WO2013162048A1 - Injectable preparation - Google Patents

Injectable preparation Download PDF

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Publication number
WO2013162048A1
WO2013162048A1 PCT/JP2013/062683 JP2013062683W WO2013162048A1 WO 2013162048 A1 WO2013162048 A1 WO 2013162048A1 JP 2013062683 W JP2013062683 W JP 2013062683W WO 2013162048 A1 WO2013162048 A1 WO 2013162048A1
Authority
WO
WIPO (PCT)
Prior art keywords
salt
injectable preparation
aripiprazole
concentration
polyethylene glycol
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/JP2013/062683
Other languages
English (en)
French (fr)
Inventor
Daiki KANEKO
Takakuni Matsuda
Yusuke HOSHIKA
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Otsuka Pharmaceutical Co Ltd
Original Assignee
Otsuka Pharmaceutical Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=48614096&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=WO2013162048(A1) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Application filed by Otsuka Pharmaceutical Co Ltd filed Critical Otsuka Pharmaceutical Co Ltd
Priority to ES13728542T priority Critical patent/ES2743706T5/es
Priority to NZ630335A priority patent/NZ630335A/en
Priority to UAA201411954A priority patent/UA115444C2/uk
Priority to HK15107658.1A priority patent/HK1206988B/en
Priority to KR1020207015451A priority patent/KR102498075B1/ko
Priority to CA2869889A priority patent/CA2869889C/en
Priority to LTEP13728542.5T priority patent/LT2841054T/lt
Priority to CN201810143716.5A priority patent/CN108186556B/zh
Priority to MX2018010879A priority patent/MX387891B/es
Priority to EA201491685A priority patent/EA026619B1/ru
Priority to AU2013253374A priority patent/AU2013253374B2/en
Priority to BR112014026307-8A priority patent/BR112014026307B1/pt
Priority to CN202210169142.5A priority patent/CN114344259B/zh
Priority to JP2015506529A priority patent/JP6234996B2/ja
Priority to EP13728542.5A priority patent/EP2841054B2/en
Priority to DK13728542.5T priority patent/DK2841054T4/da
Priority to EP19169193.0A priority patent/EP3539534A1/en
Priority to PL13728542.5T priority patent/PL2841054T5/pl
Priority to MX2014012811A priority patent/MX359241B/es
Priority to HRP20191366TT priority patent/HRP20191366T4/hr
Priority to KR1020147032714A priority patent/KR102138852B1/ko
Priority to US14/396,380 priority patent/US20150093442A1/en
Priority to KR1020247015029A priority patent/KR20240068788A/ko
Priority to CN201380021440.9A priority patent/CN104470499B/zh
Priority to KR1020217029406A priority patent/KR20210116702A/ko
Priority to SI201331550T priority patent/SI2841054T2/sl
Priority to SG11201406451SA priority patent/SG11201406451SA/en
Publication of WO2013162048A1 publication Critical patent/WO2013162048A1/en
Priority to ZA2014/07335A priority patent/ZA201407335B/en
Priority to IL235299A priority patent/IL235299B/en
Priority to PH12014502379A priority patent/PH12014502379B1/en
Anticipated expiration legal-status Critical
Priority to US15/701,202 priority patent/US20180055941A1/en
Priority to AU2017228608A priority patent/AU2017228608C1/en
Priority to US16/156,958 priority patent/US10517951B2/en
Priority to AU2019200060A priority patent/AU2019200060A1/en
Priority to PH12019500498A priority patent/PH12019500498A1/en
Priority to US16/514,973 priority patent/US20190336607A1/en
Priority to CY20191100912T priority patent/CY1122252T1/el
Priority to US16/785,268 priority patent/US20200179517A1/en
Priority to AU2020204200A priority patent/AU2020204200B2/en
Priority to US17/108,939 priority patent/US11097007B2/en
Priority to US17/444,469 priority patent/US11638757B2/en
Priority to AU2022241491A priority patent/AU2022241491B2/en
Priority to US18/148,860 priority patent/US12016927B2/en
Priority to US18/662,049 priority patent/US20250121065A1/en
Priority to AU2025200229A priority patent/AU2025200229A1/en
Ceased legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A61K9/0024—Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue

Definitions

  • the present invention relates to an injectable preparation comprising a composition comprising a drug that is poorly soluble in a dispersion medium, such as aripiprazole or a salt thereof, a specific suspending agent, and a dispersion medium, and to a prefilled syringe containing the injectable preparation.
  • a dispersion medium such as aripiprazole or a salt thereof
  • a specific suspending agent such as a specific suspending agent
  • Aripiprazole used as an active ingredient of a pharmaceutical composition is a compound represented by the
  • a pharmaceutical composition comprising aripiprazole is known an atypical antipsychotic useful for the treatment of
  • a pharmaceutical composition comprising aripiprazole as an active ingredient is known to be used, for example, in the following form.
  • a cake-like composition which is prepared by suspending aripiprazole and a vehicle therefor in a dispersion medium and freeze-drying the suspension, is mixed with a desired dispersant (preferably water for injection) before use and resuspended, and the resuspension (injectable preparation) is intramuscularly or subcutaneously injected into a patient (see, for example, Patent Literature 1 and 2 ) .
  • Patent Literature (PTL) 1 and 2 requires a vial containing a cake-like composition, a container containing a dispersion medium, and a syringe for use at the time of
  • a pharmaceutical preparation that can simplify the structure of the medical instruments used and reduce size and weight and that is more convenient for use is desired.
  • a prefilled syringe produced by filling a suspension (injectable preparation) as is into a syringe can be considered.
  • a suspension containing, as an active ingredient, a drug that is poorly soluble in water as a dispersion medium hereinafter also referred to as a "poorly soluble drug”
  • aripiprazole or a salt thereof particles of the active ingredient precipitate over time, which results in caking and makes it difficult to redisperse the suspension.
  • An object of the present invention is to provide a highly storage-stable injectable preparation comprising a composition comprising a poorly soluble drug as an active ingredient and a dispersion medium. More specifically, an object of the present invention is to provide an injectable preparation that can easily provide a suspension in which an active
  • ingredient is well dispersed at the time of use (administration to a patient ) , without caking due to precipitation of a poorly soluble drug even after prolonged storage.
  • Another object of the present invention is to provide a more compact, lightweight prefilled syringe by filling a syringe with the above-mentioned injectable preparation. More preferably, an object of the present invention is to provide a more compact, lightweight prefilled syringe that allows administration of a suspension with low viscosity by simply pressing the plunger rod of the syringe to eject an injectable preparation through a syringe needle after gently shaking the syringe or without shaking.
  • the present inventors conducted extensive research. As a result, the inventors found that when an injectable preparation comprising a poorly soluble drug as an active ingredient further comprises a dispersion medium and a specific suspending agent (hereinafter also referred to as suspending agent A) , caking due to precipitation of the active ingredient is prevented even when stored for a long period of time after production (for example, until it is administered to a patient). The inventors conducted further research and accomplished the present invention.
  • suspending agent A a specific suspending agent
  • the present invention includes the subject matter presented in the following items.
  • Item 1 An injectable preparation comprising a composition comprising a poorly soluble drug, a dispersion medium, and a suspending agent,
  • the suspending agent being at least one member selected from the group consisting of (i) and (ii):
  • composition having a viscosity of 40 Pa's or more in at least one point in the shear rate range of 0.01 to 0.02 s "1 and having a viscosity of 0.2 Pa*s or less in at least one point in the shear rate range of 900 to 1,000 s "1 , as measured by a rheometer.
  • An injectable preparation comprising a composition
  • the suspending agent being at least one member selected from the group consisting of (i) and (ii):
  • composition having a viscosity of 40 Pa*s or more in at least one point in the shear rate range of 0.01 to 0.02 s "1 and having a viscosity of 0.2 Pa*s or less in at least one point in the shear rate range of 900 to 1,000 s "1 , as measured by a rheometer at 25°C.
  • Item 3 The injectable preparation according to Item 1 or 2 comprising a composition comprising at least water as a
  • Item 4 The injectable preparation according to any one of Items 1 to 3 wherein the poorly soluble drug is aripiprazole or a salt thereof, or 7- [4- (4-benzo[b]thiophen-4-yl-piperazin-l-yl)butoxy] - lH-quinolin-2-one or a salt thereof.
  • Item 4a The injectable preparation according to any one of Items 1 to 4 wherein the poorly soluble drug has a mean primary
  • a gel composition comprising
  • the poorly soluble drug has a mean primary particle diameter of 0.5 to 30 ⁇ and is contained in a concentration of 200 to 600 mg/mL.
  • aripiprazole or a salt thereof has a mean primary particle diameter of 0.5 to 30 ⁇ and is contained in a
  • Item 6 The composition according to Item 5, 5a, or 5b wherein (i) polyvinylpyrrolidone is contained as a suspending agent in a concentration of 0.1 to 100 mg/mL.
  • Item 7 The composition according to any one of Items 5 to 6 wherein (ii) polyethylene glycol and carboxymethyl cellulose or a salt thereof are contained as suspending agents,
  • the concentration of polyethylene glycol being 0.05 to 2 mg/mL, and the concentration of carboxymethyl cellulose or a salt thereof being 0.5 to 50 mg/mL.
  • Item 8 The composition according to any one of Items 5 to 7 wherein (i) polyvinylpyrrolidone and (ii) polyethylene glycol and carboxymethyl cellulose or a salt thereof are contained as suspending agents.
  • Item 8a The composition according to Items 5 or 6 wherein (i) polyvinylpyrrolidone and (ii) polyethylene glycol and
  • carboxymethyl cellulose or a salt thereof are contained as suspending agents, the concentration of polyethylene glycol being 0.05 to 100 mg/mL.
  • Item 9 The composition according to any one of Items 5 to 8 and 8a wherein the poorly soluble drug has a mean secondary particle diameter that is up to but not exceeding three times the mean primary particle diameter thereof.
  • Item 10 The composition according to any one of Items 5 to 9 which has a viscosity of 40 Pa-s or more in at least one point in the shear rate range of 0.01 to 0.02 s "1 and which has a viscosity of 0.2 Pa's or less in at least one point in the shear rate range of 900 to 1,000 s "1 , as measured by a rheometer.
  • Item 11 The composition according to any one of Items 5 to 9 which has a viscosity of 40 Pa*s or more in at least one point in the shear rate range of 0.01 to 0.02 s "1 and which has a viscosity of 0.2 Pa's or less in at least one point in the shear rate range of 900 to 1,000 s "1 , as measured by a rheometer at 25°C.
  • Item 12 An injectable preparation comprising the composition according to any one of Items 5 to 11.
  • Item 13 A method for producing a gel composition comprising aripiprazole or a salt thereof, or 7- [ 4- ( 4-benzo[b]thiophen-4-yl- piperazin-l-yl)butoxy] -lH-quinolin-2-one or a salt thereof, the method comprising
  • liquid mixture comprising aripiprazole or a salt thereof, or 7- [4- (4-benzo[b]thiophen-4-yl-piperazin-l-yl)butoxy] - lH-quinolin-2-one or a salt thereof in a concentration of 200 to 600 mg/mL, water, and at least one suspending agent selected from the group consisting of (i) and (ii):
  • aripiprazole or a salt thereof or the 7- [4- (4- benzo[b] thiophen-4-yl-piperazin-1-yl)butoxy] -IH-quinolin-2-one or a salt thereof having a mean primary particle diameter of 0.5 to 30 ⁇ .
  • Item 13a The method for producing a gel composition comprising aripiprazole or a salt thereof according to Item 13, the method comprising
  • liquid mixture comprising aripiprazole or a salt thereof in a concentration of 200 to 600 mg/mL, water, and at least one suspending agent selected from the group consisting of ( i) and ( ii) :
  • the aripiprazole or a salt thereof having a mean primary particle diameter of 0.5 to 30 ⁇ .
  • liquid mixture comprising 7- [4- ( 4-benzo[b]thiophen-4- yl-piperazin-l-yl)butoxy] -lH-quinolin-2-one or a salt thereof in a concentration of 200 to 600 mg/mL, water, and at least one suspending agent selected from the group consisting of (i) and (ii):
  • Item 14 The method according to Item 13 comprising pulverizing aripiprazole or a salt thereof, or 7-[4-(4-benzo[b]thiophen-4-yl- piperazin-l-yl)butoxy] -lH-quinolin-2-one or a salt thereof to a mean primary particle diameter of 0.5 to 30 ⁇ in a liquid mixture comprising the aripiprazole or a salt thereof, or the 7- [ 4- ( 4-benzo[b]thiophen-4-yl-piperazin-1-y1)butoxy] -1H-quinolin-2- one or a salt thereof in a concentration of 200 to 600 mg/mL, water, and at least one suspending agent selected from the group consisting of (i) and (ii):
  • Item 14a The method for producing a gel composition comprising aripiprazole or a salt thereof according to Item 14 comprising pulverizing aripiprazole or a salt thereof to a mean primary particle diameter of 0.5 to 30 ⁇ in a liquid mixture comprising the aripiprazole or a salt thereof in a concentration of 200 to 600 mg/mL, water, and at least one suspending agent selected from the group consisting of (i) and (ii):
  • Item 14b The method for producing a gel composition comprising 7- [4- (4-benzo[b]thiophen-4-yl-piperazin-l-yl)butoxy] -lH-quinolin- 2-one or a salt thereof according to Item 14 comprising
  • Item 15 The method according to Item 13, 13a, 13b, 14, 14a, or 14b wherein the liquid mixture comprises (i) polyvinylpyrrolidone in a concentration of 0.1 to 100 mg/mL.
  • Item 16 The method according to Item 13, 13a, 13b, 14, 14a, 14b, or 15 wherein the liquid mixture comprises (ii) polyethylene glycol and carboxymethyl cellulose or a salt thereof,
  • the concentration of polyethylene glycol being 0.05 to 2 mg/mL, and the concentration of carboxymethyl cellulose or a salt thereof being 0.5 to 50 mg/mL.
  • Item 17 The method according to any one of Items 13 to 16 wherein the liquid mixture comprises (i) polyvinylpyrrolidone and (ii) polyethylene glycol and carboxymethyl cellulose or a salt thereof .
  • Item 17a The method according to any one of Items 13 to 15 wherein the liquid mixture comprises (i) polyvinylpyrrolidone and (ii) polyethylene glycol and carboxymethyl cellulose or a salt thereof ,
  • Item 18 A gel composition comprising aripiprazole or a salt thereof, or 7- [4- (4-benzo[b]thiophen-4-yl-piperazin-l-yl)butoxy] - lH-quinolin-2-one or a salt thereof, the composition being obtained by the method according to any one of Items 13 to 17. (The above phrase "Items 13 to 17" also includes Items 13a, 13b, 14a, 14b and 17a.)
  • Item 19 A method for producing a prefilled syringe that is prefilled with a gel composition comprising aripiprazole or a salt thereof, or 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-l- yl)butoxy] -lH-quinolin-2-one or a salt thereof,
  • aripiprazole or a salt thereof, or the 7- [4- (4- benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy] -1H-quinolin-2-one or a salt thereof has a mean primary particle diameter of 0.5 to 30 ⁇ ;
  • Item 19a The method for producing a prefilled syringe that is prefilled with a gel composition comprising aripiprazole or a salt thereof according to Item 19,
  • a liquid mixture comprising aripiprazole or a salt thereof in a concentration of 200 to 600 mg/mL, water, and at least one suspending agent selected from the group
  • aripiprazole or a salt thereof has a mean primary particle diameter of 0.5 to 30 ⁇ ;
  • Item 19b The method for producing a prefilled syringe that is prefilled with a gel composition comprising 7- [4- (4- benzo[b]thiophen-4-y1-piperazin-1-y1)butoxy] -1H-quinolin-2-one or a salt thereof according to Item 19,
  • Item 20 The method according to Item 19 comprising:
  • Item 20a The method for producing a prefilled syringe that is prefilled with a gel composition comprising aripiprazole or a salt thereof according to Item 20,
  • Item 20b The method for producing a prefilled syringe that is prefilled with a gel composition comprising 7- [4- (4- benzo[b] thiophen-4-yl-piperazin-l-yl)butoxy] -lH-quinolin-2-one or a salt thereof according to Item 20,
  • Item 21 The method according to Item 19, 19a, 19b, 20, 20a, or 20b wherein the liquid mixture comprises (i) polyvinylpyrrolidone, the concentration of (i ) polyvinylpyrrolidone being 0.1 to 100 mg/mL.
  • Item 22 The method according to any one of Items 19 to 21
  • liquid mixture comprises (ii) polyethylene glycol and carboxymethyl cellulose or a salt thereof, the concentration of polyethylene glycol being 0.05 to 2 g/mL, and the concentration of carboxymethyl cellulose or a salt thereof being 0.5 to 50 mg/mL.
  • Item 23 The method according to any one of Items 19 to 22
  • liquid mixture comprises (i) polyvinylpyrrolidone and (ii) polyethylene glycol and carboxymethyl cellulose or a salt thereof .
  • Item 23a The method according to any one of Items 19 to 21 wherein the liquid mixture comprises (i) polyvinylpyrrolidone and (ii) polyethylene glycol and carboxymethyl cellulose or a salt thereof, the concentration of polyethylene glycol being 0.05 to 100 mg/mL.
  • Item 24 A prefilled syringe that is prefilled with a gel
  • composition comprising aripiprazole or a salt thereof, or 7- [4-
  • Item 25 A kit comprising the prefilled syringe according to Item 24.
  • a sustained release injectable preparation comprising a composition comprising
  • the poorly soluble drug has a mean primary particle diameter of 1 to 10 um and is contained in a concentration of 200 to 400 mg/mL ,
  • composition being in the form of a gel when allowed to stand, and changing to a sol when subjected to an impact, and the preparation being administered once per month.
  • Item 27 The injectable preparation according to Item 26 wherein the poorly soluble drug has a mean primary particle diameter of 2 to 7 um.
  • a sustained release injectable preparation comprising a composition comprising
  • the poorly soluble drug has a mean primary particle diameter of 4 to 30 um and is contained in a concentration of 300 to 600 mg/mL,
  • composition being in the form of a gel when allowed to stand, and changing to a sol when subjected to an impact, and the preparation being administered once every two or three months .
  • Item 29 The injectable preparation according to Item 28 wherein the poorly soluble drug has a mean primary particle diameter of 5 to 20 ⁇ .
  • Item 30 The injectable preparation according to any one of Items 26 to 29 wherein (i) polyvinylpyrrolidone is contained as a suspending agent in a concentration of 0.1 to 100 mg/mL.
  • Item 31 The injectable preparation according to any one of Items 26 to 30 wherein (ii) polyethylene glycol and carboxymethyl cellulose or a salt thereof are contained as suspending agents, the concentration of polyethylene glycol being 0.05 to 2 mg/mL, and the concentration of carboxymethyl cellulose or a salt thereof being 0.5 to 50 mg/mL.
  • Item 32 The injectable preparation according to any one of Items 26 to 31 wherein (i) polyvinylpyrrolidone and (ii) polyethylene glycol and carboxymethyl cellulose or a salt thereof are
  • Item 33 The injectable preparation according to any one of Items 26 to 32 wherein the poorly soluble drug has a mean secondary particle diameter that is up to but not exceeding three times the mean primary particle diameter thereof.
  • Item 34 The injectable preparation according to any one of Items 26 to 33 wherein the composition has a viscosity of 40 Pa's or more in at least one point in the shear rate range of 0.01 to 0.02 s "1 and a viscosity of 0.2 Pa*s or less in at least one point in the shear rate range of 900 to 1,000 s "1 , as measured by a rheometer.
  • Item 35 The injectable preparation according to any one of Items 26 to 33 wherein the composition has a viscosity of 40 Pa*s or more in at least one point in the shear rate range of 0.01 to 0.02 s "1 and a viscosity of 0.2 Pa*s or less in at least one point in the shear rate range of 900 to 1,000 s "1 , as measured by a rheometer at 25°C.
  • Item 36 A method for treating or preventing a recurrence of schizophrenia, bipolar disorder, or depression, the method comprising administering the injectable preparation according to any one of Items 1 to 4, 12, and 26 to 35.
  • Item 37 The method according to Item 36 wherein the injectable preparation is administered intramuscularly or subcutaneously.
  • suspending agent sustained release agent
  • dispersion medium a dispersion medium
  • Item A-2 The injectable preparation according to Item A-l, which has a viscosity of 1,000 mPa's or more upon standing and a
  • Item A-3 The injectable preparation according to Item A-l or A-2, which has a viscosity of 5,000 mPa's or more upon standing and a viscosity of 300 mPa's or less upon shaking or ejection thereof through a syringe needle.
  • Items A-l to A-3 which has a viscosity of 10,000 mPa # s or more upon standing and a viscosity of 300 mPa's or less upon shaking or ejection thereof through a syringe needle.
  • Item A-5 The injectable preparation according to Item A-l or A-2, which has a viscosity of 1,000 mPa's or more upon standing and a viscosity of 200 mPa*s or less upon shaking or ejection thereof through a syringe needle.
  • Item A-6 The injectable preparation according to Item A-l, A-2, A-3, or A-5, which has a viscosity of 5,000 mPa*s or more upon standing and a viscosity of 200 mPa*s or less upon shaking or ejection thereof through a syringe needle.
  • Items A-l to A-6 which has a viscosity of 10,000 mPa's or more upon standing and a viscosity of 200 mPa's or less upon shaking or ejection thereof through a syringe needle.
  • Items A-l to A-7 which contains the poorly soluble drug in a concentration of 100 to 500 mg/mL.
  • Item A-9 The injectable preparation according to any one of Items A-l to A-8, which contains the poorly soluble drug in a concentration of 200 to 480 mg/mL.
  • Item A-10 The injectable preparation according to any one of Items A-l to A-9, which contains the poorly soluble drug in a concentration of 250 to 450 mg/mL.
  • Item A-11 The injectable preparation according to any one of Items A-l to A-10, which contains the poorly soluble drug in a concentration of about 300 mg/mL or more and becomes a gel upon standing, the gel composition becoming a fluid sol upon stirring, shaking, external shock, or the like.
  • Item A-12 The injectable preparation according to any one of Items A-l to A-11, wherein the poorly soluble drug has a mean primary particle diameter of about 0.5 to 30 ⁇ .
  • Item A-13 The injectable preparation according to any one of Items A-l to A-12, wherein the poorly soluble drug has a mean primary particle diameter of about 1.0 to 10 ⁇ .
  • Item A-14 The injectable preparation according to any one of Items A-l to A-13, wherein the poorly soluble drug has a mean primary particle diameter of about 1.0 to 5 ⁇ .
  • Item A-15 The injectable preparation according to any one of Items A-l to A-14, wherein the poorly soluble drug is
  • aripiprazole or a salt thereof the preparation comprising a composition comprising a dispersion medium and at least one suspending agent selected from the group consisting of
  • Item A-16 The injectable preparation according to Item A-15, wherein the poorly soluble drug is aripiprazole monohydrate.
  • Item A-17 The injectable preparation according to Item A-15 or A-16, wherein the poorly soluble drug is aripiprazole or a salt thereof, the preparation being storage-stable and comprising a composition comprising sodium carboxymethyl cellulose, a
  • dispersion medium and at least one suspending agent selected from the group consisting of polyvinylpyrrolidone and
  • Item A-18 A prefilled syringe comprising the injectable preparation according to any one of Items A-l to A-17.
  • the injectable preparation of the present invention has excellent storage stability with no caking caused by
  • the injectable preparation of the present invention becomes a gel upon standing, precipitation and caking of the particles of the poorly soluble drug can be inhibited, thereby providing excellent storage stability. Furthermore, because ( ⁇ ) the injectable preparation of the present invention even in the form of a gel can easily gain fluidity when subjected to a mild impact, the preparation can be easily injected at the time of use (at the time of injection). In particular, because the gelled injectable preparation (gel composition) gains fluidity (forms a sol state) by simply
  • the preparation can be smoothly ejected through the needle as is. Therefore, the preparation can be well dispersed intramuscularly or subcutaneously with relatively less local disturbance and pain at the time of injection.
  • the injectable preparation of the present invention has excellent storage stability. This allows the injectable preparation to be filled as is into a syringe to prepare a prefilled syringe, thus providing a medical instrument with reduced size and weight.
  • Fig. 1 shows a photograph of the injectable preparation obtained in Example 1 immediately after production.
  • Fig. 2 shows a photograph of the injectable preparation obtained in Example 1, which was slowly tilted after standing for a certain period.
  • Fig. 3 shows a photograph of the injectable preparation obtained in Example 1 having stood for a certain period, after which the container was tapped and tilted.
  • Fig. 4a shows photographs of the injectable
  • Fig. 4b shows photographs of the injectable
  • Fig. 4c shows photographs of the injectable
  • Fig. 5a shows the viscosities of the injectable preparations of Production Examples Al to A6 measured using a rheometer (measuring temperature: 5°C).
  • Fig. 5b shows the viscosities of the injectable preparations of Production Examples Al to A6 measured using a rheometer (measuring temperature: 25° C).
  • Fig. 5c shows the viscosities of the injectable preparations of Production Examples Al to A6 measured using a rheometer (measuring temperature: 40° C).
  • Fig. 6 shows the viscosities of the injectable preparation of Production Example B measured using a rheometer at 5°C, 25° C, or 40° C.
  • Fig. 7 shows the viscosities of the injectable preparation of Production Example C measured using a rheometer at 5°C, 25° C, or 40° C.
  • Fig. 8 shows the viscosities of the injectable preparation of Production Example D measured using a rheometer at 5 e C, 25° C, or 40° C.
  • Fig. 9a shows the viscosities of the injectable preparation of Production Example E measured using a rheometer at 5°C, 25° C, or 40° C.
  • 5d, 25d and 40d respectively indicate the measuring temperatures at 5°C, 25° C, and 40° C.
  • Fig. 9b shows the injectable preparation of Production Example E stored in a still condition at 5°C, 25° C, or 40° C for five days.
  • Fig. 9c shows the injectable preparation of Production
  • Example E stored in a still condition at 5°C, 25° C, or 40° C for five days (i.e., each shown in Fig. 9b), after which the
  • Fig. 10a shows the viscosities of the injectable preparations of Production Example Fl (Povidone K17, 0.1 mg/mL) and Production Example F2 (Povidone K17, 4 mg/mL) measured using a rheometer at 5° C or 25° C.
  • 5d and 25d indicate the measuring temperatures at 5° C and 25° C, respectively.
  • Fig. 10b shows the injectable preparations of
  • Example F2 (Povidone K17, 4 mg/mL) stored in a still condition at 5°C, 25" C, or 40° C for five days.
  • Fig. 10c shows the injectable preparations of
  • Production Example Fl (Povidone K17, 0.1 mg/mL) and Production Example F2 (Povidone K17, 4 mg/mL) stored in a still condition at 5°C, 25° C, or 40° C for five days (i.e., each shown in Fig. 10b), after which the container was slowly tilted and laid horizontally.
  • Fig. 11 shows the injectable preparations of Production Example G (containing 400 mg/mL of ethyl 4-aminobenzoate) ,
  • Production Example I (containing 300 mg/mL of cilostazol) each stored in a transparent container and allowed to stand at 5° C, 25° C, or 40° C for five days, after which the container was slowly tilted and laid horizontally.
  • Fig. 12 shows the viscosities of the injectable preparation of Production Example G measured using a rheometer at 5°C, 25° C, or 40° C.
  • Fig. 13 shows the viscosities of the injectable preparation of Production Example H measured using a rheometer at 5°C, 25° C, or 40° C.
  • Fig. 14 shows the viscosities of the injectable preparation of Production Example I measured using a rheometer at 5°C, 25° C, or 40° C.
  • Fig. 15 shows the viscosities of the injectable preparation of Production Example J measured using a rheometer at 5°C, 25° C, or 40° C.
  • 5d, 25d and 40d indicate the measuring temperatures at 5°C, 25° C, and 40° C, respectively.
  • Fig. 16 is a graph showing the mean serum
  • Fig. 17 shows the viscosities of the injectable preparations of Production Examples A3 to A6 measured after being allowed to stand at 40° C for five minutes in a rheometer and returned to 25°C.
  • Fig. 18 shows the viscosities of the injectable preparations of Production Examples B and C measured after being allowed to stand at 40° C for five minutes in a rheometer and returned to 25° C. Fig. 18 also shows the viscosities measured in Test Example 2 at 5° C or 25° C.
  • Fig. 19a shows the viscosities of the injectable preparations of Production Example E and Production Example E' measured after being allowed to stand at 40° C for five minutes in a rheometer and returned to 25° C.
  • Fig. 19a also shows the viscosities of the injectable preparation of Production Example E' measured at 5° C or 25° C in the same manner as in Test Example 3.
  • Fig. 19a further shows the viscosities of the injectable preparation of Production Example E measured at 5" C or 25° C in Test Example 3.
  • Fig. 19a shows the viscosities of the injectable preparations of Production Example E measured after being allowed to stand at 40° C for five minutes in a rheometer and returned to 25° C.
  • Fig. 19a also shows the viscosities of the injectable preparation of Production Example E' measured at 5° C or 25° C in the same manner as in Test Example 3.
  • Fig. 19a further shows the viscosities of the injectable preparation of Production Example E measured at 5" C or 25°
  • 19b shows the injectable preparation of Production Example E' (Povidone K17, 4 mg/mL) stored in a still condition at 5°C, 25° C, or 40° C for five days, after which the container was slowly tilted and laid horizontally. Only the injectable
  • Fig. 20a shows the viscosities of the injectable preparations of Production Example Ml and Production Example M2 measured using a rheometer at 5°C, 25° C, or 40° C.
  • Fig. 20b shows the injectable preparations of Production Example Ml and Production Example M2 stored in a still condition at 5°C, 25° C, or 40° C for five days, after which the container was slowly tilted and laid horizontally.
  • the injectable preparation of the present invention comprises a composition comprising a poorly soluble drug, a specific suspending agent (suspending agent (A)), and a
  • an explanation regarding the injectable preparation of the present invention is equivalent to an explanation regarding the composition.
  • the injectable preparation of the present invention comprises a certain component, it means that the injectable preparation of the present invention
  • the "poorly soluble drug” as used herein refers to a drug that is poorly soluble in water, and corresponds to "very slightly soluble” or "hardly soluble” drugs according to The Japanese Pharmacopoeia Sixteenth Edition. Specifically, after a drug is placed in water (a drug, if in the form of a solid, is pulverized and then placed in water) and vigorously shaken at
  • the poorly soluble drug contained in the injectable preparation of the present invention includes, for example, aripiprazole or a salt thereof.
  • Other examples of poorly soluble drugs include 7- [4- (4-benzo[b] thiophen-4-yl-piperazin-l- ylbutoxy) -lH-quinolin-2-one (hereinafter also referred to as
  • “brexpiprazole” or a salt thereof.
  • Other examples thereof include rebamipide, cilostazol, probucol, ethyl 4-aminobenzoate, and the like.
  • Such compounds may be in the form of a salt.
  • Aripiprazole or a salt thereof, or 7-[4-(4-benzo[b]thiophen-4-yl- piperazin-l-yl)butoxy] -lH-quinolin-2-one or a salt thereof are particularly preferable .
  • the salt is not particularly limited insofar as it is a
  • pharmaceutically acceptable salt examples thereof include alkali metal salts (e.g., sodium salts and potassium salts); alkaline earth metal salts (e.g., calcium salts and magnesium salts), and like metal salts; ammonium salts; alkali metal carbonates (e.g., lithium carbonate, potassium carbonate, sodium carbonate, and cesium carbonate); alkali metal hydrogen carbonates (e.g.,
  • lithium hydrogen carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate sodium hydrogen carbonate, potassium hydrogen carbonate
  • alkali metal hydroxides e.g., lithium hydroxide, sodium hydroxide, potassium hydroxide, and cesium hydroxide
  • salts of inorganic bases e.g., lithium hydroxide, sodium hydroxide, potassium hydroxide, and cesium hydroxide
  • tri(lower)alkylamines e.g., trimethylamine, triethylamine, and N-ethyldiisopropylamine
  • pyridine e.g., pyridine, quinoline, piperidine,
  • N- (lower)alkyl-morpholines e.g. , N-methylmorpholine
  • DABCO 4-diazabicyclo[2.2.2]octane
  • organic bases hydrochloride, hydrobromate, hydroiodide, sulfate, nitrate, phosphate, and like salts of inorganic acids
  • (lower) alkyl refers to an "alkyl having 1 to 6 carbon atoms .
  • the crystalline form of aripiprazole or a salt thereof is not particularly limited.
  • Aripiprazole or a salt thereof may be in a monohydrate form (aripiprazole hydrate A) or in various anhydrous forms, which are known to exist in the form of anhydrous crystal B, anhydrous crystal C, anhydrous crystal D, anhydrous crystal E, anhydrous crystal F, and anhydrous crystal G. All of these crystalline forms may be used as aripiprazole or a salt thereof in the injectable preparation of the present
  • a monohydrate form is preferable.
  • Such poorly soluble drugs are known compounds, and can be easily manufactured by known methods, or commercially
  • the injectable preparation of the present invention preferably comprises at least water as a dispersion medium.
  • Water, or an aqueous solvent comprising water and an organic solvent can be preferably used as a dispersion medium comprising at least water.
  • Usable organic solvents are those that are miscible with water, such as methanol, ethanol, propanol, isopropanol, and like alcohols; acetone and like ketones; tetrahydrofuran and like ethers; dimethylformamide; and mixtures thereof.
  • alcohols are preferable and ethanol is particularly preferable.
  • the amount of water in the aqueous solvent is preferably, for example, about 50 wt.% or more.
  • the dispersion medium water is preferable, and sterile water for injection is particularly preferable.
  • the specific suspending agent (suspending agent A) contained in the injectable preparation of the present invention comprises at least one suspending agent selected from the group consisting of (i) and (ii):
  • polyvinylpyrrolidone and (ii) polyethylene glycol and carboxymethyl cellulose or a salt thereof .
  • the polyvinylpyrrolidone for use preferably has a K value (Fikentscher K value) of about 10 to 90, more preferably about 12 to 30, and even more preferably about 12 to 20.
  • the polyvinylpyrrolidone for use preferably has an average molecular weight of about 2,000 to 700,000, more preferably about 2,000 to 40,000, and even more preferably about 2,000 to 10,000.
  • polyvinylpyrrolidones examples include povidone K12, povidone K17, povidone K25, povidone K30, and the like. Povidone K17 is the most preferable. Such various polyvinylpyrrolidones can be used singly or in a combination of two or more.
  • Polyethylene glycols (macrogols) for use as suspending agent A preferably have an average molecular weight of about 100 to 10,000, more preferably about 150 to 8,000, and even more preferably about 200 to 5,000.
  • the use of a polyethylene glycol having an average molecular weight within the aforementioned ranges can inhibit caking due to precipitation of particles and provide an injectable preparation with excellent storage
  • polyethylene glycols examples include commercially available polyethylene glycol 200, polyethylene glycol 300, polyethylene glycol 400, polyethylene glycol 600, polyethylene glycol 4000, polyethylene glycol 6000, polyethylene glycol 8000, and the like.
  • Polyethylene glycol 400 is the most preferable.
  • Such polyethylene glycols can be used singly or in a combination of two or more.
  • carboxymethyl cellulose or a salt thereof examples include carboxymethylcellulose and salts of
  • carboxymethylcellulose preferably such as alkali metal salts of carboxymethylcellulose and ammonium salts of carboxymethylcellulose. Specific examples thereof include sodium carboxymethylcellulose, potassium carboxymethylcellulose, lithium carboxymethylcellulose, ammonium carboxymethylcellulose, and the like. Among these, carboxymethylcellulose and sodium
  • carboxymethylcellulose are preferable and sodium
  • carboxymethylcellulose is particularly preferable.
  • carboxymethylcellulose or salts thereof can be used singly or in a combination of two or more.
  • the injectable preparation of the present invention When allowed to stand for some time after production, the injectable preparation of the present invention has a high viscosity and loses fluidity (i.e., gels). However, having once gelled, the injectable preparation regains fluidity when
  • the injectable preparation of the present invention is considered to exhibit structural viscosity.
  • Structural viscosity is a type of non-Newtonian flow and refers to the following property: as an increasing shear stress is applied, weaker bonds in the internal structure of the liquid are broken and apparent viscosity decreases, so that the flow behavior becomes closer to Newtonian flow.
  • the injectable preparation When such a fluid injectable preparation is allowed to stand again for some time, it returns to a gel state; upon mild impact (e.g., stirring, shaking, etc.), the gelled injectable preparation becomes fluid; and when allowed to stand again, the preparation becomes a gel.
  • the injectable preparation is considered to exhibit a thixotropic property (thixotropy) .
  • the rheometer is an advanced viscometer that can use various
  • a preparation of the present invention is measured by a rheometer while gradually increasing the shear rate, the viscosity tends to gradually lower.
  • a rotary rheometer is preferably used as the rheometer.
  • Such rheometers include, for example. Discovery Hybrid Rheometer-2- (DHR-2) and Discovery Hybrid Rheometer-3 (DHR-3) (manufactured by TA Instruments).
  • the injectable preparation of the present invention even in the form of a gel can easily gain fluidity when subjected to a mild impact, the preparation can be easily injected at the time of use (at the time of injection) .
  • the gelled injectable preparation gains fluidity (forms a sol state) by simply
  • the preparation can be smoothly ejected through the needle as is. Therefore, the preparation can be well dispersed intramuscularly or subcutaneously with relatively less local disturbance and pain at the time of injection.
  • the measured viscosity value is preferably about 40 to 20,000 Pa*s, more preferably about 50 to 10,000 Pa*s, even more preferably about 75 to 5,000 Pa*s, and particularly preferably about 100 to 3,000 Pa*s, in at least one point in the shear rate range of 0.01 to 0.02 s "1 . Further, in the shear rate range of 0.01 to 0.02 s "1 , the shear rate range of 0.01 to 0.02 s "1 , the shear rate range of 0.01 to 0.02 s "1 .
  • viscosity is preferably about 40 Pa's or more (particularly about 100 Pa's or more), more preferably about 40 to 20,000 Pa*s, even more preferably about 50 to about 10,000 Pa's, still more
  • the preparation exhibits a viscosity of 0.2 Pa's or less in at least one point in the shear rate range of 900 to 1,000 s "1 , as measured by a rheometer.
  • a viscosity of about 0.2 Pa's or less in at least one point in the shear rate range of 900 to 1,000 s "1 indicates that the injectable preparation being measured has acquired fluidity and is in the form of a sol.
  • the measured viscosity value is preferably about 0.1 Pa's or less, and more preferably about 0.05 Pa's or less in at least one point in the shear rate range of 900 to 1,000 s "1 .
  • the viscosity is preferably about 0.2 Pa*s or less, more preferably about 0.1 Pa's or less, and even more preferably about 0.05 Pa*s or less.
  • the injectable preparation is gelled or not (i.e., whether the preparation provides the above effect (a) or not) can be confirmed particularly by whether or not the
  • preparation being measured has lost fluidity and is in the form of a gel.
  • having a viscosity of about 100 Pa's or more in the shear rate range of 0.01 to 0.02 s "1 indicates that the injectable preparation being measured has surely lost
  • the measured viscosity value is preferably about 40 to 20,000 Pa's, more preferably about 50 to 10,000 Pa's, even more preferably about 75 to 5,000 Pa*s, and particularly preferably about 100 to 3,000 Pa*s, in at least one point in the shear rate range of 0.01 to 0.02 s "1 .
  • viscosity is preferably about 40 Pa*s or more (particularly about 100 Pa*s or more), more preferably about 40 to 20,000 Pa*s, even more preferably about 50 to about 10,000 Pa*s, still more preferably about 75 to 5,000 Pa*s, and particularly preferably about 100 to 3,000 Pa*s.
  • the injectable preparation provides the above effect ( ⁇ ) or not can be confirmed particularly by whether or not the preparation exhibits a viscosity of 0.2 Pa*s or less in at least one point in the shear rate range of 900 to 1,000 s "1 , as measured by a rheometer at 25°C.
  • having a viscosity of about 0.2 Pa's or less in the shear rate range of 900 to 1,000 s '1 indicates that the injectable preparation being measured has acquired fluidity and is in the form of a sol.
  • the measured viscosity value is preferably about 0.1 Pa*s or less, and more preferably about 0.05 Pa's or less in at least one point in the shear rate range of 900 to 1,000 s "1 .
  • the viscosity is preferably about 0.2 Pa*s or less, more preferably about 0.1 Pa*s or less, and even more preferably about 0.05 Pa*s or less.
  • the viscosity measurement in these shear rate ranges (0.01 to 0.02 s “1 and 900 to 1,000 s “1 ) is preferably performed by sequentially measuring the viscosity while starting at the lowest shear rate and gradually increasing the shear rate.
  • the viscosity is sequentially measured in the shear rate range of 0.001 to 1,000 s "1 using a rheometer.
  • having a viscosity of 40 Pa*s or more in the shear rate range of 0.01 to 0.02 s "1 means that the entire graph in the shear rate range of 0.01 ⁇ x ⁇ 0.02 satisfies y ⁇ 40.
  • having a viscosity of 0.2 Pa*s or less in at least one point in the shear rate range of 900 to 1,000 s "1 means that at least a part of the graph in the shear rate range of 900 ⁇ x ⁇ 1,000 satisfies y ⁇ 0.2.
  • having a viscosity of 0.2 Pa*s or less in the shear rate range of 900 to 1,000 s "1 means that the entire graph in the shear rate range of 900 ⁇ x ⁇ 1,000
  • the rheometer for example, the Discovery Hybrid Rheometer-2 (DHR-2) or Discovery Hybrid Rheometer-3 (DHR-3) (produced by TA Instruments) can be used.
  • DHR-2 Discovery Hybrid Rheometer-2
  • DHR-3 Discovery Hybrid Rheometer-3
  • the injectable preparation of the present invention can provide the above effects (a) and ( ⁇ ). More specifically, although a very wide variety of suspending agents for poorly soluble drugs are known, most of the suspending agents fail to provide a composition that can produce the above effects (a) and ( ⁇ ) ; the above suspending agent A is highly suitable for obtaining an injectable preparation that has the above effects (a) and ( ⁇ ). Accordingly, the injectable preparation of the present invention can be obtained by preparing a suspension using a poorly soluble drug and a dispersion medium in combination with suspending agent A, measuring the viscosity, and selecting the suspension that satisfies the above conditions.
  • the poorly soluble drug contained in the injectable preparation of the present invention typically has a mean primary particle diameter of about 0.5 to 100 ⁇ , preferably about 0.5 to 50 ⁇ , more preferably about 0.5 to 30 ⁇ , even more preferably about 1 to 20 ⁇ , still even more preferably about 1 to 10 ⁇ , yet more preferably about 1 to 5 ⁇ , and particularly preferably about 2 to 5 (rai.
  • the mean secondary particle diameter of the poorly soluble drug is preferably up to but not exceeding three times, and more preferably up to but not exceeding twice, the mean primary particle diameter thereof.
  • primary particle diameter refers to the diameter of individual particles that are not aggregated but are separate from each other.
  • Measuren primary particle diameter is calculated from the volume mean diameter calculated from a mean primary particle size distribution measured by a laser
  • the mean primary particle diameter is measured while circulating the injectable preparation in a water medium with ultrasonic
  • the secondary particle diameter refers to the diameter of particles that are aggregated.
  • “Mean secondary particle diameter” is calculated from the volume mean diameter calculated from a mean secondary particle size distribution measured by a laser diffraction scattering method. In the present invention, the mean secondary particle diameter is measured while circulating the injectable preparation in a water medium without ultrasonic irradiation.
  • the SALD-3000J (manufactured by Shimadzu Corporation) can be used to measure the mean particle diameter by the laser diffraction scattering method.
  • the mean secondary particle diameter is not smaller than the mean primary particle diameter (excluding the
  • Injectable preparations comprising a poorly soluble drug whose mean primary particle diameter and mean secondary particle diameter are almost the same (i.e., whose particles hardly aggregate) are also included within the scope of the injectable preparation of the present invention.
  • Preferable are poorly soluble drugs that have a mean secondary particle diameter that is larger than the mean primary particle diameter thereof unless a specific operation (an operation for pulverizing secondary particles into primary particles) such as ultrasonic irradiation is performed.
  • the mean primary particle diameter of the poorly soluble drug is set to 1 Mm or more and used as an injection, long-term sustained release properties can be advantageously obtained.
  • the mean primary particle diameter of the poorly soluble drug is preferably set to about 100 ⁇ or less, more preferably about 50 ⁇ or less, even more preferably about 30 ⁇ or less, still more preferably 10 ⁇ or less, and particularly preferably about 2 to 5 ⁇ , because it inhibits the precipitation of the poorly soluble drug during the production of the
  • composition of the present invention or during the period from the production thereof until administration to a patient, and also prevents clogging of the syringe needle at the time of injection.
  • a wet milling process is preferably used as a method for preparing a poorly soluble drug having the above-mentioned mean primary particle diameter.
  • the wet milling process is preferably wet ball milling, high-pressure homogenization, high-shear homogenization, or the like.
  • other low- and high-energy mills such as roller mills can also be employed.
  • Controlled crystallization, etc . can be mentioned as other usable methods.
  • an impinging jet crystallization method for which a patent application has been filed by Bristol-Myers Squibb Corp.
  • a wet milling process using a high-pressure homogenizer for which a patent application has been filed by Otsuka Pharmaceutical Co., Ltd.
  • the wet milling process (in particular, a two-step wet milling process) using a high-pressure homogenizer for which a patent application has been filed by Otsuka Pharmaceutical Co., Ltd. is more preferable.
  • the injectable preparation of the present invention preferably contains the poorly soluble drug in a concentration of about 200 to 600 mg/niL, more preferably about 200 to 500 mg/mL, even more preferably about 200 to 480 mg/mL, and still more preferably about 250 to 450 mg/mL.
  • the injectable preparation comprising the above suspending agent A and a poorly soluble drug that meets the aforementioned mean particle diameter and concentration
  • the concentration of suspending agent A (the above suspending agent (i) or (ii)) in the injectable preparation of the present invention is preferably about 0.05 to 150 mg/mL, more preferably about 0.1 to 100 mg/mL, and still more preferably about 0.2 to 50 mg/mL.
  • the injectable preparation of the present invention comprises the above suspending agents (i) and (ii) as suspending agent A
  • the total concentration thereof is preferably about 0.05 to 150 mg/mL, more preferably about 0.1 to about 100 mg/mL, and further preferably about 0.2 to 50 mg/mL.
  • the injectable preparation of the present invention may further contain a suspending agent other than suspending agent A (hereinafter also referred to as
  • sustained agent B a buffer, a pH adjuster, an excipient, a lubricant, a plasticizer, a disintegrator, a binder, a surfactant, a preservative, a flavoring agent, a perfuming agent, a tonicity agent, and like additives.
  • the additives disclosed in JP2007-509148A may be used as such additives.
  • suspending agent B examples include various polymers, low molecular weight oligomers, natural products, and surfactants (including nonionic and ionic surfactants). Specific examples thereof include cetyl pyridinium chloride, gelatin, casein, lecithin (phosphatides), dextran, glycerol, gum acacia,
  • phospholipids such as dimyristoyl phosphatidyl glycerol and dioctylsulfosuccinate (DOSS); Tetronic 1508 (registered
  • T-1508 (BASF Wyandotte Corporation), dialkylesters of sodium sulfosuccinic acid (e.g.. Aerosol OT (registered trademark) , which is a dioctyl ester of sodium sulfosuccinic acid (American Cyanamid) ) ; Duponol P (registered trademark), which is sodium lauryl sulfate (DuPont); Tritons X-200 (registered trademark), which is an alkyl aryl polyether sulfonate (Rohm and Haas); erodestas F-110 (registered trademark), which is a mixture of sucrose stearate and sucrose distearate (Croda Inc.); p- isononylphenoxypoly- (glycidol) , also known as Olin-lOG
  • suspending agents B are known pharmaceutical excipients, and are described in detail in the Handbook of
  • suspending agents B are commercially available or can be prepared by techniques known in the art.
  • the concentration of suspending agent B is preferably about 0.1 to 50 mg/mL, more preferably about 0.1 to 20 mg/mL, and more preferably about 0.3 to 15 mg/mL.
  • polyethylene glycol is preferably used in admixture therewith.
  • concentration of polyvinylpyrrolidone is preferably about 0.1 mg/mL or more, and more preferably about 0.1 to 100 mg/mL, whereas the concentration of polyethylene glycol is preferably about 0.05 to 100 mg/mL, and more preferably about 0.1 to 50 mg/mL.
  • concentration of polyethylene glycol 400 is used as a polyethylene glycol, the concentration of polyethylene glycol 400 is
  • polyethylene glycol 4000 preferably about 0.1 to 100 mg/mL, more preferably about 0.1 to 10 mg/mL, and even more preferably about 0.5 to 5 mg/mL.
  • concentration of polyethylene glycol 4000 is preferably about 0.1 to 40 mg/mL.
  • the concentration of polyethylene glycol is preferably about 0.05 to 2 mg/mL, and more preferably about 0.1 to 1 mg/mL .
  • carboxymethyl cellulose or a salt thereof When carboxymethyl cellulose or a salt thereof is used in admixture with (i) polyvinylpyrrolidone or (ii) polyethylene glycol and carboxymethyl cellulose or a salt thereof are used as suspending agents A, the concentration of carboxymethyl cellulose or a salt thereof is preferably about 0.5 to 50 mg/mL, more preferably 1 to 30 mg/mL, and even more preferably 2 to 20 mg/mL.
  • the dispersion medium is incorporated in an amount suitable for the poorly soluble drug content to fall within the above-mentioned range.
  • the dispersion medium is added in such an amount as to make a final injectable preparation volume of about 0.2 to 5.0 mL, more specifically about 0.4 to 3.0 mL, and even more preferably about 0.5 to 2.0 mL.
  • composition injectable preparation
  • dispersion medium When the composition (injectable preparation) produced using the poorly soluble drug, the dispersion medium, and
  • the resulting preparation can be preferably used as the injectable preparation of the present invention.
  • the injectable preparation gelled in such a manner meets the above conditions, and, in particular, has a viscosity of 40 Pa # s or more in at least one point in the shear rate range of 0.01 to 0.02 s "1 and has a viscosity of 0.2 Pa # s or less in at least one point in the shear rate range of 900 to 1,000 s "1 , as measured by a rheometer at 25°C
  • the preparation can be suitably used as the injectable preparation of the present invention.
  • the aging is performed by heating, for example, at about 30°C or higher (preferably about 30°C to 70°C, more
  • the standing temperature is preferably about 5°C to 70°C, more preferably about 20°C to 70°C, and even more preferably about 25°C to 65°C.
  • the standing time depends on the amount of the injectable preparation to be gelled and the standing temperature, and may be any length of time as long as it is not less than the time required to gel the preparation.
  • the standing time is preferably 5 minutes or more, more preferably 10 minutes or more, even more preferably 30 minutes or more, and still more preferably 1 hour or more.
  • a preferable standing time is 4 hours or more, more
  • the standing time may be, for example, about several days (2, 3 , 4 , or 5 days ) .
  • aging can be incorporated during standing (preferably at the beginning of standing).
  • the injectable preparation of the present invention may contain a tonicity agent.
  • the tonicity agent include, but are not limited to, sodium chloride, potassium chloride, mannitol, glycerol, sorbitol, glucose, xylitol, trehalose, maltose, maltitol, and the like.
  • Such tonicity agents can be used singly or in a combination of two or more.
  • Sodium chloride is more preferable.
  • Such a tonicity agent is added in an amount to render the composition isotonic.
  • the buffer is used to adjust the pH of the suspension to about 6 to 8, and preferably about 7.
  • the concentration of the buffer can be suitably set according to the type of buffer.
  • the concentration of the buffer is preferably about 0.02 to 2 mg/mL, and more preferably about 0.03 to 1 mg/mL.
  • buffers include, but are not limited to, sodium phosphate, monosodium hydrogen phosphate, disodium hydrogen phosphate, potassium phosphate, hydrates thereof, TRIS buffer, and the like. Such buffers can be used singly or as a mixture of two or more.
  • Such buffers can be used singly or as a mixture of two or more.
  • monosodium hydrogen phosphate, disodium hydrogen phosphate, and hydrates thereof are preferable.
  • the pH adjuster is used in an amount to adjust the aqueous suspension of the poorly soluble drug to a pH of about 6 to 7.5, and preferably about 7.
  • An acid or a base is used depending on the pH of the injectable preparation of the present invention.
  • an acidic pH adjuster such as hydrochloric acid or acetic acid
  • Hydrochloric acid is preferably used.
  • a basic pH adjuster such as sodium hydroxide, potassium hydroxide, calcium carbonate, magnesium oxide, or magnesium hydroxide, can be used.
  • Sodium hydroxide is preferably used.
  • pH adjusters can be used singly or in a combination of two or more.
  • the injectable preparation is prepared by mixing a poorly soluble drug, suspending agent A, and a dispersion medium optionally with additives. More specifically, after suspending agent A and a dispersion medium are mixed optionally with additives, the injectable preparation is prepared by mixing a poorly soluble drug, suspending agent A, and a dispersion medium optionally with additives. More specifically, after suspending agent A and a dispersion medium are mixed optionally with additives, the
  • the injectable preparation is preferably produced at a low temperature (for example, about 2 to 10°C, particularly about 5°C).
  • a storage-stable injectable preparation comprising a poorly soluble drug having a desired mean particle diameter can be obtained by the above method.
  • the injectable preparation of the present invention is suitably formulated into a dosage form that can be administered once per month, once every two months, or once every three months.
  • the injectable preparation is preferably administered intramuscularly, subcutaneous injection is also acceptable.
  • the injectable preparation is preferably used to treat schizophrenia and associated disorders (such as bipolar disorder, depression, and dementia) in human patients or to prevent the recurrence of symptoms of such
  • the injectable preparation of the present invention which contains a specific suspending agent A, inhibits caking due to the precipitation of a poorly soluble drug during the period from the production thereof until the administration to a patient and thus has excellent storage stability, and can be smoothly ejected from a syringe through a thin syringe needle at the time of injection.
  • the injectable preparation of the present invention has structural viscosity
  • the injectable preparation is in a sol state exhibiting fluidity immediately after the preparation thereof (see Fig. 1).
  • injectable preparation is allowed to stand, the injectable preparation becomes a gel and no longer flows even when tilted slowly (see Fig. 2).
  • the injectable preparation in the form of a gel is so stable that the caking of particles of a poorly soluble drug due to the precipitation of the particles does not occur even when allowed to stand for a long period of time.
  • the gelled injectable preparation quickly forms a sol state due to stirring, shaking, tapping, external impact, or the pressure from being ejected through a syringe needle (see Fig. 3).
  • the poorly soluble drug does not cake due to precipitation but is uniformly dispersed to reproduce the injectable preparation immediately after production.
  • the injectable preparation is considered to have a structure such that part of suspending agent A is attached to the particles of a poorly soluble drug in a dispersion medium;
  • the attached suspending agent A causes an interaction between the particles of the poorly soluble drug.
  • the intermolecular interaction due to suspending agent A that forms the network structure is a weak binding force.
  • the network structure collapses, with the result being that the gelled injectable preparation changes into a sol.
  • the injectable preparation is in a sol state, the network structure is reconstructed and the injectable preparation becomes a gel again upon standing.
  • the injectable preparation of the present invention is also advantageous in that it can be filled into a vial or a syringe as is.
  • aripiprazole or a salt thereof is such that a suspension
  • aripiprazole or a salt thereof as an active ingredient is prepared, and the suspension is freeze dried in a vial. Before use, water for injection is added into the vial, and the
  • the injectable preparation is filled as is into a vial or a syringe and used.
  • the injectable preparation of the present invention can be easily obtained without the need for freeze- drying in the production process.
  • the injectable preparation of the present invention can be filled as is into a syringe for use as a prefilled syringe. This simplifies the structure of the syringe and reduces size and weight.
  • a sol suspension can be administered by simply pressing the plunger rod of the syringe and ejecting the
  • injectable preparation of the invention through a syringe needle without the need to shake the syringe.
  • This provides a prefilled syringe that offers clinical convenience and operability, thus is highly useful medically and industrially.
  • a preferable example of producing such a prefilled syringe is such that an injectable preparation is produced in the manner as described above, the preparation is prefilled into a syringe, and then left to stand in the manner as described above to cause the injectable
  • the present invention also includes a kit equipped with the above-described prefilled syringe.
  • Aripiprazole or a salt thereof, or 7- [4- (4- benzo[b] thiophen-4-yl-piperazin-1-yl)butoxy] -1H-quinolin-2-one or a salt thereof is particularly preferable for use as the poorly soluble drug contained in the injectable preparation of the present invention. Therefore, more preferable embodiments of the injectable preparation containing aripiprazole or a salt thereof as a poorly soluble drug, or those of the injectable preparation containing 7- [4- (4-benzo[b] thiophen-4-yl-piperazin-l-yl)butoxy] - lH-quinolin-2-one or a salt thereof as a poorly soluble drug are explained below. However, unless otherwise defined below, the above explanations are also applicable to the injectable
  • the injectable preparation of the present invention that contains aripiprazole or a salt thereof preferably comprises aripiprazole or a salt thereof, water, and at least one
  • suspending agent selected from the group consisting of (i) and (ii):
  • aripiprazole or a salt thereof has a mean primary particle diameter of about 0.5 to 30 pm and the
  • concentration of aripiprazole or a salt thereof is 200 to 600 mg/mL.
  • the injectable preparation of the present invention comprises aripiprazole or a salt thereof (which hereunder may be referred to as "the aripiprazole injectable preparation of the present invention” )
  • the concentration of aripiprazole or a salt thereof is important.
  • concentration thereof falls outside the range of 200 to 600 mg/mL, it is difficult to obtain an injectable preparation that achieves both of the effects (a) and ( ⁇ ) described above.
  • concentration thereof is 100 mg/mL or below, the
  • the injectable preparation of the present invention comprises aripiprazole or a salt thereof, a combination of the use of a specific suspending agent (suspending agent A) and a specific concentration of
  • aripiprazole or a salt thereof 200 to 600 mg/mL and more
  • the injectable preparation of the present invention comprises a salt of aripiprazole
  • the concentration described above is preferably that calculated as aripiprazole.
  • the injectable preparation containing 7- [4- (4- benzo[b]thiophen-4-yl-piperazin-l-yl)butoxy] -lH-quinolin-2-one or a salt thereof of the present invention comprises 7- [4- (4- benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy] -1H-quinolin-2-one or a salt thereof, water, and at least one suspending agent selected from the group consisting of (i) and (ii):
  • 7- [4- (4-benzo[b]thiophen-4-yl-piperazin-1- yl)butoxy] -1H-quinolin-2-one or a salt thereof has a mean primary particle diameter of about 0.5 to 30 ⁇ , and the concentration of 7- [4- (4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy] -1H-quinolin- 2-one or a salt thereof is 200 to 600 mg/mL.
  • the injectable preparation of the present invention comprises 7- [4-(4-benzo[b]thiophen-4-yl- piperazin-l-yl)butoxy] -IH-quinolin-2-one or a salt thereof (which hereunder may be referred to as "the brexpiprazole injectable preparation of the present invention")
  • the concentration of 7- [ 4- ( 4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy] -IH-quinolin-2- one or a salt thereof is important.
  • the concentration thereof falls outside the range of 200 to 600 mg/mL, it is difficult to obtain an injectable preparation that achieves both of the effects (a) and ( ⁇ ) described above.
  • the injectable preparation of the present invention comprises 7-[4-(4-benzo[b]thiophen-4-yl- piperazin-l-yl)butoxy] -lH-quinolin-2-one or a salt thereof, a combination of the use of a specific suspending agent (suspending agent A) and a specific concentration of 7- [4- (4- benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy] -IH-quinolin-2-one or a salt thereof (200 to 600 mg/mL and more preferably 250 to 450 mg/mL) is particularly important.
  • the injectable preparation of the present invention comprises a salt of brexpiprazole
  • the concentration described above is preferably that calculated as brexpiprazole
  • the concentration of polyvinylpyrrolidone is preferably 0.1 to 100 mg/mL, more preferably 1 to 50 mg/mL, and even more preferably 2 to 20 mg/mL.
  • the aripiprazole injectable preparation of the present invention or the brexpiprazole injectable preparation of the present invention comprises (i) polyvinylpyrrolidone as suspending agent A, and further comprises one or more other suspending agents
  • at least one member selected from the group consisting of polyethylene glycol and carboxymethylcellulose or a salt thereof be contained as the one or more other suspending agents.
  • these injectable preparations of the present invention comprise (i) polyvinylpyrrolidone as suspending agent A, and when they further comprise one or more other suspending agents, they preferably comprise suspending agents of any combination of (i-1) to (i-3) shown below.
  • the concentration of polyvinylpyrrolidone is, as described above, preferably 0.1 to 100 mg/mL, more preferably 1 to 50 mg/mL, and even more preferably 2 to 20 mg/mL.
  • the concentration of polyethylene glycol is preferably about 0.05 to 100 mg/mL and more preferably about 0.1 to 50 mg/mL.
  • the concentration of carboxymethylcellulose or a salt thereof is preferably about 0.5 to 50 mg/mL, more preferably 1 to 30 mg/mL, and even more preferably 2 to 20 mg/mL.
  • the aripiprazole injectable preparation of the present invention or the brexpiprazole injectable preparation of the present invention comprises (ii) polyethylene glycol and carboxymethylcellulose or a salt thereof as suspending agent A, the concentration of polyethylene glycol is preferably about 0.05 to 2 mg/mL and more preferably about 0.1 to 1 mg/mL.
  • concentration of carboxymethylcellulose or a salt thereof is preferably about 0.5 to 50 mg/mL, more preferably 1 to 30 mg/mL, and even more preferably 2 to 20 mg/mL.
  • aripiprazole injectable preparation of the present invention or the brexpiprazole injectable preparation of the present invention comprises (ii) polyethylene glycol and carboxymethylcellulose or a salt thereof as suspending agent A, and further comprises one or more other suspending agents,
  • polyvinylpyrrolidone is preferably contained as the one or more other suspending agents.
  • the injectable preparation of the present invention comprises, as suspending agent A, (ii) polyethylene glycol and carboxymethylcellulose or a salt thereof, and when it further comprises one or more other suspending agents, it is more preferable that the suspending agents of (i-3) are contained.
  • polyvinylpyrrolidone are the same as described in (i-3) above.
  • the particularly preferable composition contains 0.5 to 20 mg/mL of polyvinylpyrrolidone, 0.1 to 100 mg/mL of polyethylene glycol, 0.5 to 50 mg/mL of carboxymethylcellulose or a salt thereof, and 250 to 450 mg/mL (more preferably 300 to 400 mg/mL) of aripiprazole or a salt thereof.
  • the polyethylene glycol be polyethylene glycol 400 or polyethylene glycol 4000.
  • the polyvinylpyrrolidone has a K value of about 12 to 20.
  • the aripiprazole or a salt thereof has a mean primary particle diameter of about 1 to 10 ⁇ .
  • the mean primary particle diameter is preferably about 0.5 to 30 ym and more preferably about 1 to 20 ym.
  • aripiprazole or a salt thereof or 7-[4-(4-benzo[b]thiophen-4-yl- piperazin-l-yl)butoxy] -lH-quinolin-2-one or a salt thereof has a mean primary particle diameter of preferably about 1 to 10 ym, and more preferably 2 to 7 ym, and even more preferably 2 to 4 ym.
  • the injectable preparation of the present invention When the injectable preparation of the present invention is in a dosage form that is administered once every two or three months, the aripiprazole or a salt thereof, or 7-[4-(4-benzo[b]thiophen- 4-yl-piperazin-l-yl)butoxy] -lH-quinolin-2-one or a salt thereof has a mean primary particle diameter of preferably about 1 to 50 ym, more preferably 4 to 30 ym, and even more preferably 5 to 20 ym.
  • the mean secondary particle diameter is preferably up to but not exceeding three times and more preferably up to but not exceeding twice the mean primary particle diameter.
  • the aripiprazole injectable preparation of the present invention is explained in further detail below.
  • concentration of aripiprazole or a salt thereof in the injectable preparation of the present invention that is administered once per month is preferably, calculated as aripiprazole, about 200 to 600 mg/mL, more preferably about 200 to 400 mg/mL, and even more preferably about 300 mg/mL.
  • the aripiprazole or a salt thereof has a mean primary particle diameter of
  • the dosage volume is preferably 0.3 to 3 mL, more preferably 0.6 to 2 mL, and even more preferably 1 to 1.5 mL.
  • the concentration of aripiprazole or a salt thereof in the injectable preparation of the present invention that is administered once every two or three months is preferably, calculated as aripiprazole, about 300 to 600 mg/mL, more preferably about 350 to 500 mg/mL, and even more preferably about 400 mg/mL.
  • the injectable preparation of the present invention that is administered once every two or three months, the
  • aripiprazole or a salt thereof has a mean primary particle diameter of preferably about 1 to 30 ⁇ , more preferably 4 to 20 ⁇ , and even more preferably 5 to 10 ⁇ m.
  • the dosage volume is preferably 0.5 to 5 mL, more preferably 1 to 3 mL, and even more preferably 1.5 to 2.5 mL.
  • the dosage volume is preferably 0.7 to 8 mL, more preferably 1.5 to 4.5 mL , and even more preferably 2 to 4 mL.
  • the brexpiprazole injectable preparation of the present invention is explained in further detail below.
  • concentration of brexpiprazole or a salt thereof in the injectable preparation of the present invention that is administered once per month is preferably, calculated as brexpiprazole, about 200 to 600 mg/mL, more preferably about 200 to 400 mg/mL, and even more preferably about 300 mg/mL.
  • the brexpiprazole or a salt thereof has a mean primary particle diameter of
  • the dosage volume is preferably 0.3 to 3 mL, more preferably 0.6 to 2 mL, and even more preferably 1 to 1.5 mL.
  • the concentration of brexpiprazole in the injectable preparation or a salt thereof of the present invention that is administered once every two or three months is preferably, calculated as brexpiprazole, about 300 to 600 mg/mL, more
  • the injectable preparation of the present invention that is administered once every two or three months, the
  • brexpiprazole or a salt thereof has a mean primary particle diameter of preferably about 1 to 30 ⁇ , more preferably 4 to 20 um, and even more preferably 5 to 10 ⁇ .
  • the dosage volume is preferably 0.5 to 5 mL, more preferably 1 to 3 mL, and even more preferably 1.5 to 2.5 mL.
  • the dosage volume is preferably 0.7 to 8 mL, more preferably 1.5 to 4.5 mL, and even more preferably 2 to 4 mL.
  • the aripiprazole injectable preparation of the present invention or the brexpiprazole injectable preparation of the present invention achieves the effects (a) and ( ⁇ ) described above. They may be in the form of a gel or they may have fluidity (i.e., they may be in the form of a sol) . As described above, the achievement of the effects of the effects (a) and ( ⁇ ) can be in the form of a gel or they may have fluidity (i.e., they may be in the form of a sol) . As described above, the achievement of the effects of the effects (a) and ( ⁇ ) can
  • a preferable method for producing the aripiprazole injectable preparation or brexpiprazole injectable preparation according to the present invention comprises preparing a liquid mixture of the starting materials and pulverizing aripiprazole or a salt thereof, or 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-l- yl)butoxy] -lH-quinolin-2-one or a salt thereof, contained in the liquid mixture to a desired mean primary particle diameter, optionally followed by aging.
  • a particularly preferable method for producing the gel aripiprazole injectable preparation according to the present invention comprises allowing a liquid mixture to stand at 5 to 70°C for 5 minutes or more, the liquid mixture comprising
  • aripiprazole or a salt thereof with a mean primary particle diameter of 0.5 to 30 ⁇ in a concentration of 200 to 600 mg/mL, water, and at least one suspending agent selected from the group consisting of (i) and (ii):
  • a production method comprising the following steps can be preferably used: pulverizing aripiprazole or a salt thereof to a mean primary particle diameter of 0.5 to 30 ⁇ in a liquid mixture comprising the aripiprazole or a salt thereof in a concentration of 200 to 600 mg/mL, water, and at least one suspending agent selected from the group consisting of (i) and (ii) :
  • a particularly preferable method for producing the gel brexpiprazole injectable preparation according to the present invention comprise allowing a liquid mixture to stand at 5 to 70°C for 5 minutes or more, the liquid mixture comprising 7- [4- (4- benzo[b] thiophen-4-yl-piperazin-1-yl)butoxy] -1H-quinolin-2-one or a salt thereof with a mean primary particle diameter of 0.5 to 30 ⁇ in a concentration of 200 to 600 mg/mL, water, and at least one suspending agent selected from the group consisting of (i) and ( ii) :
  • a production method comprising the following steps can be preferably used: pulverizing 7- [4- (4- benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy] -1H-quinolin-2-one or a salt thereof to a mean primary particle diameter of 0.5 to 30 [im in a liquid mixture comprising the 7- [4- (4-benzo[b]thiophen-4- yl-piperazin-l-yl)butoxy] -lH-quinolin-2-one or a salt thereof in a concentration of 200 to 600 mg/mL, water, and at least one suspending agent selected from the group consisting of (i) and (ii):
  • the above aging treatment conditions are less likely to cause problems, such as the evaporation of water, the firm gelling of the injectable preparation, and the inability of the injectable preparation to easily return to a sol even when an impact is applied thereto.
  • the concentration of the suspending agent contained in the liquid mixture is preferably the same as that of the
  • suspending agent contained in the injectable preparation This is because the concentration of the suspending agent in the liquid mixture will directly become the concentration thereof in the resulting injectable preparation.
  • the aripiprazole or a salt thereof added to the liquid mixture used for producing the aripiprazole injectable preparation of the present invention may be, for example, in the form of a monohydrate (aripiprazole hydrate A) and various anhydrous forms, i.e., anhydrous crystal B, anhydrous crystal C, anhydrous crystal D, anhydrous crystal E, anhydrous crystal F, or anhydrous crystal G.
  • the aripiprazole or a salt thereof is in the form of a monohydrate, and
  • aripiprazole hydrate A particularly preferably in the form of aripiprazole hydrate A. These may be used singly or in a combination of two or more.
  • the 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-l- yl)butoxy] -lH-quinolin-2-one or a salt thereof added to the liquid mixture used in producing the brexpiprazole injectable preparation of the present invention is not limited, and may be, for example, in the form of an anhydride or dihydrate, and preferably in the form of a dihydrate. These may be used singly or in a combination of two or more.
  • the method for pulverizing aripiprazole or a salt thereof, or 7- [4- (4-benzo[b]thiophen-4-yl-piperazin-l-yl)butoxy] - lH-quinolin-2-one or a salt thereof contained in the liquid mixture is not particularly limited and any known methods can be employed.
  • the methods described above may be used. More specifically, a wet milling process is preferably used.
  • wet ball milling, high pressure homogenization, high shear homogenization and the like are preferably used.
  • other low- and high-energy mills such as roller mills
  • Controlled crystallization and other methods may also be used. Further, an impinging jet
  • JP2007-200088A for which a patent application has been filed by Otsuka Pharmaceutical Co., Ltd.
  • a wet milling process using a high-pressure homogenizer in particular, a two-step wet milling process
  • a patent application has been filed by Otsuka Pharmaceutical Co. , Ltd. is more preferable.
  • the injectable preparation (gel composition) contained therein gains fluidity (becomes a sol) by simply pressing the plunger rod of the syringe and ejecting it through a syringe needle.
  • This allows the injectable preparation of the present invention to be smoothly ejected from the syringe needle as is (i.e., achieving the effect ( ⁇ ) described above) .
  • the present invention encompasses a kit comprising the prefilled syringe.
  • the suspending agent, sodium chloride, and sodium dihydrogenphosphate monohydrate shown in Table 1 were dissolved in water (water for injection) .
  • the solution was adjusted to a pH value of 7.0 using sodium hydroxide to prepare a vehicle solution.
  • An active ingredient (aripiprazole monohydrate) was suspended into the resulting vehicle solution.
  • the resulting suspension was preliminarily pulverized using a CLEARMIX SI.5 (manufactured by M Technique Co., Ltd.) and finely pulverized using a high-pressure homogenizer (Panda model NS1001L2K, manufactured by Niro Soavi) to prepare injectable preparations.
  • all of the steps for producing the injectable preparations were conducted at a temperature of 10° C or lower.
  • FIG. 1 shows a photograph of the injectable preparation of Example 1 immediately after production.
  • Fig. 2 shows a photograph of the injectable preparation
  • FIG. 3 shows a photograph of the container holding the injectable preparation of Example 1 therein after being allowed to stand, followed by tapping the container (i.e., a weak impact was applied to the gelled preparation) , and laying the container horizontally.
  • Table 1 shows the mean particle diameter (mean secondary particle diameter) of each of the resulting preparations. Table 1 also shows the mean particle diameters
  • Example 7 the measurement was performed in circulating water without ultrasonic irradiation.
  • Example 7 In Examples 1 to 6, the measurement was performed in circulating 0.2% hydroxypropylcellulose solvent with ultrasonic irradiation. In Example 7, the measurement was performed in circulating water with ultrasonic irradiation.
  • the injectable preparations having the compositions shown in Table 2 below were produced in the same manner as in Examples 1 to 7 described above (i.e., mixing the components other than the active ingredient, adjusting the pH value of the mixture to 7.0 to prepare a vehicle solution, suspending the active ingredient into the vehicle solution, and then pulverizing the suspension).
  • the mean primary particle diameter and the mean secondary particle diameter of aripiprazole monohydrate in each Production Example were measured immediately after production. The results revealed that all Production Examples had a mean primary particle diameter of about 2.0 to 4.0 ⁇ and a mean secondary particle diameter of about 2.0 to 7.5 ⁇ (Table 2) .
  • Production Example Al Production Example A2, Production Example A3, Production Example A4, Production Example A5, and Production Example A6 may
  • Measuring instrument Rheometer (Discovery Hybrid Rheometer-2 (DHR-2) or Discovery Hybrid Rheometer-3 (DHR-3) (manufactured by TA Instruments)
  • each preparation of the Production Examples was shaken by hand to form a sol, and 10 mL of each was placed in the measuring instrument. After being placed in the measuring instrument , each preparation was allowed to stand at the measuring temperatures for 5 to 10 minutes, and then the measurement was started (the intention being to form a gel in the measuring instrument by allowing it to stand in the measuring instrument, in the case where an injectable preparation can form a gel).
  • the viscosities of the injectable preparations were measured using the same measuring instrument with the same range of shear rate change as described above, wherein a concentric cylinder was also used. Furthermore, the measurement was also started after the samples were allowed to stand for 5 to 10 minutes at the measuring temperatures after being placed in the measuring instrument as described above.
  • Tables 3 to 5 summarize the data of specific viscosities obtained in each measurement, in terms of the viscosity measured at the shear rate in the range of 0.01 to 0.02 (1/s) and the viscosity measured at the shear rate in the range of 900 to 1,000 (1/s).
  • Table 3 corresponds to the data of Fig. 5a
  • Table 4 corresponds to the data of Fig. 5b
  • Table 5 corresponds to the data of Fig. 5c.
  • concentration of polyvinylpyrrolidone is about 2 to 50 mg/mL, the lowest viscosity was attained at any shear rate, and also gelling was achieved. A tendency was confirmed such that the lower the concentration of polyvinylpyrrolidone, the higher the viscosity. At high concentrations of polyvinylpyrrolidone, the viscosity tended to become low until the concentration of
  • polyvinylpyrrolidone reached about 20 to 50 mg/mL, and the viscosity tended to become high again when the concentration of polyvinylpyrrolidone reached as high as about 100 mg/mL or more.
  • Production Example B had a mean primary particle diameter of 2.2 ⁇ and a mean secondary particle diameter of 2.4 ⁇ .
  • Production Example C had a mean primary particle diameter of 4.2 m and a mean secondary particle diameter of 4.3 ⁇ .
  • Production Example D had a mean primary particle diameter of 3.9 ⁇ and a mean
  • the injectable preparations of Production Examples B to D were shaken by hand to form a sol state, and placed in a rheometer to measure the viscosity of each preparation at 5°C, 25° C, or 40° C (measuring temperature).
  • the injectable preparations of Production Examples B and C were in a form of sol.
  • the injectable preparation of Production Example D was in a form of gel.
  • Figs. 6 to 8 show the measurement results.
  • Tables 7 to 9 show the specific viscosities measured at a shear rate in the range of 0.01 to 0.02 (1/s) and those measured at a shear rate in the range of 900 to 1,000 (1/s).
  • Fig. 6 and Table 7 show the measurement results of Production Example B
  • Fig. 7 and Table 8 show the measurement results of Production Example C
  • Fig. 8 and Table 9 show the measurement results of Production Example D.
  • the injectable preparation (Production Example E) having the composition shown in Table 10 was produced in the same manner as in Examples 1 to 7 (i.e., mixing the components other than the active ingredient, adjusting the pH value of the mixture to 7.0 to prepare a vehicle solution, suspending the active ingredient into the vehicle solution, and then pulverizing the suspension) .
  • the preparation of Production Example E returned to a sol upon being gently shaken by hand even if it had once gelled.
  • the measurement results of the aripiprazole monohydrate mean particle diameter were as follows. Production Example E had a mean primary particle diameter of 5.4 ⁇ and a mean secondary particle diameter of 9.5 ⁇ .
  • Fig. 9a shows the results.
  • Table 11 shows the specific viscosities measured at a shear rate in the range of 0.01 to 0.02 (1/s) and those measured at a shear rate in the range of 900 to 1,000 (1/s).
  • the injectable preparation of Production Example E was stored in a still condition at 5 e C, 25° C or 40° C for five days.
  • the injectable preparation of Production Example E gelled under all conditions (Fig. 9b shows photographs of the injectable preparations each stored in a container in a still condition for five days, and Fig. 9c shows photographs of the containers each holding an injectable preparation therein, which were slowly tilted and laid horizontally after storage.)
  • the viscosity measurement results of Production Examples Al to E indicate that when an injectable preparation has a viscosity measured at a shear rate in the range of 0.01 to 0.02 (1/s) of about 40 (Pa-s) or higher, the preparation is in a gel state, and when the shear rate becomes large, the preparation forms a sol.
  • the results indicate that when an injectable preparation has a viscosity measured at a shear rate in the range of 900 to 1,000 (1/s) of about 0.2 Pa's or lower, the preparation can be injected as is.
  • the injectable preparations (Production Examples Fl and F2) having the compositions shown in Table 12 were produced in the same manner as in Examples 1 to 7 (i.e., mixing the components other than the active ingredient, adjusting the pH value of the mixture to 7.0 to prepare a vehicle solution, suspending the active ingredient into the vehicle solution, and then pulverizing the suspension) .
  • the injectable preparations of Production Examples Fl and F2 did not gel.
  • the measurement results of the aripiprazole monohydrate mean particle diameter were as follows.
  • Production Example Fl had a mean primary particle diameter of 3.2 ym and a mean secondary particle diameter of 5.6 ⁇ .
  • Production Example F2 had a mean primary particle diameter of 2.7 ⁇ and a mean secondary particle diameter of 2.7 ⁇ .
  • Fig. 10b shows photographs of the injectable preparations each stored in a container in a still condition for five days
  • Fig. 10c shows photographs of the containers each holding an
  • Fig. 10b shows that precipitation of particles
  • injectable preparation of the present invention that maintains uniform dispersion of particles by forming a gel.
  • Test Examples 1 to 4 revealed that when an injectable preparation comprising a poorly soluble drug is produced using polyvinylpyrrolidone as a suspending agent, an injectable preparation that gels by standing and returns to a sol upon applying a mild impact (e.g., shaking by hand) can be used.
  • a mild impact e.g., shaking by hand
  • aripiprazole is used as a poorly soluble drug
  • an injectable preparation that gels by standing and returns to a sol upon applying a mild impact (e.g., shaking by hand) can be produced by forming the preparation in such a manner that it has a specific mean primary particle diameter of aripiprazole and a
  • concentration of aripiprazole in the range of 200 mg/mL to 600 mg/mL. It was further revealed that the preparation preferably gels by being stored in a still condition at a temperature of about 20 to 70° C and returns to a sol when a slight impact is applied thereto.
  • the injectable preparations (Production Examples G, H and I) having the compositions shown in Table 14 were produced in the same manner as in Examples 1 to 7 (i.e., mixing the
  • FIG. 11 shows photographs of the containers each holding an injectable preparation, which were slowly tilted and laid horizontally after storage .
  • Production Examples was shaken well by hand, and placed in a rheometer to measure the viscosity thereof at 5°C, 25° C, or 40° C (measuring temperature) in the same manner as described above.
  • Fig. 12 shows the viscosity measurement results of Production Example G.
  • Fig. 13 shows the results of Production Example H.
  • Fig. 14 shows the results of Production Example I.
  • Tables 15 to 17 summarize the data of the specific viscosities measured at a shear rate in the range of 0.01 to 0.02 (1/s) and those measured at a shear rate in the range of 900 to 1,000 (1/s).
  • Table 15 corresponds to the data of Fig. 12
  • Table 16 corresponds to the data of Fig. 13
  • Table 17 corresponds to the data of Fig. 14.
  • the injectable preparation (Production Example J) having the composition shown in Table 18 was produced in the same manner as in Examples 1 to 7 (i.e., mixing the components other than the active ingredient, adjusting the pH value of the mixture to 7.0 to prepare a vehicle solution, suspending the active ingredient into the vehicle solution, and then pulverizing the suspension).
  • the injectable preparation of Production Example J had gelled after standing at 5°C, 25° C, or 40° C and it returned to a sol when gently shaken by hand even if it had once gelled.
  • the measurement results of the aripiprazole monohydrate mean particle diameter were as follows.
  • Production Example J had a mean primary particle diameter of 5.5 m and a mean secondary particle diameter of 6.9 ⁇ .
  • the injectable preparation of Production Example J was shaken well by hand to form a sol state, and placed in a rheometer to measure the viscosity thereof at 5°C, 25° C, or 40° C (measuring temperature).
  • Fig. 15 shows the results.
  • Table 19 shows the specific viscosities measured at a shear rate in the range of 0.01 to 0.02 (1/s) and those measured at a shear rate in the range of 900 to 1,000 (1/s).
  • the injectable preparations (Production Examples K and L) having the compositions shown in Table 20 below were produced in the same manner as in Examples 1 to 7 (i.e., mixing the components other than the active ingredient, adjusting the pH value of the mixture to 7.0 to prepare a vehicle solution, suspending the active ingredient into the vehicle solution, and then pulverizing the suspension). After production, an aging treatment was conducted by allowing the injectable preparations to stand at 60° C for 12 hours. Freeze-dried injectable
  • aripiprazole monohydrate mean particle diameter were as follows.
  • Production Example K had a mean primary particle diameter of 2.8 ⁇ and a mean secondary particle diameter of 4.3 ⁇ .
  • Production Example L had a mean primary particle diameter of 6.1 pm and a mean secondary particle diameter of 7.9 ym.
  • Comparative Example 200 had a mean primary particle diameter of 2.1 pm and a mean secondary particle diameter of 2.1 ⁇ .
  • Comparative Example 400 had a mean primary particle diameter of 2.0 jam and a mean
  • Example K and Comparative Example 200 were at a dose of 100 mg/kg (Production Example L and Comparative Example 400).
  • blood samples were collected 0.25, 1, 3, 6, 9, 14, 21, 28, 42, and 56 days after administration, and the concentration of
  • Fig. 16 shows the obtained results in the form of a graph.
  • Production Example K showed a pharmacokinetic (PK) profile of almost the same level as that of Comparative Example 200.
  • the PK profile of Production Example K was desirable for a sustained-release injectable preparation that is administered once per month.
  • Production Example L showed a lower Cmax than Comparative Example 400 and an equal or better sustained-release property. In other words, the PK profile of Production Example L is more preferable for a sustained-release injectable preparation that is administered once every two to three months.
  • Fig. 17 shows the viscosity measurement results.
  • Table 21 summarizes the data of specific viscosities measured at a shear rate in the range of 0.01 to 0.02 (1/s) and those measured at a shear rate in the range of 900 to 1,000 (1/s).
  • Fig. 18 shows the viscosity measurement results. Fig. 18 also shows the viscosities measured at 5° C and 25° C in Test Example 2. Among the results shown in Fig. 18, Table 22
  • the injectable preparation (Production Example E' ) was produced in the same manner as in producing Production Example E in Test Example 3 except that the concentration of Povidone K17 was changed from 0.1 mg/mL to 4 mg/mL. Thereafter, the concentration of Povidone K17 was changed from 0.1 mg/mL to 4 mg/mL. Thereafter, the concentration of Povidone K17 was changed from 0.1 mg/mL to 4 mg/mL. Thereafter, the concentration of Povidone K17 was changed from 0.1 mg/mL to 4 mg/mL. Thereafter, the concentration of Povidone K17 was changed from 0.1 mg/mL to 4 mg/mL. Thereafter, the concentration of Povidone K17 was changed from 0.1 mg/mL to 4 mg/mL. Thereafter, the concentration of Povidone K17 was changed from 0.1 mg/mL to 4 mg/mL. Thereafter, the concentration of Povidone K17 was changed from 0.1 mg/mL to 4 mg/mL. Thereafter, the concentration of Povidone K17
  • preparation of Production Example E' was stored at 5°-C, 25° C or 40° C.
  • the viscosities of the preparations of Production Examples E and E' after being allowed to stand at 5° C were measured in the same manner as in Test Example 3. Specifically, the injectable preparation of Production Example E' after being allowed to stand at 5° C was in a sol state; however, before being placed in a rheometer, the preparations of Production Examples E and E' were shaken by hand to confirm that they were in a sol state.
  • Fig. 19a shows the viscosity measurement results.
  • Fig. 19a also shows the viscosities of Production Example E measured at 5°C and 25° C in Test Example 3.
  • Table 23 summarizes the data of specific viscosities
  • Production Example E' may be referred to as "Povidone K17 4.0 mg/mL" ) .
  • Production Examples Ml and M2 became a sol by being gently shaken by hand.
  • the measurement results of the 7- [4- (4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy] -1H-quinolin-2-one dihydrate mean particle diameter were as follows.
  • Production Example Ml had a primary mean particle diameter of 8.8 ⁇ and a secondary mean particle diameter of 10.8 ⁇ .
  • Production Example M2 had a primary mean particle diameter of 8.3 ⁇ and a secondary mean particle diameter of 10.2 ⁇ .
  • ** The measurement was performed in a circulating water medium without ultrasonic irradiation.
  • Example M2 after being allowed to stand at 5° C was in a sol state; however, before being placed in a rheometer, both the preparations of Production Examples Ml and M2 were shaken by hand to confirm that they were in a sol state, and the viscosities thereof were measured at 5°C, 25° C, or 40" C (measuring
  • Fig. 20a shows the viscosity measurement results.
  • Table 25 summarizes the data of specific viscosities measured at a shear rate in the range of 0.01 to 0.02 (1/s) and those measured at a shear rate in the range of 900 to 1,000 (1/s).
  • Production Examples Ml and M2 were stored in a still condition at 5°C, 25° C or 40° C for five days. All of them gelled except the preparation of Production Example M2 stored at 5° C (Fig. 20b shows photographs of the containers each holding an injectable preparation, which were slowly tilted and laid horizontally after being allowed to stand for five days .
  • Fig. 20b shows photographs of the containers each holding an injectable preparation, which were slowly tilted and laid horizontally after being allowed to stand for five days .
  • Production Example Ml and Production Example M2 may respectively be referred to as "Povidone K17 0.1 mg/mL" and
  • the solution obtained above was introduced, over a period of 30 minutes, into a solution containing 25% sodium hydroxide (5.9 kg) and water (54 L) that was cooled to 0 e C, to prepare a liquid mixture with pHlO. After stirring at 5" C or below for one hour, the mixture was heated to 20 to 30° C and further stirred for seven hours to conduct solid-liquid separation. Washing with water (320 L) was performed until alkali in the solid component disappeared (i.e. , until the pH value of the filtrate became 7 ) .

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