 heteroatoms selected from oxygen, nitrogen and sulfur; preferably, the 5-10 membered heteroaryl group or the 5-10 membered heterocyclic group is a monocyclic, condensed, spiro or bridged ring structure; preferably, the 5-10 membered heteroaryl group or the 5-10 membered heterocyclic group is a 5-membered heterocyclic ring and a 5-membered heterocyclic ring or a 5-membered heterocyclic ring and a 6-membered heterocyclic ring.

4. The composite micelle composition according to claim 1, wherein The bile salts include natural bile, cholate and deoxycholate; preferably, the bile salts are deoxycholate, glycocholate, taurocholate and chenodeoxycholate; preferably, the bile salts are sodium salts or potassium salts; preferably, the bile salts are sodium salts or potassium salts of deoxycholate, glycocholate, taurocholate and chenodeoxycholate; preferably, the bile salts are selected from sodium cholate, potassium cholate, sodium deoxycholate, potassium deoxycholate, sodium chenodeoxycholate, potassium chenodeoxycholate, sodium glycocholate, potassium glycocholate, sodium taurocholate and potassium taurocholate; Preferably, the phospholipids include natural phospholipids, semi-synthetic phospholipids, fully synthetic phospholipids and their derivatives; preferably, the phospholipids are selected from soybean lecithin, egg yolk lecithin, egg phosphatidylglycerol, polyene phosphatidylcholine, phosphatidic acid, myocardial phospholipids, sphingomyelin, phosphatidic acid serine, phosphatidylinositol, hydrogenated soybean lecithin (HSPC), hydrogenated egg yolk lecithin (HEPC), distearoylphosphatidylcholine (DSPC), dioleoylphosphatidylcholine (DOPC), dipalmitoylphosphatidylcholine (DPPC), dimyristoylphosphatidylcholine (DMPC), distearoylphosphatidylcholine (DSPE), dipalmitoylphosphatidylethanolamine (DPPE), dioleoylphosphatidylethanolamine (DOPE), dimyristoylphosphatidylethanolamine (DMPE).

5. A method for preparing the composite micelle composition according to any one of claims 1 to 4, comprising: Method 1: (1) dissolving bile salt in water, adding phospholipids, and stirring to disperse; preferably, adding phospholipids at 50° C.-60° C.; (2) adding nitrate or nitrite, stirring until fully dissolved, and adjusting the pH value to 2.0-8.0, preferably 3.0-6.5; (3) Filter to obtain; Method 2: (1) dissolving bile salt in water as the aqueous phase, and dissolving phospholipid in an organic solvent as the organic phase; preferably, the organic solvent is one or more of methanol, ethanol, dichloromethane, chloroform, ethyl acetate, acetonitrile, acetone, propylene glycol, dimethyl sulfoxide, and tetrahydrofuran; (2) adding the organic phase to the aqueous phase, stirring, and adjusting the pH value to 2.0-8.0, preferably 3.0-6.5; (3) removing the organic solvent; preferably, removing the organic solvent by nitrogen blowing or reduced pressure evaporation; (3) Filter to obtain; Wherein, in the step (1), the nitrate or nitrite is dissolved in the organic phase, or in the step (2), the nitrate or nitrite is added after stirring; Method 3: (1) dissolving bile salt and phospholipid in an organic solvent and stirring to dissolve; preferably, the organic solvent is one or more of methanol, ethanol, dichloromethane, chloroform, ethyl acetate, acetonitrile, acetone, propylene glycol, dimethyl sulfoxide, and tetrahydrofuran; (2) removing the organic solvent until it becomes viscous or dry; preferably, removing the organic solvent by nitrogen blowing, reduced pressure evaporation, freeze drying or spray drying; (3) adding a hydrating medium to dissolve, fix the volume, and adjust the pH value to 2.0-8.0, preferably 3.0-6.5; preferably, the hydrating medium is distilled water, physiological saline, isotonic glucose solution or buffer solution; (4) Filter to obtain; Wherein, in the step (1), the nitrate or nitrite is dissolved in the organic phase, or in the step (3), the nitrate or nitrite is added before the volume is constant; In the method 1, method 2 and method 3, the nitrate or nitrite, phospholipid and bile salt and their molar ratio are as described in any one of claims 1 to 4; Preferably, in the method 1, method 2, and method 3, the aqueous solution obtained after filtering is freeze-dried to obtain a freeze-dried powder; Preferably, packaging and / or sterilization are performed after said filtration; Preferably, in the method one, the method two and the method three, the stirring is magnetic stirring, high-speed shearing or high-pressure homogenization.

6. A liquid preparation comprising the composite micelle composition according to any one of claims 1 to 4, water and a pharmaceutically acceptable adjuvant or excipient; Preferably, the auxiliary material or excipient is one or more of a pH regulator, a flavoring agent, a preservative, and an antioxidant; Preferably, the pH adjuster is one or more of hydrochloric acid, malic acid, formic acid and formates, phosphoric acid and phosphates, acetic acid and acetates, boric acid and borates, citric acid and citrates, ammonia water, and sodium hydroxide; Preferably, the liquid preparation is an injection or an oral solution; Preferably, the water is water for injection.

7. A solid preparation comprising the composite micelle composition according to any one of claims 1 to 4 and a pharmaceutically acceptable adjuvant or excipient; Preferably, the auxiliary material or excipient is one or more of a pH regulator, a flavoring agent, a preservative, and an antioxidant; Preferably, the pH adjuster is one or more of hydrochloric acid, malic acid, formic acid and formates, phosphoric acid and phosphates, acetic acid and acetates, boric acid and borates, citric acid and citrates, ammonia water, and sodium hydroxide; Preferably, the solid preparation is a tablet or a capsule.

8. A lyophilized preparation comprising the composite micelle composition according to any one of claims 1 and a pharmaceutically acceptable adjuvant or excipient; Preferably, the auxiliary material or excipient is one or more of a lyoprotectant, a pH adjuster, a flavoring agent, a preservative, and an antioxidant; Preferably, the freeze-drying protective agent is one or more of glucose, sucrose, lactose, trehalose, glycine, mannitol, low molecular weight dextran, cyclodextrin, and soluble starch; Preferably, the pH adjuster is one or more of hydrochloric acid, malic acid, formic acid and formates, phosphoric acid and phosphates, acetic acid and acetates, boric acid and borates, citric acid and citrates, ammonia water, and sodium hydroxide.

9. Use of phospholipids and / or bile salts in improving the solubility, bioavailability and / or stability of nitrates or nitrites; preferably, the nitrates or nitrites are nitroglycerin or nitroglycerin; preferably, the nitrates or nitrites, phospholipids and bile salts and their molar ratios are as described in any one of claims 1 to 4.

10. Use of the composite micelle composition according to any one of claims 1 to 4, the liquid preparation according to claim 6, the solid preparation according to claim 7 or the lyophilized preparation according to claim 8 in the preparation of a medicament for treating and / or preventing myocardial infarction, myocardial infarction, angina pectoris, heart failure, coronary heart disease, cor pulmonale, gastrointestinal bleeding, hypertension, and cardiogenic shock caused by liver disease; preferably, the myocardial infarction, myocardial infarction, angina pectoris, heart failure, coronary heart disease, cor pulmonale, gastrointestinal bleeding, hypertension, and cardiogenic shock caused by liver disease are acute.

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