Brexpiprazole gel for injection

Abstract

The brexpiprazole gel comprises brexpiprazole or a pharmaceutically acceptable salt thereof, at least one biocompatible biodegradable sustained-release material and at least one solvent, and based on the total mass of brexpiprazole or the pharmaceutically acceptable salt thereof, the sustained-release material and the solvent, the total mass of the brexpiprazole or the pharmaceutically acceptable salt thereof, the sustained-release material and the solvent accounts for 30-60% of the total mass of the brexpiprazole gel. The sum of three times of the content of brexpiprazole or pharmaceutically acceptable salts thereof and the content of the sustained-release material is not higher than 500mg / g.

Description

Eripiprazole gel for injection

[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 generally relates to the field of medicine, and more particularly, to an injectable epiliprazole 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, in the current treatment of patients with psychiatric conditions, oral eripiprazole has poor compliance and the risk of missed doses, leading to a high relapse rate. The development of a long-acting formulation of eripiprazole is needed to address these issues.

[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, particularly in high-concentration irinotecan gels. Reducing crystallization and enabling irinotecan gel to be administered as a clear solution is a pressing issue in developing irinotecan gel. Furthermore, enabling irinotecan gel to be released in a suitable immediate-release and sustained-release manner after administration is another pressing issue in developing irinotecan gel. One of the technical issues addressed by the present invention is to reduce crystallization and enable irinotecan gel to be injected as a clear solution. A further technical issue addressed by the present invention is enabling irinotecan gel to be released in a suitable immediate-release and sustained-release manner after administration.

[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 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.

[0010] 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.

[0011] 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.

[0012] In another aspect, the present disclosure further provides an irinotecan gel, comprising irinotecan or a pharmaceutically acceptable salt thereof, at least one biocompatible, biodegradable sustained-release material, and at least one solvent, wherein, based on the total mass of irinotecan or a pharmaceutically acceptable salt thereof, the sustained-release material, and the solvent, the sum of three times the content of irinotecan or a pharmaceutically acceptable salt thereof and the content of the sustained-release material is not higher than 500 mg / g. Within this range, the irinotecan gel can be a clear solution at room temperature, or can be a clear solution when the temperature is increased from room temperature to 60°C; alternatively, the sum of three times the content of irinotecan or a pharmaceutically acceptable salt thereof and the content of the sustained-release material is not higher than 500 mg / g. Not higher than 455 mg / g, within this range, the eriprazole gel can be a clear solution at room temperature, or a clear solution when the temperature is increased from room temperature to 40°C; optionally, the sum of 3 times the content of the eriprazole or its pharmaceutically acceptable salt and the content of the sustained-release material is not higher than 441 mg / g, within this range, the eriprazole gel can be a clear solution at room temperature, or a clear solution when the temperature is increased from room temperature to 35°C; optionally, the sum of 3 times the content of the eriprazole or its pharmaceutically acceptable salt and the content of the sustained-release material is not higher than 400 mg / g, within this range, the eriprazole gel is a clear solution at room temperature.

[0013] In some embodiments, 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 the epiriprazole or its pharmaceutically acceptable salt and the content of the sustained-release material is not higher than 499mg / g, 498mg / g, 497mg / g, 496mg / g, 495mg / g, 494mg / g, 493mg / g, 492mg / g, 491mg / g, 490mg / g, 489mg / g, 488mg / g, 487mg / g, 486mg / g, 485mg / g, 484mg / g, 483mg / g, 482mg / g, 481mg / g, 480mg / g, 479mg / g, 478mg / g, 479 ... 76mg / g, 475mg / g, 474mg / g, 473mg / g, 472mg / g, 471mg / g, 470mg / g, 469mg / g, 468mg / g, 467mg / g, 466mg / g, 465mg / g, 464mg / g, 463mg / g, 462mg / g, 461mg / g, 460mg / g, 459mg / g, 458mg / g, 457mg / g, 456mg / g, 455mg / g, 454mg / g, 453mg / g, 452mg / g, 451mg / g, 450mg / g, 449mg / g, 448mg / g, 447mg / g, 446mg / g, 445mg / g, 444mg / g, 443mg / g, 442mg / g, 441mg / g, 440mg / g, 439mg / g, 438mg / g, 437mg / g, 436mg / g, 435mg / g , 434mg / g, 433mg / g, 432mg / g, 431mg / g, 430mg / g, 429mg / g, 428mg / g, 427mg / g, 426mg / g, 425mg / g, 424mg / g, 423mg / g, 422, 421mg / g, 420 mg / g, 419mg / g, 418mg / g, 417mg / g, 416mg / g, 415mg / g, 414mg / g, 413mg / g, 412mg / g, 411mg / g, 410mg / g, 409mg / g, 408mg / g, 407mg / g, 406 mg / g, 405mg / g, 404mg / g, 403mg / g, 402mg / g, 401mg / g, 400mg / g, 399mg / g, 398mg / g, 397mg / g, 396mg / g, 395mg / g, 394mg / g, 393mg / g, 392 mg / g, 391mg / g, 390mg / g, 389mg / g, 388mg / g, 387mg / g, 386mg / g, 385mg / g, 384mg / g, 383mg / g or 380mg / g. ,

[0014] 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-102 mg / g, and further optionally in the range of 66 mg / g-73 mg / g.

[0015] In some embodiments, based on the total mass of epiriprazole or a pharmaceutically acceptable salt thereof, the sustained-release material and the solvent, the sum of three times the content of epiriprazole or a pharmaceutically acceptable salt thereof and the content of the sustained-release material is not less than 322 mg / g. Optionally, the sum of three times the content of epiriprazole or a pharmaceutically acceptable salt thereof and the content of the sustained-release material ranges from 322 mg / g to 500 mg / g, alternatively from 322 mg / g to 455 mg / g, alternatively from 322 mg / g to 441 mg / g, or alternatively from 322 mg / g to 400 mg / g.

[0016] 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 the sustained-release material is not less than 323 mg / g, 324 mg / g, 325 mg / g, 326 mg / g, 327 mg / g, 328 mg / g, 329 mg / g, 330 mg / g, 331 mg / g, 332 mg / g, 333 mg / g, 334 mg / g, 335 mg / g, 336 mg / g, 337 mg / g, 338 mg / g, 339 mg / g, 340 mg / g, 341 mg / g, 342 mg / g, 343 mg / g, 344 mg / g, 345 mg / g, 346 mg / g, 347 mg / g, 348 mg / g, 349 mg / g, 350 mg / g, 351 mg / g, 352 mg / g, 353 mg / g, 354 mg / g, 355 mg / g, 356 mg / g, 357 mg / g, 358 mg / g, 359 mg / g, 360 mg / g, 361 mg / g, 362 mg / g, 363 mg / g, 364 mg / g, 365 mg / g, 366 mg / g, 367 mg / g, 368 mg / g, 369 mg / g, 2mg / g, 343mg / g, 344mg / g, 345mg / g, 346mg / g, 347mg / g, 348mg / g, 349mg / g, 350mg / g, 351mg / g, 352mg / g, 353mg / g, 354mg / g, 355mg / g, 356mg / g, 357mg / g, 358mg / g, 359mg / g, 360mg / g, 361mg / g, 362mg / g, 363mg / g, 364mg / g, 365mg / g, 366mg / g, 367mg / g, 368mg / g, 369mg / g or 370mg / g.

[0017] In some embodiments, the sum of three times the content of the eriprazole or its pharmaceutically acceptable salt and the content of the sustained-release material is 361 mg / g-391 mg / g, alternatively 371 mg / g-391 mg / g, and further alternatively 371 mg / g-388 mg / g. The inventors unexpectedly discovered that within these ranges, the eriprazole gel has a satisfactory pore size distribution and sustained-release effect after injection.

[0018] In some embodiments, the ratio of the content of the sustained-release material to the content of the eriprazole or its pharmaceutically acceptable salt, calculated based on the total mass of the eriprazole or its pharmaceutically acceptable salt, the sustained-release material, and the solvent, is (0.8-10):1, preferably (0.8-3.3):1, and further preferably (2.0-2.3):1. The inventors unexpectedly discovered that, by further controlling the range of the ratio of the content of the sustained-release material to the content of the eriprazole or its pharmaceutically acceptable salt, in addition to controlling the sum of the content of three times the eriprazole or its pharmaceutically acceptable salt and the content of the sustained-release material, the eriprazole gel can be further improved to have a satisfactory pore size distribution and sustained-release effect after injection.

[0019] In another aspect, the present disclosure further provides use of epiprazole gel in preparing a medicament for the auxiliary treatment of major depressive disorder in adults.

[0020] In yet another aspect, the present disclosure further provides use of epiprazole gel in preparing a medicament for treating schizophrenia.

[0021] In yet another aspect, the present disclosure further provides use of epiprazole gel in preparing a medicament for the auxiliary treatment of dementia-related agitation caused by Alzheimer's disease.

[0022] In yet another aspect, the present disclosure further provides a method for assisting in the treatment of major depressive disorder in adults, comprising administering an effective amount of the gel provided by the present disclosure to a patient in need of the method.

[0023] In yet another aspect, the present disclosure further provides a method for treating schizophrenia, comprising administering an effective amount of the gel provided by the present disclosure to a patient in need thereof.

[0024] In yet another aspect, the present disclosure further provides a method for assisting in the treatment of dementia-related agitation caused by Alzheimer's disease, comprising administering an effective amount of the gel provided by the present disclosure to a patient in need of the method.

[0025] Details

[0026] 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.

[0027] Unless otherwise required in this application, throughout the specification and the appended claims, the words "including," "comprising," "containing," and "having" should be interpreted in an open, inclusive sense, that is, "including but not limited to."

[0028] As used in this disclosure and the appended claims, singular references without indications of quantity include plural references unless the context clearly dictates otherwise.

[0029] 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.

[0030] It should be understood that the singular articles "a," "an," and "the" used in the specification and appended claims of this disclosure include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to a sustained-release tablet containing "a pharmaceutically acceptable excipient" includes one pharmaceutically acceptable excipient, or two or more pharmaceutically acceptable excipients.

[0031] definition

[0032] In the present disclosure, the term "Brexpiprazole" refers to 7-[4-[4-(1-benzo[b]thiophen-4-yl)piperazin-1yl]butoxy]quin-2(1H)-one, whose English name is Brexpiprazole.

[0033] 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.

[0034] 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.

[0035] In this disclosure, the term "gel" refers to an in situ gel, also known as an injectable gel, typically composed of a biocompatible solvent and a biodegradable polymer. After injection as a liquid, the gel rapidly undergoes a phase transition from liquid to a solid or semi-solid state at the site of administration, prolonging the drug's residence time at the site of administration. Simultaneously, as the biodegradable polymer slowly degrades, the encapsulated drug is fully released over a period of weeks to months, achieving sustained or controlled release.

[0036] In the present disclosure, the term "room temperature" refers to 10 to 30°C.

[0037] The term "clear" in the present invention means that there is no precipitate or precipitate visible to the naked eye in the gel.

[0038] The term "suspension" in the present invention means that there are precipitates or precipitates visible to the naked eye in the gel. BRIEF DESCRIPTION OF THE DRAWINGS

[0039] Figure 1 shows the relationship between the effects of API concentration*3 and PLGA concentration on crystallization.

[0040] Figure 2a is a graph showing the pore size distribution test results (0-1000 nm) after gel curing.

[0041] FIG2 b is a graph showing the pore size distribution test results (0-10000 nm) after gel curing.

[0042] Figure 3a is a comparison of the PK experiments of different formulations of irinotecan long-acting gel in rats.

[0043] FIG3 b is a partially enlarged view of FIG3 a . DETAILED DESCRIPTION

[0044] 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.

[0045] 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.

[0046] 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.

[0047] In certain embodiments, illustrative examples of biocompatible, biodegradable sustained-release materials that can be used to form the gel of the present disclosure include, but are not limited to, lactide-co-glycolide copolymers having a molar ratio of lactic acid (lactide) to glycolic acid (glycolide) of about 50:50 to about 95:5. In the present application, lactide-co-glycolide copolymers and poly (lactic acid-co-glycolic acid) are the same substance, abbreviated as PLGA.

[0048] 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.

[0049] 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.

[0050] 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.

[0051] 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.

[0052] 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.

[0053] 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.

[0054] 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.

[0055] 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.

[0056] 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.

[0057] 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.

[0058] 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.

[0059] 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.

[0060] 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.

[0061] 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.

[0062] 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.

[0063] 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.

[0064] The gel of the present invention can be prepared by conventional preparation methods, for example, the following method: a prescribed amount of N-methyl-2-pyrrolidone is added to a container containing a prescribed amount of irinotecan, and after manually shaking to completely dissolve the irinotecan, a prescribed amount of poly(lactic-co-glycolic acid) is added to the container. The container is sealed, placed on a roller mixer, and mixed until dissolved or evenly suspended to obtain a gel.

[0065] The container 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.

[0066] 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.

[0067] The reagents and equipment used in the examples of this disclosure are conventional and commercially available.

[0068] Example 1

[0069] Preparation of epiriprazole gel

[0070] The formulation of the epiliprazole gel in this embodiment is shown in Table 1, wherein the API is epiliprazole, PLGA is poly(lactic acid-co-glycolic acid) 50:50, and NMP is N-methyl-2-pyrrolidone. The specific preparation method of the gel is as follows:

[0071] 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 poly(lactic-co-glycolic acid) was then added to the container, which was sealed and placed on a roller mixer (manufacturer: CRYSTAL, model specification: MR-020) for mixing at 20 RPM until the poly(lactic-co-glycolic acid) was uniformly suspended to obtain a gel. Visual observation showed that the gel was a suspension solution at room temperature (20-30°C).

[0072] Example 2-21

[0073] The preparation methods of Examples 2-21 are the same as those of Example 1, except that the formulations are different. For specific formulations, see Table 1. The API is epiriprazole, the PLGA is poly(lactic acid-co-glycolic acid) 50:50, and NMP is N-methyl-2-pyrrolidone. The PLGA used in Example 4 is poly(lactic acid-co-glycolic acid) 50:50, 0.10-0.30 dL / g, commonly referred to as 0.15 dL / g in the art, and manufactured by Ashland. The PLGA model used in Example 19 is 5050 0.20-0.40 dL / g, commonly referred to as 0.28 dL / g, and manufactured by Ashland. The PLGA specifications used in the remaining examples are all poly(lactic acid-co-glycolic acid) 50:50, 0.16-0.24 dL / g, commonly referred to as 0.21 dL / g, and manufactured by Evonik. The gels prepared in Examples 2 to 7 were suspension solutions at room temperature (20-30° C.), and the gels prepared in Examples 8 to 21 were clear solutions at room temperature (20-30° C.).

[0074] Table 1

[0075] 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%.

[0076] Experimental Example 1 Crystallization Experiment

[0077] (1) Room temperature crystallization experiment

[0078] Experimental methods and instruments:

[0079] 1) Instrument: Clarity Tester (Manufacturer: Jingtuo Instruments, Specification Model: YB-IIA)

[0080] 2) Experimental method: The freshly prepared gel sample of Example 1-21 was placed at room temperature, placed under a clarity detector, and visually observed to see if crystals were precipitated. The crystallization time was recorded.

[0081] Observe at room temperature for 2 hours after preparation: Place the freshly prepared gel sample at room temperature for 2 hours, place the gel sample under a clarity tester, and observe with the naked eye whether there is crystal precipitation.

[0082] Observe at room temperature for 24 hours after preparation: Place the freshly prepared gel sample at room temperature for 24 hours, place the gel sample under a clarity tester, and observe with the naked eye whether there is crystal precipitation.

[0083] The experimental results of the room temperature crystallization experiment are shown in Table 2:

[0084] Table 2

[0085] A graph showing the effects of API content*3 and PLGA content on crystallization was plotted with API content in mg / g as the horizontal axis and the sum of API content*3 and PLGA content (mg / g) as the vertical axis, see Figure 1.

[0086] (2) Heating crystallization experiment

[0087] Experimental methods and instruments:

[0088] 1) Instruments: Heating magnetic stirrer (manufacturer: Gongyi Yuhua Instrument, model: DF·101S), clarity tester (manufacturer: Jingtuo Instrument, specification model: YB-IIA)

[0089] 2) Experimental Method: Add a stirrer to the gel vial containing the precipitated crystals. Place the vial in a heated magnetic stirrer and heat in a 35°C waterbath with stirring for 30 minutes at 10 RPM. After 30 minutes, remove the sample and place it in a clarity meter. Visually observe whether the crystals have completely dissolved. If completely dissolved, remove the sample and place it in a clarity meter at room temperature. Visually observe the specific crystallization time. If not completely dissolved, heat in a 40°C waterbath with stirring for 30 minutes. After 30 minutes, remove the sample and observe whether the crystals have completely dissolved. If completely dissolved, remove the sample and place it in a clarity meter at room temperature. Visually observe the specific crystallization time. If not completely dissolved, repeat the above steps, heating in 50°C and 60°C waterbaths, and record the specific crystallization time.

[0090] Heating to 35°C / heating time 30 min: After heating the gel sample in a 35°C water bath for 30 min, the sample was taken out and placed under a clarity tester to observe the appearance of the sample with the naked eye.

[0091] Heating to 40°C / heating time 30 min: After heating the gel sample in a 40°C water bath for 30 min, the sample was taken out and placed under a clarity tester to observe the appearance of the sample with the naked eye.

[0092] Heating to 50°C / heating time 30 min: After heating the gel sample in a 50°C water bath for 30 min, the sample was taken out and placed under a clarity tester to observe the appearance of the sample with the naked eye.

[0093] Heating to 60°C / heating time 30 min: After heating the gel sample in a 60°C water bath for 30 min, the sample was taken out and placed under a clarity tester to observe the appearance of the sample with the naked eye.

[0094] After heating and dissolving, observe at room temperature for 3 hours: The gel sample that has been dissolved after heating is placed at room temperature for 3 hours. The sample is taken out and placed under a clarity tester to observe with the naked eye whether there is crystal precipitation.

[0095] After heating and dissolving, observe at room temperature for 3 days: The gel sample that has been dissolved after heating is placed at room temperature for 3 days. The sample is taken out and placed under a clarity tester to observe with the naked eye whether there is crystal precipitation.

[0096] The experimental results of the temperature-raising crystallization experiment are shown in Table 3:

[0097] Table 3

[0098] Experimental Example 2: Pore Size Distribution Test

[0099] 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.

[0100] Experimental methods and instruments:

[0101] a. Preparation of gel samples

[0102] Fresh gel samples were prepared according to the proportions of the components in Examples 9, 15, 17, and 20. The preparation method was the same as in the above examples, and the amounts of the components used were as follows:

[0103] The specific amounts of the components used were as follows: API 240 mg, PLGA 560 mg, and NMP 2480 mg, corresponding to the proportions in Example 9.

[0104] The specific amounts of the components used were as follows: API 180 mg, PLGA 360 mg, and NMP 1950 mg, corresponding to the proportions in Example 15.

[0105] The proportions corresponding to Example 17 are as follows: API 240 mg, PLGA 560 mg, NMP 2800 mg;

[0106] The proportions corresponding to Example 20 are as follows: the specific amounts of the components are: API 240 mg, PLGA 560 mg, and NMP 3000 mg.

[0107] Sterilize the gel sample using 25 kGy Gamma irradiation. The final product is obtained after sterilization. Before use, draw the gel sample into a 1 ml syringe and set aside.

[0108] b. Subcutaneous injection in rats

[0109] Male SD rats (purchased from Zhuhai Baishitong Biotechnology Co., Ltd.) weighing approximately 200-400 g were selected. All rats were maintained at 20-25°C and 40-70% relative humidity using a standard diet (SPF rat maintenance diet, Shenyang Maohua Biotechnology Co., Ltd.) with free access to water and food. The rats were randomly divided into four groups, corresponding to the groups treated with the gel of Examples 9, 15, 17, and 20 after treatment in step a above. The administration method was as follows: the rats were subcutaneously injected with 15 mg of ...

[0110] c. Material

[0111] 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.

[0112] d. Freeze-drying

[0113] The gel sample was placed in a 10 ml borosilicate vial and placed in a freeze dryer for freeze drying. The freeze drying equipment and freeze drying parameters were shown in Table 4:

[0114] Table 4

[0115] The samples after freeze-drying were used for porosity testing.

[0116] e. Porosity testing instrument information: mercury intrusion porosimeter, Micromeritics, Autopore 9620;

[0117] f. Porosity test experimental steps: Place the sample to be tested into the dilatometer, then insert the dilatometer into the instrument for mercury injection. The results will provide the pore volume distribution of pores with a pore size of 360μm to 0.003μm.

[0118] Calculation method of incremental intrusion (mL / g):

[0119] Select the incremental intrusion (mL / g) values ​​corresponding to the pore size diameter (nm) range of 6000-9000 and add them together to get the result.

[0120] 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.

[0121] Experimental results:

[0122] The pore size distribution test results are shown in Table 5 and Figures 2a and 2b.

[0123] The pore size distribution results showed that the incremental invasion of the inner pore volume of the gel-cured sample in the pore size range of 6000-9000 nm was positively correlated with the sum of 3 times the concentration of irinotecan or its pharmaceutically acceptable salt and the content of the sustained-release material, the burst release peak and Cmax in rats.

[0124] Table 5

[0125] Comparison of Examples 9, 17, and 20 shows that the pore size distribution after gel curing is influenced not only by the sum of the contents (API content * 3 + PLGA content) but also by the PLGA content:API content ratio. For the same PLGA content:API content ratio, the general trend is that the lower the sum of the contents, the greater the incremental invasion. By simultaneously controlling the sum of the API content * 3 + PLGA content and the PLGA content:API content ratio, the desired pore size distribution and, consequently, the desired sustained-release effect can be achieved.

[0126] Experimental Example 3 Pharmacokinetics Test in Rats

[0127] Experimental methods:

[0128] a. Preparation of gel samples

[0129] Fresh gel samples were prepared according to the proportions of the components in Examples 15 and 20. The preparation method was the same as in the above examples, and the amounts of the components were as follows:

[0130] The specific amounts of the components used were as follows: API 360 mg, PLGA 720 mg, and NMP 3900 mg, corresponding to the proportions of Example 15;

[0131] The proportions corresponding to Example 20 are as follows: the specific amounts of each component are: API 300 mg, PLGA 700 mg, and NMP 3750 mg.

[0132] Sterilize the gel sample using 25 kGy Gamma irradiation. The final product is obtained after sterilization. Before use, draw the gel sample into a 1 ml syringe and set aside.

[0133] b. Subcutaneous injection in rats

[0134] Six healthy male SD rats (purchased from Zhuhai Baishitong Biotechnology Co., Ltd.) weighing approximately 200-300 g were selected. All rats were maintained at 20-25°C and 40-70% relative humidity using a standard feed (SPF rat and mouse maintenance feed, Shenyang Maohua Biotechnology Co., Ltd.) with free access to water and food. The rats were randomly divided into two groups of three, each corresponding to the gel-administered groups of Example 15 and Example 20, respectively. A single subcutaneous injection of 18 mg / kg of irinotecan gel was administered subcutaneously to the lateral buttocks of the rats.

[0135] Rat orbital blood collection point:

[0136] The blood collection time points in Example 15 are: 0.5 hours, 2 hours, 4 hours, 8 hours, 24 hours, 3 days, 5 days, 8 days, 11 days, 14 days, 18 days, 21 days, 24 days, 28 days, 35 days, and 42 days after administration.

[0137] The blood collection time points in Example 20 are: 0.5 hours, 2 hours, 4 hours, 8 hours, 12 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.

[0138] c. Instruments and testing procedures:

[0139] 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.

[0140] d. Written description of PK curve drawing:

[0141] The PK data obtained from the test are used to draw a PK curve with time as the horizontal axis and cumulative blood drug concentration as the vertical axis.

[0142] Experimental results:

[0143] The PK results of the gel in rats are shown in Table 6 and Figures 3a and 3b. The results show that the gel of Example 15 has a better sustained-release effect than that of Example 20, allowing the release of epiriprazole to last for at least about 1 month.

[0144] Table 6 PK parameters

[0145] Note: t = 42 days for Example 15; t = 39 days for Example 20

[0146] The term "burst-release peak plasma concentration" refers to the first peak plasma concentration of a drug that is reached quickly within a short period of time after administration.

[0147] The term "second peak blood concentration" refers to a higher peak blood concentration reached again after the drug is continuously released.

[0148] The term "AUC 0-t ” refers to the area under the plasma drug concentration-time curve from time 0 to time t, where t is the time of collection of the last measurable concentration.

[0149] The term "AUC inf ” refers to the area under the plasma drug concentration-time curve from time 0 to infinity.

[0150] The term "T 1 / 2 ” refers to the time required for the blood drug concentration to drop by half.

[0151] 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.

[0152] 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 appended claims of the present disclosure.

Claims

1. 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.

2. The gel according to claim 1, 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.

3. The gel according to claim 1 or 2, wherein the gel is a clear solution at room temperature.

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. An epiprazole gel comprising epiprazole or a pharmaceutically acceptable salt thereof, at least one biocompatible biodegradable sustained-release material and at least one solvent, 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 the sustained-release material is not higher than 500 mg / g, preferably not higher than 455 mg / g, preferably not higher than 441 mg / g, or preferably not higher than 400 mg / g.

8. The gel according to claim 7, wherein the content of epiriprazole or a pharmaceutically acceptable salt thereof is not less than 28 mg / g, and optionally, the content of epiriprazole or a pharmaceutically acceptable salt thereof is in the range of 28 mg / g-102 mg / g, and optionally in the range of 66 mg / g-73 mg / g.

9. The gel 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.

10. The gel according to any one of claims 7 to 9, wherein The sum of 3 times the content of epiriprazole or its pharmaceutically acceptable salt and the content of the sustained-release material is 361 mg / g-391 mg / g, preferably 371 mg / g-391 mg / g, and further preferably 371 mg / g-388 mg / g.

11. The gel according to claim 10, wherein Calculated based on the total mass of epiriprazole or its pharmaceutically acceptable salt, sustained-release material and solvent, the ratio of the content of the sustained-release material to the content of epiriprazole or its pharmaceutically acceptable salt is (0.8-10):1, preferably (0.8:-3.3):1, and further preferably (2.0-2.3):

1.

12. Use of the gel according to any one of claims 7 to 11 in the preparation of a medicament for the auxiliary treatment of major depressive disorder in adults.

13. Use of the gel according to any one of claims 7 to 11 in the preparation of a medicament for treating schizophrenia.

14. Use of the gel according to any one of claims 7 to 11 in the preparation of a medicament for treating agitation associated with dementia caused by Alzheimer's disease.

15. 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 7 to 11 to a patient in need of said method.

16. A method for treating schizophrenia, comprising administering an effective amount of the gel according to any one of claims 7 to 11 to a patient in need of said method.

17. 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 7 to 11 to a patient in need of said method.

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