Preparation and use of targeted NANO kit

Abstract

Provided is a targeted nano-delivery kit comprising an active ingredient, a targeted guiding agent, and an optional delivery carrier and / or polymer, wherein the targeted guiding agent has the following characteristics: (1) it possesses a recognition group in its chemical structure; (2) the recognition group contains one or more of glycosyl groups of n-valent rhamnose, mannose, and galactose, and derivatives thereof; and (3) the recognition group is linked to an aglycone and / or other glycosyl groups of the targeted guiding agent by means of a covalent bond, where 1 ≤ n ≤ 10. The targeted nano-delivery kit has high drug loading and encapsulation efficiency, exhibits no intrinsic cytotoxicity, and can achieve multiple targeted deliveries. It improves the reliability of the delivery system while providing differentiated pharmacokinetic characteristics, reduces the systemic toxicity of undifferentiated system administration in the prior art, reduces first-pass metabolism, and thereby provides a safer, more reliable, and more effective treatment method.

Description

Preparation and application of a targeted nanometer kit TECHNICAL FIELD

[0001] The present application relates to the field of daily chemical and pharmaceutical technology, in particular to a preparation and application of a targeted nanometer kit. BACKGROUND

[0002] Nanotechnology is the strategic technology of the 21st century, which is to prepare and study materials at the nanometer scale and to industrialize them. In the field of pharmacy, various nanotechnologies such as nanoliposomes, polymer nanocapsules and nanospheres have been studied since the 1970s.

[0003] Nanomedicine has high specific surface effect and small size effect. By functionalizing the surface, the rapid elimination of the reticuloendothelial system is prevented, the residence time is prolonged, or the surface of the nanomedicine is modified with antibodies to provide differentiated pharmacokinetic characteristics, so as to achieve the accumulation of the drug in specific tissues and organs, improve the therapeutic effect of the drug, and reduce the systemic toxicity. Therefore, nanomedicine is becoming the most promising delivery technology in the field of targeted therapy. At present, a variety of nanomedicine preparations have been marketed, such as amphotericin B liposome, paclitaxel albumin nanoparticle, paclitaxel micelles, etc. However, ordinary nanomedicine has poor targeting and is easy to cause unintended toxicity.

[0004] At present, lipid nanoparticles, polymer nanoparticles, inorganic nanoparticles and biomimetic nanodelivery systems are mainly used for targeted delivery. On the one hand, the key carriers such as cationic lipid materials have potential toxicity, cannot achieve non-invasive drug delivery, the prepared nanoparticles have large particle size, subcutaneous injection of targeted immune system is easy to be captured by APCs in peripheral tissues and cannot reach the target tissues or organs, the patient compliance of nanometer targeted injection drug for slow disease treatment, the toxicity of multiple dose application, the intrinsic cytotoxicity of nanoparticles, the complex synthesis steps and the controllability of the preparation process become the key to restrict the clinical transformation of targeted delivery.

[0005] Therefore, the targeted therapy of nanomedicine must develop a targeted nanodelivery technology with good biocompatibility, no safety hazards for long-term use, high targeting efficiency, easy control of particle size, high drug loading and encapsulation efficiency, and simple preparation process and easy industrialization.

[0006] SUMMARY

[0007] In order to solve the above problems, the inventors have surprisingly solved the problem after a large number of experiments and obtained unexpected effects, thereby completing the present application.

[0008] In some embodiments, the present application provides a targeted nanodelivery kit, which comprises: an active ingredient and a targeting guide.

[0009] In some embodiments, the present application provides a targeted nanodelivery kit comprising: an active ingredient, a targeting guide, and a delivery vehicle.

[0010] In some embodiments, the present application provides a targeted nanodelivery kit comprising: an active ingredient, a targeting guide, a delivery vehicle, and a polymer.

[0011] In some embodiments, the targeted nanodelivery kit can contain one or more of the active ingredient, the targeting guide, the delivery vehicle, and / or the polymer described herein.

[0012] Targeting guide:

[0013] In this context, a targeting guide refers to a compound or component that is capable of targeting an active ingredient to a target site (e.g., a target tissue and / or organ). In some embodiments, the targeting guide can be prepared as a separate component in the kit (e.g., stored in a separate container) and mixed with the active ingredient at the time of use. In some embodiments, the targeting guide can be prepared as a mixture with the active ingredient stored in the same container in the kit. In some embodiments, the targeting guide preferably has the following characteristics:

[0014] (1) has a recognition group in its chemical structure;

[0015] (2) the recognition group contains one or more of n-valent rhamnose and / or mannose and / or galactose sugar groups and their derivatives (e.g., aldehyde, alcohol, acid, ester, disaccharide, trisaccharide, oligosaccharide, polysaccharide), e.g., 1 < n < 10, e.g., n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10;

[0016] (3) the recognition group is linked to the aglycone and / or other sugar groups of the targeting guide through a covalent bond.

[0017] In some embodiments, the targeting guide is as shown in structural formula (1-1):

[0018] Structural formula (1-1)

[0019] In structural formula (1-1), R1, R2 are independent, R2 is selected from a hydroxyl group or a sugar group, and R1 is selected from an n-valent (1 < n, e.g., 1 < n < 10, e.g., n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10) rhamnose, pyranorhamnose, mannose, pyranomannose, galactose, or pyranogalactose, or a combination thereof, or an oligosaccharide formed by covalent linkage of other sugars, or any of the following (1) to (4) sugar groups:

[0020] In the present context, the recognition group in the targeting guide refers to an oligosaccharide group containing n (1≤n, for example, 1≤n≤10, for example n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10) valent rhamnose, rhamnopyranose, mannose, mannopyranose, galactose or galactopyranose, or a combination thereof or an oligosaccharide formed by covalent linkage of other saccharides, which is capable of being specifically recognized by a target site (e.g. a target tissue and / or organ, a cell, a cell surface lectin, a receptor, a gut flora, an enzyme). The term "n-valent" rhamnose, rhamnopyranose, mannose, mannopyranose, galactose, galactopyranose refers to the total number of rhamnose, rhamnopyranose, mannose, mannopyranose, galactose, galactopyranose residues attached to the carrier hydrophobic backbone. In some embodiments, n can have a value of, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or higher. The saccharide residues containing n-valent rhamnose, rhamnopyranose, mannose, mannopyranose, galactose, galactopyranose are the targeting recognition groups. In some embodiments, the recognition of the n-valent recognition group can facilitate the absorption, transport, release or accumulation of the active ingredient at the target site (e.g. a target tissue and / or organ), thereby enabling differential pharmacokinetic profiles and more effective treatment and / or more precise diagnosis of the disease.

[0021] In some embodiments, the absolute configuration of the recognition group rhamnose, rhamnopyranose, mannose, mannopyranose, galactose, galactopyranose in the targeting guide is D or L, and the relative configuration of the terminal carbon is a or β. Preferably, the absolute configuration of rhamnose is L, and the relative configuration of the terminal carbon is a; the absolute configuration of mannose is D, and the relative configuration of the terminal carbon is β; the absolute configuration of galactose is preferably D, and the relative configuration of the terminal carbon is β.

[0022] In some embodiments, the R2 saccharide group in the targeting guide is selected from the group consisting of glucose, arabinose, xylose, fucose, apiose, glucuronic acid, glucuronide, glucosamine, galacturonic acid, acetylglucosamine, mannose, deoxyglucose, rhamnose, xylose, glucosamine, disaccharides, trisaccharides, oligosaccharides formed by polymerization of any number of any monosaccharides, disaccharides, trisaccharides at any position, preferably the number of monosaccharides is no more than 10.

[0023] In some embodiments, the targeting guide is preferably selected from the group consisting of:

[0024] (1) (2S,3S,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl (4R,4aS,6aR,9R,11aR,11bS)-9-hydroxy-4,11-dimethyltetradecahydro-6a,9- methanocyclohepta[a]naphthalene-4-carboxylate (STL-Man),

[0025] (2) (2S,3S,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl (4R,4aS,6aR,9S,11aR,11bS)-4,11b-dimethyl-8-methylene-9-(((2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)tetradecahydro-6a,9-methanocyclohepta[a]naphthalene-4-carboxylate (RBSD-Acid-Man),

[0026] (3) (2S,3S,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl (4R,4aS,6aR,9S,11aR,11bS)-9-((2S,3R,4S,5S,6R)-4,5-dihydroxy-6-(hydroxymethyl)-3-(((2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)tetrahydro-1H-pyran-2-yl)oxy)-4,11b-dimethyl-8-methylene tetradecahydro-6a,9-methanocyclohepta[a]naphthalene-4-carboxylate (STVB-Man),

[0027] (4) (2S,3S,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl (4R,4aS,6aR,9S,11aR,11bS)-9-((2S,3R,4S,5S,6R)-4,5-dihydroxy-6-(hydroxymethyl)-3-(((2S,3R,4R,5R,6S)-3,4,5-trihydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)tetrahydro-2H-pyran-2-yl)oxy)-4,11b-dimethyl-8-methylenetetradecahydro-6a,9-methanocyclohepta[a]naphthalene-4-carboxylate (DCS-A-Acid-Man),

[0028] (5) (2S,3S,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl (4R,4aS,6aR,9S,11aR,11bS)-9-(((2S,3R,4S,5R,6R)-5-hydroxy-6-(hydroxymethyl)-3,4-bis((2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)tetrahydro-1H-pyran-2-yl)oxy)-4,11b-dimethyl-8-methylenetetradecahydro-6a,9-methanocyclohepta[a]naphthalene-4-carboxylate (RBDS-B-Man),

[0029] (6) (2S,3S,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl (4R,4aS,6aR,9R,11aR,11bS)-9-((2S,3R,4S,5R,6R)-5-hydroxy-6-(hydroxymethyl)-4-(((2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)-3-(((2S,3R,4S,5R)-3,4,5-trihydroxytetrahydro-2H-pyran-2-yl)oxy)tetrahydro-2H-pyran-2- yl)oxy)-4,11b-dimethyltetradecahydro-6a,9-methanocyclohexa[a]naphthalene-4-carboxylate (RBDS-F-Acid-Man),

[0030] (7) (2S,3S,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl (4R,4aS,6aR,9S,11aR,11bS)-9-(((2S,3R,4S,5R,6R)-5-hydroxy-6-(hydroxymethyl)-4-(((2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)-3-(((2S,3R,4R,5R,6S)-3,4,5-trihydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)tetrahydro-2H-pyran-2-yl)oxy)-4,11b-dimethyl-8-methylenetetradecahydro-6a,9-methanocyclohexa[a]naphthalene-4-carboxylate (DCS-B-Man),

[0031] (8) (2S,3S,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl (4R,4aS,6aR,9S,11aR,11bS)-9-(((2S,3R,4S,5R,6R)-3-(((2S,3R,4R,5S,6S)-3,5-dihydroxy-6-methyl-4-(((2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)tetrahydro-2H-pyran-2-yl)oxy)-5-hydroxy-6-(hydroxymethyl)-4-(((2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)tetrahydro-2H-pyran-2-yl)oxy)-4,11b-dimethyl-8-methylenetetradecahydro-6a,9-methanocyclohexa[a]naphthalene-4-carboxylate (RBDS-H-Acid-Man),

[0032] (9) steviol (STVN)-Man,

[0033] (10) a combination of any one or more of (1) to (9),

[0034] (11) (2S,3R,4R,5R,6S)-3,4,5-trihydroxy-6-methyltetrahydro-2H-pyran-2-yl (4R,4aS,6aR,9S,11aR,11bS)-9-(((2S,3R,4S,5S,6R)-4,5-dihydroxy-6-(hydroxymethyl)-3-(((2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)tetrahydro-1H-pyran-2-yl)oxy)-4,11b-dimethyl-8-methylenetetradecahydro-6a,9-methanocyclohepta[a]naphthalene-4-carboxylate (STVB-Rha),

[0035] (12) (2S,3R,4R,5R,6S)-3,4,5-trihydroxy-6-methyltetrahydro-2H-pyran-2-yl (4R,4aS,6aR,9S,11aR,11bS)-4,11b-dimethyl-8-methylen-9-(((2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)tetradecahydro-6a,9-methanocyclohepta[a]naphthalene-4-carboxylate (RBSD-Acid-Rha),

[0036] (13) (2S,3R,4R,5R,6S)-3,4,5-trihydroxy-6-methyltetrahydro-2H-pyran-2-yl (4R,4aS,6aR,9S,11aR,11bS)-9-(((2S,3R,4S,5S,6R)-4,5-dihydroxy-6-(hydroxymethyl)-3-(((2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)tetrahydro-1H-pyran-2-yl)oxy)-4,11b-dimethyl-8-methylenetetradecahydro-6a,9-methanocyclohepta[a]naphthalene-4-carboxylate (STVB-Rha),

[0037] (14) (2S,3R,4R,5R,6S)-3,4,5-trihydroxy-6-methyltetrahydro-2H-pyran-2-yl (4R,4aS,6aR,9S,11aR,11bS)-9-(((2S,3R,4S,5S,6R)-4,5-dihydroxy-6-(hydroxymethyl)-3-(((2S,3R,4R,5R,6S)-3,4,5-trihydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)tetrahydro-2H-pyran-2-yl)oxy)-4,11b-dimethyl-8-methylenetetradecahydro-6a,9-methanocyclohepta[a]naphthalene-4-carboxylate (DCS-A-Acid-Rha),

[0038] (15) (2S,3R,4R,5R,6S)-3,4,5-trihydroxy-6-methyltetrahydro-2H-pyran-2-yl (4R,4aS,6aR,9S,11aR,11bS)-9-(((2S,3R,4S,5R,6R)-5-hydroxy-6-(hydroxymethyl)- 4-(((2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)- 3-(((2S,3R,4R,5R,6S)-3,4,5-trihydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)tetrahydro- 2H-pyran-2-yl)oxy)-4,11b-dimethyl-8-methylenetetradecahydro-6a,9- methno-cyclohepta[a]naphthalene-4-carboxylate (RBDS-B-Rha),

[0039] (16) (2S,3R,4R,5R,6S)-3,4,5-trihydroxy-6-methyltetrahydro-2H-pyran-2-yl (4R,4aS,6aR,9S,11aR,11bS)-9-(((2S,3R,4S,5R,6R)-5-hydroxy-6-(hydroxymethyl)- 4-(((2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)- 3-(((2S,3R,4R,5R,6S)-3,4,5-trihydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)tetrahydro- 2H-pyran-2-yl)oxy)-4,11b-dimethyl-8-methylenetetradecahydro-6a,9- methno-cyclohepta[a]naphthalene-4-carboxylate (DCS-B-Rha),

[0040] (17) (2S,3R,4R,5R,6S)-3,4,5-trihydroxy-6-methyltetrahydro-2H-pyran-2-yl (4R,4aS,6aR,9R,11aR,11bS)-9-((2S,3R,4S,5R,6R)-5-hydroxy-6-(hydroxymethyl)-4-(((2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)- 3-(((2S,3R,4S,5R)-3,4,5-trihydroxytetrahydro-2H-pyran-2-yl)oxy)tetrahydro-2H-pyran- 2-yl oxy)-4,11b-dimethyltetradecahydro-6a,9-methno-cyclohepta[a]naphthalene-4- carboxylate (RBDS-F-Acid-Rha),

[0041] (18) (2S,3R,4R,5R,6S)-3,4,5-trihydroxy-6-methyltetrahydro-2H-pyran-2-yl (4R,4aS,6aR,9S,11aR,11bS)-9-(((2S,3R,4S,5R,6R)-3-(((2S,3R,4R,5S,6S)-3,5-dihydroxy-6-methyl-4-(((2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)tetrahydro-1H-pyran-2-yl)oxy)-5-hydroxy-6-(hydroxymethyl)-4-(((2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)tetrahydro-1H-pyran-2-yl)oxy)-4,11b-dimethyl-8-methylenetetradecahydro-6a,9-methanocyclohepta[a]naphthalene-4-carboxylate (RBDS-H-Acid-Rha),

[0042] (19) steviol-Rha,

[0043] (20) a combination of one or more of (1)-(19),

[0044] (21) (2S,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl (4R,4aS,6aR,9S,11aR,11bS)-9-hydroxy-4,11b-dimethyl-8-methylenetetradecahydro-6a,9-methanocyclohepta[a]naphthalene-4-carboxylate (STL-Gal),

[0045] (22) (2S,3R,4R,5R,6S)-3,4,5-trihydroxy-6-methyltetrahydro-2H-pyran-2-yl (4R,4aS,6aR,9S,11aR,11bS)-4,11b-dimethyl-8-methylen-9-(((2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)tetradecahydro-6a,9-methanocyclohepta[a]naphthalene-4-carboxylate (RBSD-Acid-Gal),

[0046] (23) (2S,3R,4R,5R,6S)-3,4,5-trihydroxy-6-methyltetrahydro-2H-pyran-2-yl (4R,4aS,6aR,9S,11aR,11bS)-9-(((2S,3R,4S,5S,6R)-4,5-dihydroxy-6-(hydroxymethyl)-3-(((2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)tetrahydro-1 H-pyran-2-yl)oxy)-4,11 b-dimethyl-8-methylenetetradecahydro-6a,9-methanocyclohepta[a]naphthalene-4-carboxylate (STVB-Gal),

[0047] (24) (2S,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2- yl (4R,4aS,6aR,9S,11aR,11bS)-9-((2S,3R,4S,5R,6R)-5-hydroxy-6-(hydroxymethyl)-3,4- bis((2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy) tetrahydro-1 H-pyran-2-yl)oxy)-4,11 b-dimethyl-8-methylenetetradecahydro-6a,9- methanocyclohepta[a]naphthalene-4-carboxylate (RBDS-B-Gal),

[0048] (25) (2S,3R,4S,5R)-3,4,5-trihydroxytetrahydro-2H-pyran-2-yl (4R,4aS,6aR,9S,11aR,11bS)-9-(((2S,3R,4S,5R,6R)-5-hydroxy-6-(hydroxymethyl)-4-(((2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)-3-(((2S,3R,4R,5R,6S)-3,4,5-trihydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)tetrahydro-2H-pyran-2-yl)oxy)-4,11 b-dimethyl-8-methylenetetradecahydro-6a,9-methanocyclohepta[a]naphthalene-4-carboxylate (DCS-A-Acid-Gal),

[0049] (26) (2S,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2- yl (4R,4aS,6aR,9S,11aR,11bS)-9-(((2S,3R,4S,5R,6R)-5-hydroxy-6- (hydroxymethyl)-4-(((2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6- (hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)-3-(((2S,3R,4S,5R)-3,4,5- trihydroxytetrahydro-2H-pyran-2-yl)oxy)tetrahydro-2H-pyran-2-yl)oxy)-4,11b- dimethyl-8-methylenetetradecahydro-6a,9-methanocyclohexa[a]naphthalene-4- carboxylate (DCS-B-Gal),

[0050] (27) (2S,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2- yl (4R,4aS,6aR,9S,11aR,11bS)-9-(((2S,3R,4S,5R,6R)-5-hydroxy-6- (hydroxymethyl)-4-(((2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6- (hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)-3-(((2S,3R,4S,5R)-3,4,5- trihydroxytetrahydro-2H-pyran-2-yl)oxy)tetrahydro-2H-pyran-2-yl)oxy)-4,11b- dimethyl-8-methylenetetradecahydro-6a,9-methanocyclohexa[a]naphthalene-4- carboxylate (RBDS-F-Acid-Gal),

[0051] (28) (2S,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2- yl (4R,4aS,6aR,9S,11aR,11bS)-9-(((2S,3R,4S,5R,6R)-3-(((2S,3R,4R,5S,6S)-3,5- dihydroxy-6-methyl-4-(((2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6- (hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)tetrahydro-2H-pyran-2-yl)oxy)-5- hydroxy-6-(hydroxymethyl)-4-(((2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6- (hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)tetrahydro-2H-pyran-2-yl)oxy)-4,11b- dimethyl-8-methylenetetradecahydro-6a,9-methanocyclohexa[a]naphthalene-4- carboxylate (RBDS-H-Acid-Gal),

[0052] (29) steviol-Gal,

[0053] (30) a combination of any one or more of (1) to (29);

[0054] (31) (2S, 3S, 4S, 5S)-2,3,4,5-tetrahydroxyhexyl (4R, 4aS, 6aR, 9S, 11aR, 11bS)-9-((2S, 3R, 4S, 5R, 6R)-5-hydroxy-6-(hydroxymethyl)-3,4-bis((2S, 3R, 4S, 5S, 6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)tetrahydro-2H-pyran-2-yloxy)-4, 11b-dimethyl-8-methylenetetrahydro-6a, 9-methanocyclohepta[a]naphthalene-4-carboxylate (RBDS-B-GaOH),

[0055] (32) a derivative of steviol glycoside (dulcoside-B) with hyaluronic acid, amino acid, polypeptide, alkyl alcohol, monosaccharide, disaccharide, trisaccharide, oligosaccharide, polysaccharide, polyglutamic acid, polylysine, glycoside, polyarginine, and a cell-penetrating peptide, etc. by an ester bond, an amide bond;

[0056] (33) a combination of any one or more of (1) to (32).

[0057] The above-mentioned targeting guide can also serve as or simultaneously serve as a delivery carrier.

[0058] Delivery carrier:

[0059] In the present disclosure, the delivery carrier is not particularly limited, which can refer to a material that can assist or carry another substance(s) (such as an active ingredient) into a biological body after assembly. In some embodiments, the delivery carrier can affect the odor, solubility, stability, mucosal irritation, hydration rate, release, absorption, tissue distribution, metabolism, and / or clearance of the delivered substance during the delivery process or in the biological body. In some embodiments, the delivery carrier is composed of a covalent linkage of Unit A and Unit B, wherein Unit A is a hydrophilic moiety and Unit B is a hydrophobic moiety, wherein Unit A is located on one side or both sides of Unit B, and when Unit A is located on both sides of Unit B, Unit A can be the same or different; wherein the number ratio of Unit A to Unit B is (0: 1) to (7: 1).

[0060] In some embodiments, wherein Unit A is selected from one or more of A1 or a derivative of A1, wherein:

[0061] A1 is selected from a monosaccharide, a disaccharide, a trisaccharide, or a combination thereof in D form or L form,

[0062] wherein the monosaccharide is selected from the group consisting of glucose, rhamnose, galactose, arabinose, xylose, mannose, fucose, apiose, glucuronic acid, glucuronide, glucosamine, galacturonic acid, acetylglucosamine, and combinations thereof, and the relative configuration of the anomeric carbon of each saccharide can be either alpha or beta;

[0063] the disaccharide is selected from the group consisting of sophorose (glcl-2glc), gentiobiose (glcl-6glc), rhamnose (rhall-6glc), neohesperidose (rhall-6glc), robinobiose (rhall-6gal), and combinations thereof;

[0064] the trisaccharide is selected from the group consisting of gentiatriose, sophorotriose (glcl-2glcl-2glc), and combinations thereof;

[0065] In some embodiments, wherein the derivative of A1 is an acylate of A1, such as 2-acetylglucose, caffeylglucose.

[0066] In some embodiments, wherein unit B is selected from one or more of B1, or one or more of B2, wherein:

[0067] (1) B1 is a compound of formula (C5H8)n, wherein n = 4 or 6, and alcohols, aldehydes, ketones, carboxylic acids, or ester derivatives thereof;

[0068] (2) B2 is a compound having a basic skeleton of C6-C3-C6 with 2- phenylchromone as the basic nucleus, wherein the two benzene rings (A-ring and B-ring) are connected to each other through a central three-carbon chain, and derivatives thereof (such as halogenated compounds, such as chlorinated or fluorinated compounds, or amino acid esters, wherein the hydroxyl group on C6 is esterified with an amino acid);

[0069] Preferably, unit B is B1, more preferably a tetracyclic diterpene, a tetracyclic triterpene, a pentacyclic triterpene, or an alcohol, aldehyde, ketone, carboxylic acid, or ester derivative thereof.

[0070] Preferably, the hydrophobic unit B1 is a kaurene-type tetracyclic diterpene and derivatives thereof (such as alcohols, aldehydes, ketones, carboxylic acids, or esters).

[0071] In some embodiments, the hydrophobic unit B1 is preferably one or more of dammarane-type, tirucallane-type, cycloartane-type, lanostane-type, cucurbitane-type, meliatoxine-type, and protostane-type, and derivatives thereof (such as alcohols and esters), more preferably cucurbitane-type and derivatives thereof (such as alcohols and esters).

[0072] In some embodiments, the hydrophobic unit B1 is preferably one or more of oleanane-type, ursane-type, lupine-type, friedelane-type, hopane-type, and isohopane-type, and derivatives thereof (such as alcohols, ketones, carboxylic acids, and esters).

[0073] In some embodiments, the ester derivative of B1 is preferably an ester formed from a carboxylic acid derivative, such as a gluconate, a polyethylene glycol ester, a propylene glycol ester, a methyl ester, an ethyl ester, or a 1-aminoglycine ester.

[0074] In some embodiments, the hydrophobic unit B1 is preferably:

[0075] (1) when the unit B1 is a kaurene-type tetracyclic diterpene or a pharmaceutically acceptable salt thereof (such as a sodium salt, a potassium salt, an ammonium salt), a hydrate of a kaurene-type tetracyclic diterpene or a pharmaceutically acceptable salt thereof (such as a hydrate formed with 0.5, 1, 1.5, 2, 2.5, or 3 crystal waters), the carrier has the structure of structural formula (2-1);

[0076] Structural formula (2-1);

[0077] wherein R1, R2 are independently selected from the following groups:

[0078] or

[0079] (2) when the unit B1 is a cucurbitane-type tetracyclic triterpene or a pharmaceutically acceptable hydrate or solvate thereof, the carrier has the structure of structural formula (2-2):

[0080] Structural formula (2-2)

[0081] wherein R1 and R2 represent unit A, and R1 and R2 are present simultaneously or separately, R1, R2, R3, R4 are independently selected from the following groups:

[0082] or

[0083] (3) when the unit B1 is an oleanane-type pentacyclic triterpene or a pharmaceutically acceptable hydrate or solvate thereof, the carrier has the structure of structural formula (2-3):

[0084] Structural formula (2-3)

[0085] wherein R1 is selected from the following groups:

[0086] The unit B can be B2, selected from the group consisting of flavonols (such as represented by structural formula (2-4)), or dihydrochalcones (such as represented by structural formula (2-5)), and combinations thereof, wherein the structures of structural formula (2-4), structural formula (2-5) are as follows:

[0087] In some embodiments, the delivery vehicle is preferably selected from the group consisting of:

[0088] (1) (1R,4S,5R,9S,10R,13S)-13-[(2S,3R,4S,5R,6R)-5-hydroxy-6-(hydroxymethyl)- 3,4-bis[[(2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy]oxan- 2-yl]oxy-5,9-dimethyl-14-methylenetetradecalone-5-carboxylate sodium salt (RBDS-B-Na),

[0089] (2) (1R,4S,5R,9S,10R,13S)-13-[(2S,3R,4S,5S,6R)-4,5-dihydroxy-6-(hydroxymethyl)- 3-[(2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxyoxan-2-yl]oxy- 5,9-dimethyl-14-methylenetetradecalone-5-carboxylate sodium salt (STVB-Na),

[0090] (3) [(2S,3R,4S,5R,6R)-5-hydroxy-6-(hydroxymethyl)-3,4-bis[[(2S,3R,4S,5S,6R)-3,4,5- trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy]oxan-2-yl](1R,4S,5R,9S,10R,13S)-13-[(2S,3R,4S,5R,6R)-5-hydroxy-6-(hydroxymethyl)-3,4-bis[(2S,3R,4S,5S,6R)-3,4,5- trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy]oxan-2-yl]oxy-5,9-dimethyl-14- methylenetetradecalone-5-carboxylate (RBDS-M),

[0091] (4) (2S,3R,4S,5S,6R)-4,5-dihydroxy-6-(hydroxymethyl)-3-[(2S,3R,4S,5S,6R)-3,4,5- trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxyoxan-2-yl]oxy-5,9-dimethyl-14- methylenetetracyclo[11.2.1.01,10.04,9]hexadecane-5-carboxylate (RBDS-D),

[0092] (5) [(2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl] (1R,4S,5R,9S,10R,13S)- 13-[(2S,3R,4S,5R,6R)-5-hydroxy-6-(hydroxymethyl)-3,4-bis[[(2S,3R,4S,5S,6R)-3,4,5- trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy]oxan-2-yl]oxy-5,9-dimethyl-14- methylenetetracyclo[11.2.1.01,10.04,9]hexadecane-5-carboxylate (RBDS-A),

[0093] (6) (1R,4S,5R,9S,10R,13S)-13-[(2S,3R,4S,5R,6R)-5-hydroxy-6-(hydroxymethyl)-3,4-bis[[(2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy]oxan-2-yl]oxy-5,9- dimethyl-14-methylenetetracyclo[11.2.1.01,10.04,9]hexadecane-5-carboxylic acid (RBDS-B),

[0094] (7) [(2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl] (1R,4S,5R,9S,10R,13S)- 13-[(2S,3R,4S,5S,6R)-4,5-dihydroxy-6-(hydroxymethyl)-3-[(2S,3R,4S,5S,6R)-3,4,5- trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxyoxan-2-yl]oxy-5,9-dimethyl-14- methylenetetracyclo[11.2.1.01,10.04,9]hexadecane-5-carboxylate (STVS),

[0095] (8) (1R,4S,5R,9S,10R,13S)-13-[(2S,3R,4S,5S,6R)-4,5-dihydroxy-6- (hydroxymethyl)-3-[(2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6- (hydroxymethyl)oxan-2-yl]oxyoxan-2-yl]oxy-5,9-dimethyl-14- methylenetetracyclo[11.2.1.01,10.04,9]hexadecan-5- carboxylic acid (STVB),

[0096] (9) [(2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl] (1R,4S,5R,9S,10R,13S)-5,9-dimethyl-14-methylen-13-[(2S,3R,4S,5S,6R)-3,4,5- trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxytetracyclo[11.2.1.01,10.04,9]hexadecan-5- carboxylate (RBSD),

[0097] (10) [(2S,3R,4S,5S,6R)-4,5-dihydroxy-6-(hydroxymethyl)-3-[(2S,3R,4S,5S,6R)-3,4,5- trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxyoxan-2-yl] (1R,4S,5R,9S,10R,13S)-13-[(2S,3R,4S,5S,6R)-4,5-dihydroxy-6-(hydroxymethyl)-3-[(2S,3R,4S,5S,6R)-3,4,5- trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxyoxan-2-yl]oxy-5,9-dimethyl-14- methylenetetracyclo[11.2.1.01,10.04,9]hexadecan-5-carboxylate (RBDS-E),

[0098] (11) [(2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl] (1R,4S,5R,9S,10R,13S)-13-[(2S,3R,4S,5R,6R)-5-hydroxy-6-(hydroxymethyl)-4-[(2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6- (hydroxymethyl)oxan-2-yl]oxy-3-[(2S,3R,4S,5R)-3,4,5-trihydroxyoxan-2-yl]oxyoxan-2- yl]oxy-5,9-dimethyl-14-methylenetetracyclo[11.2.1.01,10.04,9]hexadecan-5-carboxylate (RBDS-F),

[0099] (12) (2S,3R,4S,5R,6R)-5-hydroxy-6-(hydroxymethyl)-3,4-bis(((2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)tetrahydro-2H-pyran-2-yl (4R,4aS,6aR,9S,11aR,11bS)-9-(((2S,3R,4S,5S,6R)-4,5-dihydroxy-6-(hydroxymethyl)-3-(((2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)tetrahydro-2H-pyran-2-yl)oxy)-4,11b-8-methylenetetradecahydro-6a,9-methyicyclohepta[a]naphthalene-4-carboxylic acid dimethyl ester (RBDS-AM),

[0100] (13) [(2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl](1R,4S,5R,9S,10R,13S)-13-[(2S,3R,4S,5R,6R)-5-hydroxy-6-(hydroxymethyl)-4-[(2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-3-[(2S,3R,4R,5R,6S)-3,4,5-trihydroxy-6-methyloxan-2-yl]oxyoxan-2-yl]oxy-5,9-dimethyl-14-methylenetetracyclo[11.2.1.01,10.04,9]hexadecane-5-carboxylate (RBDS-C),

[0101] (14) [(2S,3R,4S,5S,6R)-4,5-dihydroxy-6-(hydroxymethyl)-3-[(2S,3R,4R,5R,6S)-3,4,5-trihydroxy-6-methyloxan-2-yl]oxan-2-yl](1R,4S,5R,9S,10R,13S)-13-[(2S,3R,4S,5R,6R)-5-hydroxy-6-(hydroxymethyl)-3,4-bis[(2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy]oxan-2-yl]oxy-5,9-dimethyl-14-methylenetetracyclo[11.2.1.01,10.04,9]hexadecane-5-carboxylate (RBDS-J),

[0102] (15) (2S,3R,4S,5S,6R)-4,5-dihydroxy-6-(hydroxymethyl)-3-(((2S,3R,4S,5S,6R)- 3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)tetrahydro- 2H-pyran-2-yl (4R,4aS,6aR,9S,11aR,11bS)-9-(((2S,3R,4S,5R,6R)-5- hydroxy-6-(hydroxymethyl)-4-(((2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6- (hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)-3-(((2S,3R,4R,5R,6S)-3,4,5- trihydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)tetrahydro-2H-pyran-2- yl)oxy)-4,11b-dimethyl-8-methylenetetrahydro-6a,9-methanocyclohepta[a]naphthalene- 4-carboxylate (RBDS-K),

[0103] (16) [(2S,3R,4S,5R,6R)-5-hydroxy-6-(hydroxymethyl)-4-[(2S,3R,4S,5S,6R)-3,4,5- trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-3-[(2S,3R,4R,5R,6S)-3,4,5-trihydroxy- 6-methyloxan-2-yl]oxan-2-yl] (1R,4S,5R,9S,10R,13S)-13-[(2S,3R,4S,5R,6R)-5- hydroxy-6-(hydroxymethyl)-3,4-bis[[(2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6- (hydroxymethyl)oxan-2-yl]oxy]oxan-2-yl]oxy-5,9-dimethyl-14- methylenetetracyclo[l l l.2.1.01,10.04,9]eicosane-5-carboxylate (RBDS-N),

[0104] (17) [(2S,3R,4S,5R,6R)-3-[(2S,3R,4R,5S,6S)-3,5-dihydroxy-6-methyl-4-[(2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxan-2-yl]oxy-5-hydroxy-6-(hydroxymethyl)-4-[(2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxan-2-yl] (1R,4S,5R,9S,10R,13S)-13-[(2S,3R,4S,5R,6R)-5-hydroxy-6-(hydroxymethyl)-3,4-bis[[(2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy]oxy]oxan-2-yl]oxy-5,9-dimethyl-14-methylenetetradecahydro-6a,9-methenocyclohepta[a]naphthalene-4-carboxylate (RBDS-O),

[0105] (18) [(2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl] (1R,4S,5R,9S,10R,13S)-13-[(2S,3R,4S,5S,6R)-4,5-dihydroxy-6-(hydroxymethyl)-3-[(2S,3R,4R,5R,6S)-3,4,5-trihydroxy-6-methyl oxan-2-yl]oxyoxan-2-yl]oxy-5,9-dimethyl-14-methylenetetradecahydro-6a,9-methenocyclohepta[a]naphthalene-4-carboxylate (DCS-A),

[0106] (19) (4R,4aS,6aR,9S,11aR,11bS)-9-(((2S,3R,4S,5R,6R)-5-hydroxy-6-(hydroxymethyl)-4-(((2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)-3-(((2R,3R,4R,5R,6S)-3,4,5-trihydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)tetrahydro-2H-pyran-2-yl)oxy)-4,11b-dimethyl-8-methylenetetradecahydro-6a,9-methenocyclohepta[a]naphthalene-4-carboxylic acid (DCS-B),

[0107] (20) (4R,4aS,6aR,9S,11aR,11bS)-9-hydroxy-4,11b-dimethyl-8-methylenetetradecahydro-6a,9-methenocyclohepta[a]naphthalene-4-carboxylic acid (STL),

[0108] (21) Methyl (4R,4aS,6aR,9S,11aR,11bS)-9-(((2S,3R,4S,5R,6R)-5-hydroxy-6- (hydroxymethyl)-3,4-bis((2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6- (hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)tetrahydro-2H-pyran-2-yl)oxy)- 4,11b-dimethyl-8-methylenetetrahydro-6a,9-methylcyclohepta[a]naphthalene-4- carboxylate (RBDS-B-Methyl),

[0109] (22) Ethyl (4R,4aS,6aR,9S,11aR,11bS)-9-(((2S,3R,4S,5R,6R)-5-hydroxy-6- (hydroxymethyl)-3,4-bis((2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6- (hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)tetrahydro-2H-pyran-2-yl)oxy)- 4,11b-dimethyl-8-methylenetetrahydro-6a,9-methylcyclohepta[a]naphthalene-4- carboxylate (RBDS-B-Ethyl),

[0110] (23) Steviol,

[0111] (24) A group consisting of any one or more of (1) to (23);

[0112] (25) (2R,3S,4S,5R,6R)-2-(hydroxymethyl)-6-({[(2R,3S,4S,5R,6S)-3,4-dihydroxy-6- {[(3R,6R)-2-hydroxy-6-[(1R,3aS,3bS,7S,9aR,9bR,10R,11aR)-10-hydroxy-7- {[(2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-({[(2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6- (hydroxymethyl)-3,4,5,6-tetrahydro-2H-pyran-2-yl]oxy}methyl)-3,4,5,6- tetrahydro-2H-pyran-2-yl]oxy}-3a,6,6,9b,11a-pentamethyl-2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]-2- methylheptan-3-yl]oxy}-5-{[(2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6- (hydroxymethyl)-3,4,5,6-tetrahydro-2H-pyran-2-yl]oxy}-3,4,5,6-tetrahydro-2H- pyran-2-yl]methyl}oxy)tetrahydropyran-3,4,5-triol (MGSD-V, Mogroside V),

[0113] (26) (3S,8S,9R,10R,13R,14S,17R)-17-((2R,5R)-5-((((2S,3R,4S,5S,6R)-4,5- dihydroxy-3-(((2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H- pyran-2-yl)oxy)-6-((((2R,3R,4S),5S,6R)-3,4,5-trihydroxy-6- (hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)methyl)tetrahydro-2H-pyran-2- yl)oxy)-6-hydroxy-6-methylheptan-2-yl)-4,4,9,13,14-pentamethyl-3-(((2R,3R,4S,5S,6R)- 3,4,5-trihydroxy-6-((((2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6- (hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)methyl)tetrahydro-2H-pyran-2-yl)oxy)- 1,2,3,4,7,8,9,10,12,13,14,15,16,17-tetradecahydro-11H-cyclopenta[a]phenanthren-11-one (OMGSD-V, 11-Oxo-Mogroside V / 11-oxo-mogroside V),

[0114] (27) (2S,3R,4S,5S,6R)-2-(((2S,3R,4S,5S,6R)-4,5-dihydroxy-2-(((3R,6R)-2-hydroxy-6- (3S,8S,9R,10R,11R,13R,14S,17R)-11-hydroxy-4,4,9,13,14-pentamethyl-3-(((2R,3R,4S,5S,6R)- 3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2- methylheptan-3-yl)oxy)-6-((((2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6- (hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)methyl)tetrahydro-2H-pyran-3-yl)oxy)- 6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (SMSD-I, Siamenoside I / Siamenoside I),

[0115] (28) (2R,3R,4S,5S,6R)-2-(((3S,8R,9R,10S,11R,13R,14S,17R)-17-((2R,5R)-5,6- dihydroxy-6-methylheptan-2-yl)-11-hydroxy-4,4,13,14-tetramethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl)oxy)-6- (hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (MGSD-IE1, Mogroside IE1 / Luo Han Guo Glycosides IE1),

[0116] (29) a group consisting of any one or more of (24) to (27) (MGSDT),

[0117] (30) any combination of (1) to (29),

[0118] (31) (2S)-7-[(2S,3R,4S,5S,6R)-4,5-dihydroxy-6-(hydroxymethyl)-3-[(2S,3R,4R,5R,6S)-3,4,5- trihydroxy-6-methyloxan-2-yl]oxyoxan-2-yl]oxy-5-hydroxy-2-(3-hydroxy-4-methoxyphenyl)- 2,3-dihydrochromen-4-one (NHPD, Neohesperidin / new orange peel glycosides),

[0119] (32) 1-[4-[(2S,3R,4S,5S,6R)-4,5-dihydroxy-6-(hydroxymethyl)-3-[(2S,3R,4R,5R,6S)-3,4,5- trihydroxy-6-methyloxan-2-yl]oxyoxan-2-yl]oxy-2,6-dihydroxyphenyl]-3-(3-hydroxy-4- methoxyphenyl)propan-1-one (NHDC, Neohesperidin Dihydrochalcone / new orange peel glycosides dihydrochalcone),

[0120] (33) 1-[4-[(2S,3R,4S,5S,6R)-4,5-dihydroxy-6-(hydroxymethyl)-3-[(2S,3R,4R,5R,6S)-3,4,5- trihydroxy-6-methyloxan-2-yl]oxyoxan-2-yl]oxy-2,6-dihydroxyphenyl]-3-(4-hydroxyphenyl)propan- 1-one (NRGDC, Naringin dihydrochalcone / naringin dihydrochalcone),

[0121] (34) (2S)-7-[(2S,3R,4S,5S,6R)-4,5-dihydroxy-6-(hydroxymethyl)-3-[(2S,3R,4R,5R,6S)-3,4,5-trihydroxy-6-methyloxan-2-yl]oxymethyloxan-2-yl]oxy-5-hydroxy-2-(4-hydroxyphenyl)-2,3-dihydrochromen-4-one (NRG, Naringin),

[0122] (35) (2S)-5-hydroxy-2-(3-hydroxy-4-methoxyphenyl)-7-[(2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-[[(2R,3R,4R,5R,6S)-3,4,5-trihydroxy-6-methyloxan-2-yl]hydroxymethyl]oxan-2-yl]oxy-2,3-dihydrochromen-4-one (HPD, Hesperidin),

[0123] (36) (2S)-7-[(2S,3R,4R,5S,6R)-3,4-dihydroxy-5-[oxan-2-yl]oxy-6-[(2R,3R,4R,5R,6S)-3,4,5-trihydroxy-6-methyloxan-2-yl]oxymethyl]oxan-2-yl]oxy-5-hydroxy-2-(3-hydroxy-4-methoxyphenyl)-2,3-dihydrochromen-4-one (alpha-GHPD, alpha-Glucosyl hesperidin),

[0124] (37) 1 -membered group consisting of any one or more of (36).

[0125] Polymer:

[0126] In some embodiments, the polymer is selected from the group consisting of:

[0127] (1) a cellulose-based polymer such as hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose acetate succinate (HPMCAS), sodium carboxymethylcellulose (CMC-Na) or hydroxyethyl cellulose;

[0128] (2) synthetic polymers: such as polyethylene glycol (PEG), polyvinyl alcohol (PVA), polyvinylpyrrolidone (PVP), copolyvidone (PVP-VA64), polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus), polyglutamic acid (PGA), polydopamine (PDA), polylactic acid (PLA), poly-L-lactic acid (PLLA), poly(lactic-co-glycolic acid) (PLGA), sodium polyacrylate, siRNA and derivatives (alkyl chains to improve lipophilicity), mRNA and derivatives (alkyl chains to improve lipophilicity), or antisense oligonucleotides and derivatives (alkyl chains to improve lipophilicity), polyethylene glycol-15 hydroxystearate;

[0129] (3) polysaccharides, proteins and their derivatives (such as carboxymethylation, sulfonylation, phosphorylation, acylation or hydroxypropylation, cationic, anionic or other derivatives), such as carrageenan, guar gum, gum arabic, locust bean gum, konjac gum, agar, gelatin, pectin, gellan gum, hyaluronic acid (HA), aminodextran, chondroitin sulfate, dermatan sulfate, heparin, keratan sulfate, heparan sulfate, sodium alginate, propylene glycol alginate, agar, fucoidan, cyclodextrin and derivatives, chitosan and derivatives (such as acylation, carboxylation, alkylation and quaternization, etc.), soy protein, vegetable protein or bovine serum albumin;

[0130] and combinations thereof.

[0131] active ingredients:

[0132] In this context, the active ingredients included in the kit are not particularly limited, for example, the active ingredients can be bioactive agents, chemical active agents or adjuvants, dietary supplement functional ingredients. In some embodiments, the active ingredients preferably show any one or more of the following advantages when combined with the targeting guide agents described herein, and optionally the delivery carriers and / or polymers, compared to control compositions (e.g. compositions not comprising one or more components described herein or commercially available products containing the same active ingredients): are able to be specifically delivered to a specific target site (e.g. the target tissue and / or organ where the active ingredient is intended to act) or show higher drug concentration or drug exposure at the specific target site (e.g. the target tissue and / or organ where the active ingredient is intended to act) compared to non-target sites, are able to achieve multiple targeted delivery, show improved permeability, solubility, stability, drug loading, encapsulation efficiency, delivery system reliability, pharmacokinetic / pharmacodynamic specificity and / or show differential pharmacokinetic characteristics, show reduced administration dose, first-pass metabolism, intrinsic cytotoxicity, systemic toxicity and / or non-target organ toxicity, etc.

[0133] In some embodiments, the active ingredient is selected from the group consisting of: a protein / polypeptide, a polysaccharide / oligosaccharide, a nucleic acid or nucleic acid fragment, a lipid, a nutritional element, a small organic molecule compound or composition, a bacteriophage particle, a superparamagnetic substance, a vaccine, a diagnostic reagent, an imaging agent, a cell, or any combination thereof.

[0134] In some embodiments, the active ingredient is preferably those active ingredients that become a point of pain for patients and / or physicians in terms of pharmacodynamics and / or pharmacokinetics and / or pharmaceutical and / or pharmacotherapeutic properties, including but not limited to:

[0135] (1) active ingredients with very low permeability under existing delivery technologies; and / or (2) active ingredients with limited solubility and / or stability, which must be administered in large doses to achieve therapeutic purposes, resulting in poor user compliance; and / or (3) active ingredients that must be administered systemically under existing delivery technologies and have serious systemic or non-target organ toxicity; and / or (4) one or more of active ingredients that have low pharmacokinetic / pharmacodynamic specificity and / or low therapeutic index under current administration methods.

[0136] Supramolecular nanocomplexes:

[0137] In the present context, "supramolecular nanocomplex" can refer to a multi-molecular group assembled by non-covalent interaction of various components, preferably having a particle size in the range of 1-500 nm, more preferably in the range of 1-100 nm, such as 1 nm, 5 nm, 10 nm, 20 nm, 30 nm, 40 nm, 50 nm, 60 nm, 70 nm, 80 nm, 90 nm, 100 nm, 110 nm, 120 nm, 130 nm, 140 nm, 150 nm, 160 nm, 170 nm, 180 nm, 190 nm, 200 nm, 250 nm, 300 nm, 350 nm, 400 nm, 450 nm, 500 nm, or any range therebetween. The supramolecular nanocomplex of the present application can comprise an active ingredient and a targeting guide, and optionally a delivery carrier, a polymer and / or an additive, etc., preferably having a hyperbranched structure, more preferably having physical and chemical stability, and when part of the groups are metabolized by enzymes, the intermediate of the metabolized carrier still has a hyperbranched structure, and can quickly reassemble with the active ingredient, i.e., having an online editing and self-repairing function. The term "hyperbranched" refers to a class of highly branched three-dimensional molecules, which have abundant terminal functional groups due to the branched structure, and are easy to modify, and are more conducive to the formation of functional materials by self-assembly of non-covalent bonds between molecules. Such molecules can be small molecules or high molecular polymers. In some embodiments, the supramolecular nanocomplex of the present application preferably has one or more advantages compared to a control (e.g., a composition not comprising one or more components of the present application or a commercially available product containing the same active ingredient). In some embodiments, the properties and / or advantages of the supramolecular nanocomplex can be determined by comparing one or more aspects such as drug loading concentration, nanocomplex properties, particle size, PDI, Zeta potential, stability, dissolution characteristics, tissue distribution, therapeutic activity (e.g., tumor therapeutic activity), and side effects (e.g., systemic toxicity). In some embodiments, the different components in the supramolecular nanocomplex of the present application can exhibit a synergistic effect that is much better than the sum of the performance of each single component.

[0138] Dosage of each component of the targeting kit:

[0139] In some embodiments, the mass ratio of the active ingredient to the sum of [targeting guide + delivery carrier] is 1 :0.15-1 :25, preferably 1 :0.25, 1 :0.5, 1 :0.75, 1 :1, 1 :1.5, 1 :2, 1 :2.5, 1 :3, 1 :5, 1 :10, 1 :15, 1 :20, 1 :25; the targeting guide accounts for 5%-100% of the total mass of (targeting guide + delivery carrier), preferably 7%-100%, 7%-70%, 7%-65%, 10%-60%, 12.5%-100%, 15%-95%, 17.5%-90%, 20%-80%, 25%-75%, 30%-70%, 35%-65%, 40%-60%; the mass ratio of the active ingredient to the high molecular polymer is 1 :0-1 :25, preferably 1 :0-1 :20, 1 :0-1 :15, 1 :0-1 :10, 1 :0-1 :5.

[0140] In some embodiments, the active ingredient, the targeting guide, one of the delivery systems is in a liquid state or a solid state, or the active ingredient and the delivery system are both in a liquid state or a solid state. In some embodiments, the active ingredient and the targeting guide or the delivery carrier are present independently, or mixed, or prepared into a supramolecular nanocomplex.

[0141] In some embodiments, the present application provides a pharmaceutical composition, which can comprise an active ingredient and a targeting guide, and optionally a delivery carrier, a polymer and / or an additive, etc. In some embodiments, the present application provides a targeting supramolecular nanocomplex, which can comprise an active ingredient and a targeting guide, and optionally a delivery carrier, a polymer and / or an additive, etc. In this context, the targeting supramolecular nanocomplex can refer to a stable complex with targeting ability in the nanometer size range formed by different components. In some embodiments, the pharmaceutical composition and / or the targeting supramolecular nanocomplex can be in a form suitable for oral, sublingual, cavity mucosa (such as esophagus, stomach, duodenum, colon, rectum, vagina, cervix, anus), subcutaneous, subcutaneous lymph node, muscle, vein, artery, skin, lung, intranasal, ear, eye administration. In some embodiments, the pharmaceutical composition and / or the targeting supramolecular nanocomplex can be directly the drug, or can be combined with a device, such as when administered through the anus, it can be administered through the anus with the help of a drug delivery device, and can be directly delivered to the colon, or can be delivered to the rectum.

[0142] In some embodiments, the active ingredient, the targeting guide, and / or the delivery carrier, and / or the polymer can be assembled into a nanocomplex, for example in the form of micelles, nanoparticles, microspheres, microcapsules, molecular compositions or hydrogels. In some embodiments, the assembly can be assembled at any time during the preparation of the kit, during administration, upon entering the body, upon reaching the target site.

[0143] In some embodiments, when the active ingredient, targeting guide or delivery carrier are present independently, they are assembled by mixing or dissolving after use; when the active ingredient, targeting guide and the carrier are mixed, the active ingredient, targeting guide or carrier in solid state are assembled by dissolving after use.

[0144] In some embodiments, the assembly is preferably in situ, such as self-assembly in the gastrointestinal tract, self-assembly in the mucosa, self-assembly in the blood, self-assembly in the lymphatic vessels or lymph nodes or target cells.

[0145] In addition, the assembly can be between the active ingredient, targeting guide, delivery carrier, polymer and their metabolites, or between the active ingredient, targeting guide, delivery carrier, polymer and metabolites, and the metabolism can be by enzymes, microorganisms, etc.

[0146] In some embodiments, the targeting nanocomplex kit, pharmaceutical composition and / or targeting supramolecular nanocomplex can be prepared into a suitable dosage form, such as tablets, capsules, pellets, micro-tablets, micro-capsules, oral solutions, drops, gels, granules, emulsions, creams, injections, eye drops, inhalants, sprays, aerosols, patches, enemas, foams, suppositories. In some embodiments, additives can be added for shaping and use, and the additives are selected from excipients, diluents, binders, disintegrants, lubricants, flavoring agents, pH adjusters, osmotic pressure adjusters, thickening agents, plasticizers, colorants, film formers, preservatives or solvents, stabilizers and any combination thereof.

[0147] In some embodiments, the stabilizer can be one or more of a bile salt, Vitamin E polyethylene glycol succinate (TPGS), sodium lauryl sulfate (SLS), sodium docusate, lecithin, Tween 80, Tween 20, polyoxyethylene castor oil (EL35), polyoxyethylene hydrogenated castor oil, poloxamer, wherein the bile salt is one or more of Sodium taurocholate (STC), Sodium glycocholate (SGC), Sodium deoxycholate (SDC), Sodium taurodeoxycholate (STDC), Sodium glycodeoxycholate (SGDC), Sodium glycochenodeoxycholate (SGCDC), Sodium glycoursodeoxycholate (SGUDC), or a free acid or potassium salt thereof. Preferably one or both of Sodium taurodeoxycholate (STDC), Sodium glycodeoxycholate (SGDC).

[0148] In some embodiments, the targeted nanocomplex kit, pharmaceutical composition, and / or targeted supramolecular nanocomplex can be used for one or more purposes selected from the group consisting of:

[0149] (1) for the delivery of an active ingredient to a mammal (such as a rodent, a bovine, a porcine, a canine, a feline, a primate, a human) or a bird (such as a chicken, a duck, a goose);

[0150] (2) for the modulation of the release of an active ingredient or a nutritional ingredient during the delivery of the active ingredient or the nutritional ingredient to a mammal (such as a rodent, a bovine, a porcine, a canine, a feline, a primate, a human) or a bird (such as a chicken, a duck, a goose);

[0151] (3) for use as a solubilizer in agriculture, especially in formulation products containing a pesticide, a herbicide, a fungicide, or an insecticide, especially as a solubilizer for spray, drench, or soak mixtures;

[0152] (4) for use as a preservative or a conserving agent or a flavoring agent for meat, vegetables, fruits, food, beverages;

[0153] (5) for use in cosmetics, fine chemical products for solubilization, stability enhancement, penetration promotion;

[0154] (6) for use as an adjuvant for biological agents.

[0155] Advantages of the invention

[0156] The targeting nanocomplex kit, pharmaceutical composition and / or targeting supramolecular nanocomplex described herein has high drug loading and encapsulation efficiency, no intrinsic cytotoxicity, can achieve multiple targeting delivery, improve the reliability of the delivery system, provide differentiated pharmacokinetic characteristics, reduce the toxicity of the prior art non-differentiated system to the whole body, reduce first-pass metabolism, and provide a safer, more reliable and effective treatment method. BRIEF DESCRIPTION OF DRAWINGS

[0157] Figure 1 LC-MS / MS mass spectrum of STVB-Man compound prepared in Example 1 in negative ion mode;

[0158] Figure 2 H-NMR spectrum of STVB-Man compound prepared in Example 1; 1

[0159] Figure 3 LC-MS / MS mass spectrum of RBDS-B-Rha compound prepared in Example 2 in negative ion mode;

[0160] Figure 4 H-NMR spectrum of RBDS-B-Rha compound prepared in Example 2; 1

[0161] Figure 5 LC-MS / MS mass spectrum of DCS-B-Man compound prepared in Example 3 in negative ion mode;

[0162] Figure 6 H-NMR spectrum of DCS-B-Man compound prepared in Example 3; 1

[0163] Figure 7 LC-MS / MS mass spectrum of DCS-B-Rha compound prepared in Example 4 in negative ion mode;

[0164] Figure 8 H-NMR spectrum of DCS-B-Rha compound prepared in Example 4; 1

[0165] Figure 9 LC-MS / MS mass spectrum of DCS-A-Acid-Gal compound prepared in Example 5 in negative ion mode;

[0166] Figure 10 H-NMR spectrum of DCS-A-Acid-Gal compound prepared in Example 5; 1

[0167] Figure 11 LC-MS / MS mass spectrum of STVB-Gal compound prepared in Example 6 in negative ion mode;

[0168] ​​​​​Figure 12 STVB-Gal compounds prepared in Example 6 1 H-NMR spectra;

[0169] Figure 13 CCM exposure (AUC 0-t ) in each tissue of Comparative Example 1 and F1-F5;

[0170] Figure 14 CCM peak to plasma peak ratio in each tissue of Comparative Example 1 and F1-F5;

[0171] Figure 15 Dissolution profiles of different DOX formulations in biorelevant media;

[0172] Figure 16 Rat oral PK profiles of different DOX formulations;

[0173] Figure 17 Rat tissue to plasma DOX concentration ratios at 1 hour and 4 hours post gavage of F12-F14;

[0174] Figure 18 Mouse tissue to plasma PK profiles post gavage of F19 and plasma PK profile of Comparative Example 4;

[0175] Figure 19 Two-step dissolution profiles of F20-F22 supramolecular nanocomplexes in pH 1.0 HC1 to pH 6.8 PBS;

[0176] Figure 20 Two-step dissolution profiles of F23-F25 and reference formulation in 0.1 M HC1 to pH 6.8 PBS;

[0177] Figure 21 Two-step dissolution profiles of F26-F28 and reference formulation in 0.1 M HC1 to pH 6.8 PBS;

[0178] Figure 22 Comparison of PTX exposure (AUC 0-∞ ) in each tissue organ of different formulations post oral administration in mice;

[0179] Figure 23 Tumor volume versus days of treatment for different treatment groups;

[0180] Figure 24 Tumor weight after 20 days of treatment for different treatment groups. DETAILED DESCRIPTION:

[0181] In order to make the objects, technical solutions and advantages of the present application clearer, the technical solutions in the present application will be described clearly and completely in combination with the accompanying drawings in the present application. Obviously, the described embodiments are some embodiments of the present application, but not all embodiments of the present application. Based on the embodiments in the present application, all other embodiments obtained by those of ordinary skill in the art without creative work fall within the protection scope of the present application.

[0182] Unless otherwise specified in the examples, the techniques or conditions described in the literature or according to the product specification are used. Unless otherwise specified, the instruments and the like used are commercial products available from a regular channel of commerce. The methods described are general pharmacopoeia methods unless otherwise specified. The high molecular polymers, excipients, pharmaceutical adjuvants, pH regulators, reagents, surfactants, buffer salts and the like can be purchased from a regular commercial channel from a qualified supplier in the art, and are not subject to different brands unless otherwise specified. They can be obtained from public commercial channels unless otherwise specified.

[0183] Reference Listed Drug (RLD), i.e. different drugs of marketed drugs, generally refers to drugs with complete safety and effectiveness studies. For example, the RLD of apixaban should be Eliquis / Apricot / Apexaban tablets, and Bristol-Myers Squibb / Pfizer is the license holder.

[0184] The preparation and characterization of the steviol glycoside derivative designed and developed by the inventors used in the present application will be described clearly in the present application.

[0185] The preparation method of the medium used in the present application, such as the dissolution medium, is prepared according to the Technical Guidelines for Dissolution Test of Ordinary Oral Solid Preparations, while taking into account the preparation method specified in the Chinese Pharmacopoeia 2020 Edition General Rules and the current edition of the United States Pharmacopoeia. Here, no special list is given.

[0186] The preparation methods of the pre-meal simulated gastric fluid (Fasted State Simulated Gastric Fluid, FaSSGF), pre-meal simulated intestinal fluid (Fasted State Simulated Intestinal Fluid, FaSSIF), post-meal simulated gastric fluid (Fed State Simulated Gastric Fluid, FeSSGF), and post-meal simulated intestinal fluid (Fed State Simulated Intestinal Fluid, FeSSIF) used in the present application are as follows:

[0187] (1) Preparation of pre-meal simulated gastric fluid to simulated intestinal fluid

[0188] FaSSGF preparation: weigh 2 g of NaCl, 0.043 g of sodium cholate, and 0.015 g of lecithin in about 800 ml of degassed purified water, ultrasonic (40-50℃ heating) stirring and dissolving, after the lecithin is completely dissolved, adjust the pH to 1.60 with 1 mol / L HCl, then weigh in 0.1 g of pepsin, dilute to 1000 mL, and adjust the pH to 1.6.

[0189] FaSSIF-V2 preparation: 187 mL FaSSGF + 63 mL conditioning fluid (weigh 8.8056 g maleic acid, 8.8062 g NaOH, 9.9762 g NaCl, 6.618 g sodium cholate, 0.5508 g lecithin in 1000 mL degassed purified water, ultrasonic (40-50℃ heating) stirring to dissolve), if necessary, adjust pH to pH 6.5 with hydrochloric acid or sodium hydroxide solution.

[0190] (2) Postprandial simulated gastric fluid to simulated intestinal fluid preparation

[0191] FeSSGF preparation: weigh 13.85 g NaCl, 2.44 g anhydrous sodium acetate, 1.028 g glacial acetic acid in 1000 ml degassed purified water, then add 1000 mL milk, adjust pH to 5.00 with concentrated hydrochloric acid, and mix well.

[0192] FeSSIF-V2 preparation: add 100 mL conditioning fluid (weigh 15.9654 g maleic acid, 8.165 g NaOH, 7.9481 g NaCl, 13.75 g sodium cholate, 0.6089 g sodium oleate, 3.79 g lecithin in 1000 mL degassed purified water, ultrasonic stirring to dissolve) to 150 mL FeSSGF, if necessary, adjust pH to pH 5.8 with hydrochloric acid or sodium hydroxide solution.

[0193] (3) Simulated colon fluid: weigh 1.1032 g tromethamine, 1.7640 g maleic acid, and add 152 mL degassed purified water to dissolve. Weigh 0.9614 g sodium hydroxide and dissolve in 48 mL degassed purified water. Combine the above solutions and mix well. Adjust pH to 7.80 with 2 mol / L sodium hydroxide as buffer. Weigh 0.0226 g bovine bile powder and add 100 mL buffer to dissolve. Weigh 0.0449 g lecithin, 0.0056 g palmitic acid, and dissolve in 2 mL dichloromethane. After dissolving, add it to the bovine bile powder buffer and mix well. Remove dichloromethane on a rotary evaporator at 40℃, and then add the remaining buffer and 0.6049 g bovine serum albumin to the remaining aqueous solution, dissolve and mix well to obtain the simulated colon fluid.

[0194] Detection methods used in the present application:

[0195] (1) Active ingredient or carrier content determination

[0196] The content of amphotericin B, azithromycin, doxorubicin hydrochloride and paclitaxel is determined according to the content determination method in the respective monograph of Chinese Pharmacopoeia 2020 Edition Part II.

[0197] The content of curcumin, osimertinib, NRGCT, NHDC, NRG, QCT, HPD and HNK was determined by high performance liquid chromatography using the self-built method of the enterprise. The content was calculated by the external standard method. The chromatographic conditions are shown in Table 1.

[0198] Table 1 Content determination method

[0199] (2) Nanoparticle size, PDI:

[0200] Measured by NanoBrook (model: 90Plus PALS) nanoparticle size analyzer. Dynamic light scattering principle, room temperature 25℃, diffraction angle set to 90° for determination. Before determination, dilute the supramolecular self-assembly complex solution to 100 μg / ml, take 50 μl and disperse in 1 ml deionized water, ultrasonic to disperse uniformly, immediately determine, determination time set to 2 min, each sample repeated 3 times.

[0201] (3) Zeta potential determination:

[0202] Determined at room temperature 25℃, Zeta potential determination diffraction angle set to 15℃, before determination, dilute the supramolecular self-assembly complex solution to 100 μg / ml, take 50 μl and disperse in 1 ml phosphate buffer solution of different pH (6.0, 7.0, 7.4, 8.0) for determination, each sample repeated 3 times. 1 mM phosphate buffer solution is prepared by using ultrapure water, 0.1 N hydrochloric acid or sodium hydroxide solution is used to adjust pH. The sample should be transparent, and the supernatant can be taken by centrifuging the concentrated sample.

[0203] (4) Encapsulation efficiency (EE) calculation

[0204] When preparing the supramolecular self-assembly complex, remove the organic solvent by stirring at room temperature, centrifuge at 45000 rpm for 40 min, take 200 μL of supernatant, add 800 μL of acetonitrile (or methanol or ethanol, determined according to the solubility of active ingredients), detect the concentration of active ingredients in each prescription supernatant by HPLC, and calculate the encapsulation efficiency (EE, %) according to the following formula.

[0205] EE (%) = (Ct-Cf) / Ct×100%

[0206] In the formula:

[0207] Ct: total drug concentration, mg / mL;

[0208] Cf: free drug concentration in the supernatant of ultracentrifugation, mg / mL.

[0209] (5) Drug loading determination

[0210] Take a certain volume of the supernatant of the clarified supramolecular nanocomplex solution after centrifugation, and detect the content of the active ingredient using the corresponding HPLC method under the active ingredient item. Calculate the active ingredient content per unit volume (mg / mL). Take a certain volume of the supernatant and slowly evaporate it at 40°C or freeze-dry it for 48 hours (for unstable drugs). Take the corresponding concentrate or freeze-dried powder of the supernatant per unit volume, weigh it, and use it as the solid content per unit volume (mg / mL). Calculate the drug loading by the following formula:

[0211] Drug loading % = Active ingredient content per unit volume / Solid content per unit volume x 100%.

[0212] To make the purpose, technical scheme and advantages of the present application clearer, the following will be further described in detail with specific examples and reference to the accompanying drawings.

[0213] During the research process, the present inventors determined the technical scheme of the present application through a large number of experiments, screening and verification. In order to illustrate the characteristics and advantages of the present application, some experiments are provided as illustrative examples in the examples, but the content of the present application is not limited to the examples.

[0214] For convenience of expression, the abbreviations of the targeting guide agents, delivery carriers, high molecular polymers and stabilizers exemplified in the comparative examples, examples and experimental examples of the present application are as follows:

[0215] (1) Basic information of some targeting guide agents and their in vivo metabolites

[0216] (2) Code of some delivery carriers:

[0217] Delivery carriers: steviolbioside (STVB), rebaudioside B (RBDS-B), rebaudioside C (RBDS-C), stevioside (STVS), rebaudioside A (RBDS-A), neohesperidin (NHPD), neohesperidin dihydrochalcone (NHDC), naringin dihydrochalcone (NRGDC), mogroside V (MGSD-V), 11-oxomogroside V (OMGSD-V), siamenoside I (SMSD-I), mogroside 1E1 (MGSD-IE1), MGSDT (a combination of MGSD-V, OMGSD-V, SMSD-I, MGSD-IE1), glycyrrhizinic acid (GA);

[0218] (3) Polymers: polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus), hydroxypropyl methylcellulose (HPMC), polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), hydroxypropyl methylcellulose acetate succinate (HPMCAS), hyaluronic acid (HA), copovidone (PVP VA64), polyethylene glycol-15 hydroxystearate (HS-15), and the like;

[0219] (4) Stabilizers:

[0220] Polyoxyethylene castor oil (e.g., EL35), vitamin E polyethylene glycol succinate (TPGS), polyoxy(40) stearate (PSE 40), polyoxyethylene hydrogenated castor oil (RH40), sodium dodecyl sulfate (SDS).

[0221] It should be noted that the numerical values or numerical endpoints involved in the technical solutions of the present application do not limit the protection scope of the meaning or significance of the numbers themselves, and those skilled in the art can understand that they include the allowable error range widely accepted in the art, such as experimental error, measurement error, statistical error, and random error, etc., and these error ranges are all included in the scope of the present application.

[0222] In order to further illustrate the present application, specific examples will be given below, but the following examples do not constitute any limitation on the protection scope of the present application.

[0223] Example 1: Preparation of STVB-Man

[0224] (1) Synthesis of STVB-Ac

[0225] In a 2L three-necked flask, 100 g of stevioside and 800 mL of 5% potassium hydroxide aqueous solution were added, the reaction system was warmed to 60°C, and the reaction was stirred for 6 hours. The reaction system was cooled to room temperature, 6N hydrochloric acid was added to adjust the pH value of the system to 5-6, and the solid was precipitated. The filter cake was washed twice with 400 mL of purified water, the filter cake was collected, and the filter cake was dried at 40°C under reduced pressure for 6 hours to obtain 76.02 g of STVB as a white solid, with a yield of 95.2%, a HPLC purity of 97.21%, and a mass-to-charge ratio of 641.3198 [MW-H] in the negative ion mode of LC-MS / MS. - , 1 H-NMR (600 MHz, d-DMSO + D2O) δ 5.099 (s, 1H), 4.745 (s, 1H), 4.470-4.457 (d, J = 7.8 Hz, 1H), 4.372-4.359 (d, J = 7.8 Hz, 1H), 3.609-3.570 (m, 2H), 3.492-3.428 (m, 2H), 3.400-3.370 (m, 1H), 3.232-3.204 (m, 1H), 3.184-3.117 (m, 3H), 3.060-2.985 (m, 3H), 2.210-1.966 (m, 4H), 1.882-1.696 (m, 6H), 1.520-1.467 (m, 3H), 1.399-1.316 (m, 3H), 1.090 (s, 3H), 0.991-0.967 (m, 1H), 0.923-0.885 (m, 5H), 0.794-0.747 (m, 1H).

[0226] In a 2L three-necked flask, 75 g of STVB, 175 g of acetic anhydride, and 23 g of sodium acetate were added, the reaction system was warmed to 140°C, and the reaction was stirred for 6 hours. The reaction system was cooled to room temperature, 1600 mL of dichloromethane was added, and the system was washed with 800 mL of purified water three times. The organic phase was collected and rotary evaporated under reduced pressure at 40°C to obtain 96.33 g of STVB-Ac as a light brown solid, with a yield of 91.72%, a mass-to-charge ratio of 935.4012 [MW-H] in the negative ion mode of LC-MS / MS - and a mass-to-charge ratio of 980.9836 [MW+2Na-H] - .

[0227] (2) Preparation of Man-4 mannose-activated precursor

[0228] In a 2L three-necked flask, 75g of D-mannose (Man), 816g of acetic anhydride and 78.6g of sodium acetate were added, and the system was warmed to 140°C for 8 hours with stirring. After the heating was stopped, the system was naturally cooled to room temperature, and then poured into 2000mL of purified water. The mixture was extracted with 1200mL of dichloromethane three times, and the combined organic phase was washed with 2000mL of purified water three times and with 2000mL of saturated sodium chloride aqueous solution once. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure at 40°C to obtain 147g of a yellow oily compound Man-1 at a yield of 90.3%.

[0229] In a 2L three-necked flask, 145g of Man-1 and 830mL of dichloromethane were added, and 149g of hydrogen bromide in acetic acid (33%) was added dropwise with stirring at room temperature. After the dropwise addition was completed, the system was stirred at room temperature for 12 hours. The system was poured into 1600mL of ice water, and then extracted with 1600mL of dichloromethane three times. The combined organic phase was washed with 800mL of purified water three times and with 1600mL of saturated sodium chloride aqueous solution once. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure at 40°C to obtain 134g of a brownish oily compound at a yield of 89.2%.

[0230] In a 2L three-necked flask, 120g of Man-2, 1200mL of acetone and 60mL of purified water were added, and 104g of silver carbonate was added in portions. After the addition was completed, the system was stirred at room temperature for 5 hours, filtered, and the filtrate was concentrated under reduced pressure at 40°C to obtain 95g of a yellow oily compound Man-3 at a yield of 93.5%.

[0231] In a 2L three-necked flask, 90g of Man-3, 900mL of dichloromethane, 374g of trichloroacetonitrile and 7.83g of 1,8-diazabicycloundec-7-ene (DBU) were added, and the reaction system was stirred at room temperature for 5 hours. The system was concentrated under reduced pressure at 40°C, and the residue was purified using a silica gel column by medium pressure preparative chromatography with dichloromethane and ethyl acetate as eluents by gradient elution to obtain 114g of a yellow oily compound Man-4 at a yield of 89.6%. 1 H-NMR (600MHz, CDCl3) δ 8.809 (s, 1H), 6.301 (d, 1H), 5.490~5.458 (m, 1H), 5.422 (d, 2H), 4.265 (d, 1H), 4.187 (s, 1H), 4.166~4.087 (m, 1H), 2.210 (s, 3H), 2.088 (d, 6H), 2.018 (s, 3H).

[0232] (3) Preparation of STVB-Man

[0233] In a 2L flask, 40g of Man-4, 800mL of dichloromethane, 84g of STVB-Ac, 80g of molecular sieve, temperature control at -20°C, drop 4g of trimethylsilyl trifluoromethanesulfonate (TMSOTf), after drop completion, keep stirring for 5 hours, then drop 26g of triethylamine, natural temperature rise to room temperature and stir for 1 hour, filter, the filtrate is concentrated under reduced pressure at 40°C to obtain 156g of brown oil as STVB-Ac-Man crude product.

[0234] In a 2L flask, 40g of Man-4, 800mL of dichloromethane, 84g of STVB-Ac, 80g of

[0235] In a 2L flask, 152g of STVB-Ac-Man crude product, 1200mL of methanol, 21g of sodium methoxide, room temperature stirring for 5 hours, the system is concentrated under reduced pressure at 40°C to obtain foaming oil as STVB-Man crude product, purified by medium pressure preparative chromatography to obtain 49g of white solid as STVB-Man, yield: 75.4%, main peak LC-MS / MS negative ion mode mass-to-charge ratio is 803.3762 [MW-H]- and 849.3783 [MW+Na-H] - , as shown in Figure 1, 1 HNMR (600MHz, d-DMSO) δ 5.623-5.614 (d, 1H), 5.165-5.154 (d, 1H), 5.133 (s, 1H), 5.114-5.108 (d, 1H), 5.052-5.043 (d, 1H), 4.886 (s, 2H), 4.763 (s, 1H), 4.670-4.657 (d, 1H), 4.621-4.603 (t, 1H), 4.508-4.493 (m, 2H), 4.441-4.421 (m, 2H), 4.064-4.045 (t, 1H), 3.708-3.548 (m, 4H), 3.480-3.403 (m, 5H), 3.231-3.135 (m, 4H), 3.117-3.000 (m, 5H), 2.944-2.904 (m, 1H), 2.116-1.975 (m, 4H), 1.862-1.713 (m, 6H), 1.515-1.363 (m, 6H), 1.110 (s, 3H), 1.016-0.916 (m, 3H), 0.882 (s, 3H), 0.806-0.762 (m, 1H), as shown in Figure 2.

[0235] Example 2: Preparation of RBDS-B-Rha

[0236] (1) Preparation of RBDS-B-Ac

[0237] In a 1.5L flask, 75g of rebaudioside A (RBDS-A) and 540mL of 5% potassium hydroxide aqueous solution were added, the reaction system was warmed to 85-90°C, and the reaction was stirred for 4 hours. The reaction system was cooled to room temperature, 6N hydrochloric acid was added to adjust the pH of the system to 5-6, and the solid was precipitated. The filter cake was washed twice with 300mL of purified water, the filter cake was collected, and dried at 40°C under reduced pressure to obtain 62g of rebaudioside B (RBDS-B) as a light brown solid with a purity of 96.9% by HPLC. The main peak of LC-MS / MS had a mass-to-charge ratio of 803.3709 [MW-H] in negative ion mode. - ; 1 H NMR (600 MHz, d-DMSO) δ 11.957 (s, 1H), 5.610-5.601 (d, J = 5.4, 1H), 5.156-5.135 (m, 2H), 5.084-5.076 (d, J = 4.8, 1H), 5.021-5.012 (d, J = 5.4, 1H), 4.846 (s, 2H), 4.767 (s, 1H), 4.672-4.659 (d, J = 7.8, 1H), 4.596-4.579 (m, 1H), 4.509-4.491 (m, 2H), 4.442-4.408 (m, 2H), 4.033 (m, 1H), 3.714-3.545 (m, 4H), 3.482-3.392 (m, 4H), 3.233-2.986 (m, 9H), 2.945-2.918 (m, 1H), 2.078-1.932 (m, 4H), 1.874-1.698 (m, 6H), 1.529-1.344 (m, 6H), 1.112 (s, 3H), 1.025-0.928 (m, 3H), 0.844 (s, 3H), 0.807-0.767 (m, 1H).

[0238] In a 1.5L flask, 54g of rebaudioside B (RBDS-B), 135g of acetic anhydride, and 13.5g of sodium acetate were added, the reaction system was warmed to 140°C, and the reaction was stirred for 6 hours. The reaction system was cooled to room temperature, 1200mL of dichloromethane was added, the organic phase was washed with 600mL of purified water three times, the organic phase was collected, and concentrated at 40°C to obtain 82g of RBDS-B-Ac as a light yellow solid. The main peak of LC-MS / MS had a mass-to-charge ratio of 1223.4819 [MW-H] in negative ion mode and a mass-to-charge ratio of 1310.4568 [MW+2Na+MeCN-H] in positive ion mode. - and a mass-to-charge ratio of 1310.4568 [MW+2Na+MeCN-H] - .

[0239] (2) Preparation of rhamnose-activated precursor Rha-3

[0240] In a 1.5L flask, 75g of L-rhamnose (Rha) was added, 450mL of pyridine was added, the system was cooled to 0°C, 300g of acetic anhydride was added dropwise under stirring, after the dropwise addition was completed, the system was stirred at room temperature for 24 hours, 600mL of purified water was added, then 900mL of ethyl acetate was extracted three times, the organic phase was combined and washed once with 600mL of saturated sodium chloride aqueous solution, washed three times with 600mL of saturated sodium bicarbonate aqueous solution, the organic phase was separated, dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure at 40°C to obtain 133g of compound Rha-1 in the form of yellow oil, yield: 86.9%.

[0241] In a 1.5L flask, 75g of L-rhamnose (Rha) was added, 450mL of pyridine was added, the system was cooled to 0°C, 300g of acetic anhydride was added dropwise under stirring, after the dropwise addition was completed, the system was stirred at room temperature for 24 hours, 600mL of purified water was added, then 900mL of ethyl acetate was extracted three times, the organic phase was combined and washed once with 600mL of saturated sodium chloride aqueous solution, washed three times with 600mL of saturated sodium bicarbonate aqueous solution, the organic phase was separated, dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure at 40°C to obtain 133g of compound Rha-1 in the form of yellow oil, yield: 86.9%.

[0242] In a 1.5L flask, 75g of L-rhamnose (Rha) was added, 450mL of pyridine was added, the system was cooled to 0°C, 300g of acetic anhydride was added dropwise under stirring, after the dropwise addition was completed, the system was stirred at room temperature for 24 hours, 600mL of purified water was added, then 900mL of ethyl acetate was extracted three times, the organic phase was combined and washed once with 600mL of saturated sodium chloride aqueous solution, washed three times with 600mL of saturated sodium bicarbonate aqueous solution, the organic phase was separated, dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure at 40°C to obtain 133g of compound Rha-1 in the form of yellow oil, yield: 86.9%. 1 H NMR (600 MHz, CDCl3) δ 7.333-7.316 (t, 2H), 7.160-7.137 (t, 1H), 6.894-6.878 (d, 2H), 6.170 (m, 1H), 5.152-5.056 (m, 3H), 4.080-4.031 (m, 1H), 2.054 (s, 3H), 2.039 (s, 3H), 2.032 (s, 3H), 1.106-1.071 (d, 3H).

[0243] (3) Preparation of RBDS-B-Rha

[0244] In a 1.5L flask, 75g of L-rhamnose (Rha) was added, 450mL of pyridine was added, the system was cooled to 0°C, 300g of acetic anhydride was added dropwise under stirring, after the dropwise addition was completed, the system was stirred at room temperature for 24 hours, 600mL of purified water was added, then 900mL of ethyl acetate was extracted three times, the organic phase was combined and washed once with 600mL of saturated sodium chloride aqueous solution, washed three times with 600mL of saturated sodium bicarbonate aqueous solution, the organic phase was separated, dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure at 40°C to obtain 133g of compound Rha-1 in the form of yellow oil, yield: 86.9%. Molecular sieve, temperature control at -10℃, drop 4.5g of TMSOTf, after drop completion, keep stirring for 8 hours, then drop 18.0g of triethylamine, continue to stir for 14 hours after natural warming to room temperature, filter, filter liquor at 40℃ under reduced pressure, get brown oil 138g as RBDS-B-Ac-Rha crude product.

[0245] In a 1.5L three-necked flask, add 135g of RBDS-B-Ac-Rha crude product, 900mL of methanol, 24.0g of potassium tert-butoxide, stir at room temperature for 16 hours, the system is concentrated under reduced pressure at 40℃, get foaming oil as RBDS-B-Rha crude product, through medium pressure preparation separation and purification, get 36g white solid as RBDS-B-Rha, yield: 61.9%, LC-MS / MS main peak negative ion mode mass to charge ratio is 949.4298[MW-H] - and 995.3783[MW+2Na-H] - , see Figure 3, 1 H NMR (600MHz, d-DMSO) δ 5.630-5.622 (d, 1H), 5.285-5.272 (d, 1H), 5.236-5.226 (d, 1H), 5.149-5.138 (d, 1H), 5.108-5.100 (d, 1H), 5.058 (s, 1H), 5.035-5.026 (d, 1H), 4.988-4.973 (m, 3H), 4.904 (s, 1H), 4.744 (s, 1H), 4.688-4.669 (t, 1H), 4.645-4.632 (d, 1H), 4.610-4.592 (t, 1H), 4.511-4.465 (m, 3H), 4.434-4.421 (d, 1H), 4.110-4.091 (t, 1H), 3.715-3.676 (m, 2H), 3.639-3.603 (m, 2H), 3.562-3.396 (m, 5H), 3.270-3.231 (m, 1H), 3.149-3.117 (m, 6H), 3.088-3.025 (m, 4H), 3.003-2.964 (m, 1H), 2.113-1.690 (m, 10H), 1.497-1.334 (m, 6H), 1.147 (s, 3H), 1.073-0.910 (m, 3H), 0.874 (s, 3H), 0.807-0.788 (m, 1H), 0.765 (d, 3H), see Figure 4.

[0246] Example 3: Preparation of DCS-B-Man

[0247] DCS-B-Man was synthesized according to the synthetic route and method of STVB-Man in Example 1, and white solid 8 g was obtained with a yield of 57.7%. LC-MS / MS main peak mass-to-charge ratio was 949.4291 [MW-H] in negative ion mode - and 474.2373 [MW / 2-H] - as shown in Figure 5, 1 H NMR (600 MHz, d-DMSO) δ 5.698 (d, 1H), 5.353-5.340 (d, 1H), 5.304-5.294 (d, 1H), 5.217-5.129 (m, 4H), 5.094 (m, 2H), 4.972 (s, 1H), 4.812 (s, 1H), 4.756-4.660 (m, 3H), 4.575-4.489 (m, 2H), 4.178-4.159 (t, 1H), 3.783-3.671 (m, 4H), 3.601-3.464 (m, 7H), 3.337-3.240 (m, 9H), 3.189-3.071 (m, 4H), 2.180-1.789 (m, 10H), 1.564-1.423 (m, 6H), 1.293 (s, 3H), 1.212-0.978 (m, 5H), 0.942-0.871 (m, 1H), 0.851 (s, 3H), 0.851-0.834 (m, 1H), as shown in Figure 6.

[0248] Example 4: Preparation of DCS-B-Rha

[0249] DCS-B-Rha was synthesized according to the synthetic route and method of RBDS-B-Rha in Example 2, and white solid 17 g was obtained with a yield of 58.5%. LC-MS / MS main peak mass-to-charge ratio was 933.4391 [MW-H] in negative ion mode - and 979.4902 [MW+2Na-H] - as shown in Figure 7, 1H NMR (600 MHz, d-DMSO + D20) δ 5.873 (d, 1H), 5.288 (d, 1H), 5.202 (d, 1H), 5.154 (s, 1H), 5.073 (s, 1H), 4.971 (m, 1H), 4.234-4.207 (m, 1H), 4.104-4.031 (m, 2H), 4.022-3.858 (m, 2H), 3.787-3.746 (m, 7H), 3.607-3.197 (m, 8H), 2.172-2.110 (m, 2H), 2.066-1.905 (m, 5H), 1.859-1.575 (m, 9H), 1.499-1.426 (m, 2H), 1.289-1.257 (m, 1H), 1.150 (d, 3H), 1.132 (s, 3H), 1.095 (s, 3H), 0.980 (m, 4H), see Figure 8.

[0250] Example 5: Preparation of DCS-A-Acid-Gal

[0251] (1) Preparation of DCS-A-Acid-Ac

[0252] In a 500 mL three-necked flask, 30 g of Duxin A (DCS-A) and 250 mL of 5% potassium hydroxide aqueous solution were added, the reaction system was warmed to 85-90°C, and stirred for 6 hours. The reaction system was cooled to room temperature, and 6N hydrochloric acid was used to adjust the pH value of the system to 5-6. The solid was precipitated, filtered, and the filter cake was rinsed twice with 100 mL of purified water. The filter cake was collected and dried under reduced pressure at 40°C to obtain 18 g of DCS-A-Acid as a brown solid with a purity of 90.51% by HPLC, and the main peak of LC-MS / MS was at a mass-to-charge ratio of 625.3297 [MW-H] in negative ion mode and 1251.6632 [2MW-H] in positive ion mode. - - 1 ​​H NMR (600 MHz, d-DMSO) δ 11.886 (s, 1H), 5.781 (s, 1H), 5.307-4.961 (m, 4H), 4.705 (s, 1H), 4.504-4.230 (m, 3H), 3.428-3.370 (m, 4H), 3.254-3.124 (m, 4H), 3.061-2.986 (m, 3H), 2.123-1.967 (m, 4H), 1.882-1.704 (m, 6H), 1.520-1.467 (m, 3H), 1.390-1.317 (m, 3H), 1.090 (s, 3H), 1.007-0.909 (m, 9H), 0.885-0.747 (m, 1H).

[0253] In a 500 mL flask, 18 g of DCS-A-Acid, 50 g of acetic anhydride and 5.0 g of sodium acetate were added, the reaction system was heated to 140°C, and the reaction was stirred for 6 hours. The reaction system was cooled to room temperature, 400 mL of dichloromethane was added, the organic phase was separated, the organic phase was washed with 200 mL of purified water three times, and the organic phase was collected and dried under reduced pressure at 40°C to obtain 31.5 g of DCS-A-Acid-Ac as a yellow solid. The main peak of LC-MS / MS was -877.3880 [MW-H] in negative ion mode and 923.3894 [MW+2Na-H] in positive ion mode. - - .

[0254] (2) Preparation of galactose activated precursor Gal-2

[0255] In a 500 mL flask, 30 g of D-galactose (Gal) was added, 150 g of acetic anhydride and 10 g of sodium acetate were added, and the system was heated to 120°C and stirred for 8 hours. The heating was stopped and the system was naturally cooled to room temperature. The system was diluted with 500 mL of purified water, extracted with 300 mL of dichloromethane three times, the organic phase was combined and washed with 500 mL of purified water three times, and then washed with 500 mL of saturated sodium chloride aqueous solution once. The organic phase was separated, dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure at 40°C to obtain 55 g of compound Gal-1 as a yellow oil, with a yield of 84.6%.

[0256] ​In a 500 mL three-necked flask, 50 g of Gal-1, 250 mL of dichloromethane, 55 g of hydrogen bromide in acetic acid solution (33%) was added dropwise while stirring at room temperature, after dropping, it was continuously stirred at room temperature for 16 hours, the system was poured into 400 mL of ice water, extracted with 400 mL of dichloromethane three times, the organic phase was combined and washed with 200 mL of purified water three times, and then washed with 400 mL of saturated sodium chloride aqueous solution once, the organic phase was separated, dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure at 40°C to obtain 41 g of compound Gal-2 in the form of brown oil, yield: 78.2%, 1 H NMR (600 MHz, CDCl3) δ 6.688-6.681 (d, 1H), 5.527-5.522 (d, 1H,), 5.439-5.417 (m, 1H), 5.040-5.018 (m, 1H), 4.469-4.425 (m, 1H), 4.242-4.159 (m, 2H), 2.129 (s, 3H), 2.093 (s, 6H), 2.033 (s, 3H).

[0257] (3) Preparation of DCS-A-Acid-Gal

[0258] In a 500 mL three-necked flask, 30 g of DCS-A-Acid-Ac, 15 g of Gal-2, 18 g of silver carbonate, 25 g of molecular sieves and 300 mL of dichloromethane were added, and the temperature was controlled at -10°C, 1.5 g of TMSOTf was added dropwise, after the addition was completed, the temperature was naturally increased to room temperature and stirred for 18 hours, then filtered, and the filtrate was concentrated under reduced pressure at 40°C to obtain 47 g of DCS-A-Acid-Gal-Ac in the form of brown oil as a crude product.

[0259] In a 500 mL three-necked flask, 45 g of DCS-A-Acid-Gal-Ac crude product, 300 mL of methanol, 8.0 g of potassium tert-butoxide were added, and stirred at room temperature for 16 hours, then the system was concentrated under reduced pressure at 40°C to obtain foaming oil in the form of DCS-A-Acid-Gal crude product, which was purified by medium pressure preparative chromatography to obtain 8.89 g of DCS-A-Acid-Gal in the form of white solid, yield: 32.9%, LC-MS / MS main peak mass-to-charge ratio in negative ion mode was 787.3796 [MW-H] - and mass-to-charge ratio 439.1916 [MW / 2+2Na-1] - , as shown in Figure 9, 1H NMR (600 MHz, d-DMSO) δ 6.257 (d, 1H), 5.622 (d, 1H), 5.335 (s, 1H), 5.073-4.976 (m, 3H), 4.893 (s, 1H), 4.737 (s, 1H), 4.691 (s, 1H), 4.497-4.129 (m, 4H), 3.696-3.593 (m, 3H), 3.498-3.379 (m, 5H), 3.238-2.992 (m, 10H), 2.123-1.995 (m, 4H), 1.911-1.710 (m, 5H), 1.608-1.352 (m, 9H), 1.056-0.918 (m, 7H), 0.835-0.735 (m, 4H), see Figure 10.

[0260] Example 6: Preparation of STVB-Gal

[0261] STVB-Gal was prepared according to the synthesis route and preparation method of DCS-A-Acid-Gal in Example 5, and white solid 21 g was obtained with a yield of 58.6%. LC-MS / MS main peak mass-to-charge ratio was 803.3746 [MW-H] in negative ion mode - and mass-to-charge ratio was 447.1799 [MW / 2-H] - , see Figure 11, 1 H NMR (600 MHz, d-DMSO) δ 6.257 (d, 1H), 5.622 (d, 1H), 5.335 (s, 1H), 5.073-4.976 (m, 3H), 4.893 (s, 1H), 4.737 (s, 1H), 4.691 (s, 1H), 4.497-4.129 (m, 4H), 3.696-3.593 (m, 3H), 3.498-3.379 (m, 5H), 3.238-2.992 (m, 10H), 2.123-1.995 (m, 4H), 1.911-1.710 (m, 5H), 1.608-1.352 (m, 9H), 1.056-0.918 (m, 7H), 0.835-0.735 (m, 4H), see Figure 10.

[0262] Example 7. Preparation of Steviosin (STVN)-Man

[0263] STVN-Man derivatives were prepared using steviol glycosides or crude steviol glycosides extract as starting material.

[0264] The content of each steviol glycoside in the STVN used in this experiment was as follows: RBDS-A: 45.22%, STVS: 19.34%, RBDS-C: 14.56%, DCS-A: 1.98%, RBSD: 1.44%, RBDS-B: 2.18%, STVB: 1.69%, RBDS-F: 2.77%, RBDS-H: 1.76%, RBDS-E: 0.85%, RBDS-O: 0.68%, RBDS-D: 1.82%, STL: 0.38%, and RBDS-M: 2.92%, total steviol glycoside content: 97.21% (not including STL), unknown steviol glycoside about 2.41%.

[0265] About 25 g of the above STVN was placed in a 500 mL three-necked flask, and STVN-Man crude product was prepared according to the synthesis route and method of STVB-Man in Example 1. After purification by medium pressure preparative chromatography, 12.7 g of white solid was obtained, with a yield of about 70.1%.

[0266] The peak mass spectrum identification results of each component in STVN-Man are shown in the following table.

[0267] Table 2. LC / MS / MS mass spectrum identification of each component peak of STVN-Man - from large to small in polarity Note 1: absolute error.

[0268] Example 8. Preparation of STVN-Rha

[0269] The same amount of STVN as in Example 7 was used to prepare STVN-Rha.

[0270] About 25 g of the above STVN was placed in a 500 mL three-necked flask, and STVN-Rha crude product was prepared according to the preparation steps and method of RBDS-B-Rha in Example 2. After purification by medium pressure preparative chromatography, 11.4 g of white solid was obtained, with a yield of about 57.3%.

[0271] The peak mass spectrum identification results of each component in STVN-Rha are shown in the following table.

[0272] Table 3. LC / MS / MS mass spectrum identification of each component peak of STVN-Rha - from large to small in polarity Note 1: absolute error.

[0273] Example 9. Preparation of STVN-Gal

[0274] STVN-Gal was prepared using the same amount of STVN as in Example 7.

[0275] About 25 g of the above STVN was placed in a 500 mL three-necked flask, and STVN-Gal was prepared according to the preparation procedure and method of DCS-A-Acid-Gal in Example 3. The crude product was purified by medium pressure preparative chromatography to obtain 10.7 g of white solid, with a yield of about 50.5%.

[0276] The peak mass spectrum identification results of each component in STVN-Gal are shown in the following table.

[0277] Table 4. LC / MS / MS peak mass spectrum identification of each component in STVN-Gal - from large to small polarity Note 1: Absolute error.

[0278] Test Example 1:

[0279] (1) The following solutions were prepared according to the following Table 5.

[0280] Table 5. Preparation of solutions of different targeting guide agents / carriers and / or polymers

[0281] (2) The following solutions were prepared according to the following Table 6.

[0282] Table 6. Preparation of solutions of different targeting guide agents and / or carriers and / or polymers

[0283] (3) Investigation of the solubilizing effect of the solutions in Table 5 or 6 on NHDC and NRGDC

[0284] About 10 mL of each of the above solutions was taken and 0.5 g of NHDC or NRGDC was added, respectively. After heating and dissolving, the solution was divided into two parts. One part was placed at room temperature for 24 hours, and then centrifuged at 13000 rpm for 10 minutes at room temperature. The supernatant was diluted and the concentration of NHDC or NRGDC in the solution was detected by HPLC method.

[0285] The other part was placed at 2-8°C for 5 days, and then centrifuged at 13000 rpm for 10 minutes at 5°C. The supernatant was diluted and the concentration of NHDC or NRGDC in the solution was detected by HPLC method. The results are as follows:

[0286] Table 7. Effect of different solution compositions on the solubility of NRGDC and NHDC

[0287] According to the solubility of NRGCT and NHDC determined by S1-S3 as solvent, the solubilization effect of 5% polymer solution on NRGCT or NHDC is very limited, the solubility is 1.3-2.5 mg / mL at room temperature, and the solubility of NRGCT or NHDC significantly decreases to about 0.37-0.68 mg / mL after being placed at 2-8°C for 5 days;

[0288] According to the solubility of NRGCT and NHDC determined by S4-S5 as solvent, the solubilization effect of 5% RBDS-B-Man or RBDS-B-Gal solution on NRGCT and NHDC is more significant, the solubility is about 19.4-23.0 mg / mL at room temperature, and the solubility decreases to 7.84-10.3 mg / mL after being placed at 2-8°C for 5 days, although the solubility decreases with the decrease of temperature, but the decrease range is smaller compared with the polymer solution;

[0289] According to the solubility of NRGCT and NHDC determined by S6-S10 as solvent, the solubilization effect of the solution containing 5% targeting guide or different concentrations of polymer on NRGCT and NHDC is more significant compared with the effect of 5% carrier or 5% polymer as solvent, and the solubility basically has no decreasing trend after being placed at 2-8°C for 5 days, which shows obvious synergistic solubilization effect.

[0290] According to the solubility of NRGCT and NHDC determined by S11-S20 as solvent, the complex use of targeting guide, delivery carrier and high molecular polymer can completely dissolve NRGCT or NHDC compared with the complex use of targeting guide and polymer alone, and the solubility of NRGCT or NHDC is not affected by temperature change.

[0291] The inventors surprisingly found that the combination of one or more targeting guides and / or delivery carriers with polymers has significant synergistic effect, which can greatly improve the solubility of low-solubility carriers in aqueous solution, and the physical stability of the solution state is not affected by the decrease of solution temperature, which significantly expands the possibility of preparing supramolecular nanocomplexes containing active ingredients with different physical and chemical properties by the above-mentioned carriers.

[0292] Test Example 2:

[0293] When the targeting guide is rhamnose derivative, the solubility in aqueous solution is lower than that of galactose or mannose derivative.

[0294] Prepare 2.5% RBDS-B-Man, RBDS-B-Gal, RBDS-A, STVS aqueous solutions, respectively;

[0295] Formulate 1.25% RBDS-B-Man, RBDS-B-Gal, RBDS-A, STVS and PVP-VA64 aqueous solution;

[0296] The test was carried out according to the solubility test method in Chinese Pharmacopoeia 2020 Edition Volume IV Fifteenth (2). The rhamnose derivative or its composition ground into fine powder was taken according to the following table, and 10 mL of the following solvent at 25 ± 2 °C was added. Shake vigorously for 30 seconds every 5 minutes, and observe the dissolution within 30 minutes. If there are no visible solute particles, it is considered completely dissolved.

[0297] Table 8. Solution composition and dissolution

[0298] According to the above results, steviol glycoside-rhamnose derivatives can be used in combination with other residue derivatives and / or polymers to improve their solubility and meet the requirements of preparing supramolecular nanocomposites.

[0299] Example 10 and Comparative Example 1: Supramolecular nanocomposites D1 and F1-F5

[0300] Curcumin (CCM, molecular weight: 368.38; melting point: 179-182 °C; slightly soluble in hot water, insoluble in cold water). Curcumin is ranked as the first nutrient by Wiley, the world's largest independent academic book publisher. More than 10,000 global studies and 120 clinical trials have evaluated the health benefits of turmeric and curcumin; more than 370,000 studies are about how to improve the oral bioavailability of curcumin. Curcumin is a class of bioactive phenols extracted from turmeric roots, and is currently the most studied natural compound in the health field. Modern medicine and pharmacological studies have confirmed that curcumin has strong effects on regulating intestinal microecological balance, antioxidant stress, anti-inflammatory and anti-tumor. At the same time, curcumin also has good safety. Its very low water solubility and systemic first-pass metabolism or efflux lead to very low oral bioavailability (about 4.13%). According to Pharmaceutics 2021, 13, 1715, https: / / doi.org / 10.3390 / Pharmaceutics 13101715, the prior art uses polymer micelles, cyclodextrin inclusion, liposomes, non-ionic surfactant micelles or dissolves in oil and then takes with P-gp / CYP3A4 inhibitor piperine, which can make the plasma exposure of curcumin AUC 0-t reach 80 to 328 ng·hr / mL, which is significantly higher than the exposure obtained by directly taking 1 g of turmeric powder (about 10 ng or less), but still far from meeting the requirements of clinical use, not to mention targeted delivery.

[0301] The following formulation is designed with curcumin as the active ingredient:

[0302] Table 9. Formulation composition of D1, F1-F5

[0303] (1) Preparation process of D1 and F1-F5:

[0304] The CCM powder was weighed and passed through a 100-mesh sieve, and then dissolved by ultrasonic treatment in tetrahydrofuran (THF) or a mixed solvent of tetrahydrofuran and ethanol, methanol, isopropyl alcohol, or acetone to prepare a solution containing about 20% to 30% CCM. The solution was filtered and prepared for use.

[0305] The carrier and the polymer in the prescribed amount were weighed, and the carrier in each formulation was dissolved in 25 mL of a 0.08% citric acid aqueous solution. The pH of the aqueous solution was controlled at 3.0 ± 0.2, and heating (temperature not exceeding 60°C) was appropriately applied to aid dissolution. After dissolution and clarification, the polymer Soluplus was added to the solution for dissolution. The solution was naturally cooled to room temperature, and the CCM solution was added dropwise while stirring. After the dropwise addition was completed, the stirring was continued at room temperature or a rotary evaporator was used to remove the organic solvent at 40-50°C. The stirring was stopped, and the solution was left to stand at room temperature overnight. The supernatant of each formulation was collected by centrifugation at 13000 rpm for 5 minutes, and the CCM concentration in each solution was detected by HPLC.

[0306] (2) Property determination

[0307] The supramolecular nanocomposite solutions prepared in D1 and F1-F5 were sealed in Schlenk bottles and stored at room temperature or 2-8°C for 10 days and 30 days to investigate the chemical and physical stability. The results are shown in the following tables.

[0308] Table 10. Particle size, PDI, and Zeta potential determination results of D1, F1-F5 at 0 days

[0309] The supramolecular nanocomposite solutions prepared in D1 and F1-F5 were stored at room temperature for 24 hours, and no precipitation or layering was observed. The solutions were yellow and uniform. The particle size of D1 was greater than 100 nm, while the particle size of the supramolecular nanocomposite solutions prepared in F1-F5 was between 60 nm and 80 nm. The PDI of each formulation was less than 0.3, and the Zeta potential was basically neutral.

[0310] According to the detection results of the CCM concentration in the supernatant of D1 and F1-F5, except that the types of carriers used in each prescription are different, the rest are the same, under the condition of controlling the same preparation process, the assembly ability of F1-F5 and the solubilizing ability of CCM after assembly are not worse than D1, the improvement range of CCM solubility of F1-F5 is 4315 times to 5029 times of curcumin powder (the solubility of curcumin in water at 25°C is about 13.76 μg / mL), and the improvement range of D1 is 3439 times.

[0311] D2: The patent uses Tween80 as the solvent, and the concentration of CCM in the prepared solution is 0.06 mg / mL (60 mg of curcumin is contained in 1 g of Tween80);

[0312] Compared with D2, the improvement range of CCM solubility of D1 and F1-F5 is 789 times to 1153 times of the patent technology.

[0313] Table 11. Physical / chemical stability determination results of D1, F1-F5 under different storage conditions

[0314] According to the detection results of 30 days at room temperature or 2-8°C, the CCM content in the supramolecular nanocomplexes of D1 and F1-F5 has no obvious change compared with 0 days; the detection results of particle size and PDI are basically consistent with the detection results of 0 days, and the physical / chemical stability of D1 and F1-F5 is good.

[0315] (3) Drug loading and encapsulation efficiency calculation

[0316] Take 3 mL of the supramolecular nanocomplex solution prepared according to each prescription of D1 and F1-F5 into a vial with a known weight, record the weight, freeze-dry in a freeze-dryer for 48 hours, and obtain a yellow block, take out, seal with a rubber plug, and then take the weight of the solid, calculate the drug loading and encapsulation efficiency, and the results are shown in the table below.

[0317] The calculation formula of drug loading is as follows:

[0318] Drug loading % = drug content per unit volume (mg) / solid content per unit volume (mg / mL) x 100.

[0319] The drug loading of D1, F1-F5 is 22.0%, 28.6%, 28.1%, 30.1%, 29.2% and 33.0%, respectively. Under the condition that the amount of carrier used is the same, the other high molecular polymers in the prescription and the preparation process are the same, the drug loading of F1-F5 is higher than that of D1.

[0320] The encapsulation efficiency is calculated according to the following formula: EE = [amount of encapsulated drug (mg) / initial amount (mg)] x 100%.​

[0321] The encapsulation rates of D1, F1-F5 were 60.63%, 88.34%, 84.81%, 91.33%, 89.75% and 98.44%, respectively. The encapsulation rates of CCM in F1-F5 were all greater than 80%.

[0322] (4) Dissolution percentage and physical stability in different pH media

[0323] 0.5 mL of the solution of D1, D2, F1-F5 supramolecular nanocomplexes or solution was diluted 1-fold, 3-fold, 5-fold, 10-fold and 20-fold with 0.1 M hydrochloric acid or pH 6.8 phosphate buffer, respectively. After dilution, the solution was shaken in a shaking bed for 2 hours, centrifuged at 13000 rpm for 10 minutes, and the supernatant was detected for the concentration of CCM. The results are shown in the following table:

[0324] Table 11. Dilution experiment and dissolution percentage of CCM in different pH media of the comparative examples and F1-F5 Note: “--” means that the test was not carried out.

[0325] In summary, the solution of the supramolecular nanocomplexes prepared by F1-F5 was diluted 20-fold with 0.1 M hydrochloric acid, and a small amount of flocculent precipitate was observed after shaking for 2 hours. F1 and F5 were still clear solutions. After dilution 20-fold and shaking, the dissolution percentage of CCM in the supernatant of F1-F5 was all above 80%. After shaking, D1 had precipitate, and the dissolution percentage of CCM in the supernatant was 68.5% after centrifugation. The particle size of the supramolecular nanocomplexes prepared by each formula did not change significantly (± 5 nm) after dilution 20-fold. The supramolecular nanocomplexes prepared by D1, F1-F5 had good physical stability and could tolerate dilution with strong acid solution. The solution of D2 diluted 20-fold with 0.1 M hydrochloric acid was clear, but the particle concentration and mass concentration were too low, so the dissolution percentage and particle size were not detected.

[0326] The prepared supermolecular nanocomposite solution of F1-F5 was diluted 20 times with pH 6.8 phosphate buffer solution, and the solution was clear. The above solution was shaken in a shaker for 2 hours, F1 was still clear, F2-F5 had a small amount of flocculent precipitate, and the CCM dissolution percentage in the supernatant after centrifugation was more than 80%; D1 was diluted 20 times with pH 6.8 phosphate buffer solution, the solution was clear, and there was a precipitate after shaking in a shaker for 2 hours. The CCM dissolution percentage in the supernatant after centrifugation was about 71.2%, which was slightly lower than that of F1-F5. After the supermolecular nanocomposite solution prepared by D1 and F1-F5 was shaken and centrifuged, the particle size detection result of the supernatant was not obviously changed compared with before dilution, that is, the physical stability of the supermolecular nanocomposite prepared by D1 and F1-F5 was good, and it could tolerate dilution of different pH solutions. The solution of D2 was clear after being diluted 20 times with pH 6.8 phosphate buffer solution and shaking.

[0327] In summary, the supermolecular nanocomposite constructed by the above carrier derivatives has good physical stability.

[0328] (5) Tissue distribution study

[0329] 1) Experimental animals

[0330] SPF level KM male mice, weighing 18-20 g, were purchased from China Food and Drug Inspection Research Institute, license number SCXK (Jing) 2022-0002. 12 hr alternating light and dark, 22±2℃, RH 55±5% relative humidity environment for one week. The mice were fasted overnight (free water) for more than 10 hours the day before the experiment, and were deprived of water 1 hour before administration, and were allowed to drink water 2 hours after administration, and were allowed to eat 4 hours later.

[0331] 2) Experimental drugs

[0332] D1 and F1-F5 supermolecular nanocomposite solutions.

[0333] 3) Dose and route of administration

[0334] Each mouse was given different formulations by gavage, and the dose was 35 mg per mouse in terms of CCM, and was directly given by gavage with a gavage needle.

[0335] 4) Animal grouping, sampling and treatment

[0336] The mice were randomly divided into 6 groups, 20 in each group (2 more in each group as backup), 3 mice in each blood sampling point. The blood was taken by enucleation at 15 min, 30 min, 1, 2, 3 and 12 hours after administration, respectively, and was anticoagulated with sodium heparin. The plasma was separated by centrifugation at 3500 rpm for 10 minutes, and was stored in a refrigerator at -60°C until analysis. After blood sampling, the mice were executed by cervical dislocation, and the lung, liver, thymus, pancreas, brain tissue, eyeball, rectum, heart and other tissues were quickly separated. After being washed with 4°C normal saline, the tissue surface was dried with a water-absorbing paper and weighed. The tissue was cut into small pieces, mixed with normal saline (4°C, g) at a mass ratio of 1:4, homogenized with a homogenizer, frozen and thawed in liquid nitrogen for three times, centrifuged at 4°C and 13000 rpm for 10 minutes, and the supernatant was collected and stored in a refrigerator at -60°C until detection.

[0337] 5) Pretreatment of biological samples before detection

[0338] Liver, heart, lung, eyeball and brain tissue sample treatment: 150 μL of tissue homogenate was taken, 900 μL of methanol was added for protein precipitation, vortexed for 30 seconds, 130 μL of deionized water and 20 μL of lurasidone hydrochloride internal standard stock solution (800 ng / mL) were added, vortexed for another 20 seconds, and after standing for 10 minutes, centrifuged at 4°C and 13000 rpm for 10 minutes. 50 μL of supernatant was taken, 950 μL of 75% methanol was added, vortexed for 10 seconds to mix, and 20 μL of supernatant was injected for analysis;

[0339] Thymus and pancreas tissue sample treatment: 150 μL of tissue homogenate sample was taken, 900 μL of methanol was added for protein precipitation, vortexed for 30 seconds, 140 μL of deionized water was added, vortexed for another 10 seconds, 10 μL of lurasidone hydrochloride internal standard solution (80 ng / mL) was added, vortexed for another 10 seconds, and after standing for 10 minutes, centrifuged at 4°C and 13000 rpm for 10 minutes. 20 μL of supernatant was injected for analysis;

[0340] Intestinal tissue sample treatment: 150 μL of intestinal tissue homogenate was taken, 900 μL of methanol was added for protein precipitation, vortexed for 30 seconds, 140 μL of deionized water was added, vortexed for 10 seconds, 10 μL of lurasidone hydrochloride internal standard solution (800 ng / mL) was added, vortexed for another 10 seconds, and after standing for 10 minutes, centrifuged at 4°C and 13000 rpm for 10 minutes. 100 μL of supernatant was added to 900 μL of 75% methanol, vortexed for 10 seconds, and 20 μL of supernatant was injected for analysis;

[0341] Plasma sample processing: Take 75 μL experimental animal plasma and 75 μL blank plasma, vortex for 10 seconds to mix evenly, add 900 μL methanol to precipitate protein, continue to vortex for 30 seconds, add 140 μL deionized water and 10 μL internal standard solution (lurasidone hydrochloride-80 ng / mL), vortex for 10 seconds, stand for 10 min, then centrifuge at 4°C / 13000 rpm for 10 min, take 20 μL supernatant for analysis.

[0342] 2) CCM detection method in biological samples

[0343] Liquid chromatography-triple quadrupole mass spectrometry was used to analyze the content of CCM in plasma and tissue samples, and the liquid chromatography and mass spectrometry conditions are shown in the following table.

[0344] Table 12. Liquid chromatography and mass spectrometry conditions for CCM detection in biological samples

[0345] The internal standard method was used to detect the CCM concentration in plasma and different tissue samples, and according to the CCM concentration data measured at different time points, the pharmacokinetic parameters AUC 0-t , AUC 0-∞ , Cmax, Tmax and T 1 / 2 were calculated using Phoenix WinNonlin 7.0, and compared with D1.

[0346] 3) Results and discussion

[0347] The CCM exposure (AUC 0-12hr ) of D1 and F1-F5 in each tissue is shown in Figure 13, and the tissue / plasma exposure ratio of each administration group of mice is shown in Figure 14.

[0348] After oral administration by gavage in D1 and F1-F5 mice, the CCM exposure (AUC 0-12hr ) in brain and eyeball tissues of mice in D1 and F2 administration groups was the lowest, while the CCM exposure (AUC 0-12hr ) in brain and eyeball tissues of mice in F3 administration group was the highest, being 9.85 μg / g˙hr and 5.98 μg / g˙hr, but the exposure ratio of brain tissue / plasma or eyeball / plasma in mice of F5 administration group was the highest among all prescriptions, being 0.38 and 0.23, respectively. The CCM exposure (AUC 0-12hr ) in plasma and liver of mice in F3 administration group was the highest among all administration prescriptions, being 28.34 μg / mL˙hr and 173.43 μg / g˙hr, respectively, followed by F5 prescription, and the CCM exposure (AUC 0-12hr) were 13.48 μg / mL·hr and 116.67 μg / g·hr, respectively; the exposure of CCM in the pancreas tissue of the mice in the F5 administration group was the highest among all the administration prescriptions, about 94.84 μg / g·hr, followed by the F4 prescription, the exposure of CCM in the pancreas was about 81.82 μg / g·hr. The exposure of CCM in the lung tissue of the mice in the F1-F4 administration groups was significantly higher than that in the D1 and F5, about 213.22-294.64 μg / g·hr; the exposure of CCM in the thymus tissue of the mice in the F1-F5 administration groups was significantly higher than that in the D1, about 116.12-177.61 μg / g·hr, indicating that more CCM was absorbed through the lymphatic circulation; the exposure of CCM in the rectum of the mice in the F3 and F4 administration groups was significantly higher than that in the other prescriptions, about 211.34 μg / g·hr and 236.52 μg / g·hr, respectively.

[0349] Brain tissue and eyeball are the most difficult tissues or organs for clinical drugs to reach, especially for brain diseases and fundus diseases. It is very difficult for the existing technology to pass through the blood-brain barrier or blood-ocular barrier, so that the treatment in clinic can only be carried out through invasive administration, such as frequent intervention treatment methods of vitreous cavity injection, periocular injection, implantation and the like for senile macular degeneration and diabetic retinopathy, which not only brings great pain to patients, resulting in poor compliance of patients, but also may cause premature blindness of patients due to intraocular infection, eyeball hemorrhage and retinal detachment and the like. For brain diseases such as brain glioma and brain metastatic cancer, there is no safer non-invasive targeted treatment method except the invasive treatment method.

[0350] The exposure of CCM in the thymus tissue of the mice after oral administration of the delivery system constructed by using the new carrier was significantly higher than that in the D1, indicating that the proportion of CCM absorbed through the lymphatic circulation was significantly higher than that in the D1, which has great significance for solving immune-related diseases.

[0351] Example 11 Supramolecular nanocomplexes F6-F11 and Comparative Example 3

[0352] In recent years, the prevalence and incidence of invasive fungal infections have increased. The number of fungal species that can cause systemic mycoses is high, and the current antifungal treatment is far from the treatment expectations. Amphotericin B plays a key role in the treatment of severe invasive fungal diseases, and the incidence of its antifungal resistance is very low, and it has high efficacy against a variety of fungi. However, the high toxicity and infusion-related side effects of amphotericin B often require patients to be hospitalized, which greatly limits the use of the drug. The currently marketed dosage form of amphotericin B is mainly liposome, which significantly improves patient compliance, reduces renal toxicity and clinical side effects, but is still intravenous injection. In clinical practice, it is generally intravenous drip or aerosol inhalation. Limited by the high toxicity of the drug, renal toxicity, cardiotoxicity and other clinical side effects, intravenous drip needs to control the drip time for 5-6 hours, and too fast injection speed will cause tachycardia, ventricular fibrillation and hypokalemia in patients. Intravenous administration can cause thrombotic phlebitis, and intrathecal injection can cause back and lower extremity pain. Therefore, there is an urgent need in clinical practice for a product that can be self-administered orally by patients, has high oral bioavailability, and has low toxicity and side effects.

[0353] Amphotericin B, the chemical structural formula is as follows:

[0354] Molecular formula: C 47 H 73 NO 17

[0355] Molecular weight: 924.08

[0356] Solubility: soluble in dimethyl sulfoxide, slightly soluble in dimethylformamide, very slightly soluble in methanol, insoluble in water, anhydrous ethanol, chloroform and diethyl ether. Amphotericin B is easily degraded under light and strong acid conditions, therefore, the destruction of the drug by gastric acid in oral administration must be considered.

[0357] Amphotericin B (Amphotericin B, AmB) is used as the active ingredient, and the following prescription is designed to prepare a supramolecular nanocomposite containing amphotericin B.

[0358] (1) Prescription composition

[0359] Table 13. Supramolecular nanocomposite prescription of F6-F11 and Comparative Example 3

[0360] (2) Preparation process

[0361] (1) Dissolve 4 mL of dimethyl sulfoxide with amphotericin B for standby.

[0362] (2) Weigh the carrier and the high molecular polymer according to the prescription, dissolve them in 20 mL of phosphate buffer with pH 5.0-6.0, and then add the solution (1) into the solution (2) drop by drop under stirring. Continue stirring for 1 hour after the dropwise addition, and then stand still. Centrifuge at 4°C / 13000 rpm, separate the supernatant, and then place it in a freeze dryer to freeze dry for 48 hours to obtain the SAN freeze-dried powder of amphotericin B. Detect the content of amphotericin B by HPLC.

[0363] The solubility of amphotericin B is about 13.96 mg / mL to 20.35 mg / mL after it is prepared into a supramolecular nanocomplex in the pH range of 5.0-6.0, which is greatly improved.

[0364] (3) Investigation of reconstitution of amphotericin supramolecular nanocomplex and detection of particle size, PDI, and Zeta potential

[0365] Weigh the supramolecular nanocomplex freeze-dried powder (containing about 20 mg of amphotericin B) of Comparative Example 3 and F6-F11, place it in a test tube with a stopper, and then reconstitute it with 10 mL of pH 5.0 acetate buffer or pH 6.8 phosphate buffer, respectively. Shake well and observe the phenomenon. Shake the reconstituted sample at 37°C / 250 rpm for 2 hours, take a sample, centrifuge at 37°C / 15000 rpm for 8 minutes, take the supernatant, dilute it with 70% ethanol-water solution by 5 times, and then detect the content of amphotericin B in the solution by HPLC to calculate the reconstitution percentage. Detect the particle size and PDI of the supernatant after centrifugation.

[0366] Table 14. Results of reconstitution experiment of amphotericin supramolecular nanocomplex freeze-dried powder

[0367] According to the reconstitution results of the prescriptions, the dissolution percentages of the supramolecular nanocomplex freeze-dried powder of Comparative Example 3 in the pH 5.0 or pH 6.8 buffer are 81.3% and 72.6%, respectively, and there are a lot of insoluble substances after centrifugation. Except for the supramolecular nanocomplex freeze-dried powder of F11, which has a dissolution percentage of 88.4% in the pH 6.8 phosphate buffer, the other prescriptions can be completely reconstituted, and the dissolution percentage is more than 90%. The nanoparticle size of D3 and F6-F11 after reconstitution still maintains between 30-40 nm, indicating that the above-prepared amphotericin B supramolecular nanocomplex has good physical stability.

[0368] Amphotericin B is insoluble in the pH range of 5.0-7.4, and its solubility is greatly improved after it is prepared into a supramolecular nanocomplex. The nanoparticle size of the supramolecular nanocomplex prepared in F6-F11 does not change significantly after reconstitution after freeze-drying, and it has good physical stability.

[0369] Example 12 Supramolecular nanocomplexes F12-F18

[0370] Doxorubicin (DOX) is a widely used anthracycline glycoside antitumor drug in clinic. It can kill tumor cells by inhibiting the synthesis of tumor RNA and DNA. It is often used as a chemotherapeutic drug for acute leukemia, malignant lymphoma, breast cancer, lung cancer, colorectal cancer, ovarian cancer and other solid tumors. However, its therapeutic effect is limited by its serious side effects, including cumulative cardiotoxicity, hepatotoxicity, nephrotoxicity and dose-limiting myelosuppression.

[0371] Doxorubicin is classified as a high-soluble low-osmotic drug according to BCS. Its permeability is affected by P-gp, and its oral bioavailability is very low. Therefore, the currently marketed dosage forms are mainly injection dosage forms. The bioavailability of oral doxorubicin is limited due to the degradation of the drug in the stomach, the first-pass metabolism of cytochrome P450 and the P-gp efflux.

[0372] Doxorubicin is an orange crystalline powder with a density of 1.61 g / cm3 and a melting point of 205°C. It is soluble in methanol, ethanol, dimethyl sulfoxide and tetrahydrofuran, and insoluble in acetone, benzene, chloroform and diethyl ether. It can exist stably at room temperature and pressure, but it needs to be stored in a dark and cool place. The water solubility of DOX is very low (~1.18 mg / mL), and its hydrochloride salt is generally used in clinic, with a solubility of about 50.0 mg / mL.

[0373] Naringenin: Naringenin, NRG;

[0374] Quercetin: Quercetin, QCT;

[0375] Hesperidin: Hesperidin, HPD;

[0376] Honokiol: Honokiol, HNK.

[0377] (1) Prescription composition

[0378] Doxorubicin is used as an active ingredient to design the following prescription to prepare doxorubicin supramolecular nanocomplex.

[0379] Table 15. F12-F18 supramolecular nanocomplex prescription

[0380] (2) Preparation process

[0381] 1) Weigh the prescription amount of DOX, NRG or HPD or QCT or HNK, add ethanol appropriately, and dissolve it into a solution containing about 30 mg of DOX and NRG or HPD or QCT or HNK per 1 mL, ready for use.

[0382] 2) Weigh the carrier and high molecular polymer in each prescription, add 10-15 mL of pH 7.4 phosphate buffer solution, and dissolve by ultrasonic or heating to 60°C, then cool to room temperature.

[0383] 3) Slowly drop 1) into 2) while stirring, continue stirring for 1 hour, remove ethanol by rotary evaporator at 40°C, stand overnight at room temperature, centrifuge at 14000 rpm, and take the supernatant for HPLC detection of DOX, NRG, HPD, QCT, and HNK content.

[0384] (3) Measurement of particle size, PDI, and Zeta potential of supramolecular nanocomplexes

[0385] Table 16. Results of particle size, PDI, and Zeta potential detection of F12-F18 supramolecular nanocomplexes

[0386] (4) Dilution experiment

[0387] Take 1 mL of each of the above supramolecular nanocomplexes, and dilute stepwise to 20 times with 0.1 M hydrochloric acid or pH 7.4 phosphate buffer solution. Shake the sample diluted to 20 times finally in a 37°C / 250 rpm shaker for 2 hours, centrifuge at 37°C / 13000 rpm for 10 minutes, take the supernatant, dilute once with acetonitrile-water (70:30, V / V), and detect the content of DOX and NRG or HPD or QCT or HNK by HPLC. The results are shown in the table below.

[0388] Table 17. DOX nanocomplex dilution experiment

[0389] The above F12-F15, F17-F18 were diluted 20 times with 0.1 M hydrochloric acid or pH 7.4 phosphate buffer solution, and the dissolution percentage was all above 85%. After dilution 20 times, the nanoparticle size was basically the same as before dilution. The PDI of F15 and F16 after dilution with 0.1 M hydrochloric acid was greater than 0.3, and the PDI of the others was less than 0.3. F16 was diluted 20 times with 0.1 M hydrochloric acid, and the dissolution percentage was 87.5%. F16 was diluted 20 times with pH 7.4 phosphate buffer solution, and the dissolution percentage was 74.9%. There were more insoluble substances during the dilution process.

[0390] (5) Biorelevant dissolution experiment

[0391] 1) Experimental process

[0392] According to Journal of Controlled Release 125 (2008) 77-86, the intestinal flora of rats is closest to that of humans, therefore, the dissolution in a dissolution medium containing rat cecal contents was used.

[0393] DOX control solution: take DOX, add a small amount of DMSO to dissolve, then dissolve in 5% HPMCAS MG pH 7.0 phosphate buffer to 10 mg / mL suspension solution.

[0394] Before the start of the dissolution experiment, the contents of the rat rectum were collected, and the entire collection process and dissolution experiment were carried out in a nitrogen-filled glove box.

[0395] After the rat was anesthetized, the rectum was isolated and the contents of the rectum were collected, weighed, diluted to a paste with 10 mL of pH 7.0 nitrogen-filled phosphate buffer, and used as needed.

[0396] Take 1 mL of the above F12-F15, F17-F18 supramolecular nanocomplex solution and 2 mL of the control solution, respectively, and add 19 mL or 18 mL (control solution) of dissolution medium containing rectal contents to a stoppered test tube, seal, fill with nitrogen, and place in a 37°C shaking bed for 3 hours. Shake, and take 1 mL of sample at 3, 6, 8, 10, and 16 hours after the start of the timer, respectively, while supplementing with equal volume of dissolution medium at the same temperature. Each prescription is set up with 3 parallel samples.

[0397] 2) Sample pretreatment

[0398] Add 10 times the volume of 70% acetonitrile to the sample solution, vortex for 30 seconds, and centrifuge at 15000 rpm for 10 minutes. Take the supernatant and determine the content according to the DOX content determination method, and calculate the cumulative dissolution.

[0399] 3) Cumulative dissolution

[0400] The dissolution curves of different formulations in the biological relevant medium are shown in Figure 15.

[0401] According to the above dissolution results, the DOX-control 3-hour cumulative dissolution is the highest. Since there are intestinal contents in the dissolution medium, DOX gradually precipitates from the solution as time goes on. The cumulative dissolution of other formulations reaches the highest between 3 and 8 hours, among which there is a slow upward trend between 6 and 8 hours, and then a slow downward trend for each formulation, which may be related to the metabolism of intestinal microflora. Although in situ assembly occurs after metabolism, the assembled nanocomplex gradually changes from hydrophilic to lipophilic as metabolism occurs. Among them, F15 decreases the slowest at 16 hours, and F18 decreases the fastest.

[0402] (6) Rat oral pharmacokinetics of doxorubicin supramolecular nanocomplex

[0403] 1) Experimental drug: DOX-Control (10 mg / mL), F12-F14, F17-F18 supramolecular nanocomplex solution.

[0404] F12-F14, F17-F18 were diluted with pH 7.4 phosphate buffer to about 10 mg / mL solution before administration.

[0405] 2) Dose: 10 mg / kg;

[0406] 3) Administration route: oral gavage; each animal was gavaged with 0.25 mL of drug solution, and water was 0.25 mL.

[0407] 4) Experimental animals: SD male rats, weighing about 277-300 g. All experimental animals were adapted to a 12-hr day-night alternation at 25℃±5℃ / RH 45%±5% for one week before administration. All experimental animals were randomly divided into 6 groups, 5 in each group. Fasting for more than 10 hours before administration, stop water supply 1 hour before administration.

[0408] F12, F13 and F14 groups were additionally increased by 3 rats at 1 hr and 4 hr sampling points for tissue distribution investigation.

[0409] 5) The administration scheme of each group of rats is shown in the following table:

[0410] Table 18. Animal administration scheme

[0411] Blood sampling points: 0, 0.25, 0.5, 1, 1.5, 2, 4, 8, 10, 16 and 24 hr, about 0.6 mL of blood was taken from the inner canthus, anticoagulated with sodium heparin, centrifuged at 3500 rpm for 10 minutes, the plasma was separated and stored in a-60℃ refrigerator until analysis.

[0412] After blood sampling at 1 hr, 4 hr and 8 hr, 3 rats were taken at each time point, respectively, and were sacrificed under ether anesthesia, and the lung, liver, heart, kidney and other tissues of the rats were quickly separated, washed with 4℃ normal saline, the tissue surface was dried with absorbent paper and weighed, the tissue was cut into small pieces, mixed with anhydrous methanol (4℃, g) in a mass ratio of 1:5, homogenized with a homogenizer, frozen and thawed in liquid nitrogen for three times, centrifuged at 4℃ / 13000 rpm for 10 minutes, and the homogenate was collected and stored in a-70℃ refrigerator.

[0413] 6) Determination of doxorubicin in plasma samples

[0414] ① Determination method

[0415] The content of doxorubicin in plasma was detected by Waters Xevo TQ-S triple quadrupole mass spectrometer, and the excess liquid chromatography conditions were as follows:

[0416] The chromatographic column was Agilent Zorbax SB-C18 column (2.0 x 150 mm, 3 μm) with a guard column of similar packing.

[0417] Mobile phase A: 0.05% formic acid in water; mobile phase B: acetonitrile;

[0418] Gradient elution:

[0419] The detection wavelength of liquid chromatography was 210 nm.

[0420] The injection volume was 10 μL.

[0421] The column temperature was 25 °C.

[0422] Mass spectrometry conditions:

[0423] MS / MS analysis was performed in positive ion mode using an ESI source. The capillary voltage was set at 3.50 kV, the ion source temperature was 120 °C, and the solvent evaporation temperature was 400 °C. Nitrogen was used as the nebulizing gas at a flow rate of 600 L / hr. Argon was used as the collision gas at a flow rate of 0.18 mL / min.

[0424] DOX: protonated ion peak m / z 544.2→397.1;

[0425] The internal standard was Daunorubicin, DNRB: 528.2→321.1.

[0426] 2. Plasma sample pretreatment

[0427] After the plasma sample was taken out of the refrigerator, it was restored to room temperature and completely thawed. 150 μL of plasma was precisely pipetted, 50 μL of internal standard stock solution (Daunorubicin, 500 ng / mL) was added, vortexed for 1 minute, 500 μL of acetonitrile was added, vortexed for 1 minute, centrifuged at 4 °C / 13000 rpm for 10 minutes, 350 μL of supernatant was taken, diluted once with 50% acetonitrile-water (V / V), and 10 μL was precisely pipetted for injection analysis.

[0428] 3. Experimental results

[0429] The pharmacokinetic parameters (AUC 0-t , AUC 0-∞ , C max , T 1 / 2 , T max and the arithmetic mean (±SD) and geometric mean of these parameters) were calculated using Phoenix WinNonlin 7.0 software; the blood concentration-time curve was plotted; the relative bioavailability of each prescription was calculated based on the plasma exposure AUC 0-t of doxorubicin. The experimental results are shown in the following table:

[0430] The PK parameters of each prescription after oral administration in rats are shown in the following table:

[0431] Table 19. PK parameters of DOX supramolecular nanocomplexes prepared by different prescriptions in rats after oral administration (n=5)

[0432] According to the above results, the relative bioavailability of DOX prepared into supramolecular nanocomplexes was significantly improved (17.7-fold to 33.7-fold) compared with DOX solution by oral administration. The relative bioavailability of F14 was the highest. The PK curves of F12-F14 and F17-F18 supramolecular nanocomplexes showed double peaks, with one absorption peak in the upper and lower sections of the digestive tract, respectively. The 24-hour plasma concentrations of F12-F14 and F17-F18 supramolecular nanocomplexes were significantly higher than that of DOX-Control.

[0433] The plasma elimination half-life of DOX-Control was about 14.3 hr, and the plasma elimination half-lives of F12-F14 and F17-F18 were 14.5-16.4 hr, which were basically consistent with that of DOX-Control.

[0434] Specifically as shown in Figure 16.

[0435] 7) Tissue distribution

[0436] ① Tissue sample processing

[0437] Liver, lung, heart, and kidney tissues: Take the tissue homogenate from the refrigerator, thaw it in a 4°C refrigerator, take 150 μL of tissue homogenate, add 50 μL of internal standard solution (daunorubicin, 500 ng / mL), vortex for 30 seconds to mix evenly, then add 500 μL of acetonitrile, vortex for 1 minute, centrifuge at 4°C / 13000 rpm for 10 minutes, take 350 μL of supernatant, dilute it by 50% acetonitrile-water (V / V) once, and accurately take 10 μL for sample analysis.

[0438] ② Detection of tissue samples

[0439] The detection method is the same as that of plasma samples.

[0440] ③ Detection results

[0441] See Figure 17.

[0442] According to the above results, the concentration ratio of liver / plasma, heart / plasma, kidney / plasma of the supermolecular nanocomplex prepared according to the prescription of F13 is low at 1 hour and 4 hours after oral administration in rats, while the lung / plasma concentration ratio is the highest, i.e. the toxic drug exposure in non-target organs is low, while the toxic drug exposure in target organs is high; the exposure concentration ratio of heart / plasma and kidney / plasma of the prescriptions of F12 and F14 is low, but the liver / plasma exposure concentration ratio is significantly higher than that of the prescription of F13.

[0443] According to Journal of Pharmaceutical Sciences I 1381 Vol. 73, No. 10, October 1984, there is no significant difference in the tissue / plasma concentration ratio of heart, lung, kidney, liver of rats after intravenous injection of doxorubicin, belonging to the same order of magnitude.

[0444] Example 13 Supermolecular nanocomplex F19

[0445] (1) Prescription composition

[0446] The supermolecular nanocomplex containing CCM was prepared according to the following prescription:

[0447] An appropriate amount of STVN-Man, STVS, RBDS-C, RBDS-D, RBDS-B, STVB and RBSD was taken respectively and mixed uniformly, so that the mixed carriers accounted for about 25%, 23%, 25%, 5%, 0.5%, 0.5% and 17% respectively, and the mixture was used as the carrier and recorded as RBDS-Mix.

[0448] Table 20. Prescription composition of F19 supermolecular nanocomplex

[0449] (2) Preparation method

[0450] 1) Dissolve CCM with 3 times volume of tetrahydrofuran, ready for use;

[0451] 2) Dissolve the carrier and the high molecular polymer with 10 mL of 0.08% citric acid aqueous solution;

[0452] 3) Slowly add the CCM solution to the citric acid aqueous solution while stirring, continue stirring for 0.5-2 hours after the addition is completed, recover tetrahydrofuran at 40°C under reduced pressure, add 2 mL of water when the organic solvent smell is basically gone, continue to recover under reduced pressure until no liquid drops, collect the water and stand overnight, centrifuge and take the supernatant. HPLC detects the content of CCM, and detects the particle size and Zeta potential, as shown in the following table.

[0453] Table 21. Test results of F19 supermolecular nanocomplex

[0454] (3) Dilution experiment

[0455] Take 1 mL of F19 supramolecular nanocomposite and dilute it with 19 mL of 0.1 M hydrochloric acid or pH 6.8 phosphate buffer. Shake at 200 rpm for 2 hours at 37°C. Centrifuge at 13000 rpm for 10 minutes at 37°C. Take the supernatant and determine the dissolution percentage by HPLC. Perform three parallel tests for each medium.

[0456] According to the test results, F19 dissolved 85% in 0.1M hydrochloric acid and 78% in pH 6.8 phosphate buffer.

[0457] (4) Tissue distribution of mice after oral gavage

[0458] Experimental animals: KM mice, weighing 18.5-20.6g, male, otherwise the same as in Example 1 (5).

[0459] Test drug: F19 supramolecular nanocomposite and comparative example 4 (37 mg CCM dissolved in 1 mL Labrasol medium-chain fatty acid).

[0460] Grouping: 48 mice were randomly divided into 2 groups of 24 each, with 3 mice at each sampling point.

[0461] Because the concentration in Comparative Example 2 was low, each mouse was administered 2 mL by gavage; each F19 animal was administered 0.66 mL by gavage.

[0462] Sampling points: 0.25hr, 0.5, 1, 2, 3, 6, 8 and 12hr, other times the same as in Example 1.

[0463] (5) Experimental Results

[0464] Pharmacokinetic parameters (AUC) calculated using genuine Phoenix WinNonlin 7.0 software. 0-t AUC 0- ∞ Cmax, T 1 / 2 The blood drug concentration-time curve was plotted using the arithmetic mean (±SD) and geometric mean of Tmax and these parameters. The experimental results are shown in Figure 18.

[0465] The common curcumin formulations are limited by the short elimination half-life of curcumin itself, about 3 hours, which requires frequent administration, and the administration dose is at the gram level, but the absorption level is at the nanogram level. The existing marketed products of surfactant micelles, lipid-based formulations, polymer micelles or cyclodextrin inclusion have a certain improvement on the bioavailability, but the systemic exposure level still does not break through 500 ng, not to mention the tissue specificity. From the above results, it can be known that after oral administration of the mice in Comparative Example 4, curcumin is quickly eliminated from the plasma, and the peak concentration in the plasma is less than 200 ng / mL, and after 4 hours, the curcumin level in the plasma is lower than the quantitative limit (3 ng / mL). Except that 10 ng / g of curcumin is detected in the liver tissue at 0.5 hr, no detection or lower than the minimum quantitative limit is detected in other tissues and organs. Therefore, all the tissues of the mice in the experimental group are not detected.

[0466] After oral administration of the F19 supramolecular nanocomposite solution to mice, double absorption peaks appear in the plasma and tissues, wherein the first peak value is 0.5 hr to 1 hr, and the peak values of the plasma, pancreas, liver and brain tissue are 3922 ng / mL, 4267 ng / mL, 1521 ng / mL and 903 ng / mL respectively. The first absorption peak is in the upper half of the digestive tract; the second peak value appears at 3 to 6 hours, and the peak values of the plasma, pancreas, liver and brain tissue are 2640 ng / mL, 4199 ng / mL, 7834 ng / mL and 1077 ng / mL respectively. The second absorption peak is mediated by the metabolism of digestive tract enzymes and microflora, in-situ tissue and absorption. By designing the composition and ratio of the carriers in the prescription, the absorption of the active ingredient can be accurately controlled, so as to realize the sustained-release and long-acting treatment. In the F19 mouse administration group, the CCM concentrations in the plasma, pancreas, liver and brain tissue are 161, 311, 134 and 82 ng / mL respectively at 12 hours, which are significantly higher than the peak concentration of the marketed product. The CCM exposure amounts of the tissues from high to low are pancreas (32.668 μg.hr / mL) > liver (19.898 μg.hr / mL) > plasma (13.140 μg.hr / mL) > brain tissue (4.811 μg.hr / mL).

[0467] In summary, from the PK curves in the plasma of F19 and Comparative Example 4, the delivery system significantly (P<0.001) changes the PK curve characteristics of CCM, and significantly increases the exposure amount of the active ingredient in the pancreas, so as to obtain a higher exposure amount, and also indicates that a part of the active ingredient bypasses the liver first-pass metabolism.

[0468] Example 14 Supramolecular nanocomposites F20-F28

[0469] Drug resistance, also known as antimicrobial resistance, is the tolerance of microorganisms, parasites, and tumor cells to the effects of therapeutic drugs. Once drug resistance occurs, the therapeutic effect of drugs is significantly reduced. Antimicrobial drugs, including antibiotics, antiviral drugs, antifungal drugs, and antiparasitic drugs, are drugs used to prevent and treat infections in humans, animals, and plants. When bacteria, viruses, fungi, and parasites change over time and no longer respond to therapeutic drugs, making infections more difficult to treat, the risk of disease transmission, disease progression, and death increases, resulting in antimicrobial drug resistance. Chemotherapy is one of the main means of treating malignant tumors at present, but multi-drug resistance (MDR) of tumors is one of the main reasons for clinical chemotherapy failure. Due to drug resistance, antibiotics and other antimicrobial drugs become ineffective, and infections become increasingly difficult or impossible to treat. In addition to death or disability, drug resistance also brings huge economic costs and heavy economic burden to society and patients. According to a report published in The Lancet, antimicrobial resistance is an urgent global public health threat, with at least 1.27 million people worldwide dying directly from antimicrobial resistance in 2019, and nearly 5 million deaths related to antimicrobial resistance. Drug resistance has become a major problem that has plagued the global medical community.

[0470] Azithromycin is a 15-membered ring macrolide antibiotic. In vitro tests have shown that azithromycin has antibacterial effects on a variety of common pathogenic bacteria in clinical practice, including Gram-positive aerobic bacteria, Gram-negative aerobic bacteria, sexually transmitted disease microorganisms, and other microorganisms. Therefore, it is widely used in clinical practice for (1) acute pharyngitis and acute tonsillitis caused by Streptococcus pyogenes; (2) acute exacerbation of chronic bronchitis, sinusitis, and otitis media caused by sensitive bacteria; (3) pneumonia caused by Streptococcus pneumoniae, Haemophilus influenzae, and Mycoplasma pneumoniae; (4) urethritis and cervicitis caused by Chlamydia trachomatis and non-multiple drug-resistant Neisseria gonorrhoeae; (5) skin and soft tissue infections caused by sensitive bacteria.

[0471] The commercially available azithromycin dosage forms include tablets, capsules, dry suspensions, granules, powders, enteric-coated capsules / tablets, and injection forms, etc. The dosage forms commonly used by children are dry suspensions and granules. The absolute bioavailability of azithromycin tablets is about 34% when taken orally, and the peak plasma concentration is reached at 1.6-2.4 hours after oral administration

[0472] The molecular formula of azithromycin is C 38 H 72 N2O 12 , and the molecular weight is 749.0 g / mol. Azithromycin dihydrate is a thermodynamically stable crystal form and is non-hygroscopic. Azithromycin is classified as BCS II (low solubility and high permeability) in the biopharmaceutics classification system, and it is soluble in ethanol and dimethyl sulfoxide, but almost insoluble in water.

[0473] The chemical structure of azithromycin dihydrate is as follows:

[0474] Azithromycin dihydrate (molecular weight: 785.0 g / mol)

[0475] The currently marketed azithromycin formulations have a wide tissue distribution, although the lung tissue distribution is higher than that of other tissues, but with the emergence of antibiotic resistance, the clinical often needs to increase the dose of azithromycin. According to Devyani Deshpande Azithromycin Dose To Maximize Efficacy and Suppress Acquired Drug Resistance in Pulmonary Mycobacterium avium Disease, Mycobacterium avium complex (MAC) infection caused by zoonosis also caused a large area of infection of chronic pneumonia in the United States. Due to the lack of drugs for MAC infection, azithromycin is used for treatment in clinic, and the treatment dose is mainly based on the dose of azithromycin for the treatment of other bacterial pneumonia. When the recommended dose of 500 mg / day is used, 0% of the patients reach the target dose, and when the daily treatment dose is increased to 8 g per day, 87% and 54% of the patients reach the optimal killing and drug resistance inhibition related exposure, respectively. With the increasing severity of antibiotic resistance, before the new drug is marketed, the new delivery technology to improve the tissue / organ targeting of existing antibiotics, reduce systemic exposure, and reduce the impact of drug resistance is the most effective means to solve the current serious drug resistance.

[0476] In addition to anti-infective drugs, anticancer drugs also face the problem of multidrug resistance.

[0477] A supramolecular nanocomplex is prepared by taking paclitaxel (PTX), osimertinib (OSTN), and azithromycin (AZMC) as active ingredients.

[0478] (1) Prescription composition

[0479] Table 22. Prescription composition of F20-F28 supramolecular nanocomplexes

[0480] (2) Preparation process

[0481] PTX or OSTN or AZMC and corresponding high molecular polymer under the prescription were dissolved in 10 mL ethanol, the carriers under the respective prescriptions were added, while stirring, an appropriate amount of water or buffer salt solution was slowly added dropwise, stirring for 30 min, 45°C reduced pressure rotary evaporation, removal of ethanol, placed in a 37°C / 250 rpm shaking table hydration overnight. Room temperature / 15000 rpm centrifugation for 8 min, collection of supernatant. HPLC detection of content, nanoparticle size analyzer detection of particle size, PDI and Zeta potential, the results are shown in the table above.

[0482] F24 blank supramolecular nanocomplex solution was prepared by the same method, denoted as F24B.

[0483] Comparative Example 5: Preparation according to the prescription of Liporaxel (Code DHP107) (Prescription source: Efficacy and tissue distribution of DHP107, an oral paclitaxel formulation, https: / / aacrjournals.org / mct / article / 6 / 12 / 3239 / 92906 / Efficacy-and-tissue-distribution-of-DHP107-an-oral). Namely, paclitaxel was dissolved in a mixture of monoglyceride oleate, tricaprylin and Tween 80 (volume ratio 1:0.5:0.3) at 10 mg / mL, and obtained. The test results are shown in the table below:

[0484] Table 23. Test results of Liporaxel oral solution in Comparative Example 5

[0485] (3) Dissolution test

[0486] Method: small cup method (paddle method), 100 rpm, 37°C, 50 mL pH 1.0 HCl medium for 30 minutes, then adjust to 67 mL pH 6.8 medium;

[0487] Sampling: 15 min, 30 min, 45 min, 60 min, 90 min and 120 min.

[0488] Sample processing method: take 2 mL and supplement 2 mL of blank medium in the dissolution cup, take out the sample and place it in a 2 mL centrifuge tube, centrifuge at 37°C / 14000 rpm for 5 min, take 0.4 mL of supernatant, add 80% acetonitrile 3.6 mL or 7.6 mL (osimertinib, azithromycin), mix well, HPLC detection of content, calculation of cumulative dissolution.

[0489] Each dissolution cup was dosed with 50 mg of active ingredient paclitaxel or osimertinib or 100 mg of active ingredient azithromycin, and each prescription was investigated in triplicate. The dissolution curves are shown in Figures 19, 29, and 21.

[0490] As shown in Figure 19, in the dissolution medium without surfactant, the cumulative release of PTX of the F20-F22 supramolecular nanocomplexes was all above 80% in 2 hours. Among the three prescriptions of F20-F22, the cumulative dissolution of PTX in the F20 prescription was the highest in the pH 6.8 phosphate buffer, and the cumulative dissolution of PTX in the F22 prescription was the lowest, but the cumulative dissolution of PTX in the three prescriptions was significantly higher than that of the comparative example 5 (less than 30%) in the same medium.

[0491] As shown in Figure 20, the cumulative dissolution of the Tagrisso reference formulation in 0.1M HCl and then in pH 6.8 phosphate buffer was less than 50% in 2 hours, while the cumulative dissolution of the F23-F25 supramolecular nanocomplexes was all more than 90% in 2 hours under the same dissolution conditions, which was significantly higher than that of the reference formulation. The dissolution behaviors of the supramolecular nanocomplexes prepared by the F23-F25 prescriptions were basically consistent.

[0492] As shown in Figure 21, the cumulative dissolution of the reference formulation Zithromax Sus in pH 6.8 phosphate buffer was less than 20% in 2 hours, while the cumulative dissolution of the F26-F28 supramolecular nanocomplexes was all more than 80% in 2 hours under the same dissolution conditions. When the dissolution medium was changed from 0.1M HCl to pH 6.8 phosphate buffer, the cumulative dissolution of the supramolecular nanocomplexes did not decrease significantly as the reference formulation did.

[0493] (4) Particle size

[0494] The particle size detection results of the above F20-F28 in 0.1M HCl and pH 6.8 phosphate buffer for 30 minutes or 120 minutes are shown in the following table:

[0495] Table 24. Particle size detection results of the F20-F28 supramolecular nanocomplexes in different dissolution media

[0496] According to the above results, the F20-F28 supramolecular nanocomplexes and the F24B supramolecular self-assembled complex blank carrier can withstand changes and influences of different pH and still maintain good physical stability in the above different pH dissolution media.

[0497] (5) In vivo study of paclitaxel supramolecular nanocomplexes

[0498] PTX is one of the most widely used chemotherapeutic drugs in clinical application, with huge market demand. It is also the most broad-spectrum tumor chemotherapeutic drug on the market, but it is limited by the solubility of PTX, the limitation of drug loading capacity, and the existing drug delivery technology. The current marketed products can only be administered by intravenous injection, which greatly limits its application in the treatment of more solid tumors. In addition, when drug resistance occurs, the drug dosage is generally increased or combined with other tumor drugs.

[0499] Liporaxel is an oral solution developed by Hanwha for gastric cancer. It can achieve higher local exposure of gastric tumor tissue through oral administration, and also reduce the toxicity to the system caused by intravenous injection. However, the full oil formula of Liporaxel has a low drug loading capacity (10 mg / mL), and patients need to take 25 mL-40 mL each time, which has poor patient compliance.

[0500] In addition to the indications covered by existing injection of paclitaxel, paclitaxel also has good efficacy for solid tumors such as gastric cancer, colorectal cancer, gastric adenocarcinoma, esophageal cancer, cervical squamous cell carcinoma, endometrial carcinoma, etc. However, the treatment of the above-mentioned cancers in clinical practice is still in a state of few or no drugs. Non-injection administration is convenient for patients to self-administer treatment. The ideal treatment drug for these cancers is a drug that has a high exposure at the lesion site, but the lower the exposure of the drug in the plasma and the systemic tissues and organs, the higher the safety.

[0501] F20-F22 and Comparative Example 5 were used as experimental drugs and control drugs for tissue distribution study after oral administration to mice.

[0502] 1) Experimental animals and grouping

[0503] Male Kunming mice weighing 19.1-21.3 g were used, and the other conditions were the same as in (5) of Example 1. All animals were acclimated in an environment of 20-25°C / relative humidity RH 50%±5% for 12 hours of alternating day and night for one week.

[0504] 84 mice were randomly divided into 4 groups, 21 mice in each group, and 3 animals at each sampling point.

[0505] 2) Drug administration, plasma and tissue sample collection

[0506] Comparative Example 5 needs to be heated to 37°C before administration to change from a solid state to a liquid state. The other formulations F20-F22 were diluted to 10 mg / mL with pH 6.8 phosphate buffer solution, and the dosage for each animal was 50 mg / kg body weight (calculated based on 20 g). All animals were fasted for more than 10 hours before administration, and water was removed 2 hours before administration.

[0507] Table 25. Drug administration scheme of Comparative Example 5 and F20-F22 supramolecular nanocomplexes

[0508] Each animal was administered 0.2 mL of either Comparative Example 5 or F20-F22 solution via gavage, along with 0.2 mL of water. Samples were taken 2 hours after administration, and the animals were given free access to water and food 4 hours later.

[0509] Sampling points: 0.25, 0.5, 1, 2, 3, 6, and 24 hours. Mice were anesthetized with ether, enucleated to collect blood, anticoagulated with heparin, centrifuged at 5000 rpm for 10 minutes, and the plasma was separated for testing. After blood collection, mice were euthanized by cervical dislocation, and their stomach (including duodenum), liver, heart, small intestine, and rectum (equal masses were collected and combined for testing) were rapidly separated.

[0510] The stomach (including the duodenum), small intestine, and rectum / colon were longitudinally dissected, rinsed thoroughly with 4°C saline, blotted dry with absorbent paper, and weighed. The tissue was then minced, and saline was added in a homogenizer at a ratio of tissue (g):saline (g) = 1:9. The tissue was rapidly homogenized to a homogenate state and centrifuged at 4°C / 13000 rpm for 10 minutes. The supernatant was stored at -50°C. The liver, lungs, pancreas, spleen, and heart were rinsed thoroughly with 4°C saline, blotted dry with absorbent paper, and weighed. Subsequent processing was the same as for the digestive tract tissues.

[0511] 3) Pretreatment of biological samples for analysis

[0512] Stomach (including duodenum), small intestine, and colorectal tissue: Take 150 μL of each tissue homogenate, accurately add 20 μL of BHLM internal standard stock solution (50 ng / mL), vortex for 1 min, mix well, then add 430 μL of MoOH, vortex for 1 min, let stand at 4℃ for 10 min, centrifuge at 4℃ / 13000 rpm for 10 min, and take 10 μL of the supernatant for analysis;

[0513] Other tissue sample processing: Take 150 μL of tissue homogenate, add 450 μL of protein precipitant (MeOH), vortex for 30 s, let stand for 10 min, and centrifuge at 4℃ / 13000 rpm for 10 min. Then take 60 μL of the supernatant, add 530 μL of 75% MeOH and 10 μL of internal standard stock solution BHLM-100 ng / mL, vortex for 10 s. Accurately measure 10 μL and inject into the liquid chromatography-mass spectrometry (LC-MS) for analysis.

[0514] Plasma sample processing: 150 μL of plasma, precisely add 20 μL of BHLM internal standard stock solution (50 ng / mL), vortex for 1 min, mix well, then add 430 μL of MeOH, vortex for 30 s, let stand at 4℃ for 10 min, centrifuge at 4℃ / 13000 rpm for 10 min, and take 10 μL of supernatant for analysis.

[0515] 4) Analytical methods

[0516] The content of PTX in plasma and tissue samples was analyzed by liquid chromatography-single quadrupole mass spectrometer, and the liquid chromatography and mass spectrometry conditions are shown in the following table.

[0517] Table 26. Liquid chromatography and mass spectrometry conditions for detecting PTX in biological samples

[0518] The PTX concentration in plasma and tissue samples was detected by internal standard method, and the pharmacokinetic parameters Cmax, Tmax, AUC 0-24 , AUC 0-∞ , etc. were calculated by Phoenix WinNonlin 7.0 according to the PTX concentration measured at different time points, and were compared with Comparative Example 5. The comparison results of PTX exposure in tissues of each administration group are shown in Figure 22.

[0519] Among them, 2 mice in group A died at 21 hr after administration, and another mouse appeared shock at 24 hr after administration, and could not take blood, and the other animals in the administration group did not appear abnormal. Therefore, the 24-hour plasma data was not statistically analyzed, and the exposure concentration and exposure amount of PTX in tissue samples were all 21-hour data.

[0520] From the analysis results of Comparative Example 5, after oral administration, the PTX exposure amount (AUC 0- ∞ ) in the liver of Comparative Example 5 was 153.011 μg / g·hr, which was 4.1 times, 7.8 times, 3.5 times and 9.0 times of the PTX exposure amount in the stomach, colon, small intestine and heart, respectively. The liver was still the organ with the highest PTX exposure amount, followed by the stomach and small intestine with higher exposure amount. The PTX exposure amount (AUC 0-∞ ) in the heart was 5.7 times of the plasma exposure amount (AUC 0-∞ ). In the literature (Mol Cancer Ther 2007; 6(12). December 2007, Efficacy and tissue distribution of DHP107, an oral paclitaxel formulation), the ratio of PTX exposure amount (AUC 0-24hr ) in the liver, heart and intestine to the plasma exposure amount (AUC 0-24hr ) after intravenous injection of Taxol was 7.4 times, 0.8 times and 2.1 times (average of small intestine and colon), respectively. The ratio of tissue exposure amount (AUC 0-∞ ) of PTX in the liver, heart and intestine to the plasma exposure amount after oral administration of Comparative Example 5 was higher than that of Taxol (10 mg / kg intravenous injection).

[0521] After oral administration of F20 prescription, the PTX exposure amount (AUC0-∞ ) were 1.4, 0.9, 0.9 and 122.6 times of the PTX exposure (AUC 0-∞ ) in stomach, small intestine, colon and heart, respectively. The exposure in heart was the lowest, and the exposures in stomach, small intestine and colon were comparable to that in liver. Compared with the control oral solution, the PTX exposure (AUC 0-∞ ) in liver of F20 was only 0.2 times of that in the control oral solution, while the PTX exposures (AUC 0-∞ ) in stomach, small intestine, colon, liver, heart and plasma were 0.7, 0.9, 2.0 and 0.1 times of those in the control oral solution, respectively, which was obviously advantageous for the development of the treatment of digestive tract cancer.

[0522] After oral administration of F21, the PTX exposures (AUC 0-∞ ) in stomach, small intestine, colon, liver, heart and plasma were 3.0, 1.8, 1.8, 2.2, 2.4 and 2.4 times of those in F20, respectively. 0-∞

[0523] After oral administration of F22, the PTX exposures (AUC 0-∞ ) in stomach, small intestine, colon, liver, heart and plasma were 1.7, 1.9, 2.2, 2.6, 3.3 and 3.3 times of those in F20, respectively. 0-∞

[0524] Compared with F20, the PTX exposures in the digestive tract tissues of F21 and F22 were significantly higher than those of F20, but the exposures in plasma, liver and heart were slightly increased, but were still significantly lower than those of the control 5.

[0525] (6) In vivo study of F23-F25 supramolecular nanocomplexes

[0526] Female BALB / c nude mice (5-6 weeks old) were purchased from Beijing Vital River Laboratory Animal Technology Co., Ltd. All animal experiments were strictly performed in accordance with the regulations of the China Council of Animal Protection and Use. Each nude mouse was injected with 100 μL (5 x 10 6 cells) of PC9 / AZD cells in the right axillary fossa. When the size of the subcutaneous tumor was about 90 mm 3After that, the model was successfully established. The nude mice were randomly divided into 6 groups, and were respectively given physiological saline (Con.), F24B, AZD9291, F23-F25 supramolecular nanocomposite solution by gavage, wherein the dosages of AZD9291 and F23-F25 were 10 mg / kg (all in terms of AZD9291 free base), and the dosages of the drug-loaded supramolecular nanocomposites were consistent with those of the free drugs. The mice were given drugs once every 3 days, and were continuously given drugs for 5 times, and were continuously bred for 20 days. The body weight and tumor diameter of the tumor-bearing mice were recorded every 2 days. The tumor volume (V) was calculated according to the following formula: V = longest dimension x shortest dimension 2 / 2. After treatment, the nude mice were sacrificed, and the tumor tissues were collected. The results are shown in FIG. 23 and FIG. 24.

[0527] Tumor volume changes in different treatment groups

[0528] According to the results of the tumor volume growth on the 20th day, there was no significant difference in the tumor growth trend between the Con. group and the F24B group; the AZD9291 administration group had a significant difference compared with the Con. group or the F24B group (P < 0.01); the F23, F24 and F25 groups had a significant difference compared with the AZD9291 administration group (P < 0.001); the F23 group had a significant difference compared with the F25 group (P < 0.05); and the F24 treatment group had no significant difference compared with the F25 treatment group, which was consistent with the prescription of the nanocomposite.

[0529] The above results demonstrate that F23-F25 has a significant inhibitory effect on the drug-resistant strain of AZD9291.

[0530] After 20 days of treatment in different treatment groups, there was no significant difference between the Con. group and the F24B group (P > 0.05); the tumor weight of the AZD9291 group had a significant difference compared with the Con. or F24B group (P < 0.05); the tumor weight of the F23-F25 treatment group had a significant difference compared with the AZD9291 group (P < 0.001); the tumor weight of the F23 group had a significant difference compared with the F25 group (P < 0.05); and the tumor weight of the F24 and F25 groups had no significant difference (P > 0.05).

[0531] The above-described specific embodiments further illustrate the purpose, technical solutions and beneficial effects of the present application. It should be understood that the above-described specific embodiments are merely examples of the present application and are not intended to limit the present application. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principles of the present application shall be included in the protection scope of the present application.

Claims

1. A targeted nanodelivery kit comprising: an active ingredient and a targeting guide, wherein the targeting guide has the following characteristics: (1) has a recognition group in its chemical structure; (2) the recognition group contains one or more of n-valent mannose, galactose, rhamnose glycosyl and its derivatives; (3) the recognition group is linked to the aglycone of the targeting guide and / or other glycosyl through a covalent bond; Also, the targeting guide agent is represented by Structural Formula (1-1): In structural formula (1-1), R1, R2 are independent, R2 is selected from hydroxyl or glycosyl, and R1 is selected from a glycosyl group containing n-valent mannose, pyran mannose, galactose, pyran galactose, rhamnose, pyran rhamnose, or a combination thereof, or an oligosaccharide formed by covalent linkage of other sugars, or any glycosyl group in (1) to (4) below, wherein 1≤n≤10.

2. The targeted nanodelivery kit according to claim 1, having any one of the following characteristics: (1) the mannose, galactose, rhamnose derivatives include one or more of aldehyde, alcohol, acid, ester, disaccharide, trisaccharide, oligosaccharide, polysaccharide; (2) the absolute configuration of the mannose, pyranose mannose, galactose, pyranose galactose, rhamnose, pyranose rhamnose in the recognition group is D type or L type, and the relative configuration of the end group carbon is α type or β type; (3) the absolute configuration of the mannose in the recognition group is D type, and the relative configuration of the end group carbon is β type; the absolute configuration of the galactose is D type, and the relative configuration of the end group carbon is β type; the absolute configuration of the rhamnose is L type, and the relative configuration of the end group carbon is α type; (4) the glycosyl is selected from the group consisting of glucose, arabinose, xylose, fucose, apiose, glucuronic acid, glucuronide, glucosamine, galacturonic acid, acetyl amino sugar, mannose, deoxyglucose, rhamnose, xylose, glucosamine, disaccharide, trisaccharide, oligosaccharide polymerized by any number of any monosaccharide, disaccharide, trisaccharide at any position; and (5) the glycosyl is selected from the group consisting of oligosaccharide polymerized by monosaccharide, wherein the number of monosaccharide is not more than 10.

3. The targeted nanodelivery kit of claim 1 or 2, wherein, the targeting guide is selected from the group consisting of: (1) (2S, 3S, 4S, 5S, 6R)-3, 4, 5-trihydroxy-6-(hydroxymethyl) tetrahydro-2H-pyran-2-yl (4R, 4aS, 6aR, 9R, 11aR, 11bS)-9-hydroxy-4, 11-dimethyltetradecahydro-6a, 9-methanocyclohepta[a]naphthalene-4-carboxylate (STL-Man), (2) (2S, 3S, 4S, 5S, 6R)-3, 4, 5-trihydroxy-6-(hydroxymethyl) tetrahydro-2H-pyran-2-yl (4R, 4aS, 6aR, 9S, 11aR, 11bS)-4, 11b-dimethyl-8-methylene-9-(((2S, 3R, 4S, 5S, 6R)-3, 4, 5-trihydroxy-6-(hydroxymethyl) tetrahydro-2H-pyran-2-yl) oxy) tetradecahydro-6a, 9-methanocyclohepta[a]naphthalene-4-carboxylate (RBSD-Acid-Man), (3) (2S,3S,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl (4R,4aS,6aR,9S,11aR,11bS)-9-((2S,3R,4S,5S,6R)-4,5-dihydroxy-6-(hydroxymethyl)-3-(((2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)tetrahydro-1 H-pyran-2-yl)oxy)-4,11 b-dimethyl-8-methylenetetradecahydro-6a,9-methylcyclohepta[a]naphthalene-4-carboxylate (STVB-Man), (4) (2S,3S,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl (4R,4aS,6aR,9S,11aR,11bS)-9-((2S,3R,4S,5S,6R)-4,5-dihydroxy-6-(hydroxymethyl)-3-(((2S,3R,4R,5R,6S)-3,4,5-trihydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)tetrahydro-2H-pyran-2- yloxy)-4,11 b-dimethyl-8-methylenetetradecahydro-6a,9-methylcyclohepta[a]naphthalene-4-carboxylate (DCS-A-Acid-Man), (5) (2S,3S,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl (4R,4aS,6aR,9S,11aR,11bS)-9-(((2S,3R,4S,5R,6R)-5-hydroxy-6-(hydroxymethyl)-3,4-bis((2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)tetrahydro-1 H-pyran-2-yl)oxy)-4,11 b-dimethyl-8-methylenetetradecahydro-6a,9-methylcyclohepta[a]naphthalene-4-carboxylate (RBDS-B-Man), (6) (2S,3S,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl (4R,4aS,6aR,9R,11aR,11bS)-9-((2S,3R,4S,5R,6R)-5-hydroxy-6-(hydroxymethyl)-4-(((2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl) oxy)-3-(((2S,3R,4S,5R)-3,4,5-trihydroxytetrahydro-2H-pyran-2-yl)oxy)tetrahydro-2H-pyran-2-yl oxy)-4,11 b-dimethyltetradecahydro-6a,9-methylcyclohepta[a]naphthalene-4-carboxylate (RBDS-F-Acid-Man), (7) (2S,3S,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl (4R,4aS,6aR,9S,11aR,11bS)-9-(((2S,3R,4S,5R,6R)-5-hydroxy-6-(hydroxymethyl)-4-(((2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)-3-(((2S,3R,4R,5R,6S)-3,4,5-trihydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)tetrahydro-2H-pyran-2-yl)oxy)-4,11b-dimethyl-8-methylenetetradecahydro-6a,9-methanocyclohepta[a]naphthalene-4-carboxylate (DCS-B-Man), (8) (2S,3S,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl (4R,4aS,6aR,9S,11aR,11bS)-9-(((2S,3R,4S,5R,6R)-3-(((2S,3R,4R,5S,6S)-3,5-dihydroxy-6-methyl-4-(((2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)tetrahydro-2H-pyran-2-yl)oxy)-5-hydroxy-6-(hydroxymethyl)-4-(((2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)tetrahydro-2H-pyran-2-yl)oxy)-4,11b-dimethyl-8-methylenetetradecahydro-6a,9-methanocyclohepta[a]naphthalene-4-carboxylate (RBDS-H-Acid-Man), (9) steviol (STVN)-Man, (10) a combination of any one or more of (1)-(9), (11) (2S,3R,4R,5R,6S)-3,4,5-trihydroxy-6-methyltetrahydro-2H-pyran-2-yl (4R,4aS,6aR,9R,11aR,11bS)-9-hydroxy-4,11-dimethyltetradecahydro-6a,9-methanocyclohepta[a]naphthalene-4-carboxylate (STL-Rha), (12) (2S,3R,4R,5R,6S)-3,4,5-trihydroxy-6-methyltetrahydro-2H-pyran-2-yl (4R,4aS,6aR,9S,11aR,11bS)-4,11b-dimethyl-8-methylen-9-(((2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)tetradecahydro-6a,9-methanocyclohepta[a]naphthalene-4-carboxylate (RBSD-Acid-Rha), (13) (2S,3R,4R,5R,6S)-3,4,5-trihydroxy-6-methyltetrahydro-2H-pyran-2-yl (4R,4aS,6aR,9S,11aR,11bS)-9-(((2S,3R,4S,5S,6R)-4,5-dihydroxy-6-(hydroxymethyl)-3-(((2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)tetrahydro-1 H-pyran-2-yl)oxy)-4,11 b-dimethyl-8-methylenetetradecahydro-6a,9-methanocyclohepta[a]naphthalene-4-carboxylate (STVB-Rha), (14) (2S,3R,4R,5R,6S)-3,4,5-trihydroxy-6-methyltetrahydro-2H-pyran-2-yl (4R,4aS,6aR,9S,11aR,11bS)-9-(((2S,3R,4S,5S,6R)-4,5-dihydroxy-6-(hydroxymethyl)-3-(((2S,3R,4R,5R,6S)-3,4,5-trihydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)tetrahydro-2H-pyran-2-yl)oxy)-4,11 b-dimethyl-8-methylenetetradecahydro-6a,9-methanocyclohepta[a]naphthalene-4-carboxylate (DCS-A-Acid-Rha), (15) (2S,3R,4R,5R,6S)-3,4,5-trihydroxy-6-methyltetrahydro-2H-pyran-2-yl (4R,4aS,6aR,9S,11aR,11bS)-9-(((2S,3R,4S,5R,6R)-5-hydroxy-6-(hydroxymethyl)-3,4-bis((2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)tetrahydro-1 H-pyran-2-yl)oxy)-4,11 b-dimethyl-8-methylenetetradecahydro-6a,9-methanocyclohepta[a]naphthalene-4-carboxylate (RBDS-B-Rha), (16) (2S,3R,4R,5R,6S)-3,4,5-trihydroxy-6-methyltetrahydro-2H-pyran-2-yl (4R,4aS,6aR,9S,11aR,11bS)-9-(((2S,3R,4S,5R,6R)-5-hydroxy-6-(hydroxymethyl)-4-(((2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)-3-(((2S,3R,4R,5R,6S)-3,4,5-trihydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)tetrahydro-2H-pyran-2-yl)oxy)-4,11 b-dimethyl-8-methylenetetradecahydro-6a,9-methanocyclohepta[a]naphthalene-4-carboxylate (DCS-B-Rha), (17) (2S,3R,4R,5R,6S)-3,4,5-trihydroxy-6-methyltetrahydro-2H-pyran-2-yl (4R,4aS,6aR,9R,11aR,11bS)-9-((2S,3R,4S,5R,6R)-5-hydroxy-6-(hydroxymethyl)-4-(((2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)-3-(((2S,3R,4S,5R)-3,4,5-trihydroxytetrahydro-2H-pyran-2-yl)oxy)tetrahydro-2H-pyran-2-yl oxy)-4,11b-dimethyltetradecahydro-6a,9-methanocyclohexa[a]naphthalene-4-carboxylate (RBDS-F-Acid-Rha), (18) (2S,3R,4R,5R,6S)-3,4,5-trihydroxy-6-methyltetrahydro-2H-pyran-2-yl (4R,4aS,6aR,9S,11aR,11bS)-9-(((2S,3R,4S,5R,6R)-3-(((2S,3R,4R,5S,6S)-3,5-dihydroxy-6-methyl-4-(((2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)tetrahydro-1H-pyran-2-yl)oxy)-5-hydroxy-6-(hydroxymethyl)-4-(((2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)tetrahydro-1H-pyran-2-yl)oxy)-4,11b-dimethyl-8-methylenetetradecahydro-6a,9-methanocyclohexa[a]naphthalene-4-carboxylate (RBDS-H-Acid-Rha), (19) steviol-Rha, (20) a combination of one or more of any of (1) to (19), (21) (2S,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl (4R,4aS,6aR,9S,11aR,11bS)-9-hydroxy-4,11b-dimethyl-8-methylenetetradecahydro-6a,9-methanocyclohexa[a]naphthalene-4-carboxylate (STL-Gal), (22) (2S,3R,4R,5R,6S)-3,4,5-trihydroxy-6-methyltetrahydro-2H-pyran-2-yl (4R,4aS,6aR,9S,11aR,11bS)-4,11b-dimethyl-8-methylen-9-(((2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)tetradecahydro-6a,9-methanocyclohexa[a]naphthalene-4-carboxylate (RBSD-Acid-Gal), (23) (2S,3R,4R,5R,6S)-3,4,5-trihydroxy-6-methyltetrahydro-2H-pyran-2-yl (4R,4aS,6aR,9S,11aR,11bS)-9-(((2S,3R,4S,5S,6R)-4,5-dihydroxy-6-(hydroxymethyl)-3-(((2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)tetrahydro-1 H-pyran-2-yl)oxy)-4,11 b-dimethyl-8-methylenetetradecahydro-6a,9-methanocyclohepta[a]naphthalene-4-carboxylate (STVB-Gal), (24) (2S,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2- yl (4R,4aS,6aR,9S,11aR,11bS)-9-((2S,3R,4S,5R,6R)-5-hydroxy-6-(hydroxymethyl)-3,4-bis((2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)tetrahydro-1 H-pyran-2-yl)oxy)-4,11 b-dimethyl-8-methylenetetradecahydro-6a,9-methanocyclohepta[a]naphthalene-4-carboxylate (RBDS-B-Gal), (25) (2S,3R,4S,5R)-3,4,5-trihydroxytetrahydro-2H-pyran-2-yl (4R,4aS,6aR,9S,11aR,11bS)-9-(((2S,3R,4S,5R,6R)-5-hydroxy-6-(hydroxymethyl)-4-(((2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)-3-(((2S,3R,4R,5R,6S)-3,4,5-trihydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)tetrahydro-2H-pyran-2-yl)oxy)-4,11 b-dimethyl-8-methylenetetradecahydro-6a,9-methanocyclohepta[a]naphthalene-4-carboxylate (DCS-A-Acid-Gal), (26) (2S,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2- yl (4R,4aS,6aR,9S,11aR,11bS)-9-(((2S,3R,4S,5R,6R)-5-hydroxy-6- (hydroxymethyl)-4-(((2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6- (hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)-3-(((2S,3R,4S,5R)-3,4,5- trihydroxytetrahydro-2H-pyran-2-yl)oxy)tetrahydro-2H-pyran-2-yl)oxy)-4,11b- dimethyl-8-methylenetetradecahydro-6a,9-methanocyclohepta[a]naphthalene-4- carboxylate (DCS-B-Gal), (27) (2S,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2- yl (4R,4aS,6aR,9S,11aR,11bS)-9-(((2S,3R,4S,5R,6R)-5-hydroxy-6- (hydroxymethyl)-4-(((2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6- (hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)-3-(((2S,3R,4S,5R)-3,4,5- trihydroxytetrahydro-2H-pyran-2-yl)oxy)tetrahydro-2H-pyran-2-yl)oxy)-4,11b- dimethyl-8-methylenetetradecahydro-6a,9-methanocyclohepta[a]naphthalene-4- carboxylate (RBDS-F-Acid-Gal), (28) (2S,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2- yl (4R,4aS,6aR,9S,11aR,11bS)-9-(((2S,3R,4S,5R,6R)-3-(((2S,3R,4R,5S,6S)- 3,5-dihydroxy-6-methyl-4-(((2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6- (hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)tetrahydro-2H-pyran-2-yl)oxy)-5- hydroxy-6-(hydroxymethyl)-4-(((2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6- (hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)tetrahydro-2H-pyran-2-yl)oxy)-4, 11b-dimethyl-8-methylenetetradecahydro-6a,9-methanocyclohepta[a]naphthalene-4- carboxylate (RBDS-H-Acid-Gal), (29) steviol-Gal, (30) a combination of any one or more of (1) to (29); (31) (2S, 3S, 4S, 5S)-2, 3, 4, 5-tetrahydroxyhexyl (4R, 4aS, 6aR, 9S, 11aR, 11bS)-9- ((2S, 3R, 4S, 5R, 6R)-5-hydroxy-6-(hydroxymethyl)-3, 4-bis((2S, 3R, 4S, 5S, 6R)-3, 4, 5- trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)tetrahydro-2H-pyran-2- yloxy)-4, 11b-dimethyl-8-methylenetetrahydro-6a, 9-methanocyclohepta[a]naphthalene-4- carboxylate (RBDS-B-GaOH), (32) derivatives of steviol glycoside (ducoside-B) with hyaluronic acid, amino acid, polypeptide, alkyl alcohol, monosaccharide, disaccharide, trisaccharide, oligosaccharide, polysaccharide, polyglutamic acid, polylysine, glycoside, polyarginine and cell-penetrating peptide, etc. by ester bond, amide bond; (33) a combination of any one or more of (1) to (32).

4. The targeted nanodelivery kit according to any one of claims 1 to 3, wherein, Also contains one or more delivery vectors, said vector is composed of unit A and unit B covalently linked, wherein unit A is a hydrophilic part, unit B is a hydrophobic part, wherein unit A is located on one side or both sides of unit B, when unit A is located on both sides of unit B, unit A can be the same or different; wherein the number ratio of unit A to unit B is (0: 1) to (7: 1), Wherein unit B is selected from one or more of B1, or one or more of B2, wherein: (1) B1 is a compound whose molecular formula is consistent with (C5H8)n, and its alcohol, aldehyde, ketone, carboxylic acid or ester derivative, wherein n = 4 or 6; (2) B2 is a compound with C6-C3-C6 basic skeleton with 2-phenyl chromone as the basic nucleus, and its derivatives (such as halide or amino acid ester, the halide is, for example, chloro or fluoro, and the amino acid ester is, for example, an ester formed by the hydroxyl group on C6 and an amino acid); Wherein unit A is selected from one or more of A1 or a derivative of A1, wherein: A1 is selected from monosaccharide, disaccharide, trisaccharide or a combination thereof in D form or L form, Wherein the monosaccharide is selected from the group consisting of glucose, rhamnose, galactose, arabinose, xylose, mannose, fucose, apiose, glucuronic acid, glucuronide, glucosamine, galacturonic acid, acetylglucosamine and combinations thereof, and the relative configuration of each sugar end group carbon can be α or β; The disaccharide is selected from the group consisting of sophorose (glc1-2glc), gentiobiose (glC1-6glc), rhamnose (rha1-6glc), neohesperidose (rha1-6glC), robinobiose (rha1-6gal) and combinations thereof; The trisaccharide is selected from the group consisting of gentiotriose, sophorotriose (glc1-2glc1-2glc) and combinations thereof; The derivative of A1 is an acylate of A1, such as 2-acetylglucose, caffeoylglucose.

5. The targeted nanodelivery kit of claim 4, having any one of the following features: (1) the ester derivative of B1 is an ester formed from a carboxylic acid derivative of B1, such as gluconate, polyethylene glycol ester, propylene glycol ester, methyl ester, ethyl ester or 1-aminoglycine ester; (2) the hydrophobic unit B is a tetracyclic diterpene, tetracyclic triterpene, pentacyclic triterpene, or an alcohol, aldehyde, ketone, carboxylic acid or ester derivative thereof; (3) the hydrophobic unit B is a cembranoid tetracyclic diterpene and derivatives thereof, such as alcohol, aldehyde, ketone, carboxylic acid or ester; (4) the hydrophobic unit B is one or more of dammarane type, tigillicine type, cycloartane type, lanostane type, cucurbitane type, meliatoxol type and protostane type, and derivatives thereof (such as alcohol and ester), more preferably cucurbitane type and derivatives thereof (such as alcohol and ester); (5) the hydrophobic unit B is one or more of oleanane type, ursane type, lupane type, friedelane type, hopane type and isohopane type, and derivatives thereof (such as alcohol, ketone, carboxylic acid and ester); (6) Unit B1 is a bryostatin-type tetracyclic diterpene or a pharmaceutically acceptable salt thereof (such as a sodium salt, a potassium salt, an ammonium salt), a hydrate of a bryostatin-type tetracyclic diterpene or a pharmaceutically acceptable salt thereof (such as a hydrate formed with 0.5, 1, 1.5, 2, 2.5, or 3 molecules of crystalline water), when the carrier has the structure of Formula (2-1); wherein R1, R2are each selected from the following groups: (7) when Unit B1 is a cucurbitane-type tetracyclic triterpene or a pharmaceutically acceptable hydrate or solvate thereof, the carrier has the structure of Formula (2-2): wherein R1and R2represent unit A, and R1and R2are present simultaneously or separately, R1, R2, R3, R4are independently selected from the following groups: (8) when Unit B1 is a oleanane-type pentacyclic triterpene or a pharmaceutically acceptable hydrate or solvate thereof, the carrier has the structural formula (2-3) structure: wherein R1is selected from the following groups: (9) said Unit B is B2 and is selected from the group consisting of flavonol (as represented by structural formula (2-4), or dihydrochalcone (as represented by structural formula (2-5)), and combinations thereof, wherein structural formula (2-4) or structural formula (2-5) are as follows:

6. The targeted nanodelivery kit according to claim 4 or 5, characterized in that, the carrier is selected from the group consisting of: (1) (1R,4S,5R,9S,10R,13S)-13-[(2S,3R,4S,5R,6R)-5-hydroxy-6-(hydroxymethyl)-3,4-bis[[(2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy]oxan-2-yl]oxy-5,9-dimethyl-14-methylenetetra- cyclo[11.2.1.01,10.04,9]hexadecan-5-carboxylate sodium salt (RBDS-B-Na), (2) (1R,4S,5R,9S,10R,13S)-13-[(2S,3R,4S,5S,6R)-4,5-dihydroxy-6-(hydroxymethyl)-3-[(2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxyoxan-2-yl]oxy-5,9-dimethyl-14-methylenetetra- cyclo[11.2.1.01,10.04,9]hexadecan-5-carboxylate sodium salt (STVB-Na), (3) [(2S,3R,4S,5R,6R)-5-hydroxy-6-(hydroxymethyl)-3,4-bis[[(2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy]oxan-2-yl](1R,4S,5R,9S,10R,13S)-13-[(2S,3R,4S,5R,6R)-5-hydroxy-6-(hydroxymethyl)-3,4-bis[(2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy]oxan-2-yl]oxy-5,9-dimethyl-14-methylenetetra- cyclo[11.2.1.01,10.04,9]hexadecan-5-carboxylate (RBDS-M), (4) (2S,3R,4S,5S,6R)-4,5-dihydroxy-6-(hydroxymethyl)-3-[(2S,3R,4S,5S,6R)-3,4,5- trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxyoxan-2-yl]oxy-5,9-dimethyl-14- methylenetetracyclo[11.2.1.01,10.04,9]hexadecan-5-carboxylate (RBDS-D), (5) [(2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl](1R,4S,5R,9S,10R,13S)- 13-[(2S,3R,4S,5R,6R)-5-hydroxy-6-(hydroxymethyl)-3,4-bis[[(2S,3R,4S,5S,6R)-3,4,5- trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy]oxan-2-yl]oxy-5,9-dimethyl-14- methylenetetracyclo[11.2.1.01,10.04,9]hexadecan-5-carboxylate (RBDS-A), (6) (1R,4S,5R,9S,10R,13S)-13-[(2S,3R,4S,5R,6R)-5-hydroxy-6-(hydroxymethyl)-3,4-bis[[(2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy]oxan-2-yl]oxy-5,9- dimethyl-14-methylenetetracyclo[11.2.1.01,10.04,9]hexadecan-5-carboxylic acid (RBDS-B), (7) [(2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl](1R,4S,5R,9S,10R,13S)- 13-[(2S,3R,4S,5S,6R)-4,5-dihydroxy-6-(hydroxymethyl)-3-[(2S,3R,4S,5S,6R)-3,4,5- trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxyoxan-2-yl]oxy-5,9-dimethyl-14- methylenetetracyclo[11.2.1.01,10.04,9]hexadecan-5-carboxylate (STVS), (8) (1R,4S,5R,9S,10R,13S)-13-[(2S,3R,4S,5S,6R)-4,5-dihydroxy-6- (hydroxymethyl)-3-[(2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6- (hydroxymethyl)oxan-2-yl]oxyoxan-2-yl]oxy-5,9-dimethyl-14- methylenetetracyclo[11.2.1.01,10.04,9]hexadecan-5- carboxylic acid (STVB), (9) [(2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl] (1R,4S,5R,9S,10R,13S)-5,9-dimethyl-14-methylen-13-[(2S,3R,4S,5S,6R)-3,4,5- trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxytetracyclo[11.2.1.01,10.04,9] hexadecan-5-carboxylate (RBSD), (10) [(2S,3R,4S,5S,6R)-4,5-dihydroxy-6-(hydroxymethyl)-3-[(2S,3R,4S,5S,6R)-3,4,5- trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxyoxan-2-yl] (1R,4S,5R,9S,10R,13S)- 13-[(2S,3R,4S,5S,6R)-4,5-dihydroxy-6-(hydroxymethyl)-3-[(2S,3R,4S,5S,6R)- 3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxyoxan-2-yl]oxy-5,9-dimethyl- 14-methylenetetracyclo[11.2.1.01,10.04,9]hexadecan-5-carboxylate (RBDS-E), (11) [(2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl] (1R,4S,5R,9S,10R,13S)-13-[(2S,3R,4S,5R,6R)-5-hydroxy-6-(hydroxymethyl)-4-[(2S,3R,4S,5S,6R)- 3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-3-[(2S,3R,4S,5R)-3,4,5- trihydroxyoxan-2-yl]oxyoxan-2-yl]oxy-5,9-dimethyl-14-methylenetetracyclo[11.2.1.01,10.04,9]hexadecan-5-carboxylate (RBDS-F), (12) (2S,3R,4S,5R,6R)-5-hydroxy-6-(hydroxymethyl)-3,4-bis(((2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)tetrahydro-2H-pyran-2-yl (4R,4aS,6aR,9S,11aR,11bS)-9-(((2S,3R,4S,5S,6R)-4,5-dihydroxy-6-(hydroxymethyl)-3-(((2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)tetrahydro-2H-pyran-2-yl)oxy)-4,11b-8-methylenetetradecahydro-6a,9-methyicyclohepta[a]naphthalene-4-carboxylic acid dimethyl ester (RBDS-AM), (13) [(2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl](1R,4S,5R,9S,10R,13S)-13-[(2S,3R,4S,5R,6R)-5-hydroxy-6-(hydroxymethyl)-4-[(2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-3-[(2S,3R,4R,5R,6S)-3,4,5-trihydroxy-6-methyloxan-2-yl]oxyoxan-2-yl]oxy-5,9-dimethyl-14-methylenetetracyclo[11.2.1.01,10.04,9]hexadecan-5-carboxylate (RBDS-C), (14) [(2S,3R,4S,5S,6R)-4,5-dihydroxy-6-(hydroxymethyl)-3-[(2S,3R,4R,5R,6S)-3,4,5-trihydroxy-6-methyloxan-2-yl]oxan-2-yl](1R,4S,5R,9S,10R,13S)-13-[(2S,3R,4S,5R,6R)-5-hydroxy-6-(hydroxymethyl)-3,4-bis[(2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy]oxan-2-yl]oxy-5,9-dimethyl-14-methylenetetracyclo[11.2.1.01,10.04,9]hexadecan-5-carboxylate (RBDS-J), (15) (2S,3R,4S,5S,6R)-4,5-dihydroxy-6-(hydroxymethyl)-3-(((2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)tetrahydro-2H-pyran-2-yl (4R,4aS,6aR,9S,11aR,11bS)-9-(((2S,3R,4S,5R,6R)-5-hydroxy-6-(hydroxymethyl)-4-(((2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)-3-(((2S,3R,4R,5R,6S)-3,4,5-trihydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)tetrahydro-2H-pyran-2- yl)oxy)-4,11b-dimethyl-8-methylenetetrahydro-6a,9-methanocyclohepta[a]naphthalene-4-carboxylate (RBDS-K), (16) [(2S,3R,4S,5R,6R)-5-hydroxy-6-(hydroxymethyl)-4-[(2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)oxanyl-2-yl]oxy-3-[(2S,3R,4R,5R,6S)-3,4,5-trihydroxy-6-methyloxanyl-2-yl]oxanyl-2-yl] (1R,4S,5R,9S,10R,13S)-13-[(2S,3R,4S,5R,6R)-5-hydroxy-6-(hydroxymethyl)-3,4-bis[[(2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)oxanyl-2-yl]oxy]oxy-2-yl]oxy-5,9-dimethyl-14-methylenetetracyclo[l l l.2.1.01,10.04,9]eicosane-5-carboxylate (RBDS-N), (17) [(2S,3R,4S,5R,6R)-3-[(2S,3R,4R,5S,6S)-3,5-dihydroxy-6-methyl-4-[(2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)oxanyl-2-yl]oxyoxanyl-2-yl]oxy-5-hydroxy-6-(hydroxymethyl)-4-[(2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)oxanyl-2-yl]oxyoxanyl-2-yl] (1R,4S,5R,9S,10R,13S)-13-[(2S,3R,4S,5R,6R)-5-hydroxy-6-(hydroxymethyl)-3,4-bis[[(2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)oxy]oxy]oxy-2-yl]oxy-5,9-dimethyl-14-methylenetetracyclo[l l l.2.1.01,10.04,9]eicosane-5-carboxylate (RBDS-O), (18) [(2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl] (1R,4S,5R,9S,10R,13S)- 13-[(2S,3R,4S,5S,6R)-4,5-dihydroxy-6-(hydroxymethyl)-3-[(2S,3R,4R),5R,6S)-3,4,5- trihydroxy-6-methyloxan-2-yl]oxyoxan-2-yl]oxy-5,9-dimethyl-14-methylenetetradecahydro- 1 l.2.1.01 l0.04,9]hexadecan-5-carboxylate (DCS-A), (19) (4R,4aS,6aR,9S,11aR,11bS)-9-(((2S,3R,4S,5R,6R)-5-hydroxy-6-(hydroxymethyl)-4- (((2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)-3- (((2R,3R,4R,5R,6S)-3,4,5-trihydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)tetrahydro- 2H-pyran-2-yl)oxy)-4,11b-dimethyl-8-methylenetetradecahydro-6a,9-methycyclohepta[a]naphthalene- 4-carboxylic acid (DCS-B), (20) (4R,4aS,6aR,9S,11aR,11bS)-9-hydroxy-4,11b-dimethyl-8-methylenetetradecahydro- 6a,9-methycyclohepta[a]naphthalene-4-carboxylic acid (STL), (21) Methyl (4R,4aS,6aR,9S,11aR,11bS)-9-(((2S,3R,4S,5R,6R)-5-hydroxy-6- (hydroxymethyl)-3,4-bis((2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro- 2H-pyran-2-yl)oxy)tetrahydro-2H-pyran-2-yl)oxy)-4,11b-dimethyl-8-methylenetetradecahydro- 6a,9-methycyclohepta[a]naphthalene-4-carboxylate (RBDS-B-Methyl), (22) Ethyl (4R,4aS,6aR,9S,11aR,11bS)-9-(((2S,3R,4S,5R,6R)-5-hydroxy-6- (hydroxymethyl)-3,4-bis((2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro- 2H-pyran-2-yl)oxy)tetrahydro-2H-pyran-2-yl)oxy)-4,11b-dimethyl-8-methylenetetradecahydro- 6a,9-methycyclohepta[a]naphthalene-4-carboxylate (RBDS-B-Ethyl), (23) steviol, (24) a group consisting of any one or more of (1) to (23); (25) (2R,3S,4S,5R,6R)-2-(hydroxymethyl)-6-({[(2R,3S,4S,5R,6S)-3,4-dihydroxy-6-{[(3R,6R)-2-hydroxy-6-[(1R,3aS,3bS,7S,9aR,9bR,10R,11aR)-10-hydroxy-7-{[(2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-({[(2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)-3,4,5,6-tetrahydro-2H-pyran-2-yl]oxy}methyl)-3,4,5,6-tetrahydro-2H-pyran-2-yl]oxy}-3a,6,6,9b,11a-pentamethyl-2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]-2-methylheptan-3-yl]oxy}-5-{[(2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)-3,4,5,6-tetrahydro-2H-pyran-2-yl]oxy}-3,4,5,6-tetrahydro-2H-pyran-2-yl]methyl}oxy)tetrahydro-pyran-3,4,5-triol (MGSD-V, Mogroside V / Mogroside V), (26) (3S,8S,9R,10R,13R,14S,17R)-17-((2R,5R)-5-((((2S,3R,4S,5S,6R)-4,5-dihydroxy-3-(((2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)-6-((((2R,3R,4S),5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)methyl)tetrahydro-2H-pyran-2-yl)oxy)-6-hydroxy-6-methylheptan-2-yl)-4,4,9,13,14-pentamethyl-3-(((2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-((((2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)methyl)tetrahydro-2H-pyran-2-yl)oxy)-1,2,3,4,7,8,9,10,12,13,14,15,16,17-tetradecahydro-11H-cyclopenta[a]phenanthrene-11-one (OMGSD-V, 11-Oxo-Mogroside V / 11-Oxo-Mogroside V), (27) (2S,3R,4S,5S,6R)-2-(((2S,3R,4S,5S,6R)-4,5-dihydroxy-2-(((3R,6R)-2-hydroxy-6-((3S,8S,9R,10R,11R,13R,14S,17R)-11-hydroxy-4,4,9,13,14-pentamethyl-3-(((2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H- cyclopenta[a]phenanthren-17-yl)-2-methylheptan-3-yl)oxy)-6-((((2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)methyl)tetrahydro-2H-pyran-3-yl)oxy)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (SMSD-I, Siamenoside I), (28) (2R,3R,4S,5S,6R)-2-(((3S,8R,9R,10S,11R,13R,14S,17R)-17-((2R,5R)-5,6-dihydroxy-6-methylheptan-2-yl)-11-hydroxy-4,4,13,14-tetramethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl)oxy)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (MGSD-IE1, Mogroside IE1), (29) a group consisting of any one or more of (24) to (27) (MGSDT), (30) any combination of (1) to (29), (31) (2S)-7-[(2S,3R,4S,5S,6R)-4,5-dihydroxy-6-(hydroxymethyl)-3-[(2S,3R,4R,5R,6S)-3,4,5-trihydroxy-6-methyloxan-2-yl]oxyoxan-2-yl]oxy-5-hydroxy-2-(3-hydroxy-4-methoxyphenyl)-2,3-dihydrochromen-4-one (NHPD, Neohesperidin), (32) 1-[4-[(2S,3R,4S,5S,6R)-4,5-dihydroxy-6-(hydroxymethyl)-3-[(2S,3R,4R,5R,6S)-3,4,5-trihydroxy-6-methyloxan-2-yl]oxyoxan-2-yl]oxy-2,6-dihydroxyphenyl]-3-(3-hydroxy-4-methoxyphenyl)propan-1-one (NHDC, Neohesperidin Dihydrochalcone), (33) 1-[4-[(2S,3R,4S,5S,6R)-4,5-dihydroxy-6-(hydroxymethyl)-3-[(2S,3R,4R,5R,6S)-3,4,5-trihydroxy-6-methyloxan-2-yl]oxyoxan-2-yl]oxy-2,6-dihydroxyphenyl]-3-(4-hydroxyphenyl)propan-1-one (NRGDC, Naringin dihydrochalcone), (34) (2S)-7-[(2S,3R,4S,5S,6R)-4,5-dihydroxy-6-(hydroxymethyl)-3-[(2S,3R,4R,5R,6S)-3,4,5-trihydroxy-6-methyloxan-2-yl]oxyoxan-2-yl]oxy-5-hydroxy-2-(4-hydroxyphenyl)-2,3-dihydrochromen-4-one (NRG, Naringin), (35) (2S)-5-hydroxy-2-(3-hydroxy-4-methoxyphenyl)-7-[(2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-[[(2R,3R,4R,5R,6S)-3,4,5-trihydroxy-6-methyloxan-2-yl]hydroxymethyl]oxan-2-yl]oxy-2,3-dihydrochromen-4-one (HPD, Hesperidin), (36) (2S)-7-[(2S,3R,4R,5S,6R)-3,4-dihydroxy-5-[oxan-2-yl]oxy-6-[(2R,3R,4R,5R,6S)-3,4,5-trihydroxy-6-methyloxan-2-yl]oxymethyl]oxan-2-yl]oxy-5-hydroxy-2-(3-hydroxy-4-methoxyphenyl)-2,3-dihydrochromen-4-one (alpha-GHPD, alpha-Glucosyl hesperidin), (37) a group consisting of any one or more of (1) to (36).

7. The targeted nanodelivery kit according to any one of claims 1 to 6, wherein, The targeted nanodelivery kit further comprises one or more polymers selected from the group consisting of: (1) a cellulose-based polymer such as hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose acetate succinate (HPMCAS), sodium carboxymethylcellulose (CMC-Na), or hydroxyethyl cellulose; (2) a starch-based polymer such as sodium starch glycolate (SSG), starch, or pregelatinized starch (starch 1500); (2) synthetic polymers: such as polyethylene glycol (PEG), polyvinyl alcohol (PVA), polyvinylpyrrolidone (PVP), copolyvidone (PVP-VA64), polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus), polyglutamic acid (PGA), polydopamine (PDA), polylactic acid (PLA), poly-L-lactic acid (PLLA), poly(lactic-co-glycolic acid) (PLGA), sodium polyacrylate, siRNA and derivatives (alkyl chains to improve lipophilicity), mRNA and derivatives (alkyl chains to improve lipophilicity), or antisense oligonucleotides and derivatives (alkyl chains to improve lipophilicity), polyethylene glycol-15 hydroxystearate; (3) polysaccharides, proteins and their derivatives (such as carboxymethylation, sulfonylation, phosphorylation, acylation or hydroxypropylation, cationic, anionic or other derivatives), such as carrageenan, guar gum, gum arabic, locust bean gum, konjac gum, agar, gelatin, pectin, gellan gum, hyaluronic acid (HA), aminodextran, chondroitin sulfate, dermatan sulfate, heparin, keratan sulfate, heparan sulfate, sodium alginate, propylene glycol alginate, agar, fucoidan, cyclodextrin and derivatives, chitosan and derivatives (such as acylation, carboxylation, alkylation and quaternization, etc.), soy protein, vegetable protein or bovine serum albumin; and combinations thereof.

8. The targeted nanodelivery kit according to any one of claims 1-7, having any one of the following features: (1) the active ingredient is a biologically active agent, a chemically active agent or an adjuvant, a dietary supplement functional ingredient; (2) the active ingredient is selected from the group consisting of: a protein / polypeptide, a polysaccharide / oligosaccharide, a nucleic acid or nucleic acid fragment, a lipid, a nutritional element, an organic small molecule compound or composition, a bacteriophage particle, a superparamagnetic substance, a vaccine, a diagnostic reagent, an imaging agent, a cell, or any combination thereof; (3) the active ingredient includes an active ingredient that is a patient and / or physician medication pain point in terms of pharmacodynamics and / or pharmacokinetics and / or pharmaceutical and / or pharmacotherapeutic properties; (4) the active ingredient is one or more of: (A) an active ingredient with very low permeability under existing delivery technologies; (B) an active ingredient with limited solubility and / or stability, which must be administered in large doses to achieve therapeutic purposes, resulting in poor user compliance; (C) an active ingredient that must be administered systemically under existing delivery technologies and has serious systemic or non-target organ toxicity; and / or (D) an active ingredient with low pharmacokinetic / pharmacodynamic specificity and / or a low therapeutic index under the current administration method; (5) the mass ratio of the active ingredient to the sum of [targeting guide agent + delivery carrier] is 1:0.15-1:25 (preferably 1:0.25, 1:0.5, 1:0.75, 1:1, 1:1.5, 1:2, 1:2.5, 1:3, 1:5, 1:10, 1:15, 1:20, 1:25), the targeting guide agent accounts for 5%-100% (preferably 7%-100% (preferably 7%-70%, 7%-65%, 10%-60%, 12.5%-100%, 15%-95%, 17.5%-90%, 20%-80%, 25%-75%, 30%-70%, 35%-65%, 40%-60%)) of the total mass of (targeting guide agent + delivery carrier); the mass ratio of the active ingredient to the high molecular polymer is 1:0-1:25 (preferably 1:0-1:20, 1:0-1:15, 1:0-1:10, 1:0-1:5); (6) one of the active ingredient, the targeting guide agent, and the optional delivery carrier is in a liquid state or a solid state, or the active ingredient and the delivery carrier are simultaneously in a liquid state or a fixed state; (7) the active ingredient and the targeting guide agent or the delivery carrier exist independently or in a mixed state, or are prepared into a supramolecular nanocomposite.

9. The targeted nanodelivery kit according to any one of claims 1-8, which is in a form suitable for oral, sublingual, cavity mucosa (such as esophagus, stomach, duodenum, colon, rectum, vagina, cervix, anus), subcutaneous, subcutaneous lymph node, muscle, vein, artery, skin, lung, intranasal, ear, eye administration.

10. The targeted nanodelivery kit according to any one of claims 1 to 9, characterized in that The targeted nanodelivery kit is administered via an applicator through the anus, and can be directly delivered to the colon or the rectum.

11. The targeted nanodelivery kit according to any one of claims 1-10, which has any one of the following characteristics: (1) the active ingredient, the targeting guide agent, and the optional delivery carrier and / or polymer are assembled into a nanocomposite in the form of a micelle, a nanoparticle, a microsphere, a microcapsule, a molecular composition, or a hydrogel; (2) when the active ingredient, the targeting guide agent, and the optional delivery carrier exist independently, they are assembled after being mixed and dissolved in use; when the active ingredient, the targeting guide agent, and the optional carrier exist in a mixed state, the active ingredient, the targeting guide agent, or the carrier in a solid state is assembled after being dissolved; (3) the active ingredient, the targeting guide agent, and the optional delivery carrier are assembled in situ; (4) the active ingredient, the targeting guide agent, and the optional delivery carrier are self-assembled in the gastrointestinal tract, locally self-assembled in the mucosa, self-assembled in the blood, self-assembled in the lymphatic vessels or lymph nodes, or self-assembled in target cells; (5) the active ingredient, the targeting guide agent, and the optional delivery carrier are assembled in situ by the metabolic products of enzymes or microorganisms after metabolism.

12. The targeted nanodelivery kit according to any one of claims 1-11, having any one of the following features: (1) the kit comprises an additive selected from the group consisting of an excipient, a diluent, a binder, a disintegrant, a lubricant, a flavoring agent, a pH adjuster, an osmotic pressure adjuster, a thickening agent, a plasticizer, a coloring agent, a film forming agent, a preservative or a solvent, a stabilizer and any combination thereof; (2) the kit comprises a stabilizer which is one or more of a bile salt, Vitamin E polyethylene glycol succinate (TPGS), sodium lauryl sulfate (SLS), sodium docusate, lecithin, Tween 80, Tween 20, polyoxyethylene castor oil (EL35), polyoxyethylene hydrogenated castor oil, poloxamer, wherein the bile salt is one or more of Sodium taurocholate (STC), Sodium glycocholate (SGC), Sodium deoxycholate (SDC), Sodium taurodeoxycholate (STDC), Sodium glycodeoxycholate (SGDC), Sodium glycochenodeoxycholate (SGCDC), Sodium glycoursodeoxycholate (SGUDC), or a free acid or potassium salt thereof, preferably one or both of Sodium taurodeoxycholate (STDC) and Sodium glycodeoxycholate (SGDC).

13. A pharmaceutical composition comprising an active ingredient as defined in any one of claims 1-12 in combination with a targeting guide, and optionally a delivery vehicle, a polymer and / or an additive.

14. The targeted nanodelivery kit according to any one of claims 1-12 or the pharmaceutical composition according to claim 13, prepared into a dosage form selected from the group consisting of a tablet, a capsule, a pellet, a microtablet, a microcapsule, an oral solution, a drop, a gel, a granule, an emulsion, a cream, an injection, an eye drop, an inhalant, a spray, an aerosol, a patch, an enema, a foam, a suppository.

15. The targeted nanodelivery kit according to any one of claims 1-12 or the pharmaceutical composition according to claim 13, for use in a group consisting of: (1) for delivery of an active ingredient to a mammal (such as a rodent, a bovine, a porcine, a canine, a feline, a primate, a human) or a bird (such as a chicken, a duck, a goose); (2) for modulation of release of an active ingredient or a nutritional ingredient during delivery of the active ingredient or the nutritional ingredient to a mammal (such as a rodent, a bovine, a porcine, a canine, a feline, a primate, a human) or a bird (such as a chicken, a duck, a goose). ​ ​ (3) use as a solubilizer in agriculture, especially in formulation products containing pesticides, herbicides, fungicides or insecticides, especially as a solubilizer for spray, drench or dip mixtures; (4) use as a preservative or antiseptic or flavoring agent for meat, vegetables, fruits, food, beverages; (5) use for solubilization, stability enhancement, penetration enhancement in cosmetics, fine chemical products; (6) use as an adjuvant for biological agents.

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