US20050032811A1 - Methods for administering aripiprazole - Google Patents

Methods for administering aripiprazole Download PDF

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Publication number
US20050032811A1
US20050032811A1 US10/635,221 US63522103A US2005032811A1 US 20050032811 A1 US20050032811 A1 US 20050032811A1 US 63522103 A US63522103 A US 63522103A US 2005032811 A1 US2005032811 A1 US 2005032811A1
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Prior art keywords
composition
aripiprazole
injection vehicle
polysorbate
agent
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Abandoned
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US10/635,221
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Josiah Brown
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Alkermes Inc
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Alkermes Controlled Therapeutics Inc
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Application filed by Alkermes Controlled Therapeutics Inc filed Critical Alkermes Controlled Therapeutics Inc
Priority to US10/635,221 priority Critical patent/US20050032811A1/en
Assigned to ALKERMES CONTROLLED THERAPEUTICS, II reassignment ALKERMES CONTROLLED THERAPEUTICS, II ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: BROWN, JOSIAH
Priority to MXPA06001350A priority patent/MXPA06001350A/en
Priority to ES04779411T priority patent/ES2369893T3/en
Priority to JP2006522614A priority patent/JP5300194B2/en
Priority to SI200431772T priority patent/SI1660037T1/en
Priority to DK04779411.0T priority patent/DK1660037T3/en
Priority to AT04779411T priority patent/ATE522200T1/en
Priority to PL04779411T priority patent/PL1660037T3/en
Priority to NZ545037A priority patent/NZ545037A/en
Priority to CNA2004800252878A priority patent/CN1845721A/en
Priority to SE04779411T priority patent/SE1660037T5/xx
Priority to CA2534997A priority patent/CA2534997C/en
Priority to PCT/US2004/024345 priority patent/WO2005016262A2/en
Priority to EP10193459A priority patent/EP2340810A1/en
Priority to CN2011100063238A priority patent/CN102133171A/en
Priority to PT04779411T priority patent/PT1660037E/en
Priority to AU2004264886A priority patent/AU2004264886C1/en
Priority to EP04779411A priority patent/EP1660037B1/en
Publication of US20050032811A1 publication Critical patent/US20050032811A1/en
Priority to IL173441A priority patent/IL173441A/en
Priority to NO20060638A priority patent/NO339816B1/en
Priority to ZA200601385A priority patent/ZA200601385B/en
Priority to HK06112238.1A priority patent/HK1091725A1/en
Assigned to ALKERMES, INC. reassignment ALKERMES, INC. MERGER (SEE DOCUMENT FOR DETAILS). Assignors: ALKERMES CONTROLLED THERAPEUTICS, II
Priority to US12/251,656 priority patent/US8338427B2/en
Priority to JP2010173601A priority patent/JP5453194B2/en
Priority to HR20110646T priority patent/HRP20110646T1/en
Priority to CY20111100940T priority patent/CY1111874T1/en
Priority to US13/420,822 priority patent/US8338428B2/en
Priority to US13/648,544 priority patent/US8759351B2/en
Priority to JP2013212864A priority patent/JP5764634B2/en
Priority to US14/160,176 priority patent/US20140275109A1/en
Priority to US15/666,840 priority patent/US20180169005A1/en
Priority to US16/166,400 priority patent/US20190231679A1/en
Priority to US17/247,708 priority patent/US20210346282A1/en
Priority to US18/121,883 priority patent/US20230218506A1/en
Abandoned legal-status Critical Current

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    • 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
    • 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
    • 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

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.
  • poor patient compliance with oral antipsychotics has been reported.
  • 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 fuictions, 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.
  • Species and Strain Sprague-Dawley rats. Male; 450+/ ⁇ 50 grams.
  • Injection Vehicle Aqueous diluent containing 3% CMC (low viscosity), 0.1% Tween 20, in 0.9% NaCl and water.
  • 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 ⁇ L blood were collected at for each time point during the first 24 hours and 400 ⁇ L for at each time point thereafter.

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

    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 ofpolymeric 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 fuictions, 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  30%
    Drug in
    microspheres
    E 03-10-66-C 4A Bulk  50%
    Drug 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:
  • 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 ats 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.

Claims (38)

1. An injectable composition for the extended release of aripiprazole comprising a mixture of at least about 10 mg/ml aripiprazole in an injection vehicle comprising An optional viscosity enhancing agent.
2. The composition of claim 1 wherein the aripiprazole release is for at least 7 days.
3. The composition of claim 2 wherein the viscosity enhancing agent comprises carboxymethyl cellulose.
4. The composition of claim 3, wherein said injection vehicle comprises at least about 1% by volume sodium carboxymethyl cellulose.
5. The composition of claim 4, wherein said injection vehicle comprises about 3% by volume carboxymethyl cellulose.
6. The composition of claim 2 wherein the injection vehicle further comprises a wetting agent.
7. The composition of claim 6 wherein the surfactant is selected from the group consisting of polysorbate 20, polysorbate 40, and polysorbate 80.
8. The composition of claim 7 wherein the wetting agent is polysorbate 20.
9. The composition of claim 8 wherein the injection vehicle comprises about 0.1% by weight of polysorbate 20.
10. The composition of claim 2, wherein said injection vehicle comprises a density enhancing agent.
11. The composition of claim 10, wherein said density enhancing agent comprises sorbitol.
12. The composition of claim 2, wherein said injection vehicle comprises a tonicity adjusting agent.
13. The composition of claim 12, wherein said tonicity adjusting agent comprises sodium chloride.
14. The composition of claim 1, wherein said injection vehicle comprises about 1% by weight of sodium chloride.
15. A composition comprising at least about 10 mg of aripiprazole and an aqueous injection vehicle comprising water, a viscosity enhancing agent, a wetting agent and a tonicity agent.
16. A composition comprising at least about 10 mg of aripiprazole and an aqueous injection vehicle comprising water, about 3% by volume carboxymethylcellulose, about 0.1% polysorbate 20 and about 1% by weight sodium chloride.
17. A composition comprising at least about 10 mg of aripiprazole and an aqueous injection vehicle consisting essentially of water, about 3% by volume carboxymethylcellulose, about 0.1% by weight polysorbate 20 and about 0.9% by weight sodium chloride.
18. A method 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 an optional viscosity enhancing agent.
19. The method of claim 18 wherein the aripiprazole is present in an amount of at least about 20 mg/ml.
20. The method of claim 19 wherein a therapeutically effective amount of the aripiprazole is present in the plasma of the individual for at least about 7 days.
21. The method of claim 19 wherein a therapeutically effective amount of the aripiprazole is present in the plasma of the individual for at least about 14 days.
22. The method of claim 19 wherein a therapeutically effective amount of the aripiprazole is present in the plasma of the individual for at least about 21 days.
23. The method of claim 19 wherein the viscosity enhancing agent comprises carboxymethyl cellulose.
24. The method of claim 23, wherein said injection vehicle comprises at least about 1% by volume sodium carboxymethyl cellulose.
25. The method of claim 24, wherein said injection vehicle comprises about 3% by volume carboxymethyl cellulose.
26. The method of claim 25 wherein the injection vehicle further comprises a wetting agent.
27. The method of claim 26 wherein the surfactant is selected from the group consisting of polysorbate 20, polysorbate 40, and polysorbate 80.
28. The method of claim 27 wherein the wetting agent is polysorbate 20.
29. The method of claim 28 wherein the injection vehicle comprises about 0.1% by weight of polysorbate 20.
30. The method of claim 22, wherein said injection vehicle comprises a density enhancing agent.
31. The method of claim 30, wherein said density enhancing agent comprises sorbitol.
32. The method of claim 22, wherein said injection vehicle comprises a tonicity adjusting agent.
33. The method of claim 32, wherein said tonicity adjusting agent comprises sodium chloride.
34. The method of claim 21, wherein said injection vehicle comprises about 1% by weight of sodium chloride.
35. The method of claim 18 wherein the composition is administered by injection.
36. The method of claim 18 wherein the composition is administered intramuscularly or subcutaneously.
37. The method of claim 18 further comprising a second administration of the composition at least about 7 days after the first administration.
38. The method of claim 18 further comprising a second administration of the composition at least about 14 days after the first administration.
US10/635,221 2003-08-06 2003-08-06 Methods for administering aripiprazole Abandoned US20050032811A1 (en)

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US10/635,221 US20050032811A1 (en) 2003-08-06 2003-08-06 Methods for administering aripiprazole
PL04779411T PL1660037T3 (en) 2003-08-06 2004-07-29 Aripiprazole injectable suspension
AU2004264886A AU2004264886C1 (en) 2003-08-06 2004-07-29 Methods for administering aripiprazole
EP04779411A EP1660037B1 (en) 2003-08-06 2004-07-29 Aripiprazole injectable suspension
SE04779411T SE1660037T5 (en) 2003-08-06 2004-07-29
JP2006522614A JP5300194B2 (en) 2003-08-06 2004-07-29 Administration method of aripiprazole
SI200431772T SI1660037T1 (en) 2003-08-06 2004-07-29 Aripiprazole injectable suspension
DK04779411.0T DK1660037T3 (en) 2003-08-06 2004-07-29 Aripiprazole injection suspension
AT04779411T ATE522200T1 (en) 2003-08-06 2004-07-29 ARIPIPRAZOLE INJECTION SUSPENSION
MXPA06001350A MXPA06001350A (en) 2003-08-06 2004-07-29 Methods for administering aripiprazole.
NZ545037A NZ545037A (en) 2003-08-06 2004-07-29 Methods for administering aripiprazole
CNA2004800252878A CN1845721A (en) 2003-08-06 2004-07-29 Methods for administering aripiprazole
ES04779411T ES2369893T3 (en) 2003-08-06 2004-07-29 INJECTABLE SUSPENSION OF ARIPIPRAZOL.
CA2534997A CA2534997C (en) 2003-08-06 2004-07-29 Methods for administering aripiprazole
PCT/US2004/024345 WO2005016262A2 (en) 2003-08-06 2004-07-29 Methods for administering aripiprazole
EP10193459A EP2340810A1 (en) 2003-08-06 2004-07-29 Aripiprazole injectable suspension
CN2011100063238A CN102133171A (en) 2003-08-06 2004-07-29 Methods for administering aripiprazole
PT04779411T PT1660037E (en) 2003-08-06 2004-07-29 Aripiprazole injectable suspension
IL173441A IL173441A (en) 2003-08-06 2006-01-30 Injectable composition for the extended release of aripiprazole and use of a mixture of aripiprazole in an injection vehicle
NO20060638A NO339816B1 (en) 2003-08-06 2006-02-09 Injectable composition for prolonged release of aripiprazole
ZA200601385A ZA200601385B (en) 2003-08-06 2006-02-16 Methods for administering aripiprazole
HK06112238.1A HK1091725A1 (en) 2003-08-06 2006-11-07 Aripiprazole injectable suspension
US12/251,656 US8338427B2 (en) 2003-08-06 2008-10-15 Methods for administering aripiprazole
JP2010173601A JP5453194B2 (en) 2003-08-06 2010-08-02 Administration method of aripiprazole
HR20110646T HRP20110646T1 (en) 2003-08-06 2011-09-07 Aripiprazole injectable suspension
CY20111100940T CY1111874T1 (en) 2003-08-06 2011-09-29 ADMINISTRATIVE ADMINISTRATION OF ARIPIPRAZOL
US13/420,822 US8338428B2 (en) 2003-08-06 2012-03-15 Methods for administering aripiprazole
US13/648,544 US8759351B2 (en) 2003-08-06 2012-10-10 Methods for administering aripiprazole
JP2013212864A JP5764634B2 (en) 2003-08-06 2013-10-10 Administration method of 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

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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
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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
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