Preparation method for ultra-stable nanocomposite and use thereof

Abstract

An ultra-stable nanocomposite, comprising a core component, an auxiliary unit, a self-assembling carrier, and a high polymer. Also disclosed are a preparation method for the nanocomposite and use of the nanocomposite. The ratio of the core component to the auxiliary unit in the ultra-stable nanocomposite can be adjusted to prepare nanocomposites with varying proportions of the core component and the auxiliary unit. In one aspect, the performance attributes of the core component and the auxiliary unit are improved. Moreover, the stability of the assembled nanocomposite is also significantly improved, the particle size distribution of the nanocomposite is regulated, and the preparation process for the nanocomposite is simplified. The ability of the nanocomposite to resist interference from external substances is improved, and the structural integrity of the nanocomposite during gastrointestinal transport is maintained, thereby improving the delivery efficiency of functional ingredients.

Description

Preparation method and use of a super stable nanocomposite TECHNICAL FIELD

[0001] The present application belongs to the field of preparations, and particularly relates to a preparation of a super stable nanocomposite and application thereof in food / health products, medical treatment, medicine, cosmetics, medical aesthetics, aquaculture, agriculture and planting. BACKGROUND

[0002] Phenolic compounds are a class of compounds in which one or more aromatic rings are combined with one or more hydroxyl groups. The hydroxyl group on the benzene ring can easily lose hydrogen electrons, so phenolic compounds act as good electron donors and play an antioxidant function. Phenolic compounds also have diverse structures, and can be classified into phenolic acids, flavonoids, lignans, coumarins and tannins according to structure. Common phenolic acids are hydroxycinnamic acid, caffeic acid and coumaric acid. Common flavonoids include proanthocyanidins, anthocyanins, flavones, flavonols, flavanones and their glycoside derivatives, etc. Modern medical research shows that phenolic compounds have antioxidant, anti-inflammatory, intestinal flora regulation, cardiovascular disease risk reduction, and other effects, and also have certain pharmaceutical properties, such as anti-infection, anti-virus, anti-bacteria, anti-depression, anti-allergy, antipyretic, analgesic, anti-hemorrhagic and immune enhancement, etc. In addition, they can also be used in food additives, cosmetics, medicine and other fields.

[0003] Phenolic compounds related to human health mainly include soy isoflavones, catechins, quercetin, dihydroquercetin, myricetin, dihydromyricetin, hesperidin / sin, naringenin / glycoside, neohesperidin, urolithin, anthocyanin, proanthocyanidin, curcumin / javanetone / javanol, resveratrol, chlorogenic acid, puerarin, silymarin, rhodioside, etc. The biological activity and pharmacological effect of phenolic compounds are closely related to their chemical structure, and different chemical structures can lead to different biological activity and pharmacological effect.

[0004] The presence of aromatic rings in the structure of phenolic compounds leads to poor water solubility, easy oxidation of these substances, and even poor absorption of most phenolic compounds, which also limits the further application of phenolic compounds.

[0005] For example, curcumin, modern medical research has confirmed that curcumin has anti-inflammatory, antioxidant, regulation of intestinal flora, antiviral, anti-infection, antitumor, anticoagulant, anti-liver fibrosis, anti-atherosclerosis and other extensive pharmacological effects, and low toxicity, small adverse reactions. But curcumin itself has low water solubility (about 34 μg / mL at 25℃), severe first-pass metabolism and Pg-P efflux, etc. lead to oral 4-8g curcumin, the peak plasma exposure is less than 10 ng / mL, the oral bioavailability is extremely low. In addition, the half-life of curcumin in plasma is short, even if its solubility and absorption can be solved, it also needs to be taken frequently to play its benefits to health. These all limit its more extensive application. In order to solve the above problems, different preparations of curcumin have been developed to solve the problem of poor water solubility and low bioavailability of curcumin. Pharmaceutics 2021, 13, 1715 (https: / / doi.org / 10.3390 / pharmaceutics13101715) reviews the new delivery technologies currently used by all listed products, such as improving the absorption of curcumin by introducing P450 enzyme / P-gp inhibitor piperine; preparing into nanomicelles with non-ionic surfactant Tween80 / 20; preparing into liposomes or solid lipid nanoparticles; cyclodextrin inclusion, polymer micelles, metal nanocarriers, inorganic nanocarriers, etc. The curcumin products developed by applying these technologies, compared with curcumin powder prepared into dosage forms and taken directly, significantly improve the absorption of curcumin in the gastrointestinal tract, and the exposure level of curcumin in plasma can reach 80-328 ng·hr / mL, but for curcumin, it is far from the exposure level required to exert its pharmacological effects, and curcumin cannot be detected in peripheral tissues or organs. The new delivery technologies used by the above listed products can improve the water solubility of curcumin to a maximum of 5 mg / mL, but due to the interference of the contents of the gastrointestinal tract after oral administration, the microstructure of most nanomedicines is destroyed, and only a small amount of undamaged nanomicelles, liposomes, etc. can be absorbed during the transport process in the gastrointestinal tract.

[0006] In addition, in addition to phenols, alkaloids, glycosides, terpenes, phenylpropanoids, organic acids, quinones, lactones, steroidal compounds, nucleosides, tannins, antibiotics also face the above problems, which limit their further application.

[0007] SUMMARY

[0008] The inventors surprisingly found that introducing one or more types of auxiliary units that are structurally compatible or complementary to the core component (similar spatial structure, providing groups that can construct the same type of synthons as the core component under the same environment, less hydrophobic than the core component) into a supramolecular nanodelivery system of a poorly soluble component can significantly improve the stability of the assembled nanocomplex, control the particle size of the nanocomplex, improve the ability of the nanocomplex to resist interference from external substances, maintain the structural integrity of the nanocomplex during gastrointestinal transit, and thus improve the delivery efficiency of the core component and the auxiliary units.

[0009] In some embodiments, the present application provides a super-stable nanocomplex, characterized in that the super-stable nanocomplex comprises:

[0010] a) a core component;

[0011] b) an auxiliary unit;

[0012] c) a self-assembled carrier; and

[0013] d) a high molecular polymer.

[0014] In some embodiments, the core component and the auxiliary unit are structurally compatible or complementary compounds.

[0015] In some embodiments, the core component can be one or more of phenols, alkaloids, glycosides, terpenes, lignans, phenylpropanoids, quinones, lactones, steroidal compounds, tannins. In some embodiments, the core component is preferably a phenolic compound selected from one or more of phenolic acids, flavonoids, lignans, coumarins, and tannins. More preferably, it is one or more of soy isoflavones, tanshinones, quercetin, dihydroquercetin, myricetin, dihydromyricetin, hesperidin, naringenin, neohesperidin, urolithins, curcumin and its derivatives / germacrone / germacrenal, resveratrol, chlorogenic acid, puerarin, silymarin, rhodioside, vitamins A, B, D, E, K. In some embodiments, the core component is preferably one or more of curcumin and / or its derivatives, rhodioside, soy isoflavones, silymarin, dihydromyricetin, ginkgo biloba extract.

[0016] The core component is more preferably curcumin and its derivatives, which have the following structure:

[0017] Curcumin and its derivatives

[0018] In the above structure, A and B, B and C are connected by a C-C single bond,

[0019] wherein: the B group can be a seven-carbon chain with the following structure:

[0020] Group B has 0-3 C=C double bonds, wherein substituents R1, R3 are independently selected from -H, -OH, -OR6, =0, wherein R6 is selected from -CH3, -Et, -Glc; R2 is selected from -H, -CH3, -CH2-CH2-COOEt, -CH2-COOEt, -CH2-CH2-COOH, -CH2-COOH; R4, R5 are independently selected from -H, -OH, when R5 is -OH, R1 is simultaneously -OH, and the two hydroxyl groups are intramolecularly condensed to form a pyran ring; in addition, the keto-enol in the seven-carbon chain structure can also be intramolecularly condensed to form a furan ring;

[0021] Group A, C is independently selected from benzene ring, thiophene, furan with 0-4 substituents, preferably benzene ring, preferably 0-3 substituents, and the substituents are optionally selected from -OH, -OR7, -CH3, -CH2-CH3, -C(CH3)3, -N(CH3)2, -F, -Cl, -Br, -NO2, -CF3, wherein R7 is selected from -CH3, -Et, -Glc, -CH2-CH2-O-CH3, Bn, -CH2-CH2-OH, and In addition, the benzene rings of groups A, C can also be connected by -O-, -CH2- bonds.

[0022] In some embodiments, the core component is more preferably curcumin, which has the following structure:

[0023] Curcumin: R1 = R2 = OCH3

[0024] Demethoxycurcumin: R1 = OCH3, R2 = H

[0025] Bisdemethoxycurcumin: R1 = R2 = H.

[0026] In some embodiments, the auxiliary unit can be one or more selected from phenols, terpenes, alkaloids, lignans, nucleosides, polypeptides, amino acids, organic acids, anthocyanins, organic acids, quinones, proanthocyanidins, steroidal compounds, and vitamin B, C compounds. In some embodiments, the auxiliary unit is preferably one or more of quercetin and its derivatives, silymarin and its derivatives, naringenin, naringin, soy isoflavones, ginkgo biloba extract, salidroside, dihydroquercetin, puerarin, crocin, dihydromyricetin, hesperetin, punicalagin, ginkgetin, baicalein, olivetol, vitexin, delphinidin, glabridin, (2R, 3R, 5S)-2-(6-amino-9H-purin-9-yl)-5-(hydroxymethyl)tetrahydrofuran-3-ol, 9-(3-deoxy-β-D- ribofuranosyl)hypoxanthine, 9-β-D-ribofuranosyladenine, shikonin, cannabidiol, glutathione.

[0027] In some embodiments, the phenolic substances can be selected from one or more of phenolic acids, flavonoids, lignans, coumarins and tannins.

[0028] In some embodiments, the terpenoids (carotenes, carotenoids) are selected from one or more of monoterpenes, sesquiterpenes, diterpenes, sesquiterpenes, triterpenes, tetraterpenes, polyterpenes, etc.; the alkaloids are selected from one or more of organic amines, pyrrolidines, pyridines, quinolines, quinolines, quinazolones, indoles, tropanes, imidazoles, purines, steroids and terpenoid alkaloids; the nucleosides are selected from one or more of (2R,3R,5S)-2-(6-amino-9H-purin-9-yl)-5- (hydroxymethyl)tetrahydrofuran-3-ol, 9-(3'-deoxy-β-D-ribofuranosyl)hypoxanthine, 9-β-D- ribofuranosyladenine, inosine, 9-β-D-2ˊ-deoxyribonucleoside adenine, 9-(2'-deoxy-β-D- ribofuranosyl)hypoxanthine, 2',3'-dideoxyadenosine, 2',3'-dideoxyinosine, 2',3'-didehydro- 2',3'-dideoxyinosine, and derivatives thereof (e.g., monophosphate, diphosphate, triphosphate esters, amides); the lignans are selected from one or more of simple lignans, biphenyls, secoiridoids, dimeric lignans, lignan lactones, lignan lactols, and neolignans; the organic acids are selected from aliphatic and aromatic organic acids; the quinones are selected from one or more of benzoquinones, naphthoquinones, anthraquinones, and phenanthraquinones; the steroids are selected from one or more of sterols, cardiac glycosides, steroidal saponins, phytosterols, insect molting hormones, and bile acids. 21 The preferred auxiliary ingredients are selected from one or more of phenolic substances, flavonoids, terpenoids, organic acids, alkaloids, anthocyanins, proanthocyanidins, lignans, amino acids, nucleosides, polypeptides, and vitamins.

[0029] In some embodiments, the auxiliary unit is more preferably selected from one or more of quercetin and its derivatives, silymarin and its derivatives. The structure of quercetin and its derivatives is shown in the following formula:

[0030] Quercetin and its derivatives

[0031] wherein R7-R11 are independently selected from H, CH3, (CH2) n CH3(n is arbitrarily selected from 1 to 10), -COR12, halogen, haloalkyl, Bn, Glc, wherein R12 is selected from CH3, (CH2) n CH3(n is arbitrarily selected from 1 to 10).

[0032] The structure of silymarin and its derivatives is shown in the following formula:

[0033] silymarin and derivatives thereof

[0034] wherein R13to R17are independently selected from H, CH3, (CH2) n CH3(n is arbitrarily selected from 1 to 10), acyl, halogen, haloalkyl, Bn, Glc; group D is one of the following.

[0035] In some embodiments, the self-assembling carrier can comprise flavonoid glycosides and / or terpene glycosides and derivatives thereof.

[0036] In some embodiments, the flavonoid glycoside can be a glycoside having a C6-C3-C6 basic nucleus structure in which two benzene rings are connected to each other by a three-carbon chain, preferably one or more of naringin dihydrochalcone, neohesperidin dihydrochalcone, trilobatin, phloridzin, aspartame, 1-(3-beta-D-glucopyranosyl-2,4,6-trihydroxyphenyl)-3-(4-hydroxyphenyl)-1-propanone. More preferably, naringin dihydrochalcone, neohesperidin dihydrochalcone.

[0037] In some embodiments, the terpene glycoside can be a tetracyclic diterpene glycoside and / or a tetracyclic triterpene glycoside and / or a pentacyclic triterpene glycoside; wherein the tetracyclic diterpene glycoside can be a kaurene-type tetracyclic diterpene glycoside, the tetracyclic triterpene glycoside can be a cucurbitane-type tetracyclic triterpene glycoside, and the pentacyclic triterpene glycoside can be an ushane-type pentacyclic triterpene glycoside. The kaurene-type tetracyclic diterpene glycoside is preferably one or more of stevioside, rebaudioside A, rebaudioside B and salts thereof, rebaudioside C, rebaudioside D, rebaudioside E, rebaudioside F, rebaudioside M, rebaudioside N, rebaudioside O, dulcoside A, rubusoside, steviolbioside, steviol and derivatives or salts thereof, more preferably rebaudioside A, rebaudioside C, stevioside; the cucurbitane-type tetracyclic triterpene glycoside is preferably one or more of mogroside III, mogroside IV, mogroside V, mogroside IIE, mogroside IIIE, mogroside VI, mogroside A, neomogroside, siamenoside I, more preferably mogroside V; and the ushane-type pentacyclic triterpene glycoside can be (2S,3R,4S,5S,6R)-6-((((2R,3R,4R,5S,6R)-3,4-dihydroxy-6-(hydroxymethyl)-5-(((2S,3R,4R,5R,6S)-3,4,5-trihydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)tetrahydro-2H-pyran-2-yl)oxy)methyl)-3,4,5-trihydroxytetrahydro-2H-pyran-2-yl (1S,2R,4aS,6aS,6bR,8aR,9R,10R,11R,12aR,12bR,14bS)-10,11-dihydroxy 9-(hydroxymethyl)-1,2,6a,6b,9,12a-hexamethyl-1,3,4,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-octadecahydropicocene-4a(2H)-carboxylate (ASTS), (2S,3R,4S,5S,6R)-6-((((2R,3R,4R,5S,6R)-3,4-dihydroxy-6-(hydroxymethyl)-5-(((2S,3R,4R,5R,6S)-3,4,5-trihydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)tetrahydro-2H-pyran-2-yl)oxy)methyl)-3,4,5-trihydroxytetrahydro-2H-pyran-2-yl (1S,2R,4aS,6aR,6bR,8R,8aS,9R,10R,11R,12aR,12bR,14bS)-8,10,11-trihydroxy-9-(hydroxymethyl)-1,2,6a,6b,9,12a-hexamethyl-1,3,4,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-octadecahydropicocene-4a(2H)-carboxylate (HASTS), (2S,3R,4S,5S,6R)-6-((((2R,3R,4R,5S,6R)-3,4-dihydroxy-6-(hydroxymethyl)-5-(((2S,3R,4R,5R,6S)-3,4,5-trihydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)tetrahydro-2H-pyran-2-yl)oxy)methyl)-3,4,5-trihydroxytetrahydro-2H-pyran-2-yl (1S,2R,4aS,6aS,6bR,8aR,9R,10R,11R,12aR,12bR,14bS)-10,11-dihydroxy-9-(hydroxymethyl)-1,2,6a,6b,9,12a-hexamethyl-1,3,4,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-octadecahydropicocene-4a(2H)-carboxylate (ASTS), (2S,3R,4S,5S,6R)-6-((((2R,3R,4R,5S,6R)-3,4-dihydroxy-6-(hydroxymethyl)-5-(((2S,3R,4R,5R,6S)-3,4,5-trihydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)tetrahydro-2H-pyran-2-yl)oxy)methyl)-3,4,5-trihydroxytetrahydro-2H-pyran-2-yl (1S,2R,4aS,6aR,6bR,8R,8aS,9R,10R,11R,12aR,12bR,14bS)-8,10,11-trihydroxy-9-(hydroxymethyl)-1,2,6a,6b,9,12a-hexamethyl-1,3,4,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-octadecahydropicocene-4a(2H)-carboxylate (HASTS),4-dihydroxy-6-(hydroxymethyl)-5-(((2S,3R,4R,5R,6S)-3,4,5-trihydroxy-6- methyltetrahydro-2H-pyran-2-yl)oxy)tetrahydro-2H-pyran-2-yl)oxy)methyl)- 3,4,5-trihydroxytetrahydro-2H-pyran-2-yl (4aS,6aS,6bR,8R,8aS,9R,10R,11R, 12aR,12bR,14bS)-8,10,11-trihydroxy-9-(hydroxymethyl)-2,2,6a,6b,9,12a- hexamethyl-1,3,4,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b- octadecahydrooctylene-4a(2H)-carboxylate (ASTS-B), (2S,3R,4S,5S,6R)-6- ( (((2R,3R,4R,5S,6R)-3,4-dihydroxy-6-(hydroxymethyl)-5-(((2S,3R,4R,5R,6S)-3,4,5- trihydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)tetrahydro-2H-pyran-2- yl)oxy)methyl)-3,4,5-trihydroxytetrahydro-2H-pyran-2-yl (1S,2R,4aS,6aS,6bR, 8aR,9R,10R,11R,12aR,12bR,14bS)-9-(acetyloxymethyl)-10,11-dihydroxy-1,2,6a,6b,9, 12a-hexamethyl-1,3,4,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-9R,10R,11R,12aR,12bR,14bS)-10,11-dihydroxy-9-(hydroxymethyl)-1,2,6a,6b,9,12a-hexamethyl-1,3,4,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-octadecyl octene-4a(2H)-carboxylic acid ester (ASTS-E), (2S,3R,4S,5S,6R)-6-((((2R,3R,4R,5S,6R)-3,4-dihydroxy-6-(hydroxymethyl)-5-(((2S,3R,4R,5R,6S)-3,4,5-trihydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)tetrahydro- 2H-pyran-2-yl)oxy)methyl)-3,4,5-trihydroxytetrahydro-2H-pyran-2-yl(1S,2R,4aS,6aS,6bR,8aR,9R,10S,12aR,12bR,14bS)-10-hydroxy-9-(hydroxymethyl)-1,2,6a,6b,9,12a-hexamethyl-1,3,4,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-octadecylhydrooctene-4a(2H)-carboxylic acid ester (ASTS-F), (2S,3R,4S,5S,6R)-6-((((2R,3R,4R,5S,6R)-3,4-dihydroxy-6-(hydroxymethyl)-5- (((2S,3R,4R,5R,6S)-3,4,5-trihydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)tetrahydro-2H-pyran-2-yl)oxy)methyl)-3,4,5-trihydroxytetrahydro-2H-pyran-2-yl(1R,2R,4aS,6aS,6bR,8aR,9R,10R,11R,12aR,12bR,14bS)-10,11-dihydroxy-2,9-bis(hydroxymethyl)-1,6a,6b,9,12a-pentamethyl-1,3,4,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-octadecylhydrooctene-4a(2H)-carboxylic acid ester (AST) S-G), (1S,2R,4aS,6aS,6bR,8aR,9R,10R,11R,12aR,12bR,14bS)-10,11-dihydroxy-9-(hydroxymethyl)-1,2,6a,6b,9,12a-hexamethyl-1,3,4,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-octadecylhydrooctene-4a(2H)-carboxylic acid (ASTA), (1S,2R,4aS,6aS,6bR,8R,8aS,9R,10R,11R,12aR,12bR,14bS)-8,10,11-trihydroxy-9-(hydroxymethyl)-1,2,6a,6b,9,12a-Hexamethyl-1,3,4,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-octadecahydrooctene-4a(2H)-carboxylic acid (HASTA), preferably a combination of one or more of ASTS, HASTS, ASTA and HASTA.

[0038] In some embodiments, the self-assembling carrier is preferably one or more selected from RBDS-A, RBDS-B, RBDS-C, STVS, STVN, MGSDT, ASTS, HASTS, NHPD, NHDC, NRGCD.

[0039] In some embodiments, the high molecular polymer can be one or more selected from polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus), copovidone, povidone, polyethylene glycol.

[0040] In some embodiments, the amount of the auxiliary unit can be 0.1-10 times, preferably 0.3-3 times, the amount of the core component; the amount of the self-assembling carrier can be 1-50 times, preferably 2-5 times, the amount of the core component; and the amount of the high molecular polymer can be 2-10 times, preferably 2-5 times, the amount of the core component, by weight.

[0041] In some embodiments, other active ingredients may be added to the ultra-stable nanocomposite, including but not limited to ginkgolide extract, tea polyphenol extract, grape seed extract, maca extract, ginseng / leaf / fruit extract, Panax notoginseng root / flower / whole herb extract, Smilax glabra, Cirsium japonicum, Ligustrum lucidum, Cornus officinalis, Achyranthes bidentata, Fritillaria cirrhosa, Ligusticum chuanxiong, deer placenta, deer antler, deer bone, Salvia miltiorrhiza, Acanthopanax senticosus, Schisandra chinensis, Cimicifuga foetida, Asparagus cochinchinensis, Gastrodia elata, Pseudostellaria heterophylla, Morinda officinalis, Aucklandia lappa, Equisetum hyemale, Arctium lappa, Arctium lappa root, Plantago asiatica, Plantago asiatica, Adenophora stricta, Fritillaria cirrhosa, Scrophularia ningpoensis, Rehmannia glutinosa, Polygonum multiflorum, Bletilla striata, Atractylodes macrocephala, Paeonia lactiflora. White cardamom, abalone shell, dendrobium, lycium bark, angelica, bamboo shavings, safflower, rhodiola, American ginseng, evodia, achyranthes, eucommia, eucommia leaf, astragalus seed, peony bark, aloe vera, atractylodes, psoralea, twig, red peony root, polygala, ophiopogon, tortoise shell, eupatorium, arborvitae leaf, prepared rhubarb, prepared he shou wu, eleutherococcus senticosus, rose hips, lycopus lucidus, alisma, rose, roselle, anemarrhena, apocynum venetum, bitter tea, buckwheat, golden tassel, green tangerine peel, magnolia flower, turmeric, immature bitter orange, immature bitter orange. The extracts include one or more of the following: cypress seed, pearl, gynostemma pentaphyllum, fenugreek, madder root, long pepper, leek seed, fleeceflower root vine, cyperus rhizome, drynaria rhizome, codonopsis root, mulberry bark, mulberry twig, fritillaria thunbergii, motherwort, centella asiatica, epimedium, dodder seed, wild chrysanthemum, ginkgo leaf, astragalus root, fritillaria hupehensis, senna leaf, gecko, bilberry, sophora japonica fruit, cattail pollen, tribulus terrestris, propolis, tamarind, eclipta prostrata, prepared rhubarb, ganoderma lucidum, ganoderma lucidum mycelium, agaricus, birch polypore, tiger milk fungus, and mulberry fungus.

[0042] In some embodiments, the present invention provides a method for preparing an ultrastable nanocomposite, which may include the following steps:

[0043] 1) Dissolve the core components and auxiliary units simultaneously or separately in an organic solvent;

[0044] 2) Dissolve the self-assembled carrier, polymer and / or extract in water or an aqueous alcohol solution;

[0045] 3) Add solution 1) to solution 2) with stirring, for example, by reducing the pressure to recover the organic solvent to the limit specified by ICH for residual solvents, thus obtaining an ultrastable nanocomposite solution, or

[0046] 4) Optionally, depending on actual needs, solution 1) can be added to solution 2) and then spray-dried directly or freeze-dried after removing the organic solvent to prepare an ultra-stable nanocomposite powder.

[0047] In some embodiments, the present invention provides a method for preparing an ultrastable nanocomposite, which may include the following steps:

[0048] 1) Dissolve core ingredients, auxiliary units, self-assembly carriers, high molecular polymers and / or extracts in one or more organic solvents containing 0-50% water;

[0049] 2) Rotary-evaporate or spray-dry solution 1) under reduced pressure, for example by vacuum drying to residual solvent in compliance with the Chinese Pharmacopoeia residual solvent requirements, to produce ultra-stable nanocomposite powders.

[0050] In some embodiments, the present application provides a method for preparing an ultra-stable nanocomposite, which can comprise the following steps:

[0051] 1) Dissolve core ingredients (or poorly water-soluble extracts) in organic solvents;

[0052] 2) Dissolve self-assembly carriers, high molecular polymers, auxiliary units in water or aqueous alcohol solution;

[0053] 3) Add solution 1) to solution 2) under stirring, for example by recovering organic solvents under reduced pressure to the limit of ICH residual solvent requirements, to obtain a nanocomposite intermediate solution,

[0054] 4) Directly add water-soluble extracts to the above nanocomposite intermediate solution for complete dissolution; or first dissolve water-soluble extracts in water, then add to the nanocomposite intermediate solution, stir, centrifuge at 15000 rpm for 5 minutes, and the supernatant is an ultra-stable nanocomposite solution.

[0055] In some embodiments, the organic solvent in the method for preparing an ultra-stable nanocomposite can be one or more of methanol, ethanol, acetone, tetrahydrofuran, dichloromethane.

[0056] In some embodiments, the present application provides a product, composition or kit comprising the ultra-stable nanocomplex. In some embodiments, the present application provides a formulation comprising the ultra-stable nanocomplex, which can be taken orally, administered mucosally, applied topically; which dosage form can be selected from one of a tablet, a capsule, a granule, a powder, a solution, a gel, an eye drop, a nose drop, an ear drop, a cream, a tincture, a spray; for use in diabetes, kidney disease (including kidney failure, kidney injury, kidney cyst), liver disease (including liver injury, non-alcoholic / alcoholic fatty liver, liver cancer, liver fibrosis, hepatitis, liver cyst), thyroid cyst, thyroid nodule, intestinal polyp, ovarian cyst, hypertension, hyperlipidemia, myocardial infarction, insomnia, stroke, neurodegenerative disease (including epilepsy, Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis), lung and airway disease (including lung cancer, pneumonia, pulmonary fibrosis, lung nodule, chronic obstructive pulmonary disease, pulmonary hypertension, tracheitis, bronchitis), eye disease (including dry eye, conjunctivitis, keratitis, uveitis, scleritis, glaucoma, cataract, macular degeneration). In some embodiments, the present application provides an ultra-stable nanocomplex food product characterized by containing the ultra-stable nanocomplex, which can be one of a beverage, a confectionery product, a dairy product, an alcoholic beverage or a meal accompaniment. In some embodiments, the present application provides an ultra-stable nanocomplex care product characterized by containing the ultra-stable nanocomplex, which can be one of a cream, a lotion, an aqueous agent, a gel, an oil agent, a powder, a block powder or solid, a mud, an aerosol, a patch, a film, for use on any part of the face, body, hair, hand, foot, which can have one or more of the effects of emollient, moisturizing, desensitizing, anti-aging, whitening, acne-removing, acne-removing, scar repair, tattoo removal, wrinkle-removing, red blood vessel-removing, rose spot-removing, sunscreen, body fragrance, hair washing and hair care; which can be used directly or in combination with an introduction device (such as a skin introduction device, a beauty and hair care device).

[0057] In some embodiments, the present application provides the use of the ultra-stable nanocomplex, product, composition and / or kit for the preparation of a food / health product / auxiliary therapeutic or therapeutic drug, a cosmetic product, a medical aesthetic product, a human / animal care product, a catalyst, a plant regulator, a medical diagnostic reagent, a contrast agent, etc.

[0058] Definitions:

[0059] Super-stable nanocomplex: In the present context, a super-stable nanocomplex can refer to a stable complex of different components in the nanometer size range. In some embodiments, a super-stable nanocomplex of the present application preferably has one or more advantages compared to a control composition (e.g., a composition that does not comprise one or more components of the present application or a commercially available product containing the same active ingredients). In some embodiments, the properties and / or advantages of a super-stable nanocomplex can be determined by comparison of one or more aspects, such as solubility, bioavailability, stability, particle size distribution, ability to resist interference from external substances, structural integrity, delivery efficiency, etc. In some embodiments, a super-stable nanocomplex of the present application can comprise ordered assemblies formed between different molecules through non-covalent interactions, and such assemblies can exhibit properties that are far superior to the sum of the properties exhibited by each single molecule.

[0060] Structurally compatible or complementary compounds: In this context, structurally compatible (do not chemically react with each other) or complementary compounds can refer to two or more compounds that are similar in spatial structure and / or complement each other in structure when assembled into supramolecular homotypic synthons and / or are able to compensate for the absence of one or the excess of a certain group in one of them when building supramolecular homotypic synthons in the same environment, thus achieving a dynamic balance between hydrophilic groups, hydrophobic groups, hydrogen donors and hydrogen acceptors, positive and negative charges, and rigidity and flexibility in the entire system. In some embodiments, the supramolecular nanocomplexes of the present application preferably have at least one pair of structurally compatible or complementary compounds, thus being able to provide one or more aspects of improvement in solubility, bioavailability, stability, particle size distribution, ability to resist interference from external substances, structural integrity, delivery efficiency, etc. through their interaction. In some embodiments, the structurally compatible or complementary compounds can include, for example, a combination of core components and auxiliary units described herein. In some embodiments, the structurally compatible or complementary compounds can include, for example, two or more selected from curcumin or its derivatives, salidroside, soy isoflavones, silymarin, dihydromyricetin, ginkgo biloba extract, quercetin and its derivatives, naringenin, naringin, dihydroquercetin, puerarin, crocin, hesperetin, punicalagin, luteolin, olivetol, vitexin, delphinidin, glabridin, (2R, 3R, 5S)-2-(6-amino-9H-purin-9-yl)-5-(hydroxymethyl)tetrahydrofuran-3-ol, 9-(3-deoxy-beta-D- ribofuranosyl)hypoxanthine, 9-beta-D-ribofuranosyladenine, shikonin, cannabidiol, glutathione. In some embodiments, the structurally compatible or complementary compounds can include, for example, a) one or more selected from curcumin and / or its derivatives, salidroside, soy isoflavones, silymarin, dihydromyricetin, ginkgo biloba extract, and b) one or more selected from quercetin and its derivatives, silymarin and its derivatives, naringenin, naringin, soy isoflavones, ginkgo biloba extract, salidroside, dihydroquercetin, puerarin, crocin, dihydromyricetin, hesperetin, punicalagin, glabridin, luteolin, olivetol, vitexin, delphinidin, (2R, 3R, 5S)-2-(6-amino-9H-purin-9-yl)-5-(hydroxymethyl)tetrahydrofuran-3-ol, 9-(3-deoxy-beta-D- ribofuranosyl)hypoxanthine, 9-beta-D-ribofuranosyladenine, shikonin, cannabidiol, glutathione. In some embodiments, the structurally compatible or complementary compounds can be present in a mixture, which includes, for example, an extract, such as a plant extract, for example, a ginkgo biloba leaf extract (GBE), for example, a soy isoflavone (SBIF), etc.In some embodiments, the structurally compatible or complementary compounds can include, for example, a combination of two or more selected from curcumin, QCT, QCTN, SLBN, DPND, DMRCT, GKT, VTX, NRG, PURN, GGRN A, 6-SGL, HSPT, SLDS, RVRT, RVRT, DQCT, PCLG, SKN, BCL, CDCP, DOIS, ADNS, or derivatives thereof. In some embodiments, the structurally compatible or complementary compounds can include, for example, a combination of curcumin and any one or more compounds selected from QCT, QCTN, SLBN, DPND, DMRCT, GKT, VTX, NRG, PURN, GGRN A, 6-SGL, HSPT, SLDS, RVRT, RVRT, DQCT, PCLG, SKN, BCL, CDCP, DOIS, ADNS, or derivatives thereof, such as a combination of curcumin and quercetin, a combination of curcumin and silymarin, a combination of curcumin and quercetin and silymarin, a combination of curcumin and delphinidin, and the like. In some embodiments, the structurally compatible or complementary compounds can optionally further include, for example, the self-assembling carriers and / or high molecular polymers described herein. In some embodiments, the compatibility or complementarity between the compounds can be determined by measuring one or more aspects of the properties of the composition after the compounds are combined, such as solubility, bioavailability, stability, particle size distribution, ability to resist interference from external substances, structural integrity, delivery efficiency, and the like. In some embodiments, the present application is particularly suitable for, for example, low water-soluble, low bioavailability, low half-life, and / or low absorption compounds, which can significantly improve one or more aspects of the properties such as solubility, bioavailability, stability, particle size distribution, ability to resist interference from external substances, structural integrity, delivery efficiency, and the like by matching and / or including the compounds (e.g., the core components described herein) with structurally compatible or complementary compounds (e.g., the auxiliary units described herein) in the super-stable nanocomplexes of the present application.

[0061] Drug solubility: Drug solubility can be determined according to the judgment basis in the BCS classification of drugs, for example, a single dose of 150 mg can be dissolved in 250 ml of physiological medium (0.6 mg / ml) as a high-solubility drug, and cannot be dissolved as a low-solubility drug. For details, see Guideline M9: Biopharmaceutics Classification System-based Biowaivers, published by the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) in November 2019, 2.1 Solubility.

[0062] Advantages of the application

[0063] The present application improves the solubility of the core component and the auxiliary unit, significantly improves the stability of the assembled nanocomposite, regulates the particle size distribution of the nanocomposite, simplifies the preparation process of the nanocomposite, improves the ability of the nanocomposite to resist external substance interference, maintains the structural integrity of the nanocomposite during administration, and thus improves the delivery efficiency and effect of the functional component. BRIEF DESCRIPTION OF DRAWINGS

[0064] Figure 1 is a comparison chart of the release of F2 and D4 in CCM in pH 1.0 and pH 6.8 media

[0065] Figure 2 is a comparison chart of the release of F2 and D5 in QCT in pH 1.0 and pH 6.8 media

[0066] Figure 3 is a comparison chart of the particle size change of F2 and F4 diluted by 95% ethanol by different multiples

[0067] Figure 4 is a comparison chart of the particle size change of commercially available products 1 and 2 diluted by 95% ethanol by 20 times

[0068] Figure 5 is a dissolution curve chart of the preparation composition of FT61, FC62, DT10, and DC11 in FaSSGF to FaSSIF-V2 medium

[0069] Figure 6 is the detection concentration of CCM in different tissues of rats orally administered with F2

[0070] Figure 7 is the detection concentration of QCT in different tissues of rats orally administered with F2

[0071] Figure 8 is the detection concentration of CCM and QCT in the liver and pancreas of rats orally administered with F2-Sus at different times

[0072] Figure 9 is the detection concentration of CCM in different tissues of rats orally administered with F4

[0073] Figure 10 is the detection concentration of SLBN in different tissues of rats orally administered with F4

[0074] Figure 11 is the detection concentration of CCM and SLBN in the liver and pancreas of rats orally administered with F4-Sus at different times

[0075] Figure 12 is a comparison of fasting serum insulin and HOMA-IR of different groups of mice

[0076] Figure 13 is the liver index and Lee's index of different groups of mice

[0077] Figure 14 is the NAS score of different groups of mice

[0078] Figure 15 is a comparison of serum biochemical indexes of different groups of mice

[0079] Figure 16 is a liver tissue HE staining section of different groups of mice

[0080] Figure 17 Masson staining sections of liver tissues of different groups of mice. DETAILED DESCRIPTION

[0081] In order to make the objects, technical solutions and advantages of the present application clearer, the present application will be further described in detail below with reference to specific embodiments and with reference to the accompanying drawings.

[0082] In order to illustrate the features and advantages of the present application, some experiments are provided in the embodiments as illustrative examples, but the content of the present application is not limited to the embodiments. The materials and reagents used in the embodiments are all commercially available products.

[0083] Table 1 Material name and abbreviation code

[0084] Determination methods used in the present application:

[0085] (1) Nanoparticle size, PDI:

[0086] Measured by NanoBrook (model: 90Plus PALS) nanoparticle size analyzer. Dynamic light scattering principle, room temperature 25℃, diffraction angle set to 90° for measurement. Before measurement, dilute the supramolecular nanocomplex solution to 100 μg / mL, take 50 μL and disperse in 1 mL deionized water, ultrasonic to disperse uniformly, immediately measure, set the measurement time to 2 min.

[0087] (2) Zeta potential measurement:

[0088] Measured at room temperature 25℃, Zeta potential measurement diffraction angle set to 15℃, before measurement, dilute the supramolecular nanocomplex solution to 100 μg / mL, take 50 μL and disperse in 1 mL phosphate buffer (pH 6.8) for measurement. pH 6.8 phosphate buffer (1 mM) is prepared with ultrapure water, and 0.1N hydrochloric acid or sodium hydroxide solution is used to adjust the pH. After dilution, the sample should be transparent, if not clear, centrifuge to take the supernatant for measurement.

[0089] (3) Active ingredient content determination:

[0090] Measured by high performance liquid chromatography with external standard method. The chromatographic conditions are shown in the following table.

[0091] Table 2 Active ingredient content determination method

[0092] Biorelevant dissolution media used in the present application:

[0093] (1) FaSSGF preparation: Weigh 2 g NaCl, 0.043 g sodium taurocholate, 0.015 g lecithin into about 800 mL of degassed purified water, ultrasonic (40-50°C heating) stirring to dissolve, after the lecithin is completely dissolved, adjust the pH to 1.60 with 1 mol / L HCl, then weigh in 0.1 g pepsin, dilute to 1000 mL, adjust the pH to 1.60, and then get it.

[0094] (2) FaSSIF-V2 preparation: Add 63 mL of conditioning fluid (weigh about 8.806 g maleic acid, 8.806 g NaOH, 9.976 g NaCl, 6.618 g sodium taurocholate and 0.551 g lecithin, add 1000 mL of degassed purified water, ultrasonic, stirring, and dissolve at 40-50°C) to 187 mL of pre-meal gastric juice, adjust the pH to 6.5±0.2.

[0095] Other media, such as 0.1M hydrochloric acid or pH 6.8 phosphate buffer, can be prepared according to the Chinese Pharmacopoeia Appendix.

[0096] Example 1 Curcumin (CCM) nanocomplexes F1-F3, D1-D6

[0097] Curcumin and quercetin have very wide pharmacological activities, but their extremely poor water solubility, pre-systemic and post-systemic first-pass metabolism, etc. lead to very low oral bioavailability (curcumin: about 4.13%; quercetin oral 4g, the peak concentration of quercetin in plasma is less than 100 ng / mL), in addition, even if a small amount of curcumin or quercetin can be absorbed, its plasma half-life is very short (2-4 hr).

[0098] 1) Nanocomplex prescription composition

[0099] With curcumin as the core component, QCT or QCTN as the auxiliary unit, the following nanocomplexes are prepared.

[0100] Table 3 Nanocomplexes F1-F3, D1-D6 prescription

[0101] 2) Preparation process:

[0102] ① Dissolve CCM, quercetin (QCT) or quercetin (QCTN) in tetrahydrofuran (THF).

[0103] ② Dissolve RBDS-A and / or Soluplus in 10 mL of pH 3.0 citric acid aqueous solution, stir to dissolve completely, then add an appropriate amount of water;

[0104] ③ While stirring, solution ① was added dropwise into solution ②, and the rotary evaporator was used to recover tetrahydrofuran under reduced pressure until the residual solvent met the requirements of the Chinese Pharmacopoeia. The mixture was centrifuged at 15000 rpm for 5 minutes at room temperature, and the supernatant was the nanocomposite solution.

[0105] 3) Release degree in different pH media:

[0106] 1.0 mL of the nanocomposite solution was diluted with pH 1.0 HCl or pH 6.8 phosphate buffer. 1 mL of the medium was first added, shaken, then gradually added with the medium, shaken, and finally diluted to 20 mL. The diluted sample was placed in a constant temperature air bath shaker at 37°C, shaken at 250 rpm for 5 hours, sampled, centrifuged at 37°C / 15000 rpm for 5 minutes, and the concentration of the supernatant was detected to calculate the dissolution rate.

[0107] Dissolution rate Q = C1 x 10 / C0 x 100%

[0108] Wherein C1 is the concentration of the diluted solution (mg / mL)

[0109] C0 is the initial concentration of the nanocomposite solution (mg / mL)

[0110] Table 4 F1-F3, D1-D6 nanocomposite content, particle size, zeta potential and dissolution rate test results

[0111] 4) Conclusion:

[0112] ① Concentration of supramolecular nanocomposite (SAN) solution

[0113] According to the above detection results, the detection concentration of CCM and QCT or QCTN in the solution of Comparative Examples D3 and D6 without self-assembled carrier or high molecular polymer is very low, the maximum of CCM is 0.03 mg / mL, the maximum of QCT is 0.02 mg / mL, and the maximum of QCTN is 0.19 mg / mL, which is basically consistent with the solubility in water reported in the literature. The detection concentration of CCM and QCTN in the solution of Comparative Example D6 is 0.03 mg / mL and 0.19 mg / mL, respectively. Comparative Examples D1 and D2 use self-assembled carriers or high molecular polymers to prepare SAN solutions, respectively. The detection concentration of CCM and QCT in D1 and D2 is 658-826 times and 123-168 times that of D3, respectively. The solubility of CCM or QCT is greatly improved, but still does not meet the use requirements. F1-F3 use self-assembled carriers and high molecular polymers in combination. The detection concentration of CCM in the SAN samples prepared by F1-F3 is 20.7, 59.7 and 59.2 mg / mL, respectively, which is 103.5%, 99.5% and 98.7% of the theoretical concentration, respectively. The detection concentration of QCT in F1-F2 is 19.6 and 20.2 mg / mL, respectively, which is 98.0% and 101.0% of the theoretical concentration, respectively. The detection concentration of QCTN in F3 is 20.3 mg / mL, which is 101.5% of the theoretical concentration. D4 and D5 are single active ingredient SANs prepared according to the prescription of F2, and the detection concentration of CCM or QCT in D4 and D5 is 58.9 mg / mL and 19.8 mg / mL, respectively, which is close to the theoretical concentration. The detection concentration of CCM and QCTN in the SAN prepared according to the prescription of F3 is close to the theoretical concentration, and the concentration of CCM and QCTN is 1973 times and 107 times that of D6, respectively.

[0114] ②Dilution results in different pH media

[0115] Comparing D4, D5 and F2, the dilution results of CCM in pH 1.0 hydrochloric acid and pH 6.8 phosphate buffer can be known. The release degree of CCM in D4 in pH 1.0 hydrochloric acid and pH 6.8 phosphate buffer is 68.7% and 52.3%, respectively, while the release of CCM in F2 in pH 1.0 hydrochloric acid and pH 6.8 phosphate buffer is almost complete. The presence of auxiliary unit QCT in F2 significantly improves the release degree and physical stability of CCM. The release degree of QCT in F2 in the two media has no significant difference compared with Comparative Example D5, and both can be completely released. As shown in Figures 1-2.

[0116] ③The particle size of the nanocomposite dissolution solution was detected by taking F2 and D5 in 0.1M hydrochloric acid and pH 6.8 phosphate, respectively.

[0117] Table 5 Particle size determination results of F2 and D5 in different dissolution solutions

[0118] From the above results, compared with D2, F2 and D5 can tolerate different pH medium dilution, and have better physical stability.

[0119] Example 2 Nanocomposites F4-F11, D7

[0120] Silymarin (SLBN) is widely used as a hepatoprotective drug or dietary supplement, but its poor water solubility and first-pass metabolism result in an absolute oral bioavailability of only 0.95%, and there is a hepatic enteral circulation. In order to improve the oral bioavailability of silymarin, various new delivery technologies have been applied to silymarin, but the effect is not significant.

[0121] The following nanocomposites were prepared with CCM as the core component and SLBN as the auxiliary unit.

[0122] (1) Prescription composition

[0123] Table 6 Prescription of supramolecular nanocomposites F4-F11, D7

[0124] (2) Preparation process:

[0125] 1) Dissolve CCM and SLBN in THF.

[0126] 2) Dissolve the self-assembled carrier and the high molecular polymer Soluplus / VA64 / PVPK30 in the prescription in 10 mL of aqueous citric acid solution (pH 3.0) (heat if necessary), and then add 3 mL of water;

[0127] 3) While stirring, add solution 1) to solution 2), recover the organic solvent under reduced pressure to meet the requirements of the Chinese Pharmacopoeia for residual solvents, centrifuge at room temperature at 15000 rpm for 5 minutes, and the supernatant is the nanocomposite solution.

[0128] Table 7 Test results of curcumin self-assembled nanoparticles F4-F11, D7

[0129] (3) Conclusion:

[0130] 1) The detected concentration of CCM and SLBN in the SAN solution prepared by F6 is close to the theoretical value, and the concentration of SLBN is 4.5 times that of D7. The mass ratio of auxiliary unit to core component in the F4-F11 prescription is 1:10 to 2:1, and the concentration of CCM in the nanocomposite solution prepared by each prescription is more than 95% of the theoretical concentration; the release of CCM in the nanocomposite solution in different pH media is more than 85%, and the release of SLBN in the two media is 100%.

[0131] The results of nanoparticle size of the SAN prepared according to the prescriptions of F4, F6-F11 in a 0.1M hydrochloric acid or pH 6.8 phosphate buffer solution diluted 20 times show that the nanoparticle size of each prescription after dilution changes within ±10 nm, indicating that the nanocomposites prepared by the method have good physical stability and can tolerate the influence of extreme pH changes and dilution after oral administration.

[0132] 2) Comparison with commercially available similar products

[0133] Commercially available drink 1 and commercially available drink 2 are CCM-containing drinks sold on the market, and the content and particle size distribution are detected by using the same HPLC method and particle size determination method, and 0.1M hydrochloric acid and pH 6.8 phosphate buffer are used for 20 times dilution, and the dissolution of commercially available drink 1 in pH 1.0 hydrochloric acid and pH 6.8 phosphate buffer is 17.4% and 40.2% respectively, and the dissolution of commercially available drink 2 in pH 1.0 hydrochloric acid and pH 6.8 phosphate buffer is 1.0% and 4.2% respectively.

[0134] The particle size of the above-mentioned pH 1.0 hydrochloric acid and pH 6.8 phosphate buffer solution diluted 20 times is detected, and the results are as follows:

[0135] Table 8 Particle size detection results of commercially available drink 1 and 2 before and after dilution

[0136] According to the above determination results, the dissolution of commercially available drink 2 in pH 1.0 hydrochloric acid or pH 6.8 phosphate buffer is less than 5%, and cannot be dissolved. The dissolution of commercially available drink in pH 1.0 hydrochloric acid is about 17.4%, and the dissolution in pH 6.8 phosphate buffer is 40.2%, which is slightly better than that of commercially available drink 2. After being diluted 20 times with pH 1.0 hydrochloric acid or pH 6.8 phosphate buffer, the particle size of both increases by 35-84 times, indicating that the physical stability of both is poor.

[0137] (4) 95% ethanol dilution results

[0138] The above-mentioned two commercially available drinks are recommended to be drunk before, during or after drinking, and have the effect of alcoholism, therefore, 1 mL of F2, F4 nanocomposite solution and commercially available drink 1 and 2 are respectively taken, 95% ethanol is used to dilute F2, F4 and commercially available drink 1 and 2 step by step, and the properties of the diluted solutions are observed, centrifuged, and the supernatant is detected for nanoparticle size, and the results are shown in Figures 3-4.

[0139] According to the above results, commercially available drink 1 and 2 cannot tolerate ethanol dilution, and the CCM in the drink is quickly precipitated after being diluted 20 times; while the nanocomposites prepared according to the prescriptions of F2 and F4 in the present application are still nanosolution after being diluted 100 times.

[0140] Example 3 Nanocomposites F12-F20, D8-D9

[0141] (1) Nanocomposite Formulations

[0142] Table 9 Nanocomposite Formulations F12-F20, D8

[0143] (2) Preparation Process

[0144] 1) Dissolve THCCM, DPND, DMRCT, GKT or VTX in THF or methanol.

[0145] 2) Dissolve RBDS-A, RBDS-C, STVS, MGSDT, ASTS, HASTS, NRGCT, Soluplus / VA64 / PVP K90 under each formulation item in 10 mL pH 3.0 aqueous citric acid solution, and add 3-6 mL of water;

[0146] 3) Add solution 1) to solution 2) under stirring, recover the organic solvent under reduced pressure to meet the requirements of the Chinese Pharmacopoeia for residual solvents, centrifuge at 15000 rpm for 5 minutes, and the supernatant is the nanocomposite solution. The concentration, particle size, potential and dissolution results in different pH media of each nanocomposite solution are shown in the following table:

[0147] Table 10 Nanocomposite F12-F20, D8 Test Results

[0148] (3) Conclusion

[0149] The mass ratio of core components to auxiliary units is 1:0-1:10, which can all assemble into nanocomposites. However, the dissolution of D8 nanocomposite solution without auxiliary units in pH 1.0 hydrochloric acid and pH 6.8 phosphate buffer is 73.6% and 68.1%, respectively, while the dissolution of nanocomposites containing auxiliary units in the two media is more than 85%. The presence of auxiliary units improves the physical stability of nanocomposites and also improves the dissolution.

[0150] The concentration of THCCM and auxiliary units in nanocomposites prepared according to F19-F20 formulations is slightly lower than the theoretical concentration, but is much higher than the concentration achieved by existing published technologies.

[0151] Example 4 Nanocomposites F21-F30

[0152] Prepare nanocomposite solutions according to the following formulations

[0153] Table 11 Formulation and concentration detection results of nanocomplexes F21-F30

[0154] (2) Preparation process

[0155] 1) Dissolve the active ingredient in THF or methanol.

[0156] 2) Dissolve the self-assembly carrier and the high molecular polymer in 10 mL of pH 3.0 aqueous citric acid solution, and then add 3-6 mL of water.

[0157] 3) Add solution 1) to solution 2) under stirring, recover the organic solvent under reduced pressure to meet the residual solvent requirements of the Chinese Pharmacopoeia, centrifuge at 15000 rpm for 5 minutes, and the supernatant is the nanocomplex solution.

[0158] Detect the concentration of the active ingredient in the nanocomplex solution by HPLC.

[0159] (3) Conclusion:

[0160] The detected concentrations of each core component and auxiliary units 1 and 2 in the nanocomplexes prepared according to the formulations F21-F30 are close to the theoretical concentrations. The nanocomplexes constructed by the core component and one or more auxiliary units can not only greatly improve the assembly efficiency and solubility of the core component, but also significantly improve the solubility and assembly efficiency of the auxiliary units.

[0161] Example 5 Solidification and redissolution of nanocomplex solution

[0162] (1) Nanocomplex powder

[0163] 1) Place 5 mL of the nanocomplex solution prepared according to the formulations F2, F4, F11, F14, F15, F16, and F19 in a 20 mL vial, pre-freeze with dry ice + acetone, and freeze-dry in a freeze-drying machine for 48 hr to obtain nanocomplex powders of each formulation.

[0164] 2) Weigh CCM, auxiliary units, self-assembly carriers, and high molecular polymers according to the formulations F23 and F25, dissolve them in an appropriate amount of tetrahydrofuran-water (1:1) mixed solvent, spray dry, collect the powder, and continue to dry in a 40°C vacuum drying oven for 3-4 hr to prepare nanocomplex powders.

[0165] (2) Redissolution and particle size detection

[0166] According to the theoretical drug loading, the nano-complex powder was weighed, stirred with appropriate amount of purified water to dissolve, and then diluted to 2 mL with water. The stirring was continued for 5 min to obtain the redissolved solution. If the redissolution was not complete, the stirring time could be appropriately prolonged. 0.4 mL of the redissolved solution was taken, diluted 10 times with 3.6 mL of purified water, and the particle size and PDI were detected. Each sample was determined in triplicate, and the results are shown in the following table:

[0167] Table 12 Particle size and PDI detection results of the redissolved nano-complex powder

[0168] According to the above results, each prescription can be completely redissolved in about 6 minutes, and the redissolution of the nano-complex powder solidified by freeze-drying is slightly faster than that of the powder solidified by spray drying. The particle size and PDI change little before and after freeze-drying, and the solidification has little effect on the subsequent properties of the nano-complex.

[0169] Example 6 Nano-complexes F31-F40

[0170] (1) Prescription composition

[0171] Table 13 F31-F40 nano-complex prescription

[0172] (2) Preparation process

[0173] A: Preparation of F33, F34, F36, F38-F40

[0174] 1) F33, F34, F36, F38-F40 respectively, CCM and other active ingredients in the prescription were dissolved in tetrahydrofuran or methanol for standby;

[0175] 2) The self-assembled carrier and the high molecular polymer were respectively dissolved in pH 3.0 citric acid aqueous solution, and 3-6 mL of water was added after dissolution;

[0176] 3) While stirring, each solution in 1) was added dropwise into 2), and after the dropwise addition was completed, the stirring was continued for 30 minutes. The organic solvent was removed by a rotary evaporator at 40°C, and the sample was left overnight. The supernatant was obtained by centrifugation at 15000 rpm for 5 minutes, and the supernatant was the nano-complex solution of each prescription.

[0177] B: Preparation of F31, F32, F35 and F37

[0178] 1) GBE was dissolved in 50% methanol-water solution; SBIF, RVRT, SLDS, CBD, OLRP were dissolved in tetrahydrofuran solution;

[0179] 2) The self-assembled carrier and the high molecular polymer were respectively dissolved in 10 mL of purified water, and 5 mL of water was added after dissolution;

[0180] 3) While stirring, drop the solution of 1) into the solution of 2), remove the organic solvent in a rotary evaporator at 0℃, stand overnight, centrifuge at 15000 rpm for 5 minutes, and the supernatant is the solution of the nanocomplex of each formula.

[0181] wherein GBE is detected according to the content determination method specified in the Chinese Pharmacopoeia;

[0182] Other components are detected according to the solution detection method of the nanocomplex established by the enterprise; the detection method of particle size and PDI is the same as before.

[0183] (3) Experimental results

[0184] Table 14 Nanocomplex solution, particle size and PDI detection results of F31-F40

[0185] (4) Conclusion

[0186] According to the above results, the present application technology can be used not only for the simultaneous assembly of two or three components, but also for the simultaneous assembly of multiple components. F31 uses ginkgo leaf extract as the active ingredient, and the ginkgo leaf extract used meets the quality standards of ginkgo leaf extract in the Chinese Pharmacopoeia 2020 edition. Among them, quercetin, kaempferol, isorhamnetin, total flavonoid glycosides, white ginkgo lactone, ginkgolide A, B, C, etc. are counted as terpene lactones, which are the main active ingredients of GBE. The detected concentrations of total flavonoid glycosides and total terpene lactones in the nanocomplex solution prepared by F31 are close to the theoretical concentrations.

[0187] SBIF is soybean isoflavone, and the total isoflavone is calculated as the sum of daidzin, glycitein, genistin, daidzein, glycitein and genistein. F32 uses SBIF extract as the active ingredient, and the total isoflavone concentration in the prepared nanocomplex is 2.9 mg / mL, which is close to the detected content of the raw material and the theoretical calculated value.

[0188] F36 is a nanocomplex prepared with CCM and CRCN as active ingredients, wherein the detected concentration of CCM is about 70% of the theoretical concentration, and the detected concentration of CRCN is close to the theoretical value.

[0189] The detected concentrations of active ingredients in the nanocomplexes prepared by other formulas are close to the theoretical concentrations, indicating that the encapsulation rate is close to 100%.

[0190] Example 7 Supramolecular nanocomplex F41-F50

[0191] (1) Formula composition

[0192] Table 15 Formula of supramolecular nanocomplex F41-F50

[0193] (2) Preparation process

[0194] 1) Weigh the prescribed amount of GTT, self-assembly carrier, and high molecular polymer, first add 10 mL of water to dissolve the carrier and high molecular polymer, then add the prescribed amount of GTT of F43-F45, after dissolution, add 3-6 mL of water, and prepare for use.

[0195] 2) Weigh the prescribed amount of other active ingredients, dissolve in tetrahydrofuran, and prepare for use;

[0196] 3) While stirring, add 2) to 1) dropwise, continue stirring until there is no solvent smell, centrifuge at 15000 rpm for 5 minutes, and the supernatant is used as the nanocomposite solution;

[0197] 4) Prepare 10% and 5% solutions of ABME or LRE by adding water, take 5 mL of the nanocomposite solution prepared in F42 and F43, dilute one time with the ABME or LRE aqueous solution, and record as F42-1 and F43-1, respectively.

[0198] 5) The nanocomposite solution prepared in F47-F48 is first pre-frozen with acetone-dry ice, then freeze-dried in a Westlin bottle, after freeze-drying, the powder is added with GTT and SGE, AME, mixed evenly, re-dissolved, and the content and particle size are detected.

[0199] 6) Dissolve ABME and CME in water to form 5% and 10% aqueous solutions, respectively, take 5 mL of the nanocomposite solution of F49 and F50, and dilute one time with the ABME and CME aqueous solution.

[0200] (3) Active ingredient concentration determination and nanocomposite solution particle size and PDI detection

[0201] The results are shown in the following table:

[0202] Table 16 F41-F50 supramolecular nanocomposite solution, particle size and PDI determination results

[0203] The plant or traditional Chinese medicine extract has no effect on the assembly efficiency of the nanocomposite or the particle size of the nanocomposite after assembly.

[0204] Example 8 Supramolecular nanocomposite F51-F60

[0205] Nucleoside ingredients have various active effects, such as CDCP, which inhibits the growth of cancer cells, has antiviral, anticancer, antifungal, lung nourishing, kidney tonifying, and promotes bone marrow hematopoietic function, etc., and can assist in regulating chronic cough, insomnia, bronchitis, nocturia, etc. Its body content is easily metabolized by adenosine deaminase. As an auxiliary unit assembled into a nanocomposite, on the one hand, it improves the first-pass metabolism of nucleoside ingredients, and on the other hand, it can regulate the release in vivo, thereby prolonging the action time of nucleoside ingredients.

[0206] (1) Nanocomposite prescription

[0207] Table 17 Nanocomposite F51-F60 prescription

[0208] (2) Preparation process

[0209] 1) Dissolve CCM, QCT, SLBN in THF or methanol; dissolve CDCP, DOIS, ADNS in 50% THF aqueous solution.

[0210] 2) Dissolve RBDS-A, RBDS-C, STVS, MGSDT, NRGCT, Soluplus / VA64 / PVPK90 under each prescription item in 10 mL aqueous solution, and add water 3-6 mL;

[0211] 3) Add solution 1) to solution 2) under stirring, recover the organic solvent under reduced pressure to meet the requirements of Chinese Pharmacopoeia for residual solvents, centrifuge at 15000 rpm for 5 minutes, and the supernatant is the nanocomposite solution. The concentration, particle size, potential and dissolution results in different pH media of each nanocomposite solution are shown in the following table:

[0212] Table 18 Nanocomposite F51-F60 test results

[0213] (3) Conclusion:

[0214] The detection concentration of each core component and auxiliary unit in the nanocomposite prepared by F51-F52, F54-F60 prescription is close to the theoretical concentration; the detection concentration of core component CCM in the nanocomposite prepared by F53 prescription is 23.7 mg / mL, which is 79% of the theoretical concentration, while the concentration of auxiliary unit CDCP is 29.8 mg / mL, which is 99.3% of the theoretical concentration, and the detection concentration of QCT is basically close to the theoretical concentration. Therefore, by adjusting the theoretical feed amount of auxiliary units and core components in the nanocomposite formula, nanocomposites containing different composition ratios of core components and auxiliary units can be prepared to meet the treatment needs of different application scenarios.

[0215] Example 9: Preparation of Nanocomposite Formulations or Foods

[0216] The nanocomposite prepared according to the above embodiments can be prepared into oral, mucosal, or topical formulations as needed, such as tablets, capsules, granules, powders, solutions, gels, eye drops, nasal drops, ear drops, creams, and sprays. It can also be prepared into beverages, confectionery, dairy products, alcoholic beverages, and other food products.

[0217] The nanocomposite solutions prepared in Examples 1-4 and 6-8 can be directly dispensed, or bottled after adding appropriate amounts of purified water, flavoring agents, and antibacterial agents to make beverages or oral solutions; or gel carriers such as CMS-Na and Carbopol can be added to prepare gels; or creams can be prepared using nanocomposite as the aqueous phase; or gummy cans can be prepared by adding gelatin; or tablets, granules, capsules, solid beverages, etc. can be prepared by adding appropriate excipients to the nanocomposite powder prepared in Example 5.

[0218] In addition, the prescription may also include ginkgolide extract, tea polyphenol extract, grape seed extract, maca extract, ginseng / leaf / fruit extract, Panax notoginseng root / flower / whole herb extract, Smilax glabra, Cirsium japonicum, Ligustrum lucidum, Cornus officinalis, Achyranthes bidentata, Fritillaria cirrhosa, Ligusticum chuanxiong, deer placenta, deer antler, deer bone, Salvia miltiorrhiza, Acanthopanax senticosus, Schisandra chinensis, Cimicifuga foetida, Asparagus cochinchinensis, Gastrodia elata, Pseudostellaria heterophylla, Morinda officinalis, Aucklandia lappa, Equisetum hyemale, Arctium lappa, Arctium lappa root, Plantago asiatica, Plantago asiatica, Adenophora stricta, Fritillaria cirrhosa, Scrophularia ningpoensis, Rehmannia glutinosa, Polygonum multiflorum, Bletilla striata, Atractylodes macrocephala, Paeonia lactiflora, Amomum villosum, Haliotis diversicolor, Dendrobium nobile, Lycium chinense root bark, Angelica sinensis, Bambusa textilis, Carthamus tinctorius, Rhodiola rosea, Panax quinquefolius, Evodia rutaecarpa, Achyranthes bidentata, Eucommia ulmoides, Eucommia ulmoides leaf, Astragalus complanatus, Paeonia suffruticosa, Aloe vera, Atractylodes lancea, and Psoralea corylifolia. Fat, [unclear text - possibly a list of herbs or ingredients], Red Peony Root, Polygala Root, Ophiopogon Root, Tortoise Shell, Eupatorium Root, Arborvitae Leaf, Prepared Rhubarb, Prepared Polygonum Multiflorum, Acanthopanax Root, Rosa rugosa Fruit, Eupatorium Root, Alisma Rhizome, Rose Flower, Roselle, Anemarrhena Rhizome, Apocynum venetum, Kuding Tea, Fagopyrum Buckwheat, Golden Tassel Fruit, Green Tangerine Peel, Magnolia Bark Flower, Curcuma Rhizome, Bitter Orange Peel, Bitter Orange Fruit, Arborvitae Seed, Pearl, Gynostemma Pentaphyllum, Trigonella Rhizome, Rubia Root, Longan, Allium Seed, Polygonum Multiflorum Vine, Cyperus Rhizome Extracts from one or more of the following: Drynaria fortunei, Codonopsis pilosula, Morus alba root bark, Morus alba twig, Fritillaria thunbergii, Leonurus japonicus, Centella asiatica, Epimedium, Cuscuta chinensis, Chrysanthemum indicum, Ginkgo biloba leaf, Astragalus membranaceus, Fritillaria cirrhosa, Senna leaf, Gecko, Vaccaria segetalis, Sophora japonica fruit, Typha pollen, Tribulus terrestris, Propolis, Tamarix chinensis, Eclipta prostrata, Rheum palmatum, Ganoderma lucidum, Ganoderma lucidum mycelium, Agaricus blazei, Chaga mushroom, Tiger milk fungus, Phellinus linteus, etc.

[0219] (1) Preparation of oral solid dosage forms containing supramolecular nanocomposites

[0220] Nanocomposite powder preparation: Nanocomposite solutions were prepared according to formulas F2, F4, F14 and F18 respectively, dispensed into trays with a thickness ≤10mm, pre-frozen at -45℃~-50℃ for 3 hours, and then freeze-dried. The freeze-dried products were passed through an 80-mesh sieve and set aside for later use.

[0221] 1) Formulation:

[0222] Table 19 Formulation prescription composition

[0223] 2) Preparation process:

[0224] FT 61: Mix the nanocomposite powder, microcrystalline cellulose, mannitol, cross-linked polyvinylpyrrolidone, and silicon dioxide uniformly, add half of the prescribed amount of magnesium stearate and mix uniformly, dry granulation, add the remaining magnesium stearate and mix uniformly, and press into tablets to obtain nanocomposite tablets.

[0225] FC 62: Mix the nanocomposite powder, microcrystalline cellulose, lactose, cross-linked polyvinylpyrrolidone, and silicon dioxide uniformly, add magnesium stearate and mix uniformly, and fill into size 0 capsules using a capsule filling machine to obtain nanocomposite capsules.

[0226] FP 63: Mix the nanocomposite powder, mannitol, lactose, vitamins, carotene, silicon dioxide, and sodium stearyl fumarate uniformly and bag to obtain nanocomposite powder.

[0227] FG64: Mix the nanocomposite powder, lactose, cross-linked polyvinylpyrrolidone, ginkgo biloba extract, CRCN, and RVRT uniformly, dissolve polyvinylpyrrolidone K30 in water to make a 10% solution, add to the mixed powder to make a soft material, pass through an 18-mesh sieve to granulate, dry, size, and bag to obtain nanocomposite granules.

[0228] DT 10: Use crystal CCM and QCT instead of nanocomposite powder to prepare tablets according to the FT61 process.

[0229] DC11: Use crystal CCM and SLBN instead of nanocomposite powder to prepare capsules according to the FC62 process.

[0230] (2) Preparation of nanocomposite oral solution and gel

[0231] Prepare nanocomposite solution according to the F1, F8, and F25 formulation processes, and prepare oral solution and gel according to the following formulation.

[0232] 1) Formulation composition

[0233] Table 20 Formulation prescription composition

[0234] 2) Preparation process:

[0235] FO 65, FO 67: Add essence, vitamins, and SLDS to the nanocomposite solution, dilute with water to 10 mL, and obtain the product.

[0236] FGL 66: Carboxymethylcellulose sodium is swelled with a small amount of water for 24 hours, then the nanocomposite solution and essence are added and stirred uniformly, degassed, and then packed.

[0237] (3) Preparation of beverage containing nanocomposite

[0238] The nanocomposite solution is prepared according to the prescription and process of F2, F8, and F43, and the beverage is prepared according to the following prescription.

[0239] 1) Prescription composition

[0240] Table 21: Beverage prescription

[0241] 2) Preparation process:

[0242] FD 68: The nanocomposite solution, potassium sorbate, watermelon essence, and vitamins are dissolved in water, filtered with a 0.45 micron filter, and then packed.

[0243] FD 69: Tea leaves are boiled in 100 mL of water, filtered, mixed with the nanocomposite solution and milk, and then mixed uniformly. Purified water is added to 500 mL, packed, and then pasteurized.

[0244] FD 70: The original fruit juice, potassium sorbate, and nanocomposite solution are dissolved and mixed, packed, and then pasteurized.

[0245] (4) Preparation of soft candy containing nanocomposite

[0246] Nanocomposite powder preparation: Nanocomposite solutions are prepared according to the prescriptions F9, F14, F21, F41, and F49, respectively, packed into trays with a thickness of ≤10 mm, pre-frozen at -45℃ to -50℃ for 3 hours, freeze-dried, and then the freeze-dried product is sieved through an 80 mesh sieve for use.

[0247] 1) Prescription composition

[0248] The candies (CD) are prepared according to the following table.

[0249] Table 22: Prescription composition of candies

[0250] 2) Preparation process:

[0251] FCD 71:

[0252] ① Sol: Gelatin and water are mixed in a ratio of 10:20, soaked, and then sol is prepared at 40℃, and then cooled for use.

[0253] ② Mixing: Erythritol and maltitol are mixed and heated to mix uniformly.

[0254] ③Caramelization: Caramelization under normal pressure, constant stirring during caramelization, using a stirring rod to dip into the syrup, observing the concentration, when the syrup flows down the rod, forming thin and short sugar strips that are not easy to break off, the caramelization temperature is controlled below 140°C. Add the sol, mix evenly, control the temperature at about 105°C at this time.

[0255] ④Blending: When the sugar solution cools to about 90°C, add the appropriate amount of essence and acidulant, and blend evenly.

[0256] ⑤Add nano-composite powder: When the sugar solution cools to 60-70°C, add the nano-composite solution or powder, and stir evenly.

[0257] ⑥Degassing, molding: Pour into the gummy mold, cool and set, then remove the film and dry.

[0258] ⑦Drying: 25-35°C, 36-48hr.

[0259] FCD 72, FCD 73: The amount of water added during sol preparation is 1:8, and the other preparation processes are the same as FCD 71.

[0260] FCD 74: Add 10 times the amount of water to the modified starch, mix with maltitol and erythritol, caramelize, and the other preparation processes are the same as FCD 71.

[0261] FCD 75: The amount of water added during sol preparation is 1:10, and the other preparation processes are the same as FCD 71.

[0262] Experimental Example 1 FaSSGF to FaSSIF-V2 dissolution detection

[0263] Dissolution method: slurry method, small cup method, 37°C;

[0264] Speed: 100 rpm;

[0265] Dissolution medium: FaSSGF 187mL, 30min complete sampling, add 63mL of conditioning liquid, and change the medium to FaSSIF-V2.

[0266] Sampling points: 15, 30, 45, 60, 90, 120, 180min, take 4mL, add corresponding medium 4mL, filter with PTFE filter membrane, HPLC detection of CCM, QCT, SLBN content, calculate the cumulative dissolution at each time point. The results are shown in the table below and Figure 5.

[0267] Table 23 Dissolution curve

[0268] According to the above results, under the simulated empty stomach juice to intestinal juice dissolution conditions, the preparation containing the nanocomposite can be completely dissolved in the simulated stomach juice to intestinal juice dissolution medium before a meal, and is not affected by the medium pH, bile salts and enzymes. The cumulative dissolution of CCM and QCT or SLBN at each sampling point in the DT10 and DC11 samples was significantly lower than that of the preparation containing the nanocomposite.

[0269] Experimental Example 2 Tissue distribution of rats after oral gavage

[0270] (1) Experimental animals

[0271] SPF grade SD male rats, weighing 225-239 g, male, purchased from China Food and Drug Inspection Research Institute, license number SCXK (Jing) 2022-0002. 12 hr alternating light, 22±2℃, RH 55±5% x relative humidity environment for a week.

[0272] (2) Animal grouping

[0273] The animals were fasted overnight (free water) for more than 10 hours the day before the experiment, and randomly divided into 4 groups, 24 in each group (2 extra in each group for backup), 3 in each blood sampling point.

[0274] (3) Experimental drugs and dosing regimen

[0275] 1) The experimental groups were given F2 (CCM / QCT / mL: 59.7 mg / 20.2 mg / mL) and F4 (CCM / SLBN / mL: 34.9 / 35.2 mg / mL) nanocomposite solution, respectively;

[0276] 2) The same amount of CCM, QCT, SLBN, self-assembled carrier and high molecular polymer was weighed according to the F2 and F4 prescriptions, mixed uniformly, and prepared into suspension (Suspension) with pH 3.0 citric acid aqueous solution, respectively, and recorded as F2-Sup and F4-Sup, respectively, as control drugs.

[0277] Table 24 Dosing regimen

[0278] (4) Sampling time points and biological sample processing

[0279] The rats were administered intragastrically according to the dosing regimen in the above table, and allowed to drink freely 2 hours later. Blood samples (0.5 mL) were taken from the inner canthus at 15 min, 30 min, 1, 2, 3, 6, 8 and 12 hours after administration (anticoagulated with sodium heparin, centrifuged at 4°C / 4500 rpm for 10 min, separated into plasma, and stored at -70°C) and the rats were then sacrificed by ether anesthesia, and the liver, pancreas, brain tissue, lung, eyeball and other tissues were rapidly separated, washed with 4°C physiological saline, and then dried with absorbent paper and weighed. The tissues were cut into small pieces, mixed with physiological saline (4°C, g) at a mass ratio of 1:4, homogenized, frozen and thawed in liquid nitrogen three times, and the homogenate was stored at -70°C until testing.

[0280] (5) Pretreatment of biological samples before testing

[0281] 1) Plasma: 75 μL of the plasma sample of the experimental animal was taken, 75 μL of pH 7.4 phosphate buffer was added, vortexed for 10 seconds, 10 μL of internal standard solution (lurasidone hydrochloride, 80 ng / mL) was added, vortexed for 30 seconds, 900 μL of methanol was added as a protein precipitant, vortexed for 30 seconds, 140 μL of water was added, vortexed for 10 seconds, and left to stand for 10 min. The mixture was centrifuged at 4°C / 13000 rpm for 10 min, and 20 μL of the supernatant was injected for analysis.

[0282] 2) Liver, lung and colon tissue: 150 μL of the liver or lung tissue homogenate was taken, 900 μL of methanol was added as a protein precipitant, vortexed for 30 seconds, 150 μL of H2O was added, vortexed for 30 seconds, left to stand for 10 min, and centrifuged at 4°C / 13000 rpm for 10 min. 100 μL of the supernatant was taken, 890 μL of 75% MeOH and 10 μL of internal standard solution (lurasidone hydrochloride, 80 ng / mL) were added, vortexed for 10 seconds, and 20 μL was injected for analysis.

[0283] 3) Pancreas: 150 μL of the pancreas tissue homogenate was taken, 10 μL of internal standard solution (lurasidone hydrochloride, 80 ng / mL) was added, vortexed for 30 seconds, 900 μL of methanol was added for protein precipitation, vortexed for 30 seconds, 140 μL of deionized water was added, vortexed for 10 seconds, left to stand for 10 min, and centrifuged at 4°C / 13000 rpm for 10 min. 20 μL of the supernatant was injected for analysis.

[0284] 4) Eyeball: 150 μL of the eyeball tissue homogenate was taken, 10 μL of internal standard solution (lurasidone hydrochloride, 80 ng / mL) was added, vortexed and mixed for 30 seconds, 900 μL of methanol was added for protein precipitation, vortexed for 30 seconds, 140 μL of deionized water was added, vortexed for 10 seconds, left to stand for 10 min, and centrifuged at 4°C / 13000 rpm for 10 min. 20 μL of the supernatant was injected for analysis.

[0285] 5) Brain tissue: Take 150 μL of brain tissue homogenate, add 10 μL of internal standard solution (lurasidone hydrochloride, 80 ng / mL), vortex mix for 30 seconds, add 900 μL of methanol for protein precipitation, vortex for 30 seconds, add 140 μL of deionized water, vortex for 10 seconds, stand for 10 min, centrifuge at 4°C / 13000 rpm for 10 min, take 20 μL of supernatant for sample analysis.

[0286] 6) Results

[0287] The liquid chromatography and mass spectrometry conditions for detecting the content of CCM, QCT or SLBN in plasma and tissue samples are shown in the following table.

[0288] Table 25 Chromatography and mass spectrometry conditions for LC / MS / MS detection method of each active ingredient in biological samples

[0289] The concentration of CCM, QCT or SLBN in plasma was detected by internal standard method, and the pharmacokinetic parameters were calculated by Phoenix WinNonlin 7.0 using the concentration data of CCM, QCT or SLBN measured at different time points, to provide AUC 0-t , AUC 0-∞ , Cmax, Tmax and T 1 / 2 , etc. and their mean values.

[0290] ① Plasma pharmacokinetic results of F2 and F2-Sus

[0291] Table 26 Plasma pharmacokinetic parameters of F2 and F2-Sus

[0292] According to the above results, compared with F2-Sus, the oral relative bioavailability F rb of CCM and QCT of F2 nanocomplex was significantly improved, which was 25 times and 16 times of F2-Sus, respectively. Compared with F2-Sus, the improvement of CCM was significantly greater than that of QCT.

[0293] ② Exposure of CCM and QCT in tissues of F2 and F2-Sus

[0294] In addition to liver and pancreas, CCM and QCT could be detected in brain tissue and eyeball of F2-Sus administration group.

[0295] The liver, pancreas, brain tissue and eyeball tissue samples of the F2 administration group rats at 1 hr, 3 hr and 12 hr were detected for the concentrations of CCM and QCT, and the results are shown in Figures 6-7. The detection concentrations of CCM or QCT in the liver and pancreas tissue samples of the F2-Sus administration group rats at 12 hr were below the quantitative limit (10 ng), and the detection results of CCM or QCT in the liver and pancreas samples at 1 hr and 3 hr are shown in Figure 8.

[0296] It can be known from the detection results that CCM and QCT are detected in the brain tissue, pancreas, lung, eyeball and liver after the oral administration of the F2 nanocomplex to rats, and the detection amount in the lung tissue is the highest, the detection concentration levels of CCM and QCT in the lung tissue at 3 hr are 45.9 μg / g and 36 μg / g respectively, followed by the pancreas and liver, and the detection concentration levels of QCT in the pancreas and liver tissue at 3 hr are 3.3 μg / g and 2.6 μg / g respectively, and the detection concentration levels of CCM are 7.8 μg / g and 4.2 μg / g respectively. It is worth noting that the brain tissue and eyeball tissue are the most difficult to reach by drugs, and the detection concentrations in the brain tissue and eyeball at 12 hr are still 50 ng / g-180 ng / g, and the peak concentration levels in the brain tissue and eyeball at 3 hr are 380 ng / g-1100 ng / g.

[0297] After the oral administration of F2-Sus to rats, CCM and QCT are detected in the pancreas and liver at 1 hr and 3 hr, and the detection concentration level in the liver at 3 hr is the highest, which is 307 ng / g and 910 ng / g respectively; the detection concentrations of CCM and QCT in the pancreas at 3 hr are 116 ng / g and 287 ng / g respectively.

[0298] According to the literature Heliyon 6 (2020) e04408, curcumin and quercetin can block multiple targets or inflammatory factors on the pathways of various eye diseases such as glaucoma, cataract, age-related macular degeneration, diabetic retinopathy, etc., and have broad prospects for the treatment of eye diseases. Curcumin and quercetin are derived from plants that are both medicine and food, and are suitable for long-term taking. However, the extremely low oral bioavailability of the two limits their more extensive application. Due to the special physiological structure of the eye, it is difficult for drugs to reach the fundus in sufficient amount after eye drop administration, and local administration is only suitable for the treatment of anterior segment diseases of the eye. For posterior segment diseases of the eye, the current clinical treatment can only be carried out through frequent intervention treatment methods such as intravitreal injection, periocular injection and implantation, 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. Therefore, through the administration of the nanocomplex solution or other oral preparations thereof, it is expected to solve this major unmet clinical treatment demand, and enable more patients to realize the treatment of eye diseases through oral systemic administration.

[0299] According to Molecules 2022, 27, 236. https: / / doi.org / 10.3390 / molecules27010236, Int. J. Mol. Sci. 2023, 24, 6328, curcumin and quercetin have strong anti-inflammatory, antioxidant, antimicrobial, antitumor, anti-aging, and mitochondrial function maintenance pharmacological activities. Neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, tumors, multiple sclerosis, insomnia, depression, and anxiety are mainly caused by long-term low-level neuroinflammation, but the existing technology of oral curcumin or quercetin has very limited exposure into the blood plasma through the gastrointestinal tract, not to mention sufficient delivery across the blood-brain or blood-eye barrier. The nanocomplex prepared by the application realizes the delivery of CCM and QCT across the blood-brain and blood-eye barriers, providing a new means for clinical treatment.

[0300] ③F4 and F4-Sus plasma pharmacokinetic results

[0301] Table 27 F4 and F4-Sus plasma pharmacokinetic parameters

[0302] According to the above results, compared with F4-Sus, the F4 nanocomplex significantly improved the oral relative bioavailability of CCM and SLBN F rb , which are 9.7 times and 8.7 times that of F4-Sus, respectively, and the improvement rates are basically the same.

[0303] The detection levels of CCM and SLBN in F4-Sus plasma are much higher than those in rats directly orally administered with CCM (not more than 10 ng / mL) or SLBN in the literature, and it is speculated that a part of CCM or SLBN in the suspension has been assembled in situ.

[0304] ④F4 and F4-Sus tissue distribution

[0305] F4 nanocomposite rats were given by gavage, 1 hr, 3 hr and 12 hr each observation time point in the tissue can detect CCM and SLBN, in which CCM in 3 hr each tissue in the detection concentration level is higher than that of other time points, in which the detection concentration in lung tissue is the highest, which is 66 μg / g, followed by colorectal tissue, the detection concentration is 53 μg / g, the detection concentration of CCM in liver and pancreas is equivalent, which is 30 and 33 μg / g respectively; the detection concentration of CCM in brain tissue and eyeball is 350 ng / g and 476 ng / g respectively. CCM can still be detected in 12 hr each observation tissue, and the detection level is 81 ng / g-3208 ng / g. The detection concentration of SLBN in 3 hr colorectal tissue is the highest, which is 55 μg / g, followed by lung tissue, which is 53 μg / g, the detection concentration of liver and pancreas is 2.5 and 1.6 μg / g respectively, the detection concentration of eyeball and brain tissue is 259 and 388 ng / g respectively. There are different levels of detection in each tissue at 12 hr, and the detection concentration level is 53-2733 ng / g, in which the detection concentration of 12 hr eyeball tissue is the lowest, see Figures 9-10 for details.

[0306] The detection concentration of CCM or SLBN in the 12-hour tissue of F4-Sus administration group rats is close to the limit of quantification or below the limit of quantification, and the detection of CCM and SLBN in the liver and pancreas at 1 hr and 3 hr is shown in Figure 11. Among them, the highest detection concentration of CCM in the liver at 3 hr is 460 ng / g; the highest detection of SLBN in the liver tissue at 1 hr is 665 ng / g, which is significantly lower than the detection concentration of F4 nanocomposite in the corresponding tissue, but much higher than the tissue exposure concentration that can be achieved by the prior art.

[0307] According to the literature, CCM or SLBN can assist in the treatment of COVID-19, pancreatic cancer, liver cancer, colorectal cancer, bladder cancer, lung cancer, breast cancer, prostate cancer, metabolic syndrome, etc., and a large number of literature studies have further confirmed that the combination of the two can achieve a synergistic effect. Food Sci Nutr.2024;12:3097-3111 summarizes the pharmacological activities of SLBN in antioxidant stress, tumor cell apoptosis, anti-inflammatory, and changes in the degradation and reconstruction of extracellular matrix; and the powerful anti-inflammatory, antioxidant stress, multi-target effect on tumors, and regulation of intestinal flora of curcumin have been confirmed by more than 100 clinical trials, and the combination of the two can complement each other in pharmacology, target and mechanism of action, and achieve a synergistic effect, realizing the treatment of metabolic syndrome, tumors, cardiovascular diseases, aging, depression, anxiety, neurodegenerative diseases, inflammation-related diseases, fibrosis diseases, and infectious diseases.

[0308] Example 10 Pharmacological study of non-alcoholic fatty liver (NAFLD) model mice

[0309] (1) Animal modeling

[0310] SPF level 6-week-old C57BL / 6N male mice, weighing 20g ± 2g, purchased from China Food and Drug Inspection Research Institute (Certificate No: SCXK (Jing) 2022-0002), the environmental temperature is 20 ± 2℃, 12h day and night alternation adaptive feeding for one week, free feeding water. Refer to Journal of Hepatology, 2016, 65, 579-588, Journal of Hepatology, 2018, 69, 385-395, Clinical and Experimental Pharmacology and Physiology, 2013, 40, 422-430, Plos One, 2014, 9, e97136 and S1 Western diet combined with low-dose carbon tetrachloride to construct a mouse model of non-alcoholic fatty liver disease, using high fructose high fat diet modeling method (HFHFD) + CCl4 induction modeling method for modeling.

[0311] After adaptive feeding, 120 animals were divided into two groups, of which 20 were in the control group (Con) and 100 were in the model group (Mod).

[0312] According to the following modeling scheme for modeling:

[0313] The control group was fed with standard feed + purified water;

[0314] The model group: fed with high-fat feed (42% fat + 0.1% cholesterol), and drank 4.2% monosaccharide aqueous solution (23.1g fructose / L + 18.9g glucose / L). After 6 weeks of feeding, on the basis of unchanged diet, 2 times a week for 4 weeks, intraperitoneal injection of CCl4 / corn oil solution. The first injection dose of CCl4 was 0.05 μL per gram of body weight, and the second injection dose was increased to 0.1 μL per gram of body weight.

[0315] (2) Model establishment judgment

[0316] After 10 weeks of modeling, two mice from each of the Con and Mod groups were randomly dissected, and the livers were removed, washed with physiological saline, and the liver morphology of the two mice was compared by appearance. If the liver of the Mod group mouse is significantly larger than that of the Con group mouse with yellowing, it can be preliminarily judged that the NAFLD model is successfully modeled. After the liver is removed, part of it is preserved in formalin solution for histological sectioning and staining, and part of it is preserved at -80℃ for measuring the triglyceride content of the liver; if the modeling is unsuccessful, the injection of CCl4 is extended for 2 weeks. If the liver appearance of the two mice selected from the Con and Mod groups is basically inconsistent, an additional one from each group needs to be observed.

[0317] According to the dissection results of 2 mice in the Con group and the Mod group, the liver of the mice in the Con group was observed as red in color, the organ edge was sharp, the surface was smooth, and there was no greasy feeling; compared with the Con group, the Mod group was observed as brownish yellow in color, the edge was blunt, the surface roughness was high, there were obvious gully-like stripes, and there was a greasy feeling. The Masson staining results of the livers of the two mice in the Con group showed that the liver lobule structure of the two mice was complete and clear, there was no fatty degeneration, the collagen fibers in the hepatic portal area were not dilated, there was no fibrosis in the liver lobule, and the conclusions of the two mice were consistent; the liver lobule structure of the two mice in the Mod group was disordered and difficult to distinguish, the liver cells showed partial fatty degeneration, the fibrosis at the central vein was obvious, central vein-portal area fibrosis bridging occurred, and the fibrosis staging was S2 and S3, and the conclusions of the two mice were consistent. The HE staining results showed that the liver lobule structure of the mice in the Con group was complete and clear, and there was no fatty degeneration; there were a small amount of inflammatory cells in the lobule, no necrotic foci, and no ballooning degeneration model. The liver lobule structure of the mice in the Mod group was disordered, had partial fatty degeneration (≤1 / 3), and had obvious inflammatory infiltration around the veins; there were ≥4 necrotic foci under a 20-fold microscope, and ballooning degeneration was rare. The NAS scores were 3 and 4, respectively.

[0318] (3) Drug intervention

[0319] The above-mentioned mice in the Mod group were randomly divided into 4 groups, of which 24 mice were in the Mod group, and 23, 22 and 21 mice were in the treatment groups T1, T2 and T3, respectively. There were still 18 mice in the Con group after the modeling was completed. The mice in each group were treated with drug intervention according to the following drug administration scheme, and the treatment cycle was 6 weeks. The drug was administered once a day at 9:00 am.

[0320] Table 28 Drug administration scheme of animals in each group

[0321] (4) Sampling and evaluation

[0322] 1) Insulin resistance index and insulin sensitivity

[0323] At the end of the drug intervention, all animals were fasted and not water-restricted for 12 hr, blood was taken, and mouse livers were taken. The fasting blood glucose of the mice was detected before sampling.

[0324] The tail vein blood of the mice was taken, the fasting blood glucose was detected by a blood glucose meter, and the insulin resistance index (HOMA-IR) and insulin sensitivity (ISI) were calculated according to the following formula.

[0325] HOMA-IR = fasting insulin (mIU / L) x fasting blood glucose (mmol / L) / 22.5

[0326] ISI = ln[1 / (fasting insulin x fasting blood glucose)]

[0327] 2) Liver index and Lee's index

[0328] The body weight of mice was measured before anesthesia, and then the mice were anesthetized with sodium pentobarbital (3 mg / 100 g), stretched out on a tape measure, and the body length of the mice (the length from the tip of the nose to the anus) was recorded;

[0329] After dissection, the liver was removed, washed with 4°C physiological saline, and excess water was absorbed with a water-absorbing paper. The wet weight of the liver was measured. The liver index and Lee's index were calculated according to the following formula.

[0330] Lee's index = 3 √(body weight x 1000) / body length

[0331] Liver index = liver weight / body weight x 100%

[0332] 3) Blood index detection was obtained by enucleation and blood collection, without anticoagulant. The blood was left at room temperature for 4 hr, and then placed at 4°C overnight. After stratification, the serum was collected by centrifugation at 4°C / 3000 rpm for 15 min. The serum of each animal was aliquoted in an EP tube and stored at -80°C, with about 150 μL of serum per tube.

[0333] ① Fasting insulin concentration The fasting insulin concentration was detected by insulin ELISA kit for serum sample detection, with 3 parallel determinations for each sample, and the mean value was taken as the detection result, with a relative standard deviation of less than 20%. The detailed detection steps are described in the kit instruction manual or the official website of the supplier.

[0334] ② Serum malonaldehyde (Malonaldehyde, MDA)

[0335] The serum MDA kit was used for detection, and the detailed detection steps are described in the kit instruction manual.

[0336] ③ Serum biochemical index (AST, ALT, TG, TC, LDL-c, HDL-c)

[0337] The serum sample was detected by a fully automatic biochemical analyzer.

[0338] 4) Liver index detection

[0339] ① Liver pathological tissue detection

[0340] The same part of the liver of each mouse was cut and preserved in 10 times the volume of formalin solution. Tissue sections were outsourced for HE staining, oil red O staining, and histological data collection.

[0341] ② Liver triglyceride concentration detection

[0342] About 100 mg of liver tissue was taken (accurately weighed), placed in an EP tube, and stored at -80°C. The triglyceride content detection kit was used for detection.

[0343] (5) Results and evaluation

[0344] The above detection results are shown in detail in Figures 12-17, respectively.

[0345] Conclusion:

[0346] (1) The NAS score of the MOD group was significantly different from that of the CON group (***p<0.001), which was consistent with the results of glucose tolerance and liver index of the CON group and the MOD group.

[0347] (2) The histological improvement of the T1 group, the T2 group, and the T3 group was significantly different from that of the MOD group, and the improvement of the T1 group and the T2 group was better than that of the T3 group, which was consistent with the results of glucose tolerance and liver index of each group.

[0348] (3) The serum biochemical indicators ALT, AST, TG, TC, LDL-C, and HDL-C of the CON group were significantly different from those of the MOD group (***p<0.001); the serum biochemical indicators ALT, AST, TG, TC, LDL-C, and HDL-C of the T1 group, the T2 group, and the T3 group were significantly different from those of the MOD group, but the improvement of the T1 group and the T2 group was better than that of the T3 group.

[0349] (4) In reversing NAFLD, T1, T2, and T3 can improve the indicators of NAFLD, but compared with the three treatment groups, T2 is slightly better than T1, and T1 and T2 are better than T3.

[0350] In addition, for the ultra-stable nanocomposite containing CCM, QCT, SLBN and their derivatives, the trial of volunteers taking the test proved to have good effect on fatty liver, metabolic syndrome, nodules, eye pain, joint pain, shoulder periarthritis pain, high blood pressure, pelvic inflammation, and insomnia.

[0351] Finally, it should be noted that the above examples are only used to illustrate the technical solutions of the present application and do not limit the scope of protection of the present application. Although the present application has been described in detail with reference to the preferred embodiments, those skilled in the art should understand that the technical solutions of the present application can be modified or replaced by equivalents without departing from the essence and scope of the technical solutions of the present application.

Claims

1. An ultrastable nanocomposite, characterized in that The super stable nanocomplex comprises: a) a core component; b) an auxiliary unit; c) a self-assembled carrier; and d) a high molecular polymer, wherein the core component is one or more of phenols, alkaloids, glycosides, terpenoids, lignans, phenylpropanoids, quinones, lactones, steroidal compounds, tannins, preferably one or more of curcumin and / or its derivatives, salidroside, soy isoflavones, silymarin, dihydromyricetin, ginkgo biloba extract; the auxiliary unit is one or more of phenols, terpenoids, alkaloids, lignans, nucleosides, polypeptides, amino acids, organic acids, anthocyanins, organic acids, quinones, proanthocyanidins, steroidal compounds, and vitamin B, C compounds, preferably one or more of quercetin and its derivatives, silymarin and its derivatives, naringenin, naringin, soy isoflavones, ginkgo biloba extract, salidroside, dihydroquercetin, puerarin, crocin, dihydromyricetin, hesperetin, punicalagin, ginkgetin, flavonol, baicalein, oleuropein, vitexin, delphinidin, glabridin, (2R, 3R, 5S)-2-(6-amino-9H-purin-9-yl)-5-(hydroxymethyl)tetrahydrofuran-3-ol, 9-(3-deoxy-β-D- ribofuranosyl)hypoxanthine, 9-β-D-ribofuranosyladenine, shikonin, cannabidiol, glutathione; wherein the core component and the auxiliary unit are structurally compatible or complementary compounds, the self-assembled carrier is selected from one or more of flavonoid glycosides, terpene glycosides, and derivatives thereof, preferably selected from one or more of RBDS-A, RBDS-B, RBDS-C, STVS, STVN, MGSDT, ASTS, HASTS, NHPD, NHDC, NRGCD; wherein the high molecular polymer is selected from one or more of polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus), copovidone, povidone.

2. The super stable nanocomplex of claim 1, wherein the core component is a phenolic compound selected from one or more of phenolic acids, flavonoids, lignans, coumarins, and tannins, such as one or more of curcumin and / or its derivatives, soy isoflavones, tanshinone, quercetin, dihydroquercetin, myricetin, dihydromyricetin, hesperidin / sin, naringenin / glycoside, neohesperidin, urolithin, resveratrol, chlorogenic acid, puerarin, silymarin, salidroside, vitamins A, B, D, E, K.

3. The ultrastable nanocomplex of claim 1, wherein the core component is one or more of curcumin and its derivatives having the following structure: In the above structure, A and B, B and C are connected by a C-C single bond, wherein: The B group is a seven-carbon chain of the following structure: It has 0-3 C=C double bonds, wherein the substituent groups R1, R3 are independently selected from -H, -OH, -OR6=O, wherein R6 is selected from -CH3, -Et, -Glc; R2 is selected from -H, -CH3, -CH2-CH2-COOEt, -CH2-COOEt, -CH2-CH2-COOH, -CH2-COOH; R4, R5 are independently selected from -H, -OH, when R5 is -OH, R1 is simultaneously -OH, and the two hydroxyl groups are intramolecularly condensed to form a pyran ring; in addition, the keto-enol in the seven-carbon chain structure can also be intramolecularly condensed to form a furan ring; A, C groups are independently selected from phenyl ring, thiophene, furan, preferably phenyl ring, with 0-4 substituents, preferably 0-3, optionally selected from -OH, -OR7, -CH3, -CH2-CH3, -C(CH3)3, -N(CH3)2, -F, -Cl, -Br, -NO2, -CF3, wherein R7is selected from -CH3, -Et, -Glc, -CH2-CH2-O-CH3, Bn, -CH2-CH2-OH, Optionally, the benzene ring of the A, C group is connected by -O-, -CH2-.

4. The super stable nanocomplex of claim 1, wherein the auxiliary unit is selected from one or more of phenolic, flavonoid, terpenoid, organic acid, alkaloid, anthocyanin, proanthocyanidin, lignan, amino acid, nucleoside, polypeptide, quinone, steroid, and vitamin ingredients, wherein the phenolic is selected from one or more of phenolic acid, flavonoid, lignan, coumarin, and tannin; the terpenoid (carotene, carotenoid) is selected from one or more of monoterpene, sesquiterpene, diterpene, sesterterpene, triterpene, tetraterpene, polyterpene, etc.; the alkaloid is selected from one or more of organic amine, pyrrolidine, pyridine, quinoline, quinoline, quinazolone, indole, tropane, imidazolone, purine, steroid, and terpenoid alkaloid; the nucleoside is selected from one or more of (2R,3R,5S)-2-(6-amino-9H-purin-9-yl)-5-(hydroxymethyl)tetrahydrofuran-3-ol, 9-(3'-deoxy-β-D-ribofuranosyl)hypoxanthine, 9-β-D-ribofuranosyladenine, inosine, 9-β-D-2ˊ-deoxyribofuranosyladenine, 9-(2'-deoxy-β-D-ribofuranosyl)hypoxanthine, 2',3'-dideoxyadenosine, 2',3'-dideoxyinosine, 2',3'-didehydro-2',3'-dideoxyinosine, and derivatives thereof (e.g., monophosphate, diphosphate, triphosphate, amide); the lignan is selected from one or more of simple lignan, biphenylcycloocta type lignan, bisepoxy lignan, cyclic lignan, cyclic lignan lactone, lignan lactone, and neolignan; the organic acid is selected from aliphatic organic acid and aromatic organic acid; the quinone compound is selected from one or more of benzoquinone, naphthoquinone, anthraquinone, and phenanthraquinone; the steroid compound is selected from one or more of C 21 steroid, cardiac glycoside, steroidal saponin, phytosterol, insect molting hormone, and bile acid.

5. The ultrastable nanocomplex of claim 1, wherein the auxiliary unit is one or more of quercetin and its derivatives, silymarin and its derivatives, having the following structure: Quercetin and derivatives thereof wherein R7-R11 are independently selected from H, CH3, (CH2) n CH3(n is arbitrarily selected from 1 to 10), -COR12, halogen, haloalkyl, Bn, Glc, wherein R12 is selected from CH3, (CH2) n CH3(n is arbitrarily selected from 1 to 10); Silymarin and derivatives thereof wherein R13to R17are independently selected from H, CH3, (CH2) n CH3(n is arbitrarily selected from 1 to 10), acyl, halogen, haloalkyl, Bn, Glc; D is One of them.

6. The superstable nanocomplex of claim 1, wherein the flavonoid glycoside in the self-assembly carrier is a glycoside having a C6-C3-C6 basic parent nucleus structure with two benzene rings (A ring, C ring) connected to each other through a three-carbon chain; the terpene glycoside is a tetracyclic diterpene glycoside and / or a tetracyclic triterpene glycoside and / or a pentacyclic triterpene glycoside, wherein the tetracyclic diterpene glycoside is preferably a taxadiene type tetracyclic diterpene glycoside, the tetracyclic triterpene glycoside is preferably a cucurbitane type tetracyclic triterpene glycoside, and the pentacyclic triterpene glycoside is preferably an ushane type pentacyclic triterpene glycoside.

7. The ultrastable nanocomplex of claim 6, wherein the flavonoid glycoside is one or more of naringin dihydrochalcone, neohesperidin dihydrochalcone, trilobatin, phloridzin, aspartame, 1-(3-beta-D-glucopyranosyl-2,4,6-trihydroxyphenyl)-3-(4-hydroxyphenyl)-1-propanone, more preferably naringin dihydrochalcone, neohesperidin dihydrochalcone; the kaurene-type tetracyclic diterpene glycoside is one or more of stevioside, rebaudioside A, rebaudioside B and salts thereof, rebaudioside C, rebaudioside D, rebaudioside E, rebaudioside F, rebaudioside M, rebaudioside N, rebaudioside O, dulcoside A, rubusoside, steviolbioside and salts thereof, more preferably rebaudioside A, rebaudioside C, stevioside; the cucurbitane-type triterpene glycoside is one or more of mogroside III, mogroside IV, mogroside V, mogroside IIE, mogroside IIIE, mogroside VI, mogroside A, neo-mogroside, siamenoside I, more preferably mogroside V; the ursane-type pentacyclic triterpene glycoside is (2S,3R,4S,5S,6R)-6-((((2R,3R,4R,5S,6R)-3,4-dihydroxy-6-(hydroxymethyl)-5-(((2S,3R,4R,5R,6S)-3,4,5-trihydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)tetrahydro-2H-pyran-2-yl)oxy)methyl)-3,4,5-trihydroxytetrahydro-2H-pyran-2-yl (1S,2R,4aS,6aS,6bR,8aR,9R,10R,11R,12aR,12bR,14bS)-10,11-dihydroxy 9-(hydroxymethyl)-1,2,6a,6b,9,12a-hexamethyl-1,3,4,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-octadecahydooctaen-4a(2H)-carboxylate (ASTS), (2S,3R,4S,5S,6R)-6-((((2R,3R,4R,5S,6R)-3,4-dihydroxy-6-(hydroxymethyl)-5-(((2S,3R,4R,5R,6S)-3,4,5-trihydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)tetrahydro-2H-pyran-2-yl)oxy)methyl)-3,4,5-trihydroxytetrahydro-2H-pyran-2-yl (1S,2R,4aS,6aR,6bR,8R,8aS,9R,10R,11R,12aR,12bR,14bS)-8,10,11-trihydroxy-9-(hydroxymethyl)-1,2,6a,6b,9,12a-hexamethyl-1,3,4,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-octadecahydooctaen-4a(2H)-carboxylate (HASTS), (2S,3R,4S,5S,6R)-6-((((2R,3R,4R,5S,6R)-3,4-dihydroxy-6-(hydroxymethyl)-5-(((2S,3R,4R,5R,6S)-3,4,5-trihydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)tetrahydro-2H-pyran-2-yl)oxy)methyl)-3,4,5-trihydroxytetrahydro-2H-pyran-2-yl (1S,2R,4aS,6aS,6bR,8aR,9R,10R,11R,12aR,12bR,14bS)-10,11-dihydroxy-9-(hydroxymethyl)-1,2,6a,6b,9,12a-hexamethyl-1,3,4,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-octadecahydooctaen-4a(2H)-carboxylate (ASTS), (2S,3R,4S,5S,6R)-6-((((2R,3R,4R,5S,6R)-3,4-dihydroxy-6-(hydroxymethyl)-5-(((2S,3R,4R,5R,6S)-3,4,5-trihydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)tetrahydro-2H-pyran-2-yl)oxy)methyl)-3,4,5-trihydroxytetrahydro-2H-pyran-2-yl (1S,2R,4aS,6aR,6bR,8R,8aS,9R,10R,11R,12aR,12bR,14bS)-8,10,11-trihydroxy-9-(hydroxymethyl)-1,2,6a,6b,9,12a-hexamethyl-1,3,4,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-octadecahydooctaen-4a(2H)-carboxylate (HASTS), or a salt thereof.3R,4R,5S,6R)-3,4-dihydroxy-6-(hydroxymethyl)-5-(((2S,3R,4R,5R,6S)-3,4,5-trihydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)tetrahydro-2H-pyran-2-yl)oxy)methyl)-3,4,5-trihydroxytetrahydro-2H-pyran-2-yl(4aS,6aS,6bR,8R,8aS,9R,10R, 11R,12aR,12bR,14bS)-8,10,11-trihydroxy-9-(hydroxymethyl)-2,2,6a,6b,9,12a-hexamethyl-1,3,4,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-octadecyl octene-4a(2H)-carboxylic acid ester (ASTS-B), (2S,3R,4S,5S,6R) )-6-((((2R,3R,4R,5S,6R)-3,4-dihydroxy-6-(hydroxymethyl)-5-(((2S,3R,4R,5R,6S)-3,4,5-trihydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)tetrahydro-2H-pyran-2-yl)oxy)methyl)-3,4,5-trihydroxytetrahydro-2H-pyran-2-yl(1S,2R,4aS,6aS,6 bR,8aR,9R,10R,11R,12aR,12bR,14bS)-9-(acetoxymethyl)-10,11-dihydroxy-1,2,6a,6b,9,12a-hexamethyl-1,3,4,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-octadecylhydrooctene-4a(2H)-carboxylic acid ester (ASTS-C) (2S,3R,4S,5S,6R)-6-((((2R,3R,4R,5S,6R)-3,4-dihydroxy-6-(hydroxymethyl)-5-(((2S,3R,4R,5R,6S)-3,4,5-trihydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)tetrahydro-2H-pyran-2-yl)oxy)methyl)-3,4,5-trihydroxytetrahydro-2H-pyran-2-yl(1S,2R,4aS,6aS,6bR,8aR,10R,11R,12aR,12bR,14bS)-10,11-dihydroxy Heptamethyl-1,2,6a,6b,9,9,12a-heptamethyl-1,3,4,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-octadecyl-4a(2H)-carboxylic acid ester (ASTS-D), (2S,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(1S,2R,4aS,6aS,6bR,8aR,9R,10R,11R,12aR,12bR,14bS)-10,11-dihydroxy-9-(hydroxymethyl)-1,2,6a,6b,9,12a-hexamethyl-1,3,4,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-octadecyl octene-4a(2H)-carboxylic acid ester (ASTS-E), (2S,3R,4S,5S,6R)-6-((((2R,3R,4R,5S,6R)-3,4-dihydroxy-6-(hydroxymethyl)-5-(((2S,3R,4R,5R,6S)-3,4,5-trihydroxy-6-methyltetrahydro-2H -pyran-2-yl)oxy)tetrahydro-2H-pyran-2-yl)oxy)methyl)-3,4,5-trihydroxytetrahydro-2H-pyran-2-yl(1S,2R,4aS,6aS,6bR,8aR,9R,10S,12aR,12bR,14bS)-10-hydroxy-9-(hydroxymethyl)-1,2,6a,6b,9,12a-hexamethyl-1,3,4,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-octadecyloctene-4a(2H)-carboxylic acid ester (ASTS-F), (2S,3R,4S,5S,6R)-6-((((2R,3R,4R,5S,6R)-3,4-di Hydroxy-6-(hydroxymethyl)-5-(((2S,3R,4R,5R,6S)-3,4,5-trihydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)tetrahydro-2H-pyran-2-yl)oxy)methyl)-3,4,5-trihydroxytetrahydro-2H-pyran-2-yl(1R,2R,4aS,6aS,6bR,8aR,9R,10R,11R,12aR,12bR,14bS)-10,11-dihydroxy-2,9-bis(hydroxymethyl)-1,6a,6b,9,12a-pentamethyl-1,3,4,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-octadecylhydrooctene-4a( 2H)-carboxylic acid ester (ASTS-G), (1S,2R,4aS,6aS,6bR,8aR,9R,10R,11R,12aR,12bR,14bS)-10,11-dihydroxy-9-(hydroxymethyl)-1,2,6a,6b,9,12a-hexamethyl-1,3,4,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-octadecylhydrooctene-4a(2H)-carboxylic acid (ASTA), (1S,2R,4aS,6aS,6bR,8R,8aS,9R,10R,11R,12aR,12bR,14bS)-8,10,11-trihydroxy-9-(hydroxymethyl)-1,2,6a,6b,9,12a-hexamethyl-1,3,4,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-octadecahydroridane-4a(2H)-carboxylic acid (HASTA), preferably one or more of ASTS, HASTS, ASTA and HASTA.

8. The superstable nanocomplex of claim 1, wherein the high molecular polymer is a polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus), preferably, in the superstable nanocomplex, the core component is curcumin and / or its derivatives, such as CCM or THCCM, and the auxiliary unit is selected from one or more of QCT, QCTN, SLBN, DPND, DMRCT, GKT, VTX, NRG, PURN, GGRNA, 6-SGL, HSPT, SLDS, RVRT, RVRT, DQCT, PCLG, SKN, BCL, CDCP, DOIS, ADNS.

9. The superstable nanocomplex of any one of claims 1-8, wherein the auxiliary unit is used in an amount of 0.1-10 times the amount of the core component by weight; the self-assembly carrier is used in an amount of 1-50 times the amount of the core component; and the high molecular polymer is used in an amount of 2-10 times the amount of the core component.

10. The superstable nanocomplex of any one of claims 1-8, wherein the auxiliary unit is used in an amount of 0.3-3 times the amount of the core component by weight; the self-assembly carrier is used in an amount of 2-5 times the amount of the core component; and the high molecular polymer is used in an amount of 2-5 times the amount of the core component.

11. The ultra-stable nanocomposite as described in any one of claims 1-10, further comprising other active ingredients, including but not limited to ginkgolide extract, tea polyphenol extract, grape seed extract, maca extract, ginseng / leaf / fruit extract, Panax notoginseng root / flower / whole herb extract, Smilax glabra, Cirsium japonicum, Ligustrum lucidum, Cornus officinalis, Achyranthes bidentata, Fritillaria cirrhosa, Ligusticum chuanxiong, deer placenta, deer antler, deer bone, Salvia miltiorrhiza, Acanthopanax senticosus, Schisandra chinensis, Cimicifuga foetida, Asparagus cochinchinensis, Gastrodia elata, Pseudostellaria heterophylla, Morinda officinalis, Aucklandia lappa, Equisetum hyemale, Arctium lappa, Arctium lappa root, Plantago asiatica, Plantago asiatica, Glehnia littoralis, Fritillaria cirrhosa, Scrophularia ningpoensis, Rehmannia glutinosa, Polygonum multiflorum, Bletilla striata, Atractylodes macrocephala, Paeonia lactiflora, Amomum villosum, Haliotis diversicolor, Dendrobium nobile, Lycium chinense root bark, Angelica sinensis, Bambusa textilis, Carthamus tinctorius, Rhodiola rosea, Panax quinquefolius, Evodia rutaecarpa, Achyranthes bidentata, Eucommia ulmoides, Eucommia ulmoides leaf. Astragalus complanatus, Paeonia suffruticosa, Aloe vera, Atractylodes lancea, Psoralea corylifolia, Cotyledon nipponica, Paeonia lactiflora, Polygala tenuifolia, Ophiopogon japonicus, Tortoise shell, Eupatorium fortunei, Platycladus orientalis leaf, Prepared rhubarb, Prepared Polygonum multiflorum, Acanthopanax senticosus, Rosa rugosa fruit, Lycopus lucidus, Alisma plantago-aquatica, Rosa rugosa flower, Roselle, Anemarrhena asphodeloides, Apocynum venetum, Kuding tea, Fagopyrum dibotrys, Rhizoma Cynanchi, Citrus reticulata peel, Magnolia officinalis flower, Curcuma longa, Citrus aurantium, Citrus aurantium fruit, Platycladus orientalis seed, Pearl, Gynostemma pentaphyllum, Trigonella foenum-graecum, Rubia cordifolia, Piper longum, Allium tuberosum Extracts from rapeseed, Polygonum multiflorum vine, Cyperus rotundus, Drynaria fortunei, Codonopsis pilosula, Morus alba root bark, Morus alba twig, Fritillaria thunbergii, Leonurus japonicus, Centella asiatica, Epimedium, Cuscuta chinensis, Chrysanthemum indicum, Ginkgo biloba leaf, Astragalus membranaceus, Fritillaria cirrhosa, Senna leaf, Gecko, Blueberry, Sophora japonica fruit, Typha pollen, Tribulus terrestris, Propolis, Tamarix chinensis, Eclipta prostrata, Rheum palmatum, Ganoderma lucidum, Ganoderma lucidum mycelium, Agaricus blazei, Chaga mushroom, Tiger milk fungus, Phellinus linteus, etc., in one or more combinations.

12. A method for preparing the ultrastable nanocomposite according to any one of claims 1-11, wherein the method is selected from any one of A)-C), wherein method A) comprises: 1) Dissolve the core components and auxiliary units simultaneously or separately in an organic solvent; 2) Dissolve the self-assembling carrier, polymer and / or extract in water; 3) Add solution 1) to solution 2), recover the organic solvent, and obtain the ultrastable nanocomposite; or 4) After adding solution 1) to solution 2), directly spray dry or freeze dry after removing the organic solvent to prepare an ultra-stable nanocomposite powder. Wherein 1) the organic solvent is one or more of methanol, ethanol, acetone, and tetrahydrofuran; Method B) includes: 1) Dissolve the core components, auxiliary units, self-assembly carriers, polymers, or extracts in one or more organic solvents containing 0-50% water; 2) The solution 1) is evaporated under reduced pressure or spray-dried, and then vacuum-dried to prepare self-assembled nanoparticle powder. Wherein 1) the organic solvent is one or more of methanol, ethanol, acetone, tetrahydrofuran, and dichloromethane; Method C includes: 1) Dissolve the core ingredients in an organic solvent; 2) Dissolve the self-assembly carrier, polymer, and auxiliary units in water or an aqueous alcohol solution; 3) Add solution 1) to solution 2) and recover the organic solvent to obtain the nanocomposite intermediate solution; 4) adding the water-soluble extract directly into the nanocomposite intermediate solution to make it completely dissolved; or dissolving the water-soluble extract in water first, then adding it into the nanocomposite intermediate solution, recovering the supernatant to obtain the ultra-stable nanocomposite solution; wherein 1) the organic solvent is one or more of methanol, ethanol, acetone, tetrahydrofuran, dichloromethane.

13. A product or composition containing the ultra-stable nanocomposite of any one of claims 1-11 or the ultra-stable nanocomposite prepared by the method of claim 12.

14. The product or composition of claim 13, wherein: 1) the product or composition is an ultra-stable nanocomposite preparation, which is preferably administered orally, mucosally, or topically, and optionally, in a dosage form selected from one of a tablet, a capsule, a granule, a powder, a solution, a gel, an eye drop, a nose drop, an ear drop, a cream, a tincture, a spray; for use in diabetes, kidney disease (including kidney failure, kidney injury, nephritis, kidney cyst), liver disease (including liver injury, non-alcoholic / alcoholic fatty liver, liver cancer, liver cyst, liver fibrosis, hepatitis), thyroid cyst, thyroid nodule, intestinal polyp, ovarian cyst, hypertension, hyperlipidemia, myocardial infarction, insomnia, stroke, neurodegenerative disease (including epilepsy, Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis), lung and airway disease (including lung cancer, pneumonia, pulmonary fibrosis, lung nodule, chronic obstructive pulmonary disease, pulmonary hypertension, tracheitis, bronchitis), eye disease (including dry eye, conjunctivitis, uveitis, keratitis, scleritis, glaucoma, cataract, macular degeneration); 2) the product or composition is an ultra-stable nanocomposite food, which is preferably one of a beverage, a confectionery product, a dairy product, an alcoholic beverage, a table condiment; 3) the product or composition is an ultra-stable nanocomposite care product, which is preferably one of a cream, an emulsion, an aqueous agent, a gel, an oil agent, a powder, a block powder or solid, a mud, an aerosol, a patch, a film, optionally for use on any part of the face, body, hair, hand, foot, and optionally having one or more of the effects of emollient, moisturizing, desensitizing, anti-aging, whitening, acne-removing, acne-removing, scar repair, tattoo removal, wrinkle-removing, red blood cell-removing, rose spot-removing, sunscreen, body fragrance, hair washing and conditioning, dandruff-removing; optionally used directly or in combination with a delivery device (such as a skin delivery device, a beauty and hair care device).

15. Use of the ultra-stable nanocomposite of any one of claims 1-11 or the ultra-stable nanocomposite prepared by the method of claim 12 in the preparation of a food / health product / auxiliary therapeutic or therapeutic drug, a dietary supplement, a cosmetic, a medical aesthetic product, a human / animal care product, a plant regulator, a medical diagnostic reagent.

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