Non-aqueous preparation with controllable release behavior and application thereof

Abstract

The invention discloses a non-aqueous preparation with a controllable release behavior and application thereof. The invention provides a non-aqueous fat-soluble preparation and application thereof, an injection preparation and an implant preparation. Active ingredients of the non-aqueous fat-soluble preparation comprise one or more of deoxycholic acid, pharmaceutically acceptable salts of deoxycholic acid and deoxycholic acid derivatives; in a release medium which meets a leakage tank condition and has a pH value of 7.4, under the condition of 37 DEG C, the release amount of the active component within one hour does not exceed 25% of the total amount of the active component contained in the non-aqueous fat-soluble preparation, and the release amount of the active component within 168 hours is greater than 80% of the total amount of the active component contained in the non-aqueous fat-soluble preparation. The non-aqueous fat-soluble preparation can slowly release a drug at an administration part, prolongs the drug release time, and can obviously reduce adverse reactions caused by overhigh local drug concentration; meanwhile, a good fat dissolving effect is achieved.

Description

[0001] Related applications

[0002] This application claims priority to Chinese patent application No. 202311495750.6, filed on November 10, 2023, entitled “A non-aqueous formulation with controlled release behavior and its application,” the entire text of which is hereby incorporated by reference. Technical Field

[0003] The present application relates to the technical field of pharmaceutical preparations, and in particular to a non-aqueous liposoluble preparation and its application, injection preparation and implant preparation. Background Art

[0004] Lipolytic drugs have attracted considerable attention for their potential to dissolve fat for weight loss, reduce body fat, and improve aesthetics. One class of existing lipolytic drugs, primarily composed of caffeine, isoproterenol, and L-carnitine, dissolves fat by promoting metabolism. However, after subcutaneous injection, these drugs are easily metabolized by tissues, resulting in only a short-term effect on adipocytes. Fat cells, whose structure and function remain intact, are susceptible to restoring their shape through fat storage. Consequently, the effectiveness of these lipolytic drugs needs to be improved, and their safety remains clinically unproven.

[0005] Deoxycholic acid is a cytolytic drug that, when injected into body tissues, disrupts cell membranes and causes cell lysis.

[0006] Kybella, a currently marketed lipolysis drug, uses deoxycholic acid as its main ingredient and can be used to treat moderate to severe perianal fat hypertrophy in adults or eliminate moderate to severe perianal fat bulges, improving appearance. However, Kybella is a standard immediate-release injection. Upon injection, deoxycholic acid is rapidly released, causing dramatic fluctuations in blood levels of deoxycholic acid. High blood levels of deoxycholic acid after injection can cause adverse reactions. Because adverse reactions require at least four weeks to recover, the dosing interval must be as long as four weeks. For standard immediate-release injections, this long dosing interval inevitably weakens their efficacy and prolongs treatment time. Furthermore, as deoxycholic acid is metabolized in the body, a significant decrease in blood levels can render the treatment ineffective. Summary of the Invention

[0007] Based on this, it is necessary to provide a non-aqueous liposoluble preparation and its application, injection preparation and implant preparation that can both release drugs in a sustained manner to achieve effective therapeutic effects and reduce the probability of adverse reactions.

[0008] The first aspect of the present application provides a non-aqueous liposoluble preparation, wherein the active ingredient of the non-aqueous liposoluble preparation includes one or more of deoxycholic acid, a pharmaceutically acceptable salt of deoxycholic acid, and a deoxycholic acid derivative;

[0009] In a release medium with a pH value of 7.4 that meets the sink conditions, at 37°C, the release amount of the active ingredient in 1 hour does not exceed 25% of the total amount of the active ingredient contained in the non-aqueous fat-soluble preparation, and the release amount in 168 hours is greater than 80% of the total amount of the active ingredient contained in the non-aqueous fat-soluble preparation.

[0010] In some embodiments, in a release medium with a pH of 7.4 that meets the sink conditions, at 37°C, the release amount of the active ingredient in 1 hour does not exceed 20% of the total amount of the active ingredient contained in the non-aqueous fat-soluble preparation, and the release amount in 168 hours is greater than 85% of the total amount of the active ingredient contained in the non-aqueous fat-soluble preparation.

[0011] In some embodiments, the dosage form of the non-aqueous liposoluble preparation includes one or more of proliposomes, oil solutions, and in situ gels;

[0012] Optionally, the dosage form of the non-aqueous liposoluble preparation includes one or more of proliposomes, oil solutions, and in situ gels for injection or implantation;

[0013] Optionally, the amount of active ingredient remaining in the tissue of the non-aqueous liposoluble preparation 168 hours after the first single injection in vivo does not exceed 30% of the total amount of the active ingredient of the administered non-aqueous liposoluble preparation.

[0014] In some embodiments, the non-aqueous liposoluble preparation is a proliposome, and the components of the proliposome include an active ingredient, a pharmaceutical phospholipid, a release modifier, a pharmaceutical solvent, and an optional chelating agent;

[0015] Optionally, the non-aqueous liposoluble preparation has at least one of the following characteristics:

[0016] (1) The non-aqueous fat-soluble preparation comprises, by weight, 0.1-5 parts by weight of an active ingredient, 15-60 parts by weight of a pharmaceutical phospholipid, 5-65 parts by weight of a release modifier, 5-40 parts by weight of a pharmaceutical solvent, and 0-0.001 parts by weight of a chelating agent;

[0017] (2) The non-aqueous fat-soluble preparation comprises, in parts by weight, 0.1-3 parts by weight of an active ingredient, 20-50 parts by weight of a pharmaceutical phospholipid, 10-63 parts by weight of a release modifier, 10-40 parts by weight of a pharmaceutical solvent, and 0-0.001 parts by weight of a chelating agent;

[0018] (3) The non-aqueous fat-soluble preparation comprises, in parts by weight, 0.5-3 parts by weight of an active ingredient, 25-50 parts by weight of a pharmaceutical phospholipid, 15-63 parts by weight of a release modifier, 10-30 parts by weight of a pharmaceutical solvent, and 0-0.001 parts by weight of a chelating agent;

[0019] (4) The pharmaceutical lecithin comprises a combination of one or more pharmaceutically acceptable natural lecithin, semi-synthetic lecithin and synthetic lecithin;

[0020] Optionally, the natural phospholipids include one or more of egg yolk lecithin and soybean lecithin;

[0021] Optionally, the semi-synthetic phospholipids include one or more of hydrogenated egg yolk lecithin and hydrogenated soybean lecithin;

[0022] Optionally, the synthetic phospholipids include one or more of dipalmitoylphosphatidylcholine (DPPC), distearoylphosphatidylcholine (DSPC), dimyristoylphosphatidylcholine (DMPC), dilauroylphosphatidylcholine (DLPC), dioleoylphosphatidylcholine (DOPC), dipalmitoylphosphatidylethanolamine (DPPE), dipalmitoylphosphatidylglycerol (DPPG), and dioleoylphosphatidylethanolamine (DOPE);

[0023] (5) The release modifier includes one or more of methyl oleate, ethyl oleate, propyl oleate, butyl oleate, 2-butyl oleate, isopropyl oleate, hexyl oleate, octyl oleate, glyceryl monooleate, glyceryl dioleate, glyceryl trioleate, isopropyl myristate, triethyl citrate, linolenic acid, diethyl sebacate, phytantriol, natural plant oil, semi-natural plant oil and synthetic oil; more preferably, it can be one or more of ethyl oleate, glyceryl monooleate, glyceryl dioleate, glyceryl trioleate, natural plant oil and synthetic oil;

[0024] Optionally, the natural vegetable oil includes one or more of castor oil, sesame oil, soybean oil, sunflower oil, peanut oil, corn oil, rapeseed oil, olive oil and cottonseed oil;

[0025] Optionally, the semi-natural vegetable oil comprises hydrogenated castor oil;

[0026] Optionally, the artificial synthetic oil comprises one or more of medium-chain triglycerides, long-chain triglycerides, triacetin and derivatives thereof; more preferably, the medium-chain triglycerides comprise one or more of caprylic triglyceride and capric triglyceride;

[0027] (6) The pharmaceutically acceptable solvent includes one or more of benzyl alcohol, ethanol, propylene glycol, glycerol, isopropyl alcohol, N-methylpyrrolidone, dimethyl sulfoxide, liquid polyethylene glycol, dimethylacetamide, glycerol monoacetate, polyethylene glycol (mono) methyl ether, diethylene glycol monoethyl ether, ethyl lactate, ethyl acetate, propylene glycol diethyl ester, diethyl malonate, tetrahydrofuran polyethylene glycol ether and benzyl benzoate; and may be one or more of benzyl alcohol, propylene glycol, ethanol, dimethyl sulfoxide, N-methylpyrrolidone and dimethylacetamide;

[0028] (7) The chelating agent includes ethylenediaminetetraacetic acid.

[0029] In some embodiments, the non-aqueous liposoluble preparation is a proliposome, and the components of the proliposome include an active ingredient, a pharmaceutical phospholipid, a release modifier, a pharmaceutical solvent, and optionally a small molecule modulator and a chelating agent;

[0030] Optionally, the non-aqueous liposoluble preparation has at least one of the following characteristics:

[0031] (1) The non-aqueous fat-soluble preparation comprises, by weight, 0.1-5 parts by weight of an active ingredient, 15-60 parts by weight of a pharmaceutical phospholipid, 5-80 parts by weight of a release modifier, 0-40 parts by weight of a pharmaceutical solvent, 0-1 parts by weight of a small molecule modifier, and 0-0.001 parts by weight of a chelating agent;

[0032] (2) The non-aqueous fat-soluble preparation comprises, in parts by weight, 0.1-4 parts by weight of an active ingredient, 20-60 parts by weight of a pharmaceutical phospholipid, 10-77 parts by weight of a release modifier, 8-40 parts by weight of a pharmaceutical solvent, 0-1 parts by weight of a small molecule modulator, and 0-0.001 parts by weight of a chelating agent;

[0033] (3) The non-aqueous fat-soluble preparation comprises, in parts by weight, 0.2-3 parts by weight of an active ingredient, 25-55 parts by weight of a pharmaceutical phospholipid, 15-65 parts by weight of a release modifier, 10-35 parts by weight of a pharmaceutical solvent, 0-1 parts by weight of a small molecule modulator, and 0-0.001 parts by weight of a chelating agent;

[0034] (4) The pharmaceutical lecithin comprises a combination of one or more pharmaceutically acceptable natural lecithin, semi-synthetic lecithin and synthetic lecithin;

[0035] Optionally, the natural phospholipids include one or more of egg yolk lecithin and soybean lecithin;

[0036] Optionally, the semi-synthetic phospholipids include one or more of hydrogenated egg yolk lecithin and hydrogenated soybean lecithin;

[0037] Optionally, the synthetic phospholipids include one or more of dipalmitoylphosphatidylcholine (DPPC), distearoylphosphatidylcholine (DSPC), dimyristoylphosphatidylcholine (DMPC), dilauroylphosphatidylcholine (DLPC), dioleoylphosphatidylcholine (DOPC), dipalmitoylphosphatidylethanolamine (DPPE), dipalmitoylphosphatidylglycerol (DPPG), and dioleoylphosphatidylethanolamine (DOPE);

[0038] Optionally, the pharmaceutical phospholipids include one or more of egg yolk lecithin, soybean lecithin, hydrogenated egg yolk lecithin, hydrogenated soybean lecithin, dipalmitoylphosphatidylcholine (DPPC), distearoylphosphatidylcholine (DSPC), dimyristoylphosphatidylcholine (DMPC), dilauroylphosphatidylcholine (DLPC) and dioleoylphosphatidylcholine (DOPC);

[0039] Optionally, the pharmaceutical phospholipids include one or more of egg yolk lecithin, soybean lecithin, hydrogenated egg yolk lecithin, hydrogenated soybean lecithin, dipalmitoylphosphatidylcholine (DPPC), distearoylphosphatidylcholine (DSPC) and dimyristoylphosphatidylcholine (DMPC);

[0040] (5) The release modifiers include methyl oleate, ethyl oleate, propyl oleate, butyl oleate, 2-butyl oleate, isopropyl oleate, hexyl oleate, octyl oleate, glyceryl monooleate, glyceryl dioleate, glyceryl trioleate, propylene glycol monocaprylate, propylene glycol dicaprylate / dicaprate, propylene glycol laurate, propylene glycol alginate, caprylic capric acid mono- and diglycerides, caprylic capric acid mono- and triglycerides, caprylic capric acid polyethylene glycol glyceride, ricinoleic acid monoglyceride, mono- and diglycerides. One or more of olein, oleoylpolyoxyethylene glyceride, diacetyl monoglyceride, mono- and distearin, monostearin, tricaprylin, tricaprin, behenin, triacetin, isopropyl myristate, triethyl citrate, linolenic acid, diethyl sebacate, phytantriol, medium chain triglycerides, fish oil, algae oil, ethyl caprylate, ethyl caprate, ethyl linoleate, isopropyl linoleate, natural plant oil, and semi-natural plant oil;

[0041] Optionally, the release modifier comprises one or more of ethyl oleate, monoolein, diolein, triolein, propylene glycol monocaprylate, propylene glycol dicaprylate / dicaprate, propylene glycol laurate, propylene glycol alginate, caprylic and capric mono- and diglycerides, monolinolein, triacetin, medium chain triglycerides, fish oil, algae oil, and natural plant oils;

[0042] Optionally, the natural vegetable oil includes one or more of castor oil, sesame oil, soybean oil, sunflower oil, peanut oil, corn oil, rapeseed oil, olive oil, cottonseed oil, linseed oil, perilla seed oil, walnut oil, argan oil, and seaweed oil;

[0043] Optionally, the semi-natural vegetable oil comprises hydrogenated castor oil;

[0044] Optionally, the release modifier comprises one or more of ethyl oleate, monoolein, diolein, triolein, propylene glycol monocaprylate, propylene glycol dicaprylate / dicaprate, caprylic and capric mono- and diglycerides, monolinolein, triacetin, medium chain triglycerides, fish oil, algae oil, castor oil, sesame oil, soybean oil, peanut oil, corn oil, olive oil, cottonseed oil, linseed oil, perilla seed oil, walnut oil, argan oil, and laver oil;

[0045] (6) the pharmaceutically acceptable solvent includes one or more of benzyl alcohol, ethanol, propylene glycol, glycerol, isopropyl alcohol, N-methylpyrrolidone, dimethyl sulfoxide, liquid polyethylene glycol, dimethylacetamide, glycerol monoacetate, polyethylene glycol (mono) methyl ether, diethylene glycol monoethyl ether, ethyl lactate, ethyl acetate, propylene glycol diethyl ester, tetrahydrofuran polyethylene glycol ether, and benzyl benzoate;

[0046] Optionally, the pharmaceutically acceptable solvent includes one or more of benzyl alcohol, propylene glycol, ethanol, benzyl benzoate, dimethyl sulfoxide, liquid polyethylene glycol, N-methylpyrrolidone and dimethylacetamide;

[0047] Optionally, the pharmaceutically acceptable solvent includes one or more of benzyl alcohol, propylene glycol, ethanol, benzyl benzoate, dimethyl sulfoxide, N-methylpyrrolidone and dimethylacetamide.

[0048] (7) The chelating agent includes one or more of ethylenediaminetetraacetic acid, disodium ethylenediaminetetraacetate and calcium disodium ethylenediaminetetraacetate.

[0049] (8) The small molecule regulator includes an acid-base regulator and an antioxidant;

[0050] The acid-base regulator includes one or more of sodium hydroxide, meglumine, arginine, lysine, histidine, glycine, tromethamine, diethanolamine, ethylenediamine, hydrochloric acid, acetic acid, anhydrous citric acid, ascorbic acid, lactic acid, tartaric acid, methanesulfonic acid, methionine, and triethanolamine;

[0051] The antioxidant includes one or more of cysteine, α-tocopherol, α-tocopherol acetate, N-acetyl-L-cysteine, butylated hydroxyanisole, dibutylhydroxytoluene, propyl gallate, tert-butylhydroquinone, lipoic acid, tea polyphenols, L-ascorbyl palmitate, and glutathione.

[0052] In some embodiments, the non-aqueous liposoluble preparation is a proliposome, and the components of the proliposome include an active ingredient, a pharmaceutical phospholipid, a release modifier, a pharmaceutical solvent, and optionally a small molecule modulator and a chelating agent;

[0053] Optionally, the non-aqueous liposoluble preparation has at least one of the following characteristics:

[0054] (1) The non-aqueous fat-soluble preparation comprises, by weight, 0.1-5 parts by weight of an active ingredient, 15-60 parts by weight of a pharmaceutical phospholipid, 5-80 parts by weight of a release modifier, 0-40 parts by weight of a pharmaceutical solvent, 0-1 parts by weight of a small molecule modifier, and 0-0.001 parts by weight of a chelating agent;

[0055] (2) The non-aqueous fat-soluble preparation comprises, in parts by weight, 0.2-4 parts by weight of an active ingredient, 19-57 parts by weight of a pharmaceutical phospholipid, 10-77 parts by weight of a release modifier, 8-35 parts by weight of a pharmaceutical solvent, 0-1 parts by weight of a small molecule modulator, and 0-0.001 parts by weight of a chelating agent;

[0056] (3) The non-aqueous fat-soluble preparation comprises, in parts by weight, 0.3-3 parts by weight of an active ingredient, 25-55 parts by weight of a pharmaceutical phospholipid, 15-65 parts by weight of a release modifier, 10-32 parts by weight of a pharmaceutical solvent, 0-1 parts by weight of a small molecule modulator, and 0-0.001 parts by weight of a chelating agent;

[0057] (4) The pharmaceutical lecithin comprises a combination of one or more pharmaceutically acceptable natural lecithin, semi-synthetic lecithin and synthetic lecithin;

[0058] Optionally, the natural phospholipids include one or more of egg yolk lecithin and soybean lecithin;

[0059] Optionally, the semi-synthetic phospholipids include one or more of hydrogenated egg yolk lecithin and hydrogenated soybean lecithin;

[0060] Optionally, the synthetic phospholipids include one or more of dipalmitoylphosphatidylcholine (DPPC), distearoylphosphatidylcholine (DSPC), dimyristoylphosphatidylcholine (DMPC), dilauroylphosphatidylcholine (DLPC), dioleoylphosphatidylcholine (DOPC), dipalmitoylphosphatidylethanolamine (DPPE), dipalmitoylphosphatidylglycerol (DPPG), and dioleoylphosphatidylethanolamine (DOPE); optionally, the pharmaceutical phospholipids include one or more of egg yolk lecithin, soybean lecithin, hydrogenated egg yolk lecithin, hydrogenated soybean lecithin, dipalmitoylphosphatidylcholine (DPPC), distearoylphosphatidylcholine (DSPC), dimyristoylphosphatidylcholine (DMPC), dilauroylphosphatidylcholine (DLPC), and dioleoylphosphatidylcholine (DOPC);

[0061] Optionally, the pharmaceutical phospholipids include one or more of egg yolk lecithin, soybean lecithin, hydrogenated egg yolk lecithin, hydrogenated soybean lecithin, dipalmitoylphosphatidylcholine (DPPC), distearoylphosphatidylcholine (DSPC) and dimyristoylphosphatidylcholine (DMPC);

[0062] (5) The release modifiers include methyl oleate, ethyl oleate, propyl oleate, butyl oleate, 2-butyl oleate, isopropyl oleate, hexyl oleate, octyl oleate, glyceryl monooleate, glyceryl dioleate, glyceryl trioleate, propylene glycol monocaprylate, propylene glycol dicaprylate / dicaprate, propylene glycol laurate, propylene glycol alginate, caprylic capric acid mono- and diglycerides, caprylic capric acid mono- and triglycerides, caprylic capric acid polyethylene glycol glyceride, ricinoleic acid monoglyceride, mono- and diglycerides. One or more of olein, oleoylpolyoxyethylene glyceride, diacetyl monoglyceride, mono- and distearin, monostearin, tricaprylin, tricaprin, behenin, triacetin, isopropyl myristate, triethyl citrate, linolenic acid, diethyl sebacate, phytantriol, medium chain triglycerides, fish oil, algae oil, ethyl caprylate, ethyl caprate, ethyl linoleate, isopropyl linoleate, natural plant oil, and semi-natural plant oil;

[0063] Optionally, the release modifier comprises one or more of ethyl oleate, monoolein, diolein, triolein, propylene glycol monocaprylate, propylene glycol dicaprylate / dicaprate, propylene glycol laurate, propylene glycol alginate, caprylic and capric mono- and diglycerides, monolinolein, triacetin, medium chain triglycerides, fish oil, algae oil, and natural plant oils;

[0064] Optionally, the natural vegetable oil includes one or more of castor oil, sesame oil, soybean oil, sunflower oil, peanut oil, corn oil, rapeseed oil, olive oil, cottonseed oil, linseed oil, perilla seed oil, walnut oil, argan oil, and seaweed oil;

[0065] Optionally, the semi-natural vegetable oil comprises hydrogenated castor oil;

[0066] Optionally, the release modifier comprises one or more of ethyl oleate, monoolein, diolein, triolein, propylene glycol monocaprylate, propylene glycol dicaprylate / dicaprate, caprylic and capric mono- and diglycerides, monolinolein, triacetin, medium chain triglycerides, fish oil, algae oil, castor oil, sesame oil, soybean oil, peanut oil, corn oil, olive oil, cottonseed oil, linseed oil, perilla seed oil, walnut oil, argan oil, and laver oil;

[0067] (6) the pharmaceutically acceptable solvent includes one or more of benzyl alcohol, ethanol, propylene glycol, glycerol, isopropyl alcohol, N-methylpyrrolidone, dimethyl sulfoxide, liquid polyethylene glycol, dimethylacetamide, glycerol monoacetate, polyethylene glycol (mono) methyl ether, diethylene glycol monoethyl ether, ethyl lactate, ethyl acetate, propylene glycol diethyl ester, tetrahydrofuran polyethylene glycol ether, and benzyl benzoate;

[0068] Optionally, the pharmaceutically acceptable solvent includes one or more of benzyl alcohol, propylene glycol, ethanol, benzyl benzoate, dimethyl sulfoxide, liquid polyethylene glycol, N-methylpyrrolidone and dimethylacetamide;

[0069] Optionally, the pharmaceutically acceptable solvent includes one or more of benzyl alcohol, propylene glycol, ethanol, benzyl benzoate, dimethyl sulfoxide, N-methylpyrrolidone and dimethylacetamide.

[0070] (7) The chelating agent includes one or more of ethylenediaminetetraacetic acid, disodium ethylenediaminetetraacetate and calcium disodium ethylenediaminetetraacetate.

[0071] (8) The small molecule regulator includes an acid-base regulator and an antioxidant;

[0072] The acid-base regulator includes one or more of sodium hydroxide, meglumine, arginine, lysine, histidine, glycine, tromethamine, diethanolamine, ethylenediamine, hydrochloric acid, acetic acid, anhydrous citric acid, ascorbic acid, lactic acid, tartaric acid, methanesulfonic acid, methionine, and triethanolamine;

[0073] The antioxidant includes one or more of cysteine, α-tocopherol, α-tocopherol acetate, N-acetyl-L-cysteine, butylated hydroxyanisole, dibutylhydroxytoluene, propyl gallate, tert-butylhydroquinone, lipoic acid, tea polyphenols, L-ascorbyl palmitate, and glutathione.

[0074] In some embodiments, the non-aqueous liposoluble preparation is a proliposome, and the components of the proliposome include an active ingredient, a pharmaceutical phospholipid, a release modifier, a pharmaceutical solvent, and an optional chelating agent;

[0075] Optionally, the non-aqueous liposoluble preparation has at least one of the following characteristics:

[0076] (1) The non-aqueous fat-soluble preparation comprises, by weight, 0.1-5 parts by weight of an active ingredient, 15-60 parts by weight of a pharmaceutical phospholipid, 5-65 parts by weight of a release modifier, 5-40 parts by weight of a pharmaceutical solvent, and 0-0.001 parts by weight of a chelating agent;

[0077] (2) The non-aqueous fat-soluble preparation comprises, in parts by weight, 0.1-3 parts by weight of an active ingredient, 20-50 parts by weight of a pharmaceutical phospholipid, 10-63 parts by weight of a release modifier, 10-40 parts by weight of a pharmaceutical solvent, and 0-0.001 parts by weight of a chelating agent;

[0078] (3) The non-aqueous fat-soluble preparation comprises, in parts by weight, 0.5-3 parts by weight of an active ingredient, 25-50 parts by weight of a pharmaceutical phospholipid, 15-63 parts by weight of a release modifier, 10-30 parts by weight of a pharmaceutical solvent, and 0-0.001 parts by weight of a chelating agent;

[0079] (4) The pharmaceutical phospholipids include a combination of one or more pharmaceutically acceptable natural phospholipids, semi-synthetic phospholipids and synthetic phospholipids; one or more natural phospholipids may be selected;

[0080] Optionally, the natural phospholipids include one or more of egg yolk lecithin and soybean lecithin;

[0081] Optionally, the semi-synthetic phospholipids include one or more of hydrogenated egg yolk lecithin and hydrogenated soybean lecithin;

[0082] Optionally, the synthetic phospholipids include one or more of dipalmitoylphosphatidylcholine (DPPC), distearoylphosphatidylcholine (DSPC), dimyristoylphosphatidylcholine (DMPC), dilauroylphosphatidylcholine (DLPC), dioleoylphosphatidylcholine (DOPC), dipalmitoylphosphatidylethanolamine (DPPE), dipalmitoylphosphatidylglycerol (DPPG), and dioleoylphosphatidylethanolamine (DOPE);

[0083] Optionally, the pharmaceutical phospholipids include one or more of egg yolk lecithin, soybean lecithin, hydrogenated egg yolk lecithin, hydrogenated soybean lecithin, dipalmitoylphosphatidylcholine (DPPC), distearoylphosphatidylcholine (DSPC), dimyristoylphosphatidylcholine (DMPC), dilauroylphosphatidylcholine (DLPC) and dioleoylphosphatidylcholine (DOPC);

[0084] Optionally, the pharmaceutical phospholipids include one or more of egg yolk lecithin, soybean lecithin, hydrogenated egg yolk lecithin, hydrogenated soybean lecithin, dipalmitoylphosphatidylcholine (DPPC), distearoylphosphatidylcholine (DSPC) and dimyristoylphosphatidylcholine (DMPC);

[0085] (5) The release modifiers include methyl oleate, ethyl oleate, propyl oleate, butyl oleate, 2-butyl oleate, isopropyl oleate, hexyl oleate, octyl oleate, glyceryl monooleate, glyceryl dioleate, glyceryl trioleate, propylene glycol monocaprylate, propylene glycol dicaprylate / dicaprate, propylene glycol laurate, propylene glycol alginate, caprylic capric acid mono- and diglycerides, caprylic capric acid mono- and triglycerides, caprylic capric acid polyethylene glycol glyceride, ricinoleic acid monoglyceride, mono- and diglycerides. One or more of olein, oleoylpolyoxyethylene glyceride, diacetyl monoglyceride, mono- and distearin, monostearin, tricaprylin, tricaprin, behenin, triacetin, isopropyl myristate, triethyl citrate, linolenic acid, diethyl sebacate, phytantriol, medium chain triglycerides, fish oil, algae oil, ethyl caprylate, ethyl caprate, ethyl linoleate, isopropyl linoleate, natural plant oil, and semi-natural plant oil;

[0086] Optionally, the release modifier comprises one or more of ethyl oleate, monoolein, diolein, triolein, propylene glycol monocaprylate, propylene glycol dicaprylate / dicaprate, propylene glycol laurate, propylene glycol alginate, caprylic and capric mono- and diglycerides, monolinolein, triacetin, medium chain triglycerides, fish oil, algae oil, and natural plant oils;

[0087] Optionally, the natural vegetable oil includes one or more of castor oil, sesame oil, soybean oil, sunflower oil, peanut oil, corn oil, rapeseed oil, olive oil, cottonseed oil, linseed oil, perilla seed oil, walnut oil, argan oil, and seaweed oil;

[0088] Optionally, the semi-natural vegetable oil comprises hydrogenated castor oil;

[0089] Optionally, the release modifier comprises one or more of ethyl oleate, monoolein, diolein, triolein, propylene glycol monocaprylate, propylene glycol dicaprylate / dicaprate, caprylic and capric mono- and diglycerides, monolinolein, triacetin, medium chain triglycerides, fish oil, algae oil, castor oil, sesame oil, soybean oil, peanut oil, corn oil, olive oil, cottonseed oil, linseed oil, perilla seed oil, walnut oil, argan oil, and laver oil;

[0090] (6) the pharmaceutically acceptable solvent includes one or more of benzyl alcohol, ethanol, propylene glycol, glycerol, isopropyl alcohol, N-methylpyrrolidone, dimethyl sulfoxide, liquid polyethylene glycol, dimethylacetamide, glycerol monoacetate, polyethylene glycol (mono) methyl ether, diethylene glycol monoethyl ether, ethyl lactate, ethyl acetate, propylene glycol diethyl ester, tetrahydrofuran polyethylene glycol ether, and benzyl benzoate;

[0091] Optionally, the pharmaceutically acceptable solvent includes one or more of benzyl alcohol, propylene glycol, ethanol, benzyl benzoate, dimethyl sulfoxide, liquid polyethylene glycol, N-methylpyrrolidone and dimethylacetamide;

[0092] Optionally, the pharmaceutically acceptable solvent includes one or more of benzyl alcohol, propylene glycol, ethanol, benzyl benzoate, dimethyl sulfoxide, N-methylpyrrolidone and dimethylacetamide;

[0093] (7) The chelating agent includes one or more of ethylenediaminetetraacetic acid, disodium ethylenediaminetetraacetate and calcium disodium ethylenediaminetetraacetate.

[0094] In some embodiments, the non-aqueous fat-soluble preparation is an oil solution, and the ingredients of the non-aqueous fat-soluble preparation include an active ingredient, a pharmaceutically acceptable solvent, a release modifier, and an optional small molecule modifier;

[0095] Optionally, the non-aqueous liposoluble preparation has at least one of the following characteristics:

[0096] (1) The non-aqueous fat-soluble preparation comprises, by weight, 0.1-5 parts by weight of an active ingredient, 5-50 parts by weight of a pharmaceutical solvent, 50-90 parts by weight of a release modifier, and 0-10 parts by weight of a small molecule modifier;

[0097] (2) The non-aqueous fat-soluble preparation comprises, by weight, 0.1-3 parts by weight of an active ingredient, 10-40 parts by weight of a pharmaceutical solvent, 55-90 parts by weight of a release modifier, and optionally 0.1-5 parts by weight of a small molecule modifier;

[0098] (3) The non-aqueous fat-soluble preparation comprises, by weight, 0.5-3 parts by weight of an active ingredient, 10-30 parts by weight of a pharmaceutical solvent, 69-90 parts by weight of a release modifier, and optionally 0.1-3 parts by weight of a small molecule modifier;

[0099] (4) The non-aqueous fat-soluble preparation comprises, by weight, 0.5-3 parts by weight of an active ingredient, 10-30 parts by weight of a pharmaceutical solvent, 69-90 parts by weight of a release modifier, and optionally 0.1-1 parts by weight of a small molecule modifier;

[0100] (5) The release modifier includes one or more of methyl oleate, ethyl oleate, propyl oleate, butyl oleate, 2-butyl oleate, isopropyl oleate, hexyl oleate, octyl oleate, monoolein, diolein, triolein, isopropyl myristate, triethyl citrate, linolenic acid, diethyl sebacate, phytantriol, natural plant oil, semi-natural oil and synthetic oil; more preferably, it can be one or more of ethyl oleate, monoolein, diolein, triolein, natural plant oil and synthetic oil;

[0101] Optionally, the natural vegetable oil includes one or more of castor oil, sesame oil, soybean oil, sunflower oil, peanut oil, corn oil, rapeseed oil, olive oil and cottonseed oil;

[0102] Optionally, the semi-natural oil comprises hydrogenated castor oil;

[0103] Optionally, the artificial synthetic oil comprises one or more of medium-chain triglycerides, long-chain triglycerides, triacetin and derivatives thereof; more preferably, the medium-chain triglycerides comprise one or more of caprylic triglyceride and capric triglyceride;

[0104] (6) The pharmaceutical solvent includes one or more of benzyl alcohol, chlorobutanol, dimethyl sulfoxide, N-methylpyrrolidone, dimethylacetamide, propylene glycol, polyethylene glycol, polyethylene glycol (mono) methyl ether, benzyl benzoate, glycerol aldehyde, glycerol formal, ethanol and ethylene glycol diethyl ether; and can be selected from one or more of benzyl alcohol, benzyl benzoate, dimethyl sulfoxide, N-methylpyrrolidone and dimethylacetamide;

[0105] (7) The small molecule regulator includes one or more of sodium phosphate, disodium hydrogen phosphate, sodium dihydrogen phosphate, potassium phosphate, dipotassium hydrogen phosphate, potassium dihydrogen phosphate, sodium carbonate, sodium bicarbonate, meglumine, arginine, triethanolamine, citric acid, sodium chloride, glucose and mannitol.

[0106] In some embodiments, the non-aqueous fat-soluble preparation is an oil solution, and the ingredients of the non-aqueous fat-soluble preparation include an active ingredient, a pharmaceutically acceptable solvent, a release modifier, and an optional small molecule modifier;

[0107] Optionally, the non-aqueous liposoluble preparation has at least one of the following characteristics:

[0108] (1) The non-aqueous fat-soluble preparation comprises, by weight, 0.1-5 parts by weight of an active ingredient, 0-50 parts by weight of a pharmaceutical solvent, 45-95 parts by weight of a release modifier, and 0-10 parts by weight of a small molecule modifier;

[0109] (2) The non-aqueous fat-soluble preparation comprises, by weight, 0.1-4 parts by weight of an active ingredient, 10-40 parts by weight of a pharmaceutical solvent, 55-90 parts by weight of a release modifier, and 0-5 parts by weight of a small molecule modifier;

[0110] (3) The non-aqueous fat-soluble preparation comprises, by weight, 0.2-3 parts by weight of an active ingredient, 10-35 parts by weight of a pharmaceutical solvent, 60-90 parts by weight of a release modifier, and 0-3 parts by weight of a small molecule modifier;

[0111] (4) The non-aqueous fat-soluble preparation comprises, by weight, 0.5-3 parts by weight of an active ingredient, 10-30 parts by weight of a pharmaceutical solvent, 69-90 parts by weight of a release modifier, and 0-1 part by weight of a small molecule modifier;

[0112] (5) The release modifiers include methyl oleate, ethyl oleate, propyl oleate, butyl oleate, 2-butyl oleate, isopropyl oleate, hexyl oleate, octyl oleate, glyceryl monooleate, glyceryl dioleate, glyceryl trioleate, propylene glycol monocaprylate, propylene glycol dicaprylate / dicaprate, propylene glycol laurate, propylene glycol alginate, caprylic capric acid mono- and diglycerides, caprylic capric acid mono- and triglycerides, caprylic capric acid polyethylene glycol glyceride, ricinoleic acid monoglyceride, mono- and diglycerides. One or more of olein, oleoylpolyoxyethylene glyceride, diacetyl monoglyceride, mono- and distearin, monostearin, tricaprylin, tricaprin, behenin, triacetin, isopropyl myristate, triethyl citrate, linolenic acid, diethyl sebacate, phytantriol, medium chain triglycerides, fish oil, algae oil, ethyl caprylate, ethyl caprate, ethyl linoleate, isopropyl linoleate, natural plant oil, and semi-natural plant oil;

[0113] Optionally, the release modifier comprises one or more of ethyl oleate, glyceryl monooleate, glyceryl dioleate, glyceryl trioleate, propylene glycol monocaprylate, propylene glycol dicaprylate / dicaprate, propylene glycol laurate, propylene glycol alginate, caprylic and capric mono- and diglycerides, glyceryl monolinoleate, glyceryl triacetate, medium chain triglycerides and natural plant oils;

[0114] Optionally, the natural vegetable oil includes one or more of castor oil, sesame oil, soybean oil, sunflower oil, peanut oil, corn oil, rapeseed oil, olive oil, cottonseed oil, linseed oil, perilla seed oil, walnut oil, argan oil, and seaweed oil;

[0115] Optionally, the semi-natural oil comprises hydrogenated castor oil;

[0116] Optionally, the release modifier comprises one or more of ethyl oleate, monoolein, diolein, triolein, propylene glycol monocaprylate, propylene glycol dicaprylate / dicaprate, caprylic and capric mono- and diglycerides, monolinolein, triacetin, medium chain triglycerides, fish oil, algae oil, castor oil, sesame oil, soybean oil, peanut oil, corn oil, olive oil, cottonseed oil, linseed oil, perilla seed oil, walnut oil, argan oil, and laver oil;

[0117] (6) The pharmaceutically acceptable solvent includes one or more of benzyl alcohol, ethanol, propylene glycol, glycerol, isopropyl alcohol, N-methylpyrrolidone, dimethyl sulfoxide, liquid polyethylene glycol, dimethylacetamide, glycerol monoacetate, polyethylene glycol (mono) methyl ether, diethylene glycol monoethyl ether, ethylene glycol diethyl ether, glycerol furfural, glycerol formal, chlorobutanol, ethyl lactate, ethyl acetate, propylene glycol diethyl ester, tetrahydrofuran glycol ether, and benzyl benzoate;

[0118] Optionally, the pharmaceutically acceptable solvent includes one or more of benzyl alcohol, propylene glycol, ethanol, benzyl benzoate, dimethyl sulfoxide, liquid polyethylene glycol, N-methylpyrrolidone and dimethylacetamide;

[0119] Optionally, the pharmaceutically acceptable solvent includes one or more of benzyl alcohol, propylene glycol, ethanol, benzyl benzoate, dimethyl sulfoxide, N-methylpyrrolidone and dimethylacetamide;

[0120] (7) The small molecule regulator includes one or more of sodium phosphate, disodium hydrogen phosphate, sodium dihydrogen phosphate, potassium phosphate, dipotassium hydrogen phosphate, potassium dihydrogen phosphate, sodium carbonate, sodium bicarbonate, sodium hydroxide, meglumine, arginine, lysine, histidine, tromethamine, diethanolamine, ethylenediamine, hydrochloric acid, acetic acid, ascorbic acid, lactic acid, tartaric acid, methanesulfonic acid, methionine, cysteine, α-tocopherol, α-tocopheryl acetate, N-acetyl-L-cysteine, butylated hydroxyanisole, dibutylhydroxytoluene, propyl gallate, tert-butylhydroquinone, lipoic acid, tea polyphenols, L-ascorbyl palmitate, glutathione, triethanolamine, citric acid, sodium chloride, glucose and mannitol;

[0121] Optionally, the small molecule regulator includes one or more of meglumine, tromethamine, triethanolamine, sodium hydroxide, disodium hydrogen phosphate, potassium dihydrogen phosphate, sodium carbonate, sodium bicarbonate, arginine, lysine, histidine, α-tocopherol, α-tocopherol acetate, butylated hydroxyanisole, dibutylhydroxytoluene, L-ascorbyl palmitate, and glutathione;

[0122] Optionally, the small molecule regulator includes one or more of meglumine, tromethamine, arginine, lysine, histidine, α-tocopherol, α-tocopherol acetate, butylated hydroxyanisole, L-ascorbyl palmitate, and glutathione.

[0123] In some embodiments, the non-aqueous fat-soluble preparation is an oil solution, and the ingredients of the non-aqueous fat-soluble preparation include an active ingredient, a pharmaceutically acceptable solvent, a release modifier, and an optional small molecule modifier;

[0124] Optionally, the non-aqueous liposoluble preparation has at least one of the following characteristics:

[0125] (1) The non-aqueous fat-soluble preparation comprises, by weight, 0.1-5 parts by weight of an active ingredient, 0-50 parts by weight of a pharmaceutical solvent, 47-95 parts by weight of a release modifier, and 0-1 part by weight of a small molecule modifier;

[0126] (2) The non-aqueous fat-soluble preparation comprises, by weight, 0.2-4 parts by weight of an active ingredient, 10-40 parts by weight of a pharmaceutical solvent, 60-90 parts by weight of a release modifier, and 0-0.8 parts by weight of a small molecule modifier;

[0127] (3) The non-aqueous fat-soluble preparation comprises, by weight, 0.5-3 parts by weight of an active ingredient, 10-35 parts by weight of a pharmaceutical solvent, 69-90 parts by weight of a release modifier, and 0-0.4 parts by weight of a small molecule modifier;

[0128] (4) The release modifiers include methyl oleate, ethyl oleate, propyl oleate, butyl oleate, 2-butyl oleate, isopropyl oleate, hexyl oleate, octyl oleate, glyceryl monooleate, glyceryl dioleate, glyceryl trioleate, propylene glycol monocaprylate, propylene glycol dicaprylate / dicaprate, propylene glycol laurate, propylene glycol alginate, caprylic capric acid mono- and diglycerides, caprylic capric acid mono- and triglycerides, caprylic capric acid polyethylene glycol glyceride, ricinoleic acid monoglyceride, mono- and diglycerides. One or more of olein, oleoylpolyoxyethylene glyceride, diacetyl monoglyceride, mono- and distearin, monostearin, tricaprylin, tricaprin, behenin, triacetin, isopropyl myristate, triethyl citrate, linolenic acid, diethyl sebacate, phytantriol, medium chain triglycerides, fish oil, algae oil, ethyl caprylate, ethyl caprate, ethyl linoleate, isopropyl linoleate, natural plant oil, and semi-natural plant oil;

[0129] Optionally, the release modifier comprises one or more of ethyl oleate, glyceryl monooleate, glyceryl dioleate, glyceryl trioleate, propylene glycol monocaprylate, propylene glycol dicaprylate / dicaprate, propylene glycol laurate, propylene glycol alginate, caprylic and capric mono- and diglycerides, glyceryl monolinoleate, glyceryl triacetate, medium chain triglycerides and natural plant oils;

[0130] Optionally, the natural vegetable oil includes one or more of castor oil, sesame oil, soybean oil, sunflower oil, peanut oil, corn oil, rapeseed oil, olive oil, cottonseed oil, linseed oil, perilla seed oil, walnut oil, argan oil, and seaweed oil;

[0131] Optionally, the semi-natural oil comprises hydrogenated castor oil;

[0132] Optionally, the release modifier comprises one or more of ethyl oleate, monoolein, diolein, triolein, propylene glycol monocaprylate, propylene glycol dicaprylate / dicaprate, caprylic and capric mono- and diglycerides, monolinolein, triacetin, medium chain triglycerides, castor oil, sesame oil, soybean oil, peanut oil, corn oil, olive oil, and cottonseed oil;

[0133] (5) The pharmaceutically acceptable solvent includes one or more of benzyl alcohol, ethanol, propylene glycol, glycerol, isopropyl alcohol, N-methylpyrrolidone, dimethyl sulfoxide, liquid polyethylene glycol, dimethylacetamide, glycerol monoacetate, polyethylene glycol (mono) methyl ether, diethylene glycol monoethyl ether, ethylene glycol diethyl ether, glycerol furfural, glycerol formal, chlorobutanol, ethyl lactate, ethyl acetate, propylene glycol diethyl ester, tetrahydrofuran glycol ether, and benzyl benzoate;

[0134] Optionally, the pharmaceutically acceptable solvent includes one or more of benzyl alcohol, propylene glycol, ethanol, benzyl benzoate, dimethyl sulfoxide, liquid polyethylene glycol, N-methylpyrrolidone and dimethylacetamide;

[0135] Optionally, the pharmaceutically acceptable solvent includes one or more of benzyl alcohol, propylene glycol, ethanol, benzyl benzoate, dimethyl sulfoxide, N-methylpyrrolidone and dimethylacetamide;

[0136] (6) The small molecule regulator includes one or more of sodium phosphate, disodium hydrogen phosphate, sodium dihydrogen phosphate, potassium phosphate, dipotassium hydrogen phosphate, potassium dihydrogen phosphate, sodium carbonate, sodium bicarbonate, sodium hydroxide, meglumine, arginine, lysine, histidine, tromethamine, diethanolamine, ethylenediamine, hydrochloric acid, acetic acid, ascorbic acid, lactic acid, tartaric acid, methanesulfonic acid, methionine, cysteine, α-tocopherol, α-tocopheryl acetate, N-acetyl-L-cysteine, butylated hydroxyanisole, dibutylhydroxytoluene, propyl gallate, tert-butylhydroquinone, lipoic acid, tea polyphenols, L-ascorbyl palmitate, glutathione, triethanolamine, citric acid, sodium chloride, glucose and mannitol;

[0137] Optionally, the small molecule regulator includes one or more of meglumine, tromethamine, triethanolamine, sodium hydroxide, disodium hydrogen phosphate, potassium dihydrogen phosphate, sodium carbonate, sodium bicarbonate, arginine, lysine, histidine, α-tocopherol, α-tocopherol acetate, butylated hydroxyanisole, dibutylhydroxytoluene, L-ascorbyl palmitate, and glutathione;

[0138] Optionally, the small molecule regulator includes one or more of meglumine, tromethamine, arginine, lysine, histidine, α-tocopherol, α-tocopherol acetate, butylated hydroxyanisole, L-ascorbyl palmitate, and glutathione.

[0139] In some embodiments, the non-aqueous fat-soluble preparation is an oil solution, and the ingredients of the non-aqueous fat-soluble preparation include an active ingredient, a pharmaceutically acceptable solvent, a release modifier, and an optional small molecule modifier;

[0140] Optionally, the non-aqueous liposoluble preparation has at least one of the following characteristics:

[0141] (1) The non-aqueous fat-soluble preparation comprises, by weight, 0.1-5 parts by weight of an active ingredient, 5-50 parts by weight of a pharmaceutical solvent, 50-90 parts by weight of a release modifier, and 0-10 parts by weight of a small molecule modifier;

[0142] (2) The non-aqueous fat-soluble preparation comprises, by weight, 0.1-3 parts by weight of an active ingredient, 10-40 parts by weight of a pharmaceutical solvent, 55-90 parts by weight of a release modifier, and optionally 0.1-5 parts by weight of a small molecule modifier;

[0143] (3) The non-aqueous fat-soluble preparation comprises, by weight, 0.5-3 parts by weight of an active ingredient, 10-30 parts by weight of a pharmaceutical solvent, 69-90 parts by weight of a release modifier, and optionally 0.1-3 parts by weight of a small molecule modifier;

[0144] (4) The non-aqueous fat-soluble preparation comprises, by weight, 0.5-3 parts by weight of an active ingredient, 10-30 parts by weight of a pharmaceutical solvent, 69-90 parts by weight of a release modifier, and optionally 0.1-1 parts by weight of a small molecule modifier;

[0145] (5) The release modifiers include methyl oleate, ethyl oleate, propyl oleate, butyl oleate, 2-butyl oleate, isopropyl oleate, hexyl oleate, octyl oleate, glyceryl monooleate, glyceryl dioleate, glyceryl trioleate, propylene glycol monocaprylate, propylene glycol dicaprylate / dicaprate, propylene glycol laurate, propylene glycol alginate, caprylic capric acid mono- and diglycerides, caprylic capric acid mono- and triglycerides, caprylic capric acid polyethylene glycol glyceride, ricinoleic acid monoglyceride, mono- and diglycerides. One or more of olein, oleoylpolyoxyethylene glyceride, diacetyl monoglyceride, mono- and distearin, monostearin, tricaprylin, tricaprin, behenin, triacetin, isopropyl myristate, triethyl citrate, linolenic acid, diethyl sebacate, phytantriol, medium chain triglycerides, fish oil, algae oil, ethyl caprylate, ethyl caprate, ethyl linoleate, isopropyl linoleate, natural plant oil, and semi-natural plant oil;

[0146] Optionally, the release modifier comprises one or more of ethyl oleate, glyceryl monooleate, glyceryl dioleate, glyceryl trioleate, propylene glycol monocaprylate, propylene glycol dicaprylate / dicaprate, propylene glycol laurate, propylene glycol alginate, caprylic and capric mono- and diglycerides, glyceryl monolinoleate, glyceryl triacetate, medium chain triglycerides and natural plant oils;

[0147] Optionally, the natural vegetable oil includes one or more of castor oil, sesame oil, soybean oil, sunflower oil, peanut oil, corn oil, rapeseed oil, olive oil, cottonseed oil, linseed oil, perilla seed oil, walnut oil, argan oil, and seaweed oil;

[0148] Optionally, the semi-natural oil comprises hydrogenated castor oil;

[0149] Optionally, the release modifier comprises one or more of ethyl oleate, monoolein, diolein, triolein, propylene glycol monocaprylate, propylene glycol dicaprylate / dicaprate, caprylic and capric mono- and diglycerides, monolinolein, triacetin, medium chain triglycerides, fish oil, algae oil, castor oil, sesame oil, soybean oil, peanut oil, corn oil, olive oil, cottonseed oil, linseed oil, perilla seed oil, walnut oil, argan oil, and laver oil;

[0150] (6) The pharmaceutically acceptable solvent includes one or more of benzyl alcohol, ethanol, propylene glycol, glycerol, isopropyl alcohol, N-methylpyrrolidone, dimethyl sulfoxide, liquid polyethylene glycol, dimethylacetamide, glycerol monoacetate, polyethylene glycol (mono) methyl ether, diethylene glycol monoethyl ether, ethylene glycol diethyl ether, glycerol furfural, glycerol formal, chlorobutanol, ethyl lactate, ethyl acetate, propylene glycol diethyl ester, tetrahydrofuran glycol ether, and benzyl benzoate;

[0151] Optionally, the pharmaceutically acceptable solvent includes one or more of benzyl alcohol, propylene glycol, ethanol, benzyl benzoate, dimethyl sulfoxide, liquid polyethylene glycol, N-methylpyrrolidone and dimethylacetamide;

[0152] Optionally, the pharmaceutically acceptable solvent includes one or more of benzyl alcohol, propylene glycol, ethanol, benzyl benzoate, dimethyl sulfoxide, N-methylpyrrolidone and dimethylacetamide;

[0153] (7) The small molecule regulator includes one or more of sodium phosphate, disodium hydrogen phosphate, sodium dihydrogen phosphate, potassium phosphate, dipotassium hydrogen phosphate, potassium dihydrogen phosphate, sodium carbonate, sodium bicarbonate, sodium hydroxide, meglumine, arginine, lysine, histidine, tromethamine, diethanolamine, ethylenediamine, hydrochloric acid, acetic acid, ascorbic acid, lactic acid, tartaric acid, methanesulfonic acid, methionine, cysteine, α-tocopherol, α-tocopheryl acetate, N-acetyl-L-cysteine, butylated hydroxyanisole, dibutylhydroxytoluene, propyl gallate, tert-butylhydroquinone, lipoic acid, tea polyphenols, L-ascorbyl palmitate, glutathione, triethanolamine, citric acid, sodium chloride, glucose and mannitol;

[0154] Optionally, the small molecule regulator includes one or more of meglumine, tromethamine, triethanolamine, sodium hydroxide, disodium hydrogen phosphate, potassium dihydrogen phosphate, sodium carbonate, sodium bicarbonate, arginine, lysine, histidine, α-tocopherol, α-tocopherol acetate, butylated hydroxyanisole, dibutylhydroxytoluene, L-ascorbyl palmitate, and glutathione;

[0155] Optionally, the small molecule regulator includes one or more of meglumine, tromethamine, arginine, lysine, histidine, α-tocopherol, α-tocopherol acetate, butylated hydroxyanisole, dibutylhydroxytoluene, L-ascorbyl palmitate, and glutathione.

[0156] In some embodiments, the non-aqueous liposoluble preparation is an in situ gel, and the ingredients of the non-aqueous liposoluble preparation include an active ingredient, a pharmaceutically acceptable solvent, and a release modifier;

[0157] Optionally, the non-aqueous liposoluble preparation has at least one of the following characteristics:

[0158] (1) The non-aqueous fat-soluble preparation comprises, by weight, 0.1-5 parts by weight of an active ingredient, 50-90 parts by weight of a pharmaceutical solvent, and 5-40 parts by weight of a release modifier;

[0159] (2) The non-aqueous fat-soluble preparation comprises, by weight, 0.1-3 parts by weight of an active ingredient, 60-85 parts by weight of a pharmaceutical solvent, and 10-30 parts by weight of a release modifier;

[0160] (3) The non-aqueous fat-soluble preparation comprises, by weight, 0.5-3 parts by weight of an active ingredient, 69-85 parts by weight of a pharmaceutically acceptable solvent, and 13-30 parts by weight of a release modifier;

[0161] (4) The release modifier includes one or more pharmaceutically acceptable biodegradable polymers; the release modifier may be selected from one or more of polylactic acid, polylactic acid-co-glycolic acid, polyorthoester, sucrose acetate-isobutyrate, fatty acid glyceride, pegylated PLA / PLGA, PLGA-PEG-PLGA copolymer, polycaprolactone-polyethylene glycol copolymer, triethylene glycol poly(orthoester) polymer, poloxamer, and other pharmaceutically acceptable sustained-release materials for local injection; the release modifier may be selected from one or more of polylactic acid, polylactic acid-co-glycolic acid, polyorthoester, sucrose acetate-isobutyrate, pegylated PLA / PLGA, PLGA-PEG-PLGA copolymer, and poloxamer;

[0162] (5) The pharmaceutical solvent includes one or more of N-methylpyrrolidone, polyethylene glycol (mono) methyl ether, glycerol triacetate, benzyl benzoate, glycerol aldehyde, glycerol formal, propylene glycol, ethanol, ethylene glycol diethyl ether, benzyl alcohol, dimethyl sulfoxide and other pharmaceutically acceptable organic solvents; it can be selected from one or more of N-methylpyrrolidone, polyethylene glycol (mono) methyl ether, benzyl benzoate, benzyl alcohol, dimethyl sulfoxide, propylene glycol and ethanol.

[0163] In some embodiments, the non-aqueous liposoluble preparation is an in situ gel, and the ingredients of the non-aqueous liposoluble preparation include an active ingredient, a pharmaceutically acceptable solvent, and a release modifier;

[0164] Optionally, the non-aqueous liposoluble preparation has at least one of the following characteristics:

[0165] (1) The non-aqueous fat-soluble preparation comprises, by weight, 0.1-10 parts by weight of an active ingredient, 10-95 parts by weight of a pharmaceutical solvent, and 5-90 parts by weight of a release modifier;

[0166] (2) The non-aqueous fat-soluble preparation comprises, by weight, 0.1-8 parts by weight of an active ingredient, 20-90 parts by weight of a pharmaceutical solvent, and 10-75 parts by weight of a release modifier;

[0167] (3) The non-aqueous fat-soluble preparation comprises, by weight, 0.5-6 parts by weight of an active ingredient, 30-85 parts by weight of a pharmaceutical solvent, and 13-60 parts by weight of a release modifier;

[0168] (4) The release modifier comprises one or more pharmaceutically acceptable biodegradable polymers; the release modifier may be selected from one or more of polylactic acid, polylactic acid-co-glycolic acid, polyorthoester, sucrose acetate-isobutyrate, fatty acid glyceride, pegylated PLA / PLGA, PLGA-PEG-PLGA copolymer, polycaprolactone-polyethylene glycol copolymer, triethylene glycol poly(orthoester) polymer, poloxamer, and other pharmaceutically acceptable sustained-release materials for local injection;

[0169] Optionally, the release modifier comprises one or more of polylactic acid, polylactic-co-glycolic acid, polyorthoester, sucrose acetate-isobutyrate, pegylated PLA / PLGA, PLGA-PEG-PLGA copolymer, polycaprolactone-polyethylene glycol copolymer and poloxamer;

[0170] Optionally, the release modifier comprises one or more of polylactic acid, polylactic-co-glycolic acid, polyorthoester, sucrose acetate-isobutyrate, pegylated PLA / PLGA, PLGA-PEG-PLGA copolymer and poloxamer;

[0171] (5) The pharmaceutically acceptable solvent includes one or more of N-methylpyrrolidone, polyethylene glycol (mono) methyl ether, glyceryl triacetate, benzyl benzoate, glycerol furfural, glycerol formal, propylene glycol, ethanol, ethylene glycol diethyl ether, benzyl alcohol, dimethyl sulfoxide, liquid polyethylene glycol, dimethylacetamide, and other pharmaceutically acceptable organic solvents;

[0172] Optionally, the pharmaceutically acceptable solvent includes one or more of N-methylpyrrolidone, polyethylene glycol (mono) methyl ether, benzyl benzoate, benzyl alcohol, dimethyl sulfoxide, ethylene glycol diethyl ether, propylene glycol and ethanol;

[0173] Optionally, the pharmaceutically acceptable solvent includes one or more of N-methylpyrrolidone, polyethylene glycol (mono)methyl ether, benzyl benzoate, benzyl alcohol, dimethyl sulfoxide, propylene glycol and ethanol.

[0174] In some embodiments, the non-aqueous liposoluble preparation is an in situ gel, and the ingredients of the non-aqueous liposoluble preparation include an active ingredient, a pharmaceutically acceptable solvent, and a release modifier;

[0175] Optionally, the non-aqueous liposoluble preparation has at least one of the following characteristics:

[0176] (1) The non-aqueous fat-soluble preparation comprises, by weight, 0.1-10 parts by weight of an active ingredient, 10-91 parts by weight of a pharmaceutical solvent, and 5-90 parts by weight of a release modifier;

[0177] (2) The non-aqueous fat-soluble preparation comprises, by weight, 0.5-8 parts by weight of an active ingredient, 20-85 parts by weight of a pharmaceutical solvent, and 10-74 parts by weight of a release modifier;

[0178] (3) The non-aqueous fat-soluble preparation comprises, by weight, 0.5-6 parts by weight of an active ingredient, 30-84 parts by weight of a pharmaceutical solvent, and 13-60 parts by weight of a release modifier;

[0179] (4) The release modifier comprises one or more pharmaceutically acceptable biodegradable polymers; the release modifier may be selected from one or more of polylactic acid, polylactic acid-co-glycolic acid, polyorthoester, sucrose acetate-isobutyrate, fatty acid glyceride, pegylated PLA / PLGA, PLGA-PEG-PLGA copolymer, polycaprolactone-polyethylene glycol copolymer, triethylene glycol poly(orthoester) polymer, poloxamer, and other pharmaceutically acceptable sustained-release materials for local injection;

[0180] Optionally, the release modifier comprises one or more of polylactic acid, polylactic-co-glycolic acid, polyorthoester, sucrose acetate-isobutyrate, pegylated PLA / PLGA, PLGA-PEG-PLGA copolymer, polycaprolactone-polyethylene glycol copolymer and poloxamer;

[0181] Optionally, the release modifier comprises one or more of polylactic acid, polylactic-co-glycolic acid, polyorthoester, sucrose acetate-isobutyrate, pegylated PLA / PLGA, PLGA-PEG-PLGA copolymer and poloxamer;

[0182] (5) The pharmaceutically acceptable solvent includes one or more of N-methylpyrrolidone, polyethylene glycol (mono) methyl ether, glyceryl triacetate, benzyl benzoate, glycerol furfural, glycerol formal, propylene glycol, ethanol, ethylene glycol diethyl ether, benzyl alcohol, dimethyl sulfoxide, liquid polyethylene glycol, dimethylacetamide, and other pharmaceutically acceptable organic solvents;

[0183] Optionally, the pharmaceutically acceptable solvent includes one or more of N-methylpyrrolidone, polyethylene glycol (mono) methyl ether, benzyl benzoate, benzyl alcohol, dimethyl sulfoxide, ethylene glycol diethyl ether, propylene glycol and ethanol;

[0184] Optionally, the pharmaceutically acceptable solvent includes one or more of N-methylpyrrolidone, polyethylene glycol (mono)methyl ether, benzyl benzoate, benzyl alcohol, dimethyl sulfoxide, propylene glycol and ethanol.

[0185] In some embodiments, the non-aqueous liposoluble preparation is an in situ gel, and the ingredients of the non-aqueous liposoluble preparation include an active ingredient, a pharmaceutically acceptable solvent, and a release modifier;

[0186] Optionally, the non-aqueous liposoluble preparation has at least one of the following characteristics:

[0187] (1) The non-aqueous fat-soluble preparation comprises, by weight, 0.1-5 parts by weight of an active ingredient, 50-90 parts by weight of a pharmaceutical solvent, and 5-40 parts by weight of a release modifier;

[0188] (2) The non-aqueous fat-soluble preparation comprises, by weight, 0.1-3 parts by weight of an active ingredient, 60-85 parts by weight of a pharmaceutical solvent, and 10-30 parts by weight of a release modifier;

[0189] (3) The non-aqueous fat-soluble preparation comprises, by weight, 0.5-3 parts by weight of an active ingredient, 69-85 parts by weight of a pharmaceutically acceptable solvent, and 13-30 parts by weight of a release modifier;

[0190] (4) The release modifier comprises one or more pharmaceutically acceptable biodegradable polymers; the release modifier may be selected from one or more of polylactic acid, polylactic acid-co-glycolic acid, polyorthoester, sucrose acetate-isobutyrate, fatty acid glyceride, pegylated PLA / PLGA, PLGA-PEG-PLGA copolymer, polycaprolactone-polyethylene glycol copolymer, triethylene glycol poly(orthoester) polymer, poloxamer, and other pharmaceutically acceptable sustained-release materials for local injection;

[0191] Optionally, the release modifier comprises one or more of polylactic acid, polylactic-co-glycolic acid, polyorthoester, sucrose acetate-isobutyrate, pegylated PLA / PLGA, PLGA-PEG-PLGA copolymer, polycaprolactone-polyethylene glycol copolymer and poloxamer;

[0192] Optionally, the release modifier comprises one or more of polylactic acid, polylactic-co-glycolic acid, polyorthoester, sucrose acetate-isobutyrate, pegylated PLA / PLGA, PLGA-PEG-PLGA copolymer and poloxamer;

[0193] (5) The pharmaceutically acceptable solvent includes one or more of N-methylpyrrolidone, polyethylene glycol (mono) methyl ether, glyceryl triacetate, benzyl benzoate, glycerol furfural, glycerol formal, propylene glycol, ethanol, ethylene glycol diethyl ether, benzyl alcohol, dimethyl sulfoxide, liquid polyethylene glycol, dimethylacetamide, and other pharmaceutically acceptable organic solvents;

[0194] Optionally, the pharmaceutically acceptable solvent includes one or more of N-methylpyrrolidone, polyethylene glycol (mono) methyl ether, benzyl benzoate, benzyl alcohol, dimethyl sulfoxide, ethylene glycol diethyl ether, propylene glycol and ethanol;

[0195] Optionally, the pharmaceutically acceptable solvent includes one or more of N-methylpyrrolidone, polyethylene glycol (mono)methyl ether, benzyl benzoate, benzyl alcohol, dimethyl sulfoxide, propylene glycol and ethanol.

[0196] In some embodiments, the non-aqueous liposoluble formulation has at least one of the following characteristics:

[0197] (1) The deoxycholate comprises sodium deoxycholate; the deoxycholic acid derivative comprises one or more of ursodeoxycholic acid, hyodeoxycholic acid, and chenodeoxycholic acid;

[0198] (2) Based on the active ingredient, the dosage of the non-aqueous fat-soluble preparation is 0.1 mg-1000 mg; optionally 1 mg-500 mg.

[0199] In some embodiments, the non-aqueous liposoluble formulation has at least one of the following characteristics:

[0200] (1) The deoxycholate comprises sodium deoxycholate; the deoxycholic acid derivative comprises one or more of ursodeoxycholic acid, hyodeoxycholic acid, chenodeoxycholic acid, sodium ursodeoxycholate, sodium hyodeoxycholate, sodium chenodeoxycholate, cholic acid, sodium cholate, glycocholic acid, sodium glycocholate, glycodeoxycholic acid, sodium glycodeoxycholate, taurocholic acid, sodium taurocholate, glycotaurocholic acid, sodium glycotaurocholate, lithocholic acid, sodium lithocholic acid, sodium glycochenodeoxycholate, sodium phenylpropanecholate, sodium casochlate, sodium leucocholic acid, bile acid dimer, bile acid side chain amino acid conjugate, bile acid side chain PEG conjugate, and bile acid side chain glucose conjugate;

[0201] (2) Based on the active ingredient, the dosage of the non-aqueous fat-soluble preparation is 0.1 mg-1000 mg; optionally 1 mg-500 mg.

[0202] The second aspect of the present application provides a use of the non-aqueous lipolytic preparation of the first aspect in preparing a preparation having the effect of dissolving fat cells;

[0203] Optionally, the preparation having the effect of dissolving fat cells includes an injection preparation and / or an implant preparation;

[0204] More optionally, the administration sites of the injection preparation and / or the implant preparation include one or more of the abdomen, under the eyes, under the hips, under the arms, buttocks, thighs, calves, back, bra line, armpits, stomach and ankles.

[0205] The third aspect of the present application provides an injection preparation, which is prepared from the non-aqueous liposoluble preparation of the first aspect of the present application;

[0206] Optionally, the injection preparation is administered by one or more of subcutaneous injection and intramuscular injection; subcutaneous injection is optional.

[0207] The fourth aspect of the present application provides an implant preparation, which is prepared from the non-aqueous liposoluble preparation of the first aspect of the present application.

[0208] The non-aqueous liposoluble preparation provided above can slowly release the drug at the administration site, prolong the drug release time, keep the blood drug concentration in the body within the therapeutic window for a long time, and play a lasting lipolysis effect, and significantly reduce the adverse reactions caused by excessive local drug concentration, thereby improving the safety of medication; at the same time, it can avoid the problem of weakened efficacy caused by the prolonged dosing interval due to adverse reactions when using ordinary injection preparations (such as Kybella, etc.). Clinically, the dosing interval can be determined according to the efficacy to ensure a good lipolysis effect and improve the patient's experience and comfort. In addition, the non-aqueous liposoluble preparation can improve the lipolysis effect at the same dose, improve drug utilization, avoid drug waste, reduce treatment costs, and reduce the risk caused by drug accumulation. BRIEF DESCRIPTION OF THE DRAWINGS

[0209] In order to more clearly illustrate the technical solutions in the embodiments of the present application and to more fully understand the present application and its beneficial effects, the following is a brief introduction to the drawings required for describing the embodiments. Obviously, the drawings described below are only some embodiments of the present application. Those skilled in the art can also derive other drawings based on these drawings without inventive effort.

[0210] Figure 1 The in vitro release curves of Comparative Examples 1, 2, 3 and proliposomes 1-7;

[0211] Figure 2 The in vitro release curves of Comparative Example 1 and proliposomes 8-14;

[0212] Figure 3 is the in vitro release curve of proliposome 15-19;

[0213] Figure 4 is the in vitro release curve of proliposome 20-27;

[0214] Figure 5 The in vitro release curves of Comparative Example 1 and oil solutions 1-8 are shown;

[0215] Figure 6 The in vitro release curve of oil solution 9-12 is shown;

[0216] Figure 7 This is the in vitro release curve of Comparative Example 2;

[0217] Figure 8 This is the in vitro release curve of Comparative Example 4;

[0218] Figure 9 The in vitro release curves of Comparative Example 1 and in situ gels 1-11;

[0219] Figure 10 The morphological changes of inguinal fat;

[0220] Figure 11 For the changes in muscle morphology;

[0221] Figure 12 This is the injection site condition of experimental mice 24 hours after injection;

[0222] Figure 13 This is the injection site condition of experimental mice 7 days after injection;

[0223] Figure 14 The pain threshold at the injection site at different time points after administration;

[0224] Figure 15 This is the injection site condition of high-fat mice 24 hours after the first injection;

[0225] Figure 16 This is the injection site condition of high-fat mice 7 days after the first injection;

[0226] Figure 17 This is the injection site condition of high-fat mice 14 days after the first injection;

[0227] Figure 18 This is the injection site condition of high-fat mice 21 days after the first injection;

[0228] Figure 19 To investigate the drug release behavior at the injection site, (A) is the drug residual amount at the injection site, and (B) is the drug release amount at the injection site;

[0229] Figure 20 Schematic diagram of the injection position;

[0230] Figure 21The fat dissolution at the injection site in different groups;

[0231] Figure 22 The figures are the pathological section results of different groups. DETAILED DESCRIPTION

[0232] To facilitate understanding of the present application, a more comprehensive description of the present application will be provided below with reference to the accompanying drawings. The accompanying drawings illustrate preferred embodiments of the present application. However, the present application may be implemented in many different forms and is not limited to the embodiments described herein. Rather, these embodiments are provided to provide a more thorough and comprehensive understanding of the disclosure of the present application.

[0233] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this application pertains. The terms used herein in the specification of this application are for the purpose of describing specific embodiments only and are not intended to limit this application. The term "and / or" as used herein includes any and all combinations of one or more of the associated listed items.

[0234] In this application, the technical features described in an open manner include closed technical solutions composed of the listed features, and also include open technical solutions containing the listed features.

[0235] In this application, when referring to numerical ranges, unless otherwise specified, the numerical ranges are considered continuous and include the minimum and maximum values ​​of the range, as well as every value between such minimum and maximum values. Further, when a range refers to an integer, every integer between the minimum and maximum values ​​of the range is included. In addition, when multiple ranges are provided to describe a feature or characteristic, the ranges can be combined. In other words, unless otherwise specified, all ranges disclosed herein should be understood to include any and all subranges subsumed therein.

[0236] Only certain numerical ranges are specifically disclosed herein. However, any lower limit may be combined with any upper limit to form an unspecified range; and any lower limit may be combined with other lower limits to form an unspecified range, and similarly, any upper limit may be combined with any other upper limit to form an unspecified range. In addition, each individually disclosed point or single value may itself serve as a lower limit or upper limit and be combined with any other point or single value, or with other lower limits or upper limits, to form an unspecified range.

[0237] The temperature parameters in this application, unless otherwise specified, allow for both constant temperature treatment and treatment within a certain temperature range. The constant temperature treatment allows for temperature fluctuations within the precision range of instrument control.

[0238] In the description of the invention, “plurality” means at least two, for example, two, three, etc., unless otherwise clearly and specifically defined.

[0239] Unless otherwise specified, all embodiments and optional embodiments of the present application can be combined with each other to form a new technical solution. Unless otherwise specified, all technical features and optional technical features of the present application can be combined with each other to form a new technical solution.

[0240] Unless otherwise specified, all steps of the present application can be performed sequentially or randomly, preferably sequentially.

[0241] Unless otherwise specified or incompatible herewith, the terms and phrases used herein shall have the following meanings:

[0242] Herein, the “suitable” mentioned in “suitable combination”, “suitable method”, “any suitable method”, etc. shall be based on the ability to implement the technical solution of this application, solve the technical problems of this application, and achieve the expected technical effects of this application.

[0243] Herein, the terms "preferred," "better," "more preferred," and "suitable" are used solely to describe preferred implementations or examples and should not be construed as limiting the scope of protection of this application. If multiple "preferred" terms appear in a technical solution, each "preferred" term is considered independent unless otherwise specified and there are no contradictions or mutual constraints.

[0244] In this application, "further", "further", "particularly" and the like are used for descriptive purposes to indicate differences in content, but should not be understood as limiting the scope of protection of this application.

[0245] In this application, the terms "optionally," "optional," and "optional" mean optional or dispensable, i.e., they refer to either option being selected from two parallel options: "with" or "without." If a technical solution contains multiple "optional" clauses, each "optional" clause is independent unless otherwise specified and there are no contradictions or constraints.

[0246] Deoxycholic acid is a cytolytic drug that, when injected into body tissues, disrupts cell membranes and causes cell lysis. In vitro testing has shown that deoxycholic acid salts have cytolytic effects on a variety of cell types tested (such as human keratinocytes, adipocytes, fibroblasts, skeletal muscle cells, vascular endothelial cells, and peripheral nerve cells). It lacks cell selectivity and is therefore prone to causing adverse reactions.

[0247] Kybella, a lipolytic drug currently on the market, uses deoxycholic acid as its main ingredient and is a regular rapid-release injection. After injection, deoxycholic acid is rapidly released, which can cause drastic fluctuations in the blood concentration of deoxycholic acid in the body. When the local blood concentration of deoxycholic acid in the body rises sharply after injection, it may further lead to the occurrence of adverse reactions; for example, when the local blood concentration of deoxycholic acid is too high, it may damage skin cells and cause damage to the jaw nerve, leading to adverse reactions such as unnatural smile, facial muscle weakness and difficulty swallowing; in clinical use of this product, it was found that more than 50% of patients experienced hematoma, pain, edema and numbness at the injection site, and more than 10% of the subjects experienced swelling, erythema, induration, paresthesia, itching and nodules at the injection site. Among them, those who stopped the drug or terminated the study due to adverse reactions included severe pain, nerve damage, prolonged difficulty swallowing and speech disorders, and the adverse reactions were extremely serious. In addition, clinical adverse reactions require at least 4 weeks to recover, resulting in a dosing interval of 4 weeks. Kybella is a regular rapid-release injection. Too long a dosing interval will inevitably lead to a weakening of the drug's efficacy. Patients will need at least 2 months to see the therapeutic effect. Moreover, as deoxycholic acid is metabolized in the body, when the blood concentration of deoxycholic acid drops significantly, the therapeutic effect may not be achieved.

[0248] To address the above-mentioned issues, the present application discloses a non-aqueous liposoluble preparation, the active ingredient of which includes one or more of deoxycholic acid, pharmaceutically acceptable salts of deoxycholic acid, and deoxycholic acid derivatives. In a release medium having a pH of 7.4 that meets sink conditions, at 37°C, the non-aqueous liposoluble preparation releases no more than 25% of the total amount of the active ingredient in the non-aqueous liposoluble preparation over one hour, and releases greater than 80% of the total amount of the active ingredient in the non-aqueous liposoluble preparation over 168 hours. When used in vivo, the preparation achieves slow and sustained release of the active ingredient, thereby achieving both an effective therapeutic effect and a reduced likelihood of adverse reactions.

[0249] The first aspect of the present application provides a non-aqueous liposoluble preparation, the active ingredient of which includes one or more of deoxycholic acid, a pharmaceutically acceptable salt of deoxycholic acid, and a deoxycholic acid derivative; in a release medium with a pH value of 7.4 that meets the sink condition, at 37°C, the release amount of the active ingredient in 1 hour does not exceed 25% of the total amount of the active ingredient contained in the non-aqueous liposoluble preparation, and the release amount in 168 hours is greater than 80% of the total amount of the active ingredient contained in the non-aqueous liposoluble preparation.

[0250] The active ingredient remaining in the tissue of the non-aqueous liposoluble preparation provided by the present application 168 hours after the first single injection in vivo does not exceed 30% of the total amount of the active ingredient of the administered non-aqueous liposoluble preparation.

[0251] It should be noted that the release medium with a pH value of 7.4 mentioned in this article was prepared according to the preparation method of the general buffer solution in Part IV of the 2020 edition of the Chinese Pharmacopoeia.

[0252] It is easy to understand that the active ingredients mentioned in this application refer to the components in non-aqueous liposoluble preparations that have a lipolysis effect. "Non-aqueous liposoluble preparations" refer to liposoluble preparations that use a pharmaceutical non-aqueous solvent as a medium during the preparation process.

[0253] Understandably, the non-aqueous liposoluble preparation can slowly release the drug at the administration site, prolong the drug release time, keep the blood drug concentration in the body within the therapeutic window for a long time, play a lasting lipolysis effect, and significantly reduce the adverse reactions caused by excessive local drug concentration, thereby improving the safety of medication; at the same time, it can avoid the problem of weakened efficacy caused by the prolonged dosing interval due to adverse reactions when using ordinary injection preparations (such as Kybella, etc.). Clinically, the dosing interval can be determined according to the efficacy to ensure a good lipolysis effect and improve the patient's experience comfort. The non-aqueous liposoluble preparation can also improve the lipolysis effect at the same dose, improve drug utilization, avoid drug waste, reduce treatment costs, and reduce the risks caused by drug accumulation. In addition, the non-aqueous liposoluble preparation has the effect of targeted lipolysis, and the liposoluble components are concentrated in the tissues of the administration site without spreading to other parts or tissues, thereby achieving the purpose of targeted lipolysis.

[0254] Furthermore, the non-aqueous fat-soluble preparation has good stability and no drug precipitation, which can further achieve control over drug release.

[0255] It should be noted that compared with common injection preparations (such as Kybella, etc.), the non-aqueous lipolysis preparation provided in this application has an adverse reaction rate reduced by more than 20%, and the lipolysis effect at the same dose is improved by more than 20%.

[0256] Optionally, compared with common injection preparations (such as Kybella, etc.), the non-aqueous lipolysis preparation provided in the present application has an adverse reaction rate reduced by more than 30%, and the lipolysis effect at the same dose is increased by more than 30%.

[0257] More optionally, compared with common injection preparations (such as Kybella, etc.), the non-aqueous lipolysis preparation provided in the present application has an adverse reaction rate reduced by more than 50%, and the lipolysis effect at the same dose is increased by more than 50%.

[0258] The drug release time of the non-aqueous liposoluble preparation provided in the present application is ≥1 day; optionally, the drug release time of the non-aqueous liposoluble preparation provided in the present application is ≥3 days; more optionally, the drug release time of the non-aqueous liposoluble preparation provided in the present application is ≥7 days.

[0259] In some embodiments, in a release medium with a pH value of 7.4 that meets the sink conditions (according to the preparation method of the four-part general buffer solution of the Chinese Pharmacopoeia 2020 edition), under 37°C conditions, the release amount of the active ingredient in 1 hour does not exceed 20% of the total amount of the active ingredient contained in the non-aqueous liposoluble preparation, and the release amount in 168 hours is greater than 85% of the total amount of the active ingredient contained in the non-aqueous liposoluble preparation.

[0260] In some embodiments, the dosage form of the non-aqueous lipolytic preparation includes one or more of proliposomes, oil solutions, and in situ gels. This non-aqueous lipolytic preparation has a targeted lipolysis effect, whereby the liposoluble components accumulate in the tissue at the site of administration and do not diffuse to other sites or tissues, thereby achieving the purpose of targeted lipolysis and reducing adverse reactions.

[0261] In some embodiments, the non-aqueous lipolysis formulation comprises one or more of a proliposome, an oil solution, and an in situ gel for injection or implantation. By injecting or implanting the non-aqueous lipolysis formulation at the site where fat is to be digested, the formulation accumulates in the tissue at the administration site and does not spread to other areas or tissues, thereby achieving targeted lipolysis and reducing the likelihood of adverse reactions.

[0262] In some embodiments, the non-aqueous liposoluble formulation may include an active ingredient, a release modifier, a pharmaceutically acceptable solvent, and optionally one or more of a pharmaceutically acceptable small molecule modulator and an injectable solvent.

[0263] It is easy to understand that "pharmaceutically acceptable" means pharmaceutically usable.

[0264] In some embodiments, the pharmaceutically acceptable solvent comprises one or more organic solvents.

[0265] In some optional embodiments, the pharmaceutically acceptable solvent includes but is not limited to one or more of benzyl alcohol, ethanol, propylene glycol, glycerol, isopropyl alcohol, N-methylpyrrolidone, dimethyl sulfoxide, liquid polyethylene glycol, dimethylacetamide, monoacetin, polyethylene glycol monomethyl ether, diethylene glycol monoethyl ether, ethyl lactate, ethyl acetate, propylene glycol diethyl ester, diethyl malonate, tetrahydrofuran glycol ether and benzyl benzoate.

[0266] In some embodiments, the pharmaceutical phospholipids may include a combination of one or more of natural phospholipids, semi-synthetic phospholipids, and synthetic phospholipids. Alternatively, examples of natural phospholipids may include, but are not limited to, one or more of egg yolk lecithin and soybean lecithin. Alternatively, examples of semi-synthetic phospholipids may include, but are not limited to, one or more of hydrogenated egg yolk lecithin and hydrogenated soybean lecithin. Alternatively, examples of synthetic phospholipids include, but are not limited to, one or more of dipalmitoylphosphatidylcholine (DPPC), distearoylphosphatidylcholine (DSPC), dimyristoylphosphatidylcholine (DMPC), dilauroylphosphatidylcholine (DLPC), dioleoylphosphatidylcholine (DOPC), dipalmitoylphosphatidylethanolamine (DPPE), dipalmitoylphosphatidylglycerol (DPPG), and dioleoylphosphatidylethanolamine (DOPE).

[0267] In some embodiments, the release modifier may include, but is not limited to, one or more of methyl oleate, ethyl oleate, propyl oleate, butyl oleate, 2-butyl oleate, isopropyl oleate, hexyl oleate, octyl oleate, monoolein, diolein, triolein, isopropyl myristate, triethyl citrate, linolenic acid, diethyl sebacate, phytantriol, natural plant oils, semi-natural oils, and synthetic oils. For example, natural plant oils may include, but are not limited to, castor oil, sesame oil, soybean oil, sunflower oil, peanut oil, corn oil, rapeseed oil, olive oil, and cottonseed oil, or a combination of two or more thereof. For example, semi-natural grapefruit oil may include hydrogenated castor oil. For example, synthetic oils may include, but are not limited to, one or more of medium-chain triglycerides, long-chain triglycerides, triacetin, and derivatives thereof. For example, medium-chain triglycerides may include, but are not limited to, one or more of caprylic triglyceride and capric triglyceride.

[0268] In some embodiments, the release modifier is one or more pharmaceutically acceptable biodegradable polymers.

[0269] In some embodiments, the pharmaceutically acceptable biodegradable polymer may include, but is not limited to, one or more of polylactic acid (PLA), polylactic-co-glycolic acid (PLGA), polyorthoesters, sucrose acetate-isobutyrate, fatty acid glycerides, pegylated PLA / PLGA, PLGA-PEG-PLGA copolymers, triethylene glycol poly(orthoester) polymers, chitosan, carboxymethyl chitosan, silk fibroin, poly-β-hydroxybutyrate valerate, polylactide / lactide-polyethylene glycol copolymers or blends thereof, polycaprolactone-polyethylene glycol copolymers, blends of polyβ-hydroxybutyrate and polyethylene glycol, and polylactic acid / glycolic acid blends.

[0270] As a possible embodiment, the small molecule regulator may include but is not limited to one or more of a chelating agent, sodium phosphate, disodium hydrogen phosphate, sodium dihydrogen phosphate, potassium phosphate, dipotassium hydrogen phosphate, potassium dihydrogen phosphate, sodium carbonate, sodium bicarbonate, meglumine, arginine, triethanolamine, citric acid, sodium chloride, glucose and mannitol.

[0271] In some embodiments, the non-aqueous liposoluble preparation can be stored in various dosage forms or packaging kits for topical administration, such as dosage forms or packaging kits suitable for subcutaneous injection or capable of being loaded into microneedles.

[0272] As a possible embodiment, the non-aqueous liposoluble preparation is a proliposome, and the components of the proliposome include an active ingredient, a pharmaceutical phospholipid, a release regulator, a pharmaceutical solvent, and an optional chelating agent.

[0273] Proliposomes are liquid preparations that do not have a complete lipid bilayer vesicle structure and are made by appropriate methods from phospholipids, drugs, and additives. They can be converted into liposomes after dilution or hydration.

[0274] It should be understood that the above-mentioned "optional" indicates that when the non-aqueous liposoluble preparation is a proliposome, the non-aqueous liposoluble preparation may or may not contain a chelating agent.

[0275] In some optional embodiments, the non-aqueous liposoluble preparation is a proliposome, which includes, in parts by weight: 0.1-5 parts by weight of an active ingredient, 15-60 parts by weight of a pharmaceutical phospholipid, 5-80 parts by weight of a release regulator, 0-40 parts by weight of a pharmaceutical solvent, 0-1 parts by weight of a small molecule regulator, and 0-0.001 parts by weight of a chelating agent.

[0276] When the non-aqueous liposoluble preparation is a proliposome, the weight ratio of the active ingredient in the non-aqueous liposoluble preparation is 0.1-5 parts; for example, it can be, but is not limited to, 0.1, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, or a range between any two of the above parts. The weight ratio range between any two parts can include, but is not limited to, 0.1-3 parts, 0.5-3 parts, 0.5-3 parts, 1-3 parts, 1.2-3 parts, 1.5-3 parts, 2-3 parts, or 3-5 parts.

[0277] When the non-aqueous liposoluble preparation is a proliposome, the weight ratio of the pharmaceutical phospholipid in the non-aqueous liposoluble preparation is 15-60 parts; for example, it can be, but is not limited to, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60 parts, or a range between any two of the above parts. The weight range between any two parts can include, but is not limited to, 38-45 parts, 38-40 parts, 40-45 parts, 20-50 parts, or 25-50 parts.

[0278] When the non-aqueous liposoluble preparation is a proliposome, the weight ratio of the release modifier contained in the non-aqueous liposoluble preparation is 5-80 parts; for example, it can be, but is not limited to, 5 parts, 10 parts, 15 parts, 20 parts, 25 parts, 30 parts, 35 parts, 40 parts, 45 parts, 50 parts, 55 parts, 60 parts, 65 parts, 70 parts, 80 parts, or a range between any two of the above parts. The weight ratio range between any two parts can include, but is not limited to, 5-50 parts, 10-50 parts, 15-50 parts, 20-50 parts, 25-50 parts, 30-80 parts, 35-70 parts, 40-70 parts, or 40-80 parts.

[0279] When the non-aqueous liposoluble preparation is a proliposome, the weight ratio of the pharmaceutical solvent contained in the non-aqueous liposoluble preparation is 0-40 parts; for example, it can be, but is not limited to, 0 parts, 5 parts, 10 parts, 15 parts, 20 parts, 25 parts, 30 parts, 35 parts, 40 parts, or a range between any two of the above parts. The weight ratio range between any two parts can include, but is not limited to, 0-10 parts, 5-20 parts, 10-20 parts, 15-40 parts, 20-40 parts, 20-40 parts, 35-40 parts, etc.

[0280] When the non-aqueous liposoluble preparation is a proliposome, the weight ratio of the small molecule modulator contained in the non-aqueous liposoluble preparation is 0-1 part; for example, it can be but not limited to 0 part, 0.1 part, 0.2 part, 0.3 part, 0.4 part, 0.5 part, 0.6 part, 0.7 part, 0.8 part, 0.9 part, 1 part or a range between any two of the above parts.

[0281] When the non-aqueous liposoluble preparation is a proliposome, the weight ratio of the chelating agent contained in the non-aqueous liposoluble preparation is 0-0.001 parts; for example, it can be but not limited to 0 parts, 0.0002 parts, 0.0005 parts, 0.0008 parts, 0.001 parts, or a range between any two of the above parts.

[0282] It should be understood that when the weight percentage of the pharmaceutical solvent or small molecule regulator or chelating agent is 0 parts, it indicates that the non-aqueous fat-soluble preparation does not contain the pharmaceutical solvent or small molecule regulator or chelating agent.

[0283] When the non-aqueous liposoluble preparation is a proliposome, when the weight proportions of each component contained in the non-aqueous liposoluble preparation are respectively within the above ranges, the release behavior has the following characteristics: in a release medium with a pH value of 7.4 that meets the sink conditions (according to the preparation method of the buffer solution of Part Four of the 2020 edition of the Chinese Pharmacopoeia), under 37°C conditions, the release amount of the active ingredient in 1 hour does not exceed 25% of the total amount of the active ingredient contained in the non-aqueous liposoluble preparation, and the release amount in 168 hours is greater than 80% of the total amount of the active ingredient contained in the non-aqueous liposoluble preparation. The precursor liposomes with the above-mentioned release behavior have the following beneficial effects: (1) good stability and no drug precipitation; (2) can slowly release drugs at the administration site, significantly reducing adverse reactions caused by excessive local drug concentration and improving drug safety; (3) a single administration has good efficacy and can avoid the problem of weakened efficacy of Kybella caused by prolonged dosing intervals due to adverse reactions. Clinically, the dosing interval can be determined according to the efficacy to ensure a good lipolysis effect and improve the patient's experience and comfort; (4) can improve the lipolysis effect of deoxycholic acid at the same dose, improve drug utilization, avoid drug waste, reduce treatment costs, and reduce the risk caused by drug accumulation; (5) has a targeted lipolysis effect, and the lipolysis components are concentrated in the tissue of the administration site and will not spread to other parts or tissues, so as to achieve the purpose of targeted lipolysis.

[0284] In some optional embodiments, the non-aqueous liposoluble preparation is a proliposome, and the non-aqueous liposoluble preparation includes, in parts by weight: 0.2-4 parts by weight of an active ingredient, 19-57 parts by weight of a pharmaceutical phospholipid, 10-77 parts by weight of a release regulator, 8-35 parts by weight of a pharmaceutical solvent, 0-1 parts by weight of a small molecule regulator, and 0-0.001 parts by weight of a chelating agent.

[0285] In some optional embodiments, the non-aqueous liposoluble preparation is a proliposome, and the non-aqueous liposoluble preparation includes, in parts by weight: 0.3-3 parts by weight of an active ingredient, 25-55 parts by weight of a pharmaceutical phospholipid, 15-65 parts by weight of a release regulator, 10-32 parts by weight of a pharmaceutical solvent, 0-1 parts by weight of a small molecule regulator, and 0-0.001 parts by weight of a chelating agent.

[0286] In some optional embodiments, the non-aqueous liposoluble preparation is a proliposome, which includes, in parts by weight: 0.1-4 parts by weight of an active ingredient, 20-60 parts by weight of a pharmaceutical phospholipid, 10-77 parts by weight of a release regulator, 8-40 parts by weight of a pharmaceutical solvent, 0-1 parts by weight of a small molecule regulator, and 0-0.001 parts by weight of a chelating agent.

[0287] In some optional embodiments, the non-aqueous liposoluble preparation is a proliposome, and the non-aqueous liposoluble preparation includes, in parts by weight: 0.2-3 parts by weight of an active ingredient, 25-55 parts by weight of a pharmaceutical phospholipid, 15-65 parts by weight of a release regulator, 10-35 parts by weight of a pharmaceutical solvent, 0-1 parts by weight of a small molecule regulator, and 0-0.001 parts by weight of a chelating agent.

[0288] In some embodiments, the non-aqueous liposoluble preparation is a proliposome, and the pharmaceutical phospholipid comprises a combination of one or more of pharmaceutically acceptable natural phospholipids, semi-synthetic phospholipids, and synthetic phospholipids;

[0289] As an example, natural phospholipids may include, but are not limited to, one or more of egg yolk lecithin and soybean lecithin. As an example, semi-synthetic phospholipids may include, but are not limited to, one or more of hydrogenated egg yolk lecithin and hydrogenated soybean lecithin. As an example, synthetic phospholipids include, but are not limited to, one or more of dipalmitoylphosphatidylcholine (DPPC), distearoylphosphatidylcholine (DSPC), dimyristoylphosphatidylcholine (DMPC), dilauroylphosphatidylcholine (DLPC), dioleoylphosphatidylcholine (DOPC), dipalmitoylphosphatidylethanolamine (DPPE), dipalmitoylphosphatidylglycerol (DPPG), and dioleoylphosphatidylethanolamine (DOPE).

[0290] In some optional embodiments, the non-aqueous liposoluble preparation is a proliposome, and the pharmaceutical phospholipids include one or more of egg yolk lecithin, soybean lecithin, hydrogenated egg yolk lecithin, hydrogenated soybean lecithin, dipalmitoylphosphatidylcholine (DPPC), distearoylphosphatidylcholine (DSPC), dimyristoylphosphatidylcholine (DMPC), dilauroylphosphatidylcholine (DLPC) and dioleoylphosphatidylcholine (DOPC).

[0291] In some embodiments, the non-aqueous liposoluble preparation is a proliposome, and the pharmaceutical phospholipids include one or more of egg yolk lecithin, soybean lecithin, hydrogenated egg yolk lecithin, hydrogenated soybean lecithin, dipalmitoylphosphatidylcholine (DPPC), distearoylphosphatidylcholine (DSPC) and dimyristoylphosphatidylcholine (DMPC).

[0292] In some embodiments, the non-aqueous liposoluble formulation is a proliposome, and the release modifier may include but is not limited to methyl oleate, ethyl oleate, propyl oleate, butyl oleate, 2-butyl oleate, isopropyl oleate, hexyl oleate, octyl oleate, monoolein, diolein, triolein, propylene glycol monocaprylate, propylene glycol dicaprylate / dicaprate, propylene glycol laurate, propylene glycol alginate, caprylic capric acid mono- and diglycerides, caprylic capric acid mono-, di- and triglycerides, and caprylic capric acid macrogol glycerides. , monoricinoleic acid glyceryl ester, monolinoleic acid glyceryl ester, oleoyl polyoxyethylene glyceride, diacetyl monoglyceride, mono-distearic acid glyceryl ester, monostearic acid glyceryl ester, tricaprylic acid glyceryl ester, tricapric acid glyceryl ester, behenic acid glyceryl ester, triacetin, isopropyl myristate, triethyl citrate, linolenic acid, diethyl sebacate, phytantriol, medium chain triglycerides, fish oil, algae oil, ethyl caprylate, ethyl caprate, ethyl linoleate, isopropyl linoleate, natural vegetable oil and semi-natural vegetable oil. One or more of.

[0293] In some optional embodiments, the non-aqueous liposoluble preparation is a proliposome, and the release modifier includes one or more of ethyl oleate, glyceryl monooleate, glyceryl dioleate, glyceryl trioleate, propylene glycol monocaprylate, propylene glycol dicaprylate / dicaprate, propylene glycol laurate, propylene glycol alginate, caprylic and capric mono- and diglycerides, glyceryl monolinoleate, glyceryl triacetate, medium chain triglycerides and natural plant oils. As an example, natural plant oils may include but are not limited to castor oil, sesame oil, soybean oil, sunflower seed oil, peanut oil, corn oil, rapeseed oil, olive oil, cottonseed oil, linseed oil, perilla seed oil, walnut oil, argan oil, laver oil. As an example, semi-natural plant oils may include but are not limited to hydrogenated castor oil.

[0294] In some optional embodiments, the non-aqueous liposoluble preparation is a proliposome, and the release modifier includes one or more of ethyl oleate, monoolein, diolein, triolein, propylene glycol monocaprylate, propylene glycol dicaprylate / dicaprate, caprylic and capric mono- and diglycerides, monolinolein, triacetin, medium-chain triglycerides, fish oil, algae oil, castor oil, sesame oil, soybean oil, peanut oil, corn oil, olive oil, cottonseed oil, linseed oil, perilla seed oil, walnut oil, argan oil, and laver oil.

[0295] In some embodiments, the non-aqueous liposoluble preparation is a proliposome, and the pharmaceutical solvent may include but is not limited to one or more of benzyl alcohol, ethanol, propylene glycol, glycerol, isopropyl alcohol, N-methyl pyrrolidone, dimethyl sulfoxide, liquid polyethylene glycol, dimethylacetamide, glycerol monoacetate, polyethylene glycol (mono) methyl ether, diethylene glycol monoethyl ether, ethyl lactate, ethyl acetate, propylene glycol diethyl ester, tetrahydrofuran glycol ether and benzyl benzoate. Alternatively, the pharmaceutical solvent may include but is not limited to one or more of benzyl alcohol, propylene glycol, ethanol, benzyl benzoate, dimethyl sulfoxide, liquid polyethylene glycol, N-methyl pyrrolidone and dimethylacetamide. More preferably, the pharmaceutical solvent includes one or more of benzyl alcohol, propylene glycol, ethanol, benzyl benzoate, dimethyl sulfoxide, N-methyl pyrrolidone and dimethylacetamide.

[0296] In some embodiments, the chelating agent may include, but is not limited to, EDTA, disodium EDTA, and calcium disodium EDTA.

[0297] In some embodiments, small molecule modulation includes acid-base modifiers and antioxidants;

[0298] In some embodiments, the acid-base adjusting agent comprises one or more of sodium hydroxide, meglumine, arginine, lysine, histidine, glycine, tromethamine, diethanolamine, ethylenediamine, hydrochloric acid, acetic acid, anhydrous citric acid, ascorbic acid, lactic acid, tartaric acid, methanesulfonic acid, methionine, and triethanolamine;

[0299] In some embodiments, the antioxidant comprises one or more of cysteine, α-tocopherol, α-tocopheryl acetate, N-acetyl-L-cysteine, butylated hydroxyanisole, butylated hydroxytoluene, propyl gallate, tert-butylhydroquinone, lipoic acid, tea polyphenols, L-ascorbyl palmitate, and glutathione.

[0300] In some embodiments, the non-aqueous liposoluble preparation is a proliposome, and the components of the proliposome include an active ingredient, a pharmaceutically acceptable phospholipid, a release modifier, a pharmaceutically acceptable solvent, and an optional chelating agent.

[0301] In some optional embodiments, the non-aqueous liposoluble preparation is a proliposome, which includes, in parts by weight: 0.1-5 parts by weight of an active ingredient, 15-60 parts by weight of a pharmaceutical phospholipid, 5-65 parts by weight of a release regulator, 5-40 parts by weight of a pharmaceutical solvent, and 0-0.001 parts by weight of a chelating agent.

[0302] When the non-aqueous liposoluble preparation is a proliposome, the weight ratio of the active ingredient in the non-aqueous liposoluble preparation is 0.1-5 parts; for example, it can be, but is not limited to, 0.1, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, or a range between any two of the above parts. The weight ratio range between any two parts can include, but is not limited to, 0.1-3 parts, 0.5-3 parts, 0.5-3 parts, 1-3 parts, 1.2-3 parts, 1.5-3 parts, 2-3 parts, or 3-5 parts.

[0303] When the non-aqueous liposoluble preparation is a proliposome, the weight ratio of the pharmaceutical phospholipid in the non-aqueous liposoluble preparation is 15-60 parts; for example, it can be, but is not limited to, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60 parts, or a range between any two of the above parts. The weight range between any two parts can include, but is not limited to, 38-45 parts, 38-40 parts, 40-45 parts, 20-50 parts, or 25-50 parts.

[0304] When the non-aqueous liposoluble preparation is a proliposome, the weight ratio of the release modifier contained in the non-aqueous liposoluble preparation is 5-65 parts; for example, it can be, but is not limited to, 5 parts, 10 parts, 15 parts, 20 parts, 25 parts, 30 parts, 35 parts, 40 parts, 45 parts, 50 parts, 55 parts, 60 parts, 65 parts, or a range between any two of the above parts. The weight ratio range between any two parts can include, but is not limited to, 8-30 parts, 11-25 parts, 14-19 parts, 15-25 parts, 18-30 parts, 10-63 parts, or 15-63 parts.

[0305] When the non-aqueous liposoluble preparation is a proliposome, the weight ratio of the chelating agent contained in the non-aqueous liposoluble preparation is 0-0.001 parts; for example, it can be but not limited to 0 parts, 0.0002 parts, 0.0005 parts, 0.0008 parts, 0.001 parts, or a range between any two of the above parts.

[0306] It should be understood that when the weight percentage of the chelating agent is 0 parts, it indicates that the non-aqueous fat-soluble preparation does not contain the chelating agent.

[0307] When the non-aqueous liposoluble preparation is a proliposome, when the weight proportions of each component contained in the non-aqueous liposoluble preparation are respectively within the above ranges, the release behavior has the following characteristics: in a release medium with a pH value of 7.4 that meets the sink conditions (according to the preparation method of the buffer solution of Part Four of the 2020 edition of the Chinese Pharmacopoeia), under 37°C conditions, the release amount of the active ingredient in 1 hour does not exceed 25% of the total amount of the active ingredient contained in the non-aqueous liposoluble preparation, and the release amount in 168 hours is greater than 80% of the total amount of the active ingredient contained in the non-aqueous liposoluble preparation. The precursor liposomes with the above-mentioned release behavior have the following beneficial effects: (1) good stability and no drug precipitation; (2) can slowly release drugs at the administration site, significantly reducing adverse reactions caused by excessive local drug concentration and improving drug safety; (3) a single administration has good efficacy and can avoid the problem of weakened efficacy of Kybella caused by prolonged dosing intervals due to adverse reactions. Clinically, the dosing interval can be determined according to the efficacy to ensure a good lipolysis effect and improve the patient's experience and comfort; (4) can improve the lipolysis effect of deoxycholic acid at the same dose, improve drug utilization, avoid drug waste, reduce treatment costs, and reduce the risk caused by drug accumulation; (5) has a targeted lipolysis effect, and the lipolysis components are concentrated in the tissue of the administration site and will not spread to other parts or tissues, so as to achieve the purpose of targeted lipolysis.

[0308] In some optional embodiments, the non-aqueous liposoluble preparation is a proliposome, which includes, in parts by weight: 0.1-3 parts by weight of an active ingredient, 20-50 parts by weight of a pharmaceutical phospholipid, 10-63 parts by weight of a release regulator, 10-40 parts by weight of a pharmaceutical solvent, and 0-0.001 parts by weight of a chelating agent.

[0309] In some optional embodiments, the non-aqueous liposoluble preparation is a proliposome, which includes, by weight, 0.5-3 parts by weight of an active ingredient, 25-50 parts by weight of a pharmaceutical phospholipid, 15-63 parts by weight of a release regulator, 10-30 parts by weight of a pharmaceutical solvent, and 0-0.001 parts by weight of a chelating agent.

[0310] In some optional embodiments, the non-aqueous liposoluble preparation is a proliposome, and the pharmaceutical phospholipids include a combination of one or more pharmaceutically acceptable natural phospholipids, semi-synthetic phospholipids and synthetic phospholipids; one or more natural phospholipids can be selected.

[0311] As an example, natural phospholipids may include, but are not limited to, one or more of egg yolk lecithin and soybean lecithin. As an example, semi-synthetic phospholipids may include, but are not limited to, one or more of hydrogenated egg yolk lecithin and hydrogenated soybean lecithin. As an example, synthetic phospholipids include, but are not limited to, one or more of dipalmitoylphosphatidylcholine (DPPC), distearoylphosphatidylcholine (DSPC), dimyristoylphosphatidylcholine (DMPC), dilauroylphosphatidylcholine (DLPC), dioleoylphosphatidylcholine (DOPC), dipalmitoylphosphatidylethanolamine (DPPE), dipalmitoylphosphatidylglycerol (DPPG), and dioleoylphosphatidylethanolamine (DOPE).

[0312] In some optional embodiments, the pharmaceutical phospholipids may include but are not limited to one or more of egg yolk lecithin, soybean lecithin, hydrogenated egg yolk lecithin, hydrogenated soybean lecithin, dipalmitoylphosphatidylcholine (DPPC), distearoylphosphatidylcholine (DSPC), dimyristoylphosphatidylcholine (DMPC), dilauroylphosphatidylcholine (DLPC) and dioleoylphosphatidylcholine (DOPC).

[0313] As a possible embodiment, the pharmaceutical phospholipids may include but are not limited to one or more of egg yolk lecithin, soybean lecithin, hydrogenated egg yolk lecithin, hydrogenated soybean lecithin, dipalmitoylphosphatidylcholine (DPPC), distearoylphosphatidylcholine (DSPC) and dimyristoylphosphatidylcholine (DMPC).

[0314] In some embodiments, when the non-aqueous liposoluble formulation is a proliposome, the release modifier may include, but is not limited to, one or more of methyl oleate, ethyl oleate, propyl oleate, butyl oleate, 2-butyl oleate, isopropyl oleate, hexyl oleate, octyl oleate, monoolein, diolein, triolein, isopropyl myristate, triethyl citrate, linolenic acid, diethyl sebacate, phytantriol, natural plant oils, semi-natural plant oils, and synthetic oils. More optionally, the release modifier may include, but is not limited to, one or more of ethyl oleate, monoolein, diolein, triolein, natural plant oils, and synthetic oils.

[0315] As an example, natural vegetable oils may include, but are not limited to, one or more of castor oil, sesame oil, soybean oil, sunflower oil, peanut oil, corn oil, rapeseed oil, olive oil, and cottonseed oil. As an example, semi-natural vegetable oils may include, but are not limited to, hydrogenated castor oil. As an example, synthetic oils may include, but are not limited to, one or more of medium-chain triglycerides, long-chain triglycerides, triacetin, and derivatives thereof. As an example, medium-chain triglycerides may include, but are not limited to, one or more of caprylic triglyceride and capric triglyceride.

[0316] In some embodiments, when the non-aqueous liposoluble formulation is a proliposome, the release modifier may include but is not limited to methyl oleate, ethyl oleate, propyl oleate, butyl oleate, 2-butyl oleate, isopropyl oleate, hexyl oleate, octyl oleate, monoolein, diolein, triolein, propylene glycol monocaprylate, propylene glycol dicaprylate / dicaprate, propylene glycol laurate, propylene glycol alginate, caprylic capric acid mono- and diglycerides, caprylic capric acid mono-, di- and triglycerides, and caprylic capric acid polyethylene glycol glycerol. One or more of esters, monoricinoleyl glyceryl, monolinoleyl glyceryl, oleoyl polyoxyethylene glyceride, diacetyl monoglyceride, mono- and distearic glyceryl, monostearic glyceryl, tricaprylic acid glyceryl, tricapric acid glyceryl, behenic acid glyceryl, triacetin, isopropyl myristate, triethyl citrate, linolenic acid, diethyl sebacate, phytantriol, medium chain triglycerides, fish oil, algae oil, ethyl caprylate, ethyl caprate, ethyl linoleate, isopropyl linoleate, natural plant oil and semi-natural plant oil.

[0317] In some optional embodiments, when the non-aqueous liposoluble preparation is a proliposome, the release modifier may include but is not limited to one or more of ethyl oleate, monoolein, diolein, triolein, propylene glycol monocaprylate, propylene glycol dicaprylate / dicaprate, propylene glycol laurate, propylene glycol alginate, caprylic and capric mono- and diglycerides, monolinoleic acid glyceride, triacetin, medium chain triglycerides, fish oil, algae oil and natural plant oils.

[0318] As non-limiting examples, natural vegetable oils may include, but are not limited to, one or more of castor oil, sesame oil, soybean oil, sunflower oil, peanut oil, corn oil, rapeseed oil, olive oil, cottonseed oil, linseed oil, perilla seed oil, walnut oil, argan oil, and seaweed oil.

[0319] As a non-limiting example, semi-natural vegetable oils may include, but are not limited to, hydrogenated castor oil.

[0320] As a possible embodiment, the release modifier may include but is not limited to one or more of ethyl oleate, monoolein, diolein, triolein, propylene glycol monocaprylate, propylene glycol dicaprylate / dicaprate, caprylic and capric mono- and diglycerides, monolinolein, triacetin, medium-chain triglycerides, fish oil, algae oil, castor oil, sesame oil, soybean oil, peanut oil, corn oil, olive oil, cottonseed oil, linseed oil, perilla seed oil, walnut oil, argan oil, and laver oil.

[0321] In some embodiments, when the non-aqueous liposoluble preparation is a proliposome, the pharmaceutically acceptable solvent may include, but is not limited to, one or more of benzyl alcohol, ethanol, propylene glycol, glycerol, isopropyl alcohol, N-methylpyrrolidone, dimethyl sulfoxide, liquid polyethylene glycol, dimethylacetamide, glycerol monoacetate, polyethylene glycol (mono) methyl ether, diethylene glycol monoethyl ether, ethyl lactate, ethyl acetate, propylene glycol diethyl ester, diethyl malonate, tetrahydrofuran glycol ether, and benzyl benzoate. Alternatively, the pharmaceutically acceptable solvent may include, but is not limited to, one or more of benzyl alcohol, propylene glycol, ethanol, dimethyl sulfoxide, N-methylpyrrolidone, and dimethylacetamide.

[0322] In some optional embodiments, when the non-aqueous liposoluble preparation is a proliposome, the pharmaceutically acceptable solvent may include but is not limited to one or more of benzyl alcohol, propylene glycol, ethanol, benzyl benzoate, dimethyl sulfoxide, liquid polyethylene glycol, N-methylpyrrolidone and dimethylacetamide.

[0323] As a possible embodiment, when the non-aqueous liposoluble preparation is a proliposome, the pharmaceutically acceptable solvent may include but is not limited to one or more of benzyl alcohol, propylene glycol, ethanol, benzyl benzoate, dimethyl sulfoxide, N-methylpyrrolidone and dimethylacetamide.

[0324] In some embodiments, chelating agents may include, but are not limited to, ethylenediaminetetraacetic acid.

[0325] In some embodiments, when the non-aqueous liposoluble preparation is a proliposome, the chelating agent may include but is not limited to one or more of EDTA, EDTA disodium, and EDTA calcium disodium.

[0326] In some embodiments, when the non-aqueous liposoluble preparation is a proliposome, the non-aqueous liposoluble preparation may further comprise a small molecule regulator, including an acid-base regulator and an antioxidant.

[0327] In some embodiments, when the non-aqueous liposoluble preparation is a proliposome, the acid-base regulator includes one or more of sodium hydroxide, meglumine, arginine, lysine, histidine, glycine, tromethamine, diethanolamine, ethylenediamine, hydrochloric acid, acetic acid, anhydrous citric acid, ascorbic acid, lactic acid, tartaric acid, methanesulfonic acid, methionine, and triethanolamine;

[0328] In some embodiments, when the non-aqueous liposoluble preparation is a proliposome, the antioxidant includes one or more of cysteine, α-tocopherol, α-tocopheryl acetate, N-acetyl-L-cysteine, butylated hydroxyanisole, dibutylhydroxytoluene, propyl gallate, tert-butylhydroquinone, lipoic acid, tea polyphenols, L-ascorbyl palmitate, and glutathione.

[0329] As a possible embodiment, the non-aqueous liposoluble preparation is an oil solution, and the components of the non-aqueous liposoluble preparation include an active ingredient, a pharmaceutical solvent, a release regulator, and an optional small molecule regulator.

[0330] It should be noted that the above-mentioned "optional" indicates that when the non-aqueous liposoluble preparation is an oil solution, the non-aqueous liposoluble preparation may contain a small molecule regulator or may not contain a small molecule regulator.

[0331] In some optional embodiments, the non-aqueous liposoluble preparation is an oil solution, which comprises, in parts by weight, 0.1-5 parts by weight of an active ingredient, 0-50 parts by weight of a pharmaceutical solvent, 45-95 parts by weight of a release regulator, and 0-10 parts by weight of a small molecule regulator.

[0332] When the non-aqueous liposoluble preparation is an oil solution, the weight ratio of the active ingredient in the non-aqueous liposoluble preparation is 0.1 to 5 parts; for example, it can be, but is not limited to, 0.1, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5 parts, or a range between any two of the above parts. The weight ratio range between any two parts can include, but is not limited to, 0.1-3 parts, 0.5-3 parts, 1-3 parts, 2-3 parts, or 1-2 parts, etc.

[0333] When the non-aqueous liposoluble preparation is an oil solution, the weight ratio of the pharmaceutical solvent contained in the non-aqueous liposoluble preparation is 0-50 parts; for example, it can be, but is not limited to, 0, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50 parts, or a range between any two of the above parts. The weight ratio range between any two parts can include, but is not limited to, 10-40 parts, 10-30 parts, 5-20 parts, 10-20 parts, 15-20 parts, or 18-25 parts.

[0334] When the non-aqueous liposoluble preparation is an oil solution, the weight ratio of the release modifier in the non-aqueous liposoluble preparation is 45-95 parts; for example, it may be, but is not limited to, 45 parts, 50 parts, 55 parts, 60 parts, 65 parts, 70 parts, 75 parts, 80 parts, 85 parts, 90 parts, 95 parts, or a range between any two of the above parts. The weight ratio range between any two parts may include, but is not limited to, 50-90 parts, 74-82 parts, 74-80 parts, or 69-80 parts.

[0335] When the non-aqueous lipolysis preparation is an oil solution, the weight ratio of the small molecule modulator contained in the non-aqueous lipolysis preparation is 0-10 parts; for example, it can be, but is not limited to, 0 parts, 0.1 parts, 0.2 parts, 0.3 parts, 0.5 parts, 0.8 parts, 1 part, 2 parts, 3 parts, 5 parts, 8 parts, 10 parts, or a range between any two of the above parts. The weight ratio range between any two parts can include, but is not limited to, 0.1 parts-0.8 parts, 0.1 parts-0.5 parts, 0.1 parts-0.3 parts, 1 part-3 parts, 3 parts-5 parts, 3 parts-8 parts, 5 parts-8 parts, 5 parts-10 parts, 8 parts-10 parts, etc.

[0336] It should be noted that when the weight percentage of the pharmaceutical solvent and / or small molecule regulator is 0 parts, it indicates that the non-aqueous fat-soluble preparation is an oil solution and does not contain the pharmaceutical solvent and / or small molecule regulator.

[0337] When the non-aqueous liposoluble preparation is an oil solution, and the weight proportions of each component contained in the non-aqueous liposoluble preparation are respectively within the above ranges, the release behavior has the following characteristics: in a release medium with a pH value of 7.4 that meets the sink conditions (according to the preparation method of the buffer solution of Part Four of the 2020 edition of the Chinese Pharmacopoeia), under conditions of 37°C, the release amount of the active ingredient in 1 hour does not exceed 25% of the total amount of the active ingredient contained in the non-aqueous liposoluble preparation, and the release amount in 168 hours is greater than 80% of the total amount of the active ingredient contained in the non-aqueous liposoluble preparation. The oil solution with the above-mentioned release behavior has the following beneficial effects: (1) It has good stability and no drug precipitation; (2) It can slowly release the drug at the administration site, significantly reducing adverse reactions caused by excessive local drug concentration and improving drug safety; (3) It has good efficacy after a single administration and can avoid the problem of weakened efficacy of Kybella caused by prolonged dosing interval due to adverse reactions. Clinically, the dosing interval can be determined according to the efficacy to ensure a good lipolysis effect and improve the patient's experience and comfort; (4) It can improve the lipolysis effect of deoxycholic acid at the same dose, improve drug utilization, avoid drug waste, reduce treatment costs, and reduce the risk caused by drug accumulation; (5) It has a targeted lipolysis effect, and the lipolysis components are concentrated in the tissue of the administration site and will not spread to other parts or tissues, so as to achieve the purpose of targeted lipolysis.

[0338] In some optional embodiments, the non-aqueous liposoluble preparation is an oil solution, which comprises, in parts by weight, 0.1-4 parts by weight of an active ingredient, 10-40 parts by weight of a pharmaceutical solvent, 55-90 parts by weight of a release regulator, and 0-5 parts by weight of a small molecule regulator.

[0339] In some optional embodiments, the non-aqueous liposoluble preparation is an oil solution, which comprises, in parts by weight, 0.2-3 parts by weight of an active ingredient, 10-35 parts by weight of a pharmaceutical solvent, 60-90 parts by weight of a release regulator, and 0-3 parts by weight of a small molecule regulator.

[0340] In some optional embodiments, the non-aqueous liposoluble preparation is an oil solution, which comprises, in parts by weight, 0.5-3 parts by weight of an active ingredient, 10-30 parts by weight of a pharmaceutical solvent, 69-90 parts by weight of a release regulator, and 0-1 part by weight of a small molecule regulator.

[0341] In some optional embodiments, the non-aqueous liposoluble preparation is an oil solution, which comprises, in parts by weight, 0.1-5 parts by weight of an active ingredient, 5-50 parts by weight of a pharmaceutical solvent, 47-95 parts by weight of a release regulator, and 0-1 part by weight of a small molecule regulator.

[0342] In some optional embodiments, the non-aqueous liposoluble preparation is an oil solution, which comprises, in parts by weight, 0.2-4 parts by weight of an active ingredient, 10-40 parts by weight of a pharmaceutical solvent, 60-90 parts by weight of a release regulator, and 0-0.8 parts by weight of a small molecule regulator.

[0343] In some optional embodiments, the non-aqueous liposoluble preparation is an oil solution, which comprises, in parts by weight, 0.5-3 parts by weight of an active ingredient, 10-35 parts by weight of a pharmaceutical solvent, 69-90 parts by weight of a release regulator, and 0-0.4 parts by weight of a small molecule regulator.

[0344] In some embodiments, the non-aqueous liposoluble preparation is an oil solution, and the release modifier may include but is not limited to methyl oleate, ethyl oleate, propyl oleate, butyl oleate, 2-butyl oleate, isopropyl oleate, hexyl oleate, octyl oleate, monoolein, diolein, triolein, propylene glycol monocaprylate, propylene glycol dicaprylate / dicaprate, propylene glycol laurate, propylene glycol alginate, caprylic and capric mono- and diglycerides, caprylic and capric mono-, di- and triglycerides, One or more of caprylic capric macrogol glycerides, monoricinoleic glyceryl, monolinoleic glyceryl, oleoyl polyoxyethylene glycerides, diacetyl monoglyceride, mono- and distearic glyceryl, monostearic glyceryl, tricaprylic acid glyceryl, tricapric acid glyceryl, behenic acid glyceryl, triacetin, isopropyl myristate, triethyl citrate, linolenic acid, diethyl sebacate, phytantriol, medium chain triglycerides, fish oil, algae oil, natural plant oil and semi-natural plant oil.

[0345] In some optional embodiments, the non-aqueous liposoluble preparation is an oil solution, and the release modifier includes one or more of ethyl oleate, monoolein, diolein, triolein, propylene glycol monocaprylate, propylene glycol dicaprylate / dicaprate, propylene glycol laurate, propylene glycol alginate, caprylic and capric mono- and diglycerides, monolinoleic acid glyceride, triacetin, medium chain triglycerides and natural plant oils.

[0346] As an example, natural vegetable oils may include, but are not limited to, one or more of castor oil, sesame oil, soybean oil, sunflower oil, peanut oil, corn oil, rapeseed oil, olive oil, cottonseed oil, linseed oil, perilla seed oil, walnut oil, argan oil, and seaweed oil. As an example, semi-natural oils may include, but are not limited to, hydrogenated castor oil.

[0347] In some optional embodiments, the non-aqueous liposoluble preparation is an oil solution, and the release modifier includes one or more of ethyl oleate, monoolein, diolein, triolein, propylene glycol monocaprylate, propylene glycol dicaprylate / dicaprate, caprylic and capric mono- and diglycerides, monolinolein, triacetin, medium-chain triglycerides, fish oil, algae oil, castor oil, sesame oil, soybean oil, peanut oil, corn oil, olive oil, cottonseed oil, linseed oil, perilla seed oil, walnut oil, argan oil, and laver oil.

[0348] In some embodiments, the non-aqueous liposoluble preparation is an oil solution, and the pharmaceutical solvent may include but is not limited to benzyl alcohol, ethanol, propylene glycol, glycerol, isopropyl alcohol, N-methyl pyrrolidone, dimethyl sulfoxide, liquid polyethylene glycol, dimethylacetamide, glycerol monoacetate, polyethylene glycol (mono) methyl ether, diethylene glycol monoethyl ether, ethylene glycol diethyl ether, glycerol aldehyde, glycerol formal, chlorobutanol, ethyl lactate, ethyl acetate, propylene glycol diethyl ester, tetrahydrofuran glycol ether and benzyl benzoate. Alternatively, the pharmaceutical solvent may include but is not limited to benzyl alcohol, propylene glycol, ethanol, benzyl benzoate, dimethyl sulfoxide, liquid polyethylene glycol, N-methyl pyrrolidone and dimethylacetamide. More preferably, the pharmaceutical solvent includes one or more of benzyl alcohol, propylene glycol, ethanol, benzyl benzoate, dimethyl sulfoxide, N-methyl pyrrolidone and dimethylacetamide.

[0349] In some embodiments, the non-aqueous lipolysis preparation is an oil solution, and the small molecule regulator includes one or more of sodium phosphate, disodium hydrogen phosphate, sodium dihydrogen phosphate, potassium phosphate, dipotassium hydrogen phosphate, potassium dihydrogen phosphate, sodium carbonate, sodium bicarbonate, sodium hydroxide, meglumine, arginine, lysine, histidine, tromethamine, diethanolamine, ethylenediamine, hydrochloric acid, acetic acid, ascorbic acid, lactic acid, tartaric acid, methanesulfonic acid, methionine, cysteine, α-tocopherol, α-tocopheryl acetate, N-acetyl-L-cysteine, butylated hydroxyanisole, dibutylhydroxytoluene, propyl gallate, tert-butylhydroquinone, lipoic acid, tea polyphenols, L-ascorbyl palmitate, glutathione, triethanolamine, citric acid, sodium chloride, glucose and mannitol.

[0350] In some optional embodiments, the non-aqueous liposoluble preparation is an oil solution, and the small molecule regulator includes one or more of meglumine, tromethamine, triethanolamine, sodium hydroxide, disodium hydrogen phosphate, potassium dihydrogen phosphate, sodium carbonate, sodium bicarbonate, arginine, lysine, histidine, α-tocopherol, α-tocopherol acetate, butylated hydroxyanisole, dibutylhydroxytoluene, L-ascorbyl palmitate, and glutathione.

[0351] In some optional embodiments, the non-aqueous liposoluble preparation is an oil solution, and the small molecule regulator includes one or more of meglumine, tromethamine, arginine, lysine, histidine, α-tocopherol, α-tocopherol acetate, butylated hydroxyanisole, L-ascorbyl palmitate, and glutathione.

[0352] In some embodiments, the non-aqueous fat-soluble preparation is an oil solution, and the components of the non-aqueous fat-soluble preparation include an active ingredient, a pharmaceutically acceptable solvent, a release regulator, and an optional small molecule regulator.

[0353] It should be noted that the above-mentioned "optional" indicates that when the non-aqueous liposoluble preparation is an oil solution, the non-aqueous liposoluble preparation may contain a small molecule regulator or may not contain a small molecule regulator.

[0354] In some optional embodiments, the non-aqueous liposoluble preparation is an oil solution, which comprises, in parts by weight, 0.1-5 parts by weight of an active ingredient, 5-50 parts by weight of a pharmaceutical solvent, 50-90 parts by weight of a release regulator, and 0-10 parts by weight of a small molecule regulator.

[0355] When the non-aqueous liposoluble preparation is an oil solution, the weight ratio of the active ingredient in the non-aqueous liposoluble preparation is 0.1-5 parts; for example, it can be, but is not limited to, 0.1, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5 parts, or a range between any two of the above parts. The weight ratio range between any two parts can include, but is not limited to, 0.1-3 parts, 0.5-3 parts, 1-3 parts, 2-3 parts, or 1-2 parts, etc.

[0356] When the non-aqueous liposoluble preparation is an oil solution, the weight ratio of the pharmaceutical solvent contained in the non-aqueous liposoluble preparation is 5-50 parts; for example, it can be, but is not limited to, 5 parts, 10 parts, 15 parts, 20 parts, 25 parts, 30 parts, 35 parts, 40 parts, 45 parts, 50 parts, or a range between any two of the above parts. The weight ratio range between any two parts can include, but is not limited to, 10-40 parts, 10-30 parts, 5-20 parts, 10-20 parts, 15-20 parts, or 18-25 parts.

[0357] When the non-aqueous liposoluble preparation is an oil solution, the weight ratio of the release modifier contained in the non-aqueous liposoluble preparation is 50-90 parts; for example, it can be, but is not limited to, 50 parts, 55 parts, 60 parts, 65 parts, 70 parts, 75 parts, 80 parts, 85 parts, 90 parts, or a range between any two of the above parts. The weight ratio range between any two parts can include, but is not limited to, 69-90 parts, 74-82 parts, 74-80 parts, or 69-80 parts, etc.

[0358] When the non-aqueous lipolysis preparation is an oil solution, the weight ratio of the small molecule modulator contained in the non-aqueous lipolysis preparation is 0-10 parts; for example, it can be, but is not limited to, 0 parts, 0.1 parts, 1 parts, 3 parts, 5 parts, 8 parts, 10 parts, or a range between any two of the above parts. The weight ratio range between any two parts can include, but is not limited to, 0.1 parts to 5 parts, 0.1 parts to 3 parts, or 0.1 parts to 1 part, etc.

[0359] It should be noted that when the weight percentage of the small molecule regulator is 0, it indicates that the non-aqueous fat-soluble preparation is an oil solution and does not contain the small molecule regulator.

[0360] When the non-aqueous liposoluble preparation is an oil solution, and the weight proportions of each component contained in the non-aqueous liposoluble preparation are respectively within the above ranges, the release behavior has the following characteristics: in a release medium with a pH value of 7.4 that meets the sink conditions (according to the preparation method of the buffer solution of Part Four of the 2020 edition of the Chinese Pharmacopoeia), under conditions of 37°C, the release amount of the active ingredient in 1 hour does not exceed 25% of the total amount of the active ingredient contained in the non-aqueous liposoluble preparation, and the release amount in 168 hours is greater than 80% of the total amount of the active ingredient contained in the non-aqueous liposoluble preparation. The oil solution with the above-mentioned release behavior has the following beneficial effects: (1) It has good stability and no drug precipitation; (2) It can slowly release the drug at the administration site, significantly reducing adverse reactions caused by excessive local drug concentration and improving drug safety; (3) It has good efficacy after a single administration and can avoid the problem of weakened efficacy of Kybella caused by prolonged dosing interval due to adverse reactions. Clinically, the dosing interval can be determined according to the efficacy to ensure a good lipolysis effect and improve the patient's experience and comfort; (4) It can improve the lipolysis effect of deoxycholic acid at the same dose, improve drug utilization, avoid drug waste, reduce treatment costs, and reduce the risk caused by drug accumulation; (5) It has a targeted lipolysis effect, and the lipolysis components are concentrated in the tissue of the administration site and will not spread to other parts or tissues, so as to achieve the purpose of targeted lipolysis.

[0361] In some optional embodiments, the non-aqueous liposoluble preparation is an oil solution, which comprises, in parts by weight, 0.1-3 parts by weight of an active ingredient, 10-40 parts by weight of a pharmaceutical solvent, 55-90 parts by weight of a release regulator, and optionally 0.1-5 parts by weight of a small molecule regulator.

[0362] In some optional embodiments, the non-aqueous liposoluble preparation is an oil solution, which comprises, in parts by weight, 0.5-3 parts by weight of an active ingredient, 10-30 parts by weight of a pharmaceutical solvent, 69-90 parts by weight of a release modifier, and optionally 0.1-3 parts by weight of a small molecule modulator.

[0363] In some optional embodiments, the non-aqueous liposoluble preparation is an oil solution, which comprises, in parts by weight, 0.5-3 parts by weight of an active ingredient, 10-30 parts by weight of a pharmaceutical solvent, 69-90 parts by weight of a release regulator, and optionally 0.1-1 parts by weight of a small molecule regulator.

[0364] In some embodiments, the non-aqueous fat-soluble preparation is an oil solution, and the release modifier may include but is not limited to methyl oleate, ethyl oleate, propyl oleate, butyl oleate, 2-butyl oleate, isopropyl oleate, hexyl oleate, octyl oleate, monoolein, diolein, triolein, isopropyl myristate, triethyl citrate, linolenic acid, diethyl sebacate, phytantriol, natural plant oils, semi-natural oils and synthetic oils. More optionally, the release modifier may include but is not limited to one or more of ethyl oleate, monoolein, diolein, triolein, natural plant oils and medium-chain triglycerides.

[0365] As an example, natural vegetable oils may include, but are not limited to, one or more of castor oil, sesame oil, soybean oil, sunflower oil, peanut oil, corn oil, rapeseed oil, olive oil, and cottonseed oil. As an example, semi-natural oils may include, but are not limited to, hydrogenated castor oil. As an example, synthetic oils may include, but are not limited to, one or more of medium-chain triglycerides, long-chain triglycerides, triacetin, and derivatives thereof. As an example, medium-chain triglycerides may include, but are not limited to, one or more of caprylic triglyceride and capric triglyceride.

[0366] In some embodiments, the non-aqueous liposoluble preparation is an oil solution, and the release modifier may include but is not limited to methyl oleate, ethyl oleate, propyl oleate, butyl oleate, 2-butyl oleate, isopropyl oleate, hexyl oleate, octyl oleate, monoolein, diolein, triolein, propylene glycol monocaprylate, propylene glycol dicaprylate / dicaprate, propylene glycol laurate, propylene glycol alginate, caprylic and capric mono- and diglycerides, caprylic and capric mono-, di- and triglycerides, and caprylic and capric macrogol glycerides. , monoricinoleic acid glyceryl ester, monolinoleic acid glyceryl ester, oleoyl polyoxyethylene glyceride, diacetyl monoglyceride, mono-distearic acid glyceryl ester, monostearic acid glyceryl ester, tricaprylic acid glyceryl ester, tricapric acid glyceryl ester, behenic acid glyceryl ester, triacetin, isopropyl myristate, triethyl citrate, linolenic acid, diethyl sebacate, phytantriol, medium chain triglycerides, fish oil, algae oil, ethyl caprylate, ethyl caprate, ethyl linoleate, isopropyl linoleate, natural vegetable oil and semi-natural vegetable oil. One or more of.

[0367] In some optional embodiments, the non-aqueous liposoluble preparation is an oil solution, and the release modifier may include but is not limited to one or more of ethyl oleate, monoolein, diolein, triolein, propylene glycol monocaprylate, propylene glycol dicaprylate / dicaprate, propylene glycol laurate, propylene glycol alginate, caprylic and capric mono- and diglycerides, monolinoleic acid glyceride, triacetin, medium chain triglycerides and natural plant oils.

[0368] As non-limiting examples, natural vegetable oils may include, but are not limited to, one or more of castor oil, sesame oil, soybean oil, sunflower oil, peanut oil, corn oil, rapeseed oil, olive oil, cottonseed oil, linseed oil, perilla seed oil, walnut oil, argan oil, and seaweed oil.

[0369] As a non-limiting example, semi-natural oils may include, but are not limited to, hydrogenated castor oil.

[0370] As a possible embodiment, the non-aqueous liposoluble preparation is an oil solution, and the release regulator may include but is not limited to ethyl oleate, monoolein, diolein, triolein, propylene glycol monocaprylate, propylene glycol dicaprylate / dicaprate, caprylic and capric mono- and diglycerides, monolinolein, triacetin, medium-chain triglycerides, fish oil, algae oil, castor oil, sesame oil, soybean oil, peanut oil, corn oil, olive oil, cottonseed oil, linseed oil, perilla seed oil, walnut oil, argan oil, and one or more of laver oil.

[0371] In some embodiments, the non-aqueous liposoluble preparation is an oil solution, and the pharmaceutically acceptable solvent may include, but is not limited to, one or more of benzyl alcohol, chlorobutanol, dimethyl sulfoxide, N-methylpyrrolidone, dimethylacetamide, propylene glycol, polyethylene glycol, polyethylene glycol (mono) methyl ether, triacetin, benzyl benzoate, ethyl oleate, glycerol furfural, glycerol formal, ethanol, and ethylene glycol diethyl ether. Alternatively, the pharmaceutically acceptable solvent may include, but is not limited to, one or more of benzyl alcohol, benzyl benzoate, dimethyl sulfoxide, N-methylpyrrolidone, dimethylacetamide, and ethanol.

[0372] In some embodiments, the non-aqueous liposoluble preparation is an oil solution, and the pharmaceutically acceptable solvent may include but is not limited to one or more of benzyl alcohol, ethanol, propylene glycol, glycerol, isopropyl alcohol, N-methylpyrrolidone, dimethyl sulfoxide, liquid polyethylene glycol, dimethylacetamide, monoacetin, polyethylene glycol (mono) methyl ether, diethylene glycol monoethyl ether, ethylene glycol diethyl ether, glycerol furfural, glycerol formal, chlorobutanol, ethyl lactate, ethyl acetate, propylene glycol diethyl ester, tetrahydrofuran glycol ether and benzyl benzoate.

[0373] In some optional embodiments, the non-aqueous liposoluble preparation is an oil solution, and the pharmaceutically acceptable solvent may include but is not limited to one or more of benzyl alcohol, propylene glycol, ethanol, benzyl benzoate, dimethyl sulfoxide, liquid polyethylene glycol, N-methylpyrrolidone and dimethylacetamide.

[0374] As a possible embodiment, the non-aqueous liposoluble preparation is an oil solution, and the pharmaceutically acceptable solvent may include but is not limited to one or more of benzyl alcohol, propylene glycol, ethanol, benzyl benzoate, dimethyl sulfoxide, N-methylpyrrolidone and dimethylacetamide.

[0375] In some embodiments, the non-aqueous liposoluble preparation is an oil solution, and the small molecule regulator includes one or more of sodium phosphate, disodium hydrogen phosphate, sodium dihydrogen phosphate, potassium phosphate, dipotassium hydrogen phosphate, potassium dihydrogen phosphate, sodium carbonate, sodium bicarbonate, meglumine, arginine, triethanolamine, citric acid, sodium chloride, glucose and mannitol.

[0376] In some embodiments, the non-aqueous liposoluble preparation is an oil solution, and the small molecule regulator may include but is not limited to sodium phosphate, disodium hydrogen phosphate, sodium dihydrogen phosphate, potassium phosphate, dipotassium hydrogen phosphate, potassium dihydrogen phosphate, sodium carbonate, sodium bicarbonate, sodium hydroxide, meglumine, arginine, lysine, histidine, tromethamine, diethanolamine, ethylenediamine, hydrochloric acid, acetic acid, ascorbic acid, lactic acid, tartaric acid, methanesulfonic acid, methionine, cysteine, α-tocopherol, α-tocopheryl acetate, N-acetyl-L-cysteine, butylated hydroxyanisole, dibutylhydroxytoluene, propyl gallate, tert-butylhydroquinone, lipoic acid, tea polyphenols, L-ascorbyl palmitate, glutathione, triethanolamine, citric acid, sodium chloride, glucose and mannitol. One or more.

[0377] As a possible embodiment, the non-aqueous liposoluble preparation is an oil solution, and the small molecule regulator may include but is not limited to meglumine, tromethamine, triethanolamine, sodium hydroxide, disodium hydrogen phosphate, potassium dihydrogen phosphate, sodium carbonate, sodium bicarbonate, arginine, lysine, histidine, α-tocopherol, α-tocopherol acetate, butylated hydroxyanisole, dibutylhydroxytoluene, L-ascorbyl palmitate, and one or more of glutathione.

[0378] In some exemplary embodiments, the non-aqueous liposoluble preparation is an oil solution, and the small molecule regulator may include but is not limited to one or more of meglumine, tromethamine, arginine, lysine, histidine, α-tocopherol, α-tocopheryl acetate, butylated hydroxyanisole, L-ascorbyl palmitate, and glutathione.

[0379] As a possible embodiment, the non-aqueous liposoluble preparation is an in-situ gel, and the components of the non-aqueous liposoluble preparation include an active ingredient, a pharmaceutical solvent, and a release regulator.

[0380] In some optional embodiments, the non-aqueous liposoluble preparation is an in situ gel, and comprises, by weight, 0.1-10 parts by weight of an active ingredient, 10-95 parts by weight of a pharmaceutical solvent, and 5-90 parts by weight of a release modifier.

[0381] In situ gelation involves dissolving the drug and polymer in a suitable solvent and injecting it subcutaneously. At the site of administration, the polymer solidifies under physiological conditions, forming a semisolid or solid drug reservoir. This method overcomes the shortcomings of conventional emulsions, liposomes, microspheres, and micelles, offering advantages such as localized drug delivery to lesions, prolonged drug release, reduced dosage and adverse drug reactions, and a relatively simple process.

[0382] When the non-aqueous liposoluble preparation is an in situ gel, the weight ratio of the active ingredient contained in the non-aqueous liposoluble preparation is 0.1-10 parts; for example, it can be, but is not limited to, 0.1, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 9, 10 parts, or a range between any two of the above parts. The weight ratio range between any two parts can include, but is not limited to, 0.1-3, 0.5-3, 1-3, 2-3, or 1-2 parts.

[0383] When the non-aqueous liposoluble preparation is an in situ gel, the weight ratio of the pharmaceutical solvent contained in the non-aqueous liposoluble preparation is 10-95 parts; for example, it can be, but is not limited to, 10 parts, 15 parts, 20 parts, 25 parts, 30 parts, 35 parts, 40 parts, 45 parts, 50 parts, 55 parts, 60 parts, 65 parts, 70 parts, 75 parts, 80 parts, 85 parts, 90 parts, 95 parts, or a range between any two of the above parts. The weight ratio range between any two parts can include, but is not limited to, 69-85 parts, 79-85 parts, 74-80 parts, 60-85 parts, or 74-85 parts.

[0384] When the non-aqueous liposoluble preparation is an in situ gel, the weight ratio of the release modifier contained in the non-aqueous liposoluble preparation is 5-90 parts; for example, it can be, but is not limited to, 5 parts, 10 parts, 15 parts, 20 parts, 25 parts, 30 parts, 35 parts, 40 parts, 45 parts, 50 parts, 55 parts, 60 parts, 65 parts, 70 parts, 75 parts, 80 parts, 85 parts, 90 parts, or a range between any two of the above parts. The weight ratio range between any two parts can include, but is not limited to, 10-30 parts, 13-30 parts, 15-30 parts, 18-30 parts, 20-30 parts, or 25-30 parts.

[0385] When the non-aqueous liposoluble preparation is an in situ gel, when the weight proportions of each component contained in the non-aqueous liposoluble preparation are respectively within the above ranges, the release behavior has the following characteristics: in a release medium with a pH value of 7.4 that meets the sink conditions (according to the preparation method of the buffer solution of Part Four of the 2020 edition of the Chinese Pharmacopoeia), under 37°C conditions, the release amount of the active ingredient in 1 hour does not exceed 25% of the total amount of the active ingredient contained in the non-aqueous liposoluble preparation, and the release amount in 168 hours is greater than 80% of the total amount of the active ingredient contained in the non-aqueous liposoluble preparation. The in-situ gel with the above-mentioned release behavior has the following beneficial effects: (1) It has good stability and no drug precipitation; (2) It can slowly release drugs at the administration site, significantly reducing adverse reactions caused by excessive local drug concentration and improving drug safety; (3) It has good efficacy after a single administration and can avoid the problem of weakened efficacy of Kybella caused by prolonged dosing intervals due to adverse reactions. Clinically, the dosing interval can be determined according to the efficacy to ensure a good lipolysis effect and improve the patient's experience and comfort; (4) It can improve the lipolysis effect of deoxycholic acid at the same dose, improve drug utilization, avoid drug waste, reduce treatment costs, and reduce the risk caused by drug accumulation; (5) It has a targeted lipolysis effect, and the lipolysis components are concentrated in the tissue of the administration site and will not spread to other parts or tissues, so as to achieve the purpose of targeted lipolysis.

[0386] In some optional embodiments, the non-aqueous liposoluble preparation is an in situ gel, and comprises, by weight, 0.1-8 parts by weight of an active ingredient, 20-90 parts by weight of a pharmaceutical solvent, and 10-75 parts by weight of a release modifier.

[0387] In some optional embodiments, the non-aqueous liposoluble preparation is an in situ gel, and comprises, by weight, 0.5-6 parts by weight of an active ingredient, 30-85 parts by weight of a pharmaceutical solvent, and 13-60 parts by weight of a release modifier.

[0388] In some optional embodiments, the non-aqueous liposoluble preparation is an in situ gel, and comprises, by weight, 0.1-10 parts by weight of an active ingredient, 10-91 parts by weight of a pharmaceutical solvent, and 5-90 parts by weight of a release modifier.

[0389] In some optional embodiments, the non-aqueous liposoluble preparation is an in situ gel, and comprises, by weight, 0.5-8 parts by weight of an active ingredient, 20-85 parts by weight of a pharmaceutical solvent, and 10-74 parts by weight of a release modifier.

[0390] In some optional embodiments, the non-aqueous liposoluble preparation is an in situ gel, and comprises, by weight, 0.5-6 parts by weight of an active ingredient, 30-84 parts by weight of a pharmaceutical solvent, and 13-60 parts by weight of a release modifier.

[0391] In some embodiments, the non-aqueous liposoluble preparation is an in situ gel, and the release modifier may include but is not limited to one or more pharmaceutically acceptable biodegradable polymers; it may be polylactic acid, polylactic acid-glycolic acid copolymer, polyorthoester, sucrose acetate-isobutyrate, fatty acid glyceride, pegylated PLA / PLGA, PLGA-PEG-PLGA copolymer, polycaprolactone-polyethylene glycol copolymer, triethylene glycol poly (orthoester) polymer, poloxamer and other pharmaceutically acceptable local injection sustained-release materials. One or more.

[0392] It should be noted that PLA mentioned in this application refers to polylactic acid; PLGA refers to polylactic acid-co-glycolic acid; and PEG refers to polyethylene glycol.

[0393] In some optional embodiments, the non-aqueous liposoluble preparation is an in situ gel, and the release modifier includes one or more of polylactic acid, polylactic acid-glycolic acid copolymer, polyorthoester, sucrose acetate-isobutyrate, pegylated PLA / PLGA, PLGA-PEG-PLGA copolymer, polycaprolactone-polyethylene glycol copolymer and poloxamer.

[0394] In some optional embodiments, the non-aqueous liposoluble preparation is an in situ gel, and the release modifier includes one or more of polylactic acid, polylactic acid-glycolic acid copolymer, polyorthoester, sucrose acetate-isobutyrate, pegylated PLA / PLGA, PLGA-PEG-PLGA copolymer and poloxamer.

[0395] In some embodiments, the non-aqueous liposoluble preparation is an in situ gel, and the pharmaceutically acceptable solvent may include but is not limited to one or more of N-methylpyrrolidone, polyethylene glycol (mono) methyl ether, triacetin, benzyl benzoate, glycerol aldehyde, glycerol formal, propylene glycol, ethanol, ethylene glycol diethyl ether, benzyl alcohol, dimethyl sulfoxide, liquid polyethylene glycol, dimethylacetamide, and other pharmaceutically acceptable organic solvents.

[0396] In some optional embodiments, the non-aqueous liposoluble preparation is an in situ gel, and the pharmaceutically acceptable solvent may include but is not limited to one or more of N-methylpyrrolidone, polyethylene glycol (mono) methyl ether, benzyl benzoate, benzyl alcohol, dimethyl sulfoxide, ethylene glycol diethyl ether, propylene glycol and ethanol.

[0397] In some optional embodiments, the non-aqueous liposoluble preparation is an in situ gel, and the pharmaceutically acceptable solvent may include but is not limited to one or more of N-methylpyrrolidone, polyethylene glycol (mono)methyl ether, benzyl benzoate, benzyl alcohol, dimethyl sulfoxide, propylene glycol and ethanol.

[0398] In some embodiments, the non-aqueous liposoluble preparation is an in situ gel, and the components of the non-aqueous liposoluble preparation include an active ingredient, a pharmaceutically acceptable solvent, and a release regulator.

[0399] In some optional embodiments, the non-aqueous liposoluble preparation is an in situ gel, and comprises, by weight, 0.1-5 parts by weight of an active ingredient, 50-90 parts by weight of a pharmaceutical solvent, and 5-40 parts by weight of a release modifier.

[0400] In situ gelation involves dissolving the drug and polymer in a suitable solvent and injecting it subcutaneously. At the site of administration, the polymer solidifies under physiological conditions, forming a semisolid or solid drug reservoir. This method overcomes the shortcomings of conventional emulsions, liposomes, microspheres, and micelles, offering advantages such as localized drug delivery to lesions, prolonged drug release, reduced dosage and adverse drug reactions, and a relatively simple process.

[0401] When the non-aqueous liposoluble preparation is an in situ gel, the weight ratio of the active ingredient in the non-aqueous liposoluble preparation is 0.1-5 parts; for example, it can be, but is not limited to, 0.1, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, or a range between any two of the above parts. The weight ratio range between any two parts can include, but is not limited to, 0.1-3, 0.5-3, 1-3, 2-3, or 1-2 parts.

[0402] When the non-aqueous liposoluble preparation is an in situ gel, the weight ratio of the pharmaceutical solvent in the non-aqueous liposoluble preparation is 50-90 parts; for example, it may be, but is not limited to, 50, 55, 60, 65, 70, 75, 80, 85, 90 parts, or a range between any two of the above parts. The weight ratio range between any two parts may include, but is not limited to, 69-85 parts, 79-85 parts, 74-80 parts, 60-85 parts, or 74-85 parts.

[0403] When the non-aqueous liposoluble preparation is an in situ gel, the weight ratio of the release modifier in the non-aqueous liposoluble preparation is 5-40 parts; for example, it can be, but is not limited to, 5, 10, 15, 20, 25, 30, 35, 40 parts, or a range between any two of the above parts. The weight ratio range between any two parts can include, but is not limited to, 13-30 parts, 10-30 parts, 13-30 parts, 15-30 parts, 18-30 parts, 20-30 parts, or 25-30 parts.

[0404] When the non-aqueous liposoluble preparation is an in situ gel, when the weight proportions of each component contained in the non-aqueous liposoluble preparation are respectively within the above ranges, the release behavior has the following characteristics: in a release medium with a pH value of 7.4 that meets the sink conditions (according to the preparation method of the buffer solution of Part Four of the 2020 edition of the Chinese Pharmacopoeia), under 37°C conditions, the release amount of the active ingredient in 1 hour does not exceed 25% of the total amount of the active ingredient contained in the non-aqueous liposoluble preparation, and the release amount in 168 hours is greater than 80% of the total amount of the active ingredient contained in the non-aqueous liposoluble preparation. The in-situ gel with the above-mentioned release behavior has the following beneficial effects: (1) It has good stability and no drug precipitation; (2) It can slowly release drugs at the administration site, significantly reducing adverse reactions caused by excessive local drug concentration and improving drug safety; (3) It has good efficacy after a single administration and can avoid the problem of weakened efficacy of Kybella caused by prolonged dosing intervals due to adverse reactions. Clinically, the dosing interval can be determined according to the efficacy to ensure a good lipolysis effect and improve the patient's experience and comfort; (4) It can improve the lipolysis effect of deoxycholic acid at the same dose, improve drug utilization, avoid drug waste, reduce treatment costs, and reduce the risk caused by drug accumulation; (5) It has a targeted lipolysis effect, and the lipolysis components are concentrated in the tissue of the administration site and will not spread to other parts or tissues, so as to achieve the purpose of targeted lipolysis.

[0405] In some optional embodiments, the non-aqueous liposoluble preparation is an in situ gel, and comprises, by weight, 0.1-3 parts by weight of an active ingredient, 60-85 parts by weight of a pharmaceutical solvent, and 10-30 parts by weight of a release modifier.

[0406] In some optional embodiments, the non-aqueous liposoluble preparation is an in situ gel, and comprises, by weight, 0.5-3 parts by weight of an active ingredient, 69-85 parts by weight of a pharmaceutical solvent, and 13-30 parts by weight of a release modifier.

[0407] In some embodiments, the non-aqueous liposoluble preparation is an in situ gel, and the release modifier may include but is not limited to one or more pharmaceutically acceptable biodegradable polymers; it may be polylactic acid, polylactic acid-co-glycolic acid, polyorthoesters, sucrose acetate-isobutyrate, fatty acid glycerides, pegylated PLA / PLGA, PLGA-PEG-PLGA copolymer, polycaprolactone-polyethylene glycol copolymer, triethylene glycol poly(orthoester) polymer, poloxamer, and other pharmaceutically acceptable local injection sustained-release materials. Alternatively, the non-aqueous liposoluble preparation is an in situ gel, and the release modifier may include but is not limited to one or more of polylactic acid, polylactic acid-co-glycolic acid, polyorthoesters, sucrose acetate-isobutyrate, pegylated PLA / PLGA, PLGA-PEG-PLGA copolymer, polycaprolactone-polyethylene glycol copolymer, and poloxamer. Alternatively, the release modifier may include, but is not limited to, one or more of polylactic acid, polylactic-co-glycolic acid, polyorthoesters, sucrose acetate-isobutyrate, pegylated PLA / PLGA, PLGA-PEG-PLGA copolymers, and poloxamers.

[0408] It should be noted that PLA mentioned in the present invention refers to polylactic acid; PLGA refers to polylactic acid-co-glycolic acid; and PEG refers to polyethylene glycol.

[0409] In some embodiments, the non-aqueous liposoluble preparation is an in situ gel, and the pharmaceutically acceptable solvent may include but is not limited to one or more of N-methylpyrrolidone, polyethylene glycol (mono) methyl ether, glyceryl triacetate, benzyl benzoate, glycerol aldehyde, glycerol formal, propylene glycol, ethanol, ethylene glycol diethyl ether, benzyl alcohol, dimethyl sulfoxide, and other pharmaceutically acceptable organic solvents. Alternatively, the pharmaceutically acceptable solvent may include but is not limited to one or more of N-methylpyrrolidone, polyethylene glycol (mono) methyl ether, benzyl benzoate, benzyl alcohol, dimethyl sulfoxide, propylene glycol, and ethanol.

[0410] In some embodiments, the non-aqueous liposoluble preparation is an in situ gel, and the pharmaceutically acceptable solvent may include but is not limited to one or more of N-methylpyrrolidone, polyethylene glycol (mono) methyl ether, triacetin, benzyl benzoate, glycerol aldehyde, glycerol formal, propylene glycol, ethanol, ethylene glycol diethyl ether, benzyl alcohol, dimethyl sulfoxide, liquid polyethylene glycol, dimethylacetamide, and other pharmaceutically acceptable organic solvents.

[0411] In some optional embodiments, the non-aqueous liposoluble preparation is an in situ gel, and the pharmaceutically acceptable solvent may include but is not limited to one or more of N-methylpyrrolidone, polyethylene glycol (mono) methyl ether, benzyl benzoate, benzyl alcohol, dimethyl sulfoxide, ethylene glycol diethyl ether, propylene glycol and ethanol.

[0412] In some embodiments, the non-aqueous liposoluble preparation is an in situ gel, and the pharmaceutically acceptable solvent may include but is not limited to one or more of N-methylpyrrolidone, polyethylene glycol (mono)methyl ether, benzyl benzoate, benzyl alcohol, dimethyl sulfoxide, propylene glycol and ethanol.

[0413] It should be noted that when the non-aqueous liposoluble preparation provided in the present application is an in-situ gel, it can be prepared using the in-situ gel preparation method known in the art.

[0414] As an example, a solvent such as polyethylene glycol methyl ether or N-methylpyrrolidone can be used to dissolve a release regulator such as a medicinal polymer polylactic acid or polylactic acid-glycolic acid copolymer to form a solution. The solution can directly dissolve the active ingredient, or be pre-loaded in a sterile syringe with the active ingredient and the drug can be dissolved before use.

[0415] The solution after dissolving the active ingredient is locally injected into the human body. The solvent used to dissolve the release regulator is rapidly absorbed locally, and some of the dissolved drugs are also rapidly absorbed along with the absorption of the solvent. The release regulator forms a semi-solid or solid gel when it encounters an aqueous environment in the body, and most of the active ingredients dissolved or dispersed in the gel system are slowly released as the gel degrades and dissolves, thereby achieving stable drug absorption in the body and maintaining blood drug concentration.

[0416] It should be noted that materials such as polylactide / glycolide-polyethylene glycol copolymer and / or its blends, poloxamer or polycaprolactone-polyethylene glycol copolymer and other pharmaceutical additives can also be dissolved in water to prepare a temperature-sensitive gel preparation, which can be mixed with a solution of the active ingredient or pre-loaded with the active ingredient in a sterile syringe before use and then locally injected into the human body to form a gel material to adjust the drug release rate.

[0417] In some embodiments, the deoxycholate salt comprises sodium deoxycholate; the deoxycholic acid derivative comprises one or more of ursodeoxycholic acid, hyodeoxycholic acid, and chenodeoxycholic acid.

[0418] In some embodiments, the deoxycholate comprises sodium deoxycholate; the deoxycholic acid derivative comprises ursodeoxycholic acid, hyodeoxycholic acid, chenodeoxycholic acid, sodium ursodeoxycholate, sodium hyodeoxycholate, sodium chenodeoxycholate, cholic acid, sodium cholate, glycocholic acid, sodium glycocholate, glycodeoxycholic acid, sodium glycodeoxycholate, taurocholic acid, sodium taurocholate, glycotaurocholic acid, sodium glycotaurocholate, lithocholic acid, sodium lithocholic acid, sodium glycochenodeoxycholate, sodium phenylpropanecholate, sodium casochlate, sodium leukocholic acid, bile acid dimer, bile acid side chain amino acid conjugate, bile acid side chain PEG conjugate, bile acid side chain glucose conjugate or more.

[0419] In some embodiments, the dosage of the non-aqueous liposoluble formulation is 0.1 mg to 1000 mg, calculated as the active ingredient; for example, but not limited to, 0.1 mg, 1 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, or a range between any two of the foregoing doses. Alternatively, the dosage of the non-aqueous liposoluble formulation is 1 mg to 500 mg, calculated as the active ingredient.

[0420] The second aspect of the present application provides a use of the non-aqueous liposoluble preparation of the first aspect in preparing a preparation having the effect of dissolving fat cells.

[0421] In some embodiments, the preparation having the effect of dissolving adipocytes comprises an injectable preparation and / or an implantable preparation.

[0422] In some embodiments, the administration sites of the injection preparation and / or the implant preparation include one or more of the abdomen, under the eyes, under the hips, under the arms, buttocks, thighs, calves, back, bra line, underarms, stomach and ankles.

[0423] The third aspect of the present application provides an injection preparation, which is prepared from the non-aqueous liposoluble preparation of the first aspect of the present application.

[0424] In some embodiments, the administration of the injection preparation includes one or more of subcutaneous injection and intramuscular injection; subcutaneous injection is optional.

[0425] The fourth aspect of the present application provides an implant preparation, which is prepared from the non-aqueous liposoluble preparation of the first aspect of the present application.

[0426] The following is a detailed description of the technical solutions of the present application in conjunction with specific examples. It should be understood that these examples are only used to illustrate the present application and are not intended to limit the scope of the present application. For experimental methods in the following examples where specific conditions are not specified, reference should be made to the instructions given in this application, or to experimental manuals or conventional conditions in the field, or to conditions recommended by the manufacturer, or to experimental methods known in the art.

[0427] In the following specific examples, the measured parameters of raw material components may have slight deviations within the range of weighing accuracy unless otherwise specified. For temperature and time parameters, acceptable deviations caused by instrument testing accuracy or operational accuracy are allowed.

[0428] It should be noted that the dosage form of the non-aqueous liposoluble preparation in Example 1 below is proliposomes, the dosage form of the non-aqueous liposoluble preparation in Example 2 is an oil solution, and the dosage form of the non-aqueous liposoluble preparation in Example 3 is an in situ gel.

[0429] 1. Implementation

[0430] Example 1. Preparation of proliposomes

[0431] 1. The formulation composition of proliposome 1-27 is shown in Tables 1 and 2.

[0432] Table 1. Composition of different proliposome formulations

[0433]

[0434]

[0435] Table 2. Composition of different proliposome formulations

[0436]

[0437]

[0438] 2. Preparation process

[0439] Weigh the prescribed amount of active ingredient, pharmaceutical lecithin, pharmaceutical solvent, and release modifier into a pre-weighed round-bottom flask, weigh it, and add an excess of anhydrous ethanol. Place the flask in an ultrasonic bath to completely disperse the lecithin and dissolve all components. Connect the round-bottom flask to a suitable rotary evaporator and evaporate under reduced pressure until the weight change indicates that the anhydrous ethanol has been completely removed. If necessary, add additional pharmaceutical solvent to the prescribed amount and mix thoroughly. Filter the resulting solution, aliquot, fill with nitrogen, and seal to obtain a clear, transparent liquid.

[0440] Example 2: Preparation of oil solution

[0441] 1. The formulation compositions of oil solutions 1-12 are shown in Table 3.

[0442] Table 3. Formula composition of oil solutions 1-12

[0443]

[0444]

[0445] 2. Preparation process

[0446] Weigh the prescribed amount of active ingredient, add the prescribed amount of pharmaceutical solvent, vortex, and sonicate until completely dispersed. Then, add the prescribed amount of release modifier and stir to mix thoroughly. Filter the resulting solution, aliquot, nitrogen-fill, seal, and sterilize.

[0447] Example 3: Preparation of in situ gel

[0448] 1. The formulation composition of in situ gel 1-11 is shown in Table 4.

[0449] Table 4. Formula composition of in situ gels 1-11

[0450]

[0451]

[0452] 2. Preparation process

[0453] Weigh the prescribed amount of medicinal solvent, add the prescribed amount of release regulator, vortex and stir until completely dispersed; add the prescribed amount of drug, stir until evenly dispersed, filter the resulting liquid, divide it into packages, fill it with nitrogen, and seal it.

[0454] Comparative Example 1. Preparation of injection

[0455] 1. Comparative Example 1 was prepared with reference to Kybella commercially available injection, and its formulation composition is shown in Table 5.

[0456] Table 5. Prescription composition of injection

[0457]

[0458] 2. Preparation process

[0459] Weigh the prescribed amount of benzyl alcohol, disodium hydrogen phosphate, sodium chloride, and sodium hydroxide into water for injection. Stir and sonicate until completely dissolved. Add the prescribed amount of deoxycholic acid and stir and sonicate until completely dissolved. Adjust the pH to 8.3 with hydrochloric acid / sodium hydroxide to obtain a drug-containing solution. Filter, aliquot, seal, and sterilize with moist heat to obtain a clear, transparent liquid.

[0460] Comparative Example 2. Preparation of injection

[0461] 1. The prescription composition of Comparative Example 2 is shown in Table 6.

[0462] Table 6. Prescription composition of Comparative Example 2

[0463]

[0464]

[0465] 2. Preparation process

[0466] Weigh the prescribed amount of deoxycholic acid and Tween 20 in a portion of water for injection (80% of the total amount of water for injection), pre-shear at 10,000 rpm for 10 minutes to completely dissolve, and obtain a coarse particle suspension;

[0467] The coarse particle suspension was ground using a grinder with 0.3 mm zirconia ceramic grinding beads as the grinding medium until the particle size distribution D50 was ≤ 10 μm to obtain a ground suspension; anhydrous sodium dihydrogen phosphate and sodium carboxymethyl cellulose were added to the ground suspension, and the mixture was stirred at 100 rpm for 10 min to completely mix, and then sodium hydroxide was added to adjust the pH to 7.0, and the remaining water for injection was added to the target volume to obtain a deoxycholic acid suspension, i.e., Comparative Example 2.

[0468] The particle size distribution of the deoxycholic acid suspension was measured using a Malvern particle size analyzer, and the particle size distribution was D50 = 6.36 μm.

[0469] Comparative Example 3: Preparation of a formulation without a release modifier

[0470] 1. The prescription composition of Comparative Example 3 is shown in Table 7.

[0471] Table 7. Prescription composition of Comparative Example 3

[0472] Components Dosage Deoxycholic acid 100mg Anhydrous ethanol 2.5g Soybean lecithin S100 7.4g

[0473] 2. Preparation process of comparative example 3

[0474] Weigh the prescribed amount of deoxycholic acid and add it to the prescribed amount of anhydrous ethanol, and sonicate until dissolved; add the prescribed amount of soybean lecithin S100, stir and sonicate until dissolved, filter the obtained liquid, subpackage it, fill it with nitrogen, and seal it to obtain a clear and transparent liquid.

[0475] Comparative Example 4: Preparation of a formulation without a release modifier

[0476] 1. The prescription composition of Comparative Example 4 is shown in Table 8.

[0477] Table 8. Prescription composition of Comparative Example 4

[0478] Components Dosage Deoxycholic acid 100mg Anhydrous ethanol 10g

[0479] 2. Preparation process of comparative example 4

[0480] Weigh the prescribed amount of deoxycholic acid and add it to the prescribed amount of anhydrous ethanol, sonicate until dissolved, filter the resulting liquid, subpackage it, fill it with nitrogen, and seal it to obtain a clear and transparent liquid.

[0481] 2. Experimental Examples

[0482] Experimental Example 1: Stability Considerations

[0483] The non-aqueous fat-dissolving preparations prepared in the above examples were subjected to long-term testing at 25°C and 60% RH, as well as accelerated testing at 40°C and 75% RH. The content and related substances of each non-aqueous fat-dissolving preparation were determined. The content determination methods and related substance determination methods are as follows:

[0484] 1. Content

[0485] Mobile phase: Mobile phase A: 0.1% formic acid in water, mobile phase B: 0.1% formic acid in acetonitrile; perform gradient elution according to Table 9.

[0486] Table 9. Gradient elution program

[0487]

[0488]

[0489] Solvent: methanol: water = 80:20

[0490] Preparation of test solution: Accurately measure 1 ml or 1 g of the product into a 10 ml volumetric flask, add diluent (methanol: water = 80:20) to dilute to the mark, shake well, and prepare a 1 mg / ml deoxycholic acid solution as the test sample stock solution. Accurately measure 1 ml of the test sample stock solution into a 100 ml volumetric flask, add diluent (methanol: water = 80:20) to dilute to the mark, shake well, and prepare a 10 μg / ml deoxycholic acid solution as the test sample solution.

[0491] Preparation of reference solution: Accurately weigh an appropriate amount of deoxycholic acid reference substance and dilute it with diluent to a solution containing approximately 10 μg of deoxycholic acid per 1 ml as the reference solution.

[0492] Chromatographic conditions: Method: Determined according to high performance liquid chromatography (Chinese Pharmacopoeia 2020 Edition Part IV General Chapter 0512); detector: CAD detector; chromatographic column: YMC Pack Pro C18 (4.6mm×150mm, 3μm); injection volume: 25μL; column temperature: 30℃; flow rate: 1mL / min; running time: 43min.

[0493] Analytical method: Calculate the content based on the peak area using the external standard method.

[0494] 2. Related substances

[0495] Preparation of test solution: Accurately measure 1 ml of the injection solution of this product, place it in a 10 ml volumetric flask, add diluent (methanol: water = 80:20) to dilute to the scale, shake well, and prepare a 1 mg / ml deoxycholic acid solution as the test solution.

[0496] Preparation of reference solution: Accurately measure an appropriate amount of the test solution and dilute it with a diluent to a solution containing approximately 10 μg of deoxycholic acid per 1 ml as the reference solution.

[0497] The determination method and chromatographic conditions are the same as those for content determination and will not be described in detail.

[0498] The relevant substances and content determination results are shown in Table 10.

[0499] Table 10. Stability changes of non-aqueous liposoluble preparations

[0500]

[0501]

[0502] As can be seen from the results in Table 8, the non-aqueous liposoluble preparations of different dosage forms in the above embodiments showed no significant changes in content and related substances after 6 months of storage under accelerated conditions and long-term conditions, indicating that the non-aqueous liposoluble preparations provided in this application have good stability.

[0503] Experimental Example 2: Pushing Force Measurement

[0504] An appropriate amount of non-aqueous lipolytic preparation was drawn into a 1 mL syringe, and a 27G needle was attached. The pushing force was measured at room temperature at a speed of 30 mm / min. The measurement results are shown in Table 11.

[0505] Table 11. Push force results of non-aqueous lipolysis preparations

[0506]

[0507]

[0508] As shown in Table 9, the pushing force of the non-aqueous fat-soluble preparations of different dosage forms in the above embodiments is less than 15N, which meets the clinical hand suitability requirements.

[0509] Experimental Example 3: In vitro release investigation

[0510] 1. In vitro release of proliposomes 1-25 and comparative examples 1-3

[0511] Proliposomes 1-25 and Comparative Examples 1-3 were placed in dialysis bags, respectively, in a phosphate buffer solution of pH = 7.4, at a temperature of 37°C and a rotation speed of 100 rpm. At a predetermined time point, all the dialysis media were removed and replaced with fresh media. The removed media were diluted appropriately and then measured by high performance liquid chromatography to calculate the cumulative release rate. The measurements were repeated three times and the average value was taken. The release results are shown in Tables 12-16. The release curves of Comparative Example 1 and proliposomes are shown in Tables 12-16. Figure 1-4 shown. Figures 1 to 4 D1 to D3 correspond to the corresponding ratios 1 to 3, respectively, and LP1 to LP27 correspond to the proliposomes 1 to 27, respectively.

[0512] Table 12. In vitro release results of proliposomes 1-7 and comparative example 1

[0513]

[0514] Table 13. In vitro release results of proliposomes 8-14 and comparative example 1

[0515]

[0516]

[0517] Table 14. In vitro release results of proliposomes 15-19

[0518] Time / h Proliposome 15 Proliposome 16 Proliposome 17 Proliposome 18 Proliposome 19 1 12.40％ 11.82％ 13.27％ 10.88％ 12.11％ 4 16.56％ 19.37％ 20.75％ 18.56％ 25.09％ 8 31.46％ 33.12％ 26.94％ 25.20％ 36.14％ 12 44.48％ 39.82％ 38.73％ 34.57％ 44.62％ 24 53.53％ 49.39％ 49.01％ 46.66％ 54.02％ 48 68.69％ 66.92％ 61.62％ 59.46％ 72.81％ 72 78.80％ 80.19％ 75.10％ 70.31％ 81.07％ 120 86.91％ 87.82％ 83.89％ 88.55％ 86.02％ 168 95.31％ 94.21％ 97.02％ 99.21％ 91.36％

[0519] Table 15. In vitro release results of proliposomes 20-27

[0520]

[0521] Table 16. In vitro release results of Comparative Example 2 and Comparative Example 3

[0522] Time / h Comparative Example 2 Comparative Example 3 1 8.69％ 65.41％ 4 13.28％ 87.65％ 8 18.96％ 96.00％ 12 26.53％ / 24 31.15％ / 48 36.14％ / 72 43.40％ / 120 55.06％ / 168 64.23％ /

[0523] From Table 12-16 and Figure 1-4 The results show that Comparative Examples 1 and 3, both of which do not contain a release modifier, achieve a release of over 85% in 4 hours. When the non-aqueous liposoluble preparation is a proliposome, the release does not exceed 25% in 1 hour, and the release is greater than 80% in 168 hours. This indicates that the proliposome has a better sustained-release effect than Comparative Examples 1 and 3. The release of Comparative Example 2 is less than 70% in 168 hours.

[0524] 2. In vitro release of oil solutions 1-12 and comparative examples 1-2 and 4

[0525] Oil solutions 1-12, Comparative Examples 1-2, and Comparative Example 4 were placed in dialysis bags, respectively, in 0.1% Tween pH 7.4 phosphate buffer at 37°C and 75 rpm. At predetermined time points, all the dialysis media were removed and replaced with fresh media. The removed media were diluted appropriately and then measured by high performance liquid chromatography to calculate the cumulative release rate. The measurements were repeated three times and the average value was taken. The release results of Comparative Example 1 and the oil solution are shown in Table 17. The release curves of Comparative Example 1 and the oil solutions 1-12 are shown in Table 17. Figure 5-6 The release results of Comparative Examples 2 and 4 are shown in Table 18, and the release curves are shown in Figure 7 and Figure 8 As shown. Among them, Figures 5 to 8 D1, D2, and D4 correspond to comparative example 1, comparative example 2, and comparative example 4, respectively; OS1-12 correspond to oil solutions 1-12, respectively.

[0526] Table 17. In vitro release results of oil solutions 1-12 and comparative example 1

[0527]

[0528] From Table 17 to Table 18 and Figure 5-8 The results show that Comparative Examples 1 and 4, both of which do not contain a release modifier, achieve a release of more than 85% in 4 hours. When the non-aqueous fat-soluble preparation is an oil solution, its release in 1 hour does not exceed 25%, and the release in 168 hours is greater than 80%, indicating that the oil solution has a better sustained-release effect than Comparative Examples 1 and 4. The release in Comparative Example 2 after 168 hours is less than 50%.

[0529] Table 18. In vitro release results of Comparative Example 2 and Comparative Example 4

[0530] Time / h Comparative Example 2 Comparative Example 4 1 3.73％ 62.17％ 4 8.06％ 85.99％ 8 11.20％ 97.97％ 12 14.13％ / 24 18.80％ / 48 22.72％ / 72 27.36％ / 120 31.86％ / 168 40.02％ /

[0531] 3. In vitro release of in situ gels 1-11 and comparative example 1

[0532] Take the in situ gel 1-11 and comparative example 1 and place them in dialysis bags respectively, add phosphate buffer with pH=7.4 containing 0.5% Tween 80, and then place the test tube containing the gel in a constant temperature oscillator, control the temperature at 37.0℃±0.5℃, and the rotation speed at 75rpm. The test tube is sealed during the entire dissolution process to prevent water evaporation from affecting the experimental results. Samples are taken at the set time point, with a sample volume of 1mL, and 1mL of constant temperature phosphate buffer medium with pH=7.4 is added at the same time. After the sample is reasonably diluted, it is measured by high performance liquid chromatography, and then the cumulative release is calculated, and the release curve is drawn. Each sample is measured 3 times, and the average value is taken. The release results are shown in Table 19; the release curves of comparative example 1 and in situ gel 1-9 are shown in Table 19. Figure 9 shown. Figure 9 D1 corresponds to the ratio 1; ISG1 to ISG11 correspond to the in situ gels 1 to 11 respectively.

[0533] Table 19. In vitro release results of in situ gels 1-11 and comparative example 1

[0534]

[0535]

[0536] From Table 19 and Figure 9 The results show that the release amount of Comparative Example 1 (without a release regulator) reaches more than 85% in 4 hours; when the non-aqueous liposoluble preparation is an in situ gel, its release amount in 1 hour does not exceed 25%, and the release amount in 168 hours is greater than 80%, indicating that the in situ gel has a better sustained-release effect than Comparative Example 1.

[0537] Experimental Example 4: Investigation of the Dissolution of Different Ex vivo Tissues by Non-aqueous Lipolytic Preparations

[0538] Approximately 100 mg of inguinal fat and muscle were collected from 12 groups of C57 mice and placed in EP tubes. The same volume of non-aqueous lipolysis preparation was added to each tissue until it covered the tissue. Photos were taken 2 hours, 3 days, and 7 days after immersion to observe the morphological changes of each tissue. After 7 days, each tissue was removed and weighed, and the tissue loss was calculated. The results are shown in the figure and table below. Figure 10 As shown in Figure 2, the morphological changes of muscles are as follows: Figure 11 The dissolution of inguinal fat and muscle over 7 days is shown in Table 20.

[0539] Table 20. Dissolution of fat and muscle by different non-aqueous lipolysis preparations over 7 days

[0540] Group Inguinal fat muscle Comparative Example 1 15.12％ 14.85％ Comparative Example 2 1.51％ 1.08％ Proliposome 1 22.34％ 2.18％ Oil solution 1 24.82％ 1.96％ In situ gel 2 20.19％ 1.41％

[0541] From Table 20 and Figures 10-11 The results show that Comparative Example 1 has a dissolving effect on both fat and muscle, and the dissolution rates of the two are comparable; Comparative Example 2 has no obvious dissolving effect on either fat or muscle; and the non-aqueous liposoluble preparations of different dosage forms have significantly better dissolving effects on fat than Comparative Example 1, and have basically no dissolving effect on muscle; this shows that the non-aqueous liposoluble preparations of different dosage forms provided by the present application have better fat dissolving effects than Comparative Example 1, and have a selective dissolving effect on fat, which can achieve targeted lipolysis. Combining the release results of the non-aqueous preparations of the present application and Comparative Examples 1 and 2, it can be seen that the release amount of Comparative Example 1 in 4 hours can reach more than 85%, and the release amount of Comparative Example 2 in 168 hours is less than 50%; it can be seen that too fast release will cause both fat and muscle to be dissolved; too slow release will result in poor fat dissolution effect; the drug release amount needs to be controlled within a certain range to ensure good fat dissolution effect and good safety.

[0542] Experimental Example 5: Safety and efficacy assessment in mice

[0543] Experimental animals: 12-week-old male C57BL / 6 mice.

[0544] Experimental Grouping and Dosing: Mice were randomly divided into groups of 6 per group. The abdominal area of ​​the mice was depilated and disinfected with alcohol. The composition shown in Table 21 was subcutaneously injected into the inguinal fat pad of one side of the mouse. An equal amount of normal saline was injected into the other side in the same manner. The experimental groups and dosages are shown in Table 21.

[0545] Table 21. In vivo administration dosage information of non-aqueous liposoluble formulations

[0546] Composition Dosage volume Dosage mg Comparative Example 1 0.1ml*2 points 2 Comparative Example 2 0.02ml*2 points 2 Proliposome 1 0.1ml*2 points 2 Oil solution 1 0.1ml*2 points 2 In situ gel 3 0.1ml*2 points 2

[0547] The experimental mice were treated as follows:

[0548] 1. Gross observation of the injection site: The injection site of the experimental mice was photographed and recorded 24 hours and 7 days after injection; the results are shown in Table 22 and Figure 12-13 shown.

[0549] Table 22. Injection site conditions of mice at different time points after administration

[0550]

[0551] From the above table and Figures 12-13 The results show that after the mice were injected with Comparative Example 1, 83.3% of the mice had abnormalities at the injection site, while no abnormalities were found in the non-aqueous liposoluble preparation groups with different dosage forms at different time points; this indicates that the local safety of the non-aqueous liposoluble preparations with different dosage forms provided in the present application is significantly better than that of Comparative Example 1, and the incidence of adverse reactions can be reduced by at least 80%.

[0552] Kybella has severe adverse reactions in clinical practice, requiring a recovery time of at least four weeks. Therefore, the clinical dosing interval is four weeks. However, Kybella is a standard injection, and a longer dosing interval can lead to a decrease in efficacy. The non-aqueous liposoluble preparations of various dosage forms provided herein all significantly reduce adverse reactions compared to Comparative Example 1. Therefore, the non-aqueous liposoluble preparations of this application do not have dosing interval issues caused by adverse reactions. Clinically, the dosing interval can be determined based on efficacy to ensure a good lipolysis effect.

[0553] 2. Determination of pain threshold at the injection site: The pain threshold at the injection site at different time points was determined using von Frey hairs; the results are shown in Tables 23 and Figure 14 shown.

[0554] Table 23. Pain threshold at the injection site at different time points after administration

[0555] time Comparative Example 1 Proliposome 1 Oil solution 1 In situ gel 3 Before administration 3.0±1.0 2.0±1.0 2.0±0.0 2.0±1.0 24h 0.0±0.0 1.0±0.0*** 1.0±0.0*** 1.0±0.0*** 48h 0.0±0.0 1.0±0.0*** 1.0±0.0*** 1.0±0.0*** 3 days 0.0±0.0 1.0±0.0*** 1.0±0.0*** 1.0±0.0*** 5 days 0.0±0.0 1.0±0.0*** 1.0±0.0*** 1.0±0.0*** 7 days 0.0±0.0 2.0±1.0** 2.0±1.0** 2.0±0.0**

[0556] Among them, *p<0.05, **p<0.01, ***p<0.001 vs. comparison example 1.

[0557] From the above table and Figure 14 The results show that at different points after injection, the pain threshold at the injection site of mice in Comparative Example 1 was significantly lower than that of non-aqueous liposoluble preparations of different dosage forms, indicating that the non-aqueous liposoluble preparations of different dosage forms provided in this application can significantly improve the pain at the injection site compared with Comparative Example 1.

[0558] 3. Determination of fat loss effect at the injection site: Seven days after injection, the animals were killed, the inguinal fat pads were isolated and weighed, and the fat loss was quantitatively evaluated. The results are shown in Table 24.

[0559] Table 24. Fat quantitative evaluation results at different time points after administration

[0560]

[0561] As can be seen from the results in the above table, the fat weight loss of the non-aqueous liposoluble preparations of different dosage forms of the present application is greater than that of Comparative Example 1 and Comparative Example 2, indicating that the non-aqueous liposoluble preparations of different dosage forms provided by the present application have better efficacy. At a unit dose, the efficacy of the non-aqueous liposoluble preparations of different dosage forms can be increased by more than 30% compared with Comparative Example 1 and more than 6 times compared with Comparative Example 2.

[0562] 4. Determination of drug residues at the injection site: Seven days after injection, the animals were sacrificed, and tissues at the injection site were isolated and assayed for drug residues. The results are shown in Table 25.

[0563] Table 25. Drug residues at the injection site in different groups

[0564] Group Drug residue at injection site for 7 days Comparative Example 1 Not detected Comparative Example 2 73.94％ Proliposome 1 5.10％ Oil solution 1 4.89％ In situ gel 3 3.35％

[0565] As shown in Table 25, drug residues were detected in all non-aqueous liposoluble preparations of different dosage forms 7 days after administration, while no drug residues were detected in Comparative Example 1. This indicates that the non-aqueous liposoluble preparations of different dosage forms of the present application can slowly release the drug at the administration site for at least 7 days. In Comparative Example 2, the drug residue at the injection site was greater than 50% 7 days after administration.

[0566] In summary, it can be seen that the drug release in Comparative Example 1 is too fast (the release amount in 4 hours is more than 85%), which will lead to serious adverse reactions and limited fat dissolving effect; the drug release in Comparative Example 2 is too slow (the release amount in 168 hours is less than 50%), which will lead to poor fat dissolving effect; after research, it was found that the non-aqueous fat dissolving preparation provided by the present application has a release amount of no more than 25% in 1 hour and a release amount of more than 80% in 168 hours. Under a unit dose, the fat dissolving effect can be increased by at least 30% compared with Comparative Example 1, the incidence of adverse reactions can be reduced by at least 80%, and the fat dissolving effect can be increased by more than 6 times compared with Comparative Example 2. It can be seen that the composition of the present application can reasonably release the drug, and this release behavior can ensure that the safety and efficacy of the non-aqueous preparation of the present application in mice are better.

[0567] Experimental Example 6: Safety and efficacy evaluation in high-fat mice

[0568] Experimental animals: 12-week-old male C57BL / 6 mice were fed a high-fat diet for 12 weeks.

[0569] Experimental Grouping and Dosing: High-fat mice were randomly divided into groups of 6. The abdominal area of ​​the mice was depilated and disinfected with alcohol. The composition shown in the table below was subcutaneously injected into the inguinal fat pad of one side of the mouse. An equal volume of saline was injected into the other side in the same manner. Repeat injections were performed on days 1 and 14. The experimental groups and dosages are shown in Table 26.

[0570] Table 26. In vivo administration dosage information of non-aqueous liposoluble formulations

[0571] Composition Dosage volume Dosage mg Comparative Example 1 0.1ml*2 points 2 Comparative Example 3 0.1ml*2 points 2 Comparative Example 4 0.1ml*2 points 2 Proliposome 12 0.1ml*2 points 2 Oil solution 9 0.2ml*2 points 2 In situ gel 4 0.05ml*2 points 2

[0572] The experimental mice were treated as follows:

[0573] 1. Gross observation of the injection site: The injection site of the experimental mice was photographed and recorded at different time points after injection; the results are shown in Table 27 and Figure 15-18 shown.

[0574] Table 27. Injection site of high-fat mice at different time points after administration

[0575]

[0576] From the above table and Figure 15-18 The results show that adverse reactions occurred at the injection site in Comparative Examples 1, 3, and 4 at different time points after a single injection, with an incidence rate of 33% to 100%, and they were not fully recovered after 14 days, indicating that the time interval for repeated injections of commercially available injections is at least 14 days; no obvious abnormalities occurred at the injection site of the same dose of proliposomes 12, oil solution 9, and in situ gel 4, indicating that the safety of the composition of the present application after a single injection is significantly better than that of Comparative Example 1.

[0577] After repeated injections, adverse reactions occurred at the injection site in groups 1, 3, and 4 of comparative examples, with an incidence rate of 67%. However, no obvious abnormalities were observed at the injection site of the proliposomes 12, oil solution 9, and in situ gel 4 of the same dose. This indicates that the safety of the composition of the present application after repeated injections is significantly better than that of comparative example 1, and the time interval for repeated injections can be set as needed.

[0578] 2. Determination of fat reduction effect at the injection site: 7 days after the first injection and 21 days after the first injection (7 days after repeated injection), the animals were killed, the inguinal fat pads were separated and weighed, and the fat weight loss was quantitatively evaluated. The results are shown in Table 28.

[0579] Table 28. Fat quantitative evaluation results at different time points after administration

[0580]

[0581] As can be seen from the results in Table 28, after a single injection, the fat weight loss of the precursor liposome 12, oil solution 9, and in situ gel 4 at the same dose is better than that of Comparative Example 1, Comparative Example 3, and Comparative Example 4, indicating that the fat solubilization effect of the composition of the present application is better than that of Comparative Example 1, Comparative Example 3, and Comparative Example 4; at the same dose, the fat reduction effect of the composition of the present application is at least 1.4 times higher than that of Comparative Example 1; after repeated injections, the fat weight loss of the precursor liposome 12, oil solution 9, and in situ gel 4 at the same dose is better than that of Comparative Example 1, indicating that the fat solubilization effect of the composition of the present application is better than that of Comparative Example 1, and at the same dose, the fat reduction effect of the composition of the present application is at least 50% higher than that of Comparative Example 1, Comparative Example 3, and Comparative Example 4; in the same group, the fat weight loss of repeated injections is better than that of single injections, indicating that the fat solubilization effect of repeated injections is better than that of single injections.

[0582] In summary, compared with Comparative Example 1, Comparative Example 3, and Comparative Example 4 (which do not contain a release regulator), the composition of the present invention has better safety and efficacy.

[0583] Experimental Example 7: Determination of the release of the composition at the injection site

[0584] Experimental animals: 12-week-old male C57BL / 6 mice

[0585] Experimental process:

[0586] The composition (0.2 mL, n=2) was injected subcutaneously into the groin of mice. The mice were dissected at 6, 24, 48, 72, 96, 120, and 168 hours. The preparation at the injection site was removed and dissolved with an appropriate amount of isopropanol. The mixture was thoroughly vortexed and sonicated to dissolve all deoxycholic acid in the isopropanol. The mixture was centrifuged at 10,000 rpm for 15 minutes. The entire supernatant was sampled and analyzed to calculate the residual amount of deoxycholic acid in the reservoir.

[0587] All data were analyzed using GraphPad Prism 9.0 software.

[0588] The results of drug residues are shown in Table 29 and Figure 19 shown.

[0589] Table 29. Results of drug residues at the injection site of the composition

[0590] Time / h % drug residue at the injection site 6 89.08 24 49.58 48 34.93 74 30.72 96 22.57 120 16.61 168 4.76

[0591] The results show that the composition of the present application can slowly release the drug at the injection site.

[0592] Experimental Example 8: Safety and efficacy investigation in pigs

[0593] Experimental animals: Bama piglets, ~10 kg.

[0594] Experimental grouping and dosage: Six 2*3cm areas were selected on the piglet's back for hair removal and disinfection. Each area was divided into 6 grids with an interval of 1cm, such as Figure 20 shown.

[0595] exist Figure 20 The same composition was subcutaneously injected at the center point position within each grid shown in . The experimental groups and doses are shown in Table 30.

[0596] Table 30. Dosage information for in vivo pig studies

[0597] Group Single point medicine volume Saline placebo 0.4ml Comparative Example 1 0.4ml Comparative Example 2 0.08ml Proliposome 7 0.4ml Oil solution 5 0.4ml In situ gel 5 0.4ml

[0598] The experimental pigs were treated as follows:

[0599] 1. Gross observation of the injection site: The injection site of the piglets was photographed and recorded at different time points after injection; no obvious abnormalities were found in any group.

[0600] 2. Determination of fat reduction effect and drug residue at the injection site: The animals were sacrificed 7 days after injection, and the tissue at the injection site was separated to observe the fat dissolution. The volume of the fat dissolution cavity was determined by water injection method; the drug residue at the injection site was determined. The results of the fat dissolution cavity volume determination at the administration site of different groups are shown in Table 31, the drug residue results at the injection site of different groups are shown in Table 32, and the tissue dissolution at the injection site of different groups are shown in Table 33. Figure 21 shown.

[0601] Table 31. Fat reduction results at injection sites in different groups

[0602] Group Fat dissolution cavity volume ml Comparative Example 1 0.48 Comparative Example 2 0.25 Proliposome 7 1.21 Oil solution 5 1.55 In situ gel 5 1.72

[0603] Table 32. Drug residues at injection sites in different groups

[0604] Group Drug residue at the injection site Comparative Example 1 Not detected Comparative Example 2 50.25％ Proliposome 7 1.20％ Oil solution 5 1.34％ In situ gel 5 0.78％

[0605] From the above table and Figure 21 The results show that the cavitation phenomenon and fat thickness reduction caused by fat dissolution at the administration site of the non-aqueous liposoluble preparations of different dosage forms are more obvious than those of Comparative Example 1 and Comparative Example 2; at the same dose, the fat dissolution cavity volume of the non-aqueous liposoluble preparations of different dosage forms is at least 1 times higher than that of Comparative Example 1, and at least 4 times higher than that of Comparative Example 2. Drug residues were still detectable at the injection site of the piglets injected with the non-aqueous liposoluble preparations of different dosage forms 7 days after administration, while no drug residues were detected in the Comparative Example 1 group, and the tissue residue at the injection site of Comparative Example 2 was greater than 50%, indicating that the non-aqueous liposoluble preparations of different dosage forms provided in the present application can slowly release the drug at the administration site, and this release behavior can ensure that the safety and efficacy of the non-aqueous preparations of the present application are better in pigs.

[0606] 3. Observation of pathological morphology at the injection site: The animals were sacrificed 7 days after injection, and the tissues at the injection site were paraffin-sectioned and stained with HE to observe the morphology. The results were as follows: Figure 22 As shown. Among them, Figure 22 A is a blank adipose tissue section, B is a pathological section of adipose tissue corresponding to group 1 of comparative example, C is a pathological section of adipose tissue corresponding to group 2 of comparative example, D is a pathological section of adipose tissue corresponding to 7 groups of proliposomes, E is a pathological section of adipose tissue corresponding to 5 groups of oil solutions, and F is a pathological section of adipose tissue corresponding to 5 groups of in situ gels.

[0607] Depend on Figure 22 It can be seen that the overall structure of the adipose tissue in the blank fat group is normal, the adipocyte vacuoles are full, and no atrophy is observed. The groups with different dosage forms of non-aqueous liposoluble preparations showed obvious adipocyte rupture, the adipose tissue showed vacuoles, and a loose reticular structure appeared, which was more obvious than that of Comparative Example 1 and Comparative Example 2, indicating that the lipolysis effect of the non-aqueous liposoluble preparations of different dosage forms provided by the present application is better than that of Comparative Example 1 and Comparative Example 2. A large amount of inflammatory cell infiltration appeared in the injection groups of Comparative Example 1 and Comparative Example 2, and the phenomenon was more obvious than that of the non-aqueous liposoluble preparation groups of different dosage forms, indicating that the safety of the non-aqueous liposoluble preparations of different dosage forms of the present application is better.

[0608] Experimental Example 9: Safety and efficacy investigation in pigs

[0609] Experimental animals: Bama pigs, ~30 kg.

[0610] Experimental grouping and dosage: Six 2*3cm areas were selected on the piglet's back for hair removal and disinfection. Each area was divided into 6 grids with an interval of 1cm, such as Figure 20 shown.

[0611] exist Figure 20 The same composition was subcutaneously injected at the center point of each grid shown in FIG. 4 , once every other week for four consecutive injections, and the injection site was dissected 28 days after the last injection. The experimental groups and dosages are shown in Table 33.

[0612] Table 33. Dosage information for in vivo pig studies

[0613]

[0614]

[0615] The experimental pigs were treated as follows:

[0616] 1. Gross observation of the injection site: The injection site of the piglets was photographed and recorded at different time points after injection; no obvious abnormalities were found in any group.

[0617] 2. Fat Reduction Effect and Drug Residue at the Injection Site: Animals were sacrificed 28 days after the last injection. Tissues at the injection site were isolated and fat dissolution observed. Fat thickness at the injection site and surrounding areas was measured, and changes in fat thickness were calculated. The results of fat thickness measurements at the injection site for different groups are shown in Table 34.

[0618] Table 34. Fat reduction results at injection sites in different groups

[0619] Group Fat thickness reduction Comparative Example 1 12.62％ Comparative Example 2 11.15％ Proliposome 15 25.88％ Oil solution 6 26.56％ In situ gel 2 27.46％

[0620] As can be seen from the results in the table above, the fat dissolution at the administration site of the non-aqueous liposoluble preparations of different dosage forms resulted in a more significant reduction in fat thickness than that of Comparative Examples 1 and 2. At the same dose, the fat thickness reduction results of the non-aqueous liposoluble preparations of different dosage forms were at least 1-fold higher than those of Comparative Examples 1 and 2. Combined with the in vitro release data, the non-aqueous liposoluble preparations of different dosage forms provided in this application have reasonable release behaviors, ensuring that they are safer and more effective in pigs than those of Comparative Examples 1 and 2.

[0621] In summary, it can be seen that the non-aqueous liposoluble preparations of different dosage forms in the present application have better fat dissolving effects on piglets than Comparative Example 1 and Comparative Example 2. At the same dose, the fat dissolving effects of the non-aqueous liposoluble preparations of different dosage forms are at least 1 times higher than those of Comparative Example 1 and Comparative Example 2; the non-aqueous liposoluble preparations of different dosage forms in the present application can slowly release the drug at the administration site, the drug release time can reach 7 days, and the safety is significantly better than Comparative Example 1 and Comparative Example 2.

[0622] The technical features of the above-mentioned embodiments can be combined arbitrarily. In order to make the description concise, not all possible combinations of the technical features in the above-mentioned embodiments are described. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the scope of this specification.

[0623] The above-described embodiments merely represent several implementation methods of the present application. While the descriptions are relatively specific and detailed, they should not be construed as limiting the scope of the present invention. It should be noted that a person skilled in the art could make various modifications and improvements without departing from the spirit of the present application, all of which fall within the scope of protection of the present application. Therefore, the scope of protection of the present patent application shall be determined by the appended claims.

Claims

1. A non-aqueous fat-soluble preparation, characterized in that: The active ingredient of the non-aqueous lipolysis preparation includes one or more of deoxycholic acid, pharmaceutically acceptable salts of deoxycholic acid, and deoxycholic acid derivatives; In a release medium with a pH value of 7.4 that meets the sink conditions, at 37°C, the release amount of the active ingredient in 1 hour does not exceed 25% of the total amount of the active ingredient contained in the non-aqueous fat-soluble preparation, and the release amount in 168 hours is greater than 80% of the total amount of the active ingredient contained in the non-aqueous fat-soluble preparation.

2. The non-aqueous fat-soluble preparation according to claim 1, characterized in that In a release medium with a pH value of 7.4 that meets the sink conditions, at 37°C, the release amount of the active ingredient in 1 hour does not exceed 20% of the total amount of the active ingredient contained in the non-aqueous fat-soluble preparation, and the release amount in 168 hours is greater than 85% of the total amount of the active ingredient contained in the non-aqueous fat-soluble preparation.

3. The non-aqueous fat-soluble preparation according to any one of claims 1 to 2, characterized in that: The dosage form of the non-aqueous liposoluble preparation includes one or more of proliposomes, oil solutions and in situ gels; Optionally, the dosage form of the non-aqueous liposoluble preparation includes one or more of proliposomes, oil solutions and in situ gels for injection or implantation; Optionally, the active ingredient remaining in the tissue of the non-aqueous liposoluble preparation 168 hours after the first single injection in vivo does not exceed 30% of the total amount of the active ingredient of the administered non-aqueous liposoluble preparation.

4. The non-aqueous fat-soluble preparation according to claim 3, characterized in that The non-aqueous liposoluble preparation is a proliposome, and the components of the proliposome include an active ingredient, a pharmaceutical phospholipid, a release regulator, a pharmaceutical solvent, and an optional chelating agent; Optionally, the non-aqueous liposoluble preparation has at least one of the following characteristics: (1) The non-aqueous fat-soluble preparation comprises, by weight: 0.1-5 parts by weight of an active ingredient, 15-60 parts by weight of a pharmaceutical phospholipid, 5-65 parts by weight of a release regulator, 5-40 parts by weight of a pharmaceutical solvent, and 0-0.001 parts by weight of a chelating agent; (2) The non-aqueous fat-soluble preparation comprises, by weight: 0.1-3 parts by weight of an active ingredient, 20-50 parts by weight of a pharmaceutical phospholipid, 10-63 parts by weight of a release modifier, 10-40 parts by weight of a pharmaceutical solvent, and 0-0.001 parts by weight of a chelating agent; (3) The non-aqueous fat-soluble preparation comprises, by weight: 0.5-3 parts by weight of an active ingredient, 25-50 parts by weight of a pharmaceutical phospholipid, 15-63 parts by weight of a release modifier, 10-30 parts by weight of a pharmaceutical solvent, and 0-0.001 parts by weight of a chelating agent; (4) The pharmaceutical phospholipids include a combination of one or more of pharmaceutically acceptable natural phospholipids, semi-synthetic phospholipids and synthetic phospholipids; one or more of the natural phospholipids may be selected; Optionally, the natural phospholipids include one or more of egg yolk lecithin and soybean lecithin; Optionally, the semi-synthetic phospholipids include one or more of hydrogenated egg yolk lecithin and hydrogenated soybean lecithin; Optionally, the synthetic phospholipids include one or more of dipalmitoylphosphatidylcholine (DPPC), distearoylphosphatidylcholine (DSPC), dimyristoylphosphatidylcholine (DMPC), dilauroylphosphatidylcholine (DLPC), dioleoylphosphatidylcholine (DOPC), dipalmitoylphosphatidylethanolamine (DPPE), dipalmitoylphosphatidylglycerol (DPPG), and dioleoylphosphatidylethanolamine (DOPE); (5) The release modifier includes one or more of methyl oleate, ethyl oleate, propyl oleate, butyl oleate, 2-butyl oleate, isopropyl oleate, hexyl oleate, octyl oleate, monoolein, diolein, triolein, isopropyl myristate, triethyl citrate, linolenic acid, diethyl sebacate, phytantriol, natural plant oil, semi-natural plant oil and synthetic oil; more preferably, it can be one or more of ethyl oleate, monoolein, diolein, triolein, natural plant oil and synthetic oil; Optionally, the natural vegetable oil includes one or more of castor oil, sesame oil, soybean oil, sunflower oil, peanut oil, corn oil, rapeseed oil, olive oil and cottonseed oil; Optionally, the semi-natural vegetable oil comprises hydrogenated castor oil; Optionally, the artificial synthetic oil includes one or more of medium-chain triglycerides, long-chain triglycerides, triacetin and derivatives of the above substances; more optionally, the medium-chain triglycerides include one or more of caprylic triglyceride and capric triglyceride; (6) The pharmaceutical solvent includes one or more of benzyl alcohol, ethanol, propylene glycol, glycerol, isopropanol, N-methylpyrrolidone, dimethyl sulfoxide, liquid polyethylene glycol, dimethylacetamide, monoacetin, polyethylene glycol (mono) methyl ether, diethylene glycol monoethyl ether, ethyl lactate, ethyl acetate, propylene glycol diethyl ester, diethyl malonate, tetrahydrofuran polyethylene glycol ether and benzyl benzoate; it can be one or more of benzyl alcohol, propylene glycol, ethanol, benzyl benzoate, dimethyl sulfoxide, N-methylpyrrolidone and dimethylacetamide; (7) The chelating agent includes ethylenediaminetetraacetic acid.

5. The non-aqueous fat-soluble preparation according to claim 3, characterized in that: The non-aqueous fat-soluble preparation is an oil solution, and the ingredients of the non-aqueous fat-soluble preparation include active ingredients, pharmaceutical solvents, release regulators and optional small molecule regulators; Optionally, the non-aqueous liposoluble preparation has at least one of the following characteristics: (1) The non-aqueous fat-soluble preparation comprises, by weight: 0.1-5 parts by weight of an active ingredient, 5-50 parts by weight of a pharmaceutical solvent, 50-90 parts by weight of a release modifier, and 0-10 parts by weight of a small molecule modifier; (2) The non-aqueous fat-soluble preparation comprises, by weight: 0.1-3 parts by weight of an active ingredient, 10-40 parts by weight of a pharmaceutical solvent, 55-90 parts by weight of a release modifier, and optionally 0.1-5 parts by weight of a small molecule modifier; (3) In parts by weight, the non-aqueous fat-soluble preparation comprises: 0.5-3 parts by weight of an active ingredient, 10-30 parts by weight of a pharmaceutical solvent, 69-90 parts by weight of a release modifier, and optionally 0.1-3 parts by weight of a small molecule modifier; (4) In parts by weight, the non-aqueous fat-soluble preparation comprises: 0.5-3 parts by weight of an active ingredient, 10-30 parts by weight of a pharmaceutical solvent, 69-90 parts by weight of a release modifier, and optionally 0.1-1 parts by weight of a small molecule modifier; (5) The release modifier includes one or more of methyl oleate, ethyl oleate, propyl oleate, butyl oleate, 2-butyl oleate, isopropyl oleate, hexyl oleate, octyl oleate, monoolein, diolein, triolein, isopropyl myristate, triethyl citrate, linolenic acid, diethyl sebacate, phytantriol, natural plant oil, semi-natural oil and synthetic oil; more preferably, it can be one or more of ethyl oleate, monoolein, diolein, triolein, natural plant oil and synthetic oil; Optionally, the natural vegetable oil includes one or more of castor oil, sesame oil, soybean oil, sunflower oil, peanut oil, corn oil, rapeseed oil, olive oil and cottonseed oil; Optionally, the semi-natural oil comprises hydrogenated castor oil; Optionally, the artificial synthetic oil includes one or more of medium-chain triglycerides, long-chain triglycerides, triacetin and derivatives thereof; more preferably, the medium-chain triglycerides include one or more of caprylic triglyceride and capric triglyceride; (6) The pharmaceutical solvent includes one or more of benzyl alcohol, chlorobutanol, dimethyl sulfoxide, N-methylpyrrolidone, dimethylacetamide, propylene glycol, polyethylene glycol, polyethylene glycol (mono) methyl ether, benzyl benzoate, glycerol aldehyde, glycerol formal, ethanol and ethylene glycol diethyl ether; it can be one or more of benzyl alcohol, benzyl benzoate, dimethyl sulfoxide, N-methylpyrrolidone and dimethylacetamide; (7) The small molecule regulator includes one or more of sodium phosphate, disodium hydrogen phosphate, sodium dihydrogen phosphate, potassium phosphate, dipotassium hydrogen phosphate, potassium dihydrogen phosphate, sodium carbonate, sodium bicarbonate, meglumine, arginine, triethanolamine, citric acid, sodium chloride, glucose and mannitol.

6. The non-aqueous fat-soluble preparation according to claim 3, characterized in that The non-aqueous liposoluble preparation is an in-situ gel, and the ingredients of the non-aqueous liposoluble preparation include active ingredients, pharmaceutical solvents and release regulators; Optionally, the non-aqueous liposoluble preparation has at least one of the following characteristics: (1) The non-aqueous fat-soluble preparation comprises, by weight: 0.1-5 parts by weight of an active ingredient, 50-90 parts by weight of a pharmaceutical solvent, and 5-40 parts by weight of a release modifier; (2) The non-aqueous fat-soluble preparation comprises, by weight: 0.1-3 parts by weight of an active ingredient, 60-85 parts by weight of a pharmaceutical solvent, and 10-30 parts by weight of a release modifier; (3) In parts by weight, the non-aqueous fat-soluble preparation comprises: 0.5-3 parts by weight of an active ingredient, 69-85 parts by weight of a pharmaceutical solvent, and 13-30 parts by weight of a release modifier; (4) The release modifier includes one or more of pharmaceutically acceptable biodegradable polymers; it may be selected from one or more of polylactic acid, polylactic acid-co-glycolic acid copolymer, polyorthoester, sucrose acetate-isobutyrate, fatty acid glyceride, pegylated PLA / PLGA, PLGA-PEG-PLGA copolymer, polycaprolactone-polyethylene glycol copolymer, triethylene glycol poly (orthoester) polymer, poloxamer and other pharmaceutically acceptable sustained-release materials for local injection; it may be further selected from one or more of polylactic acid, polylactic acid-co-glycolic acid copolymer, polyorthoester, sucrose acetate-isobutyrate, pegylated PLA / PLGA, PLGA-PEG-PLGA copolymer and poloxamer; (5) The pharmaceutical solvent includes one or more of N-methylpyrrolidone, polyethylene glycol (mono) methyl ether, glyceryl triacetate, benzyl benzoate, glycerol aldehyde, glycerol formal, propylene glycol, ethanol, ethylene glycol diethyl ether, benzyl alcohol, dimethyl sulfoxide and other pharmaceutically acceptable organic solvents; it can be selected from one or more of N-methylpyrrolidone, polyethylene glycol (mono) methyl ether, benzyl benzoate, benzyl alcohol, dimethyl sulfoxide, propylene glycol and ethanol.

7. The non-aqueous fat-soluble preparation according to claim 3, characterized in that The non-aqueous liposoluble preparation is a proliposome, and the components of the proliposome include an active ingredient, a pharmaceutical phospholipid, a release regulator, a pharmaceutical solvent, and optional small molecule regulators and chelating agents; Optionally, the non-aqueous liposoluble preparation has at least one of the following characteristics: (1) The non-aqueous fat-soluble preparation comprises, by weight: 0.1-5 parts by weight of an active ingredient, 15-60 parts by weight of a pharmaceutical phospholipid, 5-80 parts by weight of a release regulator, 0-40 parts by weight of a pharmaceutical solvent, 0-1 parts by weight of a small molecule regulator, and 0-0.001 parts by weight of a chelating agent; (2) The non-aqueous liposoluble preparation comprises, by weight: 0.1-4 parts by weight of an active ingredient, 20-60 parts by weight of a pharmaceutical phospholipid, 10-77 parts by weight of a release modifier, 8-40 parts by weight of a pharmaceutical solvent, 0-1 parts by weight of a small molecule modifier, and 0-0.001 parts by weight of a chelating agent; (3) The non-aqueous fat-soluble preparation comprises, by weight: 0.2-3 parts by weight of an active ingredient, 25-55 parts by weight of a pharmaceutical phospholipid, 15-65 parts by weight of a release modifier, 10-35 parts by weight of a pharmaceutical solvent, 0-1 parts by weight of a small molecule modifier, and 0-0.001 parts by weight of a chelating agent; (4) The pharmaceutical lecithin includes one or more combinations of pharmaceutically acceptable natural lecithin, semi-synthetic lecithin and synthetic lecithin; Optionally, the natural phospholipids include one or more of egg yolk lecithin and soybean lecithin; Optionally, the semi-synthetic phospholipids include one or more of hydrogenated egg yolk lecithin and hydrogenated soybean lecithin; Optionally, the synthetic phospholipids include one or more of dipalmitoylphosphatidylcholine (DPPC), distearoylphosphatidylcholine (DSPC), dimyristoylphosphatidylcholine (DMPC), dilauroylphosphatidylcholine (DLPC), dioleoylphosphatidylcholine (DOPC), dipalmitoylphosphatidylethanolamine (DPPE), dipalmitoylphosphatidylglycerol (DPPG), and dioleoylphosphatidylethanolamine (DOPE); (5) The release modifiers include methyl oleate, ethyl oleate, propyl oleate, butyl oleate, 2-butyl oleate, isopropyl oleate, hexyl oleate, octyl oleate, glyceryl monooleate, glyceryl dioleate, glyceryl trioleate, propylene glycol monocaprylate, propylene glycol dicaprylate / dicaprate, propylene glycol laurate, propylene glycol alginate, caprylic capric acid mono- and di-glyceryl, caprylic capric acid mono- and tri-glyceryl, caprylic capric acid polyethylene glycol glyceride, ricinoleic acid monoglyceride, and mono- and di-glyceryl caprylate. One or more of oleic acid glyceryl, oleoyl polyoxyethylene glyceride, diacetyl monoglyceride, mono-distearic acid glyceryl, monostearic acid glyceryl, tricaprylic acid glyceryl, tricapric acid glyceryl, behenic acid glyceryl, triacetin, isopropyl myristate, triethyl citrate, linolenic acid, diethyl sebacate, phytantriol, medium chain triglycerides, fish oil, algae oil, ethyl caprylate, ethyl caprate, ethyl linoleate, isopropyl linoleate, natural plant oil and semi-natural plant oil; Optionally, the release modifier comprises one or more of ethyl oleate, monoolein, diolein, triolein, propylene glycol monocaprylate, propylene glycol dicaprylate / dicaprate, propylene glycol laurate, propylene glycol alginate, caprylic and capric mono- and diglycerides, monolinolein, triacetin, medium chain triglycerides, fish oil, algae oil, and natural plant oils; Optionally, the natural vegetable oil includes one or more of castor oil, sesame oil, soybean oil, sunflower oil, peanut oil, corn oil, rapeseed oil, olive oil, cottonseed oil, linseed oil, perilla seed oil, walnut oil, argan oil, and laver oil; Optionally, the semi-natural vegetable oil comprises hydrogenated castor oil; Optionally, the release modifier comprises one or more of ethyl oleate, monoolein, diolein, triolein, propylene glycol monocaprylate, propylene glycol dicaprylate / dicaprate, caprylic and capric mono- and diglycerides, monolinolein, triacetin, medium chain triglycerides, fish oil, algae oil, castor oil, sesame oil, soybean oil, peanut oil, corn oil, olive oil, cottonseed oil, linseed oil, perilla seed oil, walnut oil, argan oil, and laver oil; (6) the pharmaceutically acceptable solvent includes one or more of benzyl alcohol, ethanol, propylene glycol, glycerol, isopropyl alcohol, N-methylpyrrolidone, dimethyl sulfoxide, liquid polyethylene glycol, dimethylacetamide, monoacetin, polyethylene glycol (mono) methyl ether, diethylene glycol monoethyl ether, ethyl lactate, ethyl acetate, propylene glycol diethyl ester, tetrahydrofuran polyethylene glycol ether and benzyl benzoate; Optionally, the pharmaceutically acceptable solvent includes one or more of benzyl alcohol, propylene glycol, ethanol, benzyl benzoate, dimethyl sulfoxide, liquid polyethylene glycol, N-methylpyrrolidone and dimethylacetamide; Optionally, the pharmaceutically acceptable solvent includes one or more of benzyl alcohol, propylene glycol, ethanol, benzyl benzoate, dimethyl sulfoxide, N-methylpyrrolidone and dimethylacetamide; (7) The chelating agent includes one or more of EDTA, EDTA disodium and EDTA calcium disodium; (8) The small molecule regulator includes an acid-base regulator and an antioxidant; The acid-base regulator includes one or more of sodium hydroxide, meglumine, arginine, lysine, histidine, glycine, tromethamine, diethanolamine, ethylenediamine, hydrochloric acid, acetic acid, anhydrous citric acid, ascorbic acid, lactic acid, tartaric acid, methanesulfonic acid, methionine, and triethanolamine; The antioxidant includes one or more of cysteine, α-tocopherol, α-tocopherol acetate, N-acetyl-L-cysteine, butylated hydroxyanisole, dibutyl hydroxytoluene, propyl gallate, tert-butylhydroquinone, lipoic acid, tea polyphenols, L-ascorbyl palmitate, and glutathione.

8. The non-aqueous fat-soluble preparation according to claim 3, characterized in that The non-aqueous fat-soluble preparation is an oil solution, and the ingredients of the non-aqueous fat-soluble preparation include active ingredients, pharmaceutical solvents, release regulators and optional small molecule regulators; Optionally, the non-aqueous liposoluble preparation has at least one of the following characteristics: (1) The non-aqueous fat-soluble preparation comprises, by weight: 0.1-5 parts by weight of an active ingredient, 0-50 parts by weight of a pharmaceutical solvent, 45-95 parts by weight of a release modifier, and 0-10 parts by weight of a small molecule modifier; (2) The non-aqueous fat-soluble preparation comprises, by weight: 0.1-4 parts by weight of an active ingredient, 10-40 parts by weight of a pharmaceutical solvent, 55-90 parts by weight of a release modifier, and optionally 0-5 parts by weight of a small molecule modifier; (3) The non-aqueous fat-soluble preparation comprises, by weight: 0.2-3 parts by weight of an active ingredient, 10-35 parts by weight of a pharmaceutical solvent, 60-90 parts by weight of a release modifier, and optionally 0-3 parts by weight of a small molecule modifier; (4) In parts by weight, the non-aqueous fat-soluble preparation comprises: 0.5-3 parts by weight of an active ingredient, 10-30 parts by weight of a pharmaceutical solvent, 69-90 parts by weight of a release modifier, and optionally 0-1 part by weight of a small molecule modifier; (5) The release modifiers include methyl oleate, ethyl oleate, propyl oleate, butyl oleate, 2-butyl oleate, isopropyl oleate, hexyl oleate, octyl oleate, glyceryl monooleate, glyceryl dioleate, glyceryl trioleate, propylene glycol monocaprylate, propylene glycol dicaprylate / dicaprate, propylene glycol laurate, propylene glycol alginate, caprylic capric acid mono- and di-glyceryl, caprylic capric acid mono- and tri-glyceryl, caprylic capric acid polyethylene glycol glyceride, ricinoleic acid monoglyceride, and mono- and di-glyceryl caprylate. One or more of oleic acid glyceryl, oleoyl polyoxyethylene glyceride, diacetyl monoglyceride, mono-distearic acid glyceryl, monostearic acid glyceryl, tricaprylic acid glyceryl, tricapric acid glyceryl, behenic acid glyceryl, triacetin, isopropyl myristate, triethyl citrate, linolenic acid, diethyl sebacate, phytantriol, medium chain triglycerides, fish oil, algae oil, ethyl caprylate, ethyl caprate, ethyl linoleate, isopropyl linoleate, natural plant oil and semi-natural plant oil; Optionally, the release modifier comprises one or more of ethyl oleate, monoolein, diolein, triolein, propylene glycol monocaprylate, propylene glycol dicaprylate / dicaprate, propylene glycol laurate, propylene glycol alginate, caprylic and capric mono- and diglycerides, monolinolein, triacetin, medium chain triglycerides and natural vegetable oils; Optionally, the natural vegetable oil includes one or more of castor oil, sesame oil, soybean oil, sunflower oil, peanut oil, corn oil, rapeseed oil, olive oil, cottonseed oil, linseed oil, perilla seed oil, walnut oil, argan oil, and laver oil; Optionally, the semi-natural oil comprises hydrogenated castor oil; Optionally, the release modifier comprises one or more of ethyl oleate, monoolein, diolein, triolein, propylene glycol monocaprylate, propylene glycol dicaprylate / dicaprate, caprylic and capric mono- and diglycerides, monolinolein, triacetin, medium chain triglycerides, fish oil, algae oil, castor oil, sesame oil, soybean oil, peanut oil, corn oil, olive oil, cottonseed oil, linseed oil, perilla seed oil, walnut oil, argan oil, and laver oil; (6) The pharmaceutically acceptable solvent includes one or more of benzyl alcohol, ethanol, propylene glycol, glycerol, isopropyl alcohol, N-methylpyrrolidone, dimethyl sulfoxide, liquid polyethylene glycol, dimethylacetamide, glycerol monoacetate, polyethylene glycol (mono) methyl ether, diethylene glycol monoethyl ether, ethylene glycol diethyl ether, glycerol aldehyde, glycerol formal, chlorobutanol, ethyl lactate, ethyl acetate, propylene glycol diethyl ester, tetrahydrofuran glycol ether and benzyl benzoate; Optionally, the pharmaceutically acceptable solvent includes one or more of benzyl alcohol, propylene glycol, ethanol, benzyl benzoate, dimethyl sulfoxide, liquid polyethylene glycol, N-methylpyrrolidone and dimethylacetamide; Optionally, the pharmaceutically acceptable solvent includes one or more of benzyl alcohol, propylene glycol, ethanol, benzyl benzoate, dimethyl sulfoxide, N-methylpyrrolidone and dimethylacetamide; (7) The small molecule regulator includes one or more of sodium phosphate, disodium hydrogen phosphate, sodium dihydrogen phosphate, potassium phosphate, dipotassium hydrogen phosphate, potassium dihydrogen phosphate, sodium carbonate, sodium bicarbonate, sodium hydroxide, meglumine, arginine, lysine, histidine, tromethamine, diethanolamine, ethylenediamine, hydrochloric acid, acetic acid, ascorbic acid, lactic acid, tartaric acid, methanesulfonic acid, methionine, cysteine, α-tocopherol, α-tocopherol acetate, N-acetyl-L-cysteine, butylated hydroxyanisole, dibutyl hydroxytoluene, propyl gallate, tert-butylhydroquinone, lipoic acid, tea polyphenols, L-ascorbyl palmitate, glutathione, triethanolamine, citric acid, sodium chloride, glucose and mannitol; Optionally, the small molecule regulator includes one or more of meglumine, tromethamine, triethanolamine, sodium hydroxide, disodium hydrogen phosphate, potassium dihydrogen phosphate, sodium carbonate, sodium bicarbonate, arginine, lysine, histidine, α-tocopherol, α-tocopherol acetate, butylated hydroxyanisole, dibutyl hydroxytoluene, L-ascorbyl palmitate, and glutathione; Optionally, the small molecule regulator includes one or more of meglumine, tromethamine, arginine, lysine, histidine, α-tocopherol, α-tocopherol acetate, butylated hydroxyanisole, L-ascorbyl palmitate, and glutathione.

9. The non-aqueous fat-soluble preparation according to claim 3, characterized in that: The non-aqueous liposoluble preparation is an in-situ gel, and the ingredients of the non-aqueous liposoluble preparation include active ingredients, pharmaceutical solvents and release regulators; Optionally, the non-aqueous liposoluble preparation has at least one of the following characteristics: (1) The non-aqueous fat-soluble preparation comprises, by weight: 0.1-10 parts by weight of an active ingredient, 10-95 parts by weight of a pharmaceutical solvent, and 5-90 parts by weight of a release modifier; (2) The non-aqueous fat-soluble preparation comprises, by weight: 0.1-8 parts by weight of an active ingredient, 20-90 parts by weight of a pharmaceutical solvent, and 10-75 parts by weight of a release modifier; (3) The non-aqueous fat-soluble preparation comprises, by weight: 0.5-6 parts by weight of an active ingredient, 30-85 parts by weight of a pharmaceutical solvent, and 13-60 parts by weight of a release modifier; (4) The release modifier includes one or more pharmaceutically acceptable biodegradable polymers; it may be polylactic acid, polylactic acid-co-glycolic acid, polyorthoesters, sucrose acetate-isobutyrate, fatty acid glycerides, pegylated PLA / PLGA, PLGA-PEG-PLGA copolymers, polycaprolactone-polyethylene glycol copolymers, triethylene glycol poly(orthoester) polymers, poloxamers, and other pharmaceutically acceptable sustained-release materials for local injection; Optionally, the release modifier comprises one or more of polylactic acid, polylactic acid-co-glycolic acid, polyorthoester, sucrose acetate-isobutyrate, pegylated PLA / PLGA, PLGA-PEG-PLGA copolymer, polycaprolactone-co-polyethylene glycol, and poloxamer; Optionally, the release modifier comprises one or more of polylactic acid, polylactic acid-co-glycolic acid, polyorthoester, sucrose acetate-isobutyrate, pegylated PLA / PLGA, PLGA-PEG-PLGA copolymer and poloxamer; (5) The pharmaceutically acceptable solvent includes one or more of N-methylpyrrolidone, polyethylene glycol (mono) methyl ether, triacetin, benzyl benzoate, glycerol aldehyde, glycerol formal, propylene glycol, ethanol, ethylene glycol diethyl ether, benzyl alcohol, dimethyl sulfoxide, liquid polyethylene glycol, dimethylacetamide and other pharmaceutically acceptable organic solvents; Optionally, the pharmaceutically acceptable solvent includes one or more of N-methylpyrrolidone, polyethylene glycol (mono) methyl ether, benzyl benzoate, benzyl alcohol, dimethyl sulfoxide, ethylene glycol diethyl ether, propylene glycol and ethanol; Optionally, the pharmaceutically acceptable solvent includes one or more of N-methylpyrrolidone, polyethylene glycol (mono) methyl ether, benzyl benzoate, benzyl alcohol, dimethyl sulfoxide, propylene glycol and ethanol.

10. The non-aqueous fat-soluble preparation according to any one of claims 1 to 9, characterized in that: The non-aqueous lipolysis preparation has at least one of the following characteristics: (1) The deoxycholate salt comprises sodium deoxycholate; the deoxycholic acid derivative comprises one or more of ursodeoxycholic acid, hyodeoxycholic acid, and chenodeoxycholic acid; (2) Based on the active ingredient, the dosage of the non-aqueous fat-soluble preparation is 0.1 mg-1000 mg; optionally 1 mg-500 mg.

11. The non-aqueous fat-soluble preparation according to any one of claims 1 to 9, characterized in that: The non-aqueous lipolysis preparation has at least one of the following characteristics: (1) the deoxycholate comprises sodium deoxycholate; the deoxycholic acid derivative comprises one or more of ursodeoxycholic acid, hyodeoxycholic acid, chenodeoxycholic acid, sodium ursodeoxycholate, sodium hyodeoxycholate, sodium chenodeoxycholate, cholic acid, sodium cholate, glycocholic acid, sodium glycocholate, glycodeoxycholic acid, sodium glycodeoxycholate, taurocholic acid, sodium taurocholate, glycotaurocholic acid, sodium glycotaurocholate, lithocholic acid, sodium lithocholic acid, sodium glycochenodeoxycholate, sodium phenylpropanecholate, sodium caseocholate, sodium leucocholic acid, bile acid dimer, bile acid side chain amino acid conjugate, bile acid side chain PEG conjugate, bile acid side chain glucose conjugate; (2) Based on the active ingredient, the dosage of the non-aqueous fat-soluble preparation is 0.1 mg-1000 mg; optionally 1 mg-500 mg.

12. Use of the non-aqueous fat-soluble preparation according to any one of claims 1 to 10 in preparing a preparation having the effect of dissolving fat cells; Optionally, the preparation having the effect of dissolving fat cells includes an injection preparation and / or an implant preparation; More optionally, the administration sites of the injection preparation and / or the implant preparation include one or more of the abdomen, under the eyes, under the hips, under the arms, buttocks, thighs, calves, back, bra line, armpits, stomach and ankles.

13. An injection preparation, characterized in that: The injection preparation is prepared from the non-aqueous liposoluble preparation according to any one of claims 1 to 10; Optionally, the injection preparation is administered by one or more of subcutaneous injection and intramuscular injection; subcutaneous injection may be selected.

14. An implant preparation, characterized in that: The implant preparation is prepared from the non-aqueous liposoluble preparation according to any one of claims 1 to 10.

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