US20050250813A1 - Injectable depot formulation comprising crystals of iloperidone - Google Patents

Injectable depot formulation comprising crystals of iloperidone Download PDF

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Publication number
US20050250813A1
US20050250813A1 US10/521,064 US52106405A US2005250813A1 US 20050250813 A1 US20050250813 A1 US 20050250813A1 US 52106405 A US52106405 A US 52106405A US 2005250813 A1 US2005250813 A1 US 2005250813A1
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Prior art keywords
crystals
depot formulation
formulation according
iloperidone
microns
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US10/521,064
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Dierk Wieckhusen
Alexandra Glausch
Markus Ahlheim
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Novartis AG
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Application filed by Individual filed Critical Individual
Publication of US20050250813A1 publication Critical patent/US20050250813A1/en
Assigned to NOVARTIS AG reassignment NOVARTIS AG ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: AHLHEIM, MARKUS, GLAUSCH, ALEXANDRA, WIECKHUSEN, DIERK
Priority to US12/254,925 priority Critical patent/US20090099232A1/en
Priority to US13/106,417 priority patent/US8293765B2/en
Priority to US13/401,310 priority patent/US8227488B2/en
Priority to US13/618,753 priority patent/US8614232B2/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
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • 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
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia

Definitions

  • This invention relates to an injectable depot formulation comprising crystals of iloperidone or its metabolite wherein the release and absorption of the crystals in plasma can be correlated with the crystal size.
  • Microencapsulated depot formulations of iloperidone and a poly-glycolide polylactide glucose star polymer are disclosed in U.S. Patent Application Nos. 60/339,036, filed Oct. 30, 2001, and 60/339,037, filed Oct. 30, 2001.
  • U.S. Pat. No. 5,955,459 describes compositions for treating schizophrenia containing conjugates of a fatty acid and iloperidone.
  • a preferred fatty acid is cis-docosahexanoic acid.
  • the depot formulation should provide a reliable, reproducible and constant plasma concentration profile of iloperidone or its metabolite following administration to a patient.
  • the present invention provides an injectable depot formulation comprising crystals of iloperidone or its metabolite or a pharmaceutically acceptable salt, hydrate, solvate, polymorph and stereoisomer thereof, wherein the mean particle size (X 50 value) of the crystals is from 1 to 200 microns.
  • an injectable depot formulation comprising crystals having Structure (I) wherein R is and the X 50 value of the crystals is from 1 to 200 microns.
  • the invention provides crystals of iloperidone or its metabolite or a pharmaceutically acceptable salt, hydrate, solvate, polymorph and stereoisomer thereof, wherein the X 50 value of the crystals is from 1 to 200 microns.
  • the present inventors have unexpectedly determined that depot formulations containing crystals of iloperidone or its metabolite have the following advantages: (i) release of the crystals in plasma can be correlated with the size of the crystals; (ii) absorption of the crystals in plasma can be correlated with the size of the crystals; (iii) the particle size of the crystals can be controlled by crystal engineering and/or milling; and (iv) the crystals are stable upon storage, and stable to sterilization procedures, such as gamma irradiation.
  • FIG. 1 is a photomicrograph of iloperidone crystals wherein 1 grid is equal to 100 microns.
  • FIG. 2 is a photomicrograph of iloperidone crystals after milling wherein 1 grid is equal to 250 microns.
  • FIG. 3 is a graph of mean plasma concentrations in female rabbits of an iloperidone crystal depot formulation having an X 50 value of 16 microns and 30 microns over a period of time.
  • FIG. 4 is a graph of mean plasma concentrations in female rabbits of an iloperidone crystal depot formulation having an X 50 value of 170 microns over a period of time.
  • Iloperidone is 1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxyphenyl]ethanone.
  • iloperidone includes any salts, hydrates, solvates, polymorphs such as amorphous polymorphs, and/or stereoisomers thereof.
  • the metabolite of iloperidone is 1-[4-[3-[4-(6-fluoro(d)isoxazol-3-yl)-piperidin-1-yl]propoxy]-3-methoxyphenyl]ethanol.
  • metabolite of iloperidone includes any salts, hydrates, solvates, polymorphs such as amorphous polymorphs, and/or stereoisomers thereof.
  • the crystals have Structure (I) wherein R is
  • R is the crystals may exist as either the (R) or (S) enantiomer, or as a racemic mixture thereof.
  • the (S) enantiomer has Structure II
  • the crystals may be in the form of needles, trigonal forms, tetragonal forms, flat rod shaped, cubes, parallelepipeds, or plate-like.
  • the mean particle size (X 50 value) of the crystals is preferably from about 1 to about 200 microns, more preferably 10 to 170 microns, whereby application of the depot formulation to a patient can be carried out using a standard gauge (typically 18 or 20 gauge) needle. Most preferably, the mean particle size (X 50 value) of the crystals is from 15 to 70 microns.
  • the crystals may be prepared by crystal growth or engineering directly to a desired crystal size.
  • the crystals may be prepared to a larger crystal size than is desired in the depot formulations.
  • the crystals may be milled or ground to achieve crystals having a size in the desired range.
  • Such a milling step is important for achieving the desired crystal size distribution.
  • any mill can be used, for example, a pinmill.
  • the crystals may optionally be passed through a screen stack or sieve with crystals of the desired size retained while the crystals falling outside of the desired range (either too small or too large) are discarded.
  • the depot formulations of the invention as suspensions in a suitable vehicle.
  • Aqueous suspensions are preferred such as the crystals suspended in water.
  • the present inventors have determined that in the case of a suspension, the crystals are preferable administered with one or more additional ingredients.
  • Additional ingredients which may be used in the depot formulations of the invention include natural and/or artificial ingredients which are commonly used to prepare pharmaceutical compositions.
  • additional ingredients include a surfactant, solubilizer, emulsifier, preservative, isotonicity agent, dispersing agent, wetting agent, filler, solvent, buffer, stabilizer, lubricant, and thickening agent.
  • a combination of additional ingredients may also be used.
  • Preferred additional ingredients are a surfactant, isotonicity agent, and thickening agent.
  • such ingredients and their concentrations in parenteral formulations are known to those skilled in the art, and thus, only examples of the preferred additional ingredients are described.
  • the depot formulations of the invention should not be limited to the following examples of preferred additional ingredients.
  • surfactants include: sorbitan fatty acid esters such as sorbitan trioleate, phosphatides such as lecithin, acacia, tragacanth, polyoxyethylated sorbitan monooleate and other ethoxylated fatty acid esters of sorbitan, polyoxyalkylene derivatives of propylene glycol, such as those available under the trademark PLURONIICS, especially PLURONICS F68; polyoxyethylated fats, polyoxyethylated oleotriglycerides, linolizated oleotriglycerides, polyethylene oxide condensation products of fatty alcohols, alkylphenols or fatty acids or 1-methyl-3-(2-hydroxyethyl)imidazolidone-(2).
  • sorbitan fatty acid esters such as sorbitan trioleate, phosphatides such as lecithin, acacia, tragacanth, polyoxyethylated sorbitan monoole
  • polyoxyethylated means that the substances in question contain polyoxyethylene chains, the degree of polymerization of which generally is between 2 and 40, and preferably, between 10 and 20.
  • a preferred surfactant is a polyoxyalkylene derivative of propylene glycol, such as PLURONICS F68 which is available from BASF.
  • the amount of surfactant in the depot formulations of the invention is in the range known in the art for parenteral formulations, preferably from about 0.5 to about 10 mg/mL.
  • thickening agents examples include: croscarmellose sodium, sodium carboxymethyl cellulose, and hydroxypropyl cellulose.
  • a preferred thickening agent is sodium carboxymethyl cellulose.
  • the amount of thickening agent in the depot formulations of the invention is in the range known in the art for parenteral formulations, preferably from about 2 to about 25 mg/mL.
  • isotonicity agents which may impart tonicity to the depot formulations to prevent the net flow of water across a cell membrane, include: salts such as sodium chloride; sugars such as dextrose, mannitol, and lactose. Mannitol is a preferred isotonicity agent.
  • the amount of isotonicity agent in the depot formulations of the invention is in the range known in the art for parenteral formulations.
  • the amount of iloperidone or its metabolite in the depot formulations will vary depending upon the severity of the condition to be treated.
  • the depot formulations of the invention are preferably injectable and may be administered by intramuscular or subcutaneous injection.
  • the depot formulations administered by injection provide an effective treatment of diseases over an extended period, for example, from about 2 to about 8 weeks.
  • the depot formulation allows a controlled release of iloperidone or its metabolite by dissolution of the crystals, and therefore, steady state levels of the iloperidone or its metabolite are obtained over the extended period.
  • the amount of iloperidone or its metabolite administered in one injection is preferably from about 10 mg to about 1000 mg. More preferably, the amount of iloperidone or its metabolite administered in one injection is from about 100 mg to about 750 mg.
  • the crystals of defined size are filled into a glass vial, purged with nitrogen and sealed with a rubber stopper.
  • the vial may be terminal sterilized by gamma irradiation, preferably, in a range of 25-35 kGy or manufactured under aseptic conditions.
  • the iloperidone crystals are injected into the body.
  • the crystals of the metabolite of iloperidone are injected into the body.
  • the iloperidone crystals are suspended in water, and the suspension is injected into the body.
  • the crystals of the metabolite of iloperidone are suspended in water, and the suspension is injected into the body.
  • the depot formulation of the invention is useful for treating central nervous system disorders, for example, psychotic disorders such as schizophrenia.
  • the invention also provides a package comprising a container containing the depot formulation and instructions for using the depot formulation for treating schizophrenia in a patient.
  • the suspension was cooled to an internal pressure of 0° C. with a rate of 0.25 K/min and stirred for 2 to 12 hours at an internal temperature of 0° C.
  • Iloperidone, 315 g was obtained as wet, light brownish filtercake.
  • the wet product was dried at an external temperature of 50-60° C. under a vacuum of less than 2 mbar for about 16-24 hours.
  • Iloperidone, 238.3 g was obtained.
  • Theoretical yield was determined to be 94.4%.
  • the iloperidone crystals prepared in Example 1, 120 mg, having a particle size X 50 32 ⁇ m were reconstituted with 1 ml of a mixture containing sodiumcarboxymethylcellulose, Pluronics F68, and mannitol, by shaking resulting in a homogeneous suspension. The suspension was withdrawn from the vial with a syringe and injected into rabbits.
  • FIG. 3 is a graph of mean plasma concentrations in female rabbits of an iloperidone crystal depot formulation having an X 50 value of 16 microns and 30 microns over a period of time.
  • the formulations were dose normalized to 20 mg of iloperidone per kg of each rabbit. Each formulation was injected into six rabbits.
  • the depot formulations prepared with iloperidone crystals having a X 50 30 remained in the plasma of the rabbits for at least 25 days.
  • the mean dose normalized pharmacokinetic parameters of iloperidone in plasma for each crystal size are summarized in Table I. TABLE I Actual dose t max,d Iloperidone C max,d [d] Formulation [mg/kg] mean [ng/mL] mean median 16 um 16.7 53.2 6 30 um 17.0 35.3 9
  • FIG. 4 is a graph of mean plasma concentrations in female rabbits of an iloperidone crystal depot formulation having an X 50 value of 170 microns over a period of time.
  • the formulations were dose normalized to 20 mg of iloperidone per kg of each rabbit.
  • the formulation was injected into six rabbits.
  • the mean dose normalized pharmacokinetic parameters of iloperidone in plasma are summarized in Table II. TABLE II Actual dose T max,e Iloperidone C max,e [d] Formulation (mg/kg) Mean [ng/mL] (median) 170 um 15.7 ⁇ 1.9 37.4 ⁇ 11.2 10.5
  • Depot formulations containing crystals of iloperidone or its metabolite have the following advantages: (i) release of the crystals in plasma can be correlated with the size of the crystals; (ii) absorption of the crystals in plasma can be correlated with the size of the crystals; (iii) the particle size of the crystals can be controlled by crystal engineering and/or milling; and (iv) the crystals are stable upon storage, and stable to sterilization procedures, such as gamma irradiation.

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US10/521,064 2002-07-15 2003-07-14 Injectable depot formulation comprising crystals of iloperidone Abandoned US20050250813A1 (en)

Priority Applications (4)

Application Number Priority Date Filing Date Title
US12/254,925 US20090099232A1 (en) 2002-07-15 2008-10-21 Injectable depot formulation comprising crystals of iloperidone
US13/106,417 US8293765B2 (en) 2002-07-15 2011-05-12 Injectable depot formulation comprising crystals of iloperidone
US13/401,310 US8227488B2 (en) 2002-07-15 2012-02-21 Injectable depot formulation comprising crystals of iloperidone
US13/618,753 US8614232B2 (en) 2002-07-15 2012-09-14 Injectable depot formulation comprising crystals of iloperidone

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GB0216416.8 2002-07-15
GBGB0216416.8A GB0216416D0 (en) 2002-07-15 2002-07-15 Organic compounds
PCT/EP2003/007619 WO2004006886A2 (en) 2002-07-15 2003-07-14 Injectable depot formulation comprising crystals of iloperidone

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US10/521,064 Abandoned US20050250813A1 (en) 2002-07-15 2003-07-14 Injectable depot formulation comprising crystals of iloperidone
US12/254,925 Abandoned US20090099232A1 (en) 2002-07-15 2008-10-21 Injectable depot formulation comprising crystals of iloperidone
US13/106,417 Expired - Fee Related US8293765B2 (en) 2002-07-15 2011-05-12 Injectable depot formulation comprising crystals of iloperidone
US13/401,310 Expired - Fee Related US8227488B2 (en) 2002-07-15 2012-02-21 Injectable depot formulation comprising crystals of iloperidone
US13/618,753 Expired - Fee Related US8614232B2 (en) 2002-07-15 2012-09-14 Injectable depot formulation comprising crystals of iloperidone

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US12/254,925 Abandoned US20090099232A1 (en) 2002-07-15 2008-10-21 Injectable depot formulation comprising crystals of iloperidone
US13/106,417 Expired - Fee Related US8293765B2 (en) 2002-07-15 2011-05-12 Injectable depot formulation comprising crystals of iloperidone
US13/401,310 Expired - Fee Related US8227488B2 (en) 2002-07-15 2012-02-21 Injectable depot formulation comprising crystals of iloperidone
US13/618,753 Expired - Fee Related US8614232B2 (en) 2002-07-15 2012-09-14 Injectable depot formulation comprising crystals of iloperidone

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EP (1) EP1523335B1 (https=)
JP (2) JP5392961B2 (https=)
AT (1) ATE348635T1 (https=)
AU (1) AU2003281154B2 (https=)
CA (1) CA2492467C (https=)
CY (1) CY1106305T1 (https=)
DE (1) DE60310564T2 (https=)
DK (1) DK1523335T3 (https=)
ES (1) ES2279153T3 (https=)
GB (1) GB0216416D0 (https=)
NZ (1) NZ537598A (https=)
PT (1) PT1523335E (https=)
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US20090099232A1 (en) * 2002-07-15 2009-04-16 Dierk Wieckhusen Injectable depot formulation comprising crystals of iloperidone
CN101822673A (zh) * 2009-03-04 2010-09-08 北京德众万全药物技术开发有限公司 一种含有伊潘立酮的固体药物组合物
WO2011032404A1 (zh) * 2009-09-19 2011-03-24 浙江华海药业股份有限公司 伊潘立酮的一种制备方法及结晶方法
CN103599074A (zh) * 2013-11-26 2014-02-26 重庆医药工业研究院有限责任公司 一种伊潘立酮缓释微球及其制备方法
WO2014152723A1 (en) * 2013-03-15 2014-09-25 Inotek Pharmaceuticals Corporation Ophthalmic formulations
US9278991B2 (en) 2012-01-26 2016-03-08 Inotek Pharmaceuticals Corporation Anhydrous polymorphs of [(2R,3S,4R,5R)-5-(6-(cyclopentylamino)-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)} methyl nitrate and processes of preparation thereof
US9289383B2 (en) 2010-03-26 2016-03-22 Inotek Pharmaceuticals Corporation Method of reducing intraocular pressure in humans
US9370530B2 (en) 2010-01-11 2016-06-21 Inotek Pharmaceuticals Corporation Combination, kit and method of reducing intraocular pressure
US9469630B2 (en) 2010-10-18 2016-10-18 Sumitomo Dainippon Pharma Co., Ltd. Sustained-release formulation for injection
CN113164382A (zh) * 2018-12-04 2021-07-23 万达制药公司 伊潘立酮的贮库施用

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ATE411797T2 (de) 2003-10-23 2008-11-15 Otsuka Pharma Co Ltd Sterile injizierbare aripiprazol-formulierung mit kontrollierter freisetzung und verfahren
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US20100063093A1 (en) 2007-03-28 2010-03-11 Curt Wolfgang Methods for the administration of iloperidone
US20090306137A1 (en) 2006-05-22 2009-12-10 Wolfgang Curt D Treatment for depressive disorders
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MY152789A (en) 2007-07-31 2014-11-28 Otsuka Pharma Co Ltd Methods for producing aripiprazole suspension and freeze-dried formulation
EP2198048A2 (en) 2007-09-10 2010-06-23 Vanda Pharmaceuticals Inc. Prediction of qt prolongation based on snp genotype
BRPI0820993A2 (pt) 2007-12-13 2017-05-09 Vanda Pharmaceuticals Inc método e composição para tratar uma condição mediada por alfa adrenoceptor
SI2222300T1 (sl) 2007-12-13 2014-11-28 Vanda Pharmaceuticals Inc. Postopek in sestavek za zdravljenje stanja, posredovanega z receptorjem serotonina
WO2010031497A1 (en) * 2008-09-19 2010-03-25 Miklos Vertessy New process for the preparation of iloperidone
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CN102030744B (zh) * 2009-09-30 2013-04-17 天津药物研究院 伊潘立酮晶体、其制备方法及药物组合物
WO2011055188A1 (en) * 2009-11-05 2011-05-12 Orchid Chemicals And Pharmaceuticals Limited An improved process for the preparation of iloperidone
MX2012007365A (es) * 2009-12-23 2012-08-15 Lupin Ltd Composiciones farmaceuticas de liberacion lenta de iloperidona.
CN102108081A (zh) * 2009-12-25 2011-06-29 重庆医药工业研究院有限责任公司 伊潘立酮的新晶型及其制备方法
CN101822674B (zh) * 2010-05-27 2015-03-11 北京德众万全医药科技有限公司 一种伊潘立酮药物组合物及其制备方法
WO2012063269A2 (en) 2010-11-12 2012-05-18 Cadila Healthcare Limited Process for preparing iloperidone
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CN102680636A (zh) * 2011-03-11 2012-09-19 天津药物研究院 一种伊潘立酮原料药及其中间体的质量控制方法
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US8293765B2 (en) 2012-10-23
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