US20230218506A1 - Methods for administering aripiprazole - Google Patents

Methods for administering aripiprazole Download PDF

Info

Publication number
US20230218506A1
US20230218506A1 US18/121,883 US202318121883A US2023218506A1 US 20230218506 A1 US20230218506 A1 US 20230218506A1 US 202318121883 A US202318121883 A US 202318121883A US 2023218506 A1 US2023218506 A1 US 2023218506A1
Authority
US
United States
Prior art keywords
aripiprazole
composition
injection
agent
injection vehicle
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.)
Pending
Application number
US18/121,883
Inventor
Josiah Brown
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=34116189&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=US20230218506(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 US18/121,883 priority Critical patent/US20230218506A1/en
Publication of US20230218506A1 publication Critical patent/US20230218506A1/en
Pending legal-status Critical Current

Links

Images

Classifications

    • 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
    • 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
    • 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
    • A61K47/02—Inorganic compounds
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • 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
    • 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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • Aripiprazole sold under the tradename ABILIFY®, is a dopamine D 2 and serotonin 5-HT 1A receptor agonist and antagonist of the serotonin 5-HT 2A receptor. Aripiprazole is used to treat schizophrenia and other psychotic and CNS disorders. See U.S. Pat. No. 5,006,528, for example. ABILIFY®, is currently sold as a tablet for oral administration. However, poor patient compliance with oral antipsychotics has been reported. As such, there exists a need for improved methods of delivering antipsychotics, such as aripiprazole, thereby improving patient compliance and maximizing the pharmacological profile of the active agent.
  • the present invention relates, in part, to the discovery that a pharmaceutical composition comprising aripiprazole and a carrier administered in a bolus injection resulted in an extended release profile similar to that obtained by the injection of a poly lactide-co-glycolide microsphere formulation containing the active agent.
  • a pharmaceutical composition comprising aripiprazole and a carrier administered in a bolus injection resulted in an extended release profile similar to that obtained by the injection of a poly lactide-co-glycolide microsphere formulation containing the active agent.
  • the invention relates to an injectable composition for the extended release of aripiprazole comprising injecting or implanting a composition comprising aripiprazole wherein aripiprazole is present in the serum of the mammal for at least about 7 days, preferably at least about 14 days, more preferably at least about 21 days, such as about three months.
  • the composition comprises a suspension of aripiprazole in an injection vehicle, such as a suspension of an aripiprazole drug substance in an injection vehicle.
  • the aripiprazole drug substance can comprise, consist essentially of or consist of aripiprazole (in a crystalline, non-crystalline or amorphous form), an aripiprazole salt, an aripiprazole solvate (including hydrates), or other aripiprazole polymorphs.
  • the aripiprazole, or aripiprazole drug substance can be added in a specified size.
  • the aripiprazole or aripiprazole drug substance can be added after being micronized to a mass mean diameter of less than about 100 microns, preferably between about 30 and 80 microns, as determined by Coulter counter.
  • the aripiprazole or aripiprazole drug substance is injected as a mixture (including a suspension) of at least about 50 mg aripiprazole in an injection vehicle, such as at least about 70 to 210 mg or as much as about 900 to 2700 mg, e.g. less than 5400 mg.
  • the aripiprazole can be present in an amount of at least about 10 mg/ml, preferably at least about 20 mg/ml or at least about 30 mg/ml.
  • the invention also relates to methods for providing aripiprazole to an individual in an extended release injectable composition comprising administering a mixture of at least about 10 mg/ml aripiprazole in an injection vehicle comprising a viscosity enhancing agent and to compositions useful in such methods.
  • the FIGURE compares the release profiles of subcutaneous injections (SC Bolus) according to the invention with injections of aripiprazole-containing microspheres.
  • the invention relates to an injectable composition for the extended release of aripiprazole comprising a mixture of aripiprazole in an injection vehicle comprising an optional viscosity enhancing agent.
  • the aripiprazole can be present in an amount of at least about 10 mg/ml, preferably at least about 20 mg/ml or at least about 30 mg/ml.
  • the invention also relates to methods for providing aripiprazole to an individual in an extended release injectable composition comprising administering a mixture of at least about 50 mg aripiprazole in an injection vehicle.
  • the aripiprazole will be suspended in the injection vehicle.
  • the aripiprazole is supplied in a free flowing powder, substantially free of major amounts of pharmaceutical excipients or other compounds.
  • the aripiprazole can be supplied in a micronized state, consisting of or consisting essentially of aripiprazole.
  • An aripiprazole drug substance can be said to consist essentially of aripiprazole if it contains, for example, 90% by weight or more aripiprazole and minor amounts (e.g., less than 10% by weight) of other materials that are, for example, residual to its process for manufacture.
  • Compounds that may be found in a substantially pure aripiprazole drug substance can include wetting agents used, for example, to facilitate micronization, grinding or comminution, residual solvents, reaction by products or staring materials.
  • compositions of the present invention are free of sustained release matrices.
  • Sustained release matrices are polymers and other macromolecules (albumin), present in major amounts (e.g., 50% by weight or more of total solids), which when the active agent is dispersed therein, are used to slow the exposure or bioavailability of the active agent in the patient.
  • a frequently used polymeric matrix is poly lactide-co-glycolide polymers.
  • the aripiprazole drug substance and/or injectable compositions of the invention generally do not contain major amounts of PLGA polymer matrices.
  • polymers are often found in pharmaceutical compositions where the activity is not at all related to extending the release profile of the drug.
  • minor amounts of polysorbates, polyamines, polyvinylalcohol and polyethylene glycols are added to facilitate dispersibility of active agents in its vehicles.
  • the inclusion of such polymers in amounts intended to accomplish these functions, and in amounts that do not permit the formation of substantial matrix formation, is permitted.
  • the aripiprazole drug substance is added to an injection vehicle.
  • the drug substance can be dispersed or suspended in the vehicle, depending upon the solubility of the drug in the vehicle.
  • the vehicle is preferably an aqueous vehicle which suspends the drug substance.
  • the vehicle contains a viscosity enhancing agent.
  • Viscous vehicles can have, for example, a viscosity of at least 20 cp at 20° C.
  • the fluid phase of the suspension has a viscosity at 20° C. of at least about 30 cp, 40 cp, 50 cp, and 60 cp are preferred.
  • the viscosity can be achieved by adding a viscosity enhancing agent, such as a carboxymethyl cellulose, such as sodium carboxy methylcellulose.
  • the injection vehicle comprises at least about 1% by volume sodium carboxymethyl cellulose, preferably about 3% by volume carboxymethyl cellulose.
  • the injection vehicle can advantageously contain a wetting agent, such as a polysorbate.
  • a wetting agent such as a polysorbate.
  • Suitable polysorbates include polysorbate 20, polysorbate 40, and polysorbate 80, sold under the trademark TWEEN®.
  • the wetting agent can be added in an amount that enhances the dispersibility of the active agent.
  • An example of a suitable amount includes about 0.1 to 2% by weight of polysorbate 20.
  • the injection vehicle can also advantageously employ a density enhancing agent, such as a sugars, e.g. mannitol, or sorbitol and/or a tonicity adjusting agent, such as sodium chloride.
  • a density enhancing agent such as a sugars, e.g. mannitol, or sorbitol
  • a tonicity adjusting agent such as sodium chloride.
  • the tonicity adjusting agent is about 1% by weight, including 0.9% by weight.
  • the composition consists of the aripiprazole drug substance and the injection vehicle, thereby providing a surprisingly simple and elegant formulation for obtaining an extended or sustained release profile.
  • the aripiprazole drug substance can comprise, consist essentially of or consist of aripiprazole (in a crystalline, non-crystalline or amorphous form), an aripiprazole salt, an aripiprazole solvate (including ethanolates and hydrates), or other aripiprazole polymorphs.
  • Preferred salts include those salts insoluble in an aqueous vehicle.
  • Pharmaceutical salts such as the hydrochloride and hydrobromide salts are suitable.
  • the methods of the invention include administering the compositions described herein, thereby obtaining an extended release or sustained release profile in the patient.
  • An extended release profile includes deliveries that achieve a therapeutically effective amount of the aripiprazole is present in the plasma of the individual for at least about 7 days, preferably at least about 14 days, or more preferably at least about 21 days alternatively for at least 2, 3, 4, 6 or 8 weeks or as much as three months.
  • the formulations can be administered as a single or sole dose.
  • the invention is particularly beneficial for those individuals that require constant or chronic therapy, such as those that receive repeated doses over several weeks or months or more.
  • the method can comprise a first administration of a first extended release formulation and a second administration of a second extended release formulation.
  • the second formulation can be the same, substantially the same or different as the first and can include the same active agent or a different active agent.
  • the second formulation can be administered at about 7 days, or more, such as at least about 14 days, or at least about 17 days, after the first administration, where the first administration results in the release of agent for a period of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 days, or more.
  • terapéuticaally effective amount is further meant to define an amount resulting in the improvement of any parameters or clinical symptoms.
  • the actual dose may vary with each patient and does not necessarily indicate a total elimination of all disease symptoms.
  • the term “individual”, “subject” or “patient” refers to a warm blooded animal, including but not limited to humans, such as a mammal which is afflicted with a particular disease state.
  • a therapeutically effective amount of the compound used in the treatment described herein can be readily determined by the attending diagnostician, as one skilled in the art, by the use of conventional techniques and by observing results obtained under analogous circumstances.
  • determining the therapeutically effective dose a number of factors are considered by the attending diagnostician, including, but not limited to: the species of mammal; its size, age, and general health; the specific disease involved; the degree of or involvement or the severity of the disease; the response of the individual patient; the particular compound administered; the mode of administration; the bioavailability characteristic of the preparation administered; the dose regimen selected; the use of concomitant medication; and other relevant circumstances.
  • the mode of administration will generally be by injection or implantation, such as intramuscularly or subcutaneously.
  • compositions can be manufactured utilizing techniques known in the art. Typically the therapeutically effective amount of the compound will be admixed with a pharmaceutically acceptable carrier.
  • the compounds may be in a physiologically acceptable pharmaceutical carrier and administered as a suspension.
  • a physiologically acceptable pharmaceutical carrier also include water, aqueous methylcellulose solutions, saline, dextrose solutions, fructose solutions, ethanol, or oils of animal, vegetative, or synthetic origin.
  • the pharmaceutical carrier may also contain preservatives, and buffers as are known in the art.
  • composition When the composition is to be used as an injectable material, including but not limited to needle-less injection, it can be formulated into a conventional injectable carrier.
  • Suitable carriers include biocompatible and pharmaceutically acceptable solutions.
  • the size of the drug particle can be controlled.
  • the mass mean diameter of the drug particles is less than 100 microns, such as between about 1 and 100 microns, preferably about 10 and 100 microns, or about 20 and 60 microns.
  • the unit dosage form can be stored as a dry powder, for example, to be mixed for injection prior to use, or as a stable suspension ready for use.
  • Other methods for storing or administration using art recognized methods are also contemplated herein.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Inorganic Chemistry (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Dermatology (AREA)
  • Biochemistry (AREA)
  • Molecular Biology (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Biomedical Technology (AREA)
  • Neurosurgery (AREA)
  • Neurology (AREA)
  • Psychiatry (AREA)
  • Dispersion Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

The present invention relates, in part, to the discovery that a pharmaceutical composition comprising aripiprazole and a carrier administered in a bolus injection resulted in an extended release profile similar to that obtained by the injection of a poly lactide-co-glycolide microsphere formulation containing the active agent. This surprising result suggests that pharmacologically beneficial extended release formulations without the complexities and expense associated with the manufacture microspheres.

Description

    RELATED APPLICATIONS
  • This application is a continuation of U.S. application Ser. No. 13/648,544, filed Oct. 10, 2012 which is a continuation of U.S. application Ser. No. 12/251,656, filed Oct. 15, 2008, now U.S. Pat. No. 8,338,427 issued Dec. 25, 2012, which is a continuation of U.S. application Ser. No. 10/635,221, filed Aug. 6, 2003, now abandoned. The entire teachings of the above applications are incorporated herein by reference.
    • BACKGROUND OF THE INVENTION
  • Aripiprazole, sold under the tradename ABILIFY®, is a dopamine D2 and serotonin 5-HT1A receptor agonist and antagonist of the serotonin 5-HT2A receptor. Aripiprazole is used to treat schizophrenia and other psychotic and CNS disorders. See U.S. Pat. No. 5,006,528, for example. ABILIFY®, is currently sold as a tablet for oral administration. However, poor patient compliance with oral antipsychotics has been reported. As such, there exists a need for improved methods of delivering antipsychotics, such as aripiprazole, thereby improving patient compliance and maximizing the pharmacological profile of the active agent.
    • SUMMARY OF THE INVENTION
  • The present invention relates, in part, to the discovery that a pharmaceutical composition comprising aripiprazole and a carrier administered in a bolus injection resulted in an extended release profile similar to that obtained by the injection of a poly lactide-co-glycolide microsphere formulation containing the active agent. This surprising result suggests that pharmacologically beneficial extended release formulations without the complexities and expense associated with the manufacture of polymeric microspheres can be achieved.
  • Thus, the invention relates to an injectable composition for the extended release of aripiprazole comprising injecting or implanting a composition comprising aripiprazole wherein aripiprazole is present in the serum of the mammal for at least about 7 days, preferably at least about 14 days, more preferably at least about 21 days, such as about three months. In a preferred embodiment, the composition comprises a suspension of aripiprazole in an injection vehicle, such as a suspension of an aripiprazole drug substance in an injection vehicle. The aripiprazole drug substance can comprise, consist essentially of or consist of aripiprazole (in a crystalline, non-crystalline or amorphous form), an aripiprazole salt, an aripiprazole solvate (including hydrates), or other aripiprazole polymorphs. The aripiprazole, or aripiprazole drug substance, can be added in a specified size. For example, the aripiprazole or aripiprazole drug substance can be added after being micronized to a mass mean diameter of less than about 100 microns, preferably between about 30 and 80 microns, as determined by Coulter counter.
  • In one embodiment, the aripiprazole or aripiprazole drug substance is injected as a mixture (including a suspension) of at least about 50 mg aripiprazole in an injection vehicle, such as at least about 70 to 210 mg or as much as about 900 to 2700 mg, e.g. less than 5400 mg. The aripiprazole can be present in an amount of at least about 10 mg/ml, preferably at least about 20 mg/ml or at least about 30 mg/ml. The invention also relates to methods for providing aripiprazole to an individual in an extended release injectable composition comprising administering a mixture of at least about 10 mg/ml aripiprazole in an injection vehicle comprising a viscosity enhancing agent and to compositions useful in such methods.
    • BRIEF DESCRIPTION OF THE DRAWINGS
  • The FIGURE compares the release profiles of subcutaneous injections (SC Bolus) according to the invention with injections of aripiprazole-containing microspheres.
    •  DETAILED DESCRIPTION OF THE INVENTION
  • The invention relates to an injectable composition for the extended release of aripiprazole comprising a mixture of aripiprazole in an injection vehicle comprising an optional viscosity enhancing agent. The aripiprazole can be present in an amount of at least about 10 mg/ml, preferably at least about 20 mg/ml or at least about 30 mg/ml. The invention also relates to methods for providing aripiprazole to an individual in an extended release injectable composition comprising administering a mixture of at least about 50 mg aripiprazole in an injection vehicle.
  • In general, the aripiprazole will be suspended in the injection vehicle. In one embodiment, the aripiprazole is supplied in a free flowing powder, substantially free of major amounts of pharmaceutical excipients or other compounds. For example, the aripiprazole can be supplied in a micronized state, consisting of or consisting essentially of aripiprazole. An aripiprazole drug substance can be said to consist essentially of aripiprazole if it contains, for example, 90% by weight or more aripiprazole and minor amounts (e.g., less than 10% by weight) of other materials that are, for example, residual to its process for manufacture. Compounds that may be found in a substantially pure aripiprazole drug substance can include wetting agents used, for example, to facilitate micronization, grinding or comminution, residual solvents, reaction by products or staring materials.
  • The compositions of the present invention are free of sustained release matrices. Sustained release matrices are polymers and other macromolecules (albumin), present in major amounts (e.g., 50% by weight or more of total solids), which when the active agent is dispersed therein, are used to slow the exposure or bioavailability of the active agent in the patient. A frequently used polymeric matrix is poly lactide-co-glycolide polymers. Thus, the aripiprazole drug substance and/or injectable compositions of the invention generally do not contain major amounts of PLGA polymer matrices.
  • Of course, polymers are often found in pharmaceutical compositions where the activity is not at all related to extending the release profile of the drug. For example, minor amounts of polysorbates, polyamines, polyvinylalcohol and polyethylene glycols are added to facilitate dispersibility of active agents in its vehicles. The inclusion of such polymers in amounts intended to accomplish these functions, and in amounts that do not permit the formation of substantial matrix formation, is permitted.
  • The aripiprazole drug substance is added to an injection vehicle. The drug substance can be dispersed or suspended in the vehicle, depending upon the solubility of the drug in the vehicle. The vehicle is preferably an aqueous vehicle which suspends the drug substance. Preferably, the vehicle contains a viscosity enhancing agent.
  • Viscous vehicles can have, for example, a viscosity of at least 20 cp at 20° C. In other embodiments, the fluid phase of the suspension has a viscosity at 20° C. of at least about 30 cp, 40 cp, 50 cp, and 60 cp are preferred. The viscosity can be achieved by adding a viscosity enhancing agent, such as a carboxymethyl cellulose, such as sodium carboxy methylcellulose. In one embodiment, the injection vehicle comprises at least about 1% by volume sodium carboxymethyl cellulose, preferably about 3% by volume carboxymethyl cellulose.
  • The injection vehicle can advantageously contain a wetting agent, such as a polysorbate. Suitable polysorbates include polysorbate 20, polysorbate 40, and polysorbate 80, sold under the trademark TWEEN®. The wetting agent can be added in an amount that enhances the dispersibility of the active agent. An example of a suitable amount includes about 0.1 to 2% by weight of polysorbate 20.
  • The injection vehicle can also advantageously employ a density enhancing agent, such as a sugars, e.g. mannitol, or sorbitol and/or a tonicity adjusting agent, such as sodium chloride. In one embodiment, the tonicity adjusting agent is about 1% by weight, including 0.9% by weight.
  • In one embodiment, the composition consists of the aripiprazole drug substance and the injection vehicle, thereby providing a surprisingly simple and elegant formulation for obtaining an extended or sustained release profile.
  • The aripiprazole drug substance can comprise, consist essentially of or consist of aripiprazole (in a crystalline, non-crystalline or amorphous form), an aripiprazole salt, an aripiprazole solvate (including ethanolates and hydrates), or other aripiprazole polymorphs. Preferred salts include those salts insoluble in an aqueous vehicle. Pharmaceutical salts such as the hydrochloride and hydrobromide salts are suitable.
  • The methods of the invention include administering the compositions described herein, thereby obtaining an extended release or sustained release profile in the patient. An extended release profile includes deliveries that achieve a therapeutically effective amount of the aripiprazole is present in the plasma of the individual for at least about 7 days, preferably at least about 14 days, or more preferably at least about 21 days alternatively for at least 2, 3, 4, 6 or 8 weeks or as much as three months.
  • In one embodiment, the formulations can be administered as a single or sole dose. However, the invention is particularly beneficial for those individuals that require constant or chronic therapy, such as those that receive repeated doses over several weeks or months or more. In such dosing regimens, the method can comprise a first administration of a first extended release formulation and a second administration of a second extended release formulation. The second formulation can be the same, substantially the same or different as the first and can include the same active agent or a different active agent. For example, the second formulation can be administered at about 7 days, or more, such as at least about 14 days, or at least about 17 days, after the first administration, where the first administration results in the release of agent for a period of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 days, or more.
  • The term “therapeutically effective amount” is further meant to define an amount resulting in the improvement of any parameters or clinical symptoms. The actual dose may vary with each patient and does not necessarily indicate a total elimination of all disease symptoms.
  • As used herein, the term “individual”, “subject” or “patient” refers to a warm blooded animal, including but not limited to humans, such as a mammal which is afflicted with a particular disease state.
  • A therapeutically effective amount of the compound used in the treatment described herein can be readily determined by the attending diagnostician, as one skilled in the art, by the use of conventional techniques and by observing results obtained under analogous circumstances. In determining the therapeutically effective dose, a number of factors are considered by the attending diagnostician, including, but not limited to: the species of mammal; its size, age, and general health; the specific disease involved; the degree of or involvement or the severity of the disease; the response of the individual patient; the particular compound administered; the mode of administration; the bioavailability characteristic of the preparation administered; the dose regimen selected; the use of concomitant medication; and other relevant circumstances.
  • The mode of administration will generally be by injection or implantation, such as intramuscularly or subcutaneously.
  • Preferred amounts according to the selected mode of administration are able to be determined by one skilled in the art. Pharmaceutical compositions can be manufactured utilizing techniques known in the art. Typically the therapeutically effective amount of the compound will be admixed with a pharmaceutically acceptable carrier.
  • For injection, the compounds may be in a physiologically acceptable pharmaceutical carrier and administered as a suspension. Illustrative pharmaceutical carriers also include water, aqueous methylcellulose solutions, saline, dextrose solutions, fructose solutions, ethanol, or oils of animal, vegetative, or synthetic origin. The pharmaceutical carrier may also contain preservatives, and buffers as are known in the art.
  • When the composition is to be used as an injectable material, including but not limited to needle-less injection, it can be formulated into a conventional injectable carrier. Suitable carriers include biocompatible and pharmaceutically acceptable solutions.
  • In a preferred embodiment, the size of the drug particle can be controlled. Often, the mass mean diameter of the drug particles is less than 100 microns, such as between about 1 and 100 microns, preferably about 10 and 100 microns, or about 20 and 60 microns.
  • In one embodiment, the unit dosage form can be stored as a dry powder, for example, to be mixed for injection prior to use, or as a stable suspension ready for use. Other methods for storing or administration using art recognized methods are also contemplated herein.
    • Experimental: Pharmacokinetic Evaluation of Aripiprazole in Rats Following Administration of Single Subcutaneous Doses of Aripiprazole Formulations.
    • Species and Strain: Sprague-Dawley rats. Male; 450+/−50 grams.
    • Study Groups: 5 Groups, 15 subjects
      • Group A: three rats injected once SC with 10 mg of Aripiprazole.
      • Group B: three rats injected once SC with 20 mg of Aripiprazole.
      • Group C: three rats injected once SC with 30 mg of Aripiprazole.
      • Group D: three rats injected once SC with ˜67 mg of microparticles.
      • Group E: three rats injected once SC with ˜40 mg of microparticles.
    Group Conditions Table:
  • Rat
    Groups Lot # Polymer Notes % Load
    A N/A Bulk Drug 100%
    B N/A Bulk Drug 100%
    C N/A Bulk Drug 100%
    D 03-10-66-B 4A Bulk Drug  30%
    in microspheres
    E 03-10-66-C 4A Bulk Drug  50%
    in microspheres
    • Route of Injection: Subcutaneous (SC) injection into the interscapular region.
    • Injection Vehicle: Aqueous diluent containing 3% CMC (low viscosity), 0.1% Tween 20, in 0.9% NaCl and water.
    • Dose Volumes: Suspensions were formulated as follows:
      • Group A: 10 mg powder in 0.75 mL Diluent
      • Group B: 20 mg powder in 0.75 mL Diluent
      • Group C: 30 mg powder in 0.75 mL Diluent
      • Group D: ˜67 mg microparticles in 0.75 mL Diluent
      • Group E: 40 mg microparticles in 0.75 mL Diluent
    • Blood Collection: Blood samples were collected via a lateral tail vein after anesthesia with Halothane. A syringe without an anticoagulant was used for the blood collection, then the whole blood was transferred to tubes containing K2 EDTA and mixing beads (MICROTAINER®; MFG #BD365974). The blood samples were processed (the tubes are inverted 15-20 times and centrifuged for 2 minutes at >14,000 g's) to separate plasma. The plasma samples prepared in this manner were transferred to labeled plain tubes (MICROTAINER®; MFG #BD5962) and stored frozen at <−70° C.
    • Blood Volumes: At least 250 μL blood were collected at for each time point during the first 24 hours and 400 μL for at each time point thereafter.
    Time Points to Obtain Plasma:
  • 2 h 24 h 3 d 10 d 21 d
    4 h 32 h 4 d 14 d 24 d
    8 h 2 d 7 d 17 d 28 d
    Note:
    when plasma concentration was lower than the limitation of quantification, that group of rats were terminated.
  • The results obtained are reported in the FIGURE. Surprisingly, the rats that received bolus injections of aripiprazole and injection vehicle alone were substantially the same as those that received the aripiprazole dispersed within a PLGA microsphere.
  • Modifications and variations of the invention will be obvious to those skilled in the art from the foregoing detailed description of the invention. Such modifications and variations are intended to come within the scope of the appended claims.
  • All patents, patent application publications and articles cited herein are incorporated by reference in their entirety.
  • While this invention has been particularly shown and described with references to preferred embodiments thereof, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the scope of the invention encompassed by the appended claims.

Claims (18)

1.-23. (canceled)
24. An injectable composition comprising a suspension of at least about 10 mg/ml of aripiprazole in an injection vehicle comprising water, carboxymethyl cellulose or sodium carboxy methylcellulose, wherein the injectable composition is free of sustained release materials for the extended release of aripiprazole, and the aripiprazole release is for at least 7 days.
25. The composition of claim 24, wherein said injection vehicle further comprises a wetting agent.
26. The composition of claim 25, wherein said wetting agent is chosen from polysorbate 20, polysorbate 40, and polysorbate 80.
27. The composition of claim 24, wherein said injection vehicle further comprises a density enhancing agent.
28. The composition of claim 27, wherein said density enhancing agent comprises sorbitol.
29. The composition of claim 24, wherein said injection vehicle further comprises a tonicity adjusting agent.
30. The composition of claim 29, wherein said tonicity adjusting agent comprises sodium chloride.
31. A method for providing aripiprazole to an individual in an injectable composition comprising a suspension of at least about 10 mg/ml of aripiprazole in an injection vehicle comprising water, carboxymethyl cellulose or sodium carboxy methylcellulose, wherein the injectable composition is free of sustained release materials for the extended release of aripiprazole, and the aripiprazole release is for at least 7 days.
32. The method of claim 31, wherein said injection vehicle further comprises a wetting agent.
33. The method of claim 32, wherein said wetting agent is chosen from polysorbate 20, polysorbate 40, and polysorbate 80.
34. The method of claim 31, wherein said injection vehicle further comprises a density enhancing agent.
35. The method of claim 34, wherein said density enhancing agent comprises sorbitol.
36. The method of claim 31, wherein said injection vehicle further comprises a tonicity adjusting agent.
37. The method of claim 36, wherein said tonicity adjusting agent comprises sodium chloride.
38. The method of claim 31, wherein the composition is administered by injection chosen from intramuscular injection and subcutaneous injection.
39. The method of claim 31, further comprising a second administration of the composition chosen from at least about 7 days after first administration and at least about 14 days after the first administration.
40. A composition comprising a suspension of at least 50 mg of aripiprazole and an aqueous injection vehicle comprising water; carboxymethylcellulose or sodium carboxy methylcellulose; a wetting agent; and a tonicity agent; wherein the composition is free of sustained release materials; wherein the concentration of aripiprazole in the composition is at least 20 mg/ml; and wherein upon injection of the composition into an individual, the aripiprazole is present in the plasma of the individual for about 7 days or more.
US18/121,883 2003-08-06 2023-03-15 Methods for administering aripiprazole Pending US20230218506A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
US18/121,883 US20230218506A1 (en) 2003-08-06 2023-03-15 Methods for administering aripiprazole

Applications Claiming Priority (8)

Application Number Priority Date Filing Date Title
US10/635,221 US20050032811A1 (en) 2003-08-06 2003-08-06 Methods for administering aripiprazole
US12/251,656 US8338427B2 (en) 2003-08-06 2008-10-15 Methods for administering aripiprazole
US13/648,544 US8759351B2 (en) 2003-08-06 2012-10-10 Methods for administering aripiprazole
US14/160,176 US20140275109A1 (en) 2003-08-06 2014-01-21 Methods for Administering Aripiprazole
US15/666,840 US20180169005A1 (en) 2003-08-06 2017-08-02 Methods for administering aripiprazole
US16/166,400 US20190231679A1 (en) 2003-08-06 2018-10-22 Methods for administering aripiprazole
US17/247,708 US20210346282A1 (en) 2003-08-06 2020-12-21 Methods for administering aripiprazole
US18/121,883 US20230218506A1 (en) 2003-08-06 2023-03-15 Methods for administering aripiprazole

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
US17/247,708 Continuation US20210346282A1 (en) 2003-08-06 2020-12-21 Methods for administering aripiprazole

Publications (1)

Publication Number Publication Date
US20230218506A1 true US20230218506A1 (en) 2023-07-13

Family

ID=34116189

Family Applications (9)

Application Number Title Priority Date Filing Date
US10/635,221 Abandoned US20050032811A1 (en) 2003-08-06 2003-08-06 Methods for administering aripiprazole
US12/251,656 Active 2025-03-15 US8338427B2 (en) 2003-08-06 2008-10-15 Methods for administering aripiprazole
US13/420,822 Expired - Lifetime US8338428B2 (en) 2003-08-06 2012-03-15 Methods for administering aripiprazole
US13/648,544 Expired - Lifetime US8759351B2 (en) 2003-08-06 2012-10-10 Methods for administering aripiprazole
US14/160,176 Abandoned US20140275109A1 (en) 2003-08-06 2014-01-21 Methods for Administering Aripiprazole
US15/666,840 Abandoned US20180169005A1 (en) 2003-08-06 2017-08-02 Methods for administering aripiprazole
US16/166,400 Abandoned US20190231679A1 (en) 2003-08-06 2018-10-22 Methods for administering aripiprazole
US17/247,708 Abandoned US20210346282A1 (en) 2003-08-06 2020-12-21 Methods for administering aripiprazole
US18/121,883 Pending US20230218506A1 (en) 2003-08-06 2023-03-15 Methods for administering aripiprazole

Family Applications Before (8)

Application Number Title Priority Date Filing Date
US10/635,221 Abandoned US20050032811A1 (en) 2003-08-06 2003-08-06 Methods for administering aripiprazole
US12/251,656 Active 2025-03-15 US8338427B2 (en) 2003-08-06 2008-10-15 Methods for administering aripiprazole
US13/420,822 Expired - Lifetime US8338428B2 (en) 2003-08-06 2012-03-15 Methods for administering aripiprazole
US13/648,544 Expired - Lifetime US8759351B2 (en) 2003-08-06 2012-10-10 Methods for administering aripiprazole
US14/160,176 Abandoned US20140275109A1 (en) 2003-08-06 2014-01-21 Methods for Administering Aripiprazole
US15/666,840 Abandoned US20180169005A1 (en) 2003-08-06 2017-08-02 Methods for administering aripiprazole
US16/166,400 Abandoned US20190231679A1 (en) 2003-08-06 2018-10-22 Methods for administering aripiprazole
US17/247,708 Abandoned US20210346282A1 (en) 2003-08-06 2020-12-21 Methods for administering aripiprazole

Country Status (22)

Country Link
US (9) US20050032811A1 (en)
EP (2) EP2340810A1 (en)
JP (3) JP5300194B2 (en)
CN (2) CN102133171A (en)
AT (1) ATE522200T1 (en)
AU (1) AU2004264886C1 (en)
CA (1) CA2534997C (en)
CY (1) CY1111874T1 (en)
DK (1) DK1660037T3 (en)
ES (1) ES2369893T3 (en)
HK (1) HK1091725A1 (en)
HR (1) HRP20110646T1 (en)
IL (1) IL173441A (en)
MX (1) MXPA06001350A (en)
NO (1) NO339816B1 (en)
NZ (1) NZ545037A (en)
PL (1) PL1660037T3 (en)
PT (1) PT1660037E (en)
SE (1) SE1660037T5 (en)
SI (1) SI1660037T1 (en)
WO (1) WO2005016262A2 (en)
ZA (1) ZA200601385B (en)

Families Citing this family (40)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6770478B2 (en) * 2000-02-10 2004-08-03 The Regents Of The University Of California Erythrocytic cells and method for preserving cells
US20050032811A1 (en) * 2003-08-06 2005-02-10 Josiah Brown Methods for administering aripiprazole
TWI371274B (en) 2003-10-23 2012-09-01 Bristol Myers Squibb Co Process for making sterile aripiprazole of desired mean particle size
UA82561C2 (en) 2003-10-23 2008-04-25 Оцука Фармасьютикалз Ко., Лтд. Controlled release sterile aripiprazole formulation for injections, method for preparing aripiprazole formulation, and method for treating schizophrenia
EP2279727A3 (en) * 2005-09-15 2011-10-05 Elan Pharma International Limited Nanoparticulate aripiprazole formulations
JP5401095B2 (en) * 2005-11-17 2014-01-29 ゾゲニクス インコーポレーティッド Delivery method of viscous preparation by needle-free injection
US7799790B2 (en) 2006-07-20 2010-09-21 Helm Ag Amorphous aripiprazole and process for the preparation thereof
EP1880714A1 (en) * 2006-07-20 2008-01-23 Helm AG Amorphous Aripiprazole and Process for the Preparation thereof
GB0618879D0 (en) 2006-09-26 2006-11-01 Zysis Ltd Pharmaceutical compositions
KR101892745B1 (en) * 2007-06-25 2018-08-28 오쓰까 세이야꾸 가부시키가이샤 Microspheres having core/shell structure
EP2170279B1 (en) * 2007-07-31 2017-12-27 Otsuka Pharmaceutical Co., Ltd. Methods for producing aripiprazole suspension and freeze-dried formulation
US8686009B2 (en) 2009-06-25 2014-04-01 Alkermes Pharma Ireland Limited Prodrugs of NH-acidic compounds
RS56352B2 (en) * 2009-06-25 2023-02-28 Alkermes Pharma Ireland Ltd Heterocyclic compounds for the treatment of neurological and psychological disorders
ES2691671T3 (en) 2010-06-24 2018-11-28 Alkermes Pharma Ireland Limited Prodrugs of NH-acidic compounds: ester, carbonate, carbamate and phosphonate derivatives
EP2629775A4 (en) * 2010-10-18 2014-06-11 Dainippon Sumitomo Pharma Co Sustained-release formulation for injection
AR083884A1 (en) * 2010-11-16 2013-03-27 Otsuka Pharma Co Ltd DOUBLE CHAMBER AND FILLING SYRINGE OF ARIPIPRAZOL IN THE SYRINGE
CN102525915B (en) * 2010-12-14 2016-09-28 江苏豪森药业集团有限公司 A kind of ejection preparation of sustained release and its production and use
LT3156056T (en) * 2011-03-18 2024-02-26 Alkermes Pharma Ireland Limited Pharmaceutical compositions comprising sorbitan esters
JO3410B1 (en) 2011-06-07 2019-10-20 Otsuka Pharma Co Ltd Freeze-dried aripiprazole formulation
JP5952912B2 (en) 2011-12-15 2016-07-13 アルカーメス ファーマ アイルランド リミテッド Prodrugs of secondary amine compounds
CN103301461B (en) * 2012-03-08 2018-09-07 江苏豪森药业集团有限公司 A kind of long acting injection and its preparation method and application
JP6333802B2 (en) * 2012-03-19 2018-05-30 アルカームス ファーマ アイルランド リミテッド Pharmaceutical composition comprising benzyl alcohol
AU2013235519C1 (en) * 2012-03-19 2018-04-26 Alkermes Pharma Ireland Limited Pharmaaceutical compositions comprising fatty acid esters
EP2827867B1 (en) * 2012-03-19 2019-11-06 Alkermes Pharma Ireland Limited Pharmaceutical compositions comprising glycerol esters
AR090775A1 (en) * 2012-04-23 2014-12-03 Otsuka Pharma Co Ltd INJECTABLE PREPARATION
JOP20200109A1 (en) 2012-04-23 2017-06-16 Otsuka Pharma Co Ltd Injectable preparation
EP2897592B1 (en) 2012-09-19 2020-02-19 Alkermes Pharma Ireland Limited Pharmaceutical compositions having improved storage stability
US9051268B2 (en) 2013-04-30 2015-06-09 Otsuka Pharmaceutical Co., Ltd. Oral solid preparation comprising aripiprazole and method for producing oral solid preparation comprising aripiprazole
US10525057B2 (en) 2013-09-24 2020-01-07 Otsuka Pharmaceutical Co., Ltd. Method of providing aripiprazole to patients having impaired CYP2D6 or CYP3A4 enzyme function
CN106132415A (en) * 2014-03-20 2016-11-16 奥克梅斯制药爱尔兰有限公司 There is the aripiprazole formulations of the injection speed of increase
CN105078898B (en) * 2014-05-22 2018-08-28 上海现代药物制剂工程研究中心有限公司 Aripiprazole long-acting slow-release particle injection and preparation method thereof
BR112017002926A2 (en) * 2014-08-18 2017-12-12 Alkermes Pharma Ireland Ltd compositions and method for enhancing the initial pharmacokinetic release profile in vivo
PL3185867T3 (en) 2014-08-25 2021-11-22 Alkermes Pharma Ireland Limited Crystallization process of aripiprazole derivatives in extended release formulations for treatment of schizophrenia
CN106474058B (en) 2015-08-31 2020-01-07 南京诺瑞特医药科技有限公司 Injectable aripiprazole suspension formulations with extended shelf life
EP3761983A1 (en) 2018-03-05 2021-01-13 Alkermes Pharma Ireland Limited Aripiprazole dosing strategy
CN108498456B (en) 2018-05-16 2021-01-01 丽珠医药集团股份有限公司 Aripiprazole sustained-release microspheres and preparation method thereof
CN110327296B (en) * 2019-08-06 2021-10-22 深圳市泛谷药业股份有限公司 Aripiprazole long-acting injection preparation and preparation method thereof
US20230310417A1 (en) 2020-03-30 2023-10-05 Cipla Limited Injectable aripiprazole formulation
BR112022018721A2 (en) 2020-04-01 2022-11-01 Otsuka Pharma Co Ltd METHODS OF ADMINISTRATION OF AN INJECTABLE PREPARATION OF ARIPIPRAZOLE
CN115212174B (en) * 2022-07-18 2024-02-20 辉粒药业(苏州)有限公司 Aripiprazole-loaded long-acting slow-release microsphere and preparation method thereof

Family Cites Families (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5832899A (en) * 1981-08-18 1983-02-25 Takeda Chem Ind Ltd Oxendrone aqueous suspension
US5006528A (en) * 1988-10-31 1991-04-09 Otsuka Pharmaceutical Co., Ltd. Carbostyril derivatives
JP2608788B2 (en) * 1988-10-31 1997-05-14 大塚製薬 株式会社 Schizophrenia remedy
FR2663223B1 (en) 1990-06-14 1994-12-02 Af Aplicaciones Far Lab PARENTERAL GALENIC FORM.
US6294170B1 (en) * 1997-08-08 2001-09-25 Amgen Inc. Composition and method for treating inflammatory diseases
US7179486B1 (en) * 1997-04-01 2007-02-20 Nostrum Pharmaceuticals, Inc. Process for preparing sustained release tablets
US6455526B1 (en) * 1998-12-16 2002-09-24 Aventis Pharmaceuticals, Inc. Biodegradable polymer encapsulated pharmaceutical compositions and method for preparing the same
US6559128B1 (en) * 2000-01-21 2003-05-06 Northwestern University Inhibitors of G protein-mediated signaling, methods of making them, and uses thereof
US6495164B1 (en) * 2000-05-25 2002-12-17 Alkermes Controlled Therapeutics, Inc. I Preparation of injectable suspensions having improved injectability
US7071227B2 (en) * 2000-09-26 2006-07-04 The Johns Hopkins University Antiviral compositions and methods of use
DE10048868A1 (en) * 2000-10-02 2002-04-11 Basf Ag Method and device for mixing additives during the conditioning of animal feed
JP2002191256A (en) 2000-12-26 2002-07-09 Yoshikatsu Nakajima Aquarium
CN100350977C (en) * 2001-06-14 2007-11-28 大塚制药株式会社 Medicinal compositions
WO2004064752A2 (en) * 2003-01-22 2004-08-05 Alkermes Controlled Therapeutics, Inc. Method of preparing sustained release microparticles
US6987111B2 (en) * 2003-08-06 2006-01-17 Alkermes Controlled Therapeutics, Ii Aripiprazole, olanzapine and haloperidol pamoate salts
US20050032811A1 (en) * 2003-08-06 2005-02-10 Josiah Brown Methods for administering aripiprazole
UA82561C2 (en) * 2003-10-23 2008-04-25 Оцука Фармасьютикалз Ко., Лтд. Controlled release sterile aripiprazole formulation for injections, method for preparing aripiprazole formulation, and method for treating schizophrenia

Also Published As

Publication number Publication date
US20180169005A1 (en) 2018-06-21
EP1660037A4 (en) 2008-09-24
JP2014001250A (en) 2014-01-09
US20090143403A1 (en) 2009-06-04
SE1660037T5 (en) 2015-09-15
IL173441A (en) 2013-04-30
US20050032811A1 (en) 2005-02-10
JP5453194B2 (en) 2014-03-26
CN102133171A (en) 2011-07-27
SI1660037T1 (en) 2012-05-31
CA2534997A1 (en) 2005-02-24
US8338428B2 (en) 2012-12-25
PL1660037T3 (en) 2012-03-30
JP2007501236A (en) 2007-01-25
NO20060638L (en) 2006-04-26
JP5300194B2 (en) 2013-09-25
MXPA06001350A (en) 2006-08-23
CY1111874T1 (en) 2015-11-04
HRP20110646T1 (en) 2011-12-31
NO339816B1 (en) 2017-02-06
AU2004264886A1 (en) 2005-02-24
NZ545037A (en) 2008-10-31
DK1660037T3 (en) 2011-12-12
US20130090343A1 (en) 2013-04-11
US20190231679A1 (en) 2019-08-01
EP2340810A1 (en) 2011-07-06
US20140275109A1 (en) 2014-09-18
EP1660037A2 (en) 2006-05-31
WO2005016262A2 (en) 2005-02-24
HK1091725A1 (en) 2007-01-26
US8759351B2 (en) 2014-06-24
AU2004264886C1 (en) 2021-06-03
JP5764634B2 (en) 2015-08-19
JP2010248258A (en) 2010-11-04
PT1660037E (en) 2011-10-24
CN1845721A (en) 2006-10-11
IL173441A0 (en) 2006-06-11
ATE522200T1 (en) 2011-09-15
US20120289516A1 (en) 2012-11-15
US20210346282A1 (en) 2021-11-11
US8338427B2 (en) 2012-12-25
WO2005016262A3 (en) 2005-09-09
ES2369893T3 (en) 2011-12-07
ZA200601385B (en) 2007-02-28
CA2534997C (en) 2011-11-01
AU2004264886B2 (en) 2007-06-07
EP1660037B1 (en) 2011-08-31

Similar Documents

Publication Publication Date Title
US20230218506A1 (en) Methods for administering aripiprazole
US8293765B2 (en) Injectable depot formulation comprising crystals of iloperidone
US10813928B2 (en) Aripiprazole formulations having increased injection speeds
US20130243853A1 (en) Compositions and methods for treating myelofibrosis
CN1206347A (en) Aqueous suspensions of 9-hydroxyrisperidone fatty acid esters
US20070027121A1 (en) Method of treatment of diarrhea-predominant IBS in a female subject receiving contraceptive therapy
US20230049974A1 (en) Fingolimod extended release injectable suspension
US20220354828A1 (en) Controlled release injectable ondansetron formulations

Legal Events

Date Code Title Description
STPP Information on status: patent application and granting procedure in general

Free format text: DOCKETED NEW CASE - READY FOR EXAMINATION