Methods for administering aripiprazole injectable preparations

Abstract

To provide methods for administering RTU injectable preparations of aripiprazole that allows administration to a population of patients considered of having a potential risk for adherence-related relapse or suboptimal treatment outcomes, and allows achievement of therapeutic plasma concentrations without reliance on daily dosing of oral tablets.SOLUTION: The present disclosure is directed to a method for treating a patient with schizophrenia or bipolar disorder Type I by administering to the patient an injectable preparation of aripiprazole, the patient receiving the injectable preparation approximately once every two months.SELECTED DRAWING: None

Description

[Technical field]

[0001] This application claims priority to U.S. Provisional Application No. 63 / 003,544, filed April 1, 2020, the contents of which are incorporated herein by reference in their entirety. [Background technology]

[0002] Aripiprazole, a partial agonist at dopamine (D2) and serotonin 5-HT1A receptors and an antagonist at the serotonin 5-HT2A receptor, is an atypical antipsychotic that has demonstrated efficacy in clinical trials for the treatment of schizophrenia and bipolar I disorder in adults. Aripiprazole is 7-[4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butoxy]-3,4-dihydrocarbostyril. Its empirical formula is C 23 H 27 Cl 2 N 3 O 2 and its molecular weight is 448.38. The chemical structure is [ka] It is.

[0003] Pharmaceutical compositions containing aripiprazole are known as antipsychotics useful for the treatment of schizophrenia. Abilify Maintena®, an intramuscular (IM) depot formulation of aripiprazole, is an extended release suspension injection. It has been approved in many countries for the maintenance treatment of schizophrenia and bipolar disorder type I in adult patients stabilized with oral aripiprazole.

[0004] Abilify Maintena® for intramuscular injection is currently approved by the US Federal Drug Administration and includes a sustained release suspension for monthly administration of aripiprazole or its salts in doses of 160 mg, 200 mg, 300 mg, and 400 mg. These compositions and methods are described in U.S. Patent Nos. 7,807,680, 8,030,313, 8,338,427, 8,338,428, 8,399,469, 8,722,679, 8,759,351, 8,993,761, 9,089,567, and 10,525,057, all of which are incorporated herein by reference in their entirety.

[0005] Other formulations of sustained release compositions of aripiprazole include the use of injectable preparations that contain aripiprazole or a salt thereof, a crystalline form of aripiprazole or a salt thereof, a particular suspending agent (suspending agent (A)), and a dispersion medium. These injectable preparations are known as ready to use (RTU) formulations of aripiprazole; these are described at least in U.S. Pat. No. 10,517,951, which is incorporated herein by reference in its entirety. Summary of the Invention [Problem to be solved by the invention]

[0006] The RTU injectable preparation of aripiprazole allows administration to a patient population considered to be potentially at risk for adherence-related relapse or suboptimal therapeutic outcomes, and to achieve therapeutic plasma concentrations without relying on daily dosing of oral tablets. That is, the present disclosure is directed to the use of the RTU injectable preparation of aripiprazole to minimize one or more of relapse, suboptimal therapeutic outcomes, and / or achieve therapeutic plasma concentrations. For example, the present disclosure is directed to a method of treating patients with schizophrenia or bipolar disorder type I by intramuscularly administering an injectable preparation comprising aripiprazole or a salt thereof to the patient, wherein the patient receives an administration of the injectable preparation about once every two months. Administration of the injectable preparation about once every two months can improve drug compliance. [Means for solving the problem]

[0007] In some embodiments, the present disclosure is directed to a method of treating a patient with schizophrenia or bipolar disorder type I, comprising intramuscularly administering to the patient an injectable preparation comprising aripiprazole or a salt thereof, the patient receiving the injectable preparation approximately once every two months. In the methods disclosed herein, the injectable preparation comprises an amount ranging from about 650 mg to about 1200 mg of aripiprazole. Further, in the methods disclosed herein, the intramuscular administration to the patient is performed at a site selected from the deltoid muscle, the gluteal muscle, and a combination thereof, for example, at the gluteal muscle.

[0008] In a further embodiment, in the methods provided herein, the injectable preparation further comprises water and a suspending agent comprising polyvinylpyrrolidone, polyethylene glycol, and carboxymethylcellulose or a salt thereof, wherein the aripiprazole or a salt thereof has an average primary particle size ranging from about 0.5 μm to about 30 μm, and the concentration of the aripiprazole or a salt thereof ranges from about 200 mg / mL to about 600 mg / mL.Furthermore, for example, in the methods disclosed herein, one or more injectable preparations are administered.

[0009] In an embodiment of the disclosure, a method of treating a patient having schizophrenia or bipolar I disorder comprises administering to the patient's gluteal muscle an injectable preparation comprising aripiprazole or a salt thereof, wherein the patient receives an administration of the injectable preparation once about every 56 days (8 weeks, or 2 months), and wherein the amount of aripiprazole in the injectable preparation ranges from about 650 mg to about 1200 mg.

[0010] In some further aspects, the present disclosure is directed to a method of treating a patient having schizophrenia or bipolar disorder Type I, comprising administering an injectable preparation comprising aripiprazole or a salt thereof to the patient's gluteal muscle, wherein the patient receives an administration of the injectable preparation once every about 56 days, wherein the injectable preparation further comprises water, and a suspending agent comprising polyvinylpyrrolidone, polyethylene glycol, and carboxymethylcellulose or a salt thereof, and wherein a concentration of aripiprazole in the injectable preparation is 300 mg / mL.

[0011] In some further aspects, the present disclosure is directed to aripiprazole or a salt thereof for use in treating schizophrenia or bipolar disorder type I, wherein the aripiprazole or a salt thereof is administered to a patient in need thereof using the methods disclosed herein.Furthermore, the present disclosure also provides a use of aripiprazole or a salt thereof in the manufacture of a medicament for treating schizophrenia or bipolar disorder type I, wherein the aripiprazole or a salt thereof is administered to a patient in need thereof using the methods disclosed herein. [Brief description of the drawings]

[0012] [Figure 1]FIG. 1 covers the mean (SD) pharmacokinetic concentrations after first dosing of investigational medicinal product, i.e., aripiprazole two-month (2M) RTU (referred to as "Ari 2M group"), 960 mg (N=41) (one injection every 56 days), with 7 consecutive days of oral aripiprazole starting on day 1 of the first dose of Ari 2M RTU; the reference component was aripiprazole intramuscular depot (referred to as "Ari IM depot" or "IM depot"), 400 mg (N=42) (one injection every 28 days), Abilify Maintena®, with 14 consecutive days of oral aripiprazole starting on day 1 of the first dose of Ari IM depot.

[0013] [Diagram 2] FIG. 2 shows the mean (SD) pharmacokinetic concentrations after the 4th dose of aripiprazole, Ari 2M, 960 mg (N=102) (56 days apart) compared with the mean (SD) pharmacokinetic concentrations after the 7th and 8th doses of aripiprazole, IM depot, 400 mg (N=93) (28 days apart).

[0014] [Diagram 3] FIG. 3 illustrates the mean (SD) aripiprazole plasma concentration-time profiles following administration of a single dose of 780 mg (N=18) or 1200 mg (N=13) aripiprazole 2M RTU, ready-to-use, long-acting injection into the gluteal muscle in subjects with schizophrenia. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0015] As used herein, "a" or "an" entity refers to one or more of that entity; for example, "a compound" refers to one or more compounds or at least one compound, unless otherwise stated. Thus, the terms "a" (or "an"), "one or more," and "at least one" are used interchangeably herein.

[0016] As used herein, the term "about" means approximately, within the region of, roughly, or around. When the term "about" is used in conjunction with a numerical range, it modifies the range by extending the boundaries above and below the stated numerical values. In general, the term "about" is used herein to modify a numerical value with a variance of 5% above and below the stated value.

[0017] As used herein, the terms "treat", "treating" or "treatment", when used in relation to a disorder or condition, include any effect that results in an improvement of the disorder or condition, such as, for example, alleviating, reducing, modulating, ameliorating or eliminating. The improvement or reduction in the severity of any symptoms of the disorder or condition can be easily assessed according to standard methods and techniques known in the art. In some embodiments, the methods disclosed herein can be used to treat schizophrenia and bipolar disorder type I as a sole maintenance therapy. In further embodiments, the methods disclosed herein can be used to treat acute treatment of manic and mixed episodes associated with schizophrenia, bipolar disorder type I, major depressive disorder (MDD), irritability associated with autistic disorder, and Tourette's disorder.

[0018] As used herein, the reference to "aripiprazole" refers to aripiprazole or its salt, crystalline form of aripiprazole or its salt. Aripiprazole or its salt may be in monohydrate form (aripiprazole hydrate A) or various anhydrous forms, which are known to exist in the form of anhydrous crystal B, anhydrous crystal C, anhydrous crystal D, anhydrous crystal E, anhydrous crystal F, and anhydrous crystal G. All of these crystal forms can be used as aripiprazole or its salt in the injectable preparation of the present disclosure, furthermore, for example, aripiprazole is in monohydrate form. As used herein, the term "aripiprazole" or its salt refers to the structure: [ka] It refers to a compound having the formula:

[0019] The present disclosure is directed to a method of treating patients with schizophrenia or bipolar disorder type I by intramuscularly administering to said patients an injectable preparation of aripiprazole, wherein the patient receives the injectable preparation approximately once every two months.

[0020] Embodiments:

[0021] Without being limited, some embodiments of the present disclosure include:

[0022] 1. A method for treating a patient having schizophrenia or bipolar disorder type I, comprising intramuscularly administering to the patient an injectable preparation comprising aripiprazole or a salt thereof, wherein the patient receives the injectable preparation approximately once every two months.

[0023] 2. The method of embodiment 1, wherein administration of the injectable preparation provides the patient with a total amount of about 650 mg to about 1200 mg of aripiprazole every two months.

[0024] 3. The method of embodiment 2, wherein administration of the injectable preparation provides the patient with a total amount of about 960 mg of aripiprazole every two months.

[0025] 4. The method of any one of embodiments 1-3, wherein about once every two months comprises about once every 42 to 70 days.

[0026] 5. The method of embodiment 4, wherein once every 2 months includes once every about 56 days (e.g., once every 54 to 58 days).

[0027] 6. The method of any one of embodiments 1-5, wherein the patient has schizophrenia.

[0028] 7. The method of any one of embodiments 1-5, wherein the patient has bipolar disorder type I.

[0029] 8. The method of any one of embodiments 1-7, wherein intramuscular administration to the patient is performed at a site selected from the deltoid muscle, the gluteal muscle, and combinations thereof.

[0030] 9. The method of embodiment 8, wherein the site is a gluteal muscle.

[0031] 10. The method according to any one of embodiments 1 to 9, wherein the injectable preparation further comprises water and a suspending agent comprising polyvinylpyrrolidone, polyethylene glycol, and carboxymethylcellulose or a salt thereof, wherein the aripiprazole or a salt thereof has an average primary particle size of about 0.5 μm to about 30 μm, and the concentration of aripiprazole or a salt thereof is about 200 mg / mL to about 600 mg / mL.

[0032] 11. The method according to any one of embodiments 1-9, wherein the injectable preparation further comprises water for injection, and a suspending agent comprising polyvinylpyrrolidone, polyethylene glycol, and carboxymethylcellulose or a salt thereof, and the aripiprazole or a salt thereof is aripiprazole monohydrate, the aripiprazole monohydrate having an average primary particle size of about 2 μm to about 5 μm, and the concentration of aripiprazole in the injectable preparation, calculated on the anhydrous form of aripiprazole, is about 300 mg / mL.

[0033] 12. The method of any one of embodiments 1-11, wherein the area under the concentration-time curve (AUC) of aripiprazole from time zero to day 56 after administration after multiple administrations of the injectable preparation is substantially equivalent to twice the AUC of aripiprazole from time zero to day 28 after administration after multiple administrations of an aripiprazole intramuscular (IM) depot formulation, e.g., Abilify Maintena®, approximately once every month (4 weeks or 28 days), as shown, for example, in FIG. 2.

[0034] 13. The method of any one of embodiments 1-11, further comprising orally administering to the patient a solid dosage form comprising aripiprazole or a salt thereof, wherein the injectable preparation and the solid dosage form are administered to the patient on day 1, and the solid dosage form is administered for 5 to 15 consecutive days starting from day 1.

[0035] 14. A method for treating a patient having schizophrenia or bipolar disorder type I, comprising intramuscularly administering to the patient an injectable preparation comprising aripiprazole or a salt thereof, wherein the patient receives an administration of the injectable preparation approximately once every two months, and wherein the intramuscular administration to the patient is at a site selected from the deltoid muscle, the gluteal muscle, and combinations thereof.

[0036] 15. A method of treating a patient having schizophrenia or bipolar I disorder, comprising intramuscularly administering to the patient an injectable preparation comprising aripiprazole or a salt thereof, wherein the patient receives an administration of the injectable preparation approximately once every two months, wherein the intramuscular administration to the patient is at a site selected from the deltoid muscle, the gluteal muscle, and combinations thereof, and wherein approximately once every two months comprises approximately once every 42 to 70 days.

[0037] 16. A method of treating a patient having schizophrenia or bipolar disorder type I, comprising intramuscularly administering to the patient an injectable preparation comprising aripiprazole or a salt thereof, wherein the patient receives the injectable preparation once every about two months, wherein the intramuscular administration to the patient is at a site selected from the deltoid muscle, the gluteal muscle, and combinations thereof, wherein once every about two months comprises once every about 42 to 70 days, and wherein the administration of the injectable preparation provides the patient with a total amount of about 650 mg to about 1200 mg of aripiprazole every two months.

[0038] 17. A method of treating a patient having schizophrenia or bipolar disorder type I, comprising intramuscularly administering to the patient an injectable preparation comprising aripiprazole or a salt thereof, wherein the patient receives the injectable preparation once every about two months, wherein the intramuscular administration to the patient is at a site selected from the deltoid muscle, the gluteal muscle, and a combination thereof, wherein once every about two months comprises once every about 42 to 70 days, wherein the administration of the injectable preparation provides the patient with a total amount of about 650 mg to about 1200 mg of aripiprazole every two months, wherein the injectable preparation further comprises water and a suspending agent comprising polyvinylpyrrolidone, polyethylene glycol, and carboxymethylcellulose or a salt thereof, wherein the aripiprazole or salt thereof has an average primary particle size of about 0.5 μm to about 30 μm, and wherein the concentration of the aripiprazole or salt thereof is in the range of about 200 mg / mL to about 600 mg / mL.

[0039] 18. A method for treating a patient having schizophrenia or bipolar disorder type I, comprising administering to the patient's gluteal muscle an injectable preparation comprising aripiprazole or a salt thereof, wherein the patient receives the injectable preparation once every about 56 days (8 weeks, or 2 months), and the amount of aripiprazole in the injectable preparation is between about 650 mg and about 1200 mg.

[0040] 19. The method according to embodiment 18, wherein the injectable preparation further comprises water and a suspending agent comprising polyvinylpyrrolidone, polyethylene glycol, and carboxymethylcellulose or a salt thereof, wherein the aripiprazole or a salt thereof has an average primary particle size of about 0.5 μm to about 30 μm, and the concentration of aripiprazole in the injectable preparation is about 300 mg / mL.

[0041] 20. The method according to embodiment 18 or 19, wherein the injectable preparation further comprises water for injection and a suspending agent comprising polyvinylpyrrolidone, polyethylene glycol, and carboxymethylcellulose or a salt thereof, wherein the aripiprazole or a salt thereof is aripiprazole monohydrate, wherein the aripiprazole monohydrate has an average primary particle size of about 2 μm to about 5 μm, and wherein the concentration of aripiprazole in the injectable preparation, calculated on the anhydrous form of aripiprazole, is about 300 mg / mL.

[0042] 21. The method according to any one of embodiments 18 to 20, wherein the area under the concentration-time curve (AUC) of aripiprazole from time zero to day 56 after administration after multiple administrations of the injectable preparation is substantially equal to twice the AUC of aripiprazole from time zero to day 28 after administration after multiple administrations of an aripiprazole intramuscular (IM) depot formulation, e.g., Abilify Maintena®, approximately once every month (4 weeks or 28 days), as shown, for example, in FIG. 2.

[0043] 22. The method according to any one of embodiments 18-20, further comprising orally administering aripiprazole in a solid dosage form, wherein, together with the first administration of the injectable preparation, the solid dosage form is administered in an amount of 10 mg to 20 mg per day for 5 to 15 consecutive days.

[0044] 23. The method according to any one of embodiments 18-20, further comprising orally administering 10 mg to 20 mg of aripiprazole per day in a solid dosage form for 7 consecutive days together with the first administration of the injectable preparation.

[0045] 24. A method of treating a patient having schizophrenia or bipolar disorder type I, comprising administering to the patient's gluteal muscle an injectable preparation comprising aripiprazole or a salt thereof, wherein the patient receives one dose of the injectable preparation about every 56 days (8 weeks, or 2 months), wherein the injectable preparation is administered to the patient in an amount of about 650 mg to about 1200 mg of aripiprazole, wherein the injectable preparation further comprises water and a suspending agent comprising polyvinylpyrrolidone, polyethylene glycol, and carboxymethylcellulose or a salt thereof, and wherein the aripiprazole or salt thereof has an average primary particle size of about 0.5 μm to about 30 μm.

[0046] 25. The method according to embodiment 24, further comprising orally administering aripiprazole in a solid dosage form, wherein, together with the first dose of the injectable preparation, the solid dosage form is administered in an amount of 10 mg to 20 mg per day for 5 to 15 consecutive days.

[0047] 26. The method according to embodiment 24, further comprising orally administering 10 to 20 mg of aripiprazole per day in a solid dosage form for 7 consecutive days together with the first administration of the injectable preparation.

[0048] 27. A method for administering an injectable preparation containing aripiprazole or a salt thereof to a patient with schizophrenia or bipolar disorder type I, comprising: Patients should be administered 10 to 20 mg / day of aripiprazole or a salt thereof orally for 5 to 15 consecutive days starting from day 1; administering to the patient an injectable preparation intramuscularly once every 56 days (about every 8 weeks or 2 months); A method in which an injectable preparation containing about 650 mg to 1200 mg of aripiprazole is administered on day 1, with successive administrations allowing the average plasma level of aripiprazole to be maintained at or above 90 ng / mL for, for example, at least about 56 days.

[0049] 28. The method of embodiment 27, wherein the method does not include further oral administration of aripiprazole or a salt thereof.

[0050] 29. A method for administering a prefilled sol-gel formed injectable preparation comprising aripiprazole or a salt thereof to a patient in need thereof, comprising: A total of 50 to 300 mg of aripiprazole administered simultaneously or consecutively on days 1 through 15; and On day 1, administer a prefilled sol-gel injectable preparation containing 650-1200 mg of aripiprazole into the gluteal muscle; followed by administering about 650 mg to 1200 mg of aripiprazole into the gluteal muscle once about every 56 days (about every 8 weeks or 2 months); A method in which a series of doses is administered to maintain mean plasma levels of aripiprazole at or above 90 ng / mL.

[0051] 30. The method according to embodiment 29, wherein the pre-filled sol-gel formed injectable preparation comprises 300 mg / mL of aripiprazole and is an injectable preparation having thixotropic properties.

[0052] 31. The method according to embodiment 29 or 30, wherein the injectable preparation further comprises a suspending agent selected from the group consisting of polyvinylpyrrolidone, polyethylene glycol, carboxymethylcellulose or a salt thereof, and any combination thereof.

[0053] 32. A method for administering a sustained-release injectable preparation containing aripiprazole or a salt thereof to a patient in need thereof, comprising: administering to the patient an injectable preparation containing 650 to 1200 mg of aripiprazole into the patient's gluteal muscle once about every 56 days (about every 8 weeks or every 2 months); A method in which a patient has a stable plasma level of aripiprazole by receiving an administration of aripiprazole but requires additional administration of aripiprazole, and the injectable preparation is a pre-filled sol-gel formed injectable dosage form, and the successive administrations enable the average plasma level of aripiprazole to be maintained at or above 90 ng / mL.

[0054] 33. The method of embodiment 32, wherein the stable plasma level of aripiprazole is greater than or equal to 90 ng / mL.

[0055] 34. A method of treating a patient having schizophrenia or bipolar disorder type I, comprising intramuscularly administering to the patient an injectable preparation comprising aripiprazole or a salt thereof once about every two months (8 weeks or 56 days), wherein the area under the concentration-time curve (AUC) of aripiprazole from time zero to day 56 after administration after multiple administrations of the injectable preparation is substantially equal to twice the AUC of aripiprazole from time zero to day 28 after administration after multiple administrations of an aripiprazole intramuscular (IM) depot formulation, e.g., Abilify Maintena®, once about every month (4 weeks or 28 days), as shown, for example, in FIG. 2.

[0056] 35. The method of embodiment 34, wherein the aripiprazole or salt thereof is aripiprazole monohydrate.

[0057] 36. The method according to embodiment 34 or 35, wherein the multiple doses of the injectable preparation are 4 or more doses and the multiple doses of the aripiprazole intramuscular (IM) depot formulation are 7 or more doses.

[0058] 37. A method of treating a patient having schizophrenia or bipolar disorder type I, comprising intramuscularly administering to the patient an injectable preparation comprising aripiprazole or a salt thereof once about every two months (8 weeks or 56 days), wherein the plasma concentration of aripiprazole 56 days after administration after multiple administrations of the injectable preparation is substantially equal to the plasma concentration of aripiprazole 28 days after multiple administrations of an aripiprazole intramuscular (IM) depot formulation, e.g., Abilify Maintena®, once about every month (4 weeks or 28 days), as shown, for example, in FIG. 2.

[0059] 38. The method of embodiment 37, wherein the aripiprazole or salt thereof is aripiprazole monohydrate.

[0060] 39. The method according to embodiment 37 or 38, wherein the multiple doses of the injectable preparation are 4 or more doses and the multiple doses of the aripiprazole intramuscular (IM) depot formulation are 7 or more doses.

[0061] Preparations for injection

[0062] The injectable preparations of the present disclosure (e.g., 2-month ready to use (RTU) injectable preparations) include compositions comprising aripiprazole, a specific suspending agent (suspending agent (A)), and a dispersion medium. For example, the injectable preparations of the present disclosure comprise at least water as a dispersion medium. Water, or an aqueous solvent comprising water and an organic solvent, can be used as a dispersion medium comprising at least water. In some embodiments, the dispersion medium is water, further, for example, sterile water for injection.

[0063] The particular suspending agent (Suspending Agent A) contained in the injectable preparation of the present disclosure comprises at least one suspending agent selected from (i) and (ii): (i) polyvinylpyrrolidone and (ii) polyethylene glycol and carboxymethylcellulose or a salt thereof.

[0064] In some embodiments, the injectable preparation of the present disclosure comprises aripiprazole or a salt thereof, water, and at least one suspending agent selected from group (i) and (ii): (i) polyvinylpyrrolidone and (ii) polyethylene glycol and carboxymethylcellulose or a salt thereof, wherein the aripiprazole or a salt thereof has an average primary particle size ranging from about 0.5 μm to about 30 μm, and the concentration of the aripiprazole or a salt thereof ranges from about 200 mg / mL to about 600 mg / mL. The 2-month ready to use (RTU) injectable preparation disclosed herein is described in U.S. Patent No. 10,517,951, the entire contents of which are incorporated herein by reference.

[0065] For example, when the injectable preparation of the present disclosure contains aripiprazole or a salt thereof (hereinafter, referred to as the "aripiprazole injectable preparation of the present disclosure"), the concentration of aripiprazole or a salt thereof is in the range of about 200 mg / mL to about 600 mg / mL. (α) The RTU injectable preparation of aripiprazole becomes a gel upon standing, and the precipitation and solidification of aripiprazole particles can be inhibited, thereby obtaining excellent storage stability. Furthermore, (β) the injectable preparation, even in the form of a gel, can easily increase in fluidity when subjected to a slight impact, so that the preparation can be easily injected at the time of use (injection). Furthermore, the gel-like injectable preparation (gel composition) increases in fluidity (forms a sol state) simply by pushing the plunger of the syringe and pushing the preparation through the syringe needle, so that the preparation can be smoothly pushed through the needle as it is. Thus, the preparation has thixotropic properties and can be well dispersed intramuscularly or subcutaneously with relatively little local damage and pain during injection.

[0066] That is, when the concentration is 100 mg / mL or less, even if suspending agent A is used (or aging treatment is further performed), the formation of an injectable preparation that may form a gel cannot occur. Therefore, the injectable preparation of the present disclosure includes aripiprazole or a salt thereof, and a combination of a specific suspending agent (suspending agent A) and a specific concentration of aripiprazole or a salt thereof (about 200 mg / mL to about 600 mg / mL, for example, about 250 mg / mL to about 450 mg / mL, and about 300 mg / mL to about 400 mg / mL) is used. When the injectable preparation of the present disclosure includes a salt of aripiprazole, the concentration described above is calculated as aripiprazole.

[0067] In some embodiments, the RTU injectable preparation comprises aripiprazole in a concentration of about 200 mg / mL to about 600 mg / mL, such as, for example, about 200 mg / mL to about 500 mg / mL, such as, for example, about 250 mg / mL to about 450 mg / mL, further for example, about 300 mg / mL to about 400 mg / mL, and further for example, about 300 mg / mL.

[0068] In some embodiments, in the aripiprazole injectable preparation of the present disclosure, (i) when polyvinylpyrrolidone is contained as suspending agent A, the concentration of polyvinylpyrrolidone is in the range of about 0.1 mg / mL to about 100 mg / mL, for example, about 1 mg / mL to about 50 mg / mL, further for example, in the range of about 2 mg / mL to about 20 mg / mL.

[0069] In some embodiments, when the aripiprazole injection preparation of the present disclosure includes (i) polyvinylpyrrolidone as suspending agent A and further includes one or more other suspending agents, at least one member is selected from polyethylene glycol and carboxymethylcellulose or a salt thereof and is included as one or more other suspending agents. For example, when the injection preparation of the present disclosure includes (i) polyvinylpyrrolidone as suspending agent A and further includes one or more other suspending agents, they include any combination of suspending agents among (i-1) to (i-3) shown below.

[0070] (i-1) Polyvinylpyrrolidone and polyethylene glycol

[0071] (i-2) Polyvinylpyrrolidone and carboxymethylcellulose or a salt thereof, and

[0072] (i-3) Polyvinylpyrrolidone, polyethylene glycol, and carboxymethylcellulose or a salt thereof.

[0073] Regardless of which combination of (i-1) to (i-3) is included in these injectable preparations of the present disclosure, the concentration of polyvinylpyrrolidone is, as described above, about 0.1 mg / mL to about 100 mg / mL, for example, about 1 mg / mL to about 50 mg / mL, and further for example, about 2 mg / mL to about 20 mg / mL. In (i-1) or (i-3), the concentration of polyethylene glycol is about 0.05 mg / mL to about 100 mg / mL, for example, about 0.1 mg / mL to about 50 mg / mL. In (i-2) or (i-3), the concentration of carboxymethylcellulose or a salt thereof is about 0.5 mg / mL to about 50 mg / mL, for example, about 1 mg / mL to about 30 mg / mL, and further for example, about 2 mg / mL to about 20 mg / mL.

[0074] The inclusion of carboxymethylcellulose or a salt thereof can suppress the increase in viscosity during production. This allows aripiprazole or a salt thereof to be pulverized to a desired particle size in an efficient manner. In some embodiments, the molecular weight of carboxymethylcellulose or a salt thereof is in the range of 49,000 to 300,000. Furthermore, the inclusion of polyethylene glycol can prevent syneresis even when the resulting injectable preparation is stored for a long period of time. In some embodiments, the molecular weight of polyethylene glycol is in the range of 400 to 4,000. In some embodiments, (i-3) is present in the injectable preparation.

[0075] In some embodiments, when the aripiprazole injection preparation of the present disclosure includes (ii) polyethylene glycol and carboxymethylcellulose or a salt thereof as suspending agent A, the concentration of polyethylene glycol is about 0.05 mg / mL to about 2 mg / mL, for example, about 0.1 mg / mL to about 1 mg / mL. The concentration of carboxymethylcellulose or a salt thereof is about 0.5 mg / mL to about 50 mg / mL, for example, about 1 mg / mL to about 30 mg / mL, and for example, about 2 mg / mL to about 20 mg / mL.

[0076] In some embodiments, the aripiprazole injection preparation of the present disclosure comprises (ii) polyethylene glycol and carboxymethylcellulose or a salt thereof as suspending agent A, and further comprises one or more other suspending agents, and polyvinylpyrrolidone may be contained as one or more other suspending agents.For example, when the injection preparation of the present disclosure comprises (ii) polyethylene glycol and carboxymethylcellulose or a salt thereof as suspending agent A, and further comprises one or more other suspending agents, the suspending agent of (i-3) is contained.In this case, the concentrations of polyethylene glycol, carboxymethylcellulose or a salt thereof, and polyvinylpyrrolidone are the same as those described in (i-3) above.

[0077] In some embodiments, when the suspending agent (i-3) is used in the aripiprazole injection preparation of the present disclosure, the composition contains about 0.5 mg / mL to about 20 mg / mL polyvinylpyrrolidone, about 0.1 mg / mL to about 100 mg / mL polyethylene glycol, about 0.5 mg / mL to about 50 mg / mL carboxymethylcellulose or a salt thereof, and about 250 mg / mL to about 450 mg / mL (e.g., about 300 mg / mL to about 400 mg / mL) aripiprazole or a salt thereof. In this case, the polyethylene glycol may be polyethylene glycol 400 or polyethylene glycol 4000. In some embodiments, the polyvinylpyrrolidone has a K value of about 12 to about 20. In further embodiments, the aripiprazole or a salt thereof has an average primary particle size of about 1 μm to 10 μm.

[0078] Since excessively large average primary particle size of aripiprazole or its salt may cause precipitation, the average primary particle size is in the range of about 0.5 μm to about 30 μm, for example, about 1 μm to about 20 μm. When the injectable preparation of the present disclosure is in a dosage form administered once every two months, aripiprazole or its salt has an average primary particle size of about 1 μm to about 50 μm, for example, about 1 μm to about 10 μm, and further for example, about 2 μm to about 5 μm. The average secondary particle size is up to but not more than three times the particle size, and further for example, up to but not more than two times the average primary particle size.

[0079] In some embodiments, the injectable preparation of the present disclosure is appropriately formulated into a dosage form that can be administered once every two months.For example, the concentration of aripiprazole or its salt in the injectable preparation of the present disclosure that is administered once every two months is calculated as aripiprazole, and is about 200mg / mL to about 600mg / mL, for example, about 250mg / mL to about 500mg / mL, further for example, about 300mg / mL to 400mg / mL, and further for example, about 300mg / mL.When the injectable preparation is administered once every two months, the dosage volume is about 2mL to about 4mL, for example, about 2.2mL to about 3.5mL, further for example, about 2.3mL to about 3.4mL, and further for example, about 3.2mL.

[0080] In some embodiments, the aripiprazole injectable preparations of the present disclosure achieve the effects (α) and (β) described above. They may be in the form of a gel, or they may have fluidity (i.e., they may be in the form of a sol). As described above, the achievement of the effects (α) and (β) can be objectively confirmed by using a rotational rheometer. The injectable preparations can also be formulated into a loaded sol-gel-formed injection (also referred to herein as a loaded sol-gel-formed injectable preparation). The injectable preparations exhibit thixotropic properties. Furthermore, the preparations can be in the form of a gel when left to stand, and can be transformed into a sol when impacted.

[0081] In some embodiments, a method for producing an aripiprazole injectable preparation comprises the steps of preparing a liquid mixture of starting materials, milling the aripiprazole or a salt thereof contained in the liquid mixture to a desired average primary particle size, which may be optionally followed by an aging treatment.

[0082] In some embodiments, a method for producing a gel aripiprazole injection preparation according to the present invention comprises a step of allowing a liquid mixture to stand at 5 to 70° C. for 5 minutes or more, the liquid mixture comprising aripiprazole or a salt thereof at a concentration of about 200 mg / mL to about 600 mg / mL and having an average primary particle size of about 0.5 μm to about 30 μm, water, and at least one suspending agent selected from (i) and (ii): (i) polyvinylpyrrolidone and (ii) polyethylene glycol and carboxymethylcellulose or a salt thereof.

[0083] For example, in some further embodiments, a production method can be used that includes the following steps: pulverizing aripiprazole or a salt thereof to an average primary particle size of about 0.5 μm to about 30 μm in a liquid mixture containing aripiprazole or a salt thereof at a concentration of about 200 mg / mL to about 600 mg / mL, water, and at least one suspending agent selected from the group consisting of (i) and (ii): (i) polyvinylpyrrolidone and (ii) polyethylene glycol and carboxymethylcellulose or a salt thereof; and allowing the pulverized liquid mixture to stand at 5° C. to 70° C. for 5 minutes or more.

[0084] In some embodiments, the disclosure includes administering to a patient an aripiprazole injectable preparation that results in administration of a total amount of aripiprazole ranging from about 650 mg to about 1200 mg, for example, about 690 mg to about 960 mg, further for example, about 750 mg to about 960 mg, and the injectable preparation may be administered in one or more divided injections. In some further embodiments, administering the aripiprazole injectable preparation results in administration of a total amount of aripiprazole of about 960 mg to a patient, and one or more injectable preparations are administered. For example, to obtain a total amount of aripiprazole of 960 mg administered to a patient, one injection of an aripiprazole injectable preparation containing 300 mg / mL of aripiprazole is administered. The 960 mg dose may be administered in divided injections at short intervals as appropriate. The number of injections and the concentration of aripiprazole are varied taking into account the total amount of aripiprazole administered and the concentration of aripiprazole contained in each of the injectable preparations, as described above.

[0085] In some aspects, the subject is administered with the aripiprazole injection preparation by intramuscular injection.In some embodiments, intramuscular administration is carried out at a site selected from deltoid muscle, gluteal muscle, and combinations thereof.In some embodiments, the site is gluteal muscle.For example, depending on the number of injections for administration, the injection site can include various locations of deltoid muscle and / or gluteal muscle.

[0086] In some embodiments, the method of administering an injectable preparation of aripiprazole disclosed herein occurs at a frequency of about once every two months. For example, the injectable preparation is administered about once every 42-70 days or any integer in between and including the endpoints, for example, every 49-63 days, for example, every 50-60 days, i.e., every 50, 51, 52, 53, 54, 55, 56, 57, 58, 59 or 60 days. In further embodiments, the injectable preparation is administered about once every 56 days, for example, once every 54-58 days. In further embodiments, the injectable preparation is administered about once every 8 weeks, for example, once every 6-10 weeks.

[0087] In some embodiments, the methods disclosed herein include orally administering to a patient 10-20 mg / day of aripiprazole or a salt thereof for about 5-15 consecutive days, such as for about 7-14 consecutive days, further for example for about 7 consecutive days, from day 1 of administration, and intramuscularly administering to the patient an injectable preparation comprising aripiprazole or a salt thereof about once every 56 days (every 8 weeks or every 2 months), with an injectable preparation comprising about 650 mg to 1200 mg of aripiprazole being administered on day 1. The series of administrations allows the average plasma level of aripiprazole to be maintained at 90 ng / mL or higher. For example, oral administration may be performed with a solid dosage form comprising 10-20 mg / day of aripiprazole or a salt thereof, and the solid dosage form may be administered for about 5-15 consecutive days, such as for about 7-14 consecutive days, further for example for about 7 consecutive days. Further for example, solid dosage forms may be administered to a patient in a total amount of aripiprazole ranging from 50 mg to 300 mg, 60 mg to 280 mg, 70 mg to 280 mg, or 70 mg to 140 mg.

[0088] In some aspects, the solid dosage form of the present disclosure is an oral (aripiprazole) tablet. In some embodiments, the oral tablet of aripiprazole is available in active ingredient strengths of, for example, 2 mg, 5 mg, 10 mg, 15 mg, and 20 mg, and is available in a single oral dose selected from 10 mg to 20 mg. In some embodiments, the oral tablet of aripiprazole may include inactive ingredients. Inactive ingredients in the oral tablet include, for example, corn starch, hydroxypropyl cellulose, lactose monohydrate, magnesium stearate, and microcrystalline cellulose. Coloring agents include, for example, iron oxide (yellow or red) and FD&C Blue No. 2 Aluminum Lake.

[0089] In some aspects, the injectable preparation of the present disclosure can be directly loaded into a syringe for use as a pre-filled syringe. This simplifies the structure of the syringe and reduces its size and weight. When the injectable preparation of the present disclosure is loaded into a syringe, in a further embodiment, the sol suspension can be administered by simply pushing the plunger rod of the syringe and pushing out the injectable preparation of the present disclosure through the syringe needle. This provides clinical convenience and operability, and thus provides a pre-filled syringe that is extremely useful medically and industrially. One example of manufacturing a pre-filled syringe is to prepare the injectable preparation in the manner described above, pre-fill the preparation into a syringe, and then leave it to stand in the manner described above to gel the injectable preparation. The present disclosure also includes a kit with the pre-filled syringe described above. EXAMPLES

[0090] Clinical Pharmacology Trials

[0091] Example 1

[0092] This example was a Phase 1b, open-label, multiple-dose, randomized, parallel-arm, safety, tolerability, and pharmacokinetic study of aripiprazole intramuscular depot administered to the gluteal muscle in adult subjects with schizophrenia or bipolar disorder type I. Treatment was for 32 weeks with aripiprazole 2-month (2M) RTU (referred to as the "Ari 2M group"), 960 mg (one injection every 56 days) as the investigational drug, and the reference component was aripiprazole intramuscular depot (referred to as the "Ari IM depot" or "IM depot"), 400 mg (one injection every 28 days) Abilify Maintena®. Primary endpoints were (1) safety and tolerability (e.g., adverse events (AEs), vitals, ECG, lab tests, physical exam, electrophysiology tests (EPS), VAS, investigator assessment of injection, and C-SSR); and (2) pharmacokinetics, e.g., similarity of plasma concentrations on the last day of oral dosing after the last dose, and similarity of aripiprazole exposure (AUC) over the dosing interval after the last dose. Secondary endpoints were PK and efficacy after administration of 2M RTU 960 mg and IM depot 400 mg, respectively.

[0093] Aripiprazole 2 months (2M) RTU

[0094] The 2-month (2M) RTU injectable preparation was supplied by Otsuka Pharmaceutical Co., Ltd. as a ready-to-use, single-dose injection of aripiprazole IM depot 300 mg / mL. The injectable preparation contained aripiprazole monohydrate, sodium carboxymethylcellulose (5 mg / mL), povidone K17 (4 mg / mL), polyethylene glycol 400 (1 mg / mL), monobasic sodium phosphate monohydrate (0.74 mg / mL), sodium chloride (6.1 mg / mL), sodium hydroxide (pH adjuster), and water for injection. The concentration of aripiprazole in the injectable preparation was 300 mg / mL. This concentration was calculated for the anhydrous form of aripiprazole.

[0095] A two-month (2M) RTU long-acting injectable (LAI) preparation containing 300 mg / mL aripiprazole in the injectable preparation (3.2 mL / injection) was administered to adult subjects (N=41) at 56-day (± 2-day) intervals for 32 weeks (4 injections total) into the subject's gluteal muscle. One tablet of 10-20 mg aripiprazole was administered orally per day for 7 consecutive days beginning on day 1 of the first dose of the 2M RTU injectable preparation.

[0096] Aripiprazole intramuscular depot (reference)

[0097] Aripiprazole intramuscular (IM) depot formulations were supplied as single dose lyophilized 400 mg active ingredient strength vials. The listed active ingredient strength was calculated in anhydrous form (aripiprazole). In some embodiments, the inactive ingredients (per administered dose) for the 400 mg active ingredient strength product include sodium carboxymethylcellulose (16.64 mg), mannitol (83.2 mg), monobasic sodium phosphate monohydrate (1.48 mg) and sodium hydroxide (pH adjuster). The extended release injectable suspension in the 400 mg active ingredient strength vial can be used to provide dose adjustments; i.e., in patients with CYP2D6 poor metabolizers and patients who are concurrently taking CYP3A4 inhibitors or CYP2D6 inhibitors. Dosage adjustments to 200 mg and 160 mg can be made by using a 400 mg active strength vial for intramuscular injection in the deltoid or gluteal muscle for patients taking a CYP2D6 inhibitor, a CYP3A4 inhibitor, or a CYP3A4 for 14 days or more.

[0098] An intramuscular (IM) depot formulation of aripiprazole (400 mg active strength) was administered to adult subjects (N=42) at 28-day (±2-day) intervals for 32 weeks (8 injections total). Aripiprazole, 10-20 mg, was administered orally, one tablet per day, for 14 consecutive days beginning on day 1 of the first IM depot dose.

[0099] Trends: Subject baseline characteristics were balanced across treatment groups, i.e., similar diagnosis, sex, race / ethnicity, age, and body mass index (BMI), as described in Tables 2 and 3. Discontinuation rates (Table 1) were lower in the aripiprazole 2M group (23%) compared to the IM depot group (31%). Reasons for discontinuation in both treatment groups were subject withdrawal, adverse events, and loss to follow-up. [Table 1]

[0100] [Table 2]

[0101] [Table 3] SWN-S:Subjective Well-being under Neuroleptic Treatment Short Form;PANNS:Positive and Negative Syndrome Scale;CGI-Severity Score:Clinical Global Impression-Severity Score;YMARS:Young Mania Rating Scale;MADRS:Montgomery-Asberg Depression Rating Scale;CGI-BP:Clinical Global Impression-Bipolar Version

[0102] Safety: In this study, the most frequent adverse event was weight gain (22.7% Ari 2M compared to 20.9% Ari IM depot). Injection site pain was the second most frequently reported adverse event (18.2% Ari 2M compared to 9.0% Ari IM depot). Visual analog scale (VAS) perception of pain and investigator assessment of injection site were found to be mild and stable throughout the study and were comparable between treatment groups. The incidence of treatment-emergent serious adverse events (TEAEs) was similar for the Ari 2M group (4.5%) and the IM depot group (6.0%). Fewer subjects discontinued the investigational medicinal product (IMP) due to adverse events in the Ari 2M group (3.0%) compared to those in the IM depot group (7.5%). No notable differences were observed between the groups in laboratory tests, electrocardiograms (ECGs) and vital signs, except that the rate of new onset of QT, internally corrected for large proportions using Fridericia's formula (QTc) >450 ms, was lower in the Ari 2M group (0.7%) than in the IM depot group (4.5%).

[0103] Pharmacokinetics: Pharmacokinetic data are illustrated in Figures 1 and 2. Figure 1 shows the mean (SD) pharmacokinetic concentrations after the first dose of Ari 2M 960 mg aripiprazole with 7 consecutive days of oral administration of aripiprazole compared to IM depot 400 mg aripiprazole with 14 consecutive days of oral administration of aripiprazole. Table 4 below summarizes the mean (standard deviation-SD) plasma concentrations (ng / mL) of Ari 2M 960 mg and IM depot 400 mg on days 7 and 14.

[0104] Table 4: Comparison of plasma concentrations (ng / mL) of Ari 2M 960 mg and IM depot 400 mg on days 7 and 14. [Table 4]

[0105] FIG. 2 shows the mean (SD) pharmacokinetic concentrations after the 4th dose of aripiprazole 960 mg Ari 2M compared with aripiprazole 400 mg IM depot after the 7th and 8th doses.

[0106] Finally, Tables 5 and 6 below provide an overview of the PK parameters and primary PK endpoints, respectively.

[0107] [Table 5] [Table 6] 1: AUC after the fourth injection of GMR (Ari 2M RTU 960mg) 0-56 / Ari IM Depot AUC after 7th and 8th injections of 400 mg 0-28 The sum of the log-transformed PK parameters including treatment formulation and disease population as fixed effects is derived from an ANOVA. GMR refers to geometric mean ratio. 2: C after the fourth injection of GMR (Ari 2M RTU 960mg) 56 C after the 8th injection of / Ari IM depot 400 mg 28 ) is derived from an ANOVA on log-transformed PK parameters including treatment formulation, PK sampling schedule, and disease population as fixed effects. C56 refers to the plasma concentration of aripiprazole 56 days after dosing. C 28 refers to the plasma concentration of aripiprazole 28 days after dosing. 3: Derived from a one-tailed t-test of the treatment formulation within the specific ANOVA above to test the null hypothesis that the ratio of PK parameters for ARI 2M RTU 960 mg to PK parameters for Ari IM depot 400 mg is ≦0.8.

[0108] Efficacy: SWN-S, PANSS, MADRS, and YMRS total scores showed no statistically significant differences between the Ari 2M and IM depot groups. Additionally, SWN-S and PANSS showed numerical improvements in change from baseline results for the Ari 2M group for schizophrenia subjects. Overall, the treatment efficacy of the Ari 2M group is comparable to that of the IM depot for both schizophrenia and bipolar I subjects.

[0109] Summary of Efficacy Results and Conclusions: - In both treatment groups, subjects with schizophrenia remained stable with low PANSS and CGI-S scores throughout the study, and there were no clinically significant differences between treatment groups during the study. - For subjects with bipolar I disorder, no clinically significant differences were demonstrated between the two treatment groups for the MADRS total score or the YMRS total score. - The mean change from baseline for CGI-BP Severity of Illness scores for overall bipolar illness and the mean change from previous phase score for overall bipolar illness were minimal and similar between the two treatment groups at all weeks. - CGI-I mean scores were similar between the two treatment groups for subjects with schizophrenia and for subjects with bipolar I disorder. - No clinically significant differences were demonstrated between the two treatment groups for the SWN-S total score for subjects with schizophrenia or bipolar I disorder.

[0110] Overall conclusion

[0111] Trends: Completion rates for the Ari 2M group were greater than for the IM depot at week 32. Top three reasons for discontinuation for both treatment groups were subject withdrawal, adverse events, and loss to follow-up.

[0112] Safety: Administration of multiple doses of aripiprazole 2M LAI 960 mg into the gluteal muscle was generally safe and well tolerated in subjects with schizophrenia or bipolar I disorder and did not reveal any new safety concerns. The clinical safety of aripiprazole 2M LAI 960 mg was demonstrated by an overall similar incidence of TEAEs and laboratory abnormalities in both treatment groups compared to aripiprazole IM depot 400 mg. The most frequently reported TEAEs (>10% of subjects in any group) were injection site pain and weight gain, consistent with the known safety profile of aripiprazole.

[0113] Pharmacokinetics: - Aripiprazole 2M LAI 960 mg provided similar aripiprazole AUC0-28 after the 4th dose compared to aripiprazole IM depot 400 mg combined (GMR [90% CI (confidence interval)]: 1.006 [0.851, 1.190]) after the 7th and 8th doses. 0-56 had. - C after the 8th dose of aripiprazole IM depot 400 mg 28 Aripiprazole 2M LAI 960 mg had a similar aripiprazole C after the fourth dose compared with placebo (GMR[90%CI]:1.011[0.893, 1.145]). 56 had.

[0114] Efficacy: The treatment effects of aripiprazole 2M LAI 960 mg were comparable to those of aripiprazole IM depot 400 mg in terms of change from baseline in PANSS and CGI-S (for subjects with schizophrenia); MADRS, YMRS, and CGI-BP (for subjects with bipolar I disorder); and CGI-I and SWN-S (for all subjects).

[0115] Example 2

[0116] A Phase 1, Open-Label, Single Ascending Dose, Parallel-Arm Study to Determine the Pharmacokinetics, Safety, and Tolerability of a 2-Month Intramuscular Depot of Aripiprazole Administered into the Gluteal Muscle in Adult Subjects With Schizophrenia

[0117] This was an open-label, single ascending dose, parallel arm, multicenter study to determine the PK, safety, and tolerability of single dose administration of 780 mg (Cohort 1) and 1200 mg (Cohort 2) of a high dose formulation of aripiprazole 2M RTU administered into the gluteal muscle in adult subjects with schizophrenia. Data from this study are supporting information. Overall, aripiprazole 2M RTU is well tolerated when administered IM to adult subjects with schizophrenia as single doses of 780 mg and 1200 mg. In a subset of 17 subjects, administration of aripiprazole 2M RTU resulted in sustained aripiprazole plasma concentrations, and the resulting aripiprazole plasma concentrations were always above the mean PK profile following a single gluteal muscle administration of 400 mg Abilify Maintena®. Safety data from this subset of subjects was evaluated and compared to the known safety profile of Abilify Maintena®.

[0118] Aripiprazole 2M RTU exhibited sustained release for every 2-month dosing at the dose levels evaluated. The extension of the dosing interval for aripiprazole 2M RTU was achieved primarily via dose escalation while maintaining a minimum concentration of aripiprazole equivalent to Abilify Maintena® after multiple dosing. Aripiprazole 2M RTU was designed with a higher aripiprazole concentration in the drug product (300 mg / mL vs. 200 mg / mL) compared to the currently marketed / approved Abilify Maintena®, with minor changes to the vehicle. The mean particle size distribution and dissolution profile of aripiprazole for the aripiprazole 2M RTU formulation were comparable to the Abilify Maintena® formulation, and this formulation was expected to have a similar sustained release profile compared to the approved Abilify Maintena® formulation. The mean (standard deviation [SD]) aripiprazole plasma concentration-time profiles following administration of a single dose of 780 mg or 1200 mg aripiprazole into the gluteal muscle in subjects with schizophrenia are presented in FIG. 3 .

[0119] A summary of aripiprazole PK parameters following single dose administration of 780 mg or 1200 mg of aripiprazole into the gluteal muscle in subjects with schizophrenia is presented below in Table 7.

[0120] Table 7: Mean (SD) aripiprazole pharmacokinetic parameters following administration of a single dose of 780 mg or 1200 mg aripiprazole 2M RTU into the gluteal muscle in subjects with schizophrenia. [Table 7]

[0121] From Table 7, AUC∞ is the area under the concentration-time curve calculated over the entire time from time zero; AUCt is the area under the concentration-time curve calculated for the last observable concentration at time t; CL / F is the apparent clearance of the drug from plasma after extravascular administration; RTU means ready to use; tmax is the time to maximum (peak) plasma concentration; t1 / 2 is the elimination half-life. Others include: a Median(min-max); b n=14; and c n=11.

[0122] All publications and patents mentioned in this specification are herein incorporated by reference in their entirety to the same extent as if each individual publication or patent was specifically and individually indicated to be incorporated by reference.

[0123] A claim or specification including "or" or "and / or" between at least one member of a group is considered satisfied if one, more than one, or all of the group members are present, utilized, or otherwise relevant to a given product or process, unless specifically stated to the contrary or otherwise clear from the context. The present disclosure includes embodiments in which exactly one of the group is present, utilized, or otherwise relevant to a given product or process. The present disclosure includes embodiments in which more than one, or all of the group members are present, utilized, or otherwise relevant to a given product or process.

[0124] Furthermore, the disclosure encompasses all variations, combinations, and permutations where at least one limitation, element, clause, and descriptive term is introduced from at least one of the recited claims into another claim. For example, any claim that is dependent on another claim can be amended to include at least one limitation found in any other claim that is dependent on the same base claim. Where elements are presented as a list, e.g., in Markush format, each subgroup of elements is also disclosed, and any element(s) can be removed from the group. In general, where the disclosure, or aspects of the disclosure, are referred to as including certain elements and / or features, it should be understood that an embodiment of the disclosure or aspects of the disclosure consist of or consist essentially of such elements and / or features. In brief, the embodiments are not specifically described herein. Where ranges are given, the endpoints are included. Moreover, unless otherwise indicated or otherwise clear from the context and the understanding of one of ordinary skill in the art, values ​​expressed as ranges can assume any specific value or subrange within the ranges set forth in different embodiments of this disclosure, to the tenth of the unit of the lower limit of the range, unless the context clearly dictates otherwise.

[0125] Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the disclosure described herein which equivalents are intended to be encompassed by the claims.

Claims

1. A method for treating a patient having schizophrenia or bipolar disorder type I, comprising intramuscularly administering to the patient an injectable preparation comprising aripiprazole or a salt thereof, wherein the patient receives an administration of the injectable preparation approximately once every two months.

2. 10. The method of claim 1, wherein administration of the injectable preparation provides the patient with a total amount of about 650 mg to about 1200 mg of aripiprazole every two months.

3. 3. The method of claim 2, wherein administration of the injectable preparation provides the patient with a total amount of about 960 mg of aripiprazole every two months.

4. 4. The method of any one of claims 1 to 3, wherein about once every two months comprises about once every 42 to 70 days.

5. 5. The method of claim 4, wherein once every two months comprises once every 54 to 58 days.

6. The method of any one of claims 1 to 5, wherein the patient has schizophrenia.

7. The method of any one of claims 1 to 5, wherein the patient has bipolar I disorder.

8. The method according to any one of claims 1 to 7, wherein the intramuscular administration to the patient is carried out in the gluteal muscle.

9. 9. The method according to any one of claims 1 to 8, wherein the injectable preparation further comprises water and a suspending agent comprising polyvinylpyrrolidone, polyethylene glycol, and carboxymethylcellulose or a salt thereof, wherein the aripiprazole or a salt thereof has an average primary particle size of about 0.5 μm to about 30 μm, and the concentration of the aripiprazole or a salt thereof ranges from about 200 mg / mL to about 600 mg / mL.

10. 9. The method according to any one of claims 1 to 8, wherein the injectable preparation further comprises water for injection and a suspending agent comprising polyvinylpyrrolidone, polyethylene glycol, and carboxymethylcellulose or a salt thereof, the aripiprazole or a salt thereof is aripiprazole monohydrate, the aripiprazole monohydrate having an average primary particle size of about 2 μm to about 5 μm, and the concentration of aripiprazole in the injectable preparation, calculated on the basis of the anhydrous form of aripiprazole, is about 300 mg / mL.

11. The method of any one of claims 1 to 10, wherein the area under the concentration-time curve (AUC) of aripiprazole from time zero to day 56 after administration following multiple administrations of the injectable preparation is substantially equal to twice the AUC of aripiprazole from time zero to day 28 after administration following multiple administrations of an aripiprazole intramuscular (IM) depot formulation, e.g., Abilify Maintena®, about once every month (4 weeks or 28 days), as shown, for example, in Figure 2.

12. 11. The method of any one of claims 1 to 10, further comprising orally administering to the patient a solid dosage form comprising aripiprazole or a salt thereof, wherein the injectable preparation and said solid dosage form are administered to the patient on day 1, and wherein said solid dosage form is administered for 5 to 15 consecutive days starting from day 1.

13. A method for treating a patient having schizophrenia or bipolar disorder type I, comprising administering to the patient's gluteal muscle an injectable preparation comprising aripiprazole or a salt thereof, wherein the patient receives the injectable preparation approximately once every 56 days, and the amount of aripiprazole in the injectable preparation is approximately 960 mg.

14. 14. The method of claim 13, wherein the injectable preparation further comprises water and a suspending agent comprising polyvinylpyrrolidone, polyethylene glycol, and carboxymethylcellulose or a salt thereof, wherein the aripiprazole or a salt thereof has an average primary particle size of about 0.5 μm to about 30 μm, and the concentration of aripiprazole in the injectable preparation is about 300 mg / mL.

15. The method according to claim 13 or 14, wherein the injectable preparation further comprises water for injection and a suspending agent comprising polyvinylpyrrolidone, polyethylene glycol, and carboxymethylcellulose or a salt thereof, the aripiprazole or a salt thereof is aripiprazole monohydrate, the aripiprazole monohydrate having an average primary particle size of about 2 μm to about 5 μm, and the concentration of aripiprazole in the injectable preparation, calculated on the basis of the anhydrous form of aripiprazole, is about 300 mg / mL.

16. The method of any one of claims 13 to 15, wherein the area under the concentration-time curve (AUC) of aripiprazole from time zero to day 56 after administration after multiple administrations of the injectable preparation is substantially equal to twice the AUC of aripiprazole from time zero to day 28 after administration after multiple administrations of an aripiprazole intramuscular (IM) depot formulation, e.g., Abilify Maintena®, about once every month (4 weeks or 28 days), as shown, for example, in Figure 2.

17. 16. The method according to any one of claims 13 to 15, further comprising orally administering aripiprazole in a solid dosage form, said solid dosage form being administered in an amount of 10 mg to 20 mg per day for 5 to 15 consecutive days together with the first administration of the injectable preparation.

18. 16. The method according to any one of claims 13 to 15, further comprising orally administering 10 mg to 20 mg of aripiprazole per day in a solid dosage form for 7 consecutive days together with the first administration of the injectable preparation.

19. 1. A method for administering an injectable preparation containing aripiprazole or a salt thereof to a patient with schizophrenia or bipolar I disorder, comprising: orally administering to the patient 10 to 20 mg / day of aripiprazole or a salt thereof for 5 to 15 consecutive days starting from day 1; administering to said patient an injectable preparation intramuscularly once every 56 days (about every 8 weeks or 2 months); A method in which an injectable preparation containing about 650 mg to 1200 mg of aripiprazole is administered on day 1, with successive administrations allowing the mean plasma level of aripiprazole to be maintained at or above 90 ng / mL.

20. 20. The method of claim 19, which does not include further oral administration of aripiprazole or a salt thereof.

21. 1. A method for administering a pre-filled sol-gel formed injectable preparation comprising aripiprazole or a salt thereof to a patient in need thereof, comprising: a total of 50-300 mg of aripiprazole administered orally, either simultaneously or consecutively, on days 1 through 15; and On day 1, administering a pre-filled sol-gel formed injectable preparation containing 650-1200 mg of aripiprazole into the gluteal muscle; followed by administering a pre-filled sol-gel formed injectable preparation containing about 650 mg to 1200 mg of aripiprazole into the gluteal muscle about once every 56 days (about every 8 weeks or every 2 months); A method in which a series of doses allows for maintaining mean plasma levels of aripiprazole at or above 90 ng / mL.

22. 22. The method of claim 21, wherein the pre-filled sol-gel formed injectable preparation is an injectable preparation containing 300 mg / mL aripiprazole and has thixotropic properties.

23. 23. The method of claim 21 or 22, wherein the injectable preparation further comprises a suspending agent selected from the group consisting of polyvinylpyrrolidone, polyethylene glycol, carboxymethylcellulose or a salt thereof, and any combination thereof.

24. 1. A method for administering a sustained release injectable preparation comprising aripiprazole or a salt thereof to a patient in need thereof, comprising: administering to the patient an injectable preparation containing 650-1200 mg of aripiprazole once about every 56 days (about every 8 weeks or every 2 months); The method, wherein the patient has a stable plasma level of aripiprazole by receiving an administration of aripiprazole but requires an additional administration of aripiprazole, and the injectable preparation is in a pre-filled sol-gel formed injectable dosage form, and serial administrations enable the average plasma level of aripiprazole to be maintained at or above 90 ng / mL.

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