Method for dispersing aripiprazole injection preparation

Abstract

The present invention relates to a method for dispersing an injection formulation comprising aripiprazole or a salt thereof. The present invention provides a method of enhancing the sliding property of a container comprising a long-acting injection formulation comprising aripiprazole or a salt thereof, the method comprising dispersing the ingredients contained in the formulation prior to administration, also provided are injectable formulations of aripiprazole administered after dispersion, methods of administering the formulations, and uses thereof.

Description

Technical Field

[0001] The present disclosure relates to a method for dispersing an injectable formulation comprising aripiprazole or a salt thereof, and also relates to an injectable formulation of aripiprazole administered after dispersion, a method for administering the same, and a use thereof. Background Art

[0002] An injectable formulation containing aripiprazole or a salt thereof (also referred to herein as "aripiprazole injectable formulation" or "injectable formulation") turns into a gel upon standing, which can inhibit precipitation and agglomeration of aripiprazole particles, thereby providing acceptable storage stability. Furthermore, even in gel form, the injectable formulation can readily increase fluidity, meaning that the formulation turns into a sol upon slight impact, allowing for easy injection during use (PTL 1).

[0003] [Citation List]

[0004] [Patent Document]

[0005] [PTL 1] WO 2021 / 201238A1 Publication

[0006] [PTL 2] US 10,517,951B2 Summary of the Invention

[0007] [Technical Issues]

[0008] Aripiprazole injection formulations are provided as ready-to-use (RTU) formulations in the form of prefilled syringes (PTL 2). Under static or resting conditions, the homogeneity of the ingredients contained in these RTU formulations decreases. Following formulation, depending on transportation or storage conditions, some ingredients may settle, resulting in reduced sliding properties of the container containing the formulation during use or injection, and increased resistance to injection.

[0009] [Solution to the problem]

[0010] The present inventors discovered the above-mentioned problems and, after extensive studies, noted that the problems can be solved by subjecting the aripiprazole injection preparation to a specific dispersion procedure before use, thereby completing the present invention.

[0011] In one aspect, a method for enhancing the slidability of a container of a long-acting injection preparation containing aripiprazole or a salt thereof is provided, the method comprising:

[0012] Dispersing the gel of the formulation in the container before administration to form a sol or suspension of the formulation,

[0013] The long-term effect is about two months.

[0014] In another aspect, a long-acting injectable formulation for intramuscular administration for treating a subject with schizophrenia or bipolar I disorder is provided, comprising aripiprazole or a salt thereof in a container, wherein the formulation is in the form of a gel under static conditions and reverts to a sol or suspension upon dispersion, and has a long-acting effect of about two months.

[0015] In yet another aspect, provided is a method for treating a subject suffering from schizophrenia or bipolar I disorder, the method comprising dispersing an injectable formulation of aripiprazole or a salt thereof in the form of a gel into a sol or suspension in a container, and administering the injectable formulation intramuscularly to the subject, wherein the subject administers the injectable formulation approximately once every two months.

[0016] In yet another aspect, provided is the use of aripiprazole or a salt thereof in the preparation of a medicament for treating a subject suffering from schizophrenia or bipolar I disorder, wherein the medicament is a long-acting injectable formulation for intramuscular administration comprising aripiprazole or a salt thereof in a container, the formulation being in the form of a gel under static conditions and reverting to a sol or suspension upon dispersion, and having a long-acting effect of about two months.

[0017] [Advantageous Effects of the Invention]

[0018] Even if the uniformity of the components contained in the aripiprazole injection preparation becomes degraded due to transportation and delivery, etc., a dispersion procedure of the preparation before use (or administration) can allow the components to be redispersed and enhance the slip properties of the container containing the components when used or injected. BRIEF DESCRIPTION OF THE DRAWINGS

[0019] [ Figure 1 ] Figure 1 An embodiment of tapping is shown.

[0020] [ Figure 2 ] Figure 2 A shaking embodiment is shown.

[0021] [ Figure 3 ] Figure 3 The slippage signal of the sample before vibration is shown.

[0022] [ Figure 4 ] Figure 4 Shown are the slipperiness signals of the samples after 0 taps and 0 seconds of shaking following vibration.

[0023] [ Figure 5 ] Figure 5 The slipperiness signal of the sample after 5 taps and 5 seconds of shaking after shaking is shown. The dispersion procedure was performed by shaking after tapping.

[0024] [ Figure 6 ] Figure 6 The slipperiness signal of the sample after 10 taps and 10 seconds of shaking after shaking is shown. The dispersion procedure was performed by shaking after tapping.

[0025] [ Figure 7 ] Figure 7 The slipperiness signal of the sample is shown after 15 taps and 15 seconds of shaking followed by vibration. The dispersion procedure was performed by shaking followed by tapping.

[0026] [ Figure 8 ] Figure 8 Shown are the slipperiness signals of the samples after 5 taps and 0 seconds of shaking following vibration.

[0027] [ Figure 9 ] Figure 9 Shown are the slipperiness signals of the samples after 10 taps and 0 seconds of shaking following vibration.

[0028] [ Figure 10 ] Figure 10 Shown are the slipperiness signals of the samples after 15 taps and 0 seconds of shaking following vibration.

[0029] [ Figure 11 ] Figure 11 Shown are the slipperiness signals of the samples after 0 taps and 5 seconds of shaking following vibration.

[0030] [ Figure 12 ] Figure 12 Shown are the slipperiness signals of the samples after 0 taps and 10 seconds of shaking following vibration.

[0031] [ Figure 13 ] Figure 13 Shown are the slipperiness signals of the samples after 0 taps and 15 seconds of shaking following vibration.

[0032] [ Figure 14 ] Figure 14 The slipperiness signal of the sample after 50 taps and 50 seconds of shaking after shaking is shown. The dispersion procedure was performed by shaking after tapping.

[0033] [ Figure 15 ] Figure 15 The slipperiness signal of the sample after 10 taps and 10 seconds of shaking after shaking is shown. The dispersion procedure was performed by tapping followed by shaking. DETAILED DESCRIPTION

[0034] When used herein, an entity without a specific number is one or more of that entity, for example, unless otherwise specified, "a compound" refers to one or more compounds or at least one compound. Thus, references to no specific number, "one or more," and "at least one" are used interchangeably herein.

[0035] As used herein, the term "about" means approximately, in the region of, roughly, or around. When the term "about" is used in conjunction with a numerical range, it modifies that range by extending the boundaries above and below the numerical values ​​set forth. Generally, the term "about" is used herein to modify a numerical value above and below the stated value to within 5% of the stated value.

[0036] As used herein, the term "treat," when used in conjunction with a disorder or condition, includes any action that results in an improvement of the disorder or condition, such as alleviation, reduction, modulation, improvement, or elimination. The improvement or reduction in 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 as maintenance monotherapy for the treatment of schizophrenia and bipolar I disorder. In other embodiments, the methods disclosed herein can be used to treat schizophrenia, acute treatment of manic and mixed episodes associated with bipolar I disorder, major depressive disorder (MDD), irritability with autism, and Tourette's disorder.

[0037] As used herein, "aripiprazole" refers to aripiprazole or a salt thereof, or a crystalline form of aripiprazole or a salt thereof. Aripiprazole or a salt thereof may be in the form of a monohydrate (aripiprazole hydrate A) or various anhydrous forms, the anhydrous forms of which are known to exist in the form of anhydrous crystals B, anhydrous crystals C, anhydrous crystals D, anhydrous crystals E, anhydrous crystals F, and anhydrous crystals G. All of these crystalline forms can be used as aripiprazole or a salt thereof in the injectable formulations of the present disclosure. Furthermore, for example, aripiprazole is in the form of a monohydrate. As used herein, the term "aripiprazole" or a salt thereof refers to a compound having the following structure:

[0038] [Chemical Formula 1]

[0039] .

[0040] Decentralized Program

[0041] The term "dispersion procedure" or "dispersion step" in the present disclosure refers to a procedure for redispersing the ingredients contained in the injectable formulation of the present 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 procedure, but is not limited thereto. The dispersion procedure includes, for example, a procedure in which the force required to push or expel the formulation from the container as a sliding resistance is 30 N or less, such as 25 N or less and 5 N or greater. The container used herein includes any medically acceptable container commonly used in medical or clinical settings, such as a syringe or a prefilled syringe. In some embodiments, the container can be a transparent container made of a plastic such as cyclic olefin copolymer (COC). In some aspects, the dispersion procedure is a procedure performed manually by an adult (e.g., a patient and a healthcare practitioner) or using a medical device commonly used in the art, the procedure comprising tapping the formulation at least 6 times and shaking the formulation for 6 seconds until the formulation becomes homogenous. This dispersion procedure can preferably be completed in any practical time in a medical or clinical setting, for example, tapping and shaking can be completed in a total of 1 minute, which includes tapping 40 times or less and shaking for 40 seconds or less. In other aspects, the dispersion procedure may include tapping at least 8 times and shaking for at least 8 seconds, further for example tapping at least 10 times and shaking for at least 10 seconds, and further for example tapping 10 to 15 times and shaking for 10 to 15 seconds. The term "tapping" in this disclosure refers to the action or treatment of applying motion or vibration to the preparation or producing an impact thereto, for example, knocking the container containing the preparation to make the preparation homogeneous or uniform. In one embodiment, tapping is such as Figure 1 The term "shaking" in this disclosure refers to an action or process of mixing the preparation to make it uniform, such as shaking or oscillating the container containing the preparation, preferably in the longitudinal direction of the container, to make the preparation homogeneous or uniform. In one embodiment, shaking is as follows Figure 2. In certain aspects, the shaking in the dispersion procedure is performed after tapping until the formulation becomes homogenous in terms of effective dispersion. In certain aspects, the dispersion procedure is performed at ambient temperature, e.g., 1°C to 30°C. In certain aspects, after the dispersion procedure, a syringe needle suitable for the subject or patient is attached to the formulation for intramuscular administration. The dispersion procedure of the present disclosure can optionally be adjusted based on the contents and / or shape of the container (including prefilled syringes) containing the injectable formulation of the present disclosure. A reduction in the homogeneity or flowability of the ingredients contained in the injectable formulation, or a reduction in the slidability of the container containing the injectable formulation of the present disclosure, may be caused by intermittent or continuous mild vibration or shock caused by conditions during transportation or storage of the formulation after formulation (particularly at low temperatures, e.g., 1°C to 15°C or lower). When the homogeneity, flowability, or slidability are reduced, the force required to eject the formulation from the container containing the formulation (also referred to herein as "sliding resistance") may exceed 30N, thereby ejecting an excess of the contents unless the dispersion procedure of the present disclosure is performed. Since even the gelled injectable formulation of the present disclosure can be easily made fluid by simply depressing the plunger of a syringe and pushing the formulation through the syringe needle to form a sol, in certain aspects, after the formulation is subjected to the dispersion procedure of the present disclosure once, the formulation can be used as is after a certain interval (e.g., hours, days, weeks, and months) without vibration or shock caused by conditions during transportation or storage.

[0042] Injectable preparations

[0043] The injectable formulations disclosed herein include, for example, the two-month ready-to-use (RTU) injectable formulation disclosed in PTL 1, and are compositions comprising aripiprazole, a specific suspending agent (suspension agent (A)), and a dispersion medium. For example, the injectable formulations disclosed herein contain at least water as the dispersion medium. Water or an aqueous solvent containing water and an organic solvent can be used as the dispersion medium containing at least water. In certain aspects, the dispersion medium is water, with sterile water for injection being another example.

[0044] The specific suspending agent (suspending agent A) contained in the injection preparation of the present disclosure includes at least one suspending agent selected from (i) and (ii): (i) polyvinyl pyrrolidone, and (ii) polyethylene glycol and carboxymethyl cellulose or a salt thereof.

[0045] In certain aspects, the injectable formulation disclosed herein comprises aripiprazole or a salt thereof, water, and at least one suspending agent selected from (i) and (ii): (i) polyvinyl pyrrolidone, and (ii) polyethylene glycol and carboxymethyl cellulose or a salt thereof, wherein 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. The two-month ready-to-use (RTU) injectable formulation disclosed herein is described in PTL 2, which is incorporated herein by reference in its entirety.

[0046] The injectable formulations disclosed herein contain aripiprazole or a salt thereof and utilize a combination of a specific suspending agent (Suspension Agent A) and a specific concentration of aripiprazole or a salt thereof (about 200 mg / mL to about 400 mg / mL, e.g., about 250 mg / mL to about 350 mg / mL). When the injectable formulations disclosed herein contain aripiprazole salts, the aforementioned concentrations are calculated based on aripiprazole (anhydrate).

[0047] In certain aspects, in the aripiprazole injection formulations of the present disclosure, when polyvinylpyrrolidone is contained as the 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, another example is about 2 mg / mL to about 20 mg / mL, and yet another example is about 4 mg / mL to about 15 mg / mL.

[0048] In certain aspects, when the aripiprazole injection formulation of the present disclosure comprises polyethylene glycol and carboxymethyl cellulose or a salt thereof as suspending agent A, the concentration of polyethylene glycol is from about 0.05 mg / mL to about 2 mg / mL, and further, for example, from about 0.1 mg / mL to about 1 mg / mL. The concentration of carboxymethyl cellulose or a salt thereof is from about 0.5 mg / mL to about 50 mg / mL, for example, from about 1 mg / mL to about 30 mg / mL, for example, from about 2 mg / mL to about 20 mg / mL, for example, from about 5 mg / mL to about 15 mg / mL.

[0049] The inclusion of carboxymethylcellulose or its salt can suppress viscosity increases during the production process. This allows aripiprazole or its salt to be efficiently pulverized into the desired particle size. In some embodiments, the molecular weight of the carboxymethylcellulose or its salt is in the range of 49,000 to 300,000. Furthermore, the inclusion of polyethylene glycol can prevent syneresis even during prolonged storage of the resulting injectable formulation. In some embodiments, the molecular weight of the polyethylene glycol is in the range of 400 to 4,000.

[0050] In certain aspects, in the disclosed aripiprazole injectable formulations, when using several suspending agents, the composition comprises about 0.5 mg / mL to about 20 mg / mL of polyvinyl pyrrolidone, about 0.1 mg / mL to about 100 mg / mL of polyethylene glycol, about 0.5 mg / mL to about 50 mg / mL of carboxymethyl cellulose 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 can be polyethylene glycol 400 or polyethylene glycol 4000. In certain aspects, the polyvinyl pyrrolidone has a K value of about 12 to about 20 (e.g., 17). In other aspects, the aripiprazole or a salt thereof has an average primary particle size of about 1 μm to 10 μm.

[0051] Because an excessively large average primary particle size of aripiprazole or its salt may result in precipitation, the average primary particle size ranges from about 0.5 μm to about 30 μm, for example, from about 1 μm to about 20 μm. When the injectable formulation of the present disclosure is a dosage form for bimonthly administration, the average primary particle size of aripiprazole or its salt ranges from about 1 μm to about 50 μm, for example, from about 1 μm to about 10 μm, and another example is from about 2 μm to about 5 μm. As used herein, the term "primary particle size" refers to the diameter of individual particles that are not aggregated but rather separated from one another. As used herein, the term "average primary particle size" is calculated based on the volume average diameter calculated from the average primary particle size distribution measured by laser diffraction scattering. The average primary particle size used herein can be measured by circulating the injectable formulation in an aqueous medium under ultrasonic irradiation. For example, SALD-3100 and SALD-2300 (manufactured by Shimadzu Corporation) can be used to measure the average particle size by laser diffraction scattering. The average secondary particle size is at most but not more than three times the average primary particle size, and further for example at most but not more than twice the average primary particle size. "Secondary particle size" as used herein refers to the diameter of the particles that are aggregated. The term "average secondary particle size" as used herein is calculated based on the volume average diameter calculated from the average secondary particle size distribution measured by laser diffraction scattering. The average secondary particle size used herein can be measured when the injection preparation is circulated in an aqueous medium without ultrasonic radiation.

[0052] In certain aspects, the injectable formulations of the present disclosure are suitably formulated into dosage forms that can be administered once every two months (also referred to herein as "two-month dosage forms" or "two-month formulations"). For example, the concentration of aripiprazole or a salt thereof in an injectable formulation of the present disclosure administered once every two months is from about 200 mg / mL to about 400 mg / mL, for example, from about 250 mg / mL to about 350 mg / mL, for example, about 300 mg / mL of aripiprazole. When the injectable formulation is administered once every two months, the dosage volume is from about 2 mL to about 4 mL, for example, from about 2.2 mL to about 3.5 mL, for example, from about 2.3 mL to about 3.4 mL, for example, from about 2.4 mL to 3.2 mL.

[0053] In certain aspects, the injectable formulation of the present disclosure is a long-acting injectable formulation comprising aripiprazole or a salt thereof and a specific suspending agent in a sol-gel form. The formulation may be in a gel form during storage and resting, and may become a sol upon impact. In certain aspects, the injectable formulation of the present disclosure can be formulated as a pre-filled sol-gel-forming injectable formulation (also referred to herein as a "pre-filled sol-gel-forming injectable formulation"). In certain aspects, the injectable formulation of the present disclosure exhibits thixotropic properties.

[0054] In certain aspects, PTL 2 describes a method for preparing an aripiprazole injection formulation, which comprises, for example, preparing a liquid mixture of starting materials, and pulverizing aripiprazole or a salt thereof contained in the liquid mixture to a desired average primary particle size, optionally followed by aging.

[0055] In certain aspects, a method for preparing a gel injection formulation of the present disclosure comprises allowing a liquid mixture to stand at 5° C. to 70° C. for 5 minutes or longer, wherein the liquid mixture comprises aripiprazole or a salt thereof at a concentration of about 200 mg / mL to about 400 mg / mL, an average primary particle size of about 0.5 μm to about 30 μm, water, and at least one suspending agent selected from (i) polyvinyl pyrrolidone, (ii) polyethylene glycol, and carboxymethyl cellulose or a salt thereof.

[0056] For example, in certain other aspects, a preparation method comprising the steps of pulverizing aripiprazole or its salt to an average primary particle size of about 0.5 μm to about 30 μm in a liquid mixture comprising aripiprazole or its salt 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) ((i) polyvinyl pyrrolidone, (ii) polyethylene glycol, and carboxymethyl cellulose or its salt); and allowing the pulverized liquid mixture to stand at 5° C. to 70° C. for about 5 minutes or longer, about 10 minutes or longer, about 15 minutes or longer, or about 30 minutes or longer, and within about 1 hour or about 24 hours can be used.

[0057] In certain aspects, the present disclosure comprises administering an aripiprazole injection formulation as a two-month dosage form, resulting in a total amount of aripiprazole administered to the patient ranging from about 700 mg to about 1000 mg, such as about 720 mg to about 960 mg, such as about 720 mg or about 960 mg, wherein the injection formulation can optionally be administered in one or more injections. In certain other aspects, administration of the aripiprazole injection formulation results in a total amount of aripiprazole administered to the patient of about 960 mg, wherein one or more injection formulations are administered. For example, to obtain a total amount of aripiprazole administered to the patient of 960 mg, one (1) injection of an aripiprazole injection formulation comprising 300 mg / mL aripiprazole is administered. The 960 mg dose can optionally be administered in separate injections at short intervals. As described above, the number of injections and the aripiprazole concentration vary depending on the total amount of aripiprazole to be administered and the concentration of aripiprazole contained in each injection formulation.

[0058] In certain aspects, the present disclosure relates to a pre-filled syringe formulation for administering the above-mentioned formulation (i.e., an injectable formulation) to a subject, wherein the dosage volume of the formulation is about 2.0 mL or greater, e.g., 2.0 mL to 4.0 mL, e.g., 2.2 mL to 3.5 mL, e.g., 2.3 mL to 3.4 mL, e.g., 2.4 mL to 3.2 mL, e.g., 3.0 mL to 3.2 mL, e.g., about 3.2 mL.

[0059] In certain aspects, the aripiprazole formulation for injection is administered to a subject by intramuscular injection. In some embodiments, the intramuscular administration is at a site selected from the deltoid muscle, the gluteal muscle, and combinations thereof. In some embodiments, the site is the gluteal muscle. For example, depending on the number of injections administered, the injection site may encompass various locations within the deltoid muscle and / or the gluteal muscle.

[0060] In certain aspects, when the injectable formulations of the present disclosure are administered intramuscularly at sites such as the deltoid and gluteal muscles, the administration can ideally be performed at a constant rate and a slow speed. In some embodiments, the injectable formulations of the present disclosure are administered by slowly injecting substantially all of the aripiprazole contents contained in the prefilled syringe. The terms "slow" or "slowly" herein mean administration over a period of time, such as about 0.5 seconds or longer, about 1 second or longer, about 2 seconds or longer, about 3 seconds or longer, about 4 seconds or longer, about 5 seconds or longer, about 10 seconds or longer, about 15 seconds or longer, about 20 seconds or longer, or about 30 seconds or longer, and within about 1 minute, about 2 minutes, about 3 minutes, about 4 minutes, or about 5 minutes, compared to the time taken for conventional and / or gradual administration in the art and for injections other than rapid and continuous administration, and within about 1 minute, about 2 minutes, about 3 minutes, about 4 minutes, or about 5 minutes. Rapid administration of the formulation is undesirable from the perspective of irritation to the injection site.

[0061] In certain aspects, the method for using the injection preparation of the present disclosure occurs with a frequency of about once every two months. For example, the injection preparation is used once every 42 to 70 days or with any integer day between and including endpoints, 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 other aspects, the injection preparation is used once every 56 days, for example, every 54 to 58 days. In other aspects, the injection preparation is used once every 8 weeks.

[0062] In certain aspects, the injectable formulation of the present invention can be pre-filled into a container as is, for example, as a syringe for use as a pre-filled syringe. This simplifies the structure of the syringe and reduces its size and weight. In another embodiment, when the injectable formulation of the present invention is filled into a syringe, the formulation can be administered by performing the dispersion procedure of the present invention and then simply depressing the syringe's plunger and ejecting the injectable formulation of the present invention through the syringe needle. This provides a pre-filled syringe that offers clinical convenience and ease of use, and is therefore very useful in medicine and industry. One example of producing such a pre-filled syringe is to produce the injectable formulation in the manner described above, pre-fill the formulation into a syringe, and then allow the injectable formulation to gel in the manner described above. In certain aspects, the gel injectable formulation can be subjected to the dispersion procedure of the present invention prior to administration to form a homogeneous sol or suspension with sufficient fluidity. The term "sufficiently fluid" in this disclosure means, for example, that the force required to eject the formulation from the syringe container containing the formulation is 30 N or less, such as 25 N or less, which may vary depending on the contents of the container and / or the size of the syringe needle used. In certain aspects, the syringe needle of the injectable formulation of the present disclosure is a 1 to 2 inch (i.e., 25 to 51 mm) and 21 to 23 gauge hypodermic needle. In certain aspects, the syringe needle of the injectable formulation of the present 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, and can be optionally selected based on the age, sex, and body shape of the subject or patient. The present disclosure also includes a kit equipped with the above-mentioned container, such as a prefilled syringe and syringe needle.

[0063] The term "pull-out force" in the present disclosure refers to the force required to push out substantially the entire amount of the preparation from a container containing the injectable preparation of the present disclosure by a rod-shaped object, such as a plunger rod, and corresponds to the "plunger sliding force" described in U.S. Pharmacopoeia (USP) 1382 and 382. The force can be measured as sliding resistance using a measuring instrument commonly used in the art. Such measuring instruments include, for example, an SV-52NA tensile and compression tester (manufactured by IMADA-SS Corporation). The term "substantially the entire amount" herein refers to the total content of the preparation contained in the container before administration, or the amount after deducting the amount remaining in the container after the preparation is pushed out from the total content, for example, about 0.1 mL, about 0.2 mL, about 0.3 mL, about 0.4 mL, or about 0.5 mL.

[0064] Some implementations are shown below.

[0065] Item 1: A method for enhancing the slidability of a container of a long-acting injection preparation containing aripiprazole or a salt thereof, the method comprising:

[0066] Dispersing the gel of the formulation in the container before administration to form a sol or suspension of the formulation,

[0067] The long-term effect is about two months.

[0068] Item 2: The method of Item 1, wherein the dispersing step comprises tapping the container at least 8 times and shaking the container for at least 8 seconds.

[0069] Item 3: The method of Item 1, wherein the dispersing step comprises tapping the container at least 10 times and shaking the container for at least 10 seconds.

[0070] Item 4: The method according to any one of items 1 to 3, wherein after the dispersing step, the sliding resistance of the container is 30 N or less.

[0071] Clause 5: The method of any one of clauses 1 to 4, wherein the container is a pre-filled syringe.

[0072] Clause 6: The method according to any one of clauses 1 to 5, wherein the formulation is for intramuscular administration and is used to treat a subject suffering from schizophrenia or bipolar I disorder.

[0073] Clause 7: The method of any one of Clauses 1 to 6, wherein the formulation comprises aripiprazole in an amount ranging from about 700 mg to about 1000 mg.

[0074] Clause 8: The method of Clause 7, wherein the container contains the formulation in an amount of 2.0 mL or more per single administration.

[0075] Clause 9: The method according to any one of clauses 1 to 8, wherein the formulation is white to off-white and comprises:

[0076] - 720 mg or 960 mg anhydrous aripiprazole,

[0077] - sodium carboxymethyl cellulose,

[0078] - polyethylene glycol 400,

[0079] - sodium chloride,

[0080] - sodium dihydrogen phosphate monohydrate, and

[0081] - Sodium hydroxide.

[0082] Clause 10: The method of any one of clauses 1 to 9, further comprising administering the formulation in the container to a subject in need thereof after dispersing.

[0083] Clause 11: A method of treating a subject suffering from schizophrenia or bipolar I disorder, comprising slowly administering to the subject the injectable formulation obtained according to the method of any one of Clauses 1 to 10, wherein slowly is over about 0.5 seconds or longer.

[0084] Item 12: A method for treating a subject suffering from schizophrenia or bipolar I disorder, the method comprising dispersing an injectable formulation of aripiprazole or a salt thereof in the form of a gel into a sol or suspension in a container, and administering the injectable formulation intramuscularly to the subject, wherein the subject administers the injectable formulation approximately once every two months.

[0085] Clause 13: The method of Clause 12, wherein the dispersing step comprises tapping the container at least 8 times and shaking the container for at least 8 seconds.

[0086] Item 14: The method according to Item 12 or 13, wherein after the dispersing step, the sliding resistance of the container is 30 N or less.

[0087] Clause 15: The method of any one of clauses 12 to 14, wherein the container is a pre-filled syringe.

[0088] Clause 16: The method of any one of clauses 12 to 15, wherein the administering is performed to the gluteal muscle of the subject.

[0089] Clause 17: The method of any one of Clauses 12 to 16, wherein said about once every two months administration results in a total amount of aripiprazole administered to said subject in the range of about 700 mg to about 1000 mg.

[0090] Clause 18: The method according to any one of clauses 12 to 17, wherein the container contains the formulation in an amount of 2.0 mL or more per single administration.

[0091] Clause 19: The method according to any one of clauses 12 to 18, wherein the formulation is white to off-white and comprises:

[0092] - 720 mg or 960 mg anhydrous aripiprazole,

[0093] - sodium carboxymethyl cellulose,

[0094] - polyethylene glycol 400,

[0095] - sodium chloride,

[0096] - sodium dihydrogen phosphate monohydrate, and

[0097] - Sodium hydroxide.

[0098] Clause 20: The method according to any one of clauses 12 to 19, wherein the administering comprises slowly injecting the formulation for injection into the subject, and slowly is over about 0.5 seconds or more.

[0099] Item 21: A long-acting injectable formulation for intramuscular administration for treating a subject with schizophrenia or bipolar I disorder, comprising aripiprazole or a salt thereof in a container, wherein the formulation is in the form of a gel under static conditions and reverts to a sol or suspension upon dispersion, and has a long-acting duration of about two months.

[0100] Item 22: The formulation of Item 21, wherein the dispersing comprises tapping the container at least 8 times and shaking the container for at least 8 seconds.

[0101] Item 23: The formulation of Item 21 or 22, wherein after dispensing the formulation, the container has a sliding resistance of 30 N or less.

[0102] Clause 24: The formulation of any one of clauses 21 to 23, wherein the formulation is in the form of a gel before dispersion and the formulation is in the form of a sol after dispersion.

[0103] Clause 25: The formulation of any one of clauses 21 to 34, wherein the administration is by injection into the gluteal muscle of the subject.

[0104] Clause 26: The formulation of any one of clauses 21 to 25, wherein the formulation comprises aripiprazole in a total amount ranging from about 700 mg to about 1000 mg.

[0105] Clause 27: The formulation of any one of clauses 21 to 26, wherein the container is a pre-filled syringe for administration in an amount of 2.0 mL or more per single administration.

[0106] Clause 28: A formulation according to any one of clauses 21 to 27, wherein the formulation is white to off-white and comprises:

[0107] - 720 mg or 960 mg anhydrous aripiprazole,

[0108] - sodium carboxymethyl cellulose,

[0109] - polyethylene glycol 400,

[0110] - sodium chloride,

[0111] - sodium dihydrogen phosphate monohydrate, and

[0112] - Sodium hydroxide.

[0113] Item 29: Use of aripiprazole or a salt thereof in the preparation of a medicament for treating a subject suffering from schizophrenia or bipolar I disorder, wherein the medicament is a long-acting injectable formulation for intramuscular administration, which comprises aripiprazole or a salt thereof in a container, the formulation being in the form of a gel under static conditions and reverting to a sol or suspension upon dispersion, and having a long-acting effect of about two months.

[0114] Item 30: The use according to Item 29, wherein the dispersing comprises tapping the container at least 8 times and shaking the container for at least 8 seconds.

[0115] Item 31: The use according to Item 29 or 30, wherein after dispensing the formulation, the container has a sliding resistance of 30 N or less.

[0116] Item 32: Use according to any one of items 29 to 31, wherein the formulation is in the form of a gel before dispersion and the formulation is in the form of a sol after dispersion.

[0117] Clause 33: Use according to any one of clauses 29 to 32, wherein the administration is by injection into the gluteal muscle of the subject.

[0118] Clause 34: Use according to any one of clauses 29 to 33, wherein the formulation comprises aripiprazole in a total amount ranging from about 700 mg to about 1000 mg.

[0119] Clause 35: Use according to any one of clauses 29 to 34, wherein the container is a pre-filled syringe for administration in an amount of 2.0 mL or more per single administration.

[0120] Clause 36: The use according to any one of clauses 29 to 35, wherein the formulation is white to off-white and comprises:

[0121] - 720 mg or 960 mg anhydrous aripiprazole,

[0122] - sodium carboxymethyl cellulose,

[0123] - polyethylene glycol 400,

[0124] - sodium chloride,

[0125] - sodium dihydrogen phosphate monohydrate, and

[0126] - Sodium hydroxide.

[0127] Clause 37: Use according to any one of clauses 29 to 36, wherein said administering comprises slowly injecting said formulation for injection into said subject, and slowly is over about 0.5 seconds or more.

[0128] Item 38: A method for enhancing the slidability of a container containing a long-acting intramuscular injection preparation comprising aripiprazole or a salt thereof, the method comprising:

[0129] Continuously tap and shake the container before administration to convert the gel form of the formulation into a sol or suspension,

[0130] wherein the container comprises a dosage volume of 2.0 mL or more of the formulation per dose,

[0131] After said tapping and shaking, the sliding resistance of said container is 30 N or less, and

[0132] The long-term effect is about two months.

[0133] Clause 39: The method of Clause 38, wherein said administering comprises slowly injecting said formulation for injection into said subject, and slowly is over about 0.5 seconds or more.

[0134] Clause 40: The method of Clause 38 or 39, wherein the formulation comprises aripiprazole in an amount ranging from about 700 mg to about 1000 mg.

[0135] Item 41: A container comprising a long-acting injectable formulation for intramuscular administration for treating a subject with schizophrenia or bipolar I disorder, the long-acting injectable formulation comprising aripiprazole or a salt thereof, wherein the formulation is in the form of a gel under static conditions and reverts to a sol or suspension upon dispersion, and the long-acting formulation is about two months.

[0136] In one illustrative embodiment, the injectable formulation of the present disclosure is a white to off-white aqueous extended-release suspension in the form of a pre-filled syringe for intramuscular injection, comprising:

[0137] - anhydrous aripiprazole in strengths of 720 mg or 960 mg,

[0138] - Carboxymethylcellulose sodium (5 mg),

[0139] - polyethylene glycol 400 (1 mg),

[0140] - Sodium chloride (6.1 mg),

[0141] - sodium dihydrogen phosphate monohydrate (0.74 mg), and

[0142] - Sodium hydroxide for pH adjustment.

[0143] [Example]

[0144] The present invention will be described in more detail with reference to the following examples and test examples, but the present invention is not limited thereto.

[0145] Example 1: Vibration Procedure for Aripiprazole Injection Formulation (Transport Simulation)

[0146] The aripiprazole injection preparation prepared according to the method described in PTL 2 was subjected to a vibration procedure as a transportation simulation that empirically reproduced the transportation environment, and then a dispersion procedure was performed under various conditions, and the redispersion conditions that improved the slipperiness of the container containing the injection preparation were determined.

[0147] (1) Samples of injection preparations used in this example

[0148] 3.3 mL of the formulation in Table 1 was loaded into a 5-mL Schott TopPac (R) (brand name) syringes were used as samples for this example, and the samples were subjected to a vibration test under reduced pressure. The syringes were plastic syringes made of cyclic olefin copolymer (COC) and met the container closure integrity (CCI) standard at -80°C.

[0149] [Table 1]

[0150] Table 1: Preparations used

[0151]

[0152] (2) Vibration test (transportation and delivery)

[0153] The vibration test was conducted according to ASTM D4169-16 of the American Society for Testing and Materials (ASTM). Specifically, the vibration test was conducted under the conditions shown in Tables 2 to 4 at 20°C to 25°C and reduced pressure using an electrodynamic vibration test system i240 / SA3M vertical composite type manufactured by IMV Corporation.

[0154] [Table 2]

[0155] Table 2: ASTM D4169-16 Truck Condition Intermediate

[0156]

[0157] PSD = Power Spectral Density

[0158] [Table 3]

[0159] Table 3: ASTM D4169-16 Air Transport Condition Level 2

[0160]

[0161] PSD = Power Spectral Density

[0162] [Table 4]

[0163] Table 4: ASTM D4169-16 Air Transport Condition Level 2

[0164]

[0165] Example 2: Dispersion test

[0166] Tables 5 and 6 show the changes in slippage after the dispersion procedure in the samples before and after the vibration test in Example 1; that is, Table 5 shows the results for the samples before vibration, and Table 6 shows the results for the samples after vibration. The syringe containing the injectable formulation was subjected to the dispersion procedure by tapping and shaking it several times by hand, and then connected to a 22G 1.5-inch injection needle (manufactured by Terumo Corporation). The syringe's slippage was measured using an SV-52NA tensile and compression tester (manufactured by IMADA-SS Corporation) under the following conditions: range: A (50 N), displacement polarity: downward, load polarity mode: push, and test rate: 100 mm / min (V2). The slippage was measured based on the force (sliding resistance) required to push the formulation out of the syringe with the plunger rod, i.e., the plunger sliding force according to the United States Pharmacopoeia (USP). In this dispersion test, the sample was shaken after tapping. The sliding force was measured three times in each test, and the average of these three sliding force values ​​is shown in the table below as the average maximum sliding force (N) for each test.

[0167] [Table 5]

[0168]

[0169] [Table 6]

[0170]

[0171] Example 2A: Dispersion Test

[0172] Additional samples were subjected to dispersion tests according to the method described in Example 2. The dispersion test results for the shaken samples are shown in the table below. In this dispersion test, the samples were shaken and then tapped. The sliding force was measured three times in each test, and the average of the three sliding force values ​​is shown in the table below as the average maximum sliding force (N) for each test.

[0173] [Table 7]

[0174]

[0175] Example 3: Measurement of Sliding Signal

[0176] The slipperiness signals of several samples were measured. The measuring instrument and conditions were the same as those in Example 2.

[0177] The slip signal of the sample before the vibration procedure (transport simulation) is as follows Figure 3 As shown in .

[0178] The slippage signals of the samples subjected to the dispersion procedures 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 after the transport simulation are shown in FIG. Figure 4 、 5 , 6, 7 and 14. In these samples, the dispersion procedure was performed by shaking after tapping. Figure 15 The slipperiness signal of a sample subjected to a dispersion procedure of 10 seconds of shaking followed by 10 taps is shown in FIG.

[0179] The slippage signals of the samples subjected to the dispersion procedures of 5 taps and 0 s shaking, 10 taps and 0 s shaking, 15 taps and 0 s shaking, 0 taps and 5 s shaking, 0 taps and 10 s shaking or 0 taps and 15 s shaking after the transport simulation are shown in FIG. Figure 8 、 9 , 10, 11, 12 and 13.

[0180] For the samples after the transport simulation, the samples subjected to the dispersion procedures of 10 taps and 10-second shaking and 15 taps and 15-second shaking showed a maximum sliding force of 30 N or less.

[0181] Example 4: Transport Test

[0182] To confirm changes in slip properties after actual sample transport, the same formulation as in Example 1 was stored in 10 mL vials and transported by air between Japan and the United States (stored at 1°C to 15°C). Changes in slip properties were then measured. The results showed that, after this round trip, some samples, if not adequately tapped and shaken (dispersion procedure), may have resulted in insufficient release of the formulation contents.

[0183] All publications and patents mentioned herein are 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.

[0184] Claims or descriptions that include "or" or "and / or" between at least one member of a group are deemed satisfied if one, more than one, or all of the group members are present in, used in, or otherwise relevant to a given product or process, unless stated to the contrary or clear from the context to the contrary. The disclosure includes embodiments in which only one member of the group is present in, used in, or otherwise relevant to a given product or process. The disclosure includes embodiments in which more than one or all of the group members are present in, used in, or otherwise relevant to a given product or process.

[0185] Furthermore, the present disclosure encompasses all variations, combinations, and permutations in which at least one limitation, element, clause, or descriptive item from at least one of the listed claims is incorporated into another claim. For example, any claim that is dependent upon another claim can be amended to include at least one limitation present in any other claim that is dependent upon the same base claim. Where elements are presented in list form (e.g., in Markush group format), each subgroup of elements is also disclosed, and any element may be deleted from the group. It should be understood that, generally speaking, when the present disclosure or aspects of the present disclosure are referred to as comprising particular elements and / or features, embodiments of the present disclosure or aspects of the present disclosure consist of, or consist essentially of, those elements and / or features. For simplicity, those embodiments are not specifically described herein using the same terms. Where ranges are given, the endpoints are inclusive. Furthermore, unless otherwise indicated or obvious from the context and understanding of one skilled in the art, values ​​expressed as ranges may, in different embodiments of the present disclosure, be applied to any specific value or subrange within the stated range, to the nearest tenth of the unit of the lower limit of the range, unless the context clearly indicates otherwise.

[0186] 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. Such equivalents are intended to be encompassed by the claims.

[0187] [Industrial Applicability]

[0188] The dispersion procedure described herein allows for a more stable industrial supply of aripiprazole injection formulations.

Claims

1. A method for enhancing the slidability of a container of a long-acting injection preparation containing aripiprazole or a salt thereof, the method comprising: Dispersing the gel of the formulation in the container before administration to form a sol or suspension of the formulation, The long-term effect is about two months.

2. The method of claim 1, wherein the dispersing step comprises tapping the container at least 8 times and shaking the container for at least 8 seconds.

3. The method of claim 1, wherein the dispersing step comprises tapping the container at least 10 times and shaking the container for at least 10 seconds. 4 . The method according to claim 1 , wherein after the dispersing step, the sliding resistance of the container 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 of any one of claims 1 to 5, wherein the formulation is for intramuscular administration and is used to treat a subject suffering from schizophrenia or bipolar I disorder.

7. The method of any one of claims 1 to 6, wherein the formulation comprises aripiprazole in an amount ranging from about 700 mg to about 1000 mg.

8. The method of claim 7, wherein the container contains the formulation in an amount of 2.0 mL or more per single administration.

9. The method according to any one of claims 1 to 8, wherein the formulation is white to off-white and comprises: - 720 mg or 960 mg anhydrous aripiprazole, - sodium carboxymethyl cellulose, - polyethylene glycol 400, - sodium chloride, - sodium dihydrogen phosphate monohydrate, and - Sodium hydroxide.

10. The method of any one of claims 1 to 9, further comprising administering the formulation in the container to a subject in need thereof after dispersing.

11. A method of treating a subject suffering from schizophrenia or bipolar I disorder, the method comprising slowly administering to the subject the injectable formulation obtained by the method of any one of claims 1 to 10, wherein slowly is over about 0.5 seconds or longer.

12. A method for treating a subject suffering from schizophrenia or bipolar I disorder, the method comprising dispersing an injectable formulation of aripiprazole or a salt thereof in the form of a gel into a sol or suspension in a container, and administering the injectable formulation intramuscularly to the subject, wherein the subject administers the injectable formulation approximately once every two months.

13. The method of claim 12, wherein the dispersing step comprises tapping the container at least 8 times and shaking the container for at least 8 seconds.

14. The method according to claim 12 or 13, wherein after the dispersing step, the sliding resistance of the container 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 of any one of claims 12 to 15, wherein the administering is performed to the gluteal muscle of the subject.

17. The method of any one of claims 12 to 16, wherein the about bimonthly administration results in a total amount of aripiprazole administered to the subject in the range of about 700 mg to about 1000 mg.

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

19. The method of any one of claims 12 to 18, wherein the formulation is white to off-white and comprises: - 720 mg or 960 mg anhydrous aripiprazole, - sodium carboxymethyl cellulose, - polyethylene glycol 400, - sodium chloride, - sodium dihydrogen phosphate monohydrate, and - Sodium hydroxide.

20. The method of any one of claims 12 to 19, wherein the administering comprises slowly injecting the formulation for injection into the subject, and slowly is over about 0.5 seconds or more.

21. A long-acting injectable formulation for intramuscular administration for treating a subject with schizophrenia or bipolar I disorder, comprising aripiprazole or a salt thereof in a container, wherein the formulation is in the form of a gel under static conditions and reverts to a sol or suspension upon dispersion, and has a long-acting duration of about two months.

22. The formulation of claim 21, wherein the formulation comprises aripiprazole in a total amount ranging from about 700 mg to about 1000 mg.

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

24. The formulation according to any one of claims 21 to 23, wherein the formulation is white to off-white and comprises: - 720 mg or 960 mg anhydrous aripiprazole, - sodium carboxymethyl cellulose, - polyethylene glycol 400, - sodium chloride, - sodium dihydrogen phosphate monohydrate, and - Sodium hydroxide.

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