Gel for injection

Abstract

A brexpiprazole gel for injection, comprising a solution containing brexpiprazole or a pharmaceutically acceptable salt thereof, and a solution containing at least one biocompatible biodegradable sustained-release material, wherein the two solutions are mixed before being administered to a patient in need thereof, and are mixed to form a clear solution, and the solution containing brexpiprazole or a pharmaceutically acceptable salt thereof can be formed by mixing a powder of brexpiprazole or the pharmaceutically acceptable salt thereof with a solvent.

Description

Injectable gel

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to Chinese patent application No. 202311156607.4, filed with the Chinese Patent Office on September 8, 2023, and entitled “Gel”, the entire contents of which are incorporated herein by reference. Technical Field

[0003] The present disclosure relates generally to the field of medicine, and more particularly to an injectable gel. Background Art

[0004] Schizophrenia is a serious mental illness that often manifests clinically as a syndrome with varying symptoms, involving multiple disorders in perception, thinking, emotion, behavior, and incoordination of mental activities; the course of the disease is prolonged, with repeated attacks or worsening, and some patients eventually experience decline and mental disability.

[0005] Eripiprazole, a 5-HT1A receptor and dopamine D2 receptor agonist and a 5-HT2A receptor antagonist, is clinically used to treat schizophrenia, major depression, and dementia caused by Alzheimer's disease. It offers improved efficacy and tolerability, reducing adverse reactions such as akathisia, restlessness, and insomnia. However, oral eripiprazole currently has poor compliance in the treatment of patients with psychiatric conditions, leading to a high relapse rate. Therefore, the development of alternative formulations of eripiprazole is needed.

[0006] Summary of the Invention

[0007] The present invention aims to develop an irinotecan gel for easy administration by injection. However, studies have found that irinotecan gel is prone to crystallization during preparation or storage, especially at high concentrations. Reducing crystallization and enabling administration of irinotecan gel as a solution is a pressing issue in the development of irinotecan gel. Furthermore, the present invention reduces crystallization in high-concentration products that typically crystallize using conventional formulation methods, resulting in improved physical stability and clinical safety.

[0008] In one aspect, the present disclosure relates to an epiprazole gel comprising epiprazole or a pharmaceutically acceptable salt thereof, at least one biocompatible and biodegradable sustained-release material, and at least one solvent, wherein the concentration of epiprazole or a pharmaceutically acceptable salt thereof is not less than 80 mg / mL.

[0009] In another aspect, the present disclosure relates to an epiprazole gel, which comprises a solution containing epiprazole or a pharmaceutically acceptable salt thereof, and a solution containing at least one biocompatible, biodegradable sustained-release material, wherein the two solutions are mixed before administration to a patient in need thereof, and the mixed solution is a clear solution.

[0010] The solution containing epiriprazole or a pharmaceutically acceptable salt thereof can be prepared by mixing the powder of epiriprazole or a pharmaceutically acceptable salt thereof with a solvent.

[0011] In another aspect, the present disclosure relates to a method for the adjunctive treatment of major depressive disorder in adults, comprising administering to a patient in need of the method an effective amount of an epiliprazole gel comprising epiliprazole or a pharmaceutically acceptable salt thereof, at least one biocompatible, biodegradable sustained-release material, and at least one solvent, wherein the concentration of the epiliprazole or a pharmaceutically acceptable salt thereof is not less than 80 mg / mL.

[0012] In another aspect, the present disclosure relates to a method for treating schizophrenia, comprising administering to a patient in need thereof an effective amount of an epiliprazole gel, the gel comprising epiliprazole or a pharmaceutically acceptable salt thereof, at least one biocompatible, biodegradable sustained-release material, and at least one solvent, wherein the concentration of the epiliprazole or the pharmaceutically acceptable salt thereof is not less than 80 mg / mL.

[0013] In another aspect, the present disclosure relates to a method for treating dementia-related agitation caused by Alzheimer's disease, comprising administering to a patient in need thereof an effective amount of eriprazole gel, the gel comprising eriprazole or a pharmaceutically acceptable salt thereof, at least one biocompatible, biodegradable sustained-release material, and at least one solvent, wherein the concentration of the eriprazole or a pharmaceutically acceptable salt thereof is not less than 80 mg / mL.

[0014] The present disclosure also provides a method for preparing an irinotecan gel, comprising first preparing a solution containing irinotecan or a pharmaceutically acceptable salt thereof and a solution containing at least one biocompatible, biodegradable sustained-release material. Before use, the solution containing irinotecan or a pharmaceutically acceptable salt thereof and the solution containing at least one biocompatible, biodegradable sustained-release material are mixed to prepare a gel.

[0015] The present disclosure also provides a method for preparing an irinotecan gel, comprising first preparing a solution containing at least one biocompatible, biodegradable sustained-release material, and then dissolving the irinotecan or a pharmaceutically acceptable salt thereof in a solvent before use to obtain a solution containing the irinotecan or a pharmaceutically acceptable salt thereof, which is then mixed with a solution containing at least one biocompatible, biodegradable sustained-release material to prepare a gel.

[0016] In some embodiments, the content of the epiriprazole or a pharmaceutically acceptable salt thereof is not less than 28 mg / g. Optionally, the content of the epiriprazole or a pharmaceutically acceptable salt thereof is in the range of 28 mg / g-120 mg / g.

[0017] In some embodiments, when the content of the eriprazole or its pharmaceutically acceptable salt is less than 80 mg / g, calculated based on the total mass of the eriprazole or its pharmaceutically acceptable salt, the sustained-release material and the solvent, the ratio of three times the content of the eriprazole or its pharmaceutically acceptable salt in the eriprazole gel to the sustained-release material is not higher than 500 mg / g, preferably not higher than 450 mg / g.

[0018] In some embodiments, when the content of the epiriprazole or a pharmaceutically acceptable salt thereof is lower than 80 mg / g, the sum of three times the content of the epiriprazole or a pharmaceutically acceptable salt thereof and the content of the sustained-release material in the epiriprazole gel, calculated based on the total mass of the epiriprazole or a pharmaceutically acceptable salt thereof, the sustained-release material and the solvent, is not higher than 430 mg / g, preferably not higher than 415 mg / g, and more preferably not higher than 395 mg / g.

[0019] In some embodiments, based on the total mass of epiriprazole or its pharmaceutically acceptable salt, sustained-release material and solvent, the sum of 3 times the content of epiriprazole or its pharmaceutically acceptable salt and the content of sustained-release material is not less than 322 mg / g.

[0020] In some embodiments, the content of the sustained-release material is not less than 80 mg / g. Optionally, the content of the sustained-release material ranges from 80 mg / g to 300 mg / g.

[0021] In some embodiments, when the content of the epiriprazole or a pharmaceutically acceptable salt thereof is not less than 80 mg / g, the sum of the content of the epiriprazole or a pharmaceutically acceptable salt thereof and the content of the sustained-release material in the epiriprazole gel, calculated based on the total mass of the epiriprazole or a pharmaceutically acceptable salt thereof, the sustained-release material and the solvent, is not higher than 320 mg / g, preferably not higher than 270 mg / g, and more preferably not higher than 235 mg / g.

[0022] In some embodiments, when the content of the epiriprazole or a pharmaceutically acceptable salt thereof is not less than 80 mg / g, the sum of the content of the epiriprazole or a pharmaceutically acceptable salt thereof and the content of the sustained-release material in the epiriprazole gel, calculated based on the total mass of the epiriprazole or a pharmaceutically acceptable salt thereof, the sustained-release material and the solvent, is not higher than 320 mg / g, preferably not higher than 270 mg / g, and more preferably not higher than 235 mg / g.

[0023] The gel is a solution at room temperature. When the content of the eriprazole or a pharmaceutically acceptable salt thereof is not less than 80 mg / g, the sum of the content of the eriprazole or a pharmaceutically acceptable salt thereof and the content of the sustained-release material in the eriprazole gel, calculated based on the total mass of the eriprazole or a pharmaceutically acceptable salt thereof, the sustained-release material, and the solvent, is not higher than 230 mg / g, preferably not higher than 210 mg / g, and more preferably not higher than 190 mg / g.

[0024] In some embodiments, the sum of the content of epiriprazole or its pharmaceutically acceptable salt and the content of the sustained-release material is not less than 180 mg / g, calculated based on the total mass of epiriprazole or its pharmaceutically acceptable salt, the sustained-release material and the solvent.

[0025] The present disclosure also provides use of epiprazole gel in preparing a medicament for the auxiliary treatment of major depressive disorder in adults.

[0026] The present disclosure also provides use of epiprazole gel in preparing a medicament for treating schizophrenia.

[0027] The present disclosure also provides use of epiriprazole gel in preparing a medicament for assisting in the treatment of dementia-related agitation caused by Alzheimer's disease.

[0028] The present disclosure relates to a method for adjunctive treatment of major depressive disorder in adults, comprising administering an effective amount of epiprazole gel to a patient in need of the method.

[0029] The present disclosure relates to a method for treating schizophrenia, comprising administering an effective amount of epiliprazole gel to a patient in need thereof.

[0030] The present disclosure relates to a method for treating dementia-related agitation caused by Alzheimer's disease, comprising administering an effective amount of epiliprazole gel to a patient in need thereof.

[0031] Details

[0032] In the following description, certain specific details are included to provide a comprehensive understanding of each disclosed embodiment. However, one skilled in the relevant art will recognize that the embodiments can still be implemented without one or more of these specific details and with other methods, components, materials, etc.

[0033] Unless otherwise required in this application, throughout the specification, the words "include", "comprising", "containing" and "having" should be interpreted as having an open and inclusive meaning, that is, "including but not limited to".

[0034] As used in this disclosure and the accompanying specifications, singular references without indication of quantity include plural references unless the context clearly dictates otherwise.

[0035] Reference throughout this specification to "one embodiment," "an embodiment," "in another embodiment," or "in certain embodiments" means that at least one embodiment includes the specific referenced elements, structures, or features described in connection with that embodiment. Thus, appearances of the phrases "in one embodiment," "in an embodiment," "in another embodiment," or "in certain embodiments" in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the specific elements, structures, or features may be combined in any suitable manner in one or more embodiments.

[0036] It should be understood that the singular article "a," "an," and "the" used in the specification of the present disclosure includes plural referents unless the context clearly dictates otherwise. Thus, for example, a reference to a sustained-release tablet containing "a pharmaceutically acceptable excipient" includes one pharmaceutically acceptable excipient, or two or more pharmaceutically acceptable excipients.

[0037] definition

[0038] In the present disclosure, the term "epiprazole" refers to 7-[4-[4-(1-benzo[b]thiophen-4-yl)piperazin-1yl]butoxy]quin-2(1H)-one.

[0039] In the present disclosure, the term "acceptable salt" refers to an acid addition salt or base addition salt prepared from a pharmaceutically acceptable acid or base; acceptable acid addition salts include, but are not limited to, benzenesulfonic acid, acetic acid, propionic acid, oxalic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, fumaric acid, succinic acid, suberic acid, lactic acid, mandelic acid, gluconic acid, phthalic acid, p-toluenesulfonic acid, citric acid, salicylic acid, tartaric acid, methanesulfonic acid, isonicotinic acid, acid citric acid, oleic acid, tannic acid, pantothenic acid, bitartrate, ascorbic acid, gentisic acid, fumaric acid, sugar acid, formic acid, ethanesulfonic acid, amino acids, hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, carbonic acid, phosphoric acid, phosphorous acid, sulfuric acid, and the like; acceptable base addition salts include, but are not limited to, diethanolamine salts, calcium salts, ammonium salts, lithium salts, sodium salts, potassium salts, aluminum salts, magnesium salts, zinc salts, bismuth salts, and the like.

[0040] In the present disclosure, the term "biocompatible and biodegradable sustained-release material" refers to a natural or synthetic biomedical material that has biocompatibility and acceptability, can adjust the drug release rate, is continuously degraded under the action of body fluids, is absorbed or excreted from the body, and is eventually completely replaced by new tissue.

[0041] In this disclosure, the term "gel" refers to a type of injectable gel, typically composed primarily of a pharmaceutically active ingredient, a biocompatible solvent, and a biodegradable polymer. After injection, the gel undergoes a rapid phase transition from liquid to solid at the site of administration, prolonging the drug's residence time at the site of administration. Simultaneously, as the polymer slowly degrades, the encapsulated drug is fully released over a period of weeks to months, achieving sustained or controlled release.

[0042] In the present disclosure, the term "room temperature" refers to 20 to 30°C.

[0043] The term "solution" in the present invention is also called a single-phase homogeneous mixture, which refers to a dispersed system obtained by uniformly and stably distributing a pure substance in the form of molecules or ions in another pure substance, without any visible precipitate or precipitate.

[0044] The term "clear" in the present invention means that there is no precipitate or precipitate visible to the naked eye in the gel.

[0045] The term "crystallization" in the present invention means that there are precipitates or precipitates visible to the naked eye in the gel.

[0046] In this context, the term "incremental intrusion" refers to the amount of mercury that enters the pore space of a sample as pressure increases during mercury porosimetry. This method measures how the pore space is filled with mercury as pressure is applied, providing insights into the pore structure and distribution within the sample.

[0047] The term "burst-release peak blood concentration" in the present invention refers to the first peak blood concentration of a drug that is rapidly reached within a short period of time after administration.

[0048] The term "second peak blood concentration" in the present invention refers to a higher peak blood concentration reached again after the sustained release of the drug.

[0049] The term "AUC0-t" in the present invention refers to the area under the plasma drug concentration-time curve from time 0 to time t, wherein t refers to the collection time of the last measurable concentration.

[0050] The term "AUCinf" in the present invention refers to the area under the plasma drug concentration-time curve from time 0 to infinite time.

[0051] The term "T 1 / 2 ” refers to the time required for the blood drug concentration to drop by half. BRIEF DESCRIPTION OF THE DRAWINGS

[0052] FIG1 is a graph showing the effect of the sum of API content*3 and PLGA content on crystallization when the API content is not less than 80 mg / g.

[0053] FIG2 is a graph showing the effect of the sum of the API content and the PLGA content on the crystallization when the API content is not less than 80 mg / g.

[0054] FIG3 is a graph showing the effect of the sum of API content*3 and PLGA content on crystallization when the API content is lower than 80 mg / g.

[0055] FIG4 is a graph showing the pore size distribution test results of the irinotecan gel after solidification.

[0056] FIG5a is a pharmacokinetic (PK) blood concentration-time curve of epiriprazole gel in rats (abscissa 0-2 days).

[0057] FIG5 b is the pharmacokinetic (PK) blood concentration-time curve of epiriprazole gel in rats (abscissa 0-42 days). DETAILED DESCRIPTION

[0058] In one aspect, the present disclosure relates to an epiprazole gel comprising epiprazole or a pharmaceutically acceptable salt thereof, at least one biocompatible and biodegradable sustained-release material, and at least one solvent, wherein the concentration of epiprazole or a pharmaceutically acceptable salt thereof is not less than 80 mg / mL.

[0059] In certain embodiments, the concentration of eriprazole or a pharmaceutically acceptable salt thereof in the eriprazole gel of the present disclosure is not less than 81 mg / mL, 82 mg / mL, 83 mg / mL, 84 mg / mL, 85 mg / mL, 85 mg / mL, 86 mg / mL, 87 mg / mL, 88 mg / mL, 89 mg / mL, 90 mg / mL, 91 mg / mL, 92 mg / mL, 93 mg / mL, 94 mg / mL, 95 mg / mL, 96 mg / mL, 97 mg / mL, 98 mg / mL, 99 mg / mL, 100 mg / mL, 101 mg / mL, 102 mg / mL, 103 mg / mL, 104 mg / mL. g / mL, 105mg / mL, 106mg / mL, 107mg / mL, 108mg / mL, 109mg / mL, 110mg / mL, 111mg / mL, 112mg / mL, 113mg / mL, 114mg / mL, 115mg / mL, 116mg / mL, 117mg / mL, 118mg / mL, 119mg / mL, 120mg / mL, 121mg / mL, 122mg / mL, 123mg / mL, 124mg / mL, 125mg / mL, 126mg / mL, 127mg / mL, 128mg / mL, 129mg / mL or 130mg / mL.

[0060] In certain embodiments, the sum of three times the concentration of eriprazole or a pharmaceutically acceptable salt thereof and the concentration of the sustained-release material in the eriprazole gel of the present disclosure is no greater than 600 mg / mL, 595 mg / mL, 590 mg / mL, 585 mg / mL, 580 mg / mL, or 575 mg / mL, 570 mg / mL, 570 mg / mL, 565 mg / mL, 560 mg / mL, 555 mg / mL, 550 mg / mL, 545 mg / mL, 540 mg / mL, 535 mg / mL, 530 mg / mL, 525 mg / mL, 520 mg / mL, 515 mg / mL, 510 mg / mL, 505 mg / mL, 500 mg / mL, 495 mg / mL, or 490 mg / mL.

[0061] In certain embodiments, illustrative examples of biocompatible, biodegradable sustained-release materials that can be used in the gels of the present disclosure include, but are not limited to, polyamides, polyamines, polyalkylene oxalates, polyanhydrides, polyamide esters, copoly(ether-esters), polycarbonates, polyorthoesters, polylactides, polyglycolides, polylactic acid, poly(lactic-co-glycolic acid), polyorthoesters, polycaprolactones, polyphosphazenes, polysaccharides, protein polymers, polysaccharide derivatives, soluble derivatives of protein polymers, polypeptides, polyesters, polyorthoesters, and copolymers, block copolymers, homopolymers, mixtures, and combinations thereof.

[0062] In certain embodiments, illustrative examples of biocompatible, biodegradable sustained-release materials that can be used to form the microspheres of the present disclosure include, but are not limited to, poly(lactic-co-glycolic acid), also known as poly(lactic-co-glycolic acid), or PLGA, having a molar ratio of lactic acid (lactide) to glycolic acid (glycolide) of about 50:50 to about 95:5.

[0063] In certain embodiments, illustrative examples of the at least one solvent that can be used in the gels of the present disclosure include, but are not limited to, organic solvents.

[0064] In certain embodiments, exemplary organic solvents that can be used in the present disclosure include, but are not limited to, alcohol solvents, ester solvents, ether solvents, ketone solvents, and amide solvents.

[0065] In certain embodiments, illustrative examples of alcohol solvents that can be used in the present disclosure include, but are not limited to, ethanol, n-propanol, isopropanol, n-butanol, propylene glycol, glycerol, or 1,3-butanediol.

[0066] In certain embodiments, exemplary ester solvents that can be used in the present disclosure include, but are not limited to, ethyl acetate, methyl acetate, ethyl formate, butyl acetate, diethyl malonate, n-butyl acetate, or isobutyl acetate.

[0067] In certain embodiments, illustrative examples of ether solvents that can be used in the present disclosure include, but are not limited to, tetrahydrofuran, methyltetrahydrofuran, diethylene glycol monomethyl ether, or tetrahydrofuran polyglycol ether.

[0068] In certain embodiments, illustrative examples of ketone solvents that can be used in the present disclosure include, but are not limited to, acetone, methyl ethyl ketone, diethyl ketone, or methyl isobutyl ketone.

[0069] In certain embodiments, exemplary examples of amide solvents that can be used in the present disclosure include, but are not limited to, formamide, dimethylformamide, dimethylacetamide, hexamethylphosphorus triamide, N-methyl-2-pyrrolidone, N-cyclohexyl-2-pyrrolidone, N-hydroxyethyl-2-pyrrolidone, 2-pyrrolidone, or N-ethyl-2-pyrrolidone.

[0070] In another aspect, the present disclosure relates to an epiprazole gel, which comprises a solution containing epiprazole or a pharmaceutically acceptable salt thereof, and a solution containing at least one biocompatible, biodegradable sustained-release material, wherein the two solutions are mixed before administration to a patient in need thereof, and the mixed solution is a clear solution.

[0071] In certain embodiments, the solution containing eriprazole or a pharmaceutically acceptable salt thereof according to the present disclosure can be prepared by mixing powder of eriprazole or a pharmaceutically acceptable salt thereof with a solvent.

[0072] In certain embodiments, the present disclosure relates to epiriprazole gel that is a clear solution at room temperature.

[0073] In certain embodiments, the concentration of eriprazole or a pharmaceutically acceptable salt thereof in the eriprazole gel of the present disclosure is 80 mg / mL, 81 mg / mL, 82 mg / mL, 83 mg / mL, 84 mg / mL, 85 mg / mL, 85 mg / mL, 86 mg / mL, 87 mg / mL, 88 mg / mL, 89 mg / mL, 90 mg / mL, 91 mg / mL, 92 mg / mL, 93 mg / mL, 94 mg / mL, 95 mg / mL, 96 mg / mL, 97 mg / mL, 98 mg / mL, 99 mg / mL, 100 mg / mL, 101mg / mL, 102mg / mL, 103mg / mL, 104mg / mL, 105mg / mL, 106mg / mL, 107mg / mL, 108mg / mL, 109mg / mL, 110mg / mL, 111mg / mL, 112mg / mL, 113mg / mL, 114mg / mL, 115mg / mL, 116mg / mL, 117mg / mL, 118mg / mL, 119mg / mL, 120mg / mL, 121mg / mL, 122mg / mL, 123mg / mL, 124mg / mL, 125mg / mL, 126mg / mL, 127mg / mL, 128mg / mL, 129mg / mL or 130mg / mL.

[0074] In certain embodiments, the sum of three times the concentration of eriprazole or a pharmaceutically acceptable salt thereof and the concentration of the sustained-release material in the eriprazole gel of the present disclosure is no more than 600 mg / mL, 595 mg / mL, 590 mg / mL, 585 mg / mL, 580 mg / mL, or 575 mg / mL, 570 mg / mL, 570 mg / mL, 565 mg / mL, 560 mg / mL, 555 mg / mL, 550 mg / mL, 545 mg / mL, 540 mg / mL, 535 mg / mL, 530 mg / mL, 525 mg / mL, 520 mg / mL, 515 mg / mL, 510 mg / mL, 505 mg / mL, 500 mg / mL, 495 mg / mL, or 490 mg / mL.

[0075] In another aspect, the present disclosure relates to a method for the auxiliary treatment of major depressive disorder in adults, comprising administering to a patient in need thereof an effective amount of eriprazole gel, comprising eriprazole or a pharmaceutically acceptable salt thereof, at least one biocompatible, biodegradable sustained-release material, and at least one solvent, wherein the concentration of said eriprazole or a pharmaceutically acceptable salt thereof is not less than 80 mg / mL, 81 mg / mL, 82 mg / mL, 83 mg / mL, 84 mg / mL, 85 mg / mL, 85 mg / mL, 86 mg / mL, 87 mg / mL, 88 mg / mL, 89 mg / mL, 90 mg / mL, 91 mg / mL, 92 mg / mL, 93 mg / mL, 94 mg / mL, 95 mg / mL, 96 mg / mL, 97 mg / mL, 98 mg / mL, 99 mg / mL, 100 mg / mL, 101 mg / mL, 102 mg / mL, 103 mg / mL, 104 mg / mL, 105 mg / mL, 106 mg / mL, 107 mg / mL, 108 mg / mL, 109 mg / mL, 110 mg / mL, 111 mg / mL, 112 mg / mL, 113 mg / mL, 114 mg / mL, 115 mg / mL, 116 mg / mL, 117 mg / mL, 118 mg / mL, 119 mg / mL, 120 mg / mL, 121 1 15mg / mL, 116mg / mL, 117mg / mL, 118mg / mL, 119mg / mL, 120mg / mL, 121mg / mL, 122mg / mL, 123mg / mL, 124mg / mL, 125mg / mL, 126mg / mL, 127mg / mL, 128mg / mL, 129mg / mL or 130mg / mL.

[0076] In certain embodiments, the gel that can be used in the administration method of the present disclosure has a concentration of 3 times the concentration of epiriprazole or its pharmaceutically acceptable salt and the concentration of the sustained-release material of no more than 600 mg / mL, 595 mg / mL, 590 mg / mL, 585 mg / mL, 580 mg / mL, or 575 mg / mL, 570 mg / mL, 570 mg / mL, 565 mg / mL, 560 mg / mL, 555 mg / mL, 550 mg / mL, 545 mg / mL, 540 mg / mL, 535 mg / mL, 530 mg / mL, 525 mg / mL, 520 mg / mL, 515 mg / mL, 510 mg / mL, 505 mg / mL, 500 mg / mL, 495 mg / mL, or 490 mg / mL.

[0077] In certain embodiments, the gel that can be used in the administration method of the present disclosure comprises a solution containing eriprazole or a pharmaceutically acceptable salt thereof, and a solution containing at least one biocompatible, biodegradable sustained-release material, wherein the two solutions are mixed before administration to a patient in need thereof, and the mixed solution is obtained.

[0078] In another aspect, the present disclosure relates to a method for treating schizophrenia, comprising administering to a patient in need thereof an effective amount of epiprazole gel comprising epiprazole or a pharmaceutically acceptable salt thereof, at least one biocompatible, biodegradable sustained-release material, and at least one solvent.

[0079] In certain embodiments, the concentration of eriprazole or its pharmaceutically acceptable salt in the eriprazole gel that can be used in the administration method of the present disclosure is not less than 80 mg / mL, 81 mg / mL, 82 mg / mL, 83 mg / mL, 84 mg / mL, 85 mg / mL, 85 mg / mL, 86 mg / mL, 87 mg / mL, 88 mg / mL, 89 mg / mL, 90 mg / mL, 91 mg / mL, 92 mg / mL, 93 mg / mL, 94 mg / mL, 95 mg / mL, 96 mg / mL, 97 mg / mL, 98 mg / mL, 99 mg / mL, 100 mg / mL, 101 mg / mL, 102 mg / mL, 103 mg / mL, g / mL, 104mg / mL, 105mg / mL, 106mg / mL, 107mg / mL, 108mg / mL, 109mg / mL, 110mg / mL, 111mg / mL, 112mg / mL, 113mg / mL, 114mg / mL, 115mg / mL, 116mg / mL, 11 7mg / mL, 118mg / mL, 119mg / mL, 120mg / mL, 121mg / mL, 122mg / mL, 123mg / mL, 124mg / mL, 125mg / mL, 126mg / mL, 127mg / mL, 128mg / mL, 129mg / mL or 130mg / mL.

[0080] In certain embodiments, the sum of three times the concentration of the eriprazole or its pharmaceutically acceptable salt and the concentration of the sustained-release material in the eriprazole gel that can be used in the administration method of the present disclosure is no more than 600 mg / mL, 595 mg / mL, 590 mg / mL, 585 mg / mL, 580 mg / mL, or 575 mg / mL, 570 mg / mL, 570 mg / mL, 565 mg / mL, 560 mg / mL, 555 mg / mL, 550 mg / mL, 545 mg / mL, 540 mg / mL, 535 mg / mL, 530 mg / mL, 525 mg / mL, 520 mg / mL, 515 mg / mL, 510 mg / mL, 505 mg / mL, 500 mg / mL, 495 mg / mL, or 490 mg / mL.

[0081] In certain embodiments, the gel that can be used in the administration method of the present disclosure comprises a solution containing eriprazole or a pharmaceutically acceptable salt thereof, and a solution containing at least one biocompatible, biodegradable sustained-release material, wherein the two solutions are mixed before administration to a patient in need thereof, and the mixed solution is obtained.

[0082] In certain embodiments, the gels useful in the disclosed administration methods are solutions at room temperature.

[0083] In another aspect, the present disclosure relates to a method for treating dementia-related agitation caused by Alzheimer's disease, comprising administering to a patient in need thereof an effective amount of epiliprazole gel comprising epiliprazole or a pharmaceutically acceptable salt thereof, at least one biocompatible, biodegradable sustained-release material, and at least one solvent.

[0084] In certain embodiments, the concentration of eriprazole or its pharmaceutically acceptable salt in the eriprazole gel that can be used in the administration method of the present disclosure is not less than 80 mg / mL, 81 mg / mL, 82 mg / mL, 83 mg / mL, 84 mg / mL, 85 mg / mL, 85 mg / mL, 86 mg / mL, 87 mg / mL, 88 mg / mL, 89 mg / mL, 90 mg / mL, 91 mg / mL, 92 mg / mL, 93 mg / mL, 94 mg / mL, 95 mg / mL, 96 mg / mL, 97 mg / mL, 98 mg / mL, 99 mg / mL, 100 mg / mL, 101 mg / mL, 102 mg / mL, 103 mg / mL, g / mL, 104mg / mL, 105mg / mL, 106mg / mL, 107mg / mL, 108mg / mL, 109mg / mL, 110mg / mL, 111mg / mL, 112mg / mL, 113mg / mL, 114mg / mL, 115mg / mL, 116mg / mL, 11 7mg / mL, 118mg / mL, 119mg / mL, 120mg / mL, 121mg / mL, 122mg / mL, 123mg / mL, 124mg / mL, 125mg / mL, 126mg / mL, 127mg / mL, 128mg / mL, 129mg / mL or 130mg / mL.

[0085] In certain embodiments, the sum of three times the concentration of the eriprazole or its pharmaceutically acceptable salt and the concentration of the sustained-release material in the eriprazole gel that can be used in the administration method of the present disclosure is no more than 600 mg / mL, 595 mg / mL, 590 mg / mL, 585 mg / mL, 580 mg / mL, or 575 mg / mL, 570 mg / mL, 570 mg / mL, 565 mg / mL, 560 mg / mL, 555 mg / mL, 550 mg / mL, 545 mg / mL, 540 mg / mL, 535 mg / mL, 530 mg / mL, 525 mg / mL, 520 mg / mL, 515 mg / mL, 510 mg / mL, 505 mg / mL, 500 mg / mL, 495 mg / mL, or 490 mg / mL.

[0086] In certain embodiments, the gel that can be used in the administration method of the present disclosure comprises a solution containing eriprazole or a pharmaceutically acceptable salt thereof, and a solution containing at least one biocompatible, biodegradable sustained-release material, wherein the two solutions are mixed before administration to a patient in need thereof, and the mixed solution is obtained.

[0087] In certain embodiments, the gels useful in the disclosed administration methods are solutions at room temperature.

[0088] In certain embodiments, the gels of the present disclosure provide release of eriprazole or a pharmaceutically acceptable salt thereof for a duration of at least about 1 month.

[0089] In another aspect, the present disclosure also provides a method for preparing an irinotecan gel, comprising first preparing a solution containing irinotecan or a pharmaceutically acceptable salt thereof and a solution containing at least one biocompatible, biodegradable sustained-release material. Before use, the solution containing irinotecan or a pharmaceutically acceptable salt thereof and the solution containing at least one biocompatible, biodegradable sustained-release material are mixed to prepare a gel.

[0090] In certain embodiments, the solution containing eriprazole or a pharmaceutically acceptable salt thereof can be prepared by mixing eriprazole or a pharmaceutically acceptable salt thereof with a solvent. The solution containing at least one biocompatible and biodegradable sustained-release material can be prepared by mixing the sustained-release material with a solvent.

[0091] In another aspect, the present disclosure also provides a method for preparing an irinotecan gel, comprising first preparing a solution containing at least one biocompatible, biodegradable sustained-release material, and then dissolving the irinotecan or a pharmaceutically acceptable salt thereof in a solvent before use to obtain a solution containing the irinotecan or a pharmaceutically acceptable salt thereof, which is then mixed with a solution containing at least one biocompatible, biodegradable sustained-release material to obtain a gel.

[0092] The container for preparing or mixing the two solutions can be a conventional container, such as a vial, a screw-cap glass bottle, a blue-cap bottle, a polytetrafluoroethylene bottle, a polypropylene bottle, etc.

[0093] In certain embodiments, the solution containing at least one biocompatible, biodegradable sustained-release material can be prepared by mixing the sustained-release material with a solvent.

[0094] In some embodiments, when the content of the epiriprazole or a pharmaceutically acceptable salt thereof is less than 80 mg / g (e.g., not less than 28 mg / g and less than 80 mg / g), the sum of three times the content of the epiriprazole or a pharmaceutically acceptable salt thereof and the content of the sustained-release material in the epiriprazole gel, calculated based on the total mass of the epiriprazole or a pharmaceutically acceptable salt thereof, the sustained-release material and the solvent, is not higher than 500 mg / g. For example, the sum of three times the content of the epiliprazole or its pharmaceutically acceptable salt in the epiliprazole gel and the content of the sustained-release material can be 500 mg / g, 480 mg / g, 460 mg / g, 450 mg / g, 440 mg / g, 420 mg / g, 405 mg / g, 390 mg / g, 380 mg / g, 370 mg / g, 360 mg / g, 350 mg / g, 340 mg / g, 330 mg / g, 320 mg / g, 310 mg / g, 300 mg / g, 280 mg / g, 260 mg / g, 250 mg / g, 240 mg / g, 230 mg / g, 220 mg / g, 200 mg / g, 150 mg / g, 100 mg / g, 50 mg / g, or within the range of any two of the above values. For example, the content of the epiriprazole or a pharmaceutically acceptable salt thereof is 30 mg / g, 32 mg / g, 34 mg / g, 46 mg / g, 48 mg / g, 50 mg / g, 52 mg / g, 55 mg / g, 58 mg / g, 60 mg / g, 64 mg / g, 66 mg / g, 65 mg / g, 68 mg / g, 70 mg / g, 72 mg / g, 74 mg / g, 76 mg / g, 78 mg / g, 79 mg / g or within the range formed by any two of the above values.

[0095] In some embodiments, based on the total mass of the eriprazole or its pharmaceutically acceptable salt, the sustained-release material and the solvent, the sum of three times the content of the eriprazole or its pharmaceutically acceptable salt and the content of the sustained-release material is not less than 322 mg / g. For example, the sum of three times the content of the eriprazole or its pharmaceutically acceptable salt and the content of the sustained-release material in the eriprazole gel can be 500 mg / g, 480 mg / g, 460 mg / g, 450 mg / g, 440 mg / g, 420 mg / g, 405 mg / g, 390 mg / g, 380 mg / g, 370 mg / g, 360 mg / g, 350 mg / g, 340 mg / g, 330 mg / g, or within the range of any two of the above values.

[0096] In some embodiments, for example, the sum of three times the content of the iriprazole or its pharmaceutically acceptable salt in the iriprazole gel and the content of the sustained-release material can be 358.5 mg / g, 363.6 mg / g, 366.7 mg / g, 371.4 mg / g, 387.8 mg / g, 389.8 mg / g, 398.4 mg / g, 400 mg / g, 405.8 mg / g, 410.7 mg / g, 422.2 mg / g, 428.6 mg / g, 440 mg / g, 440.9 mg / g, 444.4 mg / g, 454.5 mg / g, 478.3 mg / g, or within the range formed by any two of the above values.

[0097] In some embodiments, the content of the epiriprazole or a pharmaceutically acceptable salt thereof is not less than 28 mg / g. Optionally, the content of the epiriprazole or a pharmaceutically acceptable salt thereof is in the range of 28 mg / g to 120 mg / g. For example, the content of the epiriprazole or a pharmaceutically acceptable salt thereof can be 28.6 mg / g, 45.5 mg / g, 50 mg / g, 54.5 mg / g, 55.6 mg / g, 56.6 mg / g, 61.2 mg / g, 66.7 mg / g, 80 mg / g, 87 mg / g, 90.9 mg / g, 93.8 mg / g, 95.2 mg / g, 101.7 mg / g, 107.1 mg / g, or in the range formed by any two of the above values.

[0098] In some embodiments, the content of the sustained-release material is not less than 80 mg / g. Optionally, the content of the sustained-release material is in the range of 80 mg / g to 300 mg / g. For example, the content of the sustained-release material can be 84.7 mg / g, 89.3 mg / g, 117.2 mg / g, 142.9 mg / g, 144.9 mg / g, 166.7 mg / g, 181.8 mg / g, 188.7 mg / g, 200 mg / g, 204.1 mg / g, 217.4 mg / g, 222.2 mg / g, 227.3 mg / g, 250 mg / g, 277.3 mg / g, 277.8 mg / g, 285.7 mg / g, or in the range formed by any two of the above values.

[0099] In some embodiments, when the content of the eriprazole or its pharmaceutically acceptable salt is not less than 80 mg / g, calculated based on the total mass of the eriprazole or its pharmaceutically acceptable salt, the sustained-release material, and the solvent, the sum of the content of the eriprazole or its pharmaceutically acceptable salt and the content of the sustained-release material in the eriprazole gel is not more than 320 mg / g. For example, the sum of the content of the eriprazole or its pharmaceutically acceptable salt and the content of the sustained-release material in the eriprazole gel can be 320 mg / g, 310 mg / g, 300 mg / g, 280 mg / g, 260 mg / g, 250 mg / g, 240 mg / g, 230 mg / g, 220 mg / g, 200 mg / g, 150 mg / g, 100 mg / g, 50 mg / g, or within a range formed by any two of the above values. For example, the content of epiriprazole or a pharmaceutically acceptable salt thereof is 80 mg / g, 82 mg / g, 84 mg / g, 86 mg / g, 88 mg / g, 90 mg / g, 92 mg / g, 95 mg / g, 98 mg / g, 110 mg / g, 114 mg / g, 116 mg / g, 115 mg / g, 118 mg / g, 120 mg / g or within a range formed by any two of the above values.

[0100] In some embodiments, for example, when the content of the epiriprazole or a pharmaceutically acceptable salt thereof is not less than 80 mg / g, the sum of the content of the epiriprazole or a pharmaceutically acceptable salt thereof and the content of the sustained-release material in the epiriprazole gel may be 333.3 mg / g, 331.8 mg / g, 288.9 mg / g, 300.0 mg / g, 265.3 mg / g, 314.3 mg / g, 272.7 mg / g, 216.9 mg / g, 245.3 mg / g, or within the range formed by any two of the above values.

[0101] In some embodiments, when the content of the eriprazole or its pharmaceutically acceptable salt is not less than 80 mg / g, the sum of the content of the eriprazole or its pharmaceutically acceptable salt and the content of the sustained-release material, calculated based on the total mass of the eriprazole or its pharmaceutically acceptable salt, the sustained-release material and the solvent, is not less than 180 mg / g. For example, the sum of the content of the eriprazole or its pharmaceutically acceptable salt and the content of the sustained-release material in the eriprazole gel can be 320 mg / g, 310 mg / g, 300 mg / g, 280 mg / g, 260 mg / g, 250 mg / g, 240 mg / g, 230 mg / g, 220 mg / g, 200 mg / g, 180 mg / g, or within a range formed by any two of the above values.

[0102] Hereinafter, the present disclosure will be explained in detail through the following examples in order to better understand the various aspects and advantages of the present disclosure. However, it should be understood that the following examples are non-limiting and are only used to illustrate certain embodiments of the present disclosure.

[0103] Example

[0104] The reagents and equipment used in the examples of this disclosure are conventional and commercially available.

[0105] Examples 1-18

[0106] Examples 1-18 provide a series of epiriprazole gels and preparation methods thereof. The formulations of the epiriprazole gels in each example are shown in Table 1, wherein the API is epiriprazole, PLGA is poly(lactic acid-co-glycolic acid) 50:50, and NMP is N-methyl-2-pyrrolidone.

[0107] The specific preparation methods of these gels are all as follows:

[0108] 1. The full amount of N-methyl-2-pyrrolidone in the formulation is divided into two parts. One portion of N-methyl-2-pyrrolidone serves as the solvent for the API solution, dissolving 430 mg of N-methyl-2-pyrrolidone for every 60 mg of epiriprazole. The remaining portion of N-methyl-2-pyrrolidone serves as the solvent for the polymer solution. Prepare the API solution and polymer solution separately and mix them using a prefilled syringe to create the gel.

[0109] The preparation process of the API solution and the polymer solution is described in detail below. Because there will inevitably be residues when the solution is transferred from the preparation container to the prefilled syringe, the API solution and the polymer solution are prepared at 2-15 times the mass.

[0110] 2. Preparation of API Solution

[0111] Place epiriprazole into a vial and add N-methyl-2-pyrrolidone (430 mg of N-methyl-2-pyrrolidone for every 60 mg of epiriprazole). Shake manually for 1-2 minutes to completely dissolve the epiriprazole. After the API is completely dissolved, fill the prescribed amount of epiriprazole solution into a new pre-filled syringe and set aside.

[0112] 3. Preparation of Polymer Solution

[0113] After the poly(lactic acid-co-glycolic acid) is completely dissolved with the remaining N-methyl-2-pyrrolidone to obtain a polymer solution, the prescribed amount of the polymer solution is filled into a female pre-filled syringe for later use.

[0114] 4. The sum of the components of the male and female prefilled syringes is the full prescription amount.

[0115] 5. When using, connect the male and female pre-filled syringes, push and pull to mix for 1 minute (about 60-100 times back and forth) to mix the gel evenly to obtain the gel.

[0116] For example, the preparation method of the gel in Example 2 is as follows: 180 mg of irinotecan (3 times the prescribed amount) is placed in a vial, and N-methyl-2-pyrrolidone (430 mg of N-methyl-2-pyrrolidone is added for every 60 mg of irinotecan). The vial is manually shaken for 1-2 minutes to completely dissolve the irinotecan. After the API is completely dissolved, the prescribed amount of irinotecan solution is filled into a new male prefilled syringe and set aside. Poly(lactic-co-glycolic acid) (750 mg, 5 times the prescribed amount) is completely dissolved in N-methyl-2-pyrrolidone (250 mg; the amount of NMP in the irinotecan solution in the male prefilled syringe is subtracted from the prescribed amount of NMP and multiplied by 5) to obtain a polymer solution. The prescribed amount of polymer solution is then filled into a female prefilled syringe and set aside. The sum of the material components in the male and female prefilled syringes is the full prescribed amount. When using, connect the male and female pre-filled syringes, push and pull to mix for 1 minute (about 60-100 times back and forth) to mix the gel evenly to obtain the gel.

[0117] The PLGA used in Example 5 is of model 5050 0.10-0.30 dL / g, manufactured by Ashland, and the PLGA used in Examples 1-4 and 6-18 is of model 5050 0.16-0.24 dL / g, manufactured by Evonik.

[0118] Table 1 Prescription table

[0119] In the table, API content = mass of API / (mass of API + mass of PLGA + mass of NMP)*100%; PLGA content = mass of PLGA / (mass of API + mass of PLGA + mass of NMP)*100%; API content*3+PLGA content = 3*mass of API / (mass of API + mass of PLGA + mass of NMP)*100%+mass of PLGA / (mass of API + mass of PLGA + mass of NMP)*100%.

[0120] Comparative Examples 1-11

[0121] Comparative Examples 1-11 provide a series of irinotecan gels and their preparation methods. The formulations of the irinotecan gels in each comparative example are shown in Table 2. The ratios of API, PLGA, and NMP in the formulations of the irinotecan gels in Comparative Examples 1-11 are the same as those in Examples 1-10 and 12, except that the preparation methods are different. The preparation methods of the gels in Comparative Examples 1-11 of this series are all as follows:

[0122] The prescribed amount of N-methyl-2-pyrrolidone was added to a 10 ml vial containing the prescribed amount of epiriprazole and manually shaken for 1-2 minutes to completely dissolve the epiriprazole. The prescribed amount of PLGA (poly(lactic-co-glycolic acid)) was then added to the vial, sealed, and placed on a roller mixer (manufacturer: CRYSTAL, model specification: MR-020) for mixing at a speed of 20-50 RPM until the PLGA was dissolved or evenly suspended to obtain a gel.

[0123] The PLGA used in Comparative Example 5 is of model 5050 0.10-0.30 dL / g, manufactured by Ashland, and the PLGA used in Comparative Examples 1-4 and 6-11 is of model 5050 0.16-0.24 dL / g, manufactured by Evonik.

[0124] Table 2 Prescription table

[0125] Experimental Example 1 Crystallization Experiment

[0126] In the preparation of the polymer solution for the sample of Example 1, poly(lactic acid-co-glycolic acid) and N-methyl-2-pyrrolidone were sealed and mixed. However, the poly(lactic acid-co-glycolic acid) did not dissolve after being left for 5 days, and a gel could not be prepared. Therefore, a crystallization experiment was not performed.

[0127] 1. The freshly prepared gels from Examples 2-18 were placed at room temperature and observed under a clarity meter at 0 h, 1 h, 2 h, 4 h, 8 h, 24 h, 48 h, 66 h, 72 h, 96 h, 120 h, 144 h, and longer (observed every 24 h after 72 h). The gel state was observed. See Table 3 for the experimental results.

[0128] Table 3 Crystallization test results of the gels of various examples

[0129] Note: The crystallization condition was obtained by visually observing the properties of the gel using a clarity tester (manufacturer: Jingtuo Instruments, specification model: YB-IIA).

[0130] 2. Freshly prepared gels from Comparative Examples 1-10 and 12 were placed at room temperature and continuously observed under a clarity meter for 0-1 hour. The time when crystallization was first observed was recorded. The gel state was then observed under a clarity meter at 2 hours, 4 hours, 22 hours, 24 hours, and 48 hours. The experimental results are shown in Table 4.

[0131] Table 4 Crystallization results of gels of various comparative examples

[0132] Note: The crystallization condition was obtained by visually observing the properties of the gel using a clarity tester (manufacturer: Jingtuo Instruments, specification model: YB-IIA).

[0133] It can be seen from the crystallization test results in Tables 3 and 4 that, compared with the comparative examples, except for Example 1, the gels obtained in the Examples of the present invention significantly improved the problem of easy crystallization of the epiriprazole gel during preparation or storage, indicating that the method of the present invention is conducive to preparing a solution-like and stable gel.

[0134] To investigate the crystallization of irinotecan gel and further understand the cause of crystallization in Example 1, data from various Examples were analyzed and it was found that the crystallization of irinotecan gel was not correlated with the API content. For example, when comparing Example 6 with Example 13, the API content in Example 6 was 80 mg / g, while the API content in Example 13 was 101.7 mg / g. In Example 7, crystallization first occurred in 1 hour, much earlier than the 144 hours without crystallization in Example 13. Further examples include Example 2 versus Example 10, Example 14 versus Example 4, Example 14 versus Example 5, and Example 14 versus Example 11.

[0135] Moreover, when the API content is lower than 80 mg / g, the crystallization situation (such as crystallization time) is also not related to the sum of the API content and the PLGA content. For example, comparing Example 8 with Example 15, the sum of the API content and the PLGA content in Example 8 is 288.9 mg / g, and the sum of the API content and the PLGA content in Example 15 is 314.3 mg / g. The time of the first crystallization in Example 8 is 48 h, much earlier than 144 h without crystallization in Example 15.

[0136] The inventors unexpectedly found that when the API content is lower than 80 mg / g, the crystallization situation (such as crystallization time) is related to the sum of three times the API content and the PLGA content. Moreover, the lower the sum of three times the API content and the PLGA content, the longer the gel remains in the solution state and the later the crystallization occurs. By controlling the sum of three times the API content and the PLGA content, not only can a solution-like gel be prepared to enable the injection of iloperidone gel in the form of a solution, but also the crystallization can be further reduced, the time of the solution state can be extended, the product can have better physical stability and clinical safety, and it is more convenient to use.

[0137] When 430 mg / g < the sum of three times the API content and the PLGA content ≤ 450 mg / g, the crystallization situation is further improved, and the gel remains in the solution state when placed at room temperature for more than 8 h. For example, in Examples 4 and 5, the sum of three times the API content and the PLGA content is between 440.9 mg / g and 444.4 mg / g, and the gel crystallizes when placed at room temperature for 24 h (remaining in the solution state for at least 8 h). When 415 mg / g < the sum of three times the API content and the PLGA content ≤ 430 mg / g, the crystallization situation is further improved, and the gel remains in the solution state when placed at room temperature for more than 24 h. For example, in Example 8, the sum of three times the API content and the PLGA content is 422.2 mg / g, and the gel crystallizes when placed at room temperature for 48 h (remaining in the solution state for at least 24 h). When 395 mg / g < the sum of three times the API content and the PLGA content ≤ 415 mg / g, the crystallization situation is further improved. For example, in Example 11, the sum of three times the API content and the PLGA content is 400.0 mg / g, and the gel crystallizes when placed at room temperature for 96 h (remaining in the solution state for at least 72 h). When the sum of three times the API content and the PLGA content ≤ 395 mg / g, the crystallization situation is further improved, and the gel remains in the solution state when placed at room temperature for more than 144 h. For example, in Examples 14 - 18, the sum of three times the API content and the PLGA content is between 358.5 mg / g and 387.8 mg / g, and the gel still remains in the solution state when placed at room temperature for 144 h.

[0138] The inventors unexpectedly found that when the API content is not less than 80 mg / g, the crystallization situation (such as crystallization time) is related to the sum of the API content and the PLGA content, and the lower the sum of the API content and the PLGA content, the longer the gel remains in the solution state and the later the crystallization occurs. By controlling the sum of the API content and the PLGA content, not only can a solution-like gel be prepared to enable the aripiprazole gel to be injected in the form of a solution, but also the crystallization can be further reduced, the solution state time can be extended, the product has better physical stability and clinical safety, and it is more convenient to use.

[0139] When 270 mg / g < the sum of the API content and the PLGA content ≤ 320 mg / g, a solution-like gel can be obtained by using the method of the present invention, but crystallization occurs after standing for a period of time. For example, in Examples 2, 3, and 6, the sum of the API content and the PLGA content is between 272.7 mg / g - 304.3 mg / g, and crystallization occurs when the gel is placed at room temperature for 1 h. When 235 mg / g < the sum of the API content and the PLGA content ≤ 270 mg / g, the crystallization situation is further improved. For example, in Example 7, the sum of the API content and the PLGA content is 238.1 mg / g, and crystallization occurs when the gel is placed at room temperature for 8 h (remaining in the solution state for at least 4 h). When 230 mg / g < the sum of the API content and the PLGA content ≤ 235 mg / g, the crystallization situation is further improved. For example, in Example 10, the sum of the API content and the PLGA content is 231.9 mg / g, and crystallization occurs when the gel is placed at room temperature for 66 h (remaining in the solution state for at least 48 h). When 210 mg / g < the sum of the API content and the PLGA content ≤ 230 mg / g, the crystallization situation is further improved. For example, in Example 12, the sum of the API content and the PLGA content is 210.9 mg / g, and crystallization occurs when the gel is placed at room temperature for 72 h (remaining in the solution state for at least 66 h). When 190 mg / g < the sum of the API content and the PLGA content ≤ 210 mg / g, the crystallization situation is further improved. For example, in Example 9, the sum of the API content and the PLGA content is 196.4 mg / g, and crystallization occurs when the gel is placed at room temperature for 96 h (remaining in the solution state for at least 72 h). When the sum of the API content and the PLGA content ≤ 190 mg / g, the gel remains in the solution state when placed at room temperature for more than 144 h. For example, in Example 13, the sum of the API content and the PLGA content is 186.4 mg / g.

[0140] When the API content is no less than 80 mg / g, a graph showing the effect of the sum of API content*3 and PLGA content (mg / g) on ​​crystallization is plotted (Figure 1), with the sum of API content*3 and PLGA content (mg / g) as the horizontal axis and the time to first observed crystallization (h) as the vertical axis. As can be seen from Figure 1, when the API content is no less than 80 mg / g, as the sum of the API content and PLGA content decreases by three times, the time that some gels remain in solution at room temperature increases, while others decrease.

[0141] When the API content is not less than 80 mg / g, a graph showing the effect of the sum of the API and PLGA contents on crystallization is plotted (Figure 2), with the sum of the API and PLGA contents (mg / g) as the abscissa and the time to first observed crystallization (h) as the ordinate. As can be seen from Figure 2, when the API content is not less than 80 mg / g, the gel remains in solution significantly longer at room temperature as the sum of the API and PLGA contents decreases.

[0142] When the API content is less than 80 mg / g, a graph showing the effect of API content*3 and PLGA content on crystallization is plotted (Figure 3), with the sum of API content*3 and PLGA content (mg / g) as the abscissa and the time to first observed crystallization (h) as the ordinate. As can be seen from Figure 3, when the API content is less than 80 mg / g, the gel remains in solution significantly longer at room temperature as the sum of the API content and PLGA content decreases by three times.

[0143] Experimental Example 2: Pore Size Distribution Test

[0144] The gel of the present invention solidifies after injection to form a solid. This section measures the pore size distribution inside the solid material after the gel is injected and solidified.

[0145] a. Experimental methods and instruments:

[0146] Preparation of gel samples of Example 10B and Example 17B

[0147] The contents of API, PLGA, and NMP in the gel sample of Example 10B are the same as the contents of the three substances in the prescription of Example 10. The preparation methods of the gel samples of Example 10B and Example 17B are as follows:

[0148] 1) Divide the full amount of N-methyl-2-pyrrolidone into two parts. One part is used to dissolve the API, i.e., prepare the API solution. For every 60 mg of epiriprazole, 430 mg of N-methyl-2-pyrrolidone is used to dissolve the API. The remaining N-methyl-2-pyrrolidone is used to prepare the polymer solution. Finally, the API solution and polymer solution are mixed using a prefilled syringe to obtain a gel.

[0149] 2) The preparation process of the API solution and the polymer solution is described in detail below. Because there will inevitably be residue when the solution is transferred from the preparation container to the prefilled syringe, the API solution and the polymer solution are prepared in 2-10 times the amount.

[0150] 3) Preparation of API solution

[0151] Place 25kGy Gamma irradiation sterilized epiriprazole into a vial, and add 25kGy Gamma irradiation sterilized N-methyl-2-pyrrolidone (430mg of N-methyl-2-pyrrolidone for every 60mg of epiriprazole). Manually shake for 1-2 minutes to completely dissolve the epiriprazole. After the API is completely dissolved, fill the prescribed amount of epiriprazole solution into a new male prefilled syringe and set aside.

[0152] 4) Preparation of polymer solution

[0153] After completely dissolving poly(lactic acid-co-glycolic acid) with the remaining amount of N-methyl-2-pyrrolidone, a polymer solution was obtained. After sterilization by 25 kGy Gamma irradiation, the prescribed amount of polymer solution was filled into a female prefilled syringe for later use.

[0154] 5) The sum of the components of the male and female prefilled syringes is the full prescription amount.

[0155] 6) When using, connect the male and female pre-filled syringes, push and pull to mix for 1 minute (about 60-100 times back and forth) to mix the gel evenly to obtain the gel.

[0156] Specifically, the specific formulation of the gel sample of Example 10B is as follows: API 60 mg, PLGA 100 mg, NMP 530 mg. The preparation method and the amounts of each substance used are as follows:

[0157] 1) Place 240 mg (4 times the prescribed amount) of 25 kGy Gamma irradiated epiriprazole into a vial and add 25 kGy Gamma irradiated N-methyl-2-pyrrolidone (430 mg of N-methyl-2-pyrrolidone for every 60 mg of epiriprazole). Manually shake for 1-2 minutes to completely dissolve the epiriprazole. After the API is completely dissolved, fill the prescribed amount of epiriprazole solution into a new male prefilled syringe and set aside.

[0158] 2) After completely dissolving 400 mg (4 times the prescribed amount) of poly(lactic-co-glycolic acid) in 400 mg of N-methyl-2-pyrrolidone, the solution was sterilized by 25 kGy gamma irradiation to obtain a polymer solution. The prescribed amount of polymer solution was filled into a female prefilled syringe and set aside.

[0159] 3) When using, connect the male and female pre-filled syringes, push and pull to mix for 1 minute (about 60-100 times back and forth) to mix the gel evenly to obtain the gel.

[0160] The formulation of the gel sample in Example 17B was the same as that in Example 10, and the preparation method provided in Example 10B was basically used, except that the amounts of the various substances used in the preparation of the polymer solution and the epiriprazole solution were adjusted accordingly according to the formulation in Example 17B.

[0161] b. Subcutaneous injection in rats

[0162] Male Sprague-Dawley rats weighing approximately 200-400 g were randomly divided into groups and maintained at 20-25°C and 40-70% relative humidity with a standard diet and free access to water. Two groups of rats received subcutaneous injections of the two aforementioned irinotecan gels, one on the left and one on the right side of the neck. The corresponding dose, calculated based on the weight of irinotecan, was 15 mg per injection (i.e., 15 mg on each side).

[0163] c. Material

[0164] 48 hours after administration, the rats were killed and the injection site was dissected to remove the complete solidified gel samples. The solidified gel samples with complete shape and no tissue adhesion were selected for the next freeze-drying process.

[0165] d. Freeze-drying

[0166] The gel sample was placed in a 10 ml borosilicate vial for freeze-drying. The freeze-drying equipment and freeze-drying parameters are shown in Table 5.

[0167] Table 5 Lyophilization

[0168] e. The samples after freeze-drying are used for porosity testing.

[0169] Porosity testing instrument information: mercury intrusion instrument, Micromeritics, Autopore 9620;

[0170] Porosity test steps: Place the sample to be tested into the dilatometer, insert the dilatometer into the instrument and inject mercury. The results will provide the pore volume distribution of pores with a pore size of 360μm to 0.003μm.

[0171] Calculation method of Incremental Intrusion (mL / g): Select the incremental intrusion (mL / g) values ​​(i.e., incremental pore volume) corresponding to the pore size diameter (nm) range of 6000-9000 and add them together to obtain the result.

[0172] f. Experimental results:

[0173] The pore size distribution test results are shown in Table 6 and Figure 4.

[0174] Table 6 Pore size distribution test results

[0175] Experimental Example 3 Pharmacokinetics Test in Rats

[0176] Experimental methods:

[0177] a. Example 10C Gel Sample Preparation:

[0178] The specific formulation of the gel sample of Example 10C is as follows: API 60 mg, PLGA 100 mg, NMP 530 mg. The contents of API, PLGA, and NMP in Example 10C are the same as those in Example 10, and the preparation method provided in Example 10B is used to prepare the epiriprazole gel.

[0179] b. Experimental steps:

[0180] Healthy male Sprague-Dawley rats (purchased from Zhuhai Baishitong Biotechnology Co., Ltd.) weighing approximately 200-300 g were used; three rats were maintained at 20-25°C and 40-70% relative humidity with a standard diet and free access to water and food. The rats received a single subcutaneous injection of the gel sample from Example 10C described above into the lateral buttocks at a dose of 18 mg / kg of the gel, calculated based on the mass of the gel.

[0181] Orbital blood collection points of rats: Blood was collected at 0.5 hours, 2 hours, 4 hours, 8 hours, 24 hours, 2 days, 3 days, 5 days, 8 days, 11 days, 14 days, 17 days, 21 days, 24 days, 28 days, 31 days, 35 days, and 39 days after administration.

[0182] c. Instruments and testing procedures:

[0183] High-performance liquid chromatography-triple quadrupole mass spectrometry (HPLC-MS / MS) was used to determine the concentration of eriprazole in rat plasma. The linear range was 0.05 ng / mL to 150 ng / mL. A 50 μL rat plasma sample was pretreated using protein precipitation with aripiprazole as the internal standard. The responses of eriprazole and its internal standard (aripiprazole) were then detected using an electrospray (+) ion source. The pharmacokinetic profiles of the different formulations were compared.

[0184] d. Written description of PK curve drawing:

[0185] The PK data obtained from the test were used to draw a PK curve using an EXCEL table, with the horizontal axis corresponding to time and the vertical axis corresponding to the cumulative blood drug concentration.

[0186] Experimental results:

[0187] The PK results of the gel in rats are shown in Table 7 and Figures 5a and 5b.

[0188] Table 7 PK parameters

[0189] Note: t = 39 days

[0190] As can be seen from Figures 5a and 5b, the gel of the present invention has a good sustained-release effect.

[0191] In this disclosure, relational terms such as first and second, etc. are used merely to distinguish one entity or operation from another entity or operation, but do not necessarily require or imply any actual relationship or order between these entities or operations.

[0192] It will be appreciated from the foregoing that, although specific embodiments of the present disclosure have been described for illustrative purposes, various modifications or variations may be made by those skilled in the art without departing from the spirit and scope of the present disclosure. Such modifications or variations are intended to fall within the scope of the accompanying description of the present disclosure.

Claims

1. An epiprazole gel, comprising a solution containing epiprazole or a pharmaceutically acceptable salt thereof, and a solution containing at least one biocompatible, biodegradable sustained-release material, wherein the two solutions are mixed before administration to a patient in need thereof, and the mixed solution is a clear solution; in, The solution containing epiprazole or a pharmaceutically acceptable salt thereof can be prepared by mixing powder of epiprazole or a pharmaceutically acceptable salt thereof with a solvent.

2. The gel according to claim 1, comprising at least one biocompatible, biodegradable sustained-release material and at least one solvent, wherein the concentration of epiriprazole or a pharmaceutically acceptable salt thereof is not less than 80 mg / mL.

3. The gel according to claim 1 or 2, wherein the sum of three times the concentration of the epiriprazole or its pharmaceutically acceptable salt and the concentration of the sustained-release material is not higher than 600 mg / mL.

4. A method for assisting the treatment of major depressive disorder in adults, comprising administering an effective amount of the gel according to any one of claims 1 to 3 to a patient in need of the method.

5. A method for treating schizophrenia, comprising administering an effective amount of the gel according to any one of claims 1 to 3 to a patient in need of said method.

6. A method for treating dementia-related agitation caused by Alzheimer's disease, comprising administering an effective amount of the gel according to any one of claims 1 to 3 to a patient in need of said method.

7. A method for preparing an irinotecan gel, comprising first preparing a solution containing irinotecan or a pharmaceutically acceptable salt thereof and a solution containing at least one biocompatible, biodegradable sustained-release material, and mixing the solution containing irinotecan or a pharmaceutically acceptable salt thereof and the solution containing at least one biocompatible, biodegradable sustained-release material before use to prepare a gel.

8. A method for preparing an irinotecan gel, comprising first preparing a solution containing at least one biocompatible, biodegradable sustained-release material, dissolving the irinotecan or a pharmaceutically acceptable salt thereof in a solvent before use to obtain a solution containing irinotecan or a pharmaceutically acceptable salt thereof, and then mixing the solution with a solution containing at least one biocompatible, biodegradable sustained-release material to obtain a gel.

9. The eriprazole gel according to any one of claims 1 to 3 or the eriprazole gel prepared by the preparation method according to claim 7 or 8, wherein the content of the eriprazole or its pharmaceutically acceptable salt is not less than 28 mg / g, and optionally, the content of the eriprazole or its pharmaceutically acceptable salt ranges from 28 mg / g to 120 mg / g.

10. The epiprazole gel according to any one of claims 1 to 3 or the epiprazole gel prepared by the preparation method according to claim 7 or 8, wherein When the content of the epiriprazole or its pharmaceutically acceptable salt is lower than 80 mg / g, the sum of three times the content of the epiriprazole or its pharmaceutically acceptable salt in the epiriprazole gel and the content of the sustained-release material, calculated based on the total mass of the epiriprazole or its pharmaceutically acceptable salt, the sustained-release material and the solvent, is not higher than 500 mg / g, preferably not higher than 450 mg / g.

11. The epiprazole gel according to any one of claims 1 to 3 or the epiprazole gel prepared by the preparation method according to claim 7 or 8, wherein: When the content of the epiriprazole or its pharmaceutically acceptable salt is lower than 80 mg / g, the sum of 3 times the content of the epiriprazole or its pharmaceutically acceptable salt in the epiriprazole gel and the content of the sustained-release material, calculated based on the total mass of the epiriprazole or its pharmaceutically acceptable salt, the sustained-release material and the solvent, is not higher than 430 mg / g, preferably not higher than 415 mg / g, and more preferably not higher than 395 mg / g.

12. The epiprazole gel according to any one of claims 1 to 3 or the epiprazole gel prepared by the preparation method according to claim 7 or 8, wherein: Calculated based on the total mass of epiriprazole or its pharmaceutically acceptable salt, sustained-release material and solvent, the sum of 3 times the content of epiriprazole or its pharmaceutically acceptable salt and the content of sustained-release material is not less than 322 mg / g.

13. The epiprazole gel according to any one of claims 1 to 3 or the epiprazole gel prepared by the preparation method according to claim 7 or 8, wherein the content of the sustained-release material is not less than 80 mg / g, and optionally, the content of the sustained-release material ranges from 80 mg / g to 300 mg / g.

14. The epiprazole gel according to any one of claims 1 to 3 or the epiprazole gel prepared by the preparation method according to claim 7 or 8, wherein: When the content of the epiriprazole or its pharmaceutically acceptable salt is not less than 80 mg / g, the sum of the content of the epiriprazole or its pharmaceutically acceptable salt and the content of the sustained-release material in the epiriprazole gel is not higher than 320 mg / g, preferably not higher than 270 mg / g, and more preferably not higher than 235 mg / g, calculated based on the total mass of the epiriprazole or its pharmaceutically acceptable salt, the sustained-release material and the solvent.

15. The epiprazole gel according to any one of claims 1 to 3 or the epiprazole gel prepared by the preparation method according to claim 7 or 8, wherein When the content of the epiriprazole or its pharmaceutically acceptable salt is not less than 80 mg / g, the sum of the content of the epiriprazole or its pharmaceutically acceptable salt and the content of the sustained-release material in the epiriprazole gel, calculated based on the total mass of the epiriprazole or its pharmaceutically acceptable salt, the sustained-release material and the solvent, is not higher than 230 mg / g, preferably not higher than 210 mg / g, and more preferably not higher than 190 mg / g.

16. The epiprazole gel according to any one of claims 1 to 3 or the epiprazole gel prepared by the preparation method according to claim 7 or 8, wherein: Calculated based on the total mass of epiriprazole or its pharmaceutically acceptable salt, sustained-release material and solvent, the sum of the content of epiriprazole or its pharmaceutically acceptable salt and the content of sustained-release material is not less than 180 mg / g.

17. Use of the epiprazole gel according to any one of claims 1 to 3 or the epiprazole gel prepared by the preparation method according to claim 7 or 8 in the preparation of a drug for the auxiliary treatment of major depressive disorder in adults.

18. Use of the epiprazole gel according to any one of claims 1 to 3 or the epiprazole gel prepared by the preparation method according to claim 7 or 8 in the preparation of a drug for treating schizophrenia.

19. Use of the epiprazole gel according to any one of claims 1 to 3 or the epiprazole gel prepared by the preparation method according to claim 7 or 8 in the preparation of a medicament for treating agitation associated with dementia caused by Alzheimer's disease.

20. A method for auxiliary treatment of major depressive disorder in adults, comprising administering an effective amount of the epiprazole gel prepared by the preparation method of claim 7 or 8 to a patient in need of the method.

21. A method for treating schizophrenia, comprising administering an effective amount of the epiprazole gel prepared by the preparation method of claim 7 or 8 to a patient in need of the method.

22. A method for treating dementia-related agitation caused by Alzheimer's disease, comprising administering an effective amount of the epiprazole gel prepared by the preparation method of claim 7 or 8 to a patient in need of the method.

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