Dispersion method for aripiprazole injection preparations

Abstract

This disclosure relates to a method for dispersing an injectable formulation containing aripiprazole or a salt thereof. The disclosure also provides a method for improving the lubricity of a container containing a sustained-release injectable formulation containing aripiprazole or a salt thereof, the method comprising the step of dispersing the components of the formulation before administration, an aripiprazole injectable formulation administered after said dispersion, a method of administration thereof, and a method of use thereof.

Description

Technical Field

[0001] The present disclosure relates to a method for dispersing an injection preparation containing aripiprazole or a salt thereof. The present disclosure also relates to an aripiprazole injection preparation administered after the dispersion treatment, a method for administering the same, and a method for using the same.

Background Art

[0002] An injection preparation containing aripiprazole or a salt thereof (also referred to as an "aripiprazole injection preparation" or an "injection preparation" in the present disclosure) forms a gel upon standing and can inhibit caking due to precipitation and sedimentation of aripiprazole particles, thus obtaining excellent storage stability. In addition, even in the form of a gel, the injection preparation can easily increase its fluidity when subjected to a slight impact, that is, it can form a sol state and can be easily injected during use (Patent Document 1).

Prior Art Documents

Patent Documents

[0003]

Patent Document 1

Patent Document 2

Summary of the Invention

Problems to be Solved by the Invention

[0004] Although the aripiprazole injection preparation is provided in the form of a prefilled syringe as a ready to use (RTU) preparation (Patent Document 2), depending on the transportation state or storage situation after formulation, the uniformity of its contained components decreases and a part of the contained components accumulates, and the sliding property of the container decreases during use or injection, resulting in an increased resistance during injection.

Means for Solving the Problems

[0005] The inventors of this invention were the first to identify the above problem, and after diligent research, they discovered that the above problem can be solved by subjecting the aripiprazole injection formulation to a specific dispersion treatment before use, thereby completing the present invention.

[0006] In one embodiment, a method is provided for improving the sliding properties of a container containing a sustained-release injectable formulation of aripiprazole or a salt thereof, comprising the step of dispersing the gel of the formulation in the container before administration to form a sol or suspension, wherein the sustained-release period is approximately two months.

[0007] In another embodiment, a sustained-release intramuscular injection formulation is provided for the treatment of a patient having schizophrenia or bipolar disorder type I, comprising aripiprazole or a salt thereof in a container, characterized in that the formulation is in gel form under static conditions, returns to a sol or suspension upon dispersion, and the sustained release is approximately two months.

[0008] In yet another embodiment, a method is provided for treating a patient having schizophrenia or bipolar disorder type I, comprising dispersing a gel-form injectable formulation in a container to form a sol or suspension of aripiprazole or a salt thereof, and intramuscularly administering the injectable formulation to a subject, wherein the subject receives the injectable formulation once every two months.

[0009] In yet another embodiment, there is a use of aripiprazole or a salt thereof in the manufacture of a formulation for the treatment of a patient having schizophrenia or bipolar disorder type I, wherein the formulation is a sustained-release injectable formulation for intramuscular administration, comprising aripiprazole or a salt thereof in a container, wherein the formulation is in gel form under static conditions and returns to a sol or suspension by dispersion treatment, and the sustained-release is approximately two months. [Effects of the Invention]

[0010] Even when the uniformity of the components contained in an aripiprazole injection preparation decreases due to reasons such as transportation or conveyance, by performing a dispersion treatment on the preparation before use (before administration), the components contained therein can be redispersed, and the slidability of the container containing the components can be improved during use or injection.

Brief Description of the Drawings

[0011] [Figure 1] Figure 1 shows one aspect of tapping.

[0012] [Figure 2] Figure 2 shows one aspect of shaking.

[0013] [Figure 3] Figure 3 shows the slidability signal for the sample before vibration treatment.

[0014] [Figure 4] Figure 4 shows the slidability signal for the sample that was subjected to 0 taps and 0 seconds of shaking after vibration treatment.

[0015] [Figure 5] Figure 5 shows the slidability signal for the sample that was subjected to 5 taps and 5 seconds of shaking after vibration treatment. The dispersion treatment was performed by shaking after tapping.

[0016] [Figure 6] Figure 6 shows the slidability signal for the sample that was subjected to 10 taps and 10 seconds of shaking after vibration treatment. The dispersion treatment was performed by shaking after tapping.

[0017] [Figure 7] Figure 7 shows the slidability signal for the sample that was subjected to 15 taps and 15 seconds of shaking after vibration treatment. The dispersion treatment was performed by shaking after tapping.

[0018] [Figure 8]Figure 8 shows the sliding signal of the sample that has undergone tapping 5 times and shaking for 0 seconds after the vibration treatment.

[0019] [Figure 9] Figure 9 shows the sliding signal of the sample that has undergone tapping 10 times and shaking for 0 seconds after the vibration treatment.

[0020] [Figure 10] Figure 10 shows the sliding signal of the sample that has undergone tapping 15 times and shaking for 0 seconds after the vibration treatment.

[0021] [Figure 11] Figure 11 shows the sliding signal of the sample that has undergone tapping 0 times and shaking for 5 seconds after the vibration treatment. <00001​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​As used herein, "a" or "an" refers to one or more such entities; 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.

[0027] As used herein, the term “approximately” means roughly, within the range, roughly, or around. When the term “approximately” is used in conjunction with a numerical range, it modifies the range by extending above and below the boundaries of the stated numerical value. Generally, the term “approximately” is used herein to modify a numerical value by a 5% variation above or below the stated value.

[0028] As used herein, the terms “to treat,” “treating,” or “to cure” include any effect resulting in improvement of a disorder or condition, such as reducing, decreasing, regulating, restoring, or eliminating the disorder or condition, when used in relation to the disorder or condition. Improvement or reduction in the severity of any symptom of the disorder or condition can be readily 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 monotherapy or maintenance therapy. In further embodiments, the methods disclosed herein can be used to treat schizophrenia, acute manifestations of mania and mixed symptoms associated with bipolar disorder type I, major depressive disorder (MDD), irritability associated with autism spectrum disorder, and Tourette syndrome.

[0029] As used herein, a reference to "aripiprazole" refers to aripiprazole or a salt thereof, or to a crystalline form of aripiprazole or a salt thereof. Aripiprazole or a salt thereof may be in monohydrate form (aripiprazole hydrate A) or in various anhydrous forms, which are known to exist in the form of anhydrous crystals B, C, D, E, F, and G. All of these crystalline forms may be used as aripiprazole or a salt thereof in the injectable formulations of this disclosure, and furthermore, for example, aripiprazole is in monohydrate form. As used herein, the terms "aripiprazole" or a salt thereof refer to structure: [ka] This refers to compounds that possess [a certain characteristic].

[0030] Distributed processing In this disclosure, “dispersion treatment” means, but is not limited to, a treatment to redisperse the components of the injectable formulation of this disclosure before administration in order to improve the uniformity and / or fluidity of the formulation and / or the sliding properties of the container containing the formulation compared to before the dispersion treatment. Examples of dispersion treatments include treatments such that the force used to push or release the formulation from the container is 30 N or less, for example, 25 N or less, and 5 N or more as a sliding resistance value. Containers in this disclosure include any medically acceptable container commonly used in a medical or clinical setting, such as a syringe or pre-filled syringe. In some embodiments, the container may be a transparent plastic container such as a cycloolefin copolymer (COC). In some aspects, the dispersion treatment includes at least six taps and at least six seconds of shaking of the formulation by an adult, for example, a patient or healthcare worker, manually or by a medical device commonly used in the art, until the formulation is homogenized. Such dispersion processes may preferably be completed within any practical time in a medical or clinical setting, for example, tapping and shaking may all be completed within 1 minute, such as 40 taps or less and shaking for 40 seconds or less. In other aspects, the dispersion process may include at least 8 taps and at least 8 seconds of shaking, for example, at least 10 taps and at least 10 seconds of shaking, and further, for example, 10 to 15 taps and 10 to 15 seconds of shaking. In this disclosure, the term “tapping” means an action or process that applies movement, vibration, or impact to a formulation, for example, knocking a container containing the formulation to homogenize or homogenize the formulation. In one embodiment, tapping is the action shown in Figure 1. In this disclosure, the term “shaking” means an action or process that mixes and homogenizes a formulation, for example, shaking or rocking a container containing the formulation, preferably in the longitudinal direction of the container, to homogenize or homogenize the formulation. In one embodiment, shaking is the action shown in Figure 2. In some respects, shaking during the dispersion process is carried out after tapping until the formulation is homogenized in terms of efficient dispersion. In some respects, the dispersion process is carried out at room temperature, such as 1°C to 30°C.In some respects, after dispersion, the formulation is administered intramuscularly to the subject or patient with a syringe needle appropriate for the subject. The dispersion process of the Disclosure may be appropriately adjusted depending on the volume and / or shape of the container containing the injectable formulation of the Disclosure, such as a pre-filled syringe. A decrease in the uniformity or fluidity of the components contained in the injectable formulation of the Disclosure, or a decrease in the sliding properties of the container containing the injectable formulation, may occur due to intermittent or continuous light vibrations or shocks resulting from the transportation, handling, or storage conditions of the formulation after formulation, particularly at low temperatures (e.g., below 1-15°C). If the uniformity or fluidity or sliding properties are reduced, without the dispersion process of the Disclosure, the force required to push the formulation out of the container containing the formulation (also referred to in the Disclosure as "sliding resistance") may exceed 30 N to push out more than a certain amount of the contents. Since the injectable formulations of the present disclosure can be easily made more fluid (form a sol state) even in a gel state by simply pushing the plunger of a syringe and dispensing the formulation through the syringe needle, in some embodiments, the formulations may be used after a period of time, for example several hours, several days, several weeks, and several months, provided that there is no vibration or shock due to transportation, handling, or storage conditions, after the dispersion treatment of the present disclosure has been performed on the formulation only once.

[0031] Injectable preparations Examples of injectable formulations of this disclosure include the 2-month ready-to-use (RTU) injectable formulation disclosed in Patent Document 1, which is a composition comprising, for example, aripiprazole, a specific suspending agent (suspending agent A), and a dispersion medium. For example, the injectable formulations of this disclosure include at least water as the dispersion medium. Water, or an aqueous solvent comprising water and an organic solvent, can be used as a dispersion medium containing at least water. In some embodiments, the dispersion medium is water, and furthermore, for example, water for injection.

[0032] A specific suspending agent (suspending agent A) contained in the injectable formulation 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.

[0033] In some embodiments, the injectable formulations of the present disclosure comprise aripiprazole or a salt thereof, water, and at least one suspending agent selected from (i) and (ii): (i) polyvinylpyrrolidone, and (ii) polyethylene glycol and carboxymethylcellulose or a salt thereof. Here, the aripiprazole or a salt thereof has an average primary particle size in the range of about 0.5 μm to about 30 μm, and the concentration of the aripiprazole or a salt thereof is in the range of about 200 mg / mL to about 400 mg / mL. A 2-month ready-to-use (RTU) injectable formulation disclosed herein is described in whole in Patent Document 2, which is incorporated herein by reference.

[0034] The injectable formulations of this disclosure comprise aripiprazole or a salt thereof and are used as a combination of a specific suspending agent (suspending agent A) and a specific concentration of aripiprazole or a salt thereof (approximately 200 mg / mL to approximately 400 mg / mL, for example, approximately 250 mg / mL to approximately 350 mg / mL). When the injectable formulations of this disclosure comprise a salt of aripiprazole, the concentrations described above are calculated as aripiprazole (anhydrous equivalent).

[0035] In some embodiments, when polyvinylpyrrolidone is contained as suspending agent A in the aripiprazole injection formulation of the present disclosure, 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, and further for example, about 2 mg / mL to about 20 mg / mL, and further for example, about 4 mg / mL to about 15 mg / mL.

[0036] In some embodiments, when the aripiprazole injection formulation of the present disclosure contains polyethylene glycol and carboxymethylcellulose or a salt thereof as suspending agent A, the concentration of polyethylene glycol is approximately 0.05 mg / mL to approximately 2 mg / mL, and moreover, for example, approximately 0.1 mg / mL to approximately 1 mg / mL. The concentration of carboxymethylcellulose or a salt thereof is approximately 0.5 mg / mL to approximately 50 mg / mL, for example, approximately 1 mg / mL to approximately 30 mg / mL, for example, approximately 2 mg / mL to approximately 20 mg / mL, for example, approximately 5 mg / mL to approximately 15 mg / mL.

[0037] The inclusion of carboxymethylcellulose or a salt thereof can suppress the increase in viscosity during manufacturing. This allows aripiprazole or a salt thereof to be efficiently pulverized to the desired particle size. 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 formulation 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.

[0038] In some embodiments, when multiple suspending agents are used in the aripiprazole injection formulation of the present disclosure, the composition comprises about 0.5 mg / mL to about 20 mg / mL of polyvinylpyrrolidone, about 0.1 mg / mL to about 100 mg / mL of polyethylene glycol, about 0.5 mg / mL to about 50 mg / mL of 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) of aripiprazole or a salt thereof. In this case, the polyethylene glycol may be polyethylene glycol 400 or polyethylene glycol 4000. In some embodiments, polyvinylpyrrolidone has a K value of about 12 to about 20, for example, 17. In further embodiments, aripiprazole or a salt thereof has an average primary particle diameter of about 1 μm to 10 μm.

[0039] Since excessively large mean primary particle diameters of aripiprazole or its salts can cause precipitation, the mean primary particle diameter is in the range of approximately 0.5 μm to approximately 30 μm, for example, in the range of approximately 1 μm to approximately 20 μm. If the injectable formulation of this disclosure is a dosage form administered once every two months, the aripiprazole or its salt has a mean primary particle diameter of approximately 1 μm to approximately 50 μm, for example, approximately 1 μm to approximately 10 μm, and further, for example, approximately 2 μm to approximately 5 μm. In this disclosure, the term "primary particle diameter" refers to the diameter of individual particles that are not aggregated and are separated from each other. In this disclosure, the term "mean primary particle diameter" is calculated from the volume-average diameter calculated from the mean primary particle diameter distribution measured by laser diffraction scattering. In this disclosure, the mean primary particle diameter may be measured while the injectable formulation is circulating in an aqueous medium under ultrasonic irradiation. For example, the mean particle diameter can be measured by laser diffraction scattering using SALD-3100 and SALD-2300 (Shimadzu Corporation). The average secondary particle diameter is up to three times the average primary particle diameter, but not exceeding that, and further, for example, up to twice the average primary particle diameter, but not exceeding that. In this disclosure, “secondary particle diameter” means the diameter of aggregated particles. In this disclosure, the term “average secondary particle diameter” is calculated from the volume-average diameter calculated from the average secondary particle diameter distribution measured by laser diffraction scattering. In this disclosure, the average secondary particle diameter may be measured while the injectable formulation is circulating in an aqueous medium without ultrasonic irradiation.

[0040] In some embodiments, the injectable formulations of the present disclosure are appropriately formulated into dosage forms that can be administered once every two months (hereinafter also referred to as the “two-month formulation” or “two-month formulation”). For example, the concentration of aripiprazole or a salt thereof in the injectable formulation of the present disclosure administered once every two months is approximately 200 mg / mL to approximately 400 mg / mL, calculated as aripiprazole, for example, approximately 250 mg / mL to approximately 350 mg / mL, and further, for example, approximately 300 mg / mL. When the injectable formulation is administered once every two months, the dose is approximately 2 mL to approximately 4 mL, for example, approximately 2.2 mL to approximately 3.5 mL, further, for example, approximately 2.3 mL to approximately 3.4 mL, and further, for example, approximately 2.4 mL to 3.2 mL.

[0041] In some embodiments, the injectable formulations of the present disclosure are characterized by being sustained-release injectable formulations containing aripiprazole or a salt thereof and a specific suspending agent, and are formulations exhibiting a sol-gel form. Therefore, they exhibit a gel form during storage and standing, and can change to a sol when subjected to impact. In some embodiments, the injectable formulations of the present disclosure can also be formulated into a pre-filled sol-gel injectable formulation (also referred to in the present disclosure as "sol-gel formed pre-filled injectable formulation"). In some embodiments, the injectable formulations of the present disclosure exhibit thixotropic properties.

[0042] In some embodiments, a method for producing an aripiprazole injection formulation is described in Patent Document 2, which includes, for example, the steps of preparing a liquid mixture of starting materials, and grinding the aripiprazole or a salt thereof contained in the liquid mixture to a desired mean primary particle size, followed by an aging treatment as appropriate.

[0043] In some embodiments, a method for producing a gel injection formulation of the present disclosure comprises the step of allowing a liquid mixture to stand at 5 to 70°C for 5 minutes or more, wherein the liquid mixture comprises aripiprazole or a salt thereof in a concentration of about 200 mg / mL to about 400 mg / mL 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.

[0044] For example, in some further embodiments, a manufacturing method may be used that includes the following steps: grinding 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 400 mg / mL, water, and at least one suspending agent selected from (i) and (ii); and allowing the ground liquid mixture to stand at 5°C to 70°C for about 5 minutes or more, about 10 minutes or more, about 15 minutes or more, or about 30 minutes or more, and within about 1 hour or within about 24 hours: (i) polyvinylpyrrolidone, and (ii) polyethylene glycol and carboxymethylcellulose or a salt thereof.

[0045] In some embodiments, the Disclosure includes administering an aripiprazole injection formulation to a patient in a total amount of aripiprazole ranging from about 700 mg to about 1000 mg as a two-month supply formulation, for example, about 720 mg to about 960 mg, and further, for example, about 720 mg or about 960 mg, the injection formulation may be administered as appropriate in one or more divided injections. In some further embodiments, the administration of an aripiprazole injection formulation brings the patient in a total amount of aripiprazole of about 960 mg, and one or more injection formulations are administered. For example, to obtain a total amount of 960 mg of aripiprazole to be administered to the patient, a single injection of an aripiprazole injection formulation containing 300 mg / mL of aripiprazole is administered. The 960 mg dose may be administered as appropriate in multiple injections at short intervals. The number of injections and the concentration of aripiprazole are varied as described above, taking into account the total amount of aripiprazole to be administered and the concentration of aripiprazole contained in each injection formulation.

[0046] In some embodiments, the present disclosure relates to pre-filled syringe formulations for administering the above formulation, i.e., the injectable formulation, to a subject in doses of approximately 2.0 mL or more, for example, 2.0 mL to 4.0 mL, more specifically, 2.2 mL to 3.5 mL, more specifically, 2.3 mL to 3.4 mL, more specifically, 2.4 mL to 3.2 mL, more specifically, 3.0 mL to 3.2 mL, and more specifically, approximately 3.2 mL.

[0047] In some embodiments, the administration of the aripiprazole injection formulation to the target is by intramuscular injection. In some embodiments, intramuscular administration is performed at a site selected from the deltoid muscle, gluteal muscle, and combinations thereof. In some embodiments, the site is the gluteal muscle. For example, depending on the number of injections for administration, the injection sites may include various locations in the deltoid muscle and / or gluteal muscle.

[0048] In some embodiments, when the injectable formulations of the present disclosure are administered intramuscularly, such as into the deltoid or gluteal muscles, it is desirable that the administration be carried out at a constant rate and slowly. In some embodiments, the injectable formulations of the present disclosure are administered by slowly injecting substantially the entire content of aripiprazole contained in a pre-filled syringe. Here, “slowly” means that the administration takes longer than the methods commonly used in the art, for example, about 0.5 seconds or more, about 1 second or more, about 2 seconds or more, about 3 seconds or more, about 4 seconds or more, about 5 seconds or more, about 10 seconds or more, about 15 seconds or more, about 20 seconds or more, or about 30 seconds or more, and within about 1 minute or less, about 2 minutes or less, about 3 minutes or less, about 4 minutes or less, or about 5 minutes or less, and / or is administered in stages, and not in a rapid and continuous manner. Rapid administration is undesirable from the viewpoint of irritation to the injection site.

[0049] In some embodiments, the method of administering the injectable formulation of the Disclosure occurs at a frequency of approximately once every two months. For example, the injectable formulation is administered once every 42 to 70 days or in any integer including the endpoint in between, for example, every 49 to 63 days, for example, every 50 to 62 days, for example, every 50 to 60 days, i.e., every 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, or 63 days. In further embodiments, the injectable formulation is administered once every 56 days, for example, once every 54 to 58 days. In further embodiments, the injectable formulation is administered once every 8 weeks.

[0050] In some embodiments, the injectable formulations of the present disclosure can be pre-filled into containers, for example, into syringes for use as pre-filled syringes. This simplifies the structure of the syringe and reduces its size and weight. When the injectable formulations of the present disclosure are filled into syringes, in further embodiments, the formulations can be administered by simply pushing the plunger rod of the syringe and dispensing the injectable formulations of the present disclosure through the syringe needle, after the dispersion treatment of the present disclosure has been performed. This provides clinical convenience and ease of handling, and thus provides pre-filled syringes that are extremely useful medically and industrially. One example of manufacturing a pre-filled syringe is to manufacture the injectable formulation by the method described above, pre-fill the formulation into syringes, and then allow the injectable formulation to gel by standing in the method described above. In some embodiments, the gelled injectable formulation can be subjected to the dispersion treatment of the present disclosure before administration to form a homogeneous sol or suspension with sufficient fluidity. In this disclosure, “having sufficient fluidity” means, for example, that the force used to push the formulation out of the syringe container is 30 N or less, e.g., 25 N or less, although this may vary depending on the volume of the syringe container containing the formulation and / or the size of the needle used. In some embodiments, the needle of the injectable formulation of this disclosure is a 1-2 inch (i.e., 25-51 mm), 21-23 gauge subcutaneous needle. In some embodiments, the needle of the injectable formulation of this disclosure is a 1 inch (25 mm), 23 gauge needle; a 1.5 inch (38 mm), 22 gauge needle; or a 2 inch (51 mm), 21 gauge needle, which may be appropriately selected depending on the age, sex and body type of the subject or patient. This disclosure also includes a kit comprising the above-mentioned container, e.g., a pre-filled syringe and a needle.

[0051] In this disclosure, “extrusion force” means the force required to substantially extrude the entire volume of the injectable formulation of this disclosure from a container containing the formulation using a rod-shaped object such as a plunger rod, and corresponds to the plunger glide force as defined in the United States Pharmacopeia USP 1382 and 382, ​​and may be measured as sliding resistance using measuring instruments commonly used in the art. Such measuring instruments include, for example, the SV-52NA tensile and compression testing machine (manufactured by Imada Seisakusho). Here, “substantially the entire volume” means the total volume of the formulation contained in the container before administration, or the amount remaining in the container after the formulation has been extruded, for example, about 0.1 mL, about 0.2 mL, about 0.3 mL, about 0.4 mL, or about 0.5 mL, from the total volume.

[0052] Some specific examples are given below. Item 1: A method for improving the lubricity of a container containing a sustained-release injectable formulation of aripiprazole or a salt thereof, comprising the step of dispersing the gel of the formulation in the container before administration to form a sol or suspension, wherein the sustained-release is approximately two months.

[0053] Item 2: The method according to Item 1, wherein the dispersion process includes a process of at least eight taps and at least eight seconds of shaking of the container.

[0054] Item 3: The method according to Item 1, wherein the dispersion process includes at least 10 taps and at least 10 seconds of shaking of the container.

[0055] Item 4: The method according to any one of items 1 to 3, wherein the sliding resistance value of the container after dispersion treatment is 30 N or less.

[0056] Item 5: The method according to any one of items 1 to 4, wherein the container is a pre-filled syringe.

[0057] Item 6: The method according to any one of items 1 to 5, wherein the preparation is for intramuscular administration to treat a subject having schizophrenia or bipolar disorder type I.

[0058] Item 7: The method according to any one of items 1 to 6, wherein the preparation contains approximately 700 mg to approximately 1000 mg of aripiprazole.

[0059] Item 8: The method according to item 7, wherein the container contains 2.0 mL or more of the preparation per single dose.

[0060] Item 9: The method according to any one of items 1 to 8, wherein the preparation is white to grayish-white and comprises the following components. • 720 mg or 960 mg of anhydrous aripiprazole • Sodium carboxymethylcellulose • Polyethylene glycol 400 Sodium chloride · Monosodium phosphate monohydrate, and Sodium hydroxide

[0061] Item 10: The method according to any one of items 1 to 9, further comprising administering the preparation in the container to a subject requiring it after dispersion.

[0062] Item 11: A method for treating a subject having schizophrenia or bipolar disorder type I, comprising slowly administering to the subject an injectable preparation prepared according to any one of items 1 to 10, wherein the administration takes about 0.5 seconds or more.

[0063] Item 12: A method for treating a subject having schizophrenia or bipolar disorder type I, comprising dispersing an injectable formulation of aripiprazole or a salt thereof in a container to change it from a gel to a sol or suspension, and administering the injectable formulation intramuscularly to the subject, wherein the subject is administered the injectable formulation once every two months.

[0064] Item 13: The method according to item 12, wherein the dispersion process includes a process of at least eight taps and at least eight seconds of shaking of the container.

[0065] Item 14: The method according to item 12 or 13, wherein the sliding resistance of the container after dispersion treatment is 30 N or less.

[0066] Item 15: The method according to any one of items 12 to 14, wherein the container is a pre-filled syringe.

[0067] Item 16: The method according to any one of items 12 to 15, wherein the administration is performed in the gluteal muscle of the subject.

[0068] Item 17: The method according to any one of items 12 to 16, wherein a total amount of approximately 700 mg to approximately 1000 mg of aripiprazole is delivered to the subject by administration once every approximately two months.

[0069] Item 18: The method according to any one of items 12 to 17, wherein the container contains 2.0 mL or more of the preparation per single dose.

[0070] Item 19: The method according to any one of items 12 to 18, wherein the preparation is white to grayish-white and comprises the following components. • 720 mg or 960 mg of anhydrous aripiprazole • Sodium carboxymethylcellulose • Polyethylene glycol 400 Sodium chloride · Monosodium phosphate monohydrate, and Sodium hydroxide

[0071] Item 20: The method according to any one of items 12 to 19, wherein the administration comprises slowly injecting the injectable preparation into the subject, and the injection is carried out over a period of about 0.5 seconds or more.

[0072] Item 21: A sustained-release intramuscular injection formulation for the treatment of a subject having schizophrenia or bipolar disorder type I, comprising aripiprazole or a salt thereof in a container, wherein the formulation is in gel form under static conditions, returns to a sol or suspension upon dispersion, and the sustained release is approximately two months.

[0073] Item 22: The formulation according to item 21, wherein the dispersion treatment comprises treating the container with at least eight taps and at least eight seconds of shaking.

[0074] Item 23: The formulation according to item 21 or 22, wherein the sliding resistance value of the container after dispersion treatment of the formulation is 30 N or less.

[0075] Item 24: The formulation according to any one of items 21 to 23, wherein the formulation before dispersion is in the form of a gel, and the formulation after dispersion is in the form of a sol.

[0076] Item 25: The preparation according to any one of items 21 to 24, wherein the administration is by injection into the gluteal muscle of the subject.

[0077] Item 26: The preparation according to any one of items 21 to 25, wherein the preparation contains a total amount of approximately 700 mg to approximately 1000 mg of aripiprazole.

[0078] Item 27: The preparation according to any one of items 21 to 26, wherein the container is a pre-filled syringe for administering an amount of 2.0 mL or more per single dose.

[0079] Item 28: The preparation according to any one of items 21 to 27, wherein the preparation is white to grayish-white and contains the following components. • 720 mg or 960 mg of anhydrous aripiprazole • Sodium carboxymethylcellulose • Polyethylene glycol 400 Sodium chloride · Monosodium phosphate monohydrate, and Sodium hydroxide

[0080] Item 29: Use of aripiprazole or a salt thereof in the manufacture of a formulation for the treatment of a subject having schizophrenia or bipolar disorder type I, wherein the formulation is a sustained-release injectable formulation for intramuscular administration comprising aripiprazole or a salt thereof, the formulation being in gel form under static conditions and returning to a sol or suspension by dispersion treatment, and the sustained release being approximately two months.

[0081] Item 30: The use described in Item 29, wherein the distributed processing includes processing of at least 8 taps and at least 8 seconds of shaking.

[0082] Item 31: The use according to item 29 or 30, wherein the sliding resistance of the formulation after dispersion treatment is 30 N or less.

[0083] Item 32: The use according to any one of items 29 to 31, wherein the formulation before dispersion is in the form of a gel, and the formulation after dispersion is in the form of a sol.

[0084] Item 33: The use described in any one of items 29 to 32, wherein the administration is by injection into the gluteal muscle of the subject.

[0085] Item 34: The use described in any one of items 29 to 33, wherein the preparation contains a total amount of approximately 700 mg to approximately 1000 mg of aripiprazole.

[0086] Item 35: The use described in any one of items 29 to 34, wherein the container is a pre-filled syringe for administering an amount of 2.0 mL or more per single dose.

[0087] Item 36: The use described in any one of items 29 to 35, wherein the preparation is white to grayish-white and contains the following components. • 720 mg or 960 mg of anhydrous aripiprazole • Sodium carboxymethylcellulose • Polyethylene glycol 400 Sodium chloride · Monosodium phosphate monohydrate, and Sodium hydroxide

[0088] Item 37: The use according to any one of items 29 to 36, wherein the administration comprises slowly injecting the preparation into the subject, and the injection is performed over a period of about 0.5 seconds or more.

[0089] Item 38: A method for improving the sliding properties of a container containing a sustained-release intramuscular injection formulation comprising aripiprazole or a salt thereof, wherein the method comprises tapping and shaking the container in succession before administration to change the formulation from a gel to a sol or suspension, the container contains a dose of 2.0 mL or more per administration, the sliding resistance of the container after tapping and shaking is 30 N or less, and the sustained release is approximately 2 months.

[0090] Item 39: The method of Item 38, wherein the administration comprises slowly injecting the preparation into the subject, and the injection is carried out over a period of about 0.5 seconds or more.

[0091] Item 40: The method according to item 38 or 39, wherein the preparation comprises about 700 mg to about 1000 mg of aripiprazole.

[0092] Item 41: A container comprising a sustained-release intramuscular injection formulation comprising aripiprazole or a salt thereof for the treatment of a subject having schizophrenia or bipolar disorder type I, wherein the formulation is in gel form under static conditions, returns to a sol or suspension by dispersion treatment, and the sustained release is approximately two months.

[0093] In one embodiment, the injectable formulation of the present disclosure is a white to grayish-white sustained-release aqueous suspension for intramuscular injection in the form of a pre-filled syringe, comprising the following components: Anhydrous aripiprazole containing 720 mg or 960 mg • Sodium carboxymethylcellulose (5mg) • Polyethylene glycol 400 (1 mg) • Sodium chloride (6.1 mg) • Monosodium phosphate monohydrate (0.74 mg), and • Sodium hydroxide (as a pH adjuster) [Examples]

[0094] The present invention will be described in more detail below with reference to examples and test examples, but the present invention is not limited thereto.

[0095] Example 1: Vibration treatment of aripiprazole injection formulation (transport simulation) After subjecting an aripiprazole injection formulation manufactured by the method described in Patent Document 2 to vibration treatment that experimentally reproduced the transport environment as a transport simulation, various dispersion treatments were performed to investigate redispersion conditions that improve the sliding properties of the container containing the injection formulation. (1) Sample of the injectable formulation used in this embodiment As a sample, 3.3 mL of the formulation shown in Table 1 was filled into a Schott TopPac® (trade name) 5 mL syringe and used in this example. A vibration test was performed under reduced pressure. This syringe is a plastic syringe made of cyclic olefin copolymer (COC) that meets the Container Closure Integrity (CCI) standard at -80°C. [Table 1] (2) Vibration testing (transportation) Vibration testing was conducted using a method compliant with ASTM D4169-16 of the American Society for Testing and Material (ASTM). Specifically, vibration testing was performed at 20°C to 25°C under reduced pressure using an IMV i240 / SA3M vertical composite electrodynamic vibration tester, under the conditions shown in Tables 2 to 4. [Table 2] [Table 3] [Table 4]

[0096] Example 2: Dispersed Processing Test Tables 5 and 6 show the changes in sliding properties after dispersion treatment for samples before and after the vibration test in Example 1. Table 5 shows the results for samples before the vibration test, and Table 6 shows the results for samples after the vibration test. A syringe containing an injectable formulation was manually tapped and shaken a specific number of times as a dispersion treatment. A 22G 1.5-inch injection needle (manufactured by Terumo Corporation) was then attached to the syringe, and the sliding properties of the syringe were measured using an Imada Manufacturing SV-52NA tensile and compression testing machine under the following test conditions: Range: A (50N), Displacement polarity: DOWN, Load polarity mode: PUSH, Test speed: 100 mm / min (V2). Sliding properties were measured based on the force required to push out the formulation inside the syringe using the plunger rod (sliding resistance), i.e., the glide force of the plunger in accordance with the United States Pharmacopeia (USP). In this dispersion treatment test, shaking was performed after tapping the sample. The gliding force is shown as the average of three values ​​measured three times in each test, and is presented as the average maximum gliding force (N) for each test in the table below. [Table 5] [Table 6]

[0097] Example 2A: Dispersed Processing Test Dispersion treatment tests were performed on additional samples according to the method described in Example 2. The results of the dispersion treatment tests on the samples after vibration testing are shown in the table below. In this dispersion treatment test, tapping was performed after shaking the samples. The sliding force is shown as the average of three values ​​measured three times in each test, and is expressed as the average maximum sliding force (N) for each test in the table below. [Table 7]

[0098] Example 3: Measurement of sliding signal The sliding signal was measured for several samples. The measuring equipment and conditions were the same as in Example 2. Figure 3 shows the sliding signal for the sample before vibration (transport simulation) processing. Figures 4, 5, 6, 7, and 14 show the sliding signal of samples subjected to dispersion treatments of 0 taps and 0 seconds of shaking, 5 taps and 5 seconds of shaking, 10 taps and 10 seconds of shaking, 15 taps and 15 seconds of shaking, or 50 taps and 50 seconds of shaking, respectively, after the transport simulation processing. For these samples, the dispersion treatment was performed by shaking after tapping. The sliding force is shown as the average sliding force (N) for each test in the table below, which is the average sliding force of three values ​​measured three times in each test. Figure 15 shows the sliding signal of a sample subjected to dispersion treatment of 10 taps after 10 seconds of shaking. Figures 8, 9, 10, 11, 12, and 13 show the sliding properties signals of the samples after the transport simulation processing, which were subjected to dispersion processing of 5 taps and 0 seconds of shaking, 10 taps and 0 seconds of shaking, 15 taps and 0 seconds of shaking, 0 taps and 5 seconds of shaking, 0 taps and 10 seconds of shaking, or 0 taps and 15 seconds of shaking, respectively. For the samples after the transport simulation processing, those subjected to distributed processing of 10 taps and 10 seconds of shaking, and 15 taps and 15 seconds of shaking, respectively, showed a maximum sliding force of 30N or less.

[0099] Example 4: Transportation Test To confirm the change in sliding properties after actual sample transport, the same formulation as in Example 1 was stored in a 10 mL vial and transported back and forth between Japan and the United States by air (stored at 1°C to 15°C). The results showed that, after the round trip, some samples may not have sufficient formulation content when extracted unless sufficient tapping and shaking (dispersion treatment) is performed.

[0100] All publications and patents described herein are incorporated herein by reference in whole, as if each individual publication or patent were specifically and individually indicated as being incorporated by reference.

[0101] A claim or specification containing "or" or "and / or" among at least one member of a group is considered satisfied if one, more than one, or all of the group members exist, are utilized, or otherwise related to a given product or process, unless otherwise stated to the contrary or otherwise evident from the context. This disclosure includes embodiments in which exactly one of the group exists, is utilized, or otherwise related to a given product or process. This disclosure includes embodiments in which more than one, or all, of the group members exist, are utilized, or otherwise related to a given product or process.

[0102] Furthermore, this disclosure encompasses all variations, combinations, and substitutions introduced into another claim from at least one of the enumerated claims containing at least one limitation, element, clause, and descriptive term. For example, any claim dependent on another claim may be modified to include at least one limitation found in any other claim dependent on the same base claim. Where elements are presented as a list, for example in Markush format, each subgroup of elements is also disclosed, and any element(s) may be removed from a group. Generally, where this disclosure or aspects of this disclosure are referred to as containing certain elements and / or features, it should be understood that embodiments or aspects of this disclosure consist of, or are essentially, such elements and / or features. Briefly, these embodiments are not specifically described herein as they are. Where a scope is given, it includes endpoints. Furthermore, unless otherwise noted or otherwise evident from the context and the understanding of those skilled in the art, values ​​expressed as ranges may, unless the context explicitly indicates otherwise, assume any specific value or lower range within the ranges described in the different embodiments of this disclosure, up to one-tenth of the lower limit unit of the range.

[0103] Those skilled in the art will recognize, or be able to determine, by simply using the prescribed experiments, many equivalents to the specific embodiments of the present disclosure described herein. Such equivalents are intended to be encompassed by the claims. [Industrial applicability]

[0104] The distributed processing described herein enables a more stable industrial supply of aripiprazole injection formulations.

Claims

1. A method for improving the sliding properties of a container containing a sustained-release injectable formulation of aripiprazole or a salt thereof, comprising the step of dispersing the gel of the formulation in the container before administration to form a sol or suspension, wherein the sustained release is approximately two months.

2. The method according to claim 1, wherein the dispersion process includes at least eight taps and at least eight seconds of shaking of the container.

3. The method according to claim 1, wherein the dispersion process includes at least 10 taps and at least 10 seconds of shaking of the container.

4. The method according to any one of claims 1 to 3, wherein the sliding resistance value of the container after dispersion treatment is 30 N or less.

5. The method according to any one of claims 1 to 4, wherein the container is a pre-filled syringe.

6. The method according to any one of claims 1 to 5, wherein the preparation is for intramuscular administration for the treatment of a subject having schizophrenia or bipolar disorder type I.

7. The method according to any one of claims 1 to 6, wherein the preparation contains about 700 mg to about 1000 mg of aripiprazole.

8. The method according to claim 7, wherein the container contains 2.0 mL or more of the preparation per single dose.

9. The method according to any one of claims 1 to 8, wherein the preparation is white to grayish-white and contains the following components. 720 mg or 960 mg of anhydrous aripiprazole Sodium carboxymethylcellulose Polyethylene glycol 400 Sodium chloride - Monosodium phosphate monohydrate, and Sodium hydroxide

10. The method according to any one of claims 1 to 9, further comprising administering the preparation in the container to a subject requiring it after the dispersion process.

11. A method for treating a subject having schizophrenia or bipolar disorder type I, comprising slowly administering an injectable preparation prepared according to any one of claims 1 to 10 to the subject, wherein the administration is performed over a period of approximately 0.5 seconds or more.

12. A method for treating a subject having schizophrenia or bipolar disorder type I, comprising dispersing an injectable preparation of aripiprazole or a salt thereof in a container to change it from a gel to a sol or suspension, and intramuscularly administering the injectable preparation to the subject, wherein the subject receives the injectable preparation once every two months.

13. The method according to claim 12, wherein the dispersion process includes at least eight taps and at least eight seconds of shaking of the container.

14. The method according to claim 12 or 13, wherein the sliding resistance value of the container after dispersion treatment is 30 N or less.

15. The method according to any one of claims 12 to 14, wherein the container is a pre-filled syringe.

16. The method according to any one of claims 12 to 15, wherein the administration is performed in the gluteal muscle of the subject.

17. The method according to any one of claims 12 to 16, wherein a total amount of approximately 700 mg to approximately 1000 mg of aripiprazole is delivered to the subject by administration once every approximately two months.

18. The method according to any one of claims 12 to 17, wherein the container contains the preparation in an amount of 2.0 mL or more per single dose.

19. The method according to any one of claims 12 to 18, wherein the preparation is white to grayish-white and contains the following components. 720 mg or 960 mg of anhydrous aripiprazole Sodium carboxymethylcellulose Polyethylene glycol 400 Sodium chloride - Monosodium phosphate monohydrate, and Sodium hydroxide

20. The method according to any one of claims 12 to 19, wherein the administration comprises slowly injecting the injectable preparation into the subject, and the injection is performed over a period of about 0.5 seconds or more.

21. A sustained-release intramuscular injection formulation for the treatment of subjects having schizophrenia or bipolar disorder type I, comprising aripiprazole or a salt thereof in a container, wherein the formulation is in gel form under static conditions, returns to a sol or suspension upon dispersion, and the sustained release is approximately two months.

22. The formulation according to claim 21, wherein the formulation comprises a total amount of approximately 700 mg to approximately 1000 mg of aripiprazole.

23. The formulation according to claim 21 or 22, wherein the container is a pre-filled syringe for administering an amount of 2.0 mL or more per single dose.

24. The formulation according to any one of claims 21 to 23, wherein the formulation is white to grayish-white and contains the following components. 720 mg or 960 mg of anhydrous aripiprazole Sodium carboxymethylcellulose Polyethylene glycol 400 Sodium chloride - Monosodium phosphate monohydrate, and Sodium hydroxide

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