Taxane supramolecular nanocomposite and use thereof

Abstract

A taxane supramolecular nanocomposite. The supramolecular nanocomposite comprises a taxane active substance, including but not limited to paclitaxel, docetaxel, and cabazitaxel, as well as a self-assembling carrier, a high molecular polymer, and a dissolution promoter. The dissolution promoter may comprise one or more of alcohols, polybasic organic acids, and amino acids. Also disclosed are a preparation method and use of the supramolecular nanocomposite. The supramolecular nanocomposite is suitable for oral administration and topical application, providing effects such as increased local drug exposure concentration and efficacy, reduced systemic side effects, etc.

Description

Taxane-based supramolecular nanocomposites and their applications Technical Field

[0001] This invention relates to the field of pharmaceutical technology, specifically to a taxane-based supramolecular nanocomposite and its applications. Background Technology

[0002] Cancer is a long-term and heavy disease burden. Despite significant progress in our understanding of cancer, a lack of detailed knowledge reduces treatment success rates, making cancer the leading cause of death worldwide. Nevertheless, humanity continues to seek new treatments and develop new, potent, and specific drugs. For example, repositioning drugs already approved for other indications or improving the performance of currently used anticancer drugs often yields higher success rates and greater patient benefits compared to discovering entirely new compounds. Natural compounds play a major role in the fight against cancer. Taxanes are among the most widely used. Taxanes are natural diterpenoids found in the yew tree and are widely used clinically to treat solid tumors such as ovarian cancer, breast cancer, uterine cancer, lung cancer, pancreatic cancer, and head and neck cancer. Although marketed taxane drugs, such as paclitaxel (PTX), docetaxel or docetaxel (DCTX), and cabazitaxel (CBTX), can significantly improve the overall survival rate of cancer patients, they still have significant limitations, such as extremely poor water solubility, very low oral bioavailability (≤2%) due to first-pass metabolism or efflux, clinically they can only be administered by injection, and serious side effects (many toxic side effects are caused by solubilizers, surfactants, or carriers).

[0003] The chemical structures of paclitaxel, docetaxel, and cabazitaxel are shown in formulas (I) and (II).

[0004] To address the clinical pain points of marketed taxane drugs, solutions mainly focus on two aspects: (1) structural modification, such as docetaxel, cabazitaxel, and new taxane drugs that have entered the clinical stage listed in Drug Design, Development and Therapy 2012:6 371–384, such as Tesetaxel (DJ-927), Paclitaxel Poliglumex (CT-2103, a paclitaxel derivative with α-poly-L-glutamic acid), Larotaxel (XRP9881), DHA-Paclitaxel (Taxoprexin), BMS-184476, and structural analogs of Larotaxel in the literature http: / / dx.doi.org / 10.1016 / j.ejmech.2018.07.029.

[0005] Although the above-mentioned structural analogs have some improvements over docetaxel or paclitaxel in terms of solubility, first-pass metabolism, certain side effects, blood-brain barrier crossing, and drug resistance, the serious toxic side effects of grade 3-4 with an incidence of more than 5% in clinical trials are still mainly neutropenia, leukopenia, neurotoxicity, and anemia. The actual effect is not significant, and no new taxane drug has been applied to clinical treatment.

[0006] The chemical name of paclitaxel is (2aR,4S,4aS,6R,9S,11S,12S,12aR,12bS)-1,2a,3,4,4a,6,9,10,11,12,12a,12b-dodecano-4,6,9,11,12,12b-hexahydroxy-4a,8,13,13-tetramethyl-7,11-methylene-5H-ringed decano[3,4]benzo[1,2-b]oxetane-5-one 6,12b-diacetate, 12-benzoate, 9-(2R,3S)-N-benzoyl-3-phenylisoserine ester, with the molecular formula C 47 H 51 NO 14With a molecular weight of 853.91, paclitaxel belongs to the BCS Class IV class of low-soluble and low-osmotic drugs. Paclitaxel is almost insoluble in water, with a solubility of approximately 0.2 μg / mL to 0.3 μg / mL in aqueous solutions at pH 4.0-9.0 (23℃-25℃), which is insufficient for clinical treatment requirements. Due to solubility limitations, existing products extensively utilize surfactants or co-solvents. For example, Taxol, the first-generation paclitaxel product, uses a mixed solvent of polyoxyethylene castor oil and anhydrous ethanol [50-50 (V / V)] to prepare a 6 mg / mL liquid formulation of paclitaxel. Docetaxel has slightly better water solubility than paclitaxel, and its marketed products use Tween 80 and ethanol as solvents. Taxanes can cause adverse reactions such as bone marrow suppression, neuropathy, fatigue, hair loss, nausea, and vomiting; docetaxel can cause nail damage. For traditional taxane formulations, the toxicity of solubilizing carriers, such as polyoxyethylene castor oil and Tween 80, exacerbates these adverse effects. In addition, hypersensitivity, nephrotoxicity, and hypotension are adverse reactions caused by polyoxyethylene castor oil and Tween 80. Furthermore, polyoxyethylene castor oil often causes serious adverse reactions, such as severe hypersensitivity, hyperlipidemia, abnormal lipoprotein profiles, erythrocyte aggregation, and requires pretreatment before administration. Moreover, the drug loading capacity cannot meet the treatment needs of various solid tumors, which greatly limits the wider clinical application of paclitaxel.

[0007] The application of novel nanodelivery technologies offers more ideas for addressing the clinical pain points of existing taxane drugs, such as Abraxane albumin-bound paclitaxel nanoparticles, Lipusu liposomes, and Cynviloq. TM Novel nanoformulations, such as polymer micelles, are being developed. Compared to taxol, these novel nanoformulations do not use polyoxyethylene castor oil, organic solvents, or solubilizing carriers like Tween 80. They eliminate the need for pre-treatment desensitization with hormonal injections, reducing infusion time, simplifying administration, and improving safety. However, new carrier-related toxicities have emerged, such as dose-dependent hematologic toxicity of abraxane, non-hematologic toxicities like nausea, vomiting, muscle and joint pain, and blurred or dry vision. Sensory neuropathy, neutropenia, and febrile neutropenia have also been observed. Furthermore, existing marketed products are all administered by injection, making self-administration impossible. Additionally, while existing products show some exposure in specific target organs / tissues such as the lungs, breast, pancreas, and ovaries after injection, the exposure is very limited for some gastrointestinal tumors or peripheral organ tumors due to injection administration, significantly restricting the application of paclitaxel as a broad-spectrum antitumor drug in chemotherapy for more solid tumors.

[0008] In 2016, Daehwa Corporation of South Korea and the Korea Institute of Science and Technology (KIST) jointly developed the world's first oral formulation of paclitaxel, Liporaxel, for the treatment of advanced, metastatic, or locally recurrent gastric cancer. Liporaxel's formulation consists of 1% paclitaxel (10 mg / mL), 55% oleic acid monoglyceride, 27.5% caprylic acid glyceride, and 16.5% Tween 80. To improve paclitaxel solubility, the formulation is an anhydrous, all-oil formula. This results in a poor taste and, due to the low drug loading, requires a dose of 25-40 mL per administration, leading to a high incidence of adverse reactions such as nausea and vomiting, and poor patient compliance. According to the Liporaxel instructions, Liporaxel should be stored under refrigeration (2-8°C). Before administration, the Liporaxel oral solution should be warmed with body temperature (e.g., by holding it in your hands) until the solution becomes clear, and then drawn up with a pipette. Water intake should be restricted for 30 minutes after administration. In 2021, another oral formulation, Athenex (paclitaxel + p-gp inhibitor Encequidar), had its marketing application rejected by the FDA due to the potential safety risk of increasing neutropenia-related sequelae.

[0009] For already marketed taxane drugs and new taxane molecules in clinical trials, to ensure the pharmacological activity of newly designed taxane compounds, the modified groups can have a minimal impact on the overall physicochemical properties of the compounds. Therefore, the aforementioned clinical challenges still exist.

[0010] Summary of the Invention

[0011] The inventors have surprisingly discovered a non-invasive drug delivery system for taxane drugs, characterized by high drug concentrations and convenient administration, which can be readily used in clinical applications, by encapsulating taxane drugs in supramolecular nanocomposites. The supramolecular nanocomposites, pharmaceutical compositions, and / or formulations of this invention containing taxane drugs are suitable for treating diseases treatable with taxane drugs, including, for example, cancers and proliferative diseases such as nasal cancer, vaginal cancer, cervical cancer, uterine cancer, colon cancer, rectal cancer, esophageal cancer, bladder cancer, prostate cancer, skin cancer, hypertrophic scars, etc. The supramolecular nanocomposites, pharmaceutical compositions, and / or formulations of this invention are suitable for direct topical administration of taxane drugs, such as through the esophagus, vagina, rectum, colon, bladder, mouth, stomach, nasal cavity, etc., increasing local drug exposure concentration and efficacy at the tumor site while reducing systemic side effects.

[0012] In some embodiments, the present invention provides a taxane-based supramolecular nanocomposite, characterized in that the taxane-based nanocomposite comprises:

[0013] a) Taxane-based active ingredients;

[0014] b) Self-assembly carrier;

[0015] c) Polymers; and

[0016] d) Dissolution promoters (e.g., one or more of alcohols, polybasic organic acids and amino acids).

[0017] In some embodiments, the taxane active ingredient may include one or more of paclitaxel, docetaxel, cabazitaxel, lalotaxel, and other taxane analogs.

[0018] In some embodiments, the self-assembled carrier may include terpenoid glycosides and their derivatives. The present invention has found that taxane active ingredients can exhibit significantly improved performance when combined with terpenoid glycosides (and optionally other ingredients), including improvements in one or more aspects such as drug loading concentration, nanocomposite properties, particle size, PDI, zeta potential, stability, dissolution characteristics, tissue distribution, therapeutic activity (e.g., tumor therapeutic activity), and side effects (e.g., systemic toxicity).

[0019] In some embodiments, the self-assembly carrier may include terpenoid glycosides and their derivatives, such as one or more of tetracyclic diterpenoid glycosides, tetracyclic triterpenoid glycosides, and pentacyclic triterpenoid glycosides. In some embodiments, the tetracyclic diterpenoid glycoside may include kaurene-type tetracyclic diterpenoid glycosides, the tetracyclic triterpenoid glycoside may include cucurbitane-type tetracyclic triterpenoid glycosides, and the pentacyclic triterpenoid glycoside may include ursane-type pentacyclic triterpenoid glycosides. In some embodiments, the kaurene-type tetracyclic diterpenoid glycosides are preferably one or more of stevioside, rebaudioside A, rebaudioside B and their salts, rebaudioside C, rebaudioside D, rebaudioside E, rebaudioside F, rebaudioside M, rebaudioside N, rebaudioside O, durqueside A, stevioside, stevioside disaccharide and their salts, more preferably rebaudioside A, rebaudioside C, and stevioside; the cucurbitane-type tetracyclic triterpenoid glycosides are preferably one or more of mogroside III, mogroside IV, mogroside V, mogroside IIE, mogroside IIIE, mogroside VI, mogroside A, mogroside glycoside, and symmenidine I, more preferably mogroside V. Usone-type pentacyclic triterpenoid glycosides are (2S,3R,4S,5S,6R)-6-((((2R,3R,4R,5S,6R)-3,4-dihydroxy-6-(hydroxymethyl)-5-(((2S,3R,4R,5R,6S)-3,4,5-trihydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)tetrahydro-2H-pyran-2-yl)oxy)methyl)-3,4,5-trihydroxytetrahydro-2H-pyran-2-yl(1S,2R,4 (aS,6aS,6bR,8aR,9R,10R,11R,12aR,12bR,14bS)-10,11-dihydroxy-9-(hydroxymethyl)-1,2,6a,6b,9,12a-hexamethyl-1,3,4,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-octadecyl octene-4a(2H)-carboxylic acid ester (ASTS), (2S,3R,4S,5S,6) R)-6-((((2R,3R,4R,5S,6R)-3,4-dihydroxy-6-(hydroxymethyl)-5-(((2S,3R,4R,5R,6S)-3,4,5-trihydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)tetrahydro-2H-pyran-2-yl)oxy)methyl)-3,4,5-trihydroxytetrahydro-2H-pyran-2-yl(1S,2R,4aS,6aR,6bR,8R,8aS,9R,10R ,11R,12aR,12bR,14bS)-8,10,11-trihydroxy-9-(hydroxymethyl)-1,2,6a,6b,9,12a-hexamethyl-1,3,4,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-octadecyl octene-4a(2H)-carboxylic acid ester (HASTS), (2S,3R,4S,5S,6R)-6-((((2R,3R,4R,5S,6R)-3,4-dihydroxy-6-(hydroxymethyl)-5-(((2S,3R,4R,5R,6S)-3,4,5-trihydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)tetrahydro-2H-pyran-2-yl)oxy)methyl)-3,4,5-trihydroxytetrahydro-2H-pyran-2-yl(4aS,6aS,6bR,8R,8aS,9R,10R,11R,12aR,12bR,14bS)-8,10,11-trihydroxy-9-(hydroxymethyl)-2,2,6a,6b,9,12a-hexamethyl-1,3,4,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b -Octadecahydrooctene-4a(2H)-carboxylic acid ester (ASTS-B), (2S,3R,4S,5S,6R)-6-((((2R,3R,4R,5S,6R)-3,4-dihydroxy-6-(hydroxymethyl)-5-(((2S,3R,4R,5R,6S)-3,4,5-trihydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)tetrahydro-2H-pyran-2-yl)oxy)methyl)-3,4,5-trihydroxytetrahydro-2H-pyran-2-yl(1S,2R,4aS,6aS,6bR,8aR,9R,10R,11R,12aR,12bR,14bS)-9-(acetoxymethyl)-10,11-dihydroxy-1,2,6a ,6b,9,12a-Hexamethyl-1,3,4,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-Octadecahydrooctene-4a(2H)-carboxylic acid ester (ASTS-C), (2S,3R,4S,5S,6R)-6-((((2R,3R,4R,5S,6R)-3,4-dihydroxy-6-(hydroxymethyl)-5-(((2S,3R,4R,5R,6S)-3,4,5-trihydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)tetrahydro-2H-pyran-2-yl)oxy)methyl)-3,4,5-trihydroxytetrahydro-2H-pyran-2-yl(1S,2R,4aS,6aS, 6bR,8aR,10R,11R,12aR,12bR,14bS)-10,11-dihydroxy-1,2,6a,6b,9,9,12a-heptamethyl-1,3,4,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-octadecyl octene-4a(2H)-carboxylic acid ester (ASTS-D), (2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(((((2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)methyl)tetrahydro-2H-pyran-2-yl(1S,2R,4aS,6aS,6bR,8aR,9R,10R,11R,12aR,12bR,14bS)-10,11-dihydroxy-9-(hydroxymethyl)-1,2,6a,6b,9,12a-hexamethyl-1,3,4,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-octadecylhydrooctene-4a(2H)-carboxylic acid ester (ASTS-E) (2S,3R,4S,5S,6R)-6-((((2R,3R,4R,5S,6R)-3,4-dihydroxy-6-(hydroxymethyl)-5-(((2S,3R,4R,5R,6S)-3,4,5-trihydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)tetrahydro-2H-pyran-2-yl)oxy)methyl)-3,4,5-trihydroxytetrahydro-2H-pyran-2-yl(1S,2R,4aS,6aS,6bR,8aR,9R,10S,12aR,12bR,14bS)-10-hydroxy-9-(hydroxymethyl)-1,2,6a ,6b,9,12a-Hexamethyl-1,3,4,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-Octadecahydrooctene-4a(2H)-carboxylic acid ester (ASTS-F), (2S,3R,4S,5S,6R)-6-((((2R,3R,4R,5S,6R)-3,4-dihydroxy-6-(hydroxymethyl)-5-(((2S,3R,4R,5R,6S)-3,4,5-trihydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)tetrahydro-2H-pyran-2-yl)oxy)methyl) -3,4,5-Trihydroxytetrahydro-2H-pyran-2-yl(1R,2R,4aS,6aS,6bR,8aR,9R,10R,11R,12aR,12bR,14bS)-10,11-dihydroxy-2,9-bis(hydroxymethyl)-1,6a,6b,9,12a-pentamethyl-1,3,4,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-octadecylhydrooctene-4a(2H)-carboxylic acid ester (ASTS-G), (1S,2R,4aS,6aS,6bR,8aR,9R,10 R,11R,12aR,12bR,14bS)-10,11-dihydroxy-9-(hydroxymethyl)-1,2,6a,6b,9,12a-hexamethyl-1,3,4,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-octadecylhydrooctene-4a(2H)-carboxylic acid (ASTA), (1S,2R,4aS,6aS,6bR,8R,8aS,9R,10R,11R,12aR,12bR,14bS)-8,10,11-trihydroxy-9-(hydroxymethyl)-1,2,6a,6b,The group consisting of one or more of 9,12a-hexamethyl-1,3,4,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-octadecylhydrooctene-4a(2H)-carboxylic acid (HASTA), preferably a combination of one or more of ASTS, HASTS, ASTA, and HASTA.

[0020] In some embodiments, the polymer may include polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus), povidone, copovidone, preferably Soluplus.

[0021] In some embodiments, the dissolution promoter (e.g., one or more of alcohols, polybasic organic acids, and amino acids) may include one or more of ethanol, propylene glycol, glycerol, polyethylene glycol, citric acid, malic acid, tartaric acid, serine, threonine, cysteine, tyrosine, asparagine, glutamine, selenocysteine, pyrrolidone, lysine, arginine, histidine, aspartic acid, glutamic acid, alanine, valine, leucine, isoleucine, proline, phenylalanine, tryptophan, methionine, and glycine, preferably ethanol, propylene glycol, glycerol, polyethylene glycol, citric acid, aspartic acid, and glutamic acid.

[0022] In some embodiments, the amount of self-assembled carrier by weight is 2-10 times, preferably 3-5 times, of the amount of active ingredient; the amount of polymer is 2-10 times, preferably 3-7 times, of the amount of active ingredient; and the amount of dissolution promoter (e.g., one or more of alcohols, polybasic organic acids, and amino acids) is 0.25-15 times, preferably 1-5 times, of the amount of active ingredient.

[0023] In some embodiments, the present invention provides supramolecular nanocomposites prepared by combining taxane active ingredients with terpenoids as self-assembling carriers and other components such as polymers and / or dissolution promoters, which exhibit significantly improved performance, including improvements in one or more aspects such as drug loading concentration, nanocomposite morphology, particle size, PDI, zeta potential, stability, dissolution characteristics, tissue distribution, therapeutic activity (e.g., tumor therapeutic activity), and side effects (e.g., systemic toxicity).

[0024] In some embodiments, the present invention provides a method for preparing taxane-based nanocomposites, comprising:

[0025] 1) Dissolve the active ingredient in an organic solvent;

[0026] 2) Dissolve the self-assembling carrier and polymer in water;

[0027] 3) For example, under stirring, solution 1) is added to solution 2) to recover the organic solvent (e.g., by vacuum rotary evaporation);

[0028] 4) Add a dissolution promoter (such as one or more of alcohols, polybasic organic acids and amino acids) to dissolve and obtain a supramolecular nanocomposite solution. For example, the solution can be obtained by shaking on a shaker for 1-5 hours and centrifuging to remove the precipitate.

[0029] In some implementations, the solution can be freeze-dried or the solvent evaporated as needed to produce a self-assembled nanocomposite powder.

[0030] In some embodiments, the invention provides a method for preparing taxane-based nanocomposites, comprising:

[0031] 1) Dissolve the active ingredients, self-assembled carriers, and polymers in an organic solvent-water mixture;

[0032] 2) Recover organic solvents, for example, by reducing the pressure to recover organic solvents to meet the residual solvent requirements of the Chinese Pharmacopoeia;

[0033] 3) Add a dissolution promoter (such as one or more of alcohols, polybasic organic acids and amino acids) to dissolve and obtain a supramolecular nanocomposite solution. For example, the solution can be obtained by shaking on a shaker for 1-5 hours and centrifuging to remove the precipitate.

[0034] In some implementations, the solution can be freeze-dried or solvent-evaporated to produce nanocomposite powder, as needed.

[0035] In some embodiments, the organic solvent used in the preparation method may include one or more of methanol, ethanol, acetone, and tetrahydrofuran, preferably ethanol.

[0036] In some implementations, a dissolution accelerator (e.g., ethanol) may be added during the reconstitution of the lyophilized or rotary-dried powder.

[0037] In some embodiments, the present invention provides pharmaceutical compositions, pharmaceutical formulations, and / or kits containing the aforementioned taxane nanocomposites, and optionally pharmaceutical carriers, excipients, and / or excipients. In some embodiments, any suitable excipients, pharmaceutical carriers, and / or excipients known in the art can be used, including, for example, lactose, sucrose, gelatin, starch, glucose, silica gel, sodium stearate, talc, sodium chloride, skim milk powder, water, etc. In some embodiments, the medication can be administered orally, via mucosal delivery, or topically. In some embodiments, the taxane nanocomposites, pharmaceutical compositions, and pharmaceutical formulations can be prepared in any suitable form, such as oral liquids, tablets, capsules, granules, powders, enemas, bladder irrigation solutions, foams, suppositories, gels, creams, patches, sprays, nasal drops, ointments, or mixed with a film-forming agent and directly applied to a carrier such as a scaffold.

[0038] In some embodiments, the present invention provides the supramolecular nanocomposite, pharmaceutical composition, formulation, and / or kit for treating diseases (e.g., cancer or proliferative diseases). In some embodiments, the present invention provides the use of the supramolecular nanocomposite, pharmaceutical composition, and / or formulation in the preparation of a medicament or kit for treating diseases (e.g., cancer or proliferative diseases). In some embodiments, the present invention provides a method of treating a disease (e.g., cancer or proliferative disease) comprising administering the supramolecular nanocomposite, pharmaceutical composition, and / or formulation to a subject in need. In some embodiments, the disease may include any disease treatable with taxane-based drugs, including, for example, cancer or proliferative diseases, such as gastrointestinal cancers, such as oral cancer, esophageal cancer, gastric cancer, intestinal cancer, colon cancer, gastrointestinal adenocarcinoma, polyps, rectal cancer, pancreatic cancer, bladder cancer, cervical cancer, uterine cancer, vaginal cancer, skin cancer, nasopharyngeal carcinoma, hypertrophic scars, and carcinoid tumors of the skin.

[0039] definition:

[0040] Supramolecular nanocomposites: In this paper, supramolecular nanocomposites refer to multi-molecular groups assembled from different components through non-covalent interactions, with particle sizes ranging from 1 to 500 nm, such as 1 nm, 10 nm, 20 nm, 30 nm, 40 nm, 50 nm, 100 nm, 150 nm, 200 nm, 250 nm, 300 nm, 350 nm, 400 nm, 450 nm, 500 nm, or any range thereof. The supramolecular nanocomposites constructed in this invention differ from ordinary nanocomposites in that the multi-active-site characteristics of the hyperbranched carrier and the supramolecular nanocomposites assembled from active ingredients and polymers exhibit superior physicochemical stability. Even after some groups are metabolized by enzymes, the metabolized carrier intermediate still retains its hyperbranched structure and can rapidly reassemble with active ingredients and / or polymers, thus possessing online editing and self-repair capabilities. Therefore, the supramolecular nanocomposites provided by this invention can withstand the effects of complex contents on the supramolecular nanocomposites in a non-invasive delivery environment and still achieve the delivery purpose, an advantage that ordinary nanocomposites do not possess. In some embodiments, the supramolecular nanocomposites of this invention preferably have one or more advantages compared to a control (e.g., a composition not containing one or more components of this invention or a commercially available product containing the same active ingredient). In some embodiments, the properties and / or advantages of the supramolecular nanocomposites can be determined by comparing one or more aspects such as drug loading concentration, nanocomposite morphology, particle size, PDI, zeta potential, stability, dissolution characteristics, tissue distribution, therapeutic activity (e.g., tumor therapeutic activity), and side effects (e.g., systemic toxicity). In some embodiments, the different components in the supramolecular nanocomposites of this invention can exhibit synergistic effects through interactions, with performance far exceeding the sum of the performance of each individual component.

[0041] Beneficial effects of the invention

[0042] The taxane-based nanocomposites, pharmaceutical compositions, and formulations of the present invention have one or more of the following advantages compared with the prior art:

[0043] It exhibits good chemical and physical stability; high drug concentrations, making it suitable for both oral and local administration, including mucosal administration (such as oral cavity, esophagus, stomach, intestines, bladder, vagina, uterus, nose, etc.) and skin administration. It can be used to treat cancers (including digestive tract cancers) and proliferative diseases, such as oral cancer, esophageal cancer, gastric cancer, intestinal cancer, colon cancer, rectal cancer, pancreatic cancer, bladder cancer, cervical cancer, uterine cancer, vaginal cancer, skin cancer, nasopharyngeal carcinoma, skin carcinoids, and hypertrophic scars. It increases the drug exposure concentration and amount at the target site, improves efficacy, and reduces the adverse reactions of systemic administration. Attached Figure Description

[0044] Figure 1. Exposure concentrations of various tissues in the digestive tract of mice administered the oral liquid via gavage (F17-F19, control mice).

[0045] Figure 2. PTX concentration-time curves in gastric tissue of mice (F24, F25, and control mice) after oral administration of the solution.

[0046] Figure 3. PTX concentration-time curves in the rectal tissue of mice (F24, F25, and control mice) after oral administration of the oral solution via gavage.

[0047] Figure 4. PTX concentration-time curves in the liver of mice (F24, F25, and control mice) after oral administration of the oral solution via gavage.

[0048] Figure 5. Colonic exposure concentrations at different time points after colonic administration of F28G, F30G, and control oral solutions to rats. Detailed Implementation

[0049] To make the objectives, technical solutions, and advantages of the present invention clearer, the present invention will be further described in detail below with reference to specific embodiments and accompanying drawings.

[0050] To illustrate the features and advantages of the present invention, some experiments are provided as illustrative examples in the embodiments, but the content of the present invention is not limited to the embodiments. The materials and reagents used in the embodiments are all common commercially available products.

[0051] The materials and codes used in this invention are as follows:

[0052] Table 1. Material Name, Function, Code, and Source

[0053] The measurement method used in this invention:

[0054] (1) Nanoparticle size, PDI:

[0055] The nanoparticle size distribution was determined using a NanoBrook (model: 90Plus PALS) nanoparticle size analyzer. Before measurement, the supramolecular nanocomposite solution was diluted to 100 μg / mL, and 50 μL was dispersed in 1 mL of deionized water for analysis.

[0056] (2) Zeta potential measurement:

[0057] The measurement was performed at room temperature (25℃). The diffraction angle for the Zeta potential measurement was set to 15℃. Before the measurement, the supramolecular nanocomposite solution was diluted to 100 μg / mL, and 50 μL was dispersed in 1 mL of phosphate buffer (6.8) for measurement.

[0058] (3) Determination of the content of active ingredients:

[0059] The determination was performed using high-performance liquid chromatography (HPLC) with external standard method. The chromatographic conditions are shown in the table below.

[0060] Table 2. Methods for determining the content of active ingredients

[0061] (4) Determination of related substances of active ingredients:

[0062] High-performance liquid chromatography (HPLC) was used for the detection of related substances. The chromatographic conditions are shown in the table below.

[0063] Table 3. Methods for determining related substances of active ingredients

[0064] (5) Methods for detecting active ingredients in biological samples

[0065] A single quadrupole liquid chromatography-mass spectrometry (LC-MS) system was used, and the chromatographic and mass spectrometric conditions are shown in the table below.

[0066] Table 4. Chromatographic conditions (LC-MS) for biological sample detection

[0067] Example 1. Supramolecular nanocomposites F1-F8

[0068] (1) Prescription composition:

[0069] Table 5. Composition of supramolecular nanocomposites F1-F8 (mg)

[0070] (2) Preparation process:

[0071] Add the prescribed amount of active ingredient, self-assembled carrier, and polymer to an appropriate amount of 50% ethanol-water solution, heat to dissolve, remove ethanol and concentrate using a rotary evaporator, add alcohol / poly-organic acid / amino acid to dissolve, and dilute to 10 mL with water. Place in a shaker and shake at 37℃ / 250 rpm for 2 hours, then centrifuge at 25℃ / 15000 rpm for 5 minutes. The supernatant is the supramolecular nanocomposite solution.

[0072] (3) Properties, content, particle size, PDI and zeta potential

[0073] Table 6. Properties, concentration, particle size, PDI and Zeta potential of F1-F8 supramolecular nanocomposites

[0074] Based on the above results, the particle size of the F1-F8 supramolecular nanocomposites is between 66.7 nm and 82.4 nm, the solution is clear and transparent, and the PDI is no greater than 0.3. The measured concentrations of the F1-F8 supramolecular nanocomposites are 19.4 mg / mL to 29.8 mg / mL, which are close to the theoretical concentrations of each formulation and significantly higher than the concentrations of currently marketed paclitaxel liquid formulations (10 mg / mL or 6 mg / mL).

[0075] Example 2. Supramolecular nanocomposites F9-F15, D1-D3

[0076] (1) Prescription composition:

[0077] Table 7. Formulation composition of supramolecular nanocomposites F9-F15 and D1-D3

[0078] (2) Preparation process:

[0079] 1)F9, D1-D3, F11, F13, F14

[0080] Add the prescribed amount of active ingredient, self-assembled carrier, and polymer to an appropriate amount of 50% ethanol-water solution, heat to dissolve, remove ethanol and concentrate using a rotary evaporator, add alcohol / poly-organic acid / amino acid to dissolve, and add water to make up to 10 mL. Place in a shaker and shake at 37℃ / 250 rpm for 1-5 hours, then centrifuge at 25℃ / 15000 rpm for 5 minutes. The supernatant is the supramolecular nanocomposite solution.

[0081] 2) F10, F12, F15

[0082] The active ingredient is dissolved in tetrahydrofuran, and the self-assembled carrier and polymer are dissolved in water, with heating if necessary. The active ingredient solution is slowly added to the carrier solution under stirring, and the organic solvent is recovered under reduced pressure to meet the residual solvent requirements of the Chinese Pharmacopoeia. Alcohols / poly-organic acids / amino acids are added to dissolve the solution, and the mixture is shaken on a shaker for 3 hours. The precipitate is removed by centrifugation to obtain the taxane nanocomposite solution.

[0083] (3) Properties, particle size, PDI and zeta potential

[0084] Table 8. Properties, measured concentrations, particle sizes, PDI and Zeta potentials of F9-F15 and D1-D3 supramolecular nanocomposites

[0085] Based on the above results, the particle size of the F9-F15 supramolecular nanocomposite prepared in Example 2 is between 58.9 nm and 86.7 nm. The solution is clear and transparent, with a PDI of no more than 0.3. The measured concentration of the active ingredient is between 28.9 mg / mL and 30.2 mg / mL, which is close to the theoretical concentration of each formulation.

[0086] Comparative Example D1, a formulation without ethanol, yielded a supramolecular nanocomposite solution with a measured concentration of 28.7 mg / mL, close to the theoretical concentration. Formulations D2 and D3, containing only polymers and ethanol or only self-assembled carriers and ethanol, respectively, produced supramolecular nanocomposite solutions with concentrations of 8.2 mg / mL and 5.6 mg / mL, respectively, significantly lower than the theoretical concentration of 30 mg / mL. This indicates that the presence or absence of ethanol in the formulation has no effect on increasing the drug loading of the active ingredient, while the combined use of the self-assembled carrier and polymer can significantly improve the drug loading of the nanocomposite. The particle sizes of D1, D2, and D3 were 73.5 nm, 64.1 nm, and 43.5 nm, respectively, with D3 showing a significantly smaller particle size than F9-F15 and D1 and D2.

[0087] A comparison of F9 and D1 shows that there is little difference between them in terms of content, particle size and other indicators.

[0088] Example 3: Preparation of supramolecular nanocomposite powder

[0089] Supramolecular nanocomposite solutions were prepared according to D1 and F8, and then spread evenly in trays and freeze-dried at -40℃ to obtain freeze-dried powders. The freeze-dried powders of D1 and F8 were reconstituted, and the results are shown in the table below.

[0090] Table 9. Results of resolution of supramolecular nanocomposite powder

[0091] Note: *10% ethanol solution is prepared by adding 1 ml of ethanol to 10 ml of water.

[0092] The results above show that the F8 supramolecular nanocomposite can be completely reconstituted after solidification. The particle size of the reconstituted solution is not significantly different from that before freeze-drying, and the PDI remains below 0.3. There is no obvious change before and after.

[0093] As shown in F16, alcohols / poly-organic acids / amino acids can be added during the resolution process after the supramolecular nanocomposite has been cured, and there is no significant change in any of the indicators compared with those before freeze-drying D1.

[0094] Example 4. Supramolecular nanocomposites F17-F27

[0095] (1) Prescription composition:

[0096] Table 10. Formulation composition of supramolecular nanocomposites F17-F27

[0097] (2) Preparation process:

[0098] Add the prescribed amount of active ingredient, self-assembled carrier, and polymer to an appropriate amount of 50% ethanol-water solution, heat to dissolve, remove ethanol and concentrate using a rotary evaporator, add alcohol / poly-organic acid / amino acid to dissolve, place in a shaker, shake at 37℃ / 250rpm for 1-5 hours, centrifuge at 25℃ / 15000rpm for 5 minutes, and the supernatant is the supramolecular nanocomposite solution.

[0099] (3) Properties, particle size, PDI and zeta potential

[0100] Table 11. Properties, measured concentrations, particle sizes, PDI and Zeta potentials of F17-F27 supramolecular nanocomposites

[0101] Note: *Reference injection prescription: Paclitaxel 6 mg / mL, Cremophore EL 527 mg / mL, anhydrous ethanol 49.7% (v / v). Prepared according to Taxol prescription (prescription source: Taxol instructions).

[0102] Based on the above results, the particle size of the F17-F27 supramolecular nanocomposites is between 64.9 nm and 107.0 nm, the solution is clear and transparent, and the PDI is no greater than 0.3. The measured concentration of the F17-F27 supramolecular nanocomposites is 19.6 mg / mL to 36.6 mg / mL, which is close to the theoretical concentration values ​​of each formulation and significantly higher than the concentration of currently marketed paclitaxel liquid formulations.

[0103] Example 5. Supramolecular nanocomposite formulation

[0104] (1) Preparation of gelling agent (Gel, G)

[0105] F28G and F29G: Take 5 mL of each of the F17 and F20 supramolecular nanocomposite solutions, add 0.25 g of glycyrrhizic acid monoamine, and adjust the pH to 2.5-3.5 using citric acid and lactic acid respectively to obtain the final product.

[0106] F30G: Take 5 mL of F8 supramolecular nanocomposite solution, add 1.25 g of cross-linked polyvinylpyrrolidone CL-M, stir well, and you will get the product.

[0107] The content of F28G, F29G and F30G was measured and found to be 27.2 mg / g, 26.3 mg / g and 25.5 mg / g, respectively.

[0108] (2) Preparation of tablets and capsules

[0109] Prepare freeze-dried powders of supramolecular nanocomposites according to formulations F8 and F27, and prepare tablets and capsules according to the formulations in the table below.

[0110] Table 12. Formulations of tablets and capsules containing supramolecular nanocomposites

[0111] F31T: Take F8 freeze-dried powder, 2 / 3 crospovidone, and 1 / 2 magnesium stearate, mix them evenly, granulate by dry method, add the remaining crospovidone and magnesium stearate, mix evenly, and use 18×10mm capsule-shaped punching to obtain tablets.

[0112] F32C: Take F27 freeze-dried powder, cross-linked polyvinyl chloride, and magnesium stearate, mix them evenly, granulate by dry method, and fill the granules into No. 0 capsules to obtain capsules.

[0113] Test Example 1: Investigation of Chemical Stability

[0114] The solutions of supramolecular nanocomposites F4, F8, and F9 were bottled into 10 mL brown vials, sealed, and placed in a constant temperature and humidity chamber at 25℃±2℃ / RH60%±10% to investigate their chemical stability. The results are shown in the table below.

[0115] Table 13. Results of chemical stability testing of supramolecular nanocomposite solutions

[0116] The results above show that, compared with the paclitaxel raw material, the related substances detection results of the F4, F8, and F9 nanocomposite solutions on day 0 did not show an increasing trend for each impurity, indicating that the current preparation process has little impact on the chemical stability of paclitaxel.

[0117] The supramolecular nanocomposite solutions F4, F8, and F9 were placed in a constant temperature and humidity chamber at 25℃ / RH60% for 6 months. Compared with 0 months, all of them showed newly added degradation impurities, but the maximum amount detected was about 0.04%, which was lower than the control limit for unknown single impurities.

[0118] After being stored in a constant temperature and humidity chamber at 25℃ / 60% RH for 6 months, the F4 and F9 supramolecular nanocomposite solutions showed no significant increase in impurities compared to the results of related substance testing at day 0, indicating good chemical stability of both formulations. After being stored in a constant temperature and humidity chamber at 25℃ / 60% RH for 6 months, the F8 supramolecular nanocomposite solution showed a slight increase in impurities (RRT 0.75, RRT 0.93, 7-tablet PTX, RRT 1.20) compared to the results of related substance testing at day 0, but all were below the limits specified in the quality standard of paclitaxel injection in the 2020 edition of the Chinese Pharmacopoeia, Part IV. Therefore, the F4, F8, and F9 supramolecular nanocomposite solutions exhibit good chemical stability.

[0119] Experiment 2: Investigation of dissolution curves in phosphate medium converted from pH 1.0 HCl to pH 6.8

[0120] Method: Small cup method (paddle method), 100 rpm, 37℃, first investigate in 50 mL pH 1.0 HCl medium for 30 min, then take a sample and adjust to 67 mL pH 6.8 phosphate medium;

[0121] Dosage: Each dissolution vessel should contain 50 mg of PTX.

[0122] Sampling: Take 2 mL samples at 15 min, 30 min, 45 min, 60 min, 90 min and 120 min, and add 2 mL of the same medium at 37℃ at the same time.

[0123] Sample preparation method: Take out the sample and place it in a 2 mL centrifuge tube, centrifuge at 37℃ / 14000 rpm for 3 min, take 0.4 mL of the supernatant, add 3.6 mL of 80% acetonitrile to make 4 mL, mix well, detect the content by HPLC external standard method, and calculate the cumulative dissolution rate.

[0124] Table 14. Cumulative dissolution (%) of nanocomposite solutions with different formulations in medium from pH 1.0 HCl to pH 6.8

[0125] *Note: Control oral solution preparation: Paclitaxel was dissolved at 10 mg / mL in a mixture of glyceryl monooleate, glyceryl tricaprylate, and Tween 80 (volume ratio 1:0.5:0.3). The control oral solution was prepared according to the Liporaxel (code DHP107) formulation (formulation source: Efficacy and tissue distribution of DHP107, an oral paclitaxel formulation, https: / / aacrjournals.org / mct / article / 6 / 12 / 3239 / 92906 / Efficacy-and-tissue-distribution-of-DHP107-an-oral), the same below.

[0126] The results above show that the cumulative dissolution rate of the control oral solution is significantly lower than that of the supramolecular complex solution prepared in this invention. Comparing the cumulative dissolution rates of F9 and its samples stored at 25℃ / RH60% for 6 months, the cumulative dissolution rate of the samples tested for stability showed no significant change after 6 months. Comparing F9, F16, and D1-D3, the cumulative dissolution rate of samples D1-D3 after transfer to a pH 6.8 phosphate medium is significantly lower than that of F9 and F16. This indicates that the self-assembled carrier, polymer, and dissolution promoters (alcohols / poly-organic acids / amino acids) have a synergistic effect, significantly improving the dissolution of the active ingredients.

[0127] Comparing F8, F31T and F27, F32C, it can be seen that the cumulative dissolution rate of the supramolecular nanocomposite solution is not significantly different from that of the prepared tablets or capsules.

[0128] Taste evaluation of Experiment Example 3

[0129] Supramolecular complex solutions were prepared according to F1, F6, F8, and F9, and taste tests were conducted by volunteers. The results are shown in the table below.

[0130] Table 15. Taste Evaluation of Different Samples

[0131] The results above show that the control oral solution has a poor taste and is likely to cause nausea; the commercially available injection solution contains about 50% ethanol, making it difficult to take orally; the sample of this invention contains a small amount of ethanol and has a slightly alcoholic taste, but the volunteers all found it acceptable and suitable for oral administration.

[0132] Experimental Example 4: Release of supramolecular nanocomposite solutions or formulations in simulated colonic and vaginal fluids

[0133] Preparation of simulated vaginal fluid (VFS-G) solution: Weigh 5.25g NaCl, 0.69g lactic acid, 0.31g anhydrous sodium acetate and 3.37g 60% wt sodium lactate aqueous solution, place them in a 100mL volumetric flask, then accurately add 0.79mL acetic acid, add water to the mark, mix well, and adjust the pH to 4.2 with 60% wt sodium lactate aqueous solution.

[0134] Preparation of simulated colonic fluid (FaSSCoF): Weigh 1.1032 g of tromethorphanol and 1.7640 g of maleic acid and dissolve them in 152 mL of purified water. Weigh 0.9614 g of sodium hydroxide and dissolve it in a beaker containing 48 mL of degassed purified water. Mix the above solutions thoroughly and adjust the pH to 7.80 with 2 mol / L sodium hydroxide solution to prepare the buffer solution. Take 100 mL of the buffer solution and dissolve 0.0226 g of bovine bile powder to prepare the bovine bile powder buffer solution. Weigh 0.0449 g of lecithin and 0.0056 g of palmitic acid and dissolve them in 2 mL of dichloromethane. Add the dissolved solution to the bovine bile powder buffer solution and mix well. Remove the dichloromethane using a rotary evaporator at 40 °C. Add water to the remaining solution to 100 mL, add the remaining buffer solution and 0.6049 g of bovine serum albumin, and dissolve to obtain the final solution.

[0135] Take 1 mL of supramolecular nanocomposite solution, add 9 mL of simulated biological medium, mix well, seal, place in a shaker, shake at 37℃ / 250 rpm for 8 hours, centrifuge at 37℃ / 1500 rpm for 5 minutes, take the supernatant, detect the content of active ingredients, and calculate the release rate.

[0136] Release rate (%) = C1 × 10 / C0 × 100%

[0137] in

[0138] C1 represents the concentration of the active ingredient in the release solution (mg / mL);

[0139] C0 represents the concentration (mg / mL) of the active ingredient in the supramolecular nanocomposite solution.

[0140] Table 16. Release rates (%) of different formulations in FaSSCoF and VFS-G

[0141] Except for D2 and D3, the release rates of the supramolecular nanocomposite solutions and gels containing supramolecular nanocomposites prepared with the above different formulations in FaSSCoF medium were all above 90%, approaching complete release. D3 had a slightly lower release rate of approximately 85.2%, while D2 had the lowest release rate at 76.3%. In VFS-G medium, except for D1-D3, the release rates of the supramolecular nanocomposite solutions and gels containing supramolecular nanocomposites prepared with the above different formulations were all above 90%, with D1 at 83.5%, D3 at 74.3%, and D2 at the lowest at 61.2%.

[0142] Currently available paclitaxel oral solution and paclitaxel injection are not topical preparations and have low concentrations. Based on the above release results, the product of this invention is also suitable for topical use, such as in the rectum, colon, vagina, bladder, prostate, ovary, uterus, and skin.

[0143] Study on Tissue Distribution after Intragastric Administration in Kunming Mice

[0144] (1) Experimental Animals

[0145] SPF - level KM mice, weighing 19 - 21 g, male, were purchased from the National Institutes for Food and Drug Control, with the license number SCXK(Beijing)2022 - 0002. They were acclimated for one week under a 12 - hour day - night alternating light, at 22 ± 2°C, and a relative humidity of 55 ± 5%. One day before the experiment, they were fasted overnight (allowed free access to water) for more than 10 hours. There were 12 mice in each of groups A, B, C, and D, with 3 animals at each sampling point, and 21 mice in each of groups E, F, and G, with 3 animals at each sampling point. The animals in each group were given drugs by intragastric administration as shown in the following table, and the animals in each group were allowed free access to water 2 hours after administration.

[0146] (2) Test Drugs and Administration Regimen

[0147] Table 17. Study on Tissue Distribution of Intragastric Administration in KM Mice

[0148] (3) Sampling and Tissue Processing

[0149] In groups A, B, C, and D, at 0.5 h, l h, 6 h, and 24 h after intragastric administration, blood was collected by eye - ball extraction, and then the mice were sacrificed by cervical dislocation. Tissues such as the liver, heart, stomach, duodenum, small intestine, and rectum of the mice were quickly separated.

[0150] In groups E, F, and G, at 0.25 h, 0.5 h, 1 h, 2 h, 3 h, 6 h, and 24 h after intragastric administration, blood was collected by eye - ball extraction, and then the mice were sacrificed by cervical dislocation. Tissues such as the liver, heart, stomach, duodenum, small intestine, and rectum of the mice were quickly separated.

[0151] The tissues of the stomach, small intestine, and rectum of the mice were longitudinally dissected, rinsed thoroughly with normal saline at 4°C, blotted dry on absorbent paper, weighed, then minced, and added to normal saline in a grinder at a ratio of tissue (g): normal saline (g)=1:9, and quickly ground to a homogenate state. The homogenate was centrifuged at 13000 rpm for 10 minutes at 4°C, and the supernatant of the homogenate was stored in a - 50°C refrigerator.

[0152] The liver and heart tissues were rinsed thoroughly with normal saline at 4°C, blotted dry on absorbent paper, weighed, and the subsequent processing was the same as that of the digestive tract tissues.

[0153] The plasma was anticoagulated with sodium heparin, centrifuged at 3500 rpm for 10 minutes to separate the plasma, and stored in a - 50°C refrigerator for further testing.

[0154] (4) Pretreatment of Biological Samples before Detection

[0155] Liver and heart sample processing: Take 150 μL of tissue homogenate, add 450 μL of protein precipitant (MeOH), vortex for 30 s, let stand for 10 min, centrifuge at 13000 rpm for 10 min at 4℃. Then take 60 μL of the supernatant, add 530 μL of 75% MeOH and 10 μL of internal standard stock solution BHLM-100 ng / mL, vortex for 10 s, and accurately measure 10 μL for analysis.

[0156] Stomach, small intestine, and colorectal tissue: Take 150 μL of each tissue homogenate, accurately add 20 μL of BHLM internal standard stock solution (50 ng / mL), vortex for 1 min, mix well, then add 430 μL of MeOH, vortex for 1 min, let stand at 4℃ for 10 min, centrifuge at 4℃ / 13000 rpm for 10 min, and take 10 μL of the supernatant for analysis;

[0157] Plasma sample processing: 150 μL of plasma, precisely add 20 μL of BHLM internal standard stock solution (50 ng / mL), vortex for 1 min, mix well, then add 430 μL of MeOH, vortex for 30 s, let stand at 4℃ for 10 min, centrifuge at 4℃ / 13000 rpm for 10 min, and take 10 μL of supernatant for analysis.

[0158] The content of PTX in plasma and tissue samples was determined by liquid chromatography-mass spectrometry (LC-MS / MS), and the LC and MS / MS conditions are shown in Table 4. The content of PTX in biological samples after administration of each prescription was calculated using the internal standard method, and the results are shown in the figure below.

[0159] Two mice in group G died 21 hours after administration, and another mouse developed shock 24 hours after administration, making blood collection impossible. No abnormalities were observed in the other administration groups. Therefore, plasma data at 24 hours were not statistically analyzed.

[0160] According to the test results, in the plasma samples of mice after administration of prescriptions F17, F18, and F19, the detection level of PTX in plasma samples from F18-4hr and F19-8hr was higher than the limit of quantification, at 593 ng / mL and 822 ng / mL, respectively. The detection level of PTX in plasma samples of mice at other time points and with other prescriptions was lower than the limit of quantification (10 ng / mL).

[0161] The concentrations of PTX detected in samples from the stomach, small intestine (jejunum + ileum), and rectum at different time points in each drug administration group are shown in Figure 1.

[0162] The results from the AD group show that the control oral solution had a relatively high PTX exposure concentration in the stomach and small intestine tissues within 6 hours, ranging from 17 μg / g to 44 μg / g, with the highest exposure concentration in both the stomach and small intestine tissues at 0.5 hours. The control oral solution group had the lowest PTX exposure concentration in the rectum tissue among all formulations, ranging from 1.7 μg / g to 5.1 μg / g. In the F18 treatment group, the PTX exposure concentrations in the stomach, small intestine, and rectum tissues of mice were all relatively high, with average exposure concentrations of 23-48 μg / g, 22-34 μg / g, and 14-26 μg / g in the stomach, small intestine, and rectum tissues from 0.5 hours to 6 hours, respectively. The F19 administration group had the lowest PTX exposure concentration in the gastric tissue of all formulations, ranging from 1.4 to 9.1 μg / g, but higher exposure concentrations in the small intestine and rectum, ranging from 9 to 22 μg / g and 14 to 38 μg / g, respectively. This can reduce the drug's irritation to the upper gastrointestinal tract.

[0163] F24, F25 and control oral solutions were administered to each mouse by gavage at a dose of 2 mg. The exposure concentration of PTX in the stomach and rectal tissues of mice in each treatment group versus time is shown in Figures 2 and 3.

[0164] The exposure concentration of PTX in the gastric tissue of mice in the control oral solution group was significantly higher than that in F24 and F25; while the exposure concentration of PTX in the rectal tissue was significantly lower than that in F24 and F25.

[0165] The detection levels of PTX in the hearts of animals treated with prescriptions F17, F18, F19, F24, and F25 were all below the limit of quantification.

[0166] Plasma, liver, and cardiac PTX AUC of F24, F25, and control oral solutions 0-∞ The comparison is shown in Figure 4. The results show that the PTX exposure in the livers of mice in the F24 and F25 prescription groups was approximately 23 μg / g·hr to 25 μg / g·hr, while the AUC in the livers of the control oral solution group (Group G) was significantly lower. 0-∞ The exposure was approximately 153 μg / g·hr, which is about 6-7 times that of formulations F24 and F25 at the same dosage; the cardiac AUC of mice in the control oral solution group was... 0-∞ It was 70-75 times that of the F24 and F25 prescriptions after 24 hours, and the plasma AUC of mice in the control oral solution group was [missing information]. 0-∞ It is 11-12 times that of F24 and F25. The supramolecular nanocomposite formulations F24 and F25, when used to treat gastrointestinal tumors, have significantly lower systemic toxicity than the control oral solution.

[0167] The above prescription is used for gastrointestinal tumors, such as gastric cancer, intestinal cancer, and colorectal cancer. It can ensure the local treatment effect while reducing the toxicity of the drug to the system.

[0168] Experimental Example 7: Study on Colonic Administration in Rats

[0169] (1) Experimental Animals

[0170] SPF-grade male SD rats, weighing 232 - 240 g, were purchased from the National Institutes for Food and Drug Control, with the license number SCXK(Beijing)2022 - 0002. They were acclimated for one week under a 12-hour day-night alternating light, at 22 ± 2 °C, and a relative humidity of 55 ± 5%.

[0171] (2) Animal Grouping and Administration Regimen

[0172] Overnight fasting (with free access to water) for more than 10 hours was performed on the day before the experiment. The rats were randomly divided into 3 groups, with 12 rats in each group, and 3 rats at each blood sampling point.

[0173] All rats were fasted (without water restriction) for more than 12 hours before administration, and the administration was carried out according to the administration regimen in the following table.

[0174] Table 18. Oral Gavage Administration Regimen for Rats

[0175] For groups A and B, colonic administration was performed: After the rats were anesthetized by inhaling ether, a silicone tube connected to a syringe was inserted through the anus (10 cm from the anus), and 0.5 g of the gel containing the supramolecular nanocomplex of F28G or F30G was instilled into the colon. Then, the silicone tube was slowly withdrawn, and the anus was compressed by hand while the rat's tail was lifted for 30 seconds. The rats in group C were given the control solution by gavage.

[0176] (3) Sampling and Sample Pretreatment <000039l>At 1.0, 2.0, 8.0, and 24 hours after administration, 3 rats were sacrificed respectively after being anesthetized with ether. The colon and rectum of the rats were quickly separated, rinsed thoroughly with normal saline at 4 °C, blotted dry with absorbent paper, weighed, minced, mixed at a mass ratio of tissue (g): normal saline (4 °C, g) = 1:4, homogenized with a homogenizer, frozen and thawed three times repeatedly in liquid nitrogen, and the homogenate was stored in a - 7 °C refrigerator until detection.

[0178] (5) Pretreatment of Biological Samples before Detection

[0179] For colorectal tissue: Take 150 μL of each tissue homogenate, accurately add 20 μL of the BHLM internal standard solution stock solution (50 ng / mL), vortex for 1 minute to mix evenly, then add 430 μL of MeOH, vortex for 1 minute, let it stand at 4 °C for 10 minutes, centrifuge at 4 °C / 13000 rpm for 10 minutes, and take 10 μL of the supernatant for injection analysis. The detection results are shown in Figure 5.

[0180] The analysis results show that the PTX exposure concentration in the colorectal tissue at each sampling time point of F28G was significantly higher than that of the control oral solution, while the PTX exposure concentration in the colorectal tissue at 1hr, 2hr and 8hr of F30G prescription was slightly higher than that of the control oral solution group.

[0181] The specific embodiments described above further illustrate the purpose, technical solution, and beneficial effects of the present invention. It should be understood that the above descriptions are merely 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 within the protection scope of the present invention.

Claims

1. A taxane supramolecular nanocomplex, wherein the nanocomplex comprises: a) a taxane active ingredient; b) a self-assembly carrier; c) a high molecular polymer; and d) a dissolution promoter comprising one or more of an alcohol, a polyprotic organic acid and an amino acid; wherein: a) the taxane active ingredient comprises one or more of paclitaxel, docetaxel, cabazitaxel, larotaxel and analogs thereof; b) the self-assembly carrier comprises one or more of a terpene glycoside comprising one or more of a tetracyclic diterpene glycoside, a tetracyclic triterpene glycoside, a pentacyclic triterpene glycoside; c) the high molecular polymer comprises one or more of polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus), povidone, copovidone; d) the dissolution promoter comprises one or more of ethanol, propylene glycol, glycerol, polyethylene glycol, citric acid, malic acid, tartaric acid, serine, threonine, cysteine, tyrosine, asparagine, glutamine, selenocysteine, pyrrolysine, lysine, arginine, histidine, aspartic acid, glutamic acid, alanine, valine, leucine, isoleucine, proline, phenylalanine, tryptophan, methionine, glycine.

2. The supramolecular nanocomplex of claim 1, wherein the tetracyclic diterpene glycoside is a kaurene-type tetracyclic diterpene glycoside, the tetracyclic triterpene glycoside is a cucurbitane-type tetracyclic triterpene glycoside, and the pentacyclic triterpene glycoside is an ursane-type pentacyclic triterpene glycoside.

3. The supramolecular nanocomplex of claim 2, wherein the kaurene-type tetracyclic diterpene glycoside comprises one or more of stevioside, rebaudioside A, rebaudioside B and salts thereof, rebaudioside C, rebaudioside D, rebaudioside E, rebaudioside F, rebaudioside M, rebaudioside N, rebaudioside O, dulcoside A, rubusoside, steviolbioside and salts thereof; the cucurbitane-type tetracyclic triterpene glycoside comprises one or more of mogroside III, mogroside IV, mogroside V, mogroside IIE, mogroside IIIE, mogroside VI, mogroside A, neomogroside, siamenoside I; the usnane-type pentacyclic triterpene glycoside comprises (2S,3R,4S,5S,6R)-6-((((2R,3R,4R,5S,6R)-3,4-dihydroxy-6-(hydroxymethyl)-5-(((2S,3R,4R,5R,6S)-3,4,5-trihydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)tetrahydro-2H-pyran-2-yl)oxy)methyl)-3,4,5-trihydroxytetrahydro-2H-pyran-2-yl (1S,2R,4aS,6aS,6bR,8aR,9R,10R,11R,12aR,12bR,14bS)-10,11-dihydroxy 9-(hydroxymethyl)-1,2,6a,6b,9,12a-hexamethyl-1,3,4,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-octadecahydropicocen-4a(2H)-carboxylate (ASTS), (2S,3R,4S,5S,6R)-6-((((2R,3R,4R,5S,6R)-3,4-dihydroxy-6-(hydroxymethyl)-5-(((2S,3R,4R,5R,6S)-3,4,5-trihydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)tetrahydro-2H-pyran-2-yl)oxy)methyl)-3,4,5-trihydroxytetrahydro-2H-pyran-2-yl (1S,2R,4aS,6aR,6bR,8R,8aS,9R,10R,11R,12aR,12bR,14bS)-8,10,11-trihydroxy-9-(hydroxymethyl)-1,2,6a,6b,9,12a-hexamethyl-1,3,4,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-octadecahydropicocen-4a(2H)-carboxylate (HASTS), (2S,3R,4S,5S,6R)-6-((((2R,3R,4R,5S,6R)-3,4-dihydroxy-6-(hydroxymethyl)-5-(((2S,3R,4R,5R,6S)-3,4,5-trihydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)tetrahydro-2H-pyran-2-yl)oxy)methyl)-3,4,5-trihydroxytetrahydro-2H-pyran-2-yl (4aS,6aS,6bR,8R,8aS,9R,10R,11R,12aR,12bR,14bS)-8,10,11-trihydroxy-9-(hydroxymethyl)-2,2,6a,6b,9,12a-hexamethyl-1,3,4,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-octadecyl octene-4a(2H)-carboxylic acid ester (ASTS-B), (2S,3R,4S,5S,6R)-6-((((2R,3R,4R,5S,6R)-3,4-dihydroxy-6-(hydroxymethyl)-5-(((2S,3R,4R,5R,6S)-3,4,5-trihydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy Tetrahydro-2H-pyran-2-yl)oxy)methyl)-3,4,5-trihydroxytetrahydro-2H-pyran-2-yl(1S,2R,4aS,6aS,6bR,8aR,9R,10R,11R,12aR,12bR,14bS)-9-(acetoxymethyl)-10,11-dihydroxy-1,2,6a,6b,9,12a-hexamethyl-1,3,4,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-octadecylhydrooctene-4a(2H)-carboxylic acid ester (ASTS-C), (2S,3R,4S,5S,6R)-6-((((2R,3R,4R,5S,6R)- 3,4-Dihydroxy-6-(hydroxymethyl)-5-(((2S,3R,4R,5R,6S)-3,4,5-trihydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)tetrahydro-2H-pyran-2-yl)oxy)methyl)-3,4,5-trihydroxytetrahydro-2H-pyran-2-yl(1S,2R,4aS,6aS,6bR,8aR,10R,11R,12aR,12bR,14bS)-10,11-dihydroxy-1,2,6a,6b,9,9,12a-heptamethyl-1,3,4,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-octadecylhydrooctene-4a(2 H)-carboxylic acid ester (ASTS-D), (2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(((((2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)methyl)tetrahydro-2H-pyran-2-yl(1S,2R,4aS,6aS,6bR,8aR,9R,10R,11R,12aR,12bR,14bS)-10,11-dihydroxy-9-(hydroxymethyl)-1,2,6a,6b,9,12a-hexamethyl-1,3,4,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-Octadecahydrooctaen-4a(2H)-carboxylate (ASTS-E), (2S,3R,4S,5S,6R)-6-((((2R,3R,4R,5S,6R)-3,4-dihydroxy-6-(hydroxymethyl)-5-(((2S,3R,4R,5R,6S)-3,4,5-trihydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)tetrahydro-2H-pyran-2-yl)oxy)methyl)-3,4,5-trihydroxytetrahydro-2H-pyran-2-yl (1S,2R,4aS,6aS,6bR,8aR,9R,10S,12aR,12bR,14bS)-10-hydroxy-9-(hydroxymethyl)-1,2,6a,6b,9,12a-hexamethyl-1,3,4,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-octadecahydrooctaen-4a(2H)-carboxylate (ASTS-F), (2S,3R,4S,5S,6R)-6-((((2R,3R,4R,5S,6R)-3,4-dihydroxy-6-(hydroxymethyl)-5-(((2S,3R,4R,5R,6S)-3,4,5-trihydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)tetrahydro-2H-pyran-2-yl)oxy)methyl)-3,4,5-trihydroxytetrahydro-2H-pyran-2-yl (1R,2R,4aS,6aS,6bR,8aR,9R,10R,11R,12aR,12bR,14bS)-10,11-dihydroxy-2,9-bis(hydroxymethyl)-1,6a,6b,9,12a-pentamethyl-1,3,4,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-octadecahydrooctaen-4a(2H)-carboxylate (ASTS-G), (1S,2R,4aS,6aS,6bR,8aR,9R,10R,11R,12aR,12bR,14bS)-10,11-dihydroxy-9-(hydroxymethyl)-1,2,6a,6b,9,12a-hexamethyl-1,3,4,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-octadecahydrooctaen-4a(2H)-carboxylic acid (ASTA), (1S,2R,4aS,6aS,6bR,8R,8aS,9R,10R,11R,12aR,12bR,14bS)-8,10,11-trihydroxy-9-(hydroxymethyl)-1,2,6a,6b,9,12a-hexamethyl-1,3,4,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-octadecahydrooctaen-4a(2H)-carboxylic acid (HASTA).

4. The supramolecular nanocomplex of claim 1, wherein the self-assembling carrier comprises one or more of rebaudioside A, rebaudioside C, stevioside, mogroside, (2S,3R,4S,5S,6R)-6-((((2R,3R,4R,5S,6R)-3,4-dihydroxy-6-(hydroxymethyl)-5-(((2S,3R,4R,5R,6S)-3,4,5-trihydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)tetrahydro-2H-pyran-2-yl)oxy)methyl)-3,4,5-trihydroxytetrahydro-2H-pyran-2-yl (1S,2R,4aS,6aS,6bR,8aR,9R,10R,11R,12aR,12bR,14bS)-10,11-dihydroxy 9-(hydroxymethyl)-1,2,6a,6b,9,12a-hexamethyl-1,3,4,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b- octadecahydooctene-4a(2H)-carboxylate (ASTS), (2S,3R,4S,5S,6R)-6-((((2R,3R,4R,5S,6R)-3,4-dihydroxy-6-(hydroxymethyl)-5-(((2S,3R,4R,5R,6S)-3,4,5-trihydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)tetrahydro-2H-pyran-2-yl)oxy)methyl)-3,4,5-trihydroxytetrahydro-2H-pyran-2-yl (1S,2R,4aS,6aR,6bR,8R,8aS,9R,10R,11R,12aR,12bR,14bS)-8,10,11-trihydroxy-9-(hydroxymethyl)-1,2,6a,6b,9,12a-hexamethyl-1,3,4,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b- octadecahydooctene-4a(2H)-carboxylate (HASTS), (1S,2R,4aS,6aS,6bR,8aR,9R,10R,11R,12aR,12bR,14bS)-10,11-dihydroxy-9-(hydroxymethyl)-1,2,6a,6b,9,12a-hexamethyl-1,3,4,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b- octadecahydooctene-4a(2H)-carboxylate (ASTA), (1S,2R,4aS,6aS,6bR,8R,8aS,9R,10R,11R,12aR,12bR,14bS)-8,10,11-trihydroxy-9-(hydroxymethyl)-1,2,6a,6b,9,12a-hexamethyl-1,3,4,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b- octadecahydooctene-4a(2H)-carboxylate (HASTA).

5. The supramolecular nanocomplex of any one of claims 1-4, wherein the high molecular polymer is polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus).

6. The supramolecular nanocomplex of any one of claims 1-5, wherein, The self-assembly carrier is used in an amount of 2-10 times the amount of the active ingredient by weight; the high molecular polymer is used in an amount of 2-10 times the amount of the active ingredient by weight; and the dissolution promoter is used in an amount of 0.25-15 times the amount of the active ingredient by weight.

7. The supramolecular nanocomplex of any one of claims 1-5, wherein, The self-assembly carrier is used in an amount of 3-5 times the amount of the active ingredient by weight; the high molecular polymer is used in an amount of 3-7 times the amount of the active ingredient by weight; and the dissolution promoter is used in an amount of 1-5 times the amount of the active ingredient by weight.

8. A method for preparing the taxane supramolecular nanocomplex of any one of claims 1-7, comprising: 1) dissolving the active ingredient in an organic solvent; 2) dissolving the self-assembly carrier and the high molecular polymer in water; 3) adding solution 1) to solution 2) and recovering the organic solvent; 4) adding the dissolution promoter to dissolve and obtain a supramolecular nanocomplex solution, and 5) optionally, freeze-drying or rotary-evaporating the solution to obtain a self-assembly nanoparticle powder, wherein the organic solvent comprises one or more of methanol, ethanol, acetone, tetrahydrofuran, and preferably ethanol.

9. A method for preparing the taxane supramolecular nanocomplex of any one of claims 1-7, comprising: 1) dissolving the active ingredient, the self-assembly carrier and the high molecular polymer in an organic solvent-water mixed solvent; 2) recovering the organic solvent; 3) adding the dissolution promoter to dissolve and obtain a supramolecular nanocomplex solution, and 4) optionally, freeze-drying or rotary-evaporating the solution to obtain a self-assembly nanoparticle powder, wherein the organic solvent comprises one or more of methanol, ethanol, acetone, tetrahydrofuran, preferably ethanol.

10. The method according to claim 8 or 9, wherein the dissolution promoting agent (e.g. ethanol) is added upon reconstitution of the lyophilized powder or the powder prepared after solvent evaporation.

11. A pharmaceutical composition or formulation comprising 1) the supramolecular nanocomplex according to any one of claims 1 to 7 or prepared by the method according to any one of claims 8 to 10, and 2) a pharmaceutically acceptable carrier, excipient and / or adjuvant.

12. The pharmaceutical composition or formulation according to claim 11, in a form suitable for oral, mucosal or topical administration, including but not limited to oral solutions, tablets, capsules, granules, powders, enemas, bladder irrigations, foams, suppositories, gels, creams, patches, sprays, nasal drops, creams or direct application to a stent or the like carrier mixed with a film-forming agent.

13. The supramolecular nanocomplex according to any one of claims 1 to 7, prepared by the method according to any one of claims 8 to 10, or the pharmaceutical composition or formulation according to claim 11 or 12, for use in the treatment of cancer or a proliferative disease.

14. Use of the supramolecular nanocomplex according to any one of claims 1 to 7, prepared by the method according to any one of claims 8 to 10, or the pharmaceutical composition or formulation according to claim 11 or 12, for the manufacture of a medicament or a kit for the treatment of cancer or a proliferative disease.

15. The supramolecular nanocomplex, pharmaceutical composition or formulation for use according to claim 13, or the use according to claim 14, wherein the cancer or proliferative disease comprises a cancer of the digestive tract, such as oral cancer, oesophagus cancer, stomach cancer, intestinal cancer, colon cancer, adenocarcinoma of the digestive tract, polyps, rectal cancer, pancreatic cancer, bladder cancer, cervical cancer, uterine cancer, vaginal cancer, skin cancer, proliferative scars, nasopharyngeal cancer.

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