Supramolecular nanocomposite

Abstract

Disclosed is a supramolecular nanocomposite, comprising an active ingredient, a carrier, and a penetration enhancer, wherein the penetration enhancer is composed of an anionic glycolipid and a glycoside derivative. The supramolecular nanocomposite intermediate is prepared into a supramolecular nanocomposite (ophthalmic) preparation by adding an osmotic pressure regulator, a gel carrier, an in-situ gel carrier, or a gel initiator, a pH regulator, a thickener, a bacteriostatic agent, water for injection, and the like. Compared with the prior art, the supramolecular nanocomposite can achieve a higher drug loading capacity, stronger penetrability, high affinity, long-lasting efficacy, and low irritation, such that the medication safety and efficacy are improved for patients.

Description

Supramolecular nanocomplexes Technical Field

[0001] The present invention relates to the field of medical technology, and in particular to a supramolecular nanocomposite, and its preparation and use. Background Art

[0002] Approximately 2.2 billion people worldwide suffer from vision impairment and blindness due to eye diseases such as age-related macular degeneration, glaucoma, diabetic retinopathy, dry eye, and bacterial infections such as conjunctivitis and trachoma. Eye drops, as an ocular drug delivery platform, can avoid the systemic toxicity caused by systemic administration and are more easily accepted by patients compared to methods such as intravitreal injections and implants. Eye drops account for 90% of the global ophthalmic drug market. However, the delivery of ophthalmic drugs to treat anterior chamber diseases has the following challenges:

[0003] (1) Due to the special physiological barriers and clearance pathways of the eye, the number of drugs that can reach the target tissue and produce positive effects after topical administration is very limited (bioavailability is less than 5%).

[0004] (2) The volume of the conjunctival sac of the human eye is only 7 μL under normal conditions. After a drop of eye solution is instilled, the volume of the tear film sac can quickly expand to 30 μL, of which tears account for 7 to 9 μL, and can accommodate an additional 20 μL of solution (about 1 / 2 drop).

[0005] (3) Limited by the inability of existing delivery technologies to address the pain point of low drug loading for hydrophobic drugs, approximately 80% to 90% of marketed eye drops require patients to use 1-2 drops at a time in their instructions because the drug loading cannot be further increased. Even many suspension eye drops for hydrophobic drugs require patients to shake thoroughly before use. This makes it impossible to guarantee the dosage and it is also impossible to ensure that the shaking force and frequency are consistent for each patient.

[0006] (4) The presence of conjunctival structural and enzyme barriers limits the uptake of drugs into the conjunctiva. The cornea is limited in its absorption of both hydrophilic and hydrophobic drugs due to the presence of hydrophilic (such as the stroma) and hydrophobic layers (such as the epithelium and endothelium). The blink reflex, efflux transporters, and drug binding to conjunctival mucins, tear proteins, and melanin are the main bottlenecks that contribute to the low bioavailability of topical eye drops.

[0007] (5) The disease itself causes the physiological barrier function of the eye to become more significant.

[0008] To address the above challenges, delivery technologies such as lipid-based microemulsions, self-microemulsions, polymer micelles, gels, in situ gels, nanoparticles, liposomes, prodrugs, and cyclodextrin inclusion have been applied to eye drop products in an attempt to increase drug loading, prolong the duration of action at the absorption site, increase corneal permeability, and overcome the effects of efflux transporters. For example, Macromol Biosci. 2017 Dec; 17(12), AAPS PharmSciTech (2021) 22: 107, Drug Discovery Today, Vol. 00, Num. 00, April 2016, these documents all show that in situ gel can prolong the residence of drugs at the delivery site and achieve a sustained release effect, but it will cause blurred vision, sudden drug release, etc.; gel administration can prolong the residence time of drugs on the ocular surface and achieve a certain degree of sustained release, but it will make patients feel eye discomfort and hinder oxygen permeation; polymer micelles can increase corneal penetration and even penetration of the posterior segment of the eye, but ocular surface toxicity and micelle stability are still the biggest challenges; liposomes can increase the accumulation of drugs in the cornea and achieve a certain sustained release effect, but the difficulty of large-scale production and low drug loading (less than 8%) are the biggest bottlenecks; lipid nanoparticles can improve permeability and enhance drug absorption, but batch expansion and physical stability are the biggest limitations. Cyclodextrin inclusion technology has been successfully applied in many injectable drug delivery systems to improve the solubility of hydrophobic drugs. However, due to the high polarity of the cyclodextrin surface, it can solve the solubility problem of some hydrophobic drugs when used for ocular delivery, but it has little effect on improving delivery efficiency and prolonging residence time.

[0009] In summary, nanotechnology can improve the solubility of certain hydrophobic drugs, enabling sustained release, reducing toxicity, enhancing efficacy, prolonging drug residence time, and enhancing drug penetration through the ocular barrier. However, to date, no ocular nanodelivery technology can simultaneously address the bottlenecks of high efficiency, sustained release, targeted, safe delivery, and ease of industrialization, addressing the current significant unmet clinical therapeutic needs globally.

[0010] Therefore, there is an urgent need to develop a nano-ophthalmic preparation with eye targeting, long eye retention time, low irritation, high drug loading and high absorption efficiency in clinical practice.

[0011] Summary of the Invention

[0012] In order to solve the problems existing in the existing delivery systems of ophthalmic preparations, the inventors conducted a large number of experiments, solved the problems, obtained unexpected results, and thus completed the present invention.

[0013] Specifically, the present invention provides the following technical solutions:

[0014] A supramolecular nanocomposite, characterized in that the supramolecular nanocomposite comprises an active ingredient, a carrier, and a penetration enhancer, wherein:

[0015] The penetration enhancer comprises anionic glycolipid and / or its salt (sodium salt, potassium salt, ammonium salt, quaternary ammonium salt, calcium salt, magnesium salt or a combination thereof), and cationic glycoside derivative, or consists of anionic glycolipid and / or its salt (sodium salt, potassium salt, ammonium salt, quaternary ammonium salt, calcium salt, magnesium salt or a combination thereof), and cationic glycoside derivative;

[0016] The carrier is composed of a covalently linked unit A and a unit B, wherein the unit A is located on one side or both sides of the unit B. When the unit A is located on both sides of the unit B, the units A may be the same or different; wherein the number ratio of the units A to the units B is (0:1)-(7:1), wherein the units B are selected from one or more of B1, or one or more of B2, wherein:

[0017] (1) B1 is a compound represented by the molecular formula (C5H8)n, and its alcohol, aldehyde, ketone, carboxylic acid or ester derivatives, wherein n=4 or 6;

[0018] (2) B2, a compound composed of two benzene rings (A-ring and B-ring) connected to each other by a central three-carbon chain, with 2-phenylchromone as the basic mother core, and having a basic skeleton of C6-C3-C6 and its derivatives (such as halides or amino acid esters, the halides are such as chlorine or fluorine, and the amino acid esters are such as esters formed by the hydroxyl group on C6 and amino acids).

[0019] The active ingredient is selected from one or more of the following categories, or salts, hydrates, solvates or combinations thereof: immunosuppressants such as cyclosporine, flucyclosporine, tacrolimus, sirolimus, everolimus, mycophenolate mofetil, mycophenolic acid and fingolimod; glucocorticoids such as hydrocortisone, prednisone acetate, cortisone acetate, loteprednol, methylprednisolone, fluorometholone, dexamethasone, dexamethasone sodium phosphate, prednisone sodium phosphate, triamcinolone, triamcinolone acetonide, fluocinolone acetonide, difluprednate; anti-infective drugs such as cefazolin, ceftriaxone, ceftazidime, rimexolone, chloramphenicol, tobramycin, natamycin, neomycin chlortetracycline, erythromycin, chlortetracycline, azithromycin, moxifloxacin, besifloxacin, ciprofloxacin, ofloxacin, levofloxacin, gatifloxacin, gentamicin, amikacin, penicillin G, kanamycin, methicillin, piperacillin, vancomycin, clindamycin, lincomycin, amphotericin B methyl ethyl ester, lincomycin, netilmicin, oxacillin, teicoplanin, clarithromycin, sulfamethoxazole sodium, potentiated sulfamethoxazole, amphotericin B, clotrimazole, econazole, miconazole, posaconazole, flucytosine, linezolid, tazobactam, imipenem, voriconazole, itraconazole, vorconazole, ketoconazole, caspofungin, micarbazine fungine, terbinafine, polymyxin, spiramycin, tetracycline, acetylspiramycin; prostaglandin analogs such as latanoprost, bimatoprost, travoprost, tafluprost, (Z)-7-[(1R, 2R, 3R, 5S)-3,5-dihydroxy-2-(3-oxodecanyl)cyclopentyl]hept-5-enoic acid (Unoprostone) and latanoprost nitrate; nonsteroidal anti-inflammatory drugs such as pranoprofen, diclofenac, meloxicam, indomethacin, ketorolac, flurbiprofen, flurbiprofen axetil and bromfenac; carbonic anhydrase inhibitors such as acetazolamide, methazolamide, dichlorobenzene disulfonamide, naphthalene; Pafenac, brinzolamide, and dorzolamide; beta-adrenergic antagonists such as carteolol, levobunolol, metipranolol, timolol, and betaxolol; alpha-adrenergic antagonists such as alaclonidine and brimonidine; Rho kinase inhibitors such as nafiladil and alprostadil; HMG-CoA reductase inhibitors such as atorvastatin, rosuvastatin, simvastatin, pravastatin, lovastatin, cerivastatin, and mevastatin; visual cycle inhibitors such as (1R)-3-amino-1-[3-(cyclohexylmethoxy)phenyl]propan-1-ol; levodopa; glatiramer acetate; tandospirone; trimetazidine;Vaseline lutein and its esters, zeaxanthin, folic acid, homocysteine, curcumin, B vitamins, K vitamins, A vitamins, E vitamins, ginkgo flavonoids and lactones, crocin, crocetin, VEGFR inhibitors such as bruceizumab, ranibizumab, conbercept, bevacizumab, 2-(6,7-dimethoxyquinazolin-4-yl)amino-5-methyl-1,3,4-thiadiazole, anlotinib, cabozantinib, voronib, brivanib, 5-((6-aminopyrimidin-4-yl)oxy)-N-(3-(trifluoromethyl)phenyl)-1H-indole-1-carboxamide, (Z)-3-(2,4-dihydroxybenzylidene)indole-2-yl -ketone, semaxanib, (E)-2-cyano-3-[4-hydroxy-3,5-di(propan-2-yl)phenyl]-N-(3-phenylpropyl)prop-2-enamide, apatinib, regorafenib, albendazole, axitinib, E)-1-ethyl-3-methyl-N-(3-(3-(2-(pyridin-2-yl)vinyl)-1H-indazole-6-carbonyl)phenyl)-1H-pyrazole-5-carboxamide, (E)-N-(3-(3-(2-(pyridin-2-yl)vinyl)-1H-indazole-6-carbonyl)phenyl)benzamide, pazopanib, (3aR,7S,8aS)-7-methyl-3-methylene-6-[(E)-3 -oxobut-1-enyl]-4,7,8,8a-tetrahydro-3aH-cyclohepta[b]furan-2-one, purpurogenol, 3-(2-((3,4-dihydroxyphenyl)(4-(2-(dimethylamino)ethyl)-1H-imidazol-1-yl)methyl)benzo[d][1,3]dioxolan-5-yl)propionic acid, quercetin, dihydroartemisinin, 4-chloro-3-[5-methyl-3-[4-(2-pyrrolidin-1-ethoxy)anilino]-1,2,4-benzotriazine-7-yl]phenol, [4-chloro-3-[5-methyl-3-[4-(2-pyrrolidin-1-ethoxy)anilino]-1,2,4-benzotriazine-7-yl]phenol 7-aminobenzoic acid esters; intercellular adhesion molecule inhibitors, such as lifestin; fenretinide; antiviral drugs, such as acyclovir and ganciclovir; antihistamines, such as azelastine, desmethylazelastine, levocabastine, pemirolast potassium, and emedastine; ocular anesthetics, such as proparacaine, oxybuprocaine, proancaine, mepivacaine, bupivacaine, levobupivacaine, ropivacaine, etidocaine, tetracaine, and lidocaine; anticholinergics and cholinergic agonists, such as pilocarpine, carbachol, cyclopentolate, tropicamide, cyclopentolate, pirenzepine, anisodamine, atropine, and eucatropine; mast cell stabilizers, such as lodoxamide, olopatadine, and sodium glycinate;Epinephrine, phenylephrine, cannabidiol and its derivatives, macitentan, aproracetam, bosentan, ambrisentan, pirenoxine, sildenafil, methylcobalamin, vitamin B12, aminoiodine, fluorescein sodium, ursodeoxycholic acid, danshensu, dinggongtengsu, puerarin, arecoline, fenretinide, etc.

[0020] The anionic glycolipid is composed of a hydrophilic sugar residue and a saturated or unsaturated hydrophobic fatty acid with different carbon chain lengths through a covalent bond. The hydrophilic sugar residue is selected from one or more of rhamnose, sophorose, trehalose, and mannitol. The preferred sugar residue is rhamnose or a disaccharide or trisaccharide containing rhamnose. When the sugar residue is rhamnose, the anionic glycolipid is a combination of one or more rhamnolipids. The chemical structure of the rhamnolipid (denoted as: Rha-L) is as follows:

[0021] Formula I

[0022] Wherein R1, R2, and R3 are selected from the following groups:

[0023] Preferably, the carbon chain length of R3 is C6 to C14, and the number of unsaturated double bonds is 0, 1, 2, or 3. Preferably, the carbon chain length of R3 is C8 to C12, and the number of unsaturated double bonds is 0, 1, or 2.

[0024] Rhamnolipids are preferably Rha-C10, Rha-C10:2, Rha-C10-C10, Rha-Rha-C10, Rha-Rha-C10-C10, Rha-C8, Rha-C8-C8, Rha-Rha-C8 , Rha-Rha-C8-C8, Rha-C12, Rha-C12-C12, Rha-Rha-C12, Rha-Rha-C12-C12, Rha-C10-C12, Rha-C10-C8, Rha-C8- A combination of one or more of the following: C12, Rha-C8-C10, Rha-C12-C10, Rha-C12-C8, Rha-Rha-C10-C12, Rha-Rha-C10-C8, Rha-Rha-C8-C12, Rha-Rha-C8-C10, Rha-Rha-C12-C10, Rha-Rha-C12-C8, Rha-Rha-C10-C12:1, Rha-C10-C12:1, and Rha-Rha-C10:2. (Note: C8, C10, and C12 represent saturated or unsaturated fatty acids with 8, 10, and 12 carbon atoms, respectively).

[0025] The structure of the cationic glycoside derivative is shown in Formula II:

[0026] Wherein R1 can be selected from polymers, such as polydopamine, polyarginine amide or polyglutamic acid; R1 can also be selected from amino acid residues, such as arginine, histidine, lysine or aminoamide (aminoamide is selected from the aminoamide corresponding to the amino acid); R1 can be selected from a short peptide composed of 2-20 amino acids with a positive charge under physiological conditions, preferably a cell-penetrating peptide (CPP), and the preferred cell-penetrating peptide is octaarginine cell-penetrating peptide;

[0027] When R2 is a sugar residue, R2 can be one of a monosaccharide, a disaccharide, an oligosaccharide, or a polysaccharide, preferably a D-type or L-type monosaccharide, a disaccharide, a trisaccharide, or a combination thereof, wherein the monosaccharide is selected from the group consisting of glucose, rhamnose / alcohol, galactose / alcohol, arabinose, xylose / alcohol, mannose / alcohol, fucose, celery sugar, glucuronic acid, glucosamine, galacturonic acid, acetylamino sugar, or a combination thereof, and the relative configuration of each glycosyl terminal carbon can be α-type or β-type; the disaccharide is selected from the group consisting of sophorose (glc1-2glc), gentiobiose (glC1-6glc), rutinose (rha1-6glc), neohesperidose (rha1-6glC), sophorobiose (rha1-6gal), or a combination thereof; the trisaccharide is selected from the group consisting of gentiotriose, sophorotriose (glc1-2glc1-2glc), or a combination thereof.

[0028] Preferably, the number of R2 sugar residues is ≤3, and preferably R2 has the following structure:

[0029] The glycoside derivative carries ≥1 positive charge under physiological conditions, and preferably the cationic glycoside derivative carries ≥2 positive charges at pH 5.0 to 8.5.

[0030] When unit A of the carrier is a monosaccharide, it is selected from the group consisting of glucose, rhamnose, galactose, arabinose, xylose, mannose, fucose, phlorose, glucuronic acid, glucosidase, glucosamine, galacturonic acid, acetylamino sugar or a combination thereof, and the relative configuration of the terminal carbon of each glycosyl group can be α-type or β-type; when unit A is a disaccharide, it is selected from the group consisting of sophorose (glc1-2glc), gentiobiose (glC1-6glc), rutinose (rha1-6glc), neohesperidose (rha1-6glC), sophorobiose (rha1-6gal) or a combination thereof; when unit A is a trisaccharide, it is selected from the group consisting of gentiotriose, sophorotriose (glc1-2glc1-2glc) or a combination thereof; the unit A can also be an acylated product of a monosaccharide, a disaccharide or a trisaccharide, such as 2-acetylglucose and caffeoyl glucose.

[0031] Unit B1 of the carrier is a tetracyclic diterpene, a tetracyclic triterpene, a pentacyclic triterpene, or one or more of their alcohol, aldehyde, ketone, carboxylic acid or ester derivatives, wherein the tetracyclic diterpene and its derivatives are of kaurene type; the tetracyclic triterpene and its derivatives are dammarane type, gansuane type, cycloartane type, lanolin type, cucurbitane type, melilotin type and prototerpene type, preferably of cucurbitane type; the pentacyclic triterpene and its derivatives are oleanane type, ursane type, lupeane type, suberane type, hobeane type and isohobeane type, preferably of oleanane type.

[0032] Preferred carriers of kaurene-type tetracyclic diterpenes, cucurbitane-type tetracyclic triterpenes, oleanane-type pentacyclic triterpenes and their derivatives can be described as follows:

[0033] When the kaurene-type tetracyclic diterpene or a pharmaceutically acceptable salt thereof (such as a sodium salt, potassium salt, ammonium salt), or a hydrate of a kaurene-type tetracyclic diterpene or a pharmaceutically acceptable salt thereof (such as a hydrate formed with 0.5, 1, 1.5, 2, 2.5 or 3 crystal waters), the delivery vector has a structure of Formula III;

[0034] R1 and R2 may be the same or different, and R1 and R2 are selected from the following groups:

[0035] When unit B1 is a cucurbitane-type tetracyclic triterpene or a pharmaceutically acceptable hydrate or solvate thereof, the delivery vector has a structure of formula IV:

[0036] Wherein R1, R2, R3, and R4 are selected from the following groups:

[0037] When unit B1 is an oleanane-type pentacyclic triterpene or a pharmaceutically acceptable hydrate or solvate thereof, the delivery vector has a structure of Formula V:

[0038] Wherein R1 and R2 are selected from the following groups:

[0039] The carrier B2 is a flavonoid glycoside compound, the aglycone of which is flavonoid, flavanone, 8-isopentenyl flavonoid, chalcone, dihydrochalcone and its derivatives (alcohol, aldehyde, ketone, methylation, carboxylic acid or ester), preferably dihydrochalcone and flavanone.

[0040] When the flavonoid glycoside or hydrate or solvate of the flavonoid glycoside compound with flavanone or dihydrochalcone as aglycone is used, the carrier has the structure of structural formula a or b in the following table.

[0041] The flavanone-type flavonoid glycosides and derivatives are selected from neohesperidin, hesperidin, and naringin; the dihydrochalcone flavonoid glycosides are selected from naringin dihydrochalcone and neohesperidin dihydrochalcone; or a combination thereof.

[0042] The supramolecular nanocomplex is characterized in that the amount of the anionic glycolipid and / or its salt is 0.01%-5% (w / v), the amount of the cationic glycoside derivative is 0.1%-10% (w / v), and the amount of the carrier is 0.1%-15% (w / v).

[0043] The supramolecular nanocomplex may also contain high molecular polymers such as chitosan, hyaluronic acid, sodium carboxymethyl cellulose, hydroxypropyl methyl cellulose, povidone, copovidone, hydroxypropyl methyl cellulose acetate succinate, polyethylene caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, polyethylene glycol, polyoxyethylene, polyacrylamide, One or more of polyvinyl alcohol, polyethyleneimine, polylactide-co-glycolide, polyglutamic acid, polyarginine, polydopamine, polylactic acid, poly-L-lactic acid, polylactic acid-co-glycolic acid, sodium polyacrylate, siRNA and derivatives (such as derivatives containing alkyl chains that improve lipophilicity), mRNA and derivatives (such as derivatives containing alkyl chains that improve lipophilicity) or antisense oligonucleotides and derivatives (such as derivatives containing alkyl chains that improve lipophilicity), preferably one or more of hydroxypropyl methylcellulose (HPMC), povidone (PVP), copovidone, hydroxypropyl methylcellulose acetate succinate (HPMCAS), polyethylene caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus), and hyaluronic acid (HA).

[0044] In some embodiments, the supramolecular nanocomplex and / or the supramolecular nanocomplex nanoformulation comprising the supramolecular nanocomplex may further contain a surfactant, preferably one or more of polysorbates, polyoxyethylene hydrogenated castor oils, polyoxyethylene castor oils, polyethylene glycol-15 hydroxystearate, polyoxyl stearate, sodium lauryl sulfate, vitamin E polyethylene glycol succinate and retinol ester surfactants.

[0045] The supramolecular nanocomplex is characterized in that the effective particle size range of the supramolecular nanocomplex detected by DLS method is: 5nm≤effective particle size (Effective Diameter)≤200nm, preferably 10nm≤effective particle size≤150nm.

[0046] The supramolecular nanocomposite is characterized in that the zeta potential range of the supramolecular nanocomposite is: -30mV≤Zeta potential≤50mV, preferably -20mV≤Zeta potential≤40mV.

[0047] In some embodiments, the supramolecular nanocomplex preparation comprising the supramolecular nanocomplex is characterized in that the preparation further comprises conventional excipients, such as one or more of a pH regulator, an osmotic pressure regulator, a thickener, a gel carrier, an in situ gel carrier, and an antibacterial agent. Alternatively, the preparation may be directly diluted with artificial tears.

[0048] The pH regulator is hydrochloric acid, acetic acid, citric acid, tartaric acid, succinic acid, arginine, lysine, taurine, nicotinic acid, nicotinamide, histidine, tryptophan, malic acid, lactic acid, ascorbic acid, phosphoric acid, adipic acid, fumaric acid, sulfuric acid, nitric acid, p-toluenesulfonic acid, boric acid, sodium hydroxide, sodium citrate, potassium citrate, monosodium citrate, sodium lactate, calcium hydroxide, potassium hydroxide, sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, tromethamine, meglumine, sodium phosphate, disodium hydrogen phosphate, sodium dihydrogen phosphate, potassium phosphate, phosphoric acid The osmotic pressure regulator is selected from one or more of dipotassium hydrogen, potassium dihydrogen phosphate, sodium acetate or potassium acetate; the osmotic pressure regulator is selected from glycerol, mannitol, propylene glycol, sodium chloride, potassium chloride, glucose, calcium chloride, sodium bicarbonate, sodium carbonate, sodium lactate, borax or a combination thereof; the thickener is selected from povidone, cellulose derivatives, sodium hyaluronate, polyvinyl alcohol, xanthan gum, gum arabic and any combination thereof; the antibacterial agent is at least one of benzyl alcohol, chlorobutanol, parabens, benzethonium chloride, benzalkonium chloride, benzalkonium bromide and cetaxel chloride.

[0049] The supramolecular nanocomposite preparation is characterized in that the pH range of the ophthalmic preparation is 4.0-8.0.

[0050] The supramolecular nanocomposite preparation is characterized in that the ophthalmic preparation is packaged in single doses or multiple doses.

[0051] The supramolecular nanocomplex can be added with different excipients according to actual needs to prepare dosage forms such as eye drops, drug-loaded contact lenses, gel or in-situ gel, and nanoemulsion.

[0052] In some embodiments, the present invention relates to the use of the supramolecular nanocomposite formulation in the diagnosis, treatment, or adjuvant treatment and / or prevention of (preferably ophthalmic) diseases. Preferably, the ophthalmic disease is selected from conjunctivitis, keratitis, dry eye, age-related macular degeneration, seasonal keratoconjunctivitis, corneal transplant rejection, glaucoma, diabetic retinopathy, cataract, uveitis, etc.

[0053] definition

[0054] Supramolecular nanocomplex: a nanoscale complex formed by the assembly of two or more substances through intermolecular non-covalent interactions.

[0055] Visual cycle inhibitors: The vitamin A derivative 11-cis-retinal is a key component of the phototransduction cascade. After dietary vitamin A (all-trans retinol) is absorbed into the bloodstream, it enters the retinal pigment epithelium and is converted into 11-cis-retinal. The visual cycle is a complex process, centered on the regeneration of 11-cis-retinal from all-trans retinal produced in the phototransduction cascade. Substances or drugs that inhibit this process are called visual cycle inhibitors. Examples include (1R)-3-amino-1-[3-(cyclohexylmethoxy)phenyl]propan-1-ol; levodopa; glatiramer acetate; tandospirone; and trimetazidine. Beneficial effects

[0056] The preparation of the present invention, preferably an ophthalmic preparation, has low irritation to human eyes, rapid onset of action, high main drug concentration, long retention time, can pass through multiple physiological barriers, has high permeability, and is easy to industrialize. BRIEF DESCRIPTION OF THE DRAWINGS

[0057] Figure 1 Particle size diagram of F1 supramolecular nanocomplex.

[0058] Figure 2 Particle size diagram of F4 supramolecular nanocomplex.

[0059] Figure 3 Particle size diagram of F6 supramolecular nanocomplex.

[0060] Figure 4 Particle size of F6 supramolecular nanocomplex after dilution of simulated tear fluid.

[0061] Figure 5 Particle size diagram of F11 supramolecular nanocomplex.

[0062] Figure 6 Particle size of F11 supramolecular nanocomplex after freeze-drying and reconstitution.

[0063] Figure 7 Corneal penetration rate-median time curves of supramolecular nanocomplexes with different formulations.

[0064] FIG8A Drug concentration in ocular tissue of F9 supramolecular nanocomplex eye drops (n=3).

[0065] FIG8B Drug concentration in ocular tissue of F38-formulated supramolecular nanocomplex eye drops (n=3).

[0066] FIG9 is a mass spectrum of the compound STVB-CPP-Arg8 obtained in Example 8 under LC-MS / MS positive and negative ion modes;

[0067] Figure 10 shows the compound STVB-CPP-Arg8 obtained in Example 8 1H-NMR spectrum;

[0068] FIG11 is a mass spectrum of the compound STL-CPP-Arg2 obtained in Example 9 under LC-MS / MS positive ion mode;

[0069] Figure 12 shows the compound STL-CPP-Arg2 obtained in Example 9 1 H-NMR spectrum;

[0070] FIG13 is a mass spectrum of the compound STL-CPP-Arg4 obtained in Example 10 under LC-MS / MS positive ion mode;

[0071] Figure 14 shows the compound STL-CPP-Arg4 obtained in Example 10 1 H-NMR spectrum; DETAILED DESCRIPTION

[0072] In order to make the objectives, technical solutions and advantages of the present invention more clearly understood, the present invention is further described in detail below in conjunction with specific embodiments and with reference to the accompanying drawings.

[0073] The present inventors determined the technical solution of the present invention through extensive testing, screening, and verification during the research process. To illustrate the features and advantages of the present invention, the Examples provide some experimental examples as illustrative examples, but the present invention is not limited to the Examples. The materials and reagents used in the Examples are all common commercially available products.

[0074] To further illustrate the present invention, the supplier information of the target delivery substance (also referred to as active ingredient in the present invention), carrier, high molecular weight polymer, and conventional pharmaceutical excipients used in the supramolecular nanocomplex provided by the present invention is summarized as follows in conjunction with the examples:

[0075] The raw materials, auxiliary materials, reagents and solvents such as the carrier, high molecular polymer and pH adjuster used in the present invention are not particularly limited, and commercially available conventional raw materials, auxiliary materials, reagents and solvents can be used.

[0076] Cyclosporine A, tacrolimus, fluorometholone, hydrocortisone acetate, dexamethasone, sirolimus, acetylspiramycin, rosuvastatin, cannabidiol, vitamin K1 and rhamnolipid are all commercially available products.

[0077] The code abbreviations or product models of the carriers, high molecular polymers, and surfactants cited in the comparative examples, embodiments, and experimental examples are as follows:

[0078] (1) Carrier:

[0079] Stevioside (STVB), Rebaudioside B (RBDS-B), Rebaudioside C (RBDS-C), Stevioside, Rebaudioside A (RBDS-A), Neohesperidin (NHPD), Neohesperidin Dihydrochalcone (NHDC), Naringin Dihydrochalcone (NRGDC), Glycyrrhizic Acid (GA), Mogroside V (MGSD-V), 11-Oxomogroside V (OMGSD-V), Siamenoside I (SMSD-I), Mogroside 1E1 1E1, MGSD-IE1, and MGSDT (a combination of MGSD-V, OMGSD-V, SMSD-I, and MGSD-IE1);

[0080] (2) High molecular weight polymers: polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus), hydroxypropyl methylcellulose (HPMC), polyvinyl pyrrolidone (PVP), polyethylene glycol (PEG), hydroxypropyl methylcellulose acetate succinate (HPMCAS), hyaluronic acid (HA), copovidone (PVP VA64), etc.

[0081] (3) Surfactants:

[0082] Polyoxyethylene castor oil (such as: EL35), vitamin E polyethylene glycol succinate (TPGS), polyoxyl stearate (40) esters (PSE 40), sodium lauryl sulfate (SDS).

[0083] The chemical names, structural formulas and codes of the glycoside derivatives used in the present invention are shown in Table 1 below:

[0084] Table 1. Chemical name, chemical structure and code of glycoside derivatives

[0085] The MGSDT used in the examples represents a commercially available mogroside (MGSD) extract, the main components of which are 73.2% MGSD-V, 11.4% OMGSD-V, 7.1% MGSD-IE1, and 3.9% SMSD-I.

[0086] The assay method used in the present invention is:

[0087] (1) Nanoparticle size, Polydispersity Index (PDI):

[0088] The particle size was determined using a NanoBrook (model: 90Plus PALS) nanoparticle size analyzer. Dynamic light scattering was used at room temperature (25°C) and a diffraction angle of 90°. Prior to measurement, the supramolecular nanocomplex solution was diluted to 100 μg / mL, 50 μl of which was dispersed in 1 mL of deionized water. Ultrasonication was performed to homogenize the dispersion, and the measurement was immediately performed. The measurement time was set to 2 minutes, and each sample was repeated three times.

[0089] (2) Zeta potential determination:

[0090] Measurements were performed at room temperature (25°C) with the zeta potential diffraction angle set at 15°C. Prior to measurement, the supramolecular nanocomplex solution was diluted to 100 μg / mL. 50 μl of the solution was dispersed in 1 mL of phosphate buffer at different pH values ​​(6.0, 7.0, 7.4, and 8.0) for measurement. Three replicates were performed for each sample. 1 mM phosphate buffer was prepared with ultrapure water and the pH was adjusted with 0.1 N hydrochloric acid or sodium hydroxide solution. The sample should be transparent; concentrated samples can be centrifuged and the supernatant collected.

[0091] (3) Determination of active ingredient content:

[0092] The content of each active ingredient was determined by high-performance liquid chromatography (HPLC) using the external standard method. Fluorometholone and bromfenac sodium were assayed using the methods specified in the United States Pharmacopoeia and the Japanese Pharmacopoeia, respectively. Prednisolone acetate, meloxicam, hydrocortisone acetate, acetylspiramycin, dexamethasone, and tobramycin were assayed using the methods specified in the monographs of Part II of the Chinese Pharmacopoeia. Other active ingredients were assayed using a company-developed liquid chromatography method. The chromatographic conditions for this method are shown in Table 2 below.

[0093] Table 2. Active ingredient content determination method

[0094] (4) Detection method of active ingredients in ocular tissue samples after administration

[0095] The quantitative detection of cyclosporine in biological samples was performed using a Waters Xevo TQ-S triple quadrupole mass spectrometer. The liquid chromatography and mass spectrometry detection conditions are shown in Table 3 below:

[0096] Table 3. Quantitative detection methods for cyclosporine in biological samples

[0097] (5) The composition analysis of the rhamnolipid used in the present invention was performed by high performance liquid chromatography-single quadrupole mass spectrometry for content determination, and the content was calculated using the TIC spectrum in negative ion mode. The content of the rhamnolipid used was 96.7% (including Rha-Rha-C10-C10, 29.1%, Rha-C10-C10, 15.0%, Rha-Rha-C10-C12, 12.3%, Rha-Rha-C10, 15.4%, and other rhamnolipids, 24.9%).

[0098] (6) Quantitative detection of tacrolimus in biological samples

[0099] A Waters Xevo TQ-S triple quadrupole mass spectrometer coupled to a Waters H-Class UPLC liquid chromatography-mass spectrometry system was used for detection. The liquid chromatography and mass spectrometry detection conditions were as follows:

[0100] Example 1. Preparation of supramolecular nanocomplex

[0101] The active ingredient is selected from cyclosporine.

[0102] Prescription composition and preparation process:

[0103] Table 4. Composition of Prescriptions F1-F4 and Comparative Examples D1-D3

[0104] Preparation process of prescriptions F1-F4 and comparative examples D1-D3: According to the prescription, glycolipids, glycoside derivatives, carriers, and cyclosporine were taken, 10 mL of ethanol was added, and then 11 mL of water for injection was added. The mixture was heated to 60°C to dissolve, stirred for 1 hour, and the ethanol was removed by rotary evaporation at 50°C. The volume of the supramolecular nano intermediate aqueous solution was controlled to be less than 85% of the target unit can volume.

[0105] The supramolecular nanocomplex intermediate solution can be further diluted with water for injection, and an osmotic pressure regulator and / or preservative or thickener and / or pH regulator can be added according to the target concentration of the final product. Water for injection can be added to the full amount, filtered for sterilization, filled, and sealed to prepare a supramolecular nanocomplex preparation.

[0106] Example 2. Preparation of supramolecular nanocomplex

[0107] The active ingredient is selected from cyclosporine or tacrolimus. GA is diammonium glycyrrhizinate.

[0108] The prescription composition is as follows:

[0109] Table 5. Composition of F5-F11 prescriptions

[0110] Composition of F5 eye drops to F7 eye drops: Based on the formulas of F5 to F7 in Table 5, add the components in the following table to obtain F5 eye drops to F7 eye drops.

[0111] F5-F7 preparation process:

[0112] The glycolipid, glycoside derivative, carrier, cyclosporine, high molecular weight polymer, surfactant, osmotic pressure regulator (if any) or thickener were weighed according to the prescription amount, 10 mL of ethanol was added, and then 11 mL of water for injection was added. The mixture was heated to 60°C to dissolve, and stirring was continued for 1 hour. The ethanol was removed by rotary evaporation at 50°C. The volume of the supramolecular nano intermediate aqueous solution was controlled to be less than 85% of the target unit can volume. The content of the main component was detected by HPLC. The water for injection was supplemented to 90% of the total volume according to the target concentration. The pH was measured and adjusted to the target value ±0.02. The total amount of water for injection was supplemented, the mixture was filtered through a 0.22 μm filter membrane, and the mixture was canned.

[0113] Preparation process of F8-F11: According to the prescription, glycolipids, glycoside derivatives, carriers, tacrolimus, high molecular polymers, and surfactants are taken, 15 mL of ethanol is added, and then 13 mL of phosphate buffer is added. The mixture is heated to 60°C to dissolve, stirred for 1 hour, and the ethanol is removed by rotary evaporation at 50°C. The volume of the supramolecular nano intermediate aqueous solution is controlled to be less than 85% of the target unit can volume.

[0114] Example 3. Preparation of supramolecular nanocomplex

[0115] According to Br J Ophthalmol 2004,88,708-713, Surv Ophthalmol 2021 Mar.-Apr.,66(2):327-345, Surv Ophthalmol 2021 Nov-Dec;66(6):1070-1071, cannabidiol and its derivatives have very good effects on the treatment of neuropathic eye pain or diabetic retinopathy, glaucoma, etc., but the oral bioavailability of cannabidiol substances is low, and the drug exposure to eye tissue after oral administration is very limited, and effective treatment cannot be achieved. The hydrophobicity of cannabidiol (oil-water partition coefficient LogP 6.32) is very strong. Therefore, a large number of studies have been conducted to improve its water solubility (reduce LogP) by designing cannabidiol derivatives with different structures, but they are limited by the strong hydrophobicity of the parent core structure and the effect is minimal. The structure of cannabidiol and its derivatives is as follows:

[0116] The cannabidiol derivative is a cannabidiol benzene ring H or substituent is replaced by any substituent R1-R6, wherein the substituents R1 to R6 are selected from the following groups:

[0117] Cannabidiol is the most hydrophobic of all its derivatives. The solution to the delivery of cannabidiol in ophthalmic preparations is also applicable to its derivatives.

[0118] According to Eye volume 32, (2018) 981–991, in patients with diabetic retinopathy, statins (e.g., rosuvastatin) can reduce disease progression and improve the resolution of diabetic macular edema (DMO). In patients with uveitis, statins have a protective effect by reducing the development of uveitis.

[0119] Growing evidence suggests that vitamin K plays an important role in the visual system. A study of 5,860 cardiovascular patients, published in Nutrients 2023, 15, 1948 (https: / / doi.org / 10.3390 / nu15081948), confirmed that those with the highest dietary vitamin K1 intake had a 29% lower risk of cataract surgery.

[0120] Supramolecular nanocomplexes were prepared using cannabidiol, rosuvastatin, and vitamin K1 as active ingredients, respectively. These complexes are also applicable to other cannabidiol derivatives (as shown in the table above), statins (such as atorvastatin, simvastatin, lovastatin, pravastatin, pitavastatin, etc.), and vitamin K family (such as K2, K3, K4, etc.).

[0121] Prescription composition and preparation process:

[0122] Table 6. Formulation composition of F12-F17

[0123] (1) Preparation process of F12-F13

[0124] Prepare pH 6.8 buffer solution according to the 2020 edition of the Chinese Pharmacopoeia;

[0125] Preparation of drug-containing solution: Weigh the prescribed amount of cannabidiol, dissolve it in 3 mL of anhydrous ethanol, protect from light, seal and set aside.

[0126] HPMCAS (MG), glycolipids, glycoside derivatives, carriers, pH regulators, etc. were weighed in sequence, 10 mL of pH 6.8 phosphate buffer was added, and the drug-containing solution was slowly added dropwise while stirring at room temperature. After the addition was completed, stirring was continued for 1 hour. The ethanol was removed by rotary evaporation at 40°C to control the volume of the supramolecular nano intermediate aqueous solution to be less than 85% of the target unit can volume.

[0127] (2) Preparation process of F14-F15

[0128] Prepare pH 7.4 phosphate buffer according to the current edition of the Chinese Pharmacopoeia;

[0129] Weigh the prescribed amount of rosuvastatin and dissolve it in acetone to a solution of approximately 30 mg / mL for later use;

[0130] Weigh the prescribed amount of glycolipid, glycoside derivative, carrier, high molecular polymer, and pH adjuster, add 10 mL of pH 7.4 phosphate buffer, dissolve by ultrasound, and slowly add rosuvastatin acetone solution to the aqueous solution while stirring. After the addition is complete, continue stirring for 1 hour, and remove the organic solvent using a rotary evaporator at 40°C to control the volume of the supramolecular nano intermediate aqueous solution to be less than 85% of the target unit can volume.

[0131] Since rosuvastatin has poor stability in solution, the supramolecular nanocomplex prepared above can be freeze-dried for storage.

[0132] (3) Preparation process of F16-F17

[0133] Prepare pH 7.4 phosphate buffer solution according to the Chinese Pharmacopoeia;

[0134] Weigh the prescribed amount of vitamin K1, add ethanol to dissolve it, and make a solution containing approximately 20 mg of vitamin K1 per 1 mL. Protect from light and set aside.

[0135] Weigh the prescribed amount of glycolipids, glycoside derivatives, carriers, high molecular weight polymers, and pH regulators, add 10 mL of pH 7.4 phosphate buffer, and dissolve them by ultrasound. Slowly add the ethanol solution of vitamin K1 to the aqueous solution while stirring. After the addition is complete, continue stirring for 1 hour, and remove the organic solvent using a rotary evaporator at 40°C to obtain a supramolecular nanocomplex.

[0136] The supramolecular nanocomplex of cannabidiol, rosuvastatin and vitamin K1 can be prepared into various specifications required clinically by adding injection water, pH regulator, osmotic pressure regulator or antibacterial agent according to actual treatment needs.

[0137] Example 4. Preparation of supramolecular nanocomplex

[0138] Prescription composition and preparation process:

[0139] Table 7. Composition of supramolecular nanocomplexes F18-F23

[0140] F18-F20 preparation process:

[0141] Weigh glycolipids, glycoside derivatives, carriers, high molecular weight polymers, and surfactants according to the prescription, add 10 mL of water for injection, and heat to 60°C to dissolve. This is used as the carrier solution.

[0142] Weigh the prescribed amount of fluorometholone and dissolve it in an appropriate amount of ethanol-tetrahydrofuran (1:1, v / v) by ultrasonication. Slowly add it dropwise to the carrier solution while stirring. Continue stirring for 1 hour. Remove the organic solvent using a rotary evaporator at 40°C and concentrate to 8-9 mL to prepare the supramolecular nanocomposite intermediate solution.

[0143] F21-F23 preparation process:

[0144] Weigh the prescribed amount of glycolipid, glycoside derivative, carrier, high molecular polymer and surfactant respectively, add 5 mL of water for injection and ultrasonically dissolve and clarify them. If they are insoluble, heat to 60°C and set aside.

[0145] Weigh the prescribed amount of tobramycin and add it to the aqueous phase. Dissolve it with sonication. Add an appropriate amount of ethanol to the prescribed amount of dexamethasone and sonicate to dissolve and clarify. While stirring, slowly add the aqueous solution dropwise to the organic solvent. Continue stirring for 1 hour after the addition is complete. Remove the organic solvent using a rotary evaporator at 40°C and concentrate to 3-4 mL to prepare the supramolecular complex intermediate solution.

[0146] The supramolecular nanocomplex intermediate solution can be further diluted with water for injection, and an osmotic pressure regulator and / or preservative or thickener and / or pH regulator can be added according to the concentration of the final eye drops. Water for injection can be added to the full amount, filtered for sterilization, filled, and sealed to prepare a supramolecular nanocomplex preparation.

[0147] Example 5. Preparation of supramolecular nanocomplex

[0148] Prescription composition and preparation process:

[0149] Table 8. F24-F29 prescription composition

[0150] F24-F29 preparation process:

[0151] Weigh the prescribed amount of sirolimus or acetylspiramycin respectively, add ethanol to dissolve it into a solution of about 25 mg / mL, and set aside.

[0152] Weigh the prescribed amount of hydrocortisone acetate and dissolve it in ethanol-tetrahydrofuran (1:1, V / V) to prepare a solution containing approximately 15 mg per 1 mL.

[0153] According to the prescription, glycolipid, glycoside derivative, carrier, high molecular weight polymer, surfactant are added to 15 mL of water for injection, heated to 40-60 ° C (including TPGS) to dissolve, and used as carrier solution for later use;

[0154] The carrier solution was slowly added dropwise to the drug-containing solution under stirring. After the addition was complete, stirring was continued for 1 hour. The organic solvent was removed using a rotary evaporator at 40° C. and the solution was concentrated to 7-8 mL to obtain a supramolecular nanocomplex intermediate solution.

[0155] Example 6. Preparation of supramolecular nanocomplex

[0156] Table 9 F30-F35 prescription composition

[0157] Preparation process:

[0158] Weigh the prescribed amount of prednisolone acetate, add ethanol-tetrahydrofuran (V / V, 1:1), and sonicate to dissolve it into a 17 mg / mL solution;

[0159] Weigh the prescribed amount of meloxicam, add acetone-tetrahydrofuran (V / V, 2:1), and sonicate to dissolve it into a 5 mg / mL solution;

[0160] Weigh the prescribed amount of bromfenac sodium and dissolve it in methanol to a solution of approximately 10 mg / mL;

[0161] The prescribed amount of glycolipids, glycoside derivatives, carriers, high molecular weight polymers, and surfactants were weighed separately, 10 mL of water for injection was added, and ultrasonication was performed to dissolve them. The above drug-containing solutions were slowly added dropwise to the aqueous phase while stirring. After the addition was completed, stirring was continued for 1 hour. The organic solvent was removed by rotary evaporation at 40°C, and the aqueous phase was further concentrated to less than 85% of the aqueous phase volume to obtain a supramolecular nanocomplex intermediate.

[0162] Experimental Example 1: Active ingredient content, particle size, PDI, and Zeta potential detection

[0163] The supramolecular nanocomplexes or supramolecular nanocomplex intermediates prepared in Examples 1 to 6 were centrifuged at 13,000 rpm for 10 minutes at room temperature. The supernatant was collected for content, particle size, PDI, and Zeta potential testing, and the appearance was recorded. The results are shown in the following table.

[0164] Table 10. Content, particle size, PDI, and Zeta potential of supramolecular nanocomplexes, intermediates, or eye drops

[0165] According to the test results, the content of active ingredients in the supramolecular nanocomplex intermediate or eye drops can be known as follows:

[0166] (1) Cyclosporine: The content of the F1-F7 cyclosporine supramolecular nanocomplex intermediate can reach up to 24.88 mg / mL, while the concentrations of commercially available cyclosporine micelles and cyclosporine emulsion eye drops are 0.5 mg / mL, 0.9 mg / mL, and 1 mg / mL. According to the European Journal of Pharmaceutics and Biopharmaceutics 56 (2003) 307–318, after daily oral administration of 5 mg of cyclosporine per kilogram of body weight, the exposure of cyclosporine in tears is 25 μg to 75 μg. It has a good therapeutic effect on various immune-mediated ocular surface diseases such as vernal conjunctivitis, dry eye, idiopathic keratoconjunctivitis, follicular conjunctivitis, and corneal transplant rejection. According to the currently marketed product, the maximum dosage is 1.0 mg / mL. The human conjunctival sac has a maximum fluid volume of 30 μL, with tears containing 7 to 9 μL, allowing for a maximum of 20 μL of additional drug solution. However, a single drop of eye drops has a volume of approximately 40 μL. This means that if the drug concentration is insufficient, no matter how many drops are administered, the maximum amount of cyclosporine in tears is only 10 μg to 20 μg, regardless of permeability. This means that the amount of cyclosporine in tears for currently marketed cyclosporine eye drops does not even approach the optimal effective dose of 25 to 75 μg. Therefore, the optimal concentration for topical cyclosporine ophthalmic products should be between 1.25 mg / mL and 3.75 mg / mL. Considering the permeability and clearance of cyclosporine, the ideal concentration is between 5.0 mg / mL (0.5%) and 20.0 mg / mL (2%). Alternatively, the solution can be further diluted with water for injection or artificial tears to prepare eye drops with any concentration ranging from 0.15% to 2.0%. Except for Comparative Examples 2 and 3, the supramolecular nanocomplexes described above exhibited no turbidity or precipitation after 6 months of storage at room temperature or in a 5°C refrigerator. The particle size detection spectrum for F1 is shown in Figure 1, the particle size detection spectrum for F4 is shown in Figure 2, and the particle size detection spectrum for F6 is shown in Figure 3.

[0167] (2) Tacrolimus: According to the results of F8-F11, the concentration of the tacrolimus supramolecular complex intermediate ranged from 2.8 mg / mL to 5.0 mg / mL, all of which were clear solutions. However, the commercially available 0.1% tacrolimus eye drops are suspensions (1 mg / mL) that require thorough shaking before use. This requirement is difficult to achieve for different patients, and its effectiveness and safety cannot be guaranteed.

[0168] (3) Cannabidiol: The concentrations of cannabidiol nanocomplexes measured according to F12-F13 were 34.88 mg / mL and 12.65 mg / mL, respectively, which were 11,962 to 33,219 times higher than the solid dispersion preparation technology using cyclodextrin derivatives in International Journal of Pharmaceutics 589 (2020) 119812. The above-mentioned cannabidiol supramolecular nanocomplexes can be further added with osmotic pressure regulators, pH regulators, or gel carriers and initiators or antibacterial agents and water for injection or artificial tears to prepare eye drops or gels and in situ gels of target concentrations.

[0169] (4) Rosuvastatin: The concentrations of rosuvastatin supramolecular nanocomplexes measured by F14-F15 were 6.58 mg / mL and 24.33 mg / mL, respectively, with particle sizes of 21.9 nm and 22.8 nm, respectively. The clear solutions can be further diluted with water for injection or artificial tears to prepare eye drops of any concentration from 0.05% to 1%.

[0170] (5) The vitamin K1:F16-F17 supramolecular nanocomplex has a content of 2.56 mg / mL and 12.35 mg / mL, respectively, and a clear solution with a particle size of 27.5 nm and 36.5 nm. It can be further diluted with water for injection or artificial tears to prepare eye drops with any concentration from 0.05% to 1%.

[0171] (6) Fluorometholone: ​​The contents of the F18-F20 supramolecular nanocomplexes are 2.91 mg / mL, 5.88 mg / mL, and 8.04 mg / mL, respectively, in a clear solution with a particle size of 14 nm to 20 nm. The concentration of the commercially available fluorometholone eye drops is 0.1% (1 mg / mL), and it is a suspension that requires thorough shaking. Generally, 1-2 drops are administered at a time. It is clear that the currently available fluorometholone eye drops are affected by solubility and cannot be prepared with higher concentrations. If two drops are administered at a time, the eye can only accommodate a maximum of 1 / 2 drop of the solution, and the second drop is essentially ineffective. The fluorometholone supramolecular nanocomplex prepared using the technology of the present invention can be prepared into a clear solution with any concentration of 0.1% to 0.8%, preferably 0.2% to 0.8%, according to actual needs.

[0172] (7) Tobramycin / dexamethasone composite supramolecular nanocomplex: The contents of the F21-F23 supramolecular nanocomplexes are 6.57 / 2.05 mg / mL, 10.62 / 3.54 mg / mL, and 14.14 / 4.73 mg / mL, respectively, with a clear solution size of 21 nm to 25 nm. Clear eye drops with a tobramycin / dexamethasone concentration of 3 mg / 1 mg / mL to 12 mg / 4 mg / mL can be prepared as needed.

[0173] (8) Sirolimus: The contents of the F24-F25 supramolecular nanocomplex are 2.47 mg / mL and 12.14 mg / mL, respectively, with a particle size of approximately 21 nm. The clear solution can be diluted with water for injection or artificial tears to prepare clear eye drops of any concentration from 0.1% to 1.0% as needed.

[0174] (9) Hydrocortisone acetate: The content of the F26-F27 supramolecular nanocomplex is 6.09 mg / mL to 11.93 mg / mL, respectively, with a particle size of 22-26 nm. It can be diluted with water for injection or artificial tears to produce a clear solution of 5 mg / mL to 10 mg / mL as needed. The current marketed product is a suspension and should be shaken thoroughly before use.

[0175] (10) Acetylspiramycin: The contents of the F28-F29 supramolecular nanocomplex are 6.66 mg / mL and 12.43 mg / mL, respectively, in a clear solution with a particle size of 18-21 nm. It can be diluted with injection water or artificial tears to prepare clear eye drops of any concentration from 0.05% to 1.0% according to actual needs.

[0176] (11) Prednisolone acetate: The F30-F31 supramolecular nanocomplex contains 12.87 mg / mL and 24.45 mg / mL, respectively, in a clear solution with a particle size of 21-25 nm. This solution can be diluted with water for injection or artificial tears to produce clear eye drops at any concentration from 1% (10 mg / mL) to 2.0% (20 mg / mL), depending on actual needs. The currently marketed product is a 10 mg / mL suspension eye drop that needs to be shaken thoroughly before use. One to two drops should be administered four times a day, with the first dose administered every two hours in severe cases. This indicates that the specifications of the current marketed product simply cannot meet clinical needs.

[0177] (12) Meloxicam: The contents of the F32-F33 supramolecular nanocomplex are 0.38 mg / mL and 1.41 mg / mL, respectively, in a clear solution with a particle size of 20-22 nm. It can be diluted with water for injection or artificial tears to prepare clear eye drops of any concentration from 0.03% (0.3 mg / mL) to 0.12% (1.2 mg / mL) according to actual needs.

[0178] (13) Bromfenac sodium: The contents of F34-F35 supramolecular nanocomplexes are 2.41 mg / mL and 5.13 mg / mL, respectively, in a clear solution with a particle size of 19-21 nm. It can be diluted with water for injection or artificial tears to prepare 0.1% to 0.5% clear eye drops.

[0179] The particle size of the above-mentioned supramolecular nanocomplexes is 13 to 129 nm, and the particle size of most supramolecular nanocomplexes is 15 nm to 40 nm, which is more conducive to penetration; except for D3, the PDI is lower than 0.3, and except for the comparison example, the Zeta potential is 3 mV to 40 mV, which helps to prolong the retention time of the drug on the ocular surface, prolong the absorption time, and improve the effective utilization rate of the drug.

[0180] The technology of the present invention can significantly increase the drug loading, which is very important for topically applied eye drops and directly affects the effectiveness, treatment time, patient tolerance, and safety of the eye drops. Most hydrophobic eye drops on the market require patients to use 1-2 drops at a time. Due to the maximum liquid volume of the human conjunctival sac (~30μL), excluding tears, it can only accommodate an additional 1 / 2 drop of drug solution (~20μL). Obviously, for the treatment of ocular surface diseases, if you want to achieve rapid onset, the effective concentration of the topical product directly determines the therapeutic effect and treatment period. The greater the amount of drug contained in each drop of drug solution, the faster the onset of action. Conversely, if the drug concentration is low, the therapeutic effect of administering 1 drop is basically the same as that of administering 10 drops.

[0181] Experimental Example 2. Simulated tear dilution test and percent transmittance measurement

[0182] Preparation of simulated tears: Refer to Table 14 of DOI: dx.doi.org / 10.14227 / DT180311p15, Tears 2 medium preparation method, the formula composition is as follows:

[0183] Weigh each reagent according to the prescribed amount, dissolve it in purified water, and adjust the pH to 7.4 with 1M HCl solution.

[0184] 1 mL each of D1-D3, F2, F3, F6, F9, F28 and F31 was taken, and 0.5 mL, 1 mL, 2 mL, 4 mL and 9 mL of simulated tear solution were added respectively. Each formulation was diluted 1.5-10 times, and shaken for 1.5 hours to observe whether the solution was clear. The results are shown in the table below:

[0185] Take the simulated tear dilution and use a Shimazu UV-2600 ultraviolet-visible spectrophotometer at a wavelength of 630 nm, with simulated tears as the blank matrix. Set the detection mode to transmittance mode and detect the transmittance of each supramolecular nanocomplex diluted 10 times with simulated tears at 630 nm. The dilution of each prescription was measured in parallel three times and the average value was taken.

[0186] Table 11. Results of supramolecular nanocomplex simulated tear dilution test

[0187] The particle size and PDI test results of each prescription after dilution 10 times are shown in the table below.

[0188] Table 12. Particle size and PDI test results of simulated tear solution after dilution

[0189] All formulations except D3 remained clear after 0.5- to 10-fold dilution of simulated tears. Particle size and PDI analysis of the solutions of each formulation after 10-fold dilution showed that the supramolecular nanocomplex particle size and PDI after dilution were essentially consistent with those before dilution as shown in Table 10. Particle size analysis of F6 before and after simulated tear dilution is shown in Figures 3 and 4.

[0190] After being diluted 10 times, the transmittance of each prescription except D3 was 93.46%, which was lower than 99%; the transmittance of the simulated tears of other prescriptions after dilution was 99.38% to 100%, all greater than 99%.

[0191] These experimental results further demonstrate that dilution of high-concentration supramolecular nanocomplexes with simulated tear fluid, based on the desired drug concentration, does not affect the nanoparticle structure, particle size distribution, and other characteristic parameters. These results also demonstrate that the high-concentration supramolecular nanocomplexes or supramolecular nanocomplex intermediates prepared by the present invention can be prepared into clear eye drops of target concentrations as needed.

[0192] Experimental Example 3. Refractive Index Measurement

[0193] In order to investigate the supramolecular nanocomplex prepared by the present invention and the uniformity of the solution under dilution, appropriate amounts of supramolecular nanointermediates prepared by prescriptions F24-F27 were taken and diluted with simulated tears according to the following table. The refractive index of the diluted eye drops was measured using an Abbe refractometer in accordance with the General Rules 0622 of Part IV of the 2020 edition of the Chinese Pharmacopoeia. The temperature of the test sample, ambient temperature, and water was controlled at 20°C, and the average of three times was taken as the refractive index. The dilution experiment and measurement results are shown in the following table:

[0194] Table 13. Refractive index determination of eye drops after dilution with F24-F27 simulated tears

[0195] According to the above results, the supramolecular nanocomplex intermediates prepared by formulations F24 to F27 were diluted to a specific concentration with simulated tears, and the measured refractive index results ranged from 1.358 to 1.406, among which the refractive index values ​​of F26 to F27 were slightly higher than the refractive index of simulated tears (the refractive index of simulated tears is 1.376), but did not exceed the limit value of 1.476 for known eye drops.

[0196] Experimental Example 4 Osmotic pressure molar concentration ratio and surface tension

[0197] (1) Osmolality ratio

[0198] With reference to the osmotic pressure molar concentration determination method in Part IV of the 2020 edition of the Chinese Pharmacopoeia, the instrument was calibrated with sodium chloride as the standard solution. Using the STY-1 osmotic pressure measuring instrument, 100 μl of F5-7 eye drops and simulated tears were taken respectively. According to the instrument operating instructions, two parallel measurements were performed to determine the osmotic pressure molar concentration and osmotic pressure molar concentration ratio of F5-7 eye drops and simulated tears, respectively. The results are shown in the table below.

[0199] Table 14 Osmotic pressure molar concentration ratio of supramolecular nanocomplex eye drops

[0200] The measurement results show that the eye drops prepared by using the supramolecular nanocomposite intermediate prepared by the present invention and adding an osmotic pressure regulator, a pH regulator, etc. have an osmotic pressure molar concentration of 301 to 328 mOsm / kg and an osmotic pressure molar concentration ratio of 1.05 to 1.15, which are basically equivalent to simulated tears.

[0201] (2) Surface tension

[0202] The surface tension of eye drops is a key factor influencing the adhesion and spreading of ophthalmic preparations on the cornea. Within a certain range, the lower the surface tension of an ophthalmic preparation, the more favorable its mixing with the tear film. Appropriate surface tension can also increase the retention time of the preparation on the cornea. The surface tension of supramolecular nanocomposites prepared with different formulations at room temperature was measured using the hanging drop method using an SDC-200 optical contact angle meter. The results are shown in Table 15 below:

[0203] Table 15. Surface tension of supramolecular nanocomplexes

[0204] The above measurement results show that the surface tension of the supramolecular nanocomposites prepared with different formulations ranges from 40.5 to 43.1 mN·m -1 The range for ocular preparations is 40-50 mN·m -1 .

[0205] Experimental Example 5. Lyophilization and Reconstitution

[0206] The supramolecular nanocomplex solutions of F11, F13, F15, F16, F19, F23 and F34 were taken respectively and freeze-dried at -40°C for 2 hours. After the samples were frozen solid, they were moved into a drying chamber for sublimation drying for 20 hours to obtain supramolecular nanocomplex freeze-dried powder.

[0207] Take an appropriate amount of the above lyophilized powder, add 4 mL of water for injection, shake, and make up to 5 mL with water for injection. Observe the re-dissolution of the lyophilized powder, take samples to test the active ingredient content and particle size, and calculate the re-dissolution rate according to the following formula. The results are shown in Table 16 below.

[0208] Among them A 复溶 is the active ingredient content of the reconstituted solution (mg / mL)

[0209] V 复溶 is the volume of the reconstituted solution (mL)

[0210] W 样 The sample weight of lyophilized powder (mg)

[0211] A is the active ingredient content of the supramolecular nanocomplex solution before lyophilization (mg / mL)

[0212] V is the total volume of the supramolecular nanocomplex solution before lyophilization (mL)

[0213] W 总 is the total solute mass (mg) in the supramolecular nanocomplex solution before lyophilization.

[0214] Table 16. Reconstitution of lyophilized powder of supramolecular nanocomplex intermediates

[0215] The properties of the reconstituted solutions in the table are all clear solutions, indicating that the lyophilized powders of the supramolecular nanocomplex solutions are well reconstituted. The reconstitution rate results show that all the active ingredients can be reconstituted. Except for F15 and F34, which have slightly increased particle size and PDI, there are no significant changes in other formulations.

[0216] The above results indicate that freeze-drying did not destroy the supramolecular nanocomplex. The particle size detection spectra of F11 before freeze-drying and after reconstitution after freeze-drying are shown in Figures 5 and 6.

[0217] The supramolecular nanocomplex of the present invention can withstand freeze-drying, making it possible to prepare eye drops for drugs with extremely poor chemical stability in aqueous solution. For example, the freeze-dried powder can be put into an eye drop bottle and reconstituted with injection water or other suitable solvents before use to prepare eye drops for patients.

[0218] Experimental Example 6. Corneal permeability test

[0219] Eight rabbits (half male and half female, weighing 2–3 kg and fed ad libitum) were selected for the experiment. Healthy rabbits without eye disease were sacrificed by intravenous injection of air via the ear. Following the procedures described in International Ophthalmology, Volume 17, Issue 4, April 2017, pp. 628–630, corneas were carefully isolated using ophthalmic scissors and forceps within 20 minutes of death. Excess tissue, including the sclera, iris, and ciliary body, was removed. The rabbits were then rinsed three times with GBR solution and set aside.

[0220] The fresh ex vivo cornea was carefully fixed between the donor and receiver chambers of a modified Franz vertical diffusion cell, with the epithelial layer facing the donor chamber. The effective diffusion area of ​​the diffusion cell was 0.5 cm 2The receiving pool was filled with freshly prepared 2% polysorbate 80-GBR solution [2% polysorbate 80-glutathione-sodium bicarbonate Ringer's solution, GBR: the solution is composed of solution 1 (12.40 g / L sodium chloride, 0.72 g / L potassium chloride, 0.21 g / L sodium dihydrogen phosphate and 4.91 g / L sodium bicarbonate and water for injection) and solution 2 (0.23 g / L calcium chloride, 0.32 g / L magnesium chloride, 1.80 g / L glucose, 0.18 g / L oxidized glutathione and water for injection). Solutions 1 and 2 were prepared and stored in a refrigerator at 4°C. Before use, equal volumes were mixed]. According to the literature J Pharm Sci, 2011, 100(8): 3186-3195, this medium can keep the cornea physiologically functional for 6 hours.

[0221] Supply chamber: Prepare clarified supramolecular nanocomplexes from formulations F1, F4, D1, D2, and D3, respectively. Dilute with simulated tear fluid to produce a solution containing approximately 1 mg of cyclosporine per mL, based on the actual measured cyclosporine content. Use precise pH testing to confirm that the pH is between pH 6.5 and pH 7.5, and control the osmotic pressure between 260 and 400 mOsm / kg. Prepare three replicates for each formulation.

[0222] The experimental temperature was set at 35°C ± 2°C, with magnetic stirring at 75 rpm. After equilibration for 15 minutes, 1 mL of each supramolecular nanocomplex solution (F1, F4, D1, D2, or D3) was added to the donor chamber. To prevent surface evaporation, the donor and receiving chambers were covered with plastic wrap. 1 mL of solution was withdrawn from the sampling port at 0.5, 1, 2, 3, 4, 5, and 6 hours after the start of the experiment. Simultaneously, the same volume of 2% polysorbate 80-GBR solution was added at the same temperature. The sample solutions were filtered through a 0.45 μm filter into microvials, and the concentration of the active ingredient in the receiving chamber was determined by HPLC.

[0223] Calculate Q of different prescriptions according to the formula n , Papp, Jss and τ.

[0224] The permeability parameters of the isolated cornea were calculated by the following formula.

[0225] Steady-state flow Jss = C0·Papp

[0226] Corneal diffusion coefficient (cm 2 min -1 ) is calculated by the following formula

[0227] D=δ 2 / 6τ

[0228] Where:

[0229] Qn is the cumulative transmittance per unit area;

[0230] C n is the mass concentration of the drug at time t;

[0231] C i is the mass concentration before time t;

[0232] V0 is the volume of the solution in the receiving cell (5 mL);

[0233] V is the sampling volume (1 mL);

[0234] Papp is the apparent permeability coefficient (cm·s -1 );

[0235] C0 is the initial drug concentration in the supply pool (mg / mL);

[0236] A is the effective diffusion area (0.5 cm 2 );

[0237] ΔQ / Δt can be obtained from the slope of the steady-state portion of the cumulative permeation-time curve;

[0238] Jss is the steady-state permeation rate (μg·cm 2 ·hr -1 );

[0239] δ is the corneal thickness 0.0625 cm;

[0240] τ is the time lag, which is the time point (hr) where the straight line part of the curve intersects the time axis.

[0241] According to the test results, each prescription can basically reach a steady state within 4 hours. Therefore, the corneal exposure concentration of different prescriptions was calculated from 0-4 hours.

[0242] Table 17. Comparison of 4-hour pharmacokinetics of different prescriptions in isolated cornea (mean ± SD, n = 3)

[0243] **P≤0.01, ****P≤0.0001;

[0244] The above results show that there were statistically significant differences between D2, containing only glycoside derivatives, and D3, containing only glycolipids, and D1 (P ≤ 0.01). There were also statistically significant differences between F1 and F4, containing composite penetration enhancers, and D1 (P ≤ 0.0001). There were also statistically significant differences between F1 and F4, containing different concentrations of composite penetration enhancers, and D2 (P ≤ 0.0001).

[0245] Compared with a single penetration enhancer or a formulation without a penetration enhancer, the composite penetration enhancer significantly increased the cyclosporine exposure concentration in the isolated cornea for 4 hours.

[0246] Table 18. In vitro corneal penetration parameters of different prescriptions (n=3, mean)

[0247] In summary, the in vitro corneal permeability results for Comparative Examples D1, D2, and D3 show that compared to D1, which does not contain any penetration enhancers, the apparent permeability coefficient Papp and steady-state permeation rate Jss of D3, containing only rhamnolipid, are both twice that of D1. Meanwhile, the apparent permeability coefficient Papp and steady-state permeation rate Jss of D2, containing only glycoside derivatives, are 4.3 times that of D1 and twice that of D3. However, the time lag of D2 is significantly longer, at 1.61 hours, than that of D1 and D3. The F1 formulation contains 0.1% rhamnolipid and 1.4% glycoside derivative (total 1.5%), while the D2 formulation contains only 1.5% glycoside derivative. Based on in vitro corneal permeability results, the apparent permeability coefficient (Papp) and steady-state permeation rate (Jss) of the F1 formulation are essentially the same as those of the D2 formulation, but the time lag is essentially the same as that of the D1 formulation. The combined use of rhamnolipid and glycoside derivative significantly alters the time lag effect caused by the glycoside derivative. The F4 formulation is based on the F1 formulation, but the glycoside derivative is replaced with an equal concentration of STL-CPP-Arg4. The other formulas are identical to the F1 formulation. The apparent permeability coefficient (Papp) and steady-state permeation rate (Jss) of the F4 formulation are 2.9 times that of the F1 formulation, and the time lag is consistent with that of the F1 formulation.

[0248] The permeation rate-median time curves of each prescription are shown in Figure 7.

[0249] In summary, glycolipids and glycoside derivatives, as composite penetration enhancers, significantly enhance corneal permeability through their synergistic effect while significantly shortening the time lag effect, which is very important for topical ocular medications. Normally, ocular surface medications, if not rapidly absorbed, are quickly cleared by tears, blinking, and other factors after administration.

[0250] Experimental Example 7. Corneal Hydration Level (HL)

[0251] After the in vitro corneal permeability test, the corneal area exposed to the diffusion medium was cut out and weighed (W1); after vacuum drying at 60°C for 12 hours, the weight was weighed again (W2).

[0252] The formula for calculating corneal hydration value HL is as follows:

[0253] HL=1-W2 / W1×100%

[0254] The hydration values ​​of each prescription and freshly peeled cornea of ​​Experimental Example 6 are shown in Table 19 below:

[0255] Table 19. Corneal hydration values ​​of different prescriptions (mean ± SD, n = 3)

[0256] These results indicate that all formulations, regardless of whether or not they contained a penetration enhancer, or whether they contained both, showed a slight increase in corneal hydration compared to freshly exfoliated corneas, but none exceeded 83%. Corneal hydration is an important indicator for evaluating the corneal irritation of eye drop formulations in vitro. Corneal hydration typically ranges from 76% to 83%, with values ​​exceeding 83% indicating a certain degree of corneal damage. In summary, the above formulations are minimally irritating to the cornea.

[0257] Experimental Example 8. Investigation of the irritation of supramolecular nanocomposite eye drops

[0258] Experimental animals: New Zealand white rabbits, purchased from Beijing Longan Experimental Animal Breeding Center, were male and in good condition, weighing 2-3 kg, and at least 11 weeks old. They were kept in a well-ventilated environment with alternating light and dark every 12 hours and had free access to food.

[0259] Experimental method: The experimental rabbits were randomly divided into two groups, with 6 rabbits in each group, and were treated with F7-eye drops (1% cyclosporine), Eye drops (0.1% cyclosporine, Santen Co., Ltd.) were administered 13 times, 40 μL per eye, with 30-minute intervals between doses. Ocular irritation was observed under a slit lamp 1, 6, 12, and 24 hours after the last dose and scored according to the BOCP ocular irritation scoring system (higher scores indicate greater irritation).

[0260] Table 20 Comparison of irritation of different eye drops

[0261] From the above results, it can be seen that the concentration of cyclosporine in the eye drops prepared by F7 prescription is At 10 times the irritation rate, F7 eye drops are as irritating as commercial products. Basically the same.

[0262] Experimental Example 9. Intraocular Drug Pharmacokinetics

[0263] Experimental animals: New Zealand white rabbits, male, in good condition, weighing 2-3 kg, at least 11 weeks old, housed in a well-ventilated environment with a 12-hour alternating light and dark cycle, with free access to food.

[0264] Experimental method: The experimental rabbits were randomly divided into 4 groups, 16 in each group, and treated with F1, D1, D3 (0.1% cyclosporine), Eye drops (0.1% cyclosporine) were administered as a single dose of 50 μL per eye. Blood was drawn from the ear vein of two animals per group at 0.133, 0.25, 0.5, 1, 2, 4, 8, and 24 hours after administration. The animals were euthanized by intravenous injection of sodium pentobarbital. Immediately after euthanasia, the epibulbar cornea, conjunctiva, and lacrimal glands of both eyes were obtained and frozen at -80 ± 15°C for analysis using a validated triple quadrupole mass spectrometer. Venous blood was similarly frozen.

[0265] Biological sample processing:

[0266] Tissue samples were homogenized with 1000 μL of ethyl acetate at 6000 rpm with 5 × 10-second cycles. After homogenization, the samples were centrifuged at 14000 rpm for 10 minutes at room temperature. The supernatant was collected and dried using a nitrogen purge at 40°C. The residue was reconstituted with 100 μL of 80% methanol-water (v / v), vortexed for 1 minute, and centrifuged at 14000 rpm for 2 minutes at room temperature. 10 μL of the supernatant was injected and analyzed for cyclosporine content by liquid chromatography-triple quadrupole mass spectrometry.

[0267] The intraocular pharmacokinetic parameters including Cmax, Tmax, and AUC were calculated based on the cyclosporine concentration.

[0268] Table 21 Comparison of intraocular pharmacokinetics of different cyclosporine eye drops

[0269] The above results demonstrate that F1 significantly improves bioavailability at the same dose as the commercially available IKERVIS. F1 also significantly improves bioavailability compared to D1 and D3, demonstrating that the formulation containing a penetration enhancer, glycolipid + glycoside derivative, is superior to the formulation containing a glycolipid alone or a formulation without a penetration enhancer, while maintaining essentially the same systemic bioavailability. This demonstrates that the penetration enhancer, glycolipid + glycoside derivative, can also improve bioavailability in vivo and is rapidly absorbed.

[0270] Example 7. Preparation of supramolecular nanocomplex

[0271] (1) Prescription composition

[0272] Polyethylene glycol (15)-hydroxystearate (HS-15) was purchased from BASF Chemicals.

[0273] Table 22. F36-F37 formulation composition

[0274] (2) Preparation process

[0275] F36 preparation process:

[0276] Weigh glycolipid, glycoside derivative, carrier, cyclosporine, high molecular weight polymer, and surfactant according to the prescribed amount, add 10 mL of ethanol, and then add 10 mL of 0.9% sodium chloride solution for injection. Heat to 60°C to dissolve, continue stirring for 1 hour, and remove ethanol using a rotary evaporator at 50°C to control the solution volume to approximately 8-10 mL.

[0277] F37 preparation process: According to the prescription, glycolipids, glycoside derivatives, carriers, tacrolimus, high molecular weight polymers, and surfactants are taken, 15 mL of ethanol is added, and then 13 mL of phosphate buffer is added. Heat to 60°C to dissolve, stir for 1 hour, and remove ethanol using a rotary evaporator at 50°C to control the solution volume to approximately 8-10 mL.

[0278] F38 preparation process: Weigh the prescribed amount of hydrocortisone acetate and dissolve it in ethanol-tetrahydrofuran (1:1, V / V) to make a solution containing approximately 15 mg per 1 mL.

[0279] According to the prescription, glycolipids, glycoside derivatives, carriers, high molecular polymers, and surfactants were weighed and dissolved in 10 mL of 0.9% sodium chloride solution for injection, which was used as the carrier solution. The carrier solution was slowly added dropwise to the drug-containing solution while stirring. After the addition was complete, stirring was continued for 1 hour. The organic solvent was removed using a rotary evaporator at 40°C and the solution was concentrated to 8-10 mL.

[0280] The supramolecular nanocomplex solution was allowed to stand at room temperature for 48 hours, and then centrifuged at room temperature / 13000 rpm for 10 minutes. The supernatant was collected as the supramolecular nanocomplex solution of each formulation.

[0281] Accurately measure 2 mL of each of the above solutions, place them in vials of known weight, freeze-dry them in a freeze dryer for 48 hours, take them out, seal them, and weigh them for drug loading calculation.

[0282] The calculation formula of drug loading is as follows:

[0283] Drug loading % = drug content per unit volume (mg) / solid content per unit volume (mg / mL) × 100.

[0284] (3) Characterization of physical and chemical properties

[0285] 1) Content, particle size, PDI and Zeta potential

[0286] The supramolecular nanocomposite solution prepared in Example 7 was tested for content, particle size, PDI and Zeta potential. The results are shown in the following table.

[0287] Table 23. Results of supramolecular nanocomplex content, particle size, PDI, and Zeta potential measurements

[0288] The supramolecular nanocomposites prepared by each formulation had uniform particle size distribution (PDI<0.3), an average diameter of less than 50 nm, and a zeta potential close to neutral.

[0289] 2) Encapsulation efficiency

[0290] The lyophilized powder of each of the above prescriptions (equivalent to 1 mL of supramolecular nanocomplex solution) was weighed into a 1.5 mL centrifuge tube. 1 mL of simulated tear fluid was accurately added and the mixture was vortexed for 10 seconds to reconstitute. The mixture was centrifuged at 4°C / 45,000 rpm for 40 minutes. 200 μL of the supernatant was collected and 800 μL of acetonitrile was added. The concentration of the active ingredient in the supernatant of each prescription was detected by HPLC. The encapsulation efficiency (EE, %) was calculated according to the following formula.

[0291] EE(%)=(C t -C f ) / C t ×100%

[0292] According to the results of the measurement in Table 23 (C t : total drug concentration, mg / mL) and ultracentrifugation supernatant concentration C after reconstitution f (free drug concentration, mg / mL), the encapsulation efficiencies of F36, F37, and F38 were calculated to be 96.52%, 99.38%, and 98.49, respectively.

[0293] 3) Osmotic pressure

[0294] Measure appropriate amounts of the supramolecular nanocomplexes mentioned above and adjust the pH to 6.5-7.4 with 0.1M hydrochloric acid or sodium hydroxide. To adjust the osmotic pressure, dilute F37 with 0.3% sodium chloride solution to the full amount. Add the full amount of the other two prescriptions to the target concentration of water for injection. According to the osmotic pressure molar concentration determination method 0632 of the fourth part of the Chinese Pharmacopoeia 2020 edition, the STY-1 osmotic pressure meter was used for determination. Each prescription was measured in parallel twice, and the average value was taken. The specific details are shown in the following table:

[0295] Table 24. Osmolality ratio of supramolecular nanocomplex eye drops

[0296] The osmotic pressure range that the eye can generally tolerate (osmotic pressure 260mOsm / L-400mOsm / L) is equivalent to a sodium chloride concentration of 0.8% to 1.2%. The osmotic pressure molar concentration of the above prescription is 307 to 344mOsm / kg, which meets the osmotic pressure molar concentration requirement that the eye can tolerate.

[0297] 4) Physicochemical stability

[0298] Take appropriate amounts of F36, F37, and F38, disperse them equally into a vial, half-cap and stopper, and freeze-dry for 48 hours. Remove and seal. Take the above-mentioned lyophilized powder and reconstitute it with different volumes of simulated tears. The reconstitution conditions are shown in Table 25; the particle size, PDI, and active ingredient content after reconstitution. Other samples were stored in the dark at 4℃±2℃, 25℃±2℃ / 60%RH±5%RH, and 40℃±2℃ / 75%RH±5%RH. Samples were taken in January, February, and March, respectively, to test the content, particle size, and PDI. The results are shown in Table 25 below:

[0299] Table 25. Reconstitution of each prescription after freeze-drying

[0300] The above results show that, after reconstitution and dilution of various multiples in simulated tear fluid, all formulations were clear, except for F36, which was slightly opalescent when diluted to 10 mL. The transmittance of all formulations after reconstitution to 10 mL was greater than 99%. See Table 26.

[0301] Table 26. Reconstitution and physical / chemical stability of each formulation after lyophilization

[0302] Stability results under different conditions show that the particle size and PDI of F36 increased after lyophilization and reconstitution compared to the pre-lyophilization state. After accelerated testing at 40°C / RH75% for 3 months, the particle size increased significantly compared to the reconstituted state, and the PDI was 0.294, close to 0.3, indicating that the physical stability of F36 was slightly poor. The other two formulations showed no increase in particle size or PDI compared to the pre-lyophilization state. After testing at 4°C, 25°C / RH60%, and 40°C / RH75% for 3 months, except for a slight decrease in content, the particle size and PDI showed no significant change, indicating good physical and chemical stability.

[0303] (4) Single-dose ocular tissue distribution study: Dosage formulation: The supramolecular nanocomplex intermediates of formulations F38 and F9 were added to simulated tear fluid to prepare eye drops containing 0.1% (1 mg / mL) tacrolimus, controlled at pH 7.2 ± 0.02;

[0304] Experimental animals: New Zealand white rabbits, in good condition, male, weighing 2.5-3.3 kg, at least 11 weeks old.

[0305] Experimental animals were randomly divided into two groups, A and B, with 15 animals in each group. Group A animals were administered F9, and Group B animals were administered F38. The dose was 50 μL (50 μg) per rabbit, per eye. Blood was collected from the ear vein (1 mL) before and 0.5, 1, 2, 8, and 24 hours after administration. After each blood draw, the animals were euthanized with an intravenous injection of thiopental sodium (20 mg / kg body weight). Three animals were sacrificed at each time point. Immediately after euthanasia, both eyeballs were removed from each animal, the surface of the eyeballs rinsed with cold saline, and quickly frozen at -80 ± 15°C. Ocular tissue was isolated prior to tissue sample analysis. Before separating the various parts of the eye tissue, first use a 29-gauge insulin injection needle to extract 50-60 μL of aqueous humor from each eyeball, place it in a centrifuge tube, and store it in the dark. Then separate the cornea, conjunctiva, iris and ciliary body, retina and choroid, and vitreous body, rinse the surface with saline, dry it with absorbent paper, and weigh it.

[0306] Whole blood and eye tissue sample pretreatment:

[0307] Refer to Clin Exp Optom 2011;94:2:212–218 for ocular tissue pretreatment methods: mince ocular tissue, add 10 mL of extraction solvent (a mixture of equal volumes of 10 mM sodium molybdate, 2 mM DL-dithiothreol, and 0.1 M Tris-HCl) for every 0.5 g of ocular tissue, grind it, and homogenize it three times with a 12 mm blade homogenizer for 1 min each time. Centrifuge it at 4°C / 13,000 rpm for 10 min. Transfer the supernatant to a 10 mL centrifuge tube, accurately add 20 μL of internal standard solution (cyclosporine A, 50 ng / mL), vortex it for 2 min, add 2.5 mL of dichloromethane, vortex it for 2 min, centrifuge it again for 10 min, separate the organic phase, blow dry it with a stream of nitrogen at 45°C, add 200 μL of mobile phase to reconstitute it, and take 10 μL for injection and analysis. After the aqueous humor sample was thawed and returned to room temperature, 50 μL was taken, 20 μL of internal standard solution (cyclosporine A, 50 ng / mL) was added, and the mixture was vortexed for 30 seconds. 930 μL of acetonitrile was added to precipitate proteins, and the mixture was vortexed for 2 minutes. The mixture was centrifuged at 4 μg / 13000 rpm for 10 minutes, and 10 μL of the supernatant was injected for analysis.

[0308] 130 μL of whole blood was placed in a 1.5 mL centrifuge tube. 20 μL of internal standard solution (cyclosporine A, 50 ng / mL) was precisely added and vortexed for 5 minutes. Then, 130 μL of 0.1 M NaOH and 260 μL of a mixture of methanol and 0.3 M ZnSO₄ (70:30, v / v) were added and vortexed for 5 minutes. After centrifugation at 12,000 rpm for 10 minutes, 20 μL of the supernatant was sampled and analyzed.

[0309] According to the test results, calculate Cmax, Tmax, t 1 / 2, AUC 0-24 The key PK parameters are shown in Table 27 below:

[0310] Table 27. PK parameters of tacrolimus supramolecular nanocomplex eye drops administered to New Zealand rabbits in a single dose (n=3, mean)

[0311] Note*: Whole blood, aqueous humor, Cmax unit is ng / mL, AUC 0-24 The unit is hr.ng / mL.

[0312] Based on the above results, after topical administration of both prescriptions via the ocular surface, tacrolimus can be effectively delivered to all parts of the eye, with concentrations in the aqueous humor and vitreous being above 10 ng / g, while drug concentrations in the choroid, retina, iris, and ciliary body can reach 271 ng / g to 636 ng / g. This can eliminate the need for invasive administration for the treatment of diseases of the middle and posterior segments of the eye, achieving more effective and safer treatment while significantly improving patient compliance. From a PK parameter perspective, with the exception of differences in corneal and conjunctival Tmax, there were no significant differences in other PK parameters. After topical administration of both prescriptions to the eye, drug concentrations in whole blood were less than 10 ng / mL, indicating that topical administration to the eye does not cause systemic toxic side effects.

[0313] According to Thomson AW. Interspecies comparison of the immunosuppressive efficacy and safety of FK506. Transplant Proc. 1990;22:100-105, aqueous humor tacrolimus concentrations of 2ng / mL to 10ng / mL are considered the minimum effective concentration for controlling immune-mediated ocular diseases or organ rejection. Both F9 and F38 formulations can maintain concentrations above 10ng / mL for more than 8 hours. The tissue / whole blood drug exposure ratios for the two formulations are shown in Figure 8.

[0314] Example 8. Synthesis of STVB-CPP-Arg8

[0315] The CPP is octaarginine (Arg8).

[0316] In a 250 mL three-necked flask, 3.18 g of octaarginine (cell-penetrating peptide CPP-Arg8), 50 mL of N,N-dimethylformamide, 1.35 g of diisopropylethylamine, and then 2.0 g of STVB-Ac-Cl were added. After the addition, the reaction system was stirred at room temperature for 12 hours. The reaction system was dried under reduced pressure at 40 ° C to obtain 9.2 g of STVB-Ac-CPP-Arg8 as a foamy light yellow solid.

[0317] In a 100 mL three-necked flask, 9.2 g of STVB-Ac-CPP-Arg8, 25 mL of methanol, 30 mL of N,N-dimethylformamide, and 2.0 g of sodium methoxide were added. The reaction system was stirred at room temperature for 8 hours. The reaction system was then dried under reduced pressure at 40°C to obtain crude STVB-CPP-Arg8. After preparative separation by reverse-phase HPLC, 1.8 g of STVB-CCP-Arg8 was obtained as an off-white solid with an HPLC purity of 92.33%. The main peak retention time of the LC-MS / MS liquid chromatogram was approximately 5.8 min, and the mass-to-charge ratio of the main peak in positive and negative ion modes was 946.0657 (M / 2+H), respectively. + 、993.1732(M / 2+2Na+H) + / 944.1567(M / 2-H) - 、990.5209(M / 2+Na-H) - , and its absolute error with the theoretical precise molecular weight is less than 5ppm. The high-resolution mass spectrometry positive ion mode spectrum is shown in Figure 9; 1H NMR (600MHz, d-DMSO) δ11.52(s,1H),8.41(s,8H),7.93(s,8H),6.55(s,16H),5.38-5.34(d,J=24Hz,1H),5.23(s,1H),5.15-4.82(m,5H),4.70-4.64(m,3H),4.53-4.50(d,J=18Hz,1H),4.27-4.22(m,7H),4.04-3.94(m,3H),3.76-3.72(m,1H),3.71-3.67(m,2H),3. 65-3.62(m,2H),3.44-3.40(m,1H),3.39-3.34(m,2H),3.28-3.24(m,2H),3.14-3.12(m,16H),2.59(s,8H),2.17-2.15(d,J=12Hz,1H),2.04-2.02(m,2H),1.86-1.81(m,1H),1.78-1.41(m,46H),1.30-1.26(m,1H),1.07(s,3H),1.02-1.00(m,1H),0.95(s,3H), NMR 1 The HNMR spectrum is shown in Figure 10.

[0318] Example 9. Synthesis of STL-CPP-Arg2

[0319] In a 500 mL three-necked flask, 50 g of steviol (STL), 160 g of acetic anhydride and 32.0 g of sodium acetate were added, the reaction system was heated to 140 ° C, and the reaction was stirred for 12 hours. The reaction system was cooled to room temperature, 600 mL of dichloromethane was added, and the organic phase was washed three times with 200 mL of purified water. The organic phase was collected and dried under reduced pressure at 40 ° C to obtain 65 g of STL-Ac as a light yellow foamy solid.

[0320] In a 1000mL three-necked flask, add 65g of STL-Ac and 650mL of dichloromethane, stir the reaction system until dissolved, add 1 drop of N,N-dimethylformamide, and then add 45g of oxalyl chloride dropwise at room temperature. After the addition is complete, stir and react at room temperature for 8 hours. The reaction system is dried under reduced pressure at 40°C to obtain 60g of STL-Ac-Cl as a light yellow foamy solid.

[0321] In a 100 mL three-necked flask, 2.5 g of 2-polyarginine, 50 mL of N-methylpyrrolidone, and 3.5 g of diisopropylethylamine were added, and then 2.0 g of STL-Ac-Cl was added in batches. After the addition was completed, the reaction system was stirred at room temperature for 16 hours, and then 15 mL of methanol and 1.0 g of sodium methoxide were added. The reaction system continued to stir at room temperature for 16 hours to obtain a solution of STL-CPP-Arg2 crude product in N-methylpyrrolidone. After reverse phase preparative separation, 1.6 g of STL-CPP-Arg2 was obtained as an off-white solid. The main peak retention time of the LC-MS / MS liquid chromatogram was about 9.8 min, and the mass-to-charge ratio of the main peak in the positive ion mode was 631.4226 (M+H) + 、1261.8796(2M+H) + 、Mass-to-charge ratio in negative ion mode: 629.4198 (MH) - 、1259.4659(2M-H) - The absolute error with its theoretical precise molecular weight is no more than 5ppm. The high-resolution mass spectrometry positive ion mode spectrum is shown in Figure 11. 1 H NMR (600 MHz, d-DMSO+D2O) δ 4.959 (m, 1H), 4.908 (m, 1H), 4.217-4.199 (m, 1H), 3.991-3.970 (m, 1H), 3.140-3.118 (m, 4H), 2.142-1.990 (m, 3), 1.751-1.442 (m, 23H), 1.297-1.259 (m, 1H), 1.074 (s, 3H), 1.019-1.009 (m, 1H), 0.954 (s, 3H), see Figure 12 for details. The HPLC purity was 96.75%.

[0322] Example 10. Synthesis of STL-CPP-Arg4

[0323] In a 100 mL three-necked flask, 5.0 g of 4-polyarginine, 50 mL of N-methylpyrrolidone, and 3.5 g of diisopropylethylamine were added, and then 2.0 g of STL-Ac-Cl was added in batches. After the addition, the reaction system was stirred at room temperature for 17 hours, and then 15 mL of methanol and 1.0 g of sodium methoxide were added. The reaction system continued to stir at room temperature for 17 hours to obtain a solution of STL-CPP-Arg4 crude product in N-methylpyrrolidone. After reverse phase preparative separation, 2.5 g of STL-CPP-Arg4 was obtained as an off-white solid. The retention time of the main peak of the LC-MS / MS liquid chromatogram was about 6.7 min. The mass-to-charge ratio of the main peak in the positive ion mode was 943.6235 (M+H)+ and the mass-to-charge ratio in the negative ion mode was 941.6229 (MH)-, and the absolute error with its theoretical precise molecular weight was no more than 5 ppm. The high-resolution mass spectrometry positive ion mode spectrum is shown in Figure 13. 1 H NMR (600 MHz, d-DMSO+D2O) δ 4.96 (m, 1H), 4.91-4.90 (m, 1H), 4.27-4.22 (m, 3H), 3.99-3.97 (m, 1H), 3.15-3.11 (m, 8H), 2.13-1.96 (m, 3H), 1.78-1.43 (m, 31H), 1.43-1.40 (m, 1H), 1.07-1.02 (m, 4H), 0.94 (s, 3H), see Figure 14 for details. The HPLC purity was 93.84%.

[0324] The specific embodiments described above further illustrate the objectives, technical solutions and beneficial effects of the present invention in detail. It should be understood that the above are only specific embodiments of the present invention and are not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of the present invention should be included in the scope of protection of the present invention.

Claims

1. A supramolecular nanocomposite, characterized in that: The supramolecular nanocomplex comprises an active ingredient, a carrier, and a penetration enhancer, wherein: The penetration enhancer is composed of anionic glycolipids and their salts (sodium salt, potassium salt, ammonium salt, quaternary ammonium salt, calcium salt, magnesium salt or a combination thereof) and glycoside derivatives; The carrier is composed of a covalently linked unit A and a unit B, wherein the unit A is located on one side or both sides of the unit B. When the unit A is located on both sides of the unit B, the units A may be the same or different; wherein the number ratio of the unit A to the unit B is (0:1)-(7:1), Wherein unit B is selected from one or more of B1, and / or one or more of B2, wherein: (1) B1 is a compound represented by the molecular formula (C5H8)n, and its alcohol, aldehyde, ketone, carboxylic acid or ester derivatives, wherein n=4 or 6; (2) B2, a compound composed of two benzene rings (A-ring and B-ring) connected to each other by a central three-carbon chain, with 2-phenylchromone as the basic mother nucleus and a C6-C3-C6 basic skeleton, and its derivatives (such as halides or amino acid esters, the halides are such as chlorine or fluorine, and the amino acid esters are such as esters formed by the hydroxyl group on C6 and amino acids); The unit A is selected from one or more of A1 or derivatives of A1, wherein: A1 is selected from D-type or L-type monosaccharides, disaccharides, trisaccharides or a combination thereof, wherein the monosaccharide is selected from the group consisting of glucose, rhamnose, galactose, arabinose, xylose, mannose, fucose, apiose, glucuronic acid, glucosamine, galacturonic acid, acetylamino sugars or a combination thereof, and the relative configuration of each glycosyl terminal carbon can be α-type or β-type; The disaccharide is selected from the group consisting of sophorose (glc1-2glc), gentiobiose (glC1-6glc), rutinose (rha1-6glc), neohesperidose (rha1-6glC), acaciabiose (rha1-6gal) or a combination thereof; trisaccharide selected from the group consisting of gentiotriose, sophorotriose (glc1-2glc1-2glc) or a combination thereof; The derivative of A1 is an acylated form of A1, such as 2-acetylglucose and caffeoylglucose.

2. The supramolecular nanocomposite according to claim 1, characterized in that The active ingredient is selected from one or more of the following categories in free form, salt, hydrate, solvate, or a combination thereof: immunosuppressants such as cyclosporine, flucyclosporine, tacrolimus, sirolimus, everolimus, mycophenolate mofetil, mycophenolic acid and fingolimod; glucocorticoids such as hydrocortisone, prednisone acetate, cortisone acetate, loteprednol, methylprednisolone, fluorometholone, dexamethasone, dexamethasone sodium phosphate, Prednisone sodium phosphate, triamcinolone, triamcinolone acetonide, fluocinolone acetonide, difluprednate; anti-infective drugs, such as cefazolin, ceftriaxone, ceftazidime, rimexolone, chloramphenicol, tobramycin, natamycin, neomycin, erythromycin, chlortetracycline, azithromycin, moxifloxacin, besifloxacin, ciprofloxacin, ofloxacin, levofloxacin, gatifloxacin, gentamicin, amikacin, penicillin G, kanamycin, methicillin Lin, piperacillin, vancomycin, clindamycin, lincomycin, amphotericin B methyl ethyl ester, lincomycin, netilmicin, oxacillin, teicoplanin, clarithromycin, sodium sulfamethoxazole, potentiated sulfamethoxazole, amphotericin B, clotrimazole, econazole, miconazole, posaconazole, flucytosine, linezolid, tazobactam, imipenem, voriconazole, itraconazole, vorconazole, ketoconazole, caspofungin, micafungin net, terbinafine, polymyxin, spiramycin, tetracycline, acetylspiramycin; prostaglandin analogues, such as latanoprost, bimatoprost, travoprost, tafluprost, (Z)-7-[(1R, 2R, 3R, 5S)-3,5-dihydroxy-2-(3-oxodecanyl)cyclopentyl]hept-5-enoic acid (Unoprostone) and latanoprost nitrate; nonsteroidal anti-inflammatory drugs, Such as pranoprofen, diclofenac, meloxicam, indomethacin, ketorolac, flurbiprofen, flurbiprofen axetil, and bromfenac; carbonic anhydrase inhibitors such as acetazolamide, methazolamide, diclofenac, nepafenac, brinzolamide, and dorzolamide; beta-adrenergic antagonists such as carteolol, levobunolol, metipranolol, timolol, and betaxolol; alpha-adrenergic antagonists such as alaclonidine and brimonidine; Rho kinase inhibitors such as nepafenac diltiazem, alprostadil; hyperosmolarity agents such as glycerol, mannitol, and isosorbide; HMG-CoA reductase inhibitors such as atorvastatin, rosuvastatin, simvastatin, pravastatin, lovastatin, cerivastatin, and mevastatin; visual cycle inhibitors such as (1R)-3-amino-1-[3-(cyclohexylmethoxy)phenyl]propan-1-ol; levodopa; glatiramer acetate; tandospirone; trimetazidine; Visaline;Lutein and its esters, zeaxanthin, folic acid, homocysteine, curcumin, B vitamins, vitamin K, vitamin A, vitamin E, ginkgo flavonoids and lactones, crocin, crocetin, VEGFR inhibitors such as bruceizumab, ranibizumab, conbercept, bevacizumab, 2-(6,7-dimethoxyquinazolin-4-yl)amino-5-methyl-1,3,4-thiadiazole, anlotinib, cabozantinib, voronib, brivanib, 5-((6-aminopyrimidin-4-yl)oxy)-N-(3-(trifluoromethyl)phenyl)-1H-indole-1-carboxamide, (Z)-3-(2,4-dihydroxybenzylidene)indole-2-one , semasanib, (E)-2-cyano-3-[4-hydroxy-3,5-di(propan-2-yl)phenyl]-N-(3-phenylpropyl)prop-2-enamide, apatinib, regorafenib, albendazole, axitinib, E)-1-ethyl-3-methyl-N-(3-(3-(2-(pyridin-2-yl)vinyl)-1H-indazole-6-carbonyl)phenyl)-1H-pyrazole-5-carboxamide, (E)-N-(3-(3-(2-(pyridin-2-yl)vinyl)-1H-indazole-6-carbonyl)phenyl)benzamide, pazopanib, (3aR,7S,8aS)-7-methyl-3-methylene-6-[(E)-3- oxobut-1-enyl]-4,7,8,8a-tetrahydro-3aH-cyclohepta[b]furan-2-one, purpurogenol, 3-(2-((3,4-dihydroxyphenyl)(4-(2-(dimethylamino)ethyl)-1H-imidazol-1-yl)methyl)benzo[d][1,3]dioxolan-5-yl)propionic acid, quercetin, dihydroartemisinin, 4-chloro-3-[5-methyl-3-[4-(2-pyrrolidin-1-ethoxy)anilino]-1,2,4-benzotriazin-7-yl]phenol, [4-chloro-3-[5-methyl-3-[4-(2-pyrrolidin-1-ethoxy)anilino]-1,2,4-benzotriazin-7-yl]phenol 7-aminobenzoic acid esters; intercellular adhesion molecule inhibitors such as lifestin; fenretinide; antiviral drugs such as acyclovir and ganciclovir; antihistamines such as azelastine, desmethylazelastine, levocabastine, pemirolast potassium, and emedastine; ocular anesthetics such as proparacaine, oxybuprocaine, proancaine, mepivacaine, bupivacaine, levobupivacaine, ropivacaine, etidocaine, tetracaine, and lidocaine; anticholinergics and cholinergic agonists such as pilocarpine, carbachol, cyclopentolate, tropicamide, cyclopentolate, pirenzepine, anisodamine, atropine, and eucatropine; mast cell stabilizers such as lodoxamide, olopatadine, and sodium glycinate;Epinephrine, phenylephrine, cannabidiol and its derivatives, macitentan, aproracetam, bosentan, ambrisentan, pirenoxine, sildenafil, methylcobalamin, vitamin B12, aminoiodine, fluorescein sodium, ursodeoxycholic acid, danshensu, dinggongtengsu, puerarin, arecoline, fenretinide.

3. The supramolecular nanocomposite according to claim 1, characterized in that The anionic glycolipid is composed of a hydrophilic sugar residue and a saturated or unsaturated hydrophobic fatty acid with different carbon chain lengths through a covalent bond, wherein the hydrophilic sugar residue is selected from one or more of rhamnose, sophorose, trehalose, mannitol, and erythritol, and the preferred sugar residue is rhamnose or a disaccharide or trisaccharide containing rhamnose; when the sugar residue is rhamnose, the anionic glycolipid is a combination of one or more rhamnolipids. The chemical structure of the rhamnolipid is shown in Formula I: R1, R2, R3 are selected from the following groups: in, Preferably, the carbon chain length of R3 is C6 to C14, and the number of unsaturated double bonds is 0, 1, 2, or 3. Preferably, the carbon chain length of R3 is C8 to C12, and the number of unsaturated double bonds is 0, 1, or 2.

4. The supramolecular nanocomposite according to claim 1, characterized in that The structure of the glycoside derivative is shown in Formula II, Wherein R1 is selected from the following groups: (1) R1 is selected from a polymer, such as polydopamine, polyarginine amide or polyglutamic acid; (2) R1 is selected from an amino acid residue, such as arginine, histidine, lysine or an aminoamide, wherein the aminoamide is selected from the aminoamide corresponding to the amino acid; (3) R1 is selected from a short peptide consisting of 2-20 amino acids and having a positive charge under physiological conditions, preferably a cell-penetrating peptide (CPP), and the preferred cell-penetrating peptide is an octaarginine cell-penetrating peptide; R2 is a hydroxyl group or a sugar residue. When R2 is a sugar residue, R2 is selected from a monosaccharide, a disaccharide, an oligosaccharide, and a polysaccharide. Preferably, the number of R2 sugar residues is ≤3. Preferably, R2 has the following structure:

5. The supramolecular nanocomposite according to claim 4, characterized in that The glycoside derivative carries ≥1 positive charge under physiological conditions, and preferably the glycoside derivative carries ≥2 positive charges at pH 5.0 to 8.

5.

6. The supramolecular nanocomposite according to claim 1, characterized in that The carrier unit B1 is a tetracyclic diterpene, a tetracyclic triterpene, a pentacyclic triterpene, or one or more of their alcohol, aldehyde, ketone, carboxylic acid or ester derivatives, wherein: The tetracyclic diterpenes are of the kaurene type and their derivatives; The tetracyclic triterpenes are selected from one or more of dammarane type, gansuline type, cycloartane type, lanolin type, cucurbitane type, azadirachtin type and prototerpane type and their derivatives, preferably cucurbitane type and its derivatives; The pentacyclic triterpenes are any one or more of oleanane type, ursane type, lupeane type, suberane type, hobeane type and isohobeane type and their derivatives, preferably oleanane type.

7. The supramolecular nanocomposite according to claim 6, characterized in that The chemical structures of the kaurene-type carrier, cucurbitane-type carrier and oleanane-type carrier are as follows: (1) When the carrier is a kaurene-type tetracyclic diterpene or a pharmaceutically acceptable salt thereof (such as a sodium salt, potassium salt, ammonium salt), or a hydrate of a kaurene-type tetracyclic diterpene or a pharmaceutically acceptable salt thereof (such as a hydrate formed with 0.5, 1, 1.5, 2, 2.5 or 3 waters of crystallization), the carrier has the structure of Formula III: Wherein R1 and R2 are selected from the following groups, and R1 and R2 may be the same or different: (2) When the cucurbitane-type tetracyclic triterpene or a pharmaceutically acceptable hydrate or solvate thereof, the carrier has the structure of Formula IV: Wherein R1, R2, R3, and R4 are selected from the following groups: (3) When the oleanane-type pentacyclic triterpenoid or a pharmaceutically acceptable salt (ammonium salt, potassium salt, sodium salt), hydrate or solvate thereof, the carrier has the structure of Formula V: Wherein R1 and R2 are selected from the following groups: The kaurene-type carrier is selected from one or more of steviol glycosides and their derivatives; the cucurbitane-type carrier is selected from one or more of mogrosides and their derivatives; the oleanane-type carrier is selected from one or more of glycyrrhizic acid and its derivatives, or a combination thereof.

8. The supramolecular nanocomposite according to claim 1, characterized in that The carrier is one or more flavonoid glycosides composed of unit B2 and different sugar residues by covalent bonds; The unit B2 is selected from flavonoids, flavanones, 8-isopentenyl flavonoids, chalcone, dihydrochalcone and its derivatives (alcohol, aldehyde, ketone, methylation, carboxylic acid or ester), preferably B2 is dihydrochalcone and flavanone, When the flavonoid glycoside or flavonoid glycoside compound with flavanone or dihydrochalcone as aglycone is a pharmaceutical hydrate or solvate, the carrier has a structure of formula VI, The flavanone-type flavonoid glycosides and derivatives are selected from neohesperidin, hesperidin, and naringin; the dihydrochalcone flavonoid glycosides are selected from naringin dihydrochalcone and neohesperidin dihydrochalcone; or a combination thereof.

9. The supramolecular nanocomposite according to any one of claims 1 to 8, characterized in that: The penetration enhancer is selected from the group consisting of: (1) (R)-3-(((R)-3-((2R,3R,4R,5R,6S)-4,5-dihydroxy-6-methyl-3-(((2S,3R,4R,5R,6S)-3,4,5-trihydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)tetrahydro-2H-pyran-2-yl)oxy)decanoyl)oxy)decanoic acid (Rha-Rha-C10-C10), (2) (S,E)-3-(((R)-3-(((2R,3R,4R,5R,6S)-4,5-dihydroxy-6-methyl-3-(((2S,3R,4R,5R,6S)-3,4,5-trihydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)tetrahydro-2H-pyran-2-yl)oxy)decanoyl)oxy)dodec-4-enoic acid (Rha-Rha-C10-C12:1), (3) (R)-3-(((R)-3-((2R,3R,4R,5R,6S)-3,4,5-trihydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)decanoyl)oxy)decanoic acid (Rha-C10-C10), (4) (R)-3-(((R)-3-(((2R,3R,4R,5R,6S)-4,5-dihydroxy-6-methyl-3-(((2S,3R,4R,5R,6S)-3,4,5-trihydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)tetrahydro-2H-pyran-2-yl)oxy)decanoyl)oxy)dodecanoic acid (Rha-Rha-C10-C12), (5) (S,E)-3-(((R)-3-)(((2R,3R,4R,5R,6S)-3,4,5-trihydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)decanoyl)oxy)dodec-4-enoic acid (Rha-C10-C12:1), (6) (R)-3-(((R)-3-(((2R,3R,4R,5R,6S)-3,4,5-trihydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)decanoyl)oxy)dodecanoic acid (Rha-C10-C12), (7) (S,4E,6E)-3-(((2R,3R,4R,5R,6S)-4,5-dihydroxy-6-methyl-3-(((2S,3R,4R,5R,6S)-3,4,5-trihydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)tetrahydro-2H-pyran-2-yl)oxy)decane-4,6-dienoic acid (Rha-Rha-C10:2), (8) (R)-3-(((R)-3-(((2R,3R,4R,5R,6S)-4,5-dihydroxy-6-methyl 3-(((2S,3R,4R,5R,6S)-3,4,5-trihydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)tetrahydro-2H-pyran-2-yl)oxy)decanoyl)oxy)octanoic acid (Rha-Rha-C10-C8), (9) (S,4E,6E)-3-(((2R,3R,4R,5R,6S)-3,4,5-trihydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)decadienoic acid (Rha-C10:2), (10) (R)-3-(((2R.3R.4R.5R.6S)-3.4.5-trihydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)decanoic acid (Rha-C10), (11) (R)-3-(((2R,3R,4R,5R,6S)-4,5-dihydroxy-6-methyl-3-((2S,3R,4R,5R,6S)-3,4,5-trihydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)tetrahydro-2H-pyran-2-yl)oxy)decanoic acid (Rha-Rha-C10), (12) Any combination of compounds (1) to (11), (13) (S)-2-((S)-2-((4R,4aS,6aR,9S,11aR,11bS)-9-((2S,3R,4S,5S,6R)-4,5-dihydroxy-6-(hydroxymethyl)-3-(((2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)tetrahydro-1H-pyran-2-yl)oxy)-4,11b-dimethyl-8-methylenetetrahydro-6a,9-methylcyclohepta[a]naphthalene-4-carboxamide)-5-guanidine amide)-5-guanidine valeric acid (STVB-CPP-Arg2), (14) (S)-2-((S)-2-(S)-2-[(4R,4aS,6aR,9S,11aR,11bS)-9-((2S,3R,4S,5S,6R)-4,5-dihydroxy-6-(hydroxymethyl)-3-(((2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)tetrahydro-1H-pyran-2-yl)oxy)-4,11b- dimethyl-8-methylenetetradecahydro-6a,9-methylcyclohepta[a]naphthalene-4-carboxamide)-5-guanidine amide)-5-guanidine amide)-5-guanidine amide)-5-guanidine acid (STVB-CPP-Arg3), (15)(6S,9S,12S,15S)-1-amino-6-((4R,4aS,6aR,9S,11aR,11bS)-9-(((2S,3R,4S,5S,6R)-4,5-dihydroxy-6-(hydroxymethyl)-3-(((2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H- (pyran-2-yl)oxy)tetrahydro-2H-pyran-2-yl)oxy)-4,11b-dimethyl-8-methylenetetrahydro-6a,9-methylcyclohepta[a]naphthalene-4-carboxamide)-9,12,15-tris(3-guanidinepropyl)-1-imino-7,10,13-trioxy-2,8,11,14-tetraazahexadecane-16-oic acid (STVB-CPP-Arg4), (16) (S)-5-guanidine-2-((S)-5-guanidine-2-(4R,4aS,6aR,9S,11aR,11bS)-9-hydroxy-4,11-dimethyl-8-methylenetetrahydro-6a,9-methylcyclohepta[a]naphthalene-4-amido)pentanamido)pentanoic acid (STL-CPP-Arg2), (17) (6S,9S,12S,15S)-1-amino-9,12,15-tris(3-guanidinopropyl)-6-((4R,4aS,6aR,9S,11aR,11bS)-9-hydroxy-4,11-dimethyl-8-methylenetetrahydro-6a,9-methylcyclohepta[a]naphthalene-4-carboxamide)-1-imino-7,10,13-trioxy-2,8,11,14-tetraazahexadecane-16-carboxylic acid (STL-CPP-Arg4), (18) Any combination of (13)-(17), (19) Any combination of (12)-(18) or any combination of (1)-(11) and (13)-(18).

10. The supramolecular nanocomposite according to any one of claims 1 to 9, characterized in that: The carrier is selected from the group consisting of: (1) [(2S,3R,4S,5R,6R)-5-hydroxy-6-(hydroxymethyl)-3,4-bis[[(2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)oxa-2-yl]oxy]oxa-2-yl](1R,4S,5R,9S,10R,13S)-13-[(2S,3R,4S,5R,6R)- 5-Hydroxy-6-(hydroxymethyl)-3,4-bis[(2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)oxa-2-yl]oxy]oxa-2-yl]oxy-5,9-dimethyl-14-methylenetetracyclo[11.2.1.01,10.04,9]hexadecane-5-carboxylate (Rebaudioside M / RBDS-M), (2) (2S,3R,4S,5S,6R)-4,5-dihydroxy-6-(hydroxymethyl)-3-[(2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)oxa-2-yl]oxyoxa-2-yl](1R,4S,5R,9S,10R,13S)-13-[(2S,3R,4S,5R,6R)-5-hydroxy-6-(hydroxymethyl)-3,4-bis[[(2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)oxa-2-yl]oxy]oxa-2-yl]oxy-5,9-dimethyl-14-methylenetetracyclo[11.2.1.01,10.04,9]hexadecane-5-carboxylate (Rebaudioside D / Rebaudioside D, RBDS-D), (3) [(2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)oxa-2-yl](1R,4S,5R,9S,10R,13S)-13-[(2S,3R,4S,5R,6R)-5-hydroxy-6-(hydroxymethyl)-3,4-bis[[(2S,3R),4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)oxa-2-yl]oxy]oxa-2-yl]oxy-5,9-dimethyl-14-methylenetetracyclo[11.2.1.01,10.04,9]hexadecane-5-carboxylate (Rebaudioside A / RBDS-A), (4) (1R,4S,5R,9S,10R,13S)-13-[(2S,3R,4S,5R,6R)-5-hydroxy-6-(hydroxymethyl)-3,4-bis[[(2S,3R),4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)oxa-2-yl]oxy]oxa-2-yl]oxy-5,9-dimethyl-14-methylenetetracyclo[11.2.1.01,10.04,9]hexadecane-5-carboxylic acid (Rebaudioside B / RBDS-B), (5) [(2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)oxa-2-yl] (1R,4S,5R,9S,10R,13S)-13-[(2S,3R,4S,5R,6R)-5-hydroxy-6-(hydroxymethyl)-4-[(2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)oxa-2-yl]oxy -3-[(2S,3R,4R,5R,6S)-3,4,5-trihydroxy-6-methyloxa-2-yl]oxyoxa-2-yl]oxy-5,9-dimethyl-14-methylenetetracyclo[11.2.1.01,10.04,9]hexadecane-5-carboxylate (Rebaudioside C / RBDS-C), (6) [(2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)oxa-2-yl](1R,4S,5R,9S,10R,13S)-13-[(2S,3R,4S,5S,6R)-4,5-dihydroxy-6-(hydroxymethyl)-3-[(2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)oxa-2-yl]oxyoxa-2-yl]oxy-5,9-dimethyl-14-methylenetetracyclo[11.2.1.01,10.04,9]hexadecane-5-carboxylate (Stevioside / Stevioside, STVS), (7) (1R,4S,5R,9S,10R,13S)-13-[(2S,3R,4S,5S,6R)-4,5-dihydroxy-6-(hydroxymethyl)-3-[(2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)oxa-2-yl]oxyoxa-2-yl]oxy-5,9-dimethyl-14-methylenetetracyclo[11.2.1.01,10.04,9]hexadecane-5-carboxylic acid (Steviolbioside / STVB), (8) Conjugates of steviol glycosides (stevioside, RBDS-B, STVB, RBSD)-HA or PEG (9)(2R,3S,4S,5R,6R)-2-(hydroxymethyl)-6-({[(2R,3S,4S,5R,6S)-3,4-dihydroxy-6-{[(3R,6R)-2-hydroxy-6-[(1R,3aS,3bS,7S,9aR,9bR,10R,11aR)-10-hydroxy-7-{[(2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-({[(2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)-3,4,5,6-tetrahydro-2H-pyran-2-yl]oxy}methyl)-3,4,5,6-tetrahydro- -2H-pyran-2-yl]oxy}-3a,6,6,9b,11a-pentamethyl-2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a-tetrahydro-1H-cyclopenta[1,2-a]phenanthren-1-yl]-2-methylhept-3-yl]oxy}-5-{[(2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)-3,4,5,6-tetrahydro-2H-pyran-2-yl]oxy}-3,4,5,6-tetrahydro-2H-pyran-2-yl]methyl}oxy)tetrahydropyran-3,4,5-triol (Mogroside V / MGSD-V), (10)(3S,8S,9R,10R,13R,14S,17R)-17-((2R,5R)-5-((((2S,3R,4S,5S,6R)-4,5-dihydroxy-3-(((2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)methyl)tetrahydro-2H-pyran-2-yl)oxy)-6-hydroxy-6- Methylheptane-2-yl)-4,4,9,13,14-pentamethyl-3-(((2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-((((2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)methyl)tetrahydro-2H-pyran-2-yl)oxy)-1,2,3,4,7,8,9,10,12,13,14,15,16,17-tetradecahydro-11H-cyclopenta[a]phenanthrene-11-one (11-Oxomogroside V / 11-Oxomogroside V, OMGSD-V), (11)(2S,3R,4S,5S,6R)-2-(((2S,3R,4S,5S,6R)-4,5-dihydroxy-2-(((3R,6R)-2-hydroxy-6-((3S,8S,9R,10R,11R,13R,14S,17R)-11-hydroxy-4,4,9,13,14-pentamethyl-3-(((2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)-2,3, 4,7,8,9,10,11,12,13,14,15,16,17-tetrahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-methylheptan-3-yl)oxy)-6-((((2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)methyl)tetrahydro-2H-pyran-3-yl)oxy)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (Siamenoside I / SMSD-I), (12)(2R,3R,4S,5S,6R)-2-(((3S,8R,9R,10S,11R,13R,14S,17R)-17-((2R,5R)-5,6-dihydroxy-6-methylheptane-2-yl)-11-hydroxy-4,4,13,14-tetramethyl -2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)oxy)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (Mogroside 1E1 / MGSD-IE1), (13) Any combination of (9)-(12) (MGSDT), (14) (2S)-7-[(2S,3R,4S,5S,6R)-4,5-dihydroxy-6-(hydroxymethyl)-3-[(2S,3R,4R,5R,6S)-3,4,5-trihydroxy-6-methyloxan-2-yl]oxyoxan-2-yl]oxy-5-hydroxy-2-(3-hydroxy-4-methoxyphenyl)-2,3-dihydrochromen-4-one (Neohesperidin / NHPD), (15) 1-[4-[(2S,3R,4S,5S,6R)-4,5-dihydroxy-6-(hydroxymethyl)-3-[(2S,3R,4R,5R,6S)-3,4,5-trihydroxy-6-methyloxy-2-yl]oxyoxan-2-yl]oxy-2,6-dihydroxyphenyl]-3-(3-hydroxy-4-methoxyphenyl)propan-1-one (Neohesperidin Dihydrochalcone, NHDC), (16) 1-[4-[(2S,3R,4S,5S,6R)-4,5-dihydroxy-6-(hydroxymethyl)-3-[(2S,3R,4R,5R,6S)-3,4,5-trihydroxy-6-methyloxan-2-yl]oxyoxan-2-yl]oxy-2,6-dihydroxyphenyl]-3-(4-hydroxyphenyl)propan-1-one (Neohesperidin Dihydrochalcone, NRGDC), (17) methyl (4R,4aS,6aR,9S,11aR,11bS)-9-(((2S,3R,4S,5R,6R)-5-hydroxy-6-(hydroxymethyl)-3,4-bis((2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)tetrahydro-2H-pyran-2-yl)oxy)-4,11b-dimethyl-8-methylenetetrahydro-6a,9-methylcyclohepta[a]naphthalene-4-carboxylate (RBDS-B-Methyl), (18) Ethyl (4R, 4aS, 6aR, 9S, 11aR, 11bS)-9-(((2S, 3R, 4S, 5R, 6R)-5-hydroxy-6-(hydroxymethyl)-3,4-bis((2S, 3R, 4S, 5S, 6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)tetrahydro-2H-pyran-2-yl)oxy)-4,11b-dimethyl-8-methylenetetrahydro-6a,9-methylcyclohepta[a]naphthalene-4-carboxylate (RBDS-B-Ethyl), (19)(2S,3S,4S,5R,6R)-6-(((2S,3R,4S,5S,6S)-6-carboxy-2-(((3S,4aR,6aR,6bS,8aS,11S,12aR,14aR,14bS)-11-carboxy-4,4,6a,6b,8a,11,14b-heptamethyl-14-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,14,14a,14b-eicosadien-3-yl)oxy)-4,5-dihydroxytetrahydro-2H-pyran-3-yl)oxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid (Glycyrrhizic acid / Glycyrrhizic acid) Acid,GA), (20)(2S,3S,4S,5R,6R)-6-(((2S,3R,4S,5S,6S)-6-carboxy-2-(((3S,4aR,6aR,6bS,8aS,11S,12aS,14aR,14bS)-11-carboxy-4,4,6a,6b,8a,11,14b-heptamethyl-14-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,14,14a,14b-eicosadien-3-yl)oxy)-4,5-dihydroxytetrahydro-2H-pyran-3-yl)oxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid (Isoglycyrrhizic acid / Isoglycyrrhizic acid Acid, IGA), (21) A combination of any one of (1)-(20).

11. The supramolecular nanocomposite according to any one of claims 1 to 10, characterized in that: The dosage of the carrier is 0.1%-15% (w / v), wherein the dosage of glycolipid is 0.01%-5% (w / v), and the dosage of glycoside derivative is 0.1%-10% (w / v).

12. The supramolecular nanocomposite according to any one of claims 1 to 11, characterized in that: The supramolecular nanocomposite also contains a high molecular weight polymer, such as chitosan, hyaluronic acid, sodium carboxymethyl cellulose, hydroxypropyl methylcellulose, povidone, copovidone, hydroxypropyl methylcellulose acetate succinate, polyethylene caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, polyethylene glycol, polyethylene oxide, polyacrylamide, polyvinyl alcohol, polyethyleneimine, polylactide-glycolide copolymer, polyglutamic acid, polyarginine, polydopamine, polylactic acid, poly-L-lactic acid, polylactic acid-glycolic acid copolymer, sodium polyacrylate, siRNA and its derivatives (alkyl chains for improving lipophilicity), mRNA and its derivatives (alkyl chains for improving lipophilicity) or antisense oligonucleotides and their derivatives (alkyl chains for improving lipophilicity), preferably one or more of hydroxypropyl methylcellulose (HPMC), povidone (PVP), copovidone, hydroxypropyl methylcellulose acetate succinate (HPMCAS), polyethylene caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus), and hyaluronic acid (HA).

13. The supramolecular nanocomposite according to any one of claims 1 to 12, characterized in that: The supramolecular nanocomposite further contains a surfactant, preferably one or more of polysorbates, polyoxyethylene hydrogenated castor oils, polyoxyethylene castor oils, polyoxyl stearates, polyethylene glycol-15 hydroxystearate, sodium lauryl sulfate, vitamin E polyethylene glycol succinate, and retinol ester surfactants.

14. The supramolecular nanocomposite according to any one of claims 1 to 13, characterized in that: The effective particle size range of the supramolecular nanocomplex detected by DLS method is: 5nm-200nm, preferably 10nm-150nm.

15. The supramolecular nanocomposite according to any one of claims 1 to 14, characterized in that: The zeta potential range of the supramolecular nanocomplex is: -30mV to 50mV, preferably -20mV to 40mV.

16. The supramolecular nanocomposite according to any one of claims 1 to 15, characterized in that: The supramolecular nanocomposite preparation further contains excipients (preferably ophthalmic preparation excipients), such as one or more selected from pH regulators, osmotic pressure regulators, thickeners, gel carriers, or in-situ gel carriers, and antibacterial agents. The pH regulator is preferably selected from one or more of hydrochloric acid, acetic acid, citric acid, tartaric acid, succinic acid, arginine, lysine, taurine, nicotinic acid, nicotinamide, histidine, tryptophan, malic acid, lactic acid, ascorbic acid, phosphoric acid, adipic acid, fumaric acid, sulfuric acid, nitric acid, p-toluenesulfonic acid, boric acid, sodium hydroxide, sodium citrate, potassium citrate, monosodium citrate, sodium lactate, calcium hydroxide, potassium hydroxide, sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, tromethamine, meglumine, sodium phosphate, disodium hydrogen phosphate, sodium dihydrogen phosphate, potassium phosphate, dipotassium hydrogen phosphate, potassium dihydrogen phosphate, sodium acetate or potassium acetate; The osmotic pressure regulator is preferably selected from glycerol, mannitol, propylene glycol, sodium chloride, potassium chloride, glucose, calcium chloride, sodium bicarbonate, sodium carbonate, sodium lactate, borax or a combination thereof; The thickener is preferably selected from povidone, cellulose derivatives, sodium hyaluronate, polyvinyl alcohol, xanthan gum, gum arabic and any combination thereof; The antibacterial agent is preferably at least one selected from benzyl alcohol, chlorobutanol, parabens, benzethonium chloride, benzalkonium chloride, benzalkonium bromide, and cetaxel chloride; The gel carrier is preferably selected from one or more of starch, gum arabic, pectin, agar, gelatin, algin, carrageenan, propylene glycol alginate, methylcellulose, sodium starch phosphate, hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, sodium carboxymethyl cellulose, polyvinyl alcohol, carbomer, polycarbophil, chitosan and its derivatives, and sodium hyaluronate; The in situ gel carrier is preferably selected from one or more of poloxamer, polyethylene glycol block copolymers such as PLGA-PEG-PLGA, soybean phosphatidylcholine, diolein, sucrose acetate isobutyrate, orthoesters, chitosan and its derivatives, and alginate.

17. A composition comprising the supramolecular nanocomplex according to any one of claims 1 to 16, preferably in the form of nano eye drops, drug-loaded contact lenses, gel or in situ gel.

18. Use of the supramolecular nanocomplex according to any one of claims 1 to 16 in the preparation of a preparation for diagnosis, treatment or auxiliary treatment and / or prevention of a disease (preferably an ophthalmic disease), preferably the ophthalmic disease is selected from conjunctivitis, keratitis, dry eye, age-related macular degeneration, seasonal keratoconjunctivitis, anti-corneal transplant rejection, glaucoma, diabetic retinopathy, cataract, uveitis.

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