Fat-dissolving composition and use thereof

Abstract

The present invention provides a fat-dissolving composition and a use thereof. The fat-dissolving composition of the present invention comprises a pharmaceutically active ingredient, an inclusion material, a pH regulator optionally selected from one or more of a buffer, a stabilizer, an osmotic pressure regulator, and a complexing agent, and optionally purified water, wherein the pharmaceutically active ingredient is selected from one or more of deoxycholic acid, a pharmaceutically acceptable salt of deoxycholic acid, and a deoxycholic acid derivative, and the amount of the inclusion material ranges from 4% to 35% on the basis of the total weight of the fat-dissolving composition. Compared with conventional formulations at the same dose, the fat-dissolving composition of the present invention can significantly reduce adverse effects at the administration site while having a good fat-dissolving effect, and has higher safety.

Description

A lipolysis composition and application thereof TECHNICAL FIELD

[0001] The present application relates to the technical field of injection lipolysis pharmaceutical formulations, in particular to a lipolysis composition and application thereof, and an injection formulation. BACKGROUND

[0002] Injection lipolysis is to inject drugs into subcutaneous adipose tissue to directly destroy fat cells or induce apoptosis of fat cells to achieve the purpose of fat reduction. Compared with liposuction, the requirements for operators are low, no general anesthesia and sterile environment are required, and no skin relaxation, unevenness and other problems have been found, and the treatment risk is significantly reduced. Compared with lipolysis of medical equipment such as cryolipolysis, it has the advantages of lower price, obvious effect, adjustable lipolysis site according to injection depth, and less rebound, and occupies an important position in the field of local fat reduction.

[0003] Deoxycholic acid is a cell lysing drug that can destroy cell membranes and cause cell lysis when injected into body tissues. The currently marketed lipolysis drug Kybella uses deoxycholic acid as the main component and is a conventional injection solution. It is found in clinical use that more than 50% of the subjects have injection site hematomas, pain, edema and numbness, more than 10% of the subjects have injection site swelling, erythema, induration, paresthesia, pruritus and nodules, and some subjects stop taking the drug or discontinue the study due to adverse reactions. The overall incidence of adverse reactions is as high as more than 90%. At the same time, the adverse reactions that occur in clinical practice take at least 4 weeks to recover, resulting in a 4-week drug administration interval. A long drug administration interval will inevitably cause a decrease or even disappearance of drug efficacy, and patients need at least 2 months to see the effect. The serious adverse reactions of this product have severely limited its clinical application.

[0004] CN110302082A discloses a body introduction preparation of deoxycholic acid, which belongs to the field of cosmetics. The preparation is prepared from deoxycholic acid, lipid metabolism related enzymes and tricarboxylic acid cycle related enzymes, and requires the use of multiple compounds for fat reduction. CN104971058B discloses a transdermal administration preparation of deoxycholic acid, which uses hyaluronic acid, adhesives, humectants and penetration enhancers as adjuvants to maintain good mechanical properties and transdermal properties of the deoxycholic acid sodium patch within the effective period, and effectively slows down the deterioration of deoxycholic acid sodium. The above preparations are all transdermal administration, and deoxycholic acid needs to pass through the epidermis and dermis to reach the target tissue, and in this process, the drug will inevitably be lost, causing waste of the drug. In addition, due to the mechanism of action of deoxycholic acid, it will cause damage to the epidermis and dermis, resulting in unnecessary adverse reactions.

[0005] CN115721599A discloses a deoxycholic acid microneedle preparation. By utilizing the characteristics of microneedles that can directly penetrate the skin to reach the target site, the preparation can achieve the effect of targeting fat dissolution and reducing pain. However, the material used in the microneedle has a risk of biocompatibility; the thickness of the skin from fat varies with different obesity levels or different parts, and the same type of microneedle cannot meet the needs of all people, and may cause the risk of administration to the wrong position such as the dermis or nerve tissue, and the use of different types of microneedles will lead to inconvenient clinical use.

[0006] CN116617160A discloses a deoxycholic acid aqueous suspension, which comprises deoxycholic acid, stabilizing agent, suspending agent, buffer and wetting agent. The drug in this patent application is not dissolved, but in a suspended state, which can significantly reduce the plasma peak concentration compared with ordinary injection solution. This patent application lacks specific actual safety and efficacy results, and the PK-PD correlation of the drug is not clear because the drug works locally, and the safety and effectiveness are not clear.

[0007] CN115867321A discloses a deoxycholic acid-peptide conjugate, which is a composition for treating obesity, and the composition contains a pharmaceutically acceptable carrier, excipient and diluent, such as physiological saline, sterile water, Ringer's solution, buffered physiological saline, glucose solution, malt dextrin solution, glycerol or ethanol, etc.; the deoxycholic acid-peptide conjugate is obtained by conjugating the synthesized peptide with deoxycholic acid, and compared with a single substance, it has high solubility in water and significantly improved anti-obesity activity. Although this invention has good lipolysis effect, the peptide is a newly synthesized substance, and its safety in the body is unknown.

[0008] It can be seen that it has important clinical value to develop a safe and effective fat-dissolving preparation. SUMMARY

[0009] Based on the above problems, the present application has obtained a fat-dissolving composition with high safety and effectiveness through research. The composition uses conventional pharmaceutical excipients known to be safe in the art, and the composition has selectivity for fat cell dissolution and has little or no effect on other tissues, while having good fat-dissolving effect, reducing adverse reactions at the administration site and improving the safety of the administration site; the composition can shorten the administration interval, and the administration interval can be determined according to the drug efficacy in clinical practice to ensure good fat-dissolving effect; the composition has simple composition and convenient clinical application.

[0010] The first aspect of the present application provides a fat-dissolving composition, which comprises:

[0011] a pharmaceutically active ingredient,

[0012] a clathrate material,

[0013] pH adjusting agent,

[0014] optionally one or more selected from the group consisting of a buffer, a stabilizer, an osmotic pressure adjusting agent, and a complexing agent, and

[0015] optionally purified water,

[0016] wherein the pharmaceutically active ingredient is one or more selected from the group consisting of deoxycholic acid, a pharmaceutically acceptable salt of deoxycholic acid, and a deoxycholic acid derivative,

[0017] wherein the amount of the inclusion material ranges from 4 to 35% based on the total weight of the lipolytic composition.

[0018] In some embodiments, the inclusion material is one or more selected from the group consisting of cyclodextrin and derivatives thereof; preferably one or more selected from the group consisting of hydroxypropyl-β-cyclodextrin, sulfobutyl-β-cyclodextrin, methyl-β-cyclodextrin, carboxymethyl-β-cyclodextrin, hydroxyethyl-β-cyclodextrin, glucosyl-β-cyclodextrin, hydroxypropyl-γ-cyclodextrin, a-cyclodextrin, 2,6-dimethyl β-cyclodextrin; more preferably one or both of hydroxypropyl-β-cyclodextrin and sulfobutyl-β-cyclodextrin.

[0019] In some embodiments, the cyclodextrin and derivatives thereof include non-ionized form and ionized form and combinations thereof, the ionized form is preferably in the form of a salt, in particular sodium salt or potassium salt; the sulfobutyl-β-cyclodextrin and carboxymethyl-β-cyclodextrin include non-ionized form and ionized form and combinations thereof, the ionized form is preferably in the form of a salt, in particular sodium salt or potassium salt, more particularly, the ionized form of the sulfobutyl-β-cyclodextrin and carboxymethyl-β-cyclodextrin is sulfobutyl-β-cyclodextrin sodium and carboxymethyl-β-cyclodextrin sodium, respectively.

[0020] In some embodiments, the lipolytic composition has at least one of the following characteristics (1)-(10):

[0021] (1) the lipolytic composition comprises 0.1-5% of the pharmaceutically active ingredient, 4-35% of the inclusion material, 0.01-5% of the pH adjusting agent, 0-10% of the stabilizer, 0-5% of the buffer, 0-5% of the osmotic pressure adjusting agent, 0-1% of the complexing agent, and 0-500 ml of purified water per g of the pharmaceutically active ingredient based on the total weight of the lipolytic composition;

[0022] (2) the lipolytic composition comprises 0.2-4% of the pharmaceutically active ingredient, 5-30% of the inclusion material, 0.02-3% of the pH adjusting agent, 0-8% of the stabilizer, 0.01-3% of the buffer, 0-3% of the osmotic pressure adjusting agent, 0-0.8% of the complexing agent, and 0-400 ml of purified water per g of the pharmaceutically active ingredient based on the total weight of the lipolytic composition;

[0023] (3) the fat-dissolving composition comprises 0.3-3% of the pharmaceutical active ingredient, 8-30% of the inclusion material, 0.03-2% of the pH adjuster, 0-5% of the stabilizer, 0.03-2% of the buffer, 0-2% of the osmotic pressure adjuster, 0-0.5% of the complexing agent, and 0-300 ml of purified water per g of the pharmaceutical active ingredient, based on the total weight of the fat-dissolving composition;

[0024] (4) the fat-dissolving composition comprises 0.5-2% of the pharmaceutical active ingredient, 10-28% of the inclusion material, 0.05-1% of the pH adjuster, 0-3% of the stabilizer, 0.05-1% of the buffer, 0-1% of the osmotic pressure adjuster, 0-0.3% of the complexing agent, and 0-200 ml of purified water per g of the pharmaceutical active ingredient, based on the total weight of the fat-dissolving composition;

[0025] (5) the pharmaceutically acceptable salt of deoxycholic acid is sodium deoxycholate; the deoxycholic acid derivative is one or more selected from the group consisting of hyodeoxycholic acid, ursodeoxycholic acid, chenodeoxycholic acid, sodium hyodeoxycholate, sodium ursodeoxycholate, sodium chenodeoxycholate, cholic acid, sodium cholate, glycocholic acid, sodium glycocholate, glycodeoxycholic acid, sodium glycodeoxycholate, taurocholic acid, sodium taurocholate, tauroursodeoxycholic acid, tauroursodeoxycholic acid, taurine hyodeoxycholic acid, taurine chenodeoxycholic acid, taurine chenodeoxycholic acid, glycochenodeoxycholic acid, sodium glycochenodeoxycholate, benzylphenylalanine cholate, sodium tyrocholate, sodium whitish cholate, cholic acid dimer, cholic acid side chain amino acid conjugate, cholic acid side chain PEG conjugate, cholic acid side chain glucose conjugate;

[0026] (6) the stabilizer is one or more selected from the group consisting of injectable solvents and surfactants; the injectable solvent can be one or more selected from the group consisting of propylene glycol, ethanol, benzyl alcohol, dimethyl sulfoxide, N-methyl pyrrolidone, liquid polyethylene glycol, dimethylacetamide, tetrahydrofuran polyethylene glycol ether, diethylene glycol monoethyl ether, benzyl benzoate; the surfactant can be one or more selected from the group consisting of phosphatidylcholine, sorbitan fatty acid ester, polysorbate, polyoxyethylene fatty acid ester, polyoxyethylene fatty alcohol ether, poloxamer, hyaluronic acid, sodium hyaluronate;

[0027] (7) the pH adjuster is one or more selected from the group consisting of pharmaceutically acceptable non-organic acids, organic acids, non-organic bases, and organic bases; preferably one or more selected from the group consisting of hydrochloric acid, phosphoric acid, acetic acid, sulfuric acid, citric acid, boric acid, lactic acid, methanesulfonic acid, maleic acid, tartaric acid, succinic acid, histidine, lysine, arginine, butylamine, meglumine, ethylenediamine, ethanolamine, triethylamine, sodium hydroxide, potassium hydroxide;

[0028] (8) the buffering agent is one or more selected from the group consisting of disodium hydrogen phosphate, dipotassium hydrogen phosphate, potassium dihydrogen phosphate, sodium dihydrogen phosphate, sodium phosphate, potassium phosphate, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, sodium citrate, potassium citrate, sodium acetate, potassium acetate, tris, tris hydrochloride, potassium hydrogen phthalate, sodium hydrogen phthalate, sodium tetraborate, potassium tetraborate, sodium barbital, glycine;

[0029] (9) the osmotic pressure regulator is one or more selected from the group consisting of lactose, trehalose, xylitol, levulose, sorbitol, maltose, glycine, sarcosine, sodium chloride, potassium chloride, glucose, sucrose and mannitol; preferably one or more selected from the group consisting of trehalose, lactose, sodium chloride, potassium chloride, glucose, sucrose and mannitol;

[0030] (10) the complexing agent is one or more selected from the group consisting of ethylenediaminetetraacetic acid, disodium ethylenediaminetetraacetate and calcium disodium ethylenediaminetetraacetate.

[0031] In the lipolysis composition of the present application, a part of the pharmaceutically active ingredient is associated with the clathrate material to form a clathrate, which part is referred to as the associated part; and the part of the pharmaceutically active ingredient that is not associated with the clathrate material to form a clathrate is referred to as the free part. In some embodiments, the free part accounts for <30% of the total pharmaceutically active ingredient in the composition of the present application by mass; optionally <20%.

[0032] In some embodiments, the total daily dose of the lipolysis composition is 0.1 mg-1000 mg; preferably 1 mg-500 mg, based on the pharmaceutically active ingredient.

[0033] The second aspect of the present application provides use of the lipolysis composition of the first aspect in the preparation of a medicament for preventing or treating a fat-related disease.

[0034] In some embodiments, the fat-related disease includes but is not limited to one or more of fat accumulation, lipoma, painful lipoma, cellulite, lipedema, lipohypertrophy, lipodystrophy, lipomatosis, post-liposuction fat deposition, and obstructive sleep apnea; optionally, the dosage form of the medicament is an injection preparation; more optionally, the injection site includes but is not limited to one or more of the abdomen, below the eyes, below the chin, below the arms, the hips, the thighs, the calves, the back, the bra line, the armpits, the stomach and the ankles.

[0035] The third aspect of the present application provides an injection preparation prepared from the lipolysis composition of the first aspect of the present application.

[0036] Optionally, the injection preparation is used in a manner of administration via an injection route, including but not limited to one or more of subcutaneous injection, intramuscular injection, intravenous injection and intralesional injection.

[0037] The drug active ingredient and the inclusion material in the lipolysis composition of the present application are associated, and have the following advantages:

[0038] ① The lipolysis has selectivity for adipocytes, which can reduce adverse reactions at the administration site and improve drug safety;

[0039] ② The lipolysis composition plays a sustained lipolysis role, ensuring good lipolysis effect;

[0040] ③ The lipolysis composition can avoid the problem of reduced drug efficacy caused by prolonged administration interval due to adverse reactions when Kybella is used, and the administration interval can be determined according to the drug efficacy in clinical practice to ensure good lipolysis effect and improve patient experience comfort.

[0041] Compared with the conventional preparation of the same dose (the same dose of the drug active ingredient), the lipolysis composition of the present application can significantly reduce adverse reactions at the administration site while having good lipolysis effect. For example, the incidence of adverse reactions at the administration site can be reduced by more than 10%, preferably more than 20%, and more preferably more than 30%.

[0042] As can be seen from the above, compared with the conventional preparation of the same dose (the same dose of the drug active ingredient), the lipolysis composition of the present application can significantly improve safety while having good lipolysis effect, which has not been reported in the art. BRIEF DESCRIPTION OF DRAWINGS

[0043] In order to more clearly illustrate the technical solutions in the embodiments of the present application, more completely understand the present application and its beneficial effects, the drawings needed in the embodiment description will be briefly introduced, but the present application is not limited thereto.

[0044] FIG. 1 is a photograph showing the injection site of the mouse injection of Comparative Example 1 at different time points;

[0045] FIG. 2 is a photograph showing the injection site of the mouse injection of Comparative Example 2 at different time points;

[0046] FIG. 3 is a photograph showing the injection site of the mouse injection of Comparative Example 3 at different time points;

[0047] FIG. 4 is a photograph showing the injection site of the mouse injection of Composition 5 at different time points;

[0048] FIG. 5 is a photograph showing the injection site of the mouse injection of Composition 6 at different time points;

[0049] Figure 6 is a photograph showing the injection site of mice injected with Composition 7 at different time points;

[0050] Figure 7 is a graph showing the observation results of tissue sections in different tissues of mice 21 days after injection of different compositions;

[0051] Figure 8 is a photograph showing the injection site of mice injected with Comparative Example 9 (single injection) at different time points;

[0052] Figure 9 is a photograph showing the injection site of mice injected with Comparative Example 10 (single injection) at different time points;

[0053] Figure 10 is a photograph showing the injection site of mice injected with Comparative Example 11 (single injection) at different time points;

[0054] Figure 11 is a photograph showing the injection site of mice injected with Composition Z36 (single injection) at different time points;

[0055] Figure 12 is a photograph showing the injection site of mice injected with Composition Z36 (repeated injection) at different time points;

[0056] Figure 13 is a photograph showing the injection site of mice injected with Composition Z31 (single injection) at different time points;

[0057] Figure 14 is a photograph showing the injection site of mice injected with Composition Z35 (single injection) at different time points;

[0058] Figure 15 is a graph showing the survival percentage of each cell in different compositions. DETAILED DESCRIPTION

[0059] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. The terminology used in the description herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the application. As used herein, the term "and / or" includes any and all combinations of one or more of the associated listed items.

[0060] In the present application, the technical features described in an open way include both the closed technical solution consisting of the listed features and the open technical solution containing the listed features.

[0061] In the present application, the numerical ranges are involved, such as without special instructions, the numerical ranges are considered to be continuous, and include the minimum and maximum values of the range, and every value between the minimum and maximum values. Further, when the 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 a characteristic, the ranges can be combined. In other words, unless otherwise specified, all ranges disclosed herein should be understood to include any and all sub-ranges subsumed therein.

[0062] Only some numerical ranges are specifically disclosed herein. However, any lower limit can be combined with any upper limit to form a range not explicitly recited; and any lower limit can be combined with other lower limits to form a range not explicitly recited, and likewise any upper limit can be combined with any other upper limit to form a range not explicitly recited. In addition, each individual disclosed point or single numerical value can itself be combined with any other point or single numerical value as a lower limit or an upper limit to form a range not explicitly recited.

[0063] In the present application, the temperature parameters, unless otherwise specified, allow for constant temperature treatment, and also allow for treatment within a certain temperature range. The constant temperature treatment allows the temperature to fluctuate within the accuracy range controlled by the instrument.

[0064] In the description of the application, the meaning of "multiple" is at least two, such as two, three, etc., unless otherwise specifically limited.

[0065] If not specifically stated, all embodiments and optional embodiments of the present application can be combined to form new technical solutions. If not specifically stated, all technical features and optional technical features of the present application can be combined to form new technical solutions.

[0066] If not specifically stated, all steps of the present application can be performed in sequence, or randomly, preferably in sequence.

[0067] Unless otherwise stated or contradictory, the terms or phrases used herein have the following meanings:

[0068] In this paper, "suitable combination", "suitable way", "any suitable way" and the like are described as "suitable", which can implement the technical solutions of the present application, solve the technical problems of the present application, and achieve the expected technical effects of the present application.

[0069] In the present document, "preferably", "more preferably", "even more preferably", "suitably" and the like are used to describe embodiments or examples of the invention and are not used to limit the scope of the invention. If a technical solution appears in multiple places in the specification, each "preferably", "more preferably", "even more preferably", "suitably" and the like is independent of each other unless otherwise specified.

[0070] In the present document, "further", "even further", "in particular" and the like are used to describe the purpose and are not understood as limiting the scope of the invention.

[0071] In the present document, "optionally", "optional" and "may" mean that the component can or can not be present, i.e. selected from "yes" or "no". If a technical solution appears in multiple places in the specification, each "optionally", "optional" and "may" is independent of each other unless otherwise specified.

[0072] In the present document, "conventional formulation" refers to a formulation that does not contain a clathrate material or a clathrate material of a type and proportion outside the scope of the present invention, such as the commercially available injection Kybella or Comparative Examples 2-11.

[0073] The first aspect of the present invention provides a lipolysis composition comprising a pharmaceutically active ingredient, a clathrate material, a pH adjuster, optionally one or more selected from a stabilizer, an osmotic pressure adjuster and a complexing agent, and optionally purified water.

[0074] It is understood that the pharmaceutically active ingredient mentioned in the present invention refers to the component in the lipolysis composition that has a lipolysis effect.

[0075] It is noted that "optionally" means that the lipolysis composition can or can not contain the component.

[0076] Without being limited to any theory, the lipolysis composition of the present invention has selectivity in dissolving fat cells, can keep the drug concentration in the local tissue at the treatment window at the administration site to have a sustained lipolysis effect, ensure good lipolysis effect, reduce adverse reactions at the administration site, improve drug safety, and avoid the problem of reduced drug efficacy caused by prolonged administration interval due to adverse reactions when using Kybella, so that the administration interval can be determined according to the drug efficacy to ensure good lipolysis effect.

[0077] It is noted that compared with the conventional lipolysis formulation of the same dose (the same dose of the pharmaceutically active ingredient), the incidence of adverse reactions of the lipolysis composition provided by the present invention is reduced by more than 10% under the condition of good lipolysis effect, optionally, by more than 20%, and more optionally, by more than 30%.

[0078] In some embodiments, the lipolysis composition comprises 0.1-5% of the pharmaceutically active ingredient, 4-35% of the inclusion material, 0.01-5% of the pH regulator, 0-10% of the stabilizer, 0-5% of the buffer, 0-5% of the osmotic pressure regulator, 0-1% of the complexing agent, and 0-500 ml of purified water per gram of the pharmaceutically active ingredient, based on the total weight of the lipolysis composition.

[0079] It should be noted that the lipolysis composition provided by the present application can reduce adverse reactions at the administration site after loading the drug.

[0080] The amount of the pharmaceutically active ingredient contained in the lipolysis composition is 0.1-5%, based on the total weight of the lipolysis composition; for example, it can be but is not limited to 0.1%, 0.2%, 0.3%, 0.5%, 1%, 2%, 3%, 5%, or a range between any two of the above amounts.

[0081] The amount of the inclusion material contained in the lipolysis composition is 4-35%, based on the total weight of the lipolysis composition; for example, it can be but is not limited to 4%, 5%, 8%, 10%, 15%, 20%, 25%, 30%, 35%, or a range between any two of the above amounts.

[0082] The amount of the stabilizer contained in the lipolysis composition is 0-10%, based on the total weight of the lipolysis composition; for example, it can be but is not limited to 0%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, or a range between any two of the above amounts.

[0083] The amount of the pH regulator contained in the lipolysis composition is 0.01-5%, based on the total weight of the lipolysis composition; for example, it can be but is not limited to 0.01%, 1%, 2%, 3%, 4%, 5%, or a range between any two of the above amounts.

[0084] The amount of the buffer contained in the lipolysis composition is 0-5%, based on the total weight of the lipolysis composition; for example, it can be but is not limited to 0%, 0.1%, 0.2%, 0.3%, 0.5%, 1%, 2%, 3%, 4%, 5%, or a range between any two of the above amounts.

[0085] The amount of the osmotic pressure regulator contained in the lipolysis composition is 0-5%, based on the total weight of the lipolysis composition; for example, it can be but is not limited to 0%, 0.1%, 0.2%, 0.3%, 0.5%, 0.8%, 1%, 2%, 3%, 5%, or a range between any two of the above amounts.

[0086] The complexing agent is included in the lipolysis composition in an amount of 0-1% by weight based on the total weight of the lipolysis composition; for example, but not limited to, 0%, 0.1%, 0.2%, 0.3%, 0.5%, 0.8%, 1.0%, or a range between any two of the foregoing.

[0087] It should be noted that when the amount by weight is 0, it means that the lipolysis composition does not contain the component.

[0088] When the weight proportions of the components included in the lipolysis composition are within the above ranges, respectively, the following beneficial effects are achieved: ①selectivity in the dissolution of fat cells, which can reduce adverse reactions at the administration site and improve drug safety; ②sustained lipolysis effect, which ensures good lipolysis effect; ③avoiding the problem of prolonged administration interval and long treatment cycle caused by adverse reactions when using commercially available injection Kybella, which can ensure good lipolysis effect according to the drug efficacy in clinical practice, and improve the comfort of patient experience.

[0089] In some embodiments, the lipolysis composition comprises 0.2-4% of the pharmaceutically active ingredient, 5-30% of the inclusion material, 0.02-3% of the pH adjuster, 0-8% of the stabilizer, 0.01-3% of the buffer, 0-3% of the osmotic pressure regulator, 0-0.8% of the complexing agent, and 0-400 ml of purified water per g of the pharmaceutically active ingredient based on the total weight of the lipolysis composition.

[0090] In some embodiments, the lipolysis composition comprises 0.3-3% of the pharmaceutically active ingredient, 8-30% of the inclusion material, 0.03-2% of the pH adjuster, 0-5% of the stabilizer, 0.03-2% of the buffer, 0-2% of the osmotic pressure regulator, 0-0.5% of the complexing agent, and 0-300 ml of purified water per g of the pharmaceutically active ingredient based on the total weight of the lipolysis composition.

[0091] In some embodiments, the lipolysis composition comprises 0.5-2% of the pharmaceutically active ingredient, 10-28% of the inclusion material, 0.05-1% of the pH adjuster, 0-3% of the stabilizer, 0.05-1% of the buffer, 0-1% of the osmotic pressure regulator, 0-0.3% of the complexing agent, and 0-200 ml of purified water per g of the pharmaceutically active ingredient based on the total weight of the lipolysis composition.

[0092] In some embodiments, the pharmaceutically active ingredient of the lipolysis composition includes one or more selected from deoxycholic acid, pharmaceutically acceptable salts of deoxycholic acid, and derivatives of deoxycholic acid.

[0093] Deoxycholic acid is also called deoxycholic acid, English Deoxycholic acid, also known as 3α, 12α-dihydroxy-5β-cholan-24-oic acid, 3α, 12α-dihydroxy-5β-cholan-24-oic acid, the structure is as follows:

[0094] The pharmaceutically acceptable salt of deoxycholic acid is preferably an alkali metal salt, such as a sodium salt or a potassium salt, more preferably a sodium salt.

[0095] The deoxycholic acid derivative can be one or more selected from the group consisting of pig deoxycholic acid, ursodeoxycholic acid, chenodeoxycholic acid, pig deoxycholic acid sodium, ursodeoxycholic acid sodium, chenodeoxycholic acid sodium, cholic acid, cholic acid sodium, glycocholic acid, glycocholic acid sodium, glycodeoxycholic acid, glycodeoxycholic acid sodium, taurocholic acid, taurocholic acid sodium, tauroursodeoxycholic acid, tauroursodeoxycholic acid, taurine pig deoxycholic acid, taurine pig deoxycholic acid, taurine chenodeoxycholic acid, glycocholic acid, glycocholic acid sodium, phenylalanine cholic acid sodium, tyrocholic acid sodium, white cholic acid sodium, cholic acid dimer, cholic acid side chain amino acid conjugate, cholic acid side chain PEG conjugate, cholic acid side chain glucose conjugate, but not limited to.

[0096] In some embodiments, the inclusion material is one or more selected from the group consisting of cyclodextrin derivatives; preferably one or more selected from the group consisting of hydroxypropyl-β-cyclodextrin, sulfobutyl-β-cyclodextrin, methyl-β-cyclodextrin, carboxymethyl-β-cyclodextrin, hydroxyethyl-β-cyclodextrin, glucosyl-β-cyclodextrin, hydroxypropyl-γ-cyclodextrin, a-cyclodextrin, 2,6-dimethyl β-cyclodextrin; more preferably one or two selected from the group consisting of hydroxypropyl-β-cyclodextrin, sulfobutyl-β-cyclodextrin.

[0097] In some embodiments, the cyclodextrin and its derivatives include non-ionized forms and ionized forms and combinations thereof, the ionized form is preferably a salt form, in particular sodium salt or potassium salt; the sulfobutyl-β-cyclodextrin, carboxymethyl-β-cyclodextrin includes non-ionized forms and ionized forms and combinations thereof, the ionized form is preferably a salt form, in particular sodium salt or potassium salt, more particularly, the ionized form of sulfobutyl-β-cyclodextrin, carboxymethyl-β-cyclodextrin is sulfobutyl-β-cyclodextrin sodium, carboxymethyl-β-cyclodextrin sodium, respectively.

[0098] In some embodiments, the stabilizer is one or more selected from injectable solvents and surfactants; the injectable solvent can be one or more of propylene glycol, ethanol, benzyl alcohol, dimethyl sulfoxide, N-methyl pyrrolidone, liquid polyethylene glycol, dimethylacetamide, tetrahydrofuran polyethylene glycol ether, diethylene glycol monoethyl ether, benzyl benzoate, and the surfactant can be one or more selected from phosphatidylcholine, sorbitan fatty acid ester, polysorbate, polyoxyethylene fatty acid ester, polyoxyethylene fatty alcohol ether, poloxamer, hyaluronic acid, sodium hyaluronate.

[0099] In some embodiments, the pH adjusting agent is one or more selected from pharmaceutically acceptable non-organic acids, organic acids, non-organic bases, and organic bases; preferably one or more selected from hydrochloric acid, phosphoric acid, acetic acid, sulfuric acid, citric acid, boric acid, lactic acid, methanesulfonic acid, maleic acid, tartaric acid, succinic acid, histidine, lysine, arginine, butyric acid, meglumine, ethylenediamine, ethanolamine, triethylamine, sodium hydroxide, potassium hydroxide.

[0100] In some embodiments, the buffer is one or more selected from disodium hydrogen phosphate, dipotassium hydrogen phosphate, potassium dihydrogen phosphate, sodium dihydrogen phosphate, sodium phosphate, potassium phosphate, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, sodium citrate, potassium citrate, sodium acetate, potassium acetate, tris-hydroxymethyl aminomethane, tris-hydroxymethyl aminomethane hydrochloride, potassium hydrogen phthalate, sodium hydrogen phthalate, sodium tetraborate, potassium tetraborate, barbital sodium, glycine.

[0101] In some embodiments, the osmotic pressure adjusting agent is one or more selected from lactose, trehalose, xylitol, levoglucosan, sorbitol, maltose, glycine, sarcosine, sodium chloride, potassium chloride, glucose, sucrose, and mannitol; preferably one or more selected from trehalose, lactose, sodium chloride, potassium chloride, glucose, sucrose, and mannitol.

[0102] In some embodiments, the complexing agent is one or more selected from ethylenediaminetetraacetic acid, disodium ethylenediaminetetraacetate, and calcium disodium ethylenediaminetetraacetate.

[0103] In the fat-dissolving composition of the present application, a part of the pharmaceutically active ingredient is associated with the clathrate material to form a clathrate, referred to as the associated part; further optionally, the part of the pharmaceutically active ingredient that is not associated with the clathrate material to form a clathrate is referred to as the free part. In some embodiments, the mass fraction of the free part in the pharmaceutically active ingredient is <30%; optionally <20%.

[0104] In some embodiments, the total daily dosage of the lipolysis composition is 0.1 mg to 1000 mg, optionally 1 mg to 500 mg, in terms of the pharmaceutically active ingredient. The administration of the single daily dosage is mainly related to the area of the target fat-reducing region, the fat amount of the target fat-reducing region, etc., and a person skilled in the art can adjust the single daily dosage based on the above factors. The dosage of each treatment course is related to the area of the target fat-reducing region, the fat amount of the target fat-reducing region, the target fat-reducing amount, etc., and a person skilled in the art can adjust the dosage of each treatment course based on the above factors.

[0105] The second aspect of the present application provides a use of the lipolysis composition in the preparation of a medicament for preventing or treating a fat-related disease.

[0106] In some embodiments, the fat-related disease includes, but is not limited to, one or more of fat accumulation, lipoma, painful lipoma, cellulite, lipedema, lipohyperplasia, lipodystrophy, lipomatosis, post-liposuction fat deposition, and obstructive sleep apnea. Optionally, the dosage form of the medicament can be an injection preparation. More optionally, the injection site of the injection preparation includes one or more of the abdomen, below the eyes, below the chin, below the arms, the hips, the thighs, the calves, the back, the bra line, the armpits, the stomach, and the ankles.

[0107] The third and fourth aspects of the present application respectively provide an injection preparation prepared from the lipolysis composition of the first aspect of the present application.

[0108] Optionally, the injection preparation is administered by an injection route, including but not limited to one or more selected from subcutaneous injection, intramuscular injection, intravenous injection, and intralesional injection.

[0109] In some embodiments, the lipolysis composition can be prepared by the following method:

[0110] (1) Dissolve the buffer in purified water, adjust the pH value to 10.0-11.0 using a pH adjuster, and add the prescribed amount of the pharmaceutically active ingredient to completely dissolve; (2) Add the prescribed amount of the inclusion material to the above solution and mix until clear and transparent; (3) Adjust the pH value of the solution to 7.0-9.0 using a pH adjuster; (4) Filter using a 0.22 μm microporous filter; (5) Perform filling according to the drug content; (6) Optionally, freeze-dry the filled solution; or optionally, sterilize the filled solution.

[0111] If the prescription contains a stabilizer, an osmotic pressure regulator, and / or a complexing agent, the above substances can be added at any step of (1), (2), and (3).

[0112] In some embodiments, the lipolysis composition can be prepared by the following method:

[0113] (1) adding a prescribed amount of a pharmaceutical active ingredient and a buffer to purified water, adjusting to complete dissolution of the pharmaceutical active ingredient using a pH adjuster to obtain a clear and transparent solution; (2) adding a prescribed amount of a clathrate material to the above solution and mixing to be clear and transparent; (3) adjusting the pH of the solution to 7.0 to 9.0 using a pH adjuster; (4) filtering using a 0.22 μm micropore filter; (5) filling according to the drug content; (6) optionally, freeze-drying the filled solution; or (7) optionally, sterilizing the filled solution.

[0114] If a stabilizer, an osmotic pressure adjuster, and / or a complexing agent is contained in the prescription, the above substances can be added at any step of (1), (2), and (3).

[0115] In some embodiments, the lipolysis composition can be prepared by the following method:

[0116] (1) adding a prescribed amount of a buffer to purified water and stirring to complete dissolution; (2) adding a prescribed amount of an active ingredient and stirring, and adjusting to complete dissolution of the pharmaceutical active ingredient using a pH adjuster to obtain a clear and transparent solution; (3) adding a prescribed amount of a clathrate material to the above solution and mixing to be clear and transparent; (4) adjusting the pH of the solution to 7.0 to 9.0 using a pH adjuster; (5) filtering using a 0.22 μm micropore filter; (6) filling according to the drug content; (7) optionally, freeze-drying the filled solution.

[0117] If a stabilizer, an osmotic pressure adjuster, and / or a complexing agent is contained in the prescription, the above substances can be added at any step of (1), (2), and (3).

[0118] In some embodiments, the lipolysis composition can be prepared by the following method:

[0119] (1) adding a prescribed amount of a buffer to purified water and stirring to complete dissolution; (2) adding a prescribed amount of an active ingredient and stirring, and adjusting to complete dissolution of the pharmaceutical active ingredient using a pH adjuster to obtain a clear and transparent solution; (3) adding a prescribed amount of a clathrate material to the above solution and mixing to be clear and transparent; (4) adjusting the pH of the solution to 7.0 to 9.0 using a pH adjuster; (5) filtering using a 0.22 μm micropore filter; (6) filling according to the drug content; (7) optionally, freeze-drying the filled solution.

[0120] If a stabilizer, an osmotic pressure adjuster, and / or a complexing agent is contained in the prescription, the above substances can be added at any step of (1), (2), and (3).

[0121] In some embodiments, the lipolysis composition can be prepared by the following method:

[0122] (1) Weigh the prescription amount of pH adjuster, buffer, stabilizer into purified water, stir until completely dissolved, to obtain a clear and transparent solution; (2) add the prescription amount of active pharmaceutical ingredient to the above solution, completely dissolved, adjust the pH of the drug solution to 9.0-10.0; (3) add the prescription amount of inclusion material to the drug solution of step (2) and mix well, adjust the pH to 7.0-9.0; (4) add purified water to the full amount; (5) filter the solution of step (4) using a 0.22 μm microporous filter; (6) according to the drug content, fill the solution.

[0123] If the prescription contains stabilizers, osmotic pressure regulators and / or complexing agents, the above substances can be added at any step of (1), (2) and (3).

[0124] In the preparation method of the composition of the present application, if the active pharmaceutical ingredient is dissolved first, it needs to be dissolved and clarified before adding cyclodextrin to the solution for inclusion; if cyclodextrin is dissolved first, the cyclodextrin solution needs to be adjusted to alkaline before adding the active pharmaceutical ingredient for inclusion. The preparation method of the composition of the present application can also include a sterilization step.

[0125] It should be noted that the composition prepared by the present application is a clear and transparent solution or a clear and transparent solution before lyophilization.

[0126] It should be noted that the pH value of the composition prepared by the present application is 7.0-9.0.

[0127] The lipolysis composition of the present application can reduce adverse reactions at the administration site and improve drug safety when used in vivo compared with conventional lipolysis preparations; can make the drug free from the association of drug-inclusion material, ensuring good lipolysis effect; can avoid the problem of reduced drug efficacy caused by prolonged administration interval due to adverse reactions when using commercially available injection Kybella, and can determine the administration interval according to the drug efficacy in clinical practice to ensure good lipolysis effect and improve the comfort of patient experience.

[0128] The technical solutions of the present application are described in detail in the following specific examples. It should be understood that these examples are only used to illustrate the present application and not to limit the scope of the present application. If the experimental method is not specified in the following examples, the priority is given to the guidance given in the present application, and the experimental manual or conventional conditions in the art can also be used, or the conditions suggested by the manufacturer can be used, or the known experimental methods in the art can be used.

[0129] In the following specific examples, the amount of raw material components is measured, and if not specifically stated, there may be slight deviations within the weighing accuracy range. The temperature and time parameters allow for acceptable deviations caused by instrument testing accuracy or operation accuracy.

[0130] Examples

[0131] For the purposes of promoting an understanding of the principles of the application, the application will now be described more fully with reference to the associated drawings. The preferred embodiments of the application are shown in the drawings. However, the application can be embodied in many different forms and should not be construed as limited to the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete. The embodiments are described below with reference to the drawings.

[0132] Example 1, Preparation of the composition

[0133] 1, The prescription of the composition Z1 to Z14 is shown in Table 1.

[0134] 2, Preparation process of Z1-Z5:

[0135] (1) Precisely weigh the prescription amount of buffer, stabilizer into the prescription amount of purified water, stir until completely dissolved;

[0136] (2) Slowly add the prescription amount of pharmaceutical active ingredient to the above solution, stir;

[0137] (3) Add the prescription amount of sodium hydroxide, stir until the solution is clear;

[0138] (4) Add the prescription amount of inclusion material, stir at 60°C for 2h until the solution is clear; add the osmotic pressure regulator and stir until the solution is clear, adjust the pH value of the solution to 7.0-9.0 with hydrochloric acid;

[0139] (5) Filter the above solution with a 0.22μm microporous filter membrane to obtain a clear and transparent solution;

[0140] (6) Package and sterilize the composition Z3, Z4, and you get it;

[0141] (7) Package and freeze-dry the composition Z1, Z2, Z5 to obtain a freeze-dried preparation, and you get it.

[0142] 3, Preparation process of Z6-Z14:

[0143] (1) Precisely weigh the prescription amount of inclusion material, stabilizer into the prescription amount of purified water, stir to dissolve at 60°C to obtain a clear and transparent solution;

[0144] (2) Weigh the prescription amount of buffer and sodium hydroxide into the solution obtained in (1), ultrasonic until dissolved to obtain a clear and transparent solution;

[0145] (3) Weigh the prescription amount of pharmaceutical active ingredient into the solution obtained in (2), stir at 60°C for 2h until the solution is clear; add the osmotic pressure regulator and stir until the solution is clear, adjust the pH value of the solution to 7.0-9.0 with hydrochloric acid;

[0146] (4) The above solution is filtered with a 0.22 μm microporous filter to obtain a clear and transparent solution;

[0147] (5) The compositions Z6, Z7, Z8 and Z10 are divided, sterilized and obtained.

[0148] (6) The compositions Z9, Z11, Z12, Z13 and Z14 are divided, lyophilized and obtained.

[0149] Example 2, Preparation of Compositions

[0150] 1. The prescription of the compositions Z15 to Z28 is shown in Table 2.

[0151] 2. Preparation process of Z15 to Z21:

[0152] (1) The buffer and stabilizer in the prescription amount are precisely weighed into purified water in the prescription amount, and stirred until completely dissolved;

[0153] (2) The active ingredient in the prescription amount is slowly added to the above solution, and stirred;

[0154] (3) The sodium hydroxide in the prescription amount is added, and stirred until the solution is clear;

[0155] (4) The inclusion material in the prescription amount is added, and stirred at 60°C for 2h until the solution is clear; the pH value of the solution is adjusted to 7.0-9.0 with hydrochloric acid;

[0156] (5) The above solution is filtered with a 0.22 μm microporous filter to obtain a clear and transparent solution;

[0157] (6) The compositions Z17, Z18, Z19, Z20 and Z21 are divided, sterilized and obtained.

[0158] (7) The compositions Z15 and Z16 are divided, lyophilized and obtained.

[0159] 3. Preparation process of Z22 to Z28:

[0160] (1) The buffer and stabilizer in the prescription amount are precisely weighed into purified water in the prescription amount, and the pH value is adjusted to 10.0-11.0 with a pH adjuster;

[0161] (2) The active ingredient in the prescription amount is added, and stirred until completely dissolved;

[0162] (3) The inclusion material in the prescription amount is added, and stirred at 60°C for 2h until the solution is clear; the pH value of the solution is adjusted to 7.0-9.0 with hydrochloric acid;

[0163] (4) The above solution is filtered by using 0.22 μm microporous filter membrane to obtain a clear and transparent solution;

[0164] (5) The composition Z22, Z23, Z24 is divided, sterilized, and thus obtained.

[0165] (6) The composition Z25, Z26, Z27, Z28 is divided, lyophilized, and thus obtained.

[0166] Example 3, Preparation of the composition

[0167] 1, The prescription of the composition Z29 to Z36 is shown in Table 3.

[0168] Table 3. Composition of the composition

[0169] 2, Preparation process of Z29-Z32:

[0170] 1) Weigh the prescription amount of 90% of water for injection in a beaker, and heat to 60℃±5℃;

[0171] 2) Precisely weigh the prescription amount of citric acid and sodium hydroxide, buffer, stabilizer in the beaker of step 1), and dissolve under the condition of 60℃±5℃ stirring;

[0172] 3) Weigh the prescription amount of the active pharmaceutical ingredient, and dissolve under the condition of 60℃±5℃ stirring;

[0173] 4) Adjust the pH of the drug solution to 9.45-9.55 with hydrochloric acid;

[0174] 5) Weigh the inclusion material according to the prescription into the drug solution of step 4), and stir at 60℃±5℃ for 2h;

[0175] 6) Adjust the pH to 7.5-8.5 with hydrochloric acid.

[0176] 7) Weigh the remaining amount of water for injection to make up the full amount;

[0177] 8) Filter the drug solution of step 7) by using 0.45 μm+0.22 μm microporous filter membrane;

[0178] 9) The filtered solution is divided, sterilized, and thus obtained.

[0179] 3, Preparation process of Z33-Z36:

[0180] (1) Precisely weigh the prescription amount of the active pharmaceutical ingredient, buffer, stabilizer into the prescription amount of purified water, and stir;

[0181] (2) Add the prescription amount of sodium hydroxide, and stir until the solution is clear;

[0182] (3) Add the prescription amount of inclusion material, stir at 60°C for 2h until the solution is clear; adjust the pH of the solution to 7.0-9.0 with hydrochloric acid;

[0183] (4) Filter the above solution with a 0.22 μm microporous filter to obtain a clear and transparent solution;

[0184] (5) The filtered solution is divided, sterilized and obtained.

[0185] Example 4, Preparation of the composition

[0186] 1. The prescription of the composition Z37 to Z41 is shown in Table 4.

[0187] Table 4. Composition of the composition

[0188] 2. Preparation process of Z37-Z41:

[0189] 1) Weigh the prescription amount of 90% of water for injection in a beaker, heat to 60°C±5°C;

[0190] 2) Precisely weigh the prescription amount of acetic acid and sodium hydroxide, buffer, stabilizer in step 1) beaker, stir and dissolve at 60°C±5°C;

[0191] 3) Weigh the prescription amount of the active pharmaceutical ingredient, stir and dissolve at 60°C±5°C;

[0192] 4) Adjust the pH of the drug solution to 9.45-9.55 with hydrochloric acid;

[0193] 5) Weigh the inclusion material according to the prescription into the drug solution of step 4), stir at 60°C±5°C for 2h;

[0194] 6) Adjust the pH to 7.5-8.5 with hydrochloric acid.

[0195] 7) Weigh the remaining amount of water for injection to make up the full amount;

[0196] 8) Filter the drug solution of step 7) through a 0.45 μm+0.22 μm microporous filter;

[0197] 9) The filtered solution is divided, sterilized and obtained.

[0198] Preparation of commercially available injection liquid

[0199] 1. Refer to the preparation of commercially available injection liquid Kybella for Comparative Example 1, and its prescription composition is shown in Table 5.

[0200] Table 5. Prescription composition of Kybella injection liquid

[0201] 2. Preparation process

[0202] Weigh the prescribed amount of benzyl alcohol, disodium hydrogen phosphate, sodium chloride, sodium hydroxide into water for injection, stir, ultrasonic to completely dissolved, add the prescribed amount of deoxycholic acid, stirring, ultrasonic to completely dissolved. Slowly adjust the pH value to 8.3 with hydrochloric acid / sodium hydroxide to obtain a drug-containing solution, filter and pack, seal, then wet heat sterilization, to get a clear transparent liquid, ready.

[0203] Preparation of different amounts of cyclodextrin formulations in Comparative Example 2-3

[0204] 1. Change the ratio of inclusion materials to prepare formulations, the prescription composition is as follows.

[0205] Table 6. Prescription composition of Comparative Example 2-3

[0206] 2. Preparation process

[0207] (1) Precisely weigh the prescribed amount of potassium hydrogen phosphate, potassium dihydrogen phosphate into the prescribed amount of purified water, stir until completely dissolved;

[0208] (2) Slowly add the prescribed amount of active pharmaceutical ingredients to the above solution, stir;

[0209] (3) Add the prescribed amount of sodium hydroxide, stir until the solution is clear;

[0210] (4) Add the prescribed amount of inclusion material, stir at 60°C for 2h until the solution is clear; adjust the pH of the solution to 7.0-9.0 with hydrochloric acid;

[0211] (5) Filter the above solution with a 0.22μm microporous filter to obtain a clear and transparent solution;

[0212] (6) Pack and sterilize Comparative Example 2 and Comparative Example 3 to obtain.

[0213] Preparation of different types of cyclodextrin formulations in Comparative Example 4-5

[0214] 1. Change the type of inclusion material to prepare formulations, the prescription composition is as follows.

[0215] Table 7. Prescription composition of Comparative Example 4 and Comparative Example 5

[0216] 2. Preparation process

[0217] (1) Precisely weigh the prescribed amount of potassium hydrogen phosphate, potassium dihydrogen phosphate into the prescribed amount of purified water, stir until completely dissolved;

[0218] (2) Slowly add the prescribed amount of active pharmaceutical ingredients to the above solution, stir;

[0219] (3) Add the prescribed amount of sodium hydroxide and stir until the solution is clear;

[0220] (4) Add the prescribed amount of inclusion material and stir at 60°C for 2h; adjust the pH of the solution to 7.0-9.0 using hydrochloric acid;

[0221] (5) Filter the above solution using a 0.22μm microporous filter membrane;

[0222] It was found through preparation that the solutions of Comparative Example 4 and Comparative Example 5 were both milky white liquids. It can be seen that using γ-cyclodextrin or β-cyclodextrin as the inclusion material, a clear and transparent composition cannot be prepared.

[0223] Preparation of different amounts of cyclodextrin formulations in Comparative Examples 6-11

[0224] 1. Change the proportion of inclusion material to prepare the formulation, and the prescription composition is as follows.

[0225] Table 8. Prescription composition of Comparative Examples 6-11

[0226] 2. Preparation process

[0227] 1) Weigh the prescribed amount of 90% water for injection into a beaker and heat to 60°C±5°C;

[0228] 2) Precisely weigh the prescribed amount of sodium hydroxide and buffer into the beaker of step 1) and stir to dissolve at 60°C±5°C;

[0229] 3) Weigh the prescribed amount of the active pharmaceutical ingredient and stir to dissolve at 60°C±5°C;

[0230] 4) Add the surfactant and adjust the pH of the drug solution to 9.45-9.55 using hydrochloric acid;

[0231] 5) Weigh the inclusion material according to the prescription into the drug solution of step 4) and stir at 60°C±5°C for 2h;

[0232] 6) Adjust the pH to 7.5-8.5 using hydrochloric acid.

[0233] 7) Weigh the remaining amount of water for injection to make up the full amount;

[0234] 8) Filter the drug solution of step 7) through a 0.45μm+0.22μm microporous filter membrane;

[0235] 9) Dispense and sterilize the filtered solution to obtain it.

[0236] It was found through preparation that the clarity of Comparative Examples 6-8 after sterilization did not meet the requirements.

[0237] Experimental Example 1, Inclusion Rate Determination

[0238] The preparation solution prepared in Example 1 or the solution prepared by adding the lyophilized preparation to an appropriate amount of water was added to an ultrafiltration tube (molecular weight 0.3 kDa), and centrifugation was performed at 4000 rpm for 15 min. The total drug active ingredient content and the free drug active ingredient content of the preparation solution were measured, and the inclusion rate of the composition was calculated.

[0239] The inclusion rate was calculated as follows:

[0240] Inclusion rate (%) = (total drug active ingredient content - free drug active ingredient content) / total drug active ingredient content.

[0241] The results are shown in Table 9.

[0242] Table 9. Inclusion rate results of different compositions

[0243] As can be seen from the results, the inclusion rate of the composition of the present application is as high as 80% or more, i.e., the drug active ingredient associated with the inclusion material to form an associated substance can account for 80% or more of the total drug active ingredient.

[0244] Experimental Example 2, Stability Considerations

[0245] Each lipolytic composition prepared in Example 1 was subjected to a long-term test at 25°C ± 2°C and 60% ± 5% RH, and an accelerated test at 40°C ± 2°C and 75% ± 5% RH, and the drug active ingredient content, related substance content, and pH value of each lipolytic composition were measured. The drug active ingredient content measurement method and the related substance measurement method are as follows, respectively.

[0246] 1. Drug active ingredient content

[0247] Mobile phase: mobile phase A: 0.1% formic acid-water solution, mobile phase B: 0.1% formic acid-acetonitrile solution; gradient elution was performed according to Table 10.

[0248] Table 10. Gradient elution program

[0249] Preparation of test sample solution: First, the sample was prepared into a drug solution containing about 10 μg / ml as a test sample solution using a solvent (methanol: water = 80:20, v / v).

[0250] Preparation of control sample solution: An appropriate amount of drug active ingredient control sample was accurately weighed and diluted with a solvent (methanol: water = 80:20, v / v) to a drug solution containing about 10 μg / ml as a control sample solution.

[0251] Chromatographic conditions: Method: determined according to high performance liquid chromatography (Chinese Pharmacopoeia 2020 edition four general rules 0512); detector: CAD detector; chromatographic column: YMC Pack Pro C18 (4.6mmx150mm, 3um); injection volume: 25ul; column temperature: 30 degrees C; flow rate: 1ml / min; running time: 43min.

[0252] Analysis method: the content is calculated by peak area according to external standard method.

[0253] 2. Related substances

[0254] The determination method and chromatographic conditions are the same as those for content determination, which will not be described in detail.

[0255] The related substance and drug active ingredient content determination results are shown in Table 11.

[0256] Table 11. Composition stability during placement Drug active ingredient content and related substance content determination results

[0257] From the above table results, the drug active ingredient content and related substance content of the above-mentioned compositions did not change significantly after being placed under accelerated conditions and long-term conditions for 6 months, indicating that the composition provided by the present application has good stability.

[0258] 3. The pH value determination results of the composition are shown in the following table.

[0259] Table 12. pH value determination results of the composition during stability placement

[0260] From the above table results, the pH value of the above-mentioned compositions did not change significantly after being placed under accelerated conditions and long-term conditions for 6 months, and the change value was not more than 0.5. It can be seen that the pH value of the composition of the present application can remain stable during stability placement, and is maintained between 7.0-9.0.

[0261] Experimental example 3, safety and effectiveness of high-fat mice in vivo

[0262] Experimental animals: 12-week-old male C57BL / 6 mice were fed with high-fat feed for 12 weeks.

[0263] Source of experimental animals: Experimental Animal Center of Shanghai Institute of Materia Medica, Chinese Academy of Sciences

[0264] Experimental animal IACUC number: 2023-10-GY-71

[0265] Experimental animal breeding conditions: 25±5 degrees C, 60±5% RH

[0266] Experimental grouping and dosing: The high-fat mice were randomly grouped, 6 mice per group. The abdominal area of the mice was depilated and alcohol-disinfected. The compositions shown in the following table were injected subcutaneously into the inguinal fat pad of one side of the mouse by subcutaneous injection of the bilateral inguinal fat tissue, and the same amount of normal saline was injected into the other side in the same way. The injection was repeated on day 1 and day 14, and the experimental groups and doses are shown in Table 13.

[0267] Table 13. Dosing information for fat-dissolving preparation in vivo study

[0268] *Note: When the preparation is a lyophilized preparation, it is reconstituted with water for injection to a concentration of 10 mg / ml before use.

[0269] #Note: 2-point injection was used for each inguinal region, with 0.1 ml injected per point.

[0270] &Note: Total dose mg per animal per administration.

[0271] The experimental mice were treated as follows:

[0272] 1. Incidence of adverse reactions at the injection site:

[0273] The injection sites of the experimental mice were photographed and recorded at different time points after injection; the results are shown in Table 14 and Figures 1-6.

[0274] Table 14. Injection site conditions of high-fat mice at different time points after administration

[0275] From the above table and the results of Figures 1-6, it can be seen that at different time points after a single injection, the injection sites of Comparative Example 1 and Comparative Example 2 both showed adverse reactions, with an incidence of 100%, and did not fully recover after 14 days, indicating that the time interval for repeated injection of Comparative Example 1 and Comparative Example 2 is at least 14 days; the injection sites of compositions Z5, Z6, and Z7 of the same dose did not show obvious abnormalities, with an incidence of 0%, indicating that the safety of a single injection of the composition of the present application is significantly better than that of Comparative Example 1 and Comparative Example 2, and the incidence of adverse reactions at the injection site can be reduced by at least 60% compared to Comparative Example 1 and Comparative Example 2.

[0276] After repeated injection, the injection sites of Comparative Example 1 and Comparative Example 2 showed adverse reactions, with an incidence of 67%; while the injection sites of compositions Z5, Z6, and Z7 of the same dose did not show obvious abnormalities, with an incidence of 0%; indicating that the safety of repeated injection of the composition of the present application is significantly better than that of Comparative Example 1 and Comparative Example 2, and the time interval for repeated injection can be set according to the needs, and the incidence of adverse reactions at the injection site can be reduced by 67% compared to Comparative Example 1 and Comparative Example 2.

[0277] 2. Fat reduction effect determination of injection site:

[0278] The animals were sacrificed 7 days after the first injection and 21 days after the first injection (7 days after repeated injection), the inguinal fat pads were separated and weighed, and the fat reduction was quantitatively evaluated, and the results are shown in Table 15.

[0279] Table 15. Results of fat quantitative evaluation at different time points after administration

[0280] As can be seen from the above table, after a single injection, the fat reduction of compositions Z5, Z6 and Z7 was 22.54-24.98%, and the fat reduction of Comparative Example 1 was 16.53%, indicating that the compositions of the present application have good fat-dissolving effect after a single injection. After repeated injection, the fat reduction of compositions Z5, Z6 and Z7 was 26.26-33.53%, and the fat reduction of Comparative Example 1 was 21.98%, indicating that the compositions of the present application have good fat-dissolving effect after repeated injection.

[0281] The commercially available injection Kybella (i.e. Comparative Example 1 of the present application) has a recovery time of at least 4 weeks due to serious adverse reactions in clinical use, and therefore the administration interval in clinical use is 4 weeks. Kybella is a common injection, and a long administration interval will result in a decrease in drug efficacy. The aqueous fat-dissolving preparation of the present application significantly reduces adverse reactions compared to Comparative Example 1, and therefore the aqueous fat-dissolving preparation of the present application does not have the problem of administration interval caused by adverse reactions, and the administration interval can be determined according to the drug efficacy in clinical use to ensure good fat-dissolving effect.

[0282] Comparing Comparative Examples 2 and 3 with Z5, Z6 and Z7, it can be seen that Comparative Example 2 contains 3% of the inclusion material, and serious adverse reactions at the injection site occurred in the mouse study; Comparative Example 3 contains 40% of the inclusion material, and although no obvious adverse reactions occurred in the mouse study, the therapeutic effect was significantly lower than that of the compositions of the present application; and the compositions of the present application can significantly reduce the incidence of adverse reactions at the administration site while ensuring good fat-dissolving effect, indicating that the inclusion material of the compositions of the present application has a required dosage range, and the dosage range of the inclusion material is higher than 3% and lower than 40%.

[0283] 3. Observation results of tissue sections of injection site:

[0284] The animals were sacrificed 21 days after the first injection (7 days after repeated injection), the fat tissue, muscle injection and epidermis tissue at the injection site were separated, paraffin sections were prepared, and HE staining was performed, and the morphology was observed, and the results are shown in Table 16 and Figure 7 (since Comparative Example 3 was observed by naked eye without obvious abnormalities, no tissue section investigation was performed).

[0285] Table 16. Pathological section results of different tissues at the injection site of different compositions

[0286] As shown by the results of the tissue section of Figure 7 and Table 16, the degree of fat dissolution is moderate to severe in compositions Z5, Z6 and Z7, and moderate in Comparative Example 1 and Comparative Example 2, which shows that the degree of fat dissolution of the compositions of the present application is better than that of Comparative Example 1. The muscle tissue is not obviously abnormal in compositions Z5, Z6 and Z7, and slightly fibrotic in Comparative Example 1 and Comparative Example 2, which shows that the compositions of the present application have less stimulation to muscle than Comparative Example 1 and Comparative Example 2. The skin tissue is slightly inflamed and slightly fibrotic in compositions Z5 and Z6, and not obviously abnormal in composition Z7, while the inflammation and fibrosis in Comparative Example 1 and Comparative Example 2 are more severe than in compositions Z5, Z6 and Z7, and in addition, there are reactions such as hemorrhage and epidermal hyperplasia, which shows that the compositions Z5, Z6 and Z7 have much less stimulation to skin than Comparative Example 1 and Comparative Example 2.

[0287] The results of the tissue section study show that the degree of fat dissolution of compositions Z5, Z6 and Z7 of the present application is greater than that of Comparative Example 1 and Comparative Example 2, but the stimulation to muscle and skin is less than that of Comparative Example 1 and Comparative Example 2.

[0288] In summary, in combination with the results of the observation of adverse reactions at the injection site and the results of the tissue section study, the safety of the compositions of the present application is significantly improved compared with Comparative Example 1 and Comparative Example 2. In combination with the results of the determination of the fat-reducing effect at the injection site, the efficacy of the compositions of the present application is significantly improved compared with Comparative Example 1 and Comparative Example 2.

[0289] Experimental Example 4: Safety and effectiveness in mice in vivo

[0290] Experimental animals: 12-week-old male C57BL / 6 mice

[0291] Source of experimental animals: Experimental Animal Center of Shanghai Institute of Materia Medica, Chinese Academy of Sciences

[0292] IACUC number of experimental animals: 2024-12-GY-82

[0293] Experimental animal feeding conditions: 25±5℃, 60±5% RH

[0294] Experimental grouping and dosing: The mice were randomly divided into groups, with 6 mice in each group. The abdominal area of the mice was shaved and alcohol-disinfected. The compositions shown in the following table were injected subcutaneously into the inguinal fat pad of one side of the mouse by double inguinal fat tissue subcutaneous injection (2-point injection, 0.1 ml per point), and the same amount of normal saline was injected into the other side in the same way. The groups and doses of the test are shown in Table 17.

[0295] Table 17. Dosing information for fat-dissolving preparations in vivo

[0296] *Note: When the preparation is a lyophilized preparation, it is reconstituted with water for injection to a concentration of 10 mg / ml before use.

[0297] #Note: 2-point injection is used for each unilateral groin, with 0.1 ml injected at each point.

[0298] The experimental mice were treated as follows:

[0299] 1. Incidence of adverse reactions at the injection site:

[0300] The injection sites of the experimental mice were photographed and recorded at different time points after injection; the results are shown in Table 18 and Figs. 8-14.

[0301] Table 18. Mouse injection site conditions at different time points after administration

[0302] From the above table and the results of Figs. 8-14, it can be seen that at different time points after a single injection, the injection sites of Comparative Examples 9, 10, and 11 all showed adverse reactions, with an incidence of 50% to 66.7%, and not fully recovered after 14 days; the injection sites of the same dose of compositions Z31, Z35, and Z36 all showed no obvious abnormalities, with an incidence of 0%, indicating that the safety of the compositions of the present application after a single injection is significantly better than that of Comparative Examples 9, 10, and 11, and can significantly reduce the incidence of adverse reactions at the injection site.

[0303] After repeated injection of the composition Z36 of the present application, the injection sites all showed no obvious abnormalities, with an incidence of 0%; indicating that the safety of the composition of the present application after repeated injection is good, and is significantly better than that of single injection of Comparative Examples 9, 10, and 11.

[0304] 2. Fat reduction effect determination at the injection site:

[0305] The animals were sacrificed 14 days after the first injection, the inguinal fat pads were separated and weighed, and the fat weight loss was quantitatively evaluated, with the results shown in Table 19.

[0306] Table 19. Quantitative evaluation results of fat at different time points after administration

[0307] As can be seen from the above table, after a single injection, the fat loss of the composition was 20.12-22.36%, and the fat loss of Comparative Examples 9, 10, and 11 was 14.46-16.96%, indicating that the composition of the present application has good fat-dissolving effect after a single injection. After repeated injection, the fat loss of composition Z36 was 28.66%, indicating that the composition of the present application has good fat-dissolving effect after repeated injection.

[0308] Safety and effectiveness of the composition in pigs

[0309] Experimental animal: Bama pig, ~30 kg.

[0310] Source of experimental animals: Shanghai University of Traditional Chinese Medicine

[0311] IACUC number of experimental animals: PZSHUTCM2211070010

[0312] Experimental animal feeding conditions: 25±5℃, 60±5% RH

[0313] Experimental grouping and dosing: The back of the piglet was selected for depilation and disinfection in four 2*3 cm areas. Each area was divided into 6 grids at intervals of 1 cm.

[0314] At the center point of each grid, the same composition was injected into the fat layer, once every other week for four consecutive injections, and the injection site was dissected 28 days after the last injection. The experimental groups and doses are shown in Table 20.

[0315] Table 20. Dosing information for in vivo investigation of experimental pigs

[0316] *Note: When the preparation is a lyophilized preparation, it is reconstituted and diluted to the corresponding concentration with water for injection before use (the drug concentrations after dilution of Z9 and Z13 are 12 mg / ml and 10 mg / ml, respectively).

[0317] The experimental pigs were treated as follows:

[0318] 1. Incidence of adverse reactions at the injection site:

[0319] The injection site of the piglet was photographed and recorded at different time points after injection, and the results are shown in Table 21 below.

[0320] Table 21. General observation of injection sites in experimental pigs

[0321] The results show that Comparative Example 1 can cause the injection site to become hard, with an adverse reaction incidence of 100%, and the injection site of Comparative Example 1 also has a slight bulge. However, the compositions 3, 9, and 13 of the present application did not show any abnormalities in the pigs, indicating that the compositions of the present application have better safety than Comparative Example 1, and can reduce the incidence of adverse reactions at the injection site by 100%.

[0322] 1. Lipid reduction effect at the injection site and drug residue determination: The animals were sacrificed 28 days after the last injection, and the injection site tissue was isolated to observe the fat dissolution at the injection site, measure the fat thickness at the injection site and the fat thickness around the injection site, and calculate the fat thickness change. The fat thickness measurement results at the injection site of different groups are shown in Table 22.

[0323] Table 22. Fat reduction results of injection sites in different groups

[0324] From the above table results, the fat thickness reduction ratio of the administration site of the composition of the present application is 31.85-33.74%, and it can be seen that the composition of the present application has a good fat-dissolving effect.

[0325] Experimental Example 6, Cell Test Investigation

[0326] 1. Cell type

[0327] (1) Adipocytes (3T3-L1), from Shanghai Institute of Materia Medica, Chinese Academy of Sciences;

[0328] (2) Skeletal muscle cells (C2C12; mouse muscle cells, based on the 2nd passage), from Shanghai Institute of Materia Medica, Chinese Academy of Sciences;

[0329] (3) Vascular endothelial cells (HUVEC: human endothelium, based on the 3rd passage), from Shanghai Institute of Materia Medica, Chinese Academy of Sciences;

[0330] (4) Human epidermal keratinocytes (HACAT), from Shanghai Institute of Materia Medica, Chinese Academy of Sciences.

[0331] 2. Research process

[0332] Comparative Example 1 and compositions Z6, Z9 and Z10 were each diluted to a concentration of 125 μg / ml of the pharmaceutically active ingredient, and then 100 μl of each was added to each type of cell in good growth condition, and CCK-8 reagent was added, and then placed in a cell culture box for conventional culture for 1 day, and cell viability was detected.

[0333] 3. Detection results

[0334] The survival percentages of each cell in different compositions are shown in Table 23 and Figure 15. The difference and ratio of the survival percentages of different cells and the survival percentage of adipocytes are shown in Tables 24-25.

[0335] Table 23. Survival percentages of each cell in different compositions

[0336] Table 24. Difference in survival percentages of each cell in different compositions relative to the survival percentage of Comparative Example 1

[0337] Table 25. Ratio of survival percentages of different cells in different compositions and the survival percentage of adipocytes

[0338] From the results of Tables 24-25, it can be seen that, in addition to having a destructive effect on adipocytes, Comparative Example 1 also has a destructive effect on muscle cells, epidermal cells and endothelial cells. At the same concentration, the inventive composition can increase the survival percentage of cells other than adipocytes (such as muscle cells, epidermal keratinocytes, and venous endothelial cells) by at least 17% compared to Comparative Example 1.

[0339] As can be seen from Table 25, the ratio of the viability of other cells (such as adipocytes, epidermal cells and venous endothelial cells) to adipocytes is less than 1, indicating that the destructive intensity of Comparative Example 1 on other cells is greater than that on adipocytes; while the destructive intensity of the inventive composition on other cells is less than that on adipocytes, indicating that the inventive composition has selectivity for dissolving adipocytes compared to Comparative Example 1, and can reduce the attack or destruction on other cells, further verifying that the inventive composition has better safety.

[0340] At the same drug concentration, the survival percentage of adipocytes of Comparative Example 1 is higher than that of the inventive composition, indicating that the fat dissolving effect of the inventive composition is higher than that of Comparative Example 1.

[0341] The technical features of the above-described embodiments can be combined in any manner. To make the description concise, not all possible combinations of the technical features in the above-described embodiments are described, but as long as the combinations of the technical features do not contradict each other, they should be considered within the scope of the present disclosure.

[0342] The above-described embodiments only express several embodiments of the present application, and the description is more specific and detailed, but it should not be understood as limiting the scope of the patent. It should be noted that for those skilled in the art, without departing from the concept of the present application, a number of modifications and improvements can be made, which are within the scope of the present application. Therefore, the scope of protection of the present patent should be subject to the appended claims.

Claims

1. A lipolytic composition comprising: a pharmaceutically active ingredient, an inclusion material, a pH adjusting agent, optionally one or more selected from a buffer, a stabilizer, an osmotic pressure adjusting agent, and a complexing agent, and optionally purified water, wherein the pharmaceutically active ingredient being one or more selected from deoxycholic acid, a pharmaceutically acceptable salt of deoxycholic acid, and a deoxycholic acid derivative, wherein the inclusion material is used in an amount ranging from 4 to 35% based on the total weight of the lipolytic composition.

2. The lipolysis composition according to claim 1, wherein the inclusion material being one or more selected from cyclodextrin and derivatives thereof; preferably one or more selected from hydroxypropyl-β-cyclodextrin, sulfobutyl-β-cyclodextrin, methyl-β-cyclodextrin, carboxymethyl-β-cyclodextrin, hydroxyethyl-β-cyclodextrin, glucosyl-β-cyclodextrin, hydroxypropyl-γ-cyclodextrin, a-cyclodextrin, 2,6-dimethyl-β-cyclodextrin; more preferably one or both of hydroxypropyl-β-cyclodextrin and sulfobutyl-β-cyclodextrin.

3. The lipolytic composition according to claim 2, wherein the cyclodextrin and derivatives thereof include non-ionized forms and ionized forms and combinations thereof, the ionized forms being preferably in the form of a salt, in particular sodium or potassium salt; the sulfobutyl-β-cyclodextrin and carboxymethyl-β-cyclodextrin include non-ionized forms and ionized forms and combinations thereof, the ionized forms being preferably in the form of a salt, in particular sodium or potassium salt, more particularly, the ionized forms of the sulfobutyl-β-cyclodextrin and carboxymethyl-β-cyclodextrin are sulfobutyl-β-cyclodextrin sodium and carboxymethyl-β-cyclodextrin sodium, respectively.

4. The lipolysis composition according to any one of claims 1 to 3, wherein, the lipolytic composition has at least one of the following characteristics (1) to (10): (1) the lipolytic composition comprises 0.1 to 5% of the pharmaceutically active ingredient, 4 to 35% of the inclusion material, 0.01 to 5% of the pH adjusting agent, 0 to 10% of the stabilizer, 0 to 5% of the buffer, 0 to 5% of the osmotic pressure adjusting agent, 0 to 1% of the complexing agent, and 0 to 500 ml of purified water per g of the pharmaceutically active ingredient based on the total weight of the lipolytic composition; (2) the lipolytic composition comprises 0.2 to 4% of the pharmaceutically active ingredient, 5 to 30% of the inclusion material, 0.02 to 3% of the pH adjusting agent, 0 to 8% of the stabilizer, 0.01 to 3% of the buffer, 0 to 3% of the osmotic pressure adjusting agent, 0 to 0.8% of the complexing agent, and 0 to 400 ml of purified water per g of the pharmaceutically active ingredient based on the total weight of the lipolytic composition; (3) the lipolytic composition comprises 0.3 to 3% of the pharmaceutically active ingredient, 8 to 30% of the inclusion material, 0.03 to 2% of the pH adjusting agent, 0 to 5% of the stabilizer, 0.03 to 2% of the buffer, 0 to 2% of the osmotic pressure adjusting agent, 0 to 0.5% of the complexing agent, and 0 to 300 ml of purified water per g of the pharmaceutically active ingredient based on the total weight of the lipolytic composition; (4) Based on the total weight of the lipolysis composition, the lipolysis composition contains 0.5-2% of the active pharmaceutical ingredient, 10-28% of the inclusion material, 0.05-1% of the pH adjuster, 0-3% of the stabilizer, 0.05-1% of the buffer, 0-1% of the osmotic pressure adjuster, 0-0.3% of the complexing agent, and 0-200 ml of purified water / g of active pharmaceutical ingredient; (5) The pharmaceutically acceptable salt of the deoxycholic acid is sodium deoxycholate; the deoxycholic acid derivative is selected from one or more of the following: porcine deoxycholic acid, ursodeoxycholic acid, chenodeoxycholic acid, sodium porcine deoxycholate, sodium ursodeoxycholate, sodium chenodeoxycholate, cholic acid, sodium cholate, glycocholic acid, sodium glycocholate, glycodeoxycholic acid, sodium glycodeoxycholate, taurocholic acid, sodium taurocholate, taurodeoxycholic acid, tauroursodeoxycholic acid, tauroporcine deoxycholic acid, taurochenodeoxycholic acid, glycotaurocholic acid, sodium glycotaurocholate, lithocholic acid, sodium lithocholic acid, sodium glycodeoxycholate, sodium phenylpropanecholate, sodium tyrosylcholate, sodium leucocholate, cholic acid dimer, cholic acid side chain amino acid conjugate, cholic acid side chain PEG conjugate, and cholic acid side chain glucose conjugate. (6) The stabilizer is selected from one or more of injectable solvents and surfactants; the injectable solvent may be one or more of propylene glycol, ethanol, benzyl alcohol, dimethyl sulfoxide, N-methylpyrrolidone, liquid polyethylene glycol, dimethylacetamide, tetrahydrofuran polyethylene glycol ether, diethylene glycol monoethyl ether, and benzyl benzoate; the surfactant may be one or more of phosphatidylcholine, sorbitan fatty acid ester, polysorbate, polyoxyethylene fatty acid ester, polyoxyethylene fatty alcohol ether, poloxamer, hyaluronic acid, and sodium hyaluronate. (7) The pH adjuster is selected from one or more of pharmaceutically acceptable non-organic acids, organic acids, non-organic bases and organic bases; preferably selected from one or more of hydrochloric acid, phosphoric acid, acetic acid, sulfuric acid, citric acid, boric acid, lactic acid, methanesulfonic acid, maleic acid, tartaric acid, succinic acid, histidine, lysine, arginine, butyric acid, meglumine, ethylenediamine, ethanolamine, triethylamine, sodium hydroxide and potassium hydroxide; (8) The buffer is selected from one or more of the following: disodium hydrogen phosphate, dipotassium hydrogen phosphate, potassium dihydrogen phosphate, sodium dihydrogen phosphate, sodium phosphate, potassium phosphate, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, sodium citrate, potassium citrate, sodium acetate, potassium acetate, tris(hydroxymethyl)aminomethane, tris(hydroxymethyl)aminomethane hydrochloride, potassium hydrogen phthalate, sodium hydrogen phthalate, sodium tetraborate, potassium tetraborate, sodium barbital, and glycine. (9) The osmotic pressure regulator is selected from one or more of lactose, trehalose, xylitol, levonorgestrel, sorbitol, maltose, glycine, sarcosine, sodium chloride, potassium chloride, glucose, sucrose and mannitol; preferably selected from one or more of trehalose, lactose, sodium chloride, potassium chloride, glucose, sucrose and mannitol; (10) The complexing agent is selected from one or more of ethylenediaminetetraacetic acid, disodium ethylenediaminetetraacetic acid and calcium disodium ethylenediaminetetraacetic acid.

5. The lipolysis composition according to claim 1, wherein The pharmaceutical active ingredient comprises an associated part associated with the clathrate material to form a clathrate, and optionally, a free part not associated with the clathrate material to form a clathrate, preferably, the mass fraction of the free part in the pharmaceutical active ingredient is < 30%, optionally < 20%.

6. The lipolysis composition according to claim 1, wherein The total daily dose of the lipolytic composition is 0.1 mg-1000 mg, preferably 1 mg-500 mg, based on the pharmaceutical active ingredient.

7. Use of the lipolytic composition of any one of claims 1-6 in the preparation of a medicament for preventing or treating a fat-related disease.

8. Use according to claim 7, wherein, The fat-related disease includes, but is not limited to, one or more of fat accumulation, lipoma, painful lipoma, cellulite, lipedema, lipohypertrophy, lipodystrophy, lipomatosis, post-liposuction fat deposition, and obstructive sleep apnea; optionally, the dosage form of the medicament is an injection preparation; more optionally, the injection site of the injection preparation includes, but is not limited to, one or more of the abdomen, below the eyes, below the chin, below the arms, the hips, the thighs, the calves, the back, the bra line, the armpits, the stomach, and the ankles.

9. An injection preparation prepared from the lipolytic composition of any one of claims 1-6.

10. The injectable formulation according to claim 9, wherein, The injection preparation is used by injection, including, but not limited to, one or more of subcutaneous injection, intramuscular injection, intravenous injection, and intralesional injection.

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