Injectable gel formulation

Abstract

Disclosed is a brexpiprazole injection gel formulation comprising a solution containing brexpiprazole or a pharmaceutically acceptable salt thereof, and a solution containing at least one biocompatible, biodegradable, sustained-release material. The two solutions are mixed before administration to a patient requiring the use of the solution, and after mixing, a clear solution is obtained. The solution containing brexpiprazole or a pharmaceutically acceptable salt thereof is obtained by mixing powder of brexpiprazole or a pharmaceutically acceptable salt thereof with a solvent.

Description

Cross-Reference to Related Applications

[0001] This application claims the priority of the Chinese patent application filed with the China National Intellectual Property Administration on September 8, 2023, with application number 202311156607.4 and the title of the invention being "Gel", and the entire content of said application is incorporated herein by reference. Technical Field

[0002] The present disclosure generally relates to the pharmaceutical field, and specifically relates to an injectable gel preparation. Background Art

[0003] Schizophrenia is a serious mental disorder, and clinically it often manifests as a syndrome accompanied by various symptoms including various disorders of perception, thinking, emotion and behavior, as well as coordination disorder of mental activity. The disease condition is prolonged, recurs and worsens repeatedly, and may eventually cause decline and mental disorder in some patients.

[0004] Brexpiprazole functions as a 5-HT1A receptor and dopamine D2 receptor agonist, and a 5-HT2A receptor antagonist. When clinically used for the treatment of schizophrenia, major depressive disorder and Alzheimer-type dementia, it has excellent efficacy and tolerability, and can reduce adverse reactions in patients such as restlessness, anxiety and insomnia. However, in the treatment of patients with mental disorders, oral administration of brexpiprazole has low compliance, resulting in a high recurrence rate of the disease. Development of other formulations of brexpiprazole is therefore needed. Summary of the Invention Problem to be Solved by the Invention

[0005] The objective of the present invention is to develop a gel formulation of brexpiprazole to facilitate injection administration. However, studies have shown that gel formulations of brexpiprazole, particularly high-concentration gel formulations of brexpiprazole, are prone to crystal precipitation during manufacturing or storage. Therefore, how to reduce crystal precipitation and enable the administration of brexpiprazole gel formulations in solution form is an urgent issue to be resolved in the development of brexpiprazole gel formulations. Furthermore, the present invention can reduce crystal precipitation even in high-concentration products that crystallize using conventional manufacturing methods, thereby providing the product with better physical stability and clinical safety. [Means for solving the problem]

[0006] In one embodiment, the present disclosure relates to a gel formulation of brexpiprazole comprising brexpiprazole or a pharmaceutically acceptable salt thereof, at least one biocompatible, biodegradable, sustained-release material, and at least one solvent, wherein the concentration of the brexpiprazole or a pharmaceutically acceptable salt thereof is 80 mg / mL or higher.

[0007] In another aspect, the present disclosure relates to a gel formulation of brexpiprazole 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 administration to a patient requiring the same, and the mixed solution is a clear solution.

[0008] A solution containing brexpiprazole or a pharmaceutically acceptable salt thereof may be a mixture of powder brexpiprazole or a pharmaceutically acceptable salt thereof and a solvent.

[0009] In a further embodiment, the present disclosure relates to a method for adjunctively treating major depressive disorder in adults, comprising administering an effective amount of a gel formulation of brexpiprazole to a patient in need of the method, wherein the gel formulation of brexpiprazole comprises brexpiprazole or a pharmaceutically acceptable salt thereof, at least one biocompatible, biodegradable, sustained-release material, and at least one solvent, wherein the concentration of the brexpiprazole or a pharmaceutically acceptable salt thereof is 80 mg / mL or higher.

[0010] In yet another aspect, the present disclosure relates to a method for treating schizophrenia, comprising administering an effective amount of a gel formulation of brexpiprazole to a patient requiring the method, wherein the gel formulation of brexpiprazole comprises brexpiprazole or a pharmaceutically acceptable salt thereof, at least one biocompatible, biodegradable, sustained-release material, and at least one solvent, wherein the concentration of the brexpiprazole or a pharmaceutically acceptable salt thereof is 80 mg / mL or higher.

[0011] In a further embodiment, the present disclosure relates to a method for treating agitation associated with Alzheimer's disease, comprising administering an effective amount of a gel formulation of brexpiprazole to a patient requiring the method, wherein the gel formulation of brexpiprazole comprises brexpiprazole or a pharmaceutically acceptable salt thereof, at least one biocompatible, biodegradable, sustained-release material, and at least one solvent, wherein the concentration of the brexpiprazole or a pharmaceutically acceptable salt thereof is 80 mg / mL or higher.

[0012] This disclosure provides a method for producing a gel formulation of brexpiprazole, comprising first preparing a solution containing brexpiprazole or a pharmaceutically acceptable salt thereof and a solution containing at least one biocompatible, biodegradable, sustained-release material, and further providing a method for obtaining a gel formulation by mixing the solution containing brexpiprazole or a pharmaceutically acceptable salt thereof and the solution containing at least one biocompatible, biodegradable, sustained-release material before use.

[0013] This disclosure further provides a method for producing a gel formulation of brexpiprazole, comprising: first, preparing a solution containing at least one biocompatible, biodegradable, sustained-release material; first, dissolving the brexpiprazole or a pharmaceutically acceptable salt thereof in a solvent to obtain a solution containing the brexpiprazole or a pharmaceutically acceptable salt thereof; and then mixing it with the solution containing at least one biocompatible, biodegradable, sustained-release material to obtain a gel formulation.

[0014] In some implementations, the content of brexpiprazole or a pharmaceutically acceptable salt thereof is 28 mg / g or more, and optionally, the content range of brexpiprazole or a pharmaceutically acceptable salt thereof is 28 mg / g to 120 mg / g.

[0015] In some embodiments, when the content of brexpiprazole or a pharmaceutically acceptable salt is less than 80 mg / g, the sum of the total mass of brexpiprazole or a pharmaceutically acceptable salt, sustained-release material, and solvent, which is three times the content of brexpiprazole or a pharmaceutically acceptable salt in the brexpiprazole gel formulation plus the sustained-release material, is 500 mg / g or less, preferably 450 mg / g or less.

[0016] In some embodiments, when the content of brexpiprazole or a pharmaceutically acceptable salt is less than 80 mg / g, the sum of the total mass of brexpiprazole or a pharmaceutically acceptable salt, sustained-release material, and solvent, which is three times the content of brexpiprazole or a pharmaceutically acceptable salt in the brexpiprazole gel formulation and the content of the sustained-release material, is 430 mg / g or less, preferably 415 mg / g or less, and more preferably 395 mg / g or less.

[0017] In some implementations, the sum of three times the content of brexpiprazole or a pharmaceutically acceptable salt, a sustained-release material, and a solvent, plus the content of the sustained-release material, is 322 mg / g or more.

[0018] In some implementations, the content of the sustained-release material is 80 mg / g or more, and optionally, the content range of the sustained-release material is 80 mg / g to 300 mg / g.

[0019] In some embodiments, when the content of brexpiprazole or a pharmaceutically acceptable salt thereof is 80 mg / g or more, the sum of the content of brexpiprazole or a pharmaceutically acceptable salt thereof and the content of the sustained-release material in the gel formulation of brexpiprazole, based on the total mass of brexpiprazole or a pharmaceutically acceptable salt thereof, the sustained-release material, and the solvent, is 320 mg / g or less, preferably 270 mg / g or less, and more preferably 235 mg / g or less.

[0020] In some embodiments, when the content of brexpiprazole or a pharmaceutically acceptable salt thereof is 80 mg / g or more, the sum of the content of brexpiprazole or a pharmaceutically acceptable salt thereof and the content of the sustained-release material in the gel formulation of brexpiprazole, based on the total mass of brexpiprazole or a pharmaceutically acceptable salt thereof, the sustained-release material, and the solvent, is 320 mg / g or less, preferably 270 mg / g or less, and more preferably 235 mg / g or less.

[0021] The gel formulation is a solution at room temperature. When the content of brexpiprazole or a pharmaceutically acceptable salt thereof is 80 mg / g or more, the sum of the content of brexpiprazole or a pharmaceutically acceptable salt thereof and the content of the sustained-release material in the brexpiprazole gel formulation is 230 mg / g or less, preferably 210 mg / g or less, and more preferably 190 mg / g or less, based on the total mass of brexpiprazole or a pharmaceutically acceptable salt thereof, the sustained-release material, and the solvent.

[0022] In some embodiments, based on the total mass of brexpiprazole or a pharmaceutically acceptable salt thereof, a sustained-release material, and a solvent, the sum of the content of said brexpiprazole or a pharmaceutically acceptable salt thereof and the content of said sustained-release material is 180 mg / g or more.

[0023] The present disclosure further provides the use of a gel formulation of brexpiprazole in the manufacture of a medicament for the adjuvant treatment of major depressive disorder in adults.

[0024] The present disclosure further provides the use of a gel formulation of brexpiprazole in the manufacture of a medicament for treating schizophrenia.

[0025] The present disclosure further provides the use of a gel formulation of brexpiprazole in the manufacture of a medicament for treating agitation associated with Alzheimer's dementia.

[0026] The present disclosure relates to a method for adjuvant treatment of major depressive disorder in adults, comprising administering an effective amount of a gel formulation of brexpiprazole to a patient in need of said method.

[0027] The present disclosure relates to a method for treating schizophrenia, comprising administering an effective amount of a gel formulation of brexpiprazole to a patient in need of said method.

[0028] The present disclosure relates to a method for treating agitation associated with Alzheimer's dementia, comprising administering an effective amount of a gel formulation of brexpiprazole to a patient in need of said method.

[0029] Detailed Description The following description contains specific details to enable a comprehensive understanding of the various disclosed embodiments. However, those skilled in the art will understand that the embodiments may be practiced using other methods, components, materials, etc., without employing one or more of these specific details.

[0030] Unless otherwise specifically required in this application, the terms “include,” “contain,” “contain,” and “have” throughout this specification should be understood in an open and comprehensive sense, that is, “include, but not limited to.”

[0031] As used in this disclosure and the attached claims, a singular designation without a quantity also includes a plural designation unless the context explicitly states otherwise.

[0032] Throughout this specification, the terms “one embodiment,” “another embodiment,” or “several embodiments” mean that at least one embodiment contains a specific reference element, structure, or feature associated with that embodiment. Therefore, the phrases “in one embodiment,” “in an embodiment,” “in another embodiment,” or “several embodiments” appearing in different places throughout this specification do not necessarily all refer to the same embodiment. Furthermore, specific elements, structures, or features may be combined in any suitable manner in one or more embodiments.

[0033] In this disclosure and the attached claims, the singular article "one" (corresponding to the English "a," "an," and "the") should be understood to include multiple subjects unless otherwise specified herein. Therefore, for example, a sustained-release tablet containing the above-mentioned "pharmaceutically acceptable auxiliary materials" may contain one, two, or more pharmaceutically acceptable auxiliary materials.

[0034] definition In this disclosure, the term "brexpiprazole" refers to 7-[4-[4-(1-benzo[b]thiophen-4-yl)piperazine-1-yl]butoxy]quinoline-2(1H)-one.

[0035] In this disclosure, the term “acceptable salt” refers to an acid 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, acidic citric acid, oleic acid, tannic acid, pantothenic acid, hydrogen tartrate, ascorbic acid, gentisic acid, fumaric acid, saccharic acid, formic acid, ethanesulfonic acid, amino acids, hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, carbonic acid, phosphoric acid, phosphorous acid, sulfuric acid, and others. 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, and bismuth salts.

[0036] In this disclosure, the term “biocompatible, biodegradable, sustained-release material” means a natural or synthetic biomedical material that is biocompatible and tolerable, has a modulated drug release rate, is continuously broken down by the action of bodily fluids, is absorbed or excreted in the body, and is ultimately completely replaced by new tissue.

[0037] In this disclosure, the term “gel” is also referred to as an injection gel and typically consists primarily of a pharmaceutically active ingredient, a biocompatible solvent, and a biodegradable polymer. After being administered by injection in a liquid state, the gel undergoes a rapid phase transition at the injection site, changing from a liquid state to a solid state, thereby extending the residence time of the drug at the injection site. Furthermore, with the gradual degradation of the high-molecular-weight polymer, the encapsulated drug is completely released within several weeks to several months, thereby achieving the objectives of sustained-release and controlled-release.

[0038] In this disclosure, the term "room temperature" refers to 20-30°C.

[0039] In this invention, the term "solution" is also referred to as a single-phase homogeneous mixture and refers to a dispersion system in which one type of pure substance is uniformly and stably distributed within another pure substance in the form of molecules or ions, and no visible precipitates or deposits are present.

[0040] In this invention, the term "clear" means that the gel does not contain any visible precipitates or deposits.

[0041] In this invention, the term "crystal precipitation" means that the gel contains visible precipitates or deposits.

[0042] In this invention, the term "incremental intrusion" refers to the amount of mercury that penetrates the pore space of a sample as the pressure increases when testing pores in the mercury intrusion method. This is a method for measuring how mercury fills the pore space under pressure and provides results regarding the pore structure and distribution inside the sample.

[0043] In this invention, the term "burst-release blood peak concentration" refers to the first peak blood concentration that the drug rapidly reaches within a short period of time after administration.

[0044] In this invention, the term "second blood peak concentration" refers to a higher blood concentration peak value reached again by the drug after sustained release.

[0045] In this invention, "AUC 0-t The term "area under the plasma drug concentration-time curve" refers to the area under the plasma drug concentration-time curve from 0 hours to t hours, where t represents the time of collection of the final measurable concentration.

[0046] In this invention, "AUC inf The term "area under the plasma drug concentration-time curve" refers to the area under the plasma drug concentration-time curve from 0 hours to infinity. "T 1 / 2 The term "times" refers to the time required for the concentration of a drug in the blood to decrease by half. [Brief explanation of the drawing]

[0047] [Figure 1] This diagram shows the relationship between the effect of the sum of the API content*3 and the PLGA content on crystal precipitation when the API content is 80 mg / g or more. [Figure 2] This diagram shows the relationship between the effect of the sum of the API content and PLGA content on crystal precipitation when the API content is 80 mg / g or more. [Figure 3] This diagram shows the relationship between the effect of the sum of the API content*3 and PLGA content on crystal precipitation when the API content is less than 80 mg / g. [Figure 4] This is a diagram showing the pore size distribution test results after hardening of the brexpiprazole gel formulation. [Figure 5a] This is a blood concentration-time curve of the pharmacokinetics (PK) of brexpiprazole gel formulation in rats (horizontal axis: 0 to 2 days). [Figure 5b] This is a blood concentration-time curve of the pharmacokinetics (PK) of brexpiprazole gel formulation in rats (horizontal axis: 0 to 42 days). [Modes for carrying out the invention]

[0048] In one embodiment, the present disclosure relates to a gel formulation of brexpiprazole comprising brexpiprazole or a pharmaceutically acceptable salt thereof, at least one biocompatible, biodegradable, sustained-release material, and at least one solvent, wherein the concentration of the brexpiprazole or a pharmaceutically acceptable salt thereof is 80 mg / mL or higher.

[0049] In some implementations, the gel formulation of brexpiprazole of the present disclosure has concentrations of brexpiprazole or a pharmaceutically acceptable salt thereof of 81 mg / mL or higher, 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, 1 03mg / 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, 117 mg / mL, 118 mg / mL, 119 mg / mL, 120 mg / mL, 121 mg / mL, 122 mg / mL, 123 mg / mL, 124 mg / mL, 125 mg / mL, 126 mg / mL, 127 mg / mL, 128 mg / mL, 129 mg / mL, or 130 mg / mL.

[0050] In some embodiments, in the gel formulation of brexpiprazole of the present disclosure, the sum of three times the concentration of brexpiprazole or a pharmaceutically acceptable salt thereof and the concentration of the sustained-release material is 600 mg / mL or less, 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.

[0051] In some embodiments, exemplary examples of biocompatible, biodegradable, sustained-release materials that may be used in the gel formulations of the present disclosure include, but are not limited to, polyamides, polyamines, polyalkylene oxalates, polyanhydrides, polyamide esters, coplio(ether-esters), polycarbonates, polyorthoesters, polylactides, polyglycolides, polylactic acid, polylactic acid-glycolic acid copolymers, polyorthoesters, polycaprolactone, polyphosphazenes, polysaccharides, protein polymers, polysaccharide derivatives, soluble derivatives of protein polymers, polypeptides, polyesters, polyorthoesters, and copolymers, block copolymers, homopolymers, mixtures, and compositions thereof.

[0052] In some embodiments, exemplary biocompatible, biodegradable, sustained-release materials that can be used to form the microspheres of the present disclosure include, but are not limited to, polylactic acid-glycolic acid copolymers, i.e., poly(lactic acid-coglycolic acid) (abbreviated as PLGA), having a molar ratio of lactide to glycolic acid of about 50:50 to about 95:5.

[0053] In some embodiments, exemplary examples of at least one solvent that may be used in the gel formulations of the present disclosure include, but are not limited to, organic solvents.

[0054] In some embodiments, exemplary organic solvents usable in this disclosure include, but are not limited to, alcoholic solvents, esteric solvents, etheric solvents, ketoneic solvents, and amideic solvents.

[0055] In some embodiments, exemplary alcoholic solvents usable in this disclosure include, but are not limited to, ethanol, n-propanol, isopropanol, n-butanol, propylene glycol, glycerol, or 1,3-butanediol.

[0056] In some embodiments, exemplary ester solvents usable in this disclosure include, but are not limited to, ethyl acetate, methyl acetate, ethyl formate, butyl acetate, diethyl malonate, n-butyl acetate, or isobutyl acetate.

[0057] In some embodiments, exemplary ether solvents usable in this disclosure include, but are not limited to, tetrahydrofuran, methyltetrahydrofuran, diethylene glycol monomethyl ether, or tetrahydrofuran polyethylene glycol ether.

[0058] In some embodiments, exemplary ketone solvents usable in this disclosure include, but are not limited to, acetone, methyl ethyl ketone, diethyl ketone, or methyl isobutyl ketone.

[0059] In some embodiments, exemplary amide solvents usable in this disclosure include, but are not limited to, formamide, dimethylformamide, dimethylacetamide, hexamethylphosphoric triamide, N-methyl-2-pyrrolidone, N-cyclohexyl-2-pyrrolidone, N-hydroxyethyl-2-pyrrolidone, 2-pyrrolidone, or N-ethyl-2-pyrrolidone.

[0060] In a further embodiment, the present disclosure relates to a gel formulation of brexpiprazole 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 administration to a patient requiring it, and the mixed liquid is a clear solution.

[0061] In some embodiments, the solution containing brexpiprazole or a pharmaceutically acceptable salt relating to this disclosure may be a mixture of powder of brexpiprazole or a pharmaceutically acceptable salt thereof and a solvent.

[0062] In some embodiments, the gel formulation of brexpiprazole relating to this disclosure is a clear solution at room temperature.

[0063] In some embodiments, the concentrations of brexpiprazole or its pharmaceutically acceptable salts in the gel formulation of brexpiprazole of the present disclosure are 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, and 102 mg / mL. L, 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, 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.

[0064] In some embodiments, in the gel formulation of brexpiprazole of the present disclosure, the sum of three times the concentration of brexpiprazole or a pharmaceutically acceptable salt thereof and the concentration of the sustained-release material is 600 mg / mL or less, 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.

[0065] In yet another aspect, the disclosure provides a method for adjunctive treatment of major depressive disorder in adults, comprising administering an effective dose of a gel formulation of brexpiprazole to a patient requiring the method, wherein the gel formulation of brexpiprazole comprises brexpiprazole or a pharmaceutically acceptable salt thereof, at least one biocompatible, biodegradable, sustained-release material, and at least one solvent, wherein the concentration of the brexpiprazole or a pharmaceutically acceptable salt thereof is 80 mg / mL or greater, 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 mL, 95mg / mL, 96mg / mL, 97mg / mL, 98mg / mL, 99mg / mL, 100mg / mL, 101mg / mL, 102mg / mL, 103mg / mL, 104m g / mL, 105mg / mL, 106mg / mL, 107mg / mL, 108mg / mL, 109mg / mL, 110mg / mL, 111mg / mL, 112mg / mL, 113mg / m The method relating to L, 114 mg / mL, 115 mg / mL, 116 mg / mL, 117 mg / mL, 118 mg / mL, 119 mg / mL, 120 mg / mL, 121 mg / mL, 122 mg / mL, 123 mg / mL, 124 mg / mL, 125 mg / mL, 126 mg / mL, 127 mg / mL, 128 mg / mL, 129 mg / mL, or 130 mg / mL.

[0066] In some embodiments, in a gel formulation usable in the administration method of the present disclosure, the sum of three times the concentration of brexpiprazole or a pharmaceutically acceptable salt thereof and the concentration of the sustained-release material is 600 mg / mL or less, 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.

[0067] In some embodiments, a gel formulation usable in the administration method of the present disclosure comprises 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 requiring it, and after mixing become a solution.

[0068] In a further embodiment, the present disclosure relates to a method for treating schizophrenia, comprising administering an effective amount of a gel formulation of brexpiprazole to a patient requiring the method, wherein the gel formulation of brexpiprazole comprises brexpiprazole or a pharmaceutically acceptable salt thereof, at least one biocompatible, biodegradable, sustained-release material, and at least one solvent.

[0069] In some implementations, in a gel formulation of brexpiprazole usable in the administration method of this disclosure, the concentration of brexpiprazole or a pharmaceutically acceptable salt thereof is 80 mg / mL or greater, 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, 1 02mg / 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.

[0070] In some embodiments, in a gel formulation of brexpiprazole usable in the administration method of the present disclosure, the sum of three times the concentration of brexpiprazole or a pharmaceutically acceptable salt thereof and the concentration of the sustained-release material is 600 mg / mL or less, 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.

[0071] In some embodiments, a gel formulation usable in the administration method of the present disclosure comprises 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 requiring it, and after mixing become a solution.

[0072] In some embodiments, the gel formulation usable in the administration method of this disclosure is a solution at room temperature.

[0073] In yet another aspect, the present disclosure relates to a method for treating agitation associated with Alzheimer's disease, comprising administering an effective amount of a gel formulation of brexpiprazole to a patient requiring the method, wherein the gel formulation of brexpiprazole comprises brexpiprazole or a pharmaceutically acceptable salt thereof, at least one biocompatible, biodegradable, sustained-release material, and at least one solvent.

[0074] In some implementations, in a gel formulation of brexpiprazole usable in the administration method of this disclosure, the concentration of brexpiprazole or a pharmaceutically acceptable salt thereof is 80 mg / mL or greater, 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, 1 02mg / 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.

[0075] In some embodiments, in a gel formulation of brexpiprazole usable in the administration method of the present disclosure, the sum of three times the concentration of brexpiprazole or a pharmaceutically acceptable salt thereof and the concentration of the sustained-release material is 600 mg / mL or less, 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.

[0076] In some embodiments, a gel formulation usable in the administration method of the present disclosure comprises 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 requiring it, and after mixing become a solution.

[0077] In some embodiments, the gel formulation usable in the administration method of this disclosure is a solution at room temperature.

[0078] In some implementations, the duration of release of brexpiprazole or a pharmaceutically acceptable salt thereof in the gel formulation of the present disclosure is at least about one month.

[0079] In yet another aspect, the disclosure further provides a method for producing a gel formulation of brexpiprazole, the first method of producing a solution containing brexpiprazole or a pharmaceutically acceptable salt thereof and a solution containing at least one biocompatible, biodegradable, sustained-release material, and before use, the method of mixing the solution containing brexpiprazole or a pharmaceutically acceptable salt thereof and the solution containing at least one biocompatible, biodegradable, sustained-release material to obtain a gel formulation.

[0080] In some implementations, a solution containing brexpiprazole or a pharmaceutically acceptable salt thereof may be a mixture of brexpiprazole or a pharmaceutically acceptable salt thereof and a solvent. A solution containing at least one biocompatible, biodegradable, sustained-release material may be a mixture of the sustained-release material and a solvent.

[0081] In yet another aspect, the present disclosure further provides a method for producing a gel formulation of brexpiprazole, the method comprising: first, preparing a solution containing at least one biocompatible, biodegradable, sustained-release material; first, dissolving the brexpiprazole or a pharmaceutically acceptable salt thereof in a solvent to obtain a solution containing the brexpiprazole or a pharmaceutically acceptable salt thereof; and then mixing it with the solution containing at least one biocompatible, biodegradable, sustained-release material to obtain a gel formulation.

[0082] Conventional containers such as vials, glass bottles with screw caps, blue-capped bottles, PTFE bottles, and polypropylene bottles can be used for the preparation or mixing of two solutions.

[0083] In some embodiments, the solution containing at least one biocompatible, biodegradable, sustained-release material may be a mixture of the sustained-release material and a solvent.

[0084] In some embodiments, when the content of brexpiprazole or a pharmaceutically acceptable salt is less than 80 mg / g (for example, 28 mg / g or more and less than 80 mg / g), the sum of three times the content of brexpiprazole or a pharmaceutically acceptable salt in the brexpiprazole gel formulation and the content of the sustained-release material, based on the total mass of brexpiprazole or a pharmaceutically acceptable salt, sustained-release material, and solvent, is 500 mg / g or less. For example, the sum of three times the content of brexpiprazole or a pharmaceutically acceptable salt in the brexpiprazole gel formulation and the content of the sustained-release material may be a value within the range of 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 any two of the above values. For example, the content of brexpiprazole or a pharmaceutically acceptable salt thereof may be within the range of 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 any two of the above values.

[0085] In some embodiments, the sum of three times the content of brexpiprazole or a pharmaceutically acceptable salt, a sustained-release material, and a solvent, in total mass, is 322 mg / g or more. Exemplarially, the sum of three times the content of brexpiprazole or a pharmaceutically acceptable salt and the content of the sustained-release material in the brexpiprazole gel formulation may be within the range of 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 any two of these values.

[0086] In some implementations, for example, the sum of three times the content of brexpiprazole or a pharmaceutically acceptable salt thereof in the brexpiprazole gel formulation and the content of the sustained-release material may be within the range of 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 any two of the above values.

[0087] In some implementations, the content of brexpiprazole or a pharmaceutically acceptable salt thereof may be 28 mg / g or more, and optionally, the content range of brexpiprazole or a pharmaceutically acceptable salt thereof is 28 mg / g to 120 mg / g. Exemplarily, the content of brexpiprazole or a pharmaceutically acceptable salt thereof may 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 any two of the above values.

[0088] In some implementations, the content of the sustained-release material is 80 mg / g or more, and optionally, the content range of the sustained-release material is 80 mg / g to 300 mg / g. For example, the content of the sustained-release material may 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 any two of the above values.

[0089] In some embodiments, if the total mass of brexpiprazole or a pharmaceutically acceptable salt, sustained-release material, and solvent contains 80 mg / g or more of brexpiprazole or a pharmaceutically acceptable salt, the sum of the content of brexpiprazole or a pharmaceutically acceptable salt and the content of the sustained-release material in the brexpiprazole gel formulation is 320 mg / g or less. Exemplarily, the sum of the content of brexpiprazole or a pharmaceutically acceptable salt and the content of the sustained-release material in the brexpiprazole gel formulation may be within the range of 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 any two of these values. For example, the content of brexpiprazole or a pharmaceutically acceptable salt thereof is within the range of 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 any two of the above values.

[0090] In some implementations, for example, if the content of brexpiprazole or a pharmaceutically acceptable salt thereof is 80 mg / g or more, the sum of the content of brexpiprazole or a pharmaceutically acceptable salt thereof in the brexpiprazole gel formulation and the content of the sustained-release material may be within the range of 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 any two of the above values.

[0091] In some embodiments, if the content of brexpiprazole or a pharmaceutically acceptable salt is 80 mg / g or more, the sum of the content of brexpiprazole or a pharmaceutically acceptable salt and the content of the sustained-release material in the total mass of brexpiprazole or a pharmaceutically acceptable salt, the sustained-release material, and the solvent is 180 mg / g or more. Exemplarily, the sum of the content of brexpiprazole or a pharmaceutically acceptable salt and the content of the sustained-release material in the brexpiprazole gel formulation may be within the range of 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 any two of the above values.

[0092] The following examples will provide a more detailed description of the disclosure in order to better understand its various aspects and benefits. However, it should be understood that these examples are not limiting and are used only to illustrate some of the means of implementing the disclosure. [Examples]

[0093] All reagents and equipment used in the examples of this disclosure are conventional and commercially available.

[0094] Examples 1-18 Examples 1 to 18 provide a series of brexpiprazole gel formulations and methods for producing the same, where the formulation of the brexpiprazole gel formulation in each example is shown in Table 1. The API is brexpiprazole, the PLGA is poly(lactic acid-coglycolic acid) 50:50, and the NMP is N-methyl-2-pyrrolidone.

[0095] The specific manufacturing methods for these gel formulations are as follows:

[0096] 1. The total prescription amount of N-methyl-2-pyrrolidone was divided into two parts. Part of the N-methyl-2-pyrrolidone was used as the solvent for the API solution, dissolving 60 mg of brexpiprazole in 430 mg of N-methyl-2-pyrrolidone. The remaining N-methyl-2-pyrrolidone was used as the solvent for the polymer solution. After preparing the API solution and polymer solution separately, both were mixed using a pre-filled syringe to obtain the gel formulation.

[0097] The manufacturing processes for API solutions and polymer solutions are described in detail below. Since some residue is unavoidable when transferring the solution from the manufacturing container to the pre-filled syringe, both API solutions and polymer solutions are manufactured at a mass ratio of 2 to 15 times.

[0098] 2. Preparation of API solution Brexpiprazole was placed in a vial, and N-methyl-2-pyrrolidone (430 mg of N-methyl-2-pyrrolidone was used per 60 mg of brexpiprazole) was added. The vial was shaken manually for 1-2 minutes to completely dissolve the brexpiprazole. After the API was completely dissolved, the prescribed amount of brexpiprazole solution was filled into a new male pre-filled syringe and prepared for use.

[0099] 3. Production of polymer solution The remaining N-methyl-2-pyrrolidone completely dissolved the poly(lactic acid-coglycolic acid) to obtain a polymer solution. The prescribed amount of polymer solution was filled into a scalpel-type pre-filled syringe and prepared for use.

[0100] 4. The total amount of each component in the male and female pre-filled syringes constituted the total prescribed amount.

[0101] 5. When using, connect the male pre-filled syringe and the female pre-filled syringe, and mix by pushing and pulling for 1 minute (approximately 60-100 back-and-forth movements) to uniformly mix the gel and obtain the gel formulation.

[0102] For example, the method for producing the gel formulation in Example 2 is as follows: Breexpiprazole (180 mg used, 3 times the prescribed amount) was placed in a vial, and N-methyl-2-pyrrolidone (430 mg of N-methyl-2-pyrrolidone was used for every 60 mg of brexpiprazole) was added. The mixture was shaken manually for 1-2 minutes to completely dissolve the brexpiprazole. After the API was completely dissolved, the prescribed amount of brexpiprazole solution was filled into a new male prefilled syringe and prepared for use. Poly(lactic acid-coglycolic acid) (750 mg used, 5 times the prescribed amount) was completely dissolved in N-methyl-2-pyrrolidone (250 mg used, calculated by multiplying the amount of NMP obtained by subtracting the amount of NMP used in the brexpiprazole solution in the male prefilled syringe from the prescribed amount of NMP by 5) to obtain a polymer solution. The prescribed amount of polymer solution was filled into a female prefilled syringe and prepared for use. The total prescription volume was the sum of the components in the male and female pre-filled syringes. When using the product, the male and female pre-filled syringes were connected and mixed for 1 minute (approximately 60-100 back-and-forth movements) by pushing and pulling to uniformly mix the gel and obtain the gel formulation.

[0103] In Example 5, Ashland PLGA Model 5050 at 0.10–0.30 dL / g was used. In Examples 1–4 and 6–18, Evonik PLGA Model 5050 at 0.16–0.24 dL / g was used.

[0104] [Table 1]

[0105] 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%.

[0106] Comparative Examples 1-11 Comparative Examples 1 to 11 provide a series of brexpiprazole gel formulations and methods for producing the same. The formulations of the brexpiprazole gel formulations in each comparative example are shown in Table 2. In the formulations of the brexpiprazole gel formulations in Comparative Examples 1 to 11, the proportions of API, PLGA, and NMP are the same as in Examples 1 to 10 and Example 12, but the manufacturing methods differ. The manufacturing methods for the gel formulations in this series of Comparative Examples 1 to 11 are as follows.

[0107] A 10 ml vial containing the prescribed amount of brexpiprazole was then mixed with the prescribed amount of N-methyl-2-pyrrolidone. The vial was shaken manually for 1-2 minutes to completely dissolve the brexpiprazole. Next, the prescribed amount of PLGA (poly(lactic acid-coglycolic acid)) was added to the vial, sealed, and placed in a roller mixer (manufacturer: CRYSTAL, model number: MR-020). The mixture was stirred at a rotation speed of 20-50 RPM until the PLGA was dissolved or uniformly suspended to obtain a gel formulation.

[0108] In Comparative Example 5, Ashland's PLGA Model 5050 at 0.10–0.30 dL / g was used. In Comparative Examples 1–4 and 6–11, Evonik's PLGA Model 5050 at 0.16–0.24 dL / g was used.

[0109] [Table 2]

[0110] Experimental Example 1: Crystallization Experiment In the preparation of the polymer solution sample in Example 1, poly(lactic acid-coglycolic acid) and N-methyl-2-pyrrolidone were mixed in a sealed container and left for 5 days. However, the poly(lactic acid-coglycolic acid) still did not dissolve, and a gel formulation could not be produced. Therefore, a crystal precipitation experiment was not performed.

[0111] 1. The gel formulations prepared in Examples 2-18 were left at room temperature and observed using a clarity meter at 0h, 1h, 2h, 4h, 8h, 24h, 48h, 66h, 72h, 96h, 120h, 144h, and longer (observed once every 24 hours after 72h). The experimental results are shown in Table 3.

[0112] [Table 3] TIFF2026532614000005.tif239164 TIFF2026532614000006.tif240164

[0113] 2. The gel formulations prepared in Comparative Examples 1-10 and Comparative Example 12 were left at room temperature, and the state of the gel was continuously observed using a clarity meter from 0 to 1 hour. The time at which crystal precipitation was first observed was recorded. Subsequently, the state of the gel was observed using a clarity meter at 2 hours, 4 hours, 22 hours, 24 hours, and 48 hours, respectively. The experimental results are shown in Table 4.

[0114] [Table 4]

[0115] As can be seen from the crystal precipitation experiment results in Tables 3 and 4, compared to each comparative example, with the exception of Example 1, the gel formulations obtained in each example of the present invention significantly improved the problem of brexpiprazole gel formulations being prone to crystal precipitation during manufacturing or storage, indicating that the method of the present invention is advantageous for producing stable gel formulations in solution.

[0116] To investigate the crystal precipitation status of brexpiprazole gel formulations and to further understand the cause of crystal precipitation in Example 1, data from each example were analyzed. The results revealed that the crystal precipitation status of brexpiprazole gel formulations is unrelated to the API content. For example, comparing Example 6 and Example 13, the API content in Example 6 was 80 mg / g, while in Example 13 it was 101.7 mg / g. In Example 7, the initial time of crystal precipitation was 1 hour, which was much earlier than the 144 hours at which no crystal precipitation was observed in Example 13. Other examples include Example 2 and Example 10, Example 14 and Example 4, Example 14 and Example 5, and Example 14 and Example 11.

[0117] Furthermore, when the API content is less than 80 mg / g, the crystal precipitation status (e.g., crystal precipitation time) is independent of the sum of the API content and PLGA content. For example, comparing Example 8 and Example 15, in Example 8 the sum of the API content and PLGA content was 288.9 mg / g, while in Example 15 the sum of the API content and PLGA content was 314.3 mg / g. In Example 8, the initial crystal precipitation time was 48 hours, which was much earlier than the 144 hours at which no crystal precipitation was observed in Example 15.

[0118] The inventors unexpectedly discovered that when the API content is less than 80 mg / g, the crystal precipitation status (e.g., crystal precipitation time) is related to the sum of three times the API content and the PLGA content. Furthermore, the lower the sum of three times the API content and the PLGA content, the longer the gel formulation remains in solution and the later the crystal precipitation appears. By controlling the sum of three times the API content and the PLGA content, it is possible to manufacture a gel formulation in solution form, allowing the brexpiprazole gel formulation to be injected in solution form, further reducing crystal precipitation, extending the time in solution, providing the product with better physical stability and clinical safety, and improving usability.

[0119] When 430 mg / g < the sum of three times the API content and the PLGA content ≤ 450 mg / g, the crystal precipitation condition is further improved, and the gel preparation maintains a solution state even when left standing at room temperature for 8 hours or more. For example, in Example 4 and Example 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 crystal precipitation occurs in the gel preparation after being left standing at room temperature for 24 hours (the solution state is maintained for at least 8 hours). When 415 mg / g < the sum of three times the API content and the PLGA content ≤ 430 mg / g, the crystal precipitation condition is further improved, and the gel preparation maintains a solution state even when left standing at room temperature for 24 hours or more. For example, in Example 8, the sum of three times the API content and the PLGA content is 422.2 mg / g, and crystal precipitation occurs in the gel preparation after being left standing at room temperature for 48 hours (the solution state is maintained for at least 24 hours). When 395 mg / g < the sum of three times the API content and the PLGA content ≤ 415 mg / g, the crystal precipitation condition 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 crystal precipitation occurs in the gel preparation after being left standing at room temperature for 96 hours (the solution state is maintained for at least 72 hours). When the sum of three times the API content and the PLGA content ≤ 395 mg / g, the crystal precipitation condition is further improved, and the gel preparation maintains a solution state even when left standing at room temperature for 144 hours or more. For example, in Examples 14 to 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 preparation maintains a solution state even when left standing at room temperature for 144 hours.

[0120] The inventors unexpectedly discovered that when the API content is 80 mg / g or higher, the crystal precipitation status (e.g., crystal precipitation time) is related to the sum of the API content and the PLGA content. Furthermore, the lower the sum of the API content and PLGA content, the longer the gel formulation remains in solution and the later the crystal precipitation appears. By controlling the sum of the API content and PLGA content, it is possible to manufacture a gel formulation in solution form, allowing the brexpiprazole gel formulation to be injected in solution form, further reducing crystal precipitation, extending the time in solution, providing the product with better physical stability and clinical safety, and improving usability.

[0121] When 270 mg / g < sum of API content and PLGA content ≤ 320 mg / g, a solution-form gel preparation can be obtained using the method of the present invention, but crystal precipitation occurs after standing for a certain period of time. For example, in Example 2, Example 3, and Example 6, the sum of API content and PLGA content is between 272.7 mg / g and 304.3 mg / g, and crystal precipitation occurred in the gel preparation after standing at room temperature for 1 h. When 235 mg / g < sum of API content and PLGA content ≤ 270 mg / g, the crystal precipitation situation is further improved. For example, in Example 7, the sum of API content and PLGA content is 238.1 mg / g, and crystal precipitation occurred in the gel preparation after standing at room temperature for 8 h (maintaining a solution state for at least 4 h). When 230 mg / g < sum of API content and PLGA content ≤ 235 mg / g, the crystal precipitation situation is further improved. For example, in Example 10, the sum of API content and PLGA content is 231.9 mg / g, and crystal precipitation occurred in the gel preparation after standing at room temperature for 66 h (maintaining a solution state for at least 48 h). When 210 mg / g < sum of API content and PLGA content ≤ 230 mg / g, the crystal precipitation situation is further improved. For example, in Example 12, the sum of API content and PLGA content is 210.9 mg / g, and crystal precipitation occurred in the gel preparation after standing at room temperature for 72 h (maintaining a solution state for at least 66 h). When 190 mg / g < sum of API content and PLGA content ≤ 210 mg / g, the crystal precipitation situation is further improved. For example, in Example 9, the sum of API content and PLGA content is 196.4 mg / g, and crystal precipitation occurred in the gel preparation after standing at room temperature for 96 h (maintaining a solution state for at least 72 h). When the sum of API content and PLGA content is ≤ 190 mg / g, the gel preparation remains in a solution state even after being left to stand at room temperature for 144 h or more. For example, in Example 13, the sum of API content and PLGA content was 186.4 mg / g.

[0122] When the API content is 80 mg / g or more, the relationship between the sum of the API content*3 and the PLGA content (mg / g) and the effect of crystal precipitation was plotted on crystal precipitation, with the x-coordinate being the sum of the API content*3 and the PLGA content (mg / g) and the y-coordinate being the time (h) at which crystal precipitation is first observed.Figure 1 shows that when the API content is less than 80 mg / g, as the sum of the API content*3 and the PLGA content decreases, some gel formulations maintain a solution state at room temperature for a longer time, while others maintain a shorter time.

[0123] When the API content was 80 mg / g or higher, the relationship between the sum of the API content and PLGA content and its effect on crystal precipitation was plotted (Figure 2), with the sum of the API content and PLGA content (mg / g) as the x-coordinate and the time (h) at which crystal precipitation was first observed as the y-coordinate. From Figure 2, it was found that when the API content was 80 mg / g or higher, the time at which the gel formulation remained in solution at room temperature increased significantly as the sum of the API content and PLGA content decreased.

[0124] When the API content is less than 80 mg / g, the relationship between the effects of API content*3 and PLGA content on crystal precipitation was plotted (Figure 3) with the sum of API content*3 and PLGA content as the x-coordinate and the time (h) at which crystal precipitation is first observed as the y-coordinate. From Figure 3, it was found that when the API content is less than 80 mg / g, as the sum of three times the API content and the PLGA content decreases, the time at which the gel formulation remains in solution at room temperature increases significantly.

[0125] Experimental Example 2: Pore Size Distribution Test The gel formulation of the present invention hardens after injection and becomes a solid. In this section, the pore size distribution within the hardened solid substance of the injected gel formulation was measured.

[0126] a. Experimental methods and equipment: Preparation of gel formulation samples in Examples 10B and 17B The content of API, PLGA, and NMP in the gel formulation sample of Example 10B is the same as the content of these three substances in the formulation of Example 10. The method for producing the gel formulation samples in Example 10B and Example 17B is as follows.

[0127] 1) The total prescription amount of N-methyl-2-pyrrolidone was divided into two parts. One part was used to dissolve the API, i.e., to prepare the API solution. 60 mg of brexpiprazole was dissolved in 430 mg of N-methyl-2-pyrrolidone. The remaining N-methyl-2-pyrrolidone was used to prepare the polymer solution. Finally, the API solution and the polymer solution were mixed using a pre-filled syringe to obtain the gel formulation.

[0128] 2) The manufacturing processes for the API solution and polymer solution are described in detail below. Since some residue is unavoidable when transferring the solution from the manufacturing container to the pre-filled syringe, both the API solution and polymer solution were manufactured in quantities of 2 to 10 times the original volume.

[0129] 3) Preparation of API solution Brexpiprazole sterilized by 25 kGy gamma irradiation was placed in a vial, and sterilized N-methyl-2-pyrrolidone sterilized by 25 kGy gamma irradiation (430 mg of N-methyl-2-pyrrolidone was used per 60 mg of brexpiprazole) was added. The vial was manually shaken for 1-2 minutes to completely dissolve the brexpiprazole. After the API was completely dissolved, the prescribed amount of brexpiprazole solution was filled into a new male pre-filled syringe and prepared for use.

[0130] 4) Production of polymer solution Poly(lactic acid-coglycolic acid) was completely dissolved with the remaining N-methyl-2-pyrrolidone to obtain a polymer solution. After sterilization by 25 kGy of gamma irradiation, the prescribed amount of polymer solution was filled into a scalpel-type pre-filled syringe and prepared for use.

[0131] 5) The total amount of each component in the male and female pre-filled syringes constitutes the total prescribed amount.

[0132] 6) When using, connect the male pre-filled syringe and the female pre-filled syringe, and mix by pushing and pulling for 1 minute (approximately 60-100 back-and-forth movements) to uniformly mix the gel and obtain a gel formulation.

[0133] Specifically, the specific formulation of the gel formulation sample in Example 10B is API 60 mg, PLGA 100 mg, and NMP 530 mg. The manufacturing method and the amount of each substance used are as follows.

[0134] 1) Place 240 mg of 25 kGy-sterilized brexpiprazole (four times the prescribed dose) into a vial and add 25 kGy-sterilized N-methyl-2-pyrrolidone (using 430 mg of N-methyl-2-pyrrolidone per 60 mg of brexpiprazole). Shake manually for 1-2 minutes to completely dissolve the brexpiprazole. After the API was completely dissolved, fill a new male pre-filled syringe with the prescribed amount of brexpiprazole solution and prepare it for use.

[0135] 2) 400 mg of poly(lactic acid-coglycolic acid) (four times the prescribed amount) was completely dissolved in 400 mg of N-methyl-2-pyrrolidone, and then sterilized by 25 kGy gamma irradiation to obtain a polymer solution. The prescribed amount of polymer solution was filled into a scalpel-type pre-filled syringe and prepared for use.

[0136] 3) When using, connect the male pre-filled syringe and the female pre-filled syringe, and mix by pushing and pulling for 1 minute (approximately 60-100 back-and-forth movements) to uniformly mix the gel and obtain a gel formulation.

[0137] The formulation of the gel formulation sample in Example 17B was the same as in Example 10, and the manufacturing method was basically the same as in Example 10B, except that the amount of each substance used in the process of producing the polymer solution and the brexpiprazole solution was appropriately adjusted according to the formulation of Example 17B.

[0138] b. Subcutaneous injection into rats Male SD rats weighing approximately 200-400g were selected and randomly divided into groups. All rats were fed a standard diet at 20-25°C and 40-70% RH, and were allowed free access to food and water. The two groups of test rats received one subcutaneous injection each into the left and right sides of the shoulder and neck. In terms of mass, the corresponding dose of brexpiprazole was 15 mg per injection (i.e., 15 mg injected into each side).

[0139] c. Material collection 48 hours after administration, the rats were sacrificed and the injection sites were dissected. Completely hardened gel formulation samples were taken out, and hardened gel formulation samples that were intact and free from tissue adhesion were selected for the subsequent lyophilization process.

[0140] d.Lyophilization The extracted gel formulation samples were placed in 10 ml borosilicate vials and freeze-dried. The freeze-drying equipment and parameters are shown in Table 5.

[0141] [Table 5]

[0142] e. Samples after freeze-drying were used to detect porosity.

[0143] Information on porosity detection device: Mercury porosimeter, manufactured by Micromeritics, Autopore 9620

[0144] Experimental steps for detecting porosity: After placing the test sample in an dilator, the dilator was inserted into the instrument and mercury was injected. From this result, the pore volume distribution of pores ranging in size from 360 μm to 0.003 μm was obtained.

[0145] How to calculate incremental intrusion (mL / g): The incremental intrusion (mL / g) values ​​(i.e., incremental pore volume) corresponding to pore size diameters (nm) in the range of 6000 to 9000 were summed up to calculate the incremental pore volume.

[0146] f. Experimental results: The results of the pore size distribution test are shown in Table 6 and Figure 4.

[0147] [Table 6]

[0148] Experimental Example 3: Pharmacokinetic Study in Rats Experimental method: a. Preparation of gel formulation samples in Example 10C: The specific formulation of the gel formulation sample in Example 10C was 60 mg of API, 100 mg of PLGA, and 530 mg of NMP. The content of API, PLGA, and NMP in Example 10C was the same as the content of these three substances in the formulation of Example 10, and the brexpiprazole gel formulation was manufactured using the manufacturing method described in Example 10B.

[0149] b. Experimental steps: Three healthy male SD rats weighing approximately 200-300g (purchased from Zhuhai Baishitong Biotechnology Co., Ltd.) were selected. All rats were fed a standard diet in an environment of 20-25°C and 40-70% RH, and were allowed free access to food and water. The gel formulation sample described in Example 10C above was administered subcutaneously once to the outer posterior region of the test rats. The dose of brexpiprazole, calculated by mass, was 18 mg / kg.

[0150] Blood samples were collected from the rat orbit at the following times: 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.

[0151] c. Equipment and detection steps: Breexpiprazole concentrations in rat plasma were measured using high-performance liquid chromatography-triple quadrupole mass spectrometry (HPLC-MS / MS). The linear range was 0.05 ng / mL to 150 ng / mL. 50 μL rat plasma samples were used. Aripiprazole was used as an internal standard. Samples were pretreated by protein precipitation, and then the responses of brexpiprazole and its internal standard (aripiprazole) were detected under electrospray ionization (+) conditions. Differences in pharmacokinetic properties between different formulations were compared.

[0152] d. Written description of the PK curve plot: The detected PK data is plotted as a PK curve in an Excel spreadsheet, with the horizontal axis corresponding to time and the vertical axis corresponding to cumulative blood concentration.

[0153] Experimental results: The results of PK in gel formulation rats are shown in Table 7 and Figures 5a and 5b.

[0154] [Table 7]

[0155] As can be seen from Figures 5a and 5b, the gel formulation of the present invention exhibited good sustained-release effect.

[0156] In this disclosure, relational terms such as "first" and "second" are used solely to distinguish one entity or operation from another, and do not necessarily imply or require any actual relationship or order between these entities or operations.

[0157] As can be seen from the foregoing, the specific means of implementation of this disclosure are for illustrative purposes only, but those skilled in the art can make various modifications and improvements without departing from the spirit and scope of this disclosure. Any such modifications and improvements shall be included in the claims attached to this disclosure.

Claims

1. A gel formulation of brexpiprazole 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 administration to a patient requiring it, and after mixing, the two solutions become a clear solution. A solution containing brexpiprazole or a pharmaceutically acceptable salt thereof is a gel formulation of brexpiprazole, obtained by mixing powder of brexpiprazole or a pharmaceutically acceptable salt thereof with a solvent.

2. The gel formulation according to claim 1, comprising at least one biocompatible, biodegradable, sustained-release material and at least one solvent, wherein the concentration of brexpiprazole or a pharmaceutically acceptable salt thereof is 80 mg / mL or more.

3. The gel formulation according to claim 1 or 2, wherein the sum of three times the concentration of brexpiprazole or a pharmaceutically acceptable salt thereof and the concentration of the sustained-release material is 600 mg / mL or less.

4. A method for adjunctively treating major depressive disorder in adults, comprising administering an effective amount of the gel formulation described in any one of claims 1 to 3 to a patient requiring the method.

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

6. A method for treating agitation associated with Alzheimer's disease, comprising administering an effective amount of the gel formulation described in any one of claims 1 to 3 to a patient requiring the method.

7. A method for producing a gel formulation of brexpiprazole, comprising: first, preparing a solution containing brexpiprazole or a pharmaceutically acceptable salt thereof, and a solution containing at least one biocompatible, biodegradable, sustained-release material; and before use, mixing the solution containing brexpiprazole or a pharmaceutically acceptable salt thereof, and the solution containing at least one biocompatible, biodegradable, sustained-release material to obtain a gel formulation.

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

9. A gel formulation of brexpiprazole according to any one of claims 1 to 3, wherein the content of brexpiprazole or a pharmaceutically acceptable salt thereof is 28 mg / g or more, and optionally the content range of brexpiprazole or a pharmaceutically acceptable salt thereof is 28 mg / g to 120 mg / g, or a gel formulation of brexpiprazole produced by the manufacturing method according to claim 7 or 8.

10. If the content of brexpiprazole or a pharmaceutically acceptable salt thereof is less than 80 mg / g, the sum of three times the content of brexpiprazole or a pharmaceutically acceptable salt thereof in the brexpiprazole gel formulation and the content of the sustained-release material, in terms of the total mass of brexpiprazole or a pharmaceutically acceptable salt thereof, a sustained-release material, and a solvent, is 500 mg / g or less, preferably 450 mg / g or less, a brexpiprazole gel formulation according to any one of claims 1 to 3, or a brexpiprazole gel formulation produced by the manufacturing method according to claim 7 or 8.

11. If the content of brexpiprazole or a pharmaceutically acceptable salt thereof is less than 80 mg / g, the sum of three times the content of brexpiprazole or a pharmaceutically acceptable salt thereof in the brexpiprazole gel formulation and the content of the sustained-release material, in terms of the total mass of brexpiprazole or a pharmaceutically acceptable salt thereof, a sustained-release material, and a solvent, is 430 mg / g or less, preferably 415 mg / g or less, more preferably 395 mg / g or less, the brexpiprazole gel formulation according to any one of claims 1 to 3, or the brexpiprazole gel formulation produced by the manufacturing method according to claim 7 or 8.

12. A gel formulation of brexpiprazole according to any one of claims 1 to 3, wherein the total mass of brexpiprazole or a pharmaceutically acceptable salt thereof, a sustained-release material, and a solvent is such that the sum of three times the content of brexpiprazole or a pharmaceutically acceptable salt thereof and the content of the sustained-release material is 322 mg / g or more, or a gel formulation of brexpiprazole produced by the manufacturing method according to claim 7 or 8.

13. A gel formulation of brexpiprazole according to any one of claims 1 to 3, wherein the content of the sustained-release material is 80 mg / g or more, and optionally the content range of the sustained-release material is 80 mg / g to 300 mg / g, or a gel formulation of brexpiprazole manufactured by the manufacturing method according to claim 7 or 8.

14. If the content of brexpiprazole or a pharmaceutically acceptable salt thereof is 80 mg / g or more, the sum of the content of brexpiprazole or a pharmaceutically acceptable salt thereof and the content of the sustained-release material in the brexpiprazole gel formulation is 320 mg / g or less, preferably 270 mg / g or less, and more preferably 235 mg / g or less, according to any one of claims 1 to 3, or a brexpiprazole gel formulation produced by the manufacturing method according to claim 7 or 8.

15. If the content of brexpiprazole or a pharmaceutically acceptable salt thereof is 80 mg / g or more, the sum of the content of brexpiprazole or a pharmaceutically acceptable salt thereof and the content of the sustained-release material in the brexpiprazole gel formulation is 230 mg / g or less, preferably 210 mg / g or less, and more preferably 190 mg / g or less, according to any one of claims 1 to 3, or a brexpiprazole gel formulation produced by the manufacturing method according to claim 7 or 8.

16. A gel formulation of brexpiprazole according to any one of claims 1 to 3, wherein the total mass of brexpiprazole or a pharmaceutically acceptable salt thereof, a sustained-release material, and a solvent is such that the sum of the content of brexpiprazole or a pharmaceutically acceptable salt thereof and the content of the sustained-release material is 180 mg / g or more, or a gel formulation of brexpiprazole produced by the manufacturing method according to claim 7 or 8.

17. Use of a gel formulation of brexpiprazole according to any one of claims 1 to 3, or a gel formulation of brexpiprazole manufactured by the manufacturing method according to claim 7 or 8, in the manufacture of a drug for the adjunctive treatment of major depressive disorder in adults.

18. Use of a gel formulation of brexpiprazole according to any one of claims 1 to 3, or a gel formulation of brexpiprazole produced by the manufacturing method according to claim 7 or 8, in the manufacture of a drug for treating schizophrenia.

19. Use of a gel formulation of brexpiprazole according to any one of claims 1 to 3, or a gel formulation of brexpiprazole manufactured by the manufacturing method according to claim 7 or 8, in the manufacture of a drug for treating agitation associated with Alzheimer's disease.

20. A method for adjunctively treating major depressive disorder in adults, comprising administering to a patient requiring the method a gel formulation of brexpiprazole manufactured by the manufacturing method described in claim 7 or 8 in an effective amount.

21. A method for treating schizophrenia, comprising administering to a patient requiring the method an effective amount of a gel formulation of brexpiprazole manufactured by the manufacturing method described in claim 7 or 8.

22. A method for treating agitation associated with Alzheimer's disease, comprising administering an effective amount of a gel formulation of brexpiprazole manufactured by the manufacturing method described in claim 7 or 8 to a patient requiring the method.

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