WO1997033577A1 - Method for treating bipolar disorder - Google Patents

Method for treating bipolar disorder Download PDF

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Publication number
WO1997033577A1
WO1997033577A1 PCT/US1996/019575 US9619575W WO9733577A1 WO 1997033577 A1 WO1997033577 A1 WO 1997033577A1 US 9619575 W US9619575 W US 9619575W WO 9733577 A1 WO9733577 A1 WO 9733577A1
Authority
WO
WIPO (PCT)
Prior art keywords
bipolar disorder
olanzapine
effective amount
treating
patient
Prior art date
Application number
PCT/US1996/019575
Other languages
English (en)
French (fr)
Inventor
Charles M. Beasley, Jr.
Gary D. Tollefson
Original Assignee
Eli Lilly And Company
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
Application filed by Eli Lilly And Company filed Critical Eli Lilly And Company
Priority to IL12616296A priority Critical patent/IL126162A0/xx
Priority to AU13307/97A priority patent/AU734011B2/en
Priority to EA199800819A priority patent/EA000758B1/ru
Priority to CA 2248905 priority patent/CA2248905A1/en
Priority to BR9612548A priority patent/BR9612548A/pt
Priority to PL96328925A priority patent/PL328925A1/xx
Priority to JP9532570A priority patent/JP2000506859A/ja
Priority to EP96944772A priority patent/EP0889725A4/en
Priority to NZ326031A priority patent/NZ326031A/en
Publication of WO1997033577A1 publication Critical patent/WO1997033577A1/en
Priority to NO984189A priority patent/NO984189D0/no

Links

Classifications

    • 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
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants

Definitions

  • This invention provides a method for using 2- methyl-4- (4-methyl-l-piperazinyl) -lOH-thieno[2,3-b] [1,5] benzodiazepine, (hereinafter referred as "olanzapine”), for the treatment of bipolar disorder.
  • Bipolar Disorder is a psychiatric condition which is prevelant across cultures and age groups. The lifetime prevalence of Bipolar Disorder can be as high as 1.6%. DSM- IV. p. 353 (American Psychiatric Association, Washington, D.C. 1994) . Bipolar Disorder is a recurrent disorder characterized by one or more Manic Episodes immediately before or after a Major Depressive Episode or may be characterized by one or more Major Depressive Episodes accompanied by at least one Hypomanic Episode. Additionally, the symptoms must cause clinically significant distress or impairment in social, occupational, or other important areas of functioning.
  • Bipolar Disorder In some cases the Hypomanic Episodes themselves do not cause impairment; however, the impairment may result from the Major Depressive Episodes or from a chronic pattern of unpredictable mood episodes and fluctuating unreliable interpersonal and occupational functioning.
  • the symptoms of Bipolar Disorder must not be better accounted for by a psychotic condition or due to the direct physiological effects of a medication, other somatic treatments for depression, drugs of abuse, or toxin exposure.
  • Bipolar Disorder is associated with a significant risk of completed suicide. Further, the patient suffering from Bipolar Disorder is likely to suffer from school truancy, school failure, occupational failure, or divorce. Therefore, Bipolar Disorder is a serious, fairly prevelant, psychological condition which is clearly distinguished from psychotic conditions such as schizophrenia.
  • DSM-IV. p. 353 American Psychiatric Association, Washington, D.C. 1994
  • DSM-IV. p. 353 American Psychiatric Association, Washington, D.C. 1994
  • DSM-IV. p. 353 American Psychiatric Association, Washington, D.C
  • olanzapine can provide antipsychotic activity and is currently undergoing investigation for this purpose.
  • Olanzapine is a known compound and described in U.S. Patent No. 5,229,382 as being useful for the treatment of schizophrenia, schizophreniform disorder, acute mania, mild anxiety states, and psychosis.
  • U.S. Patent No. 5,229,382 is herein incorporated by reference in its entirety.
  • olanzapine was not known to be useful for the treatment of Bipolar Disorder. Applicants have discovered that olanzapine can be useful for the treatment of bipolar disorder. Olanzapine could address a long felt need for treatments which provide a favorable safety profile and effectively provide relief for the patient suffering from Bipolar Disorder.
  • olanzapine can be useful for treating Bipolar Disorder, Major Depressive Episode.
  • olanzapine can be a useful treatment for Bipolar Disorder wherein the Bipolar Disorder is not characterized by a manic episode.
  • the presently claimed invention provides a method for treating bipolar disorder, comprising administering an effective amount of olanzapine or a pharmaceutically acceptable salt thereof to a patient in need of such treatment.
  • the present invention provides a method for treating depressive/depressive bipolar disorder, comprising administering an effective amount of olanzapine or a pharmaceutically acceptable salt thereof to a patient in need of such treatment.
  • the present invention provides a method for treating Bipolar Disorder, Major Depressive episode, comprising administering an effective amount of olanzapine or a pharmaceutically acceptable salt thereof to a patient in need of such treatment.
  • Olanzapine is of the formula
  • Bipolar Disorder involves at least one manic episode; however, some patients suffering from Bipolar Disorder experience Major Depressive episodes.
  • the present invention provides a method for treating the patient suffering from or susceptible to Bipolar Disorder, wherein the patient fails to experience a manic episode.
  • olanzapine will be the Form II olanzapine polymorph having a typical x-ray powder diffraction pattern as represented by the following interplanar spacings:
  • a typical example of an x-ray diffraction pattern for Form II is as follows wherein d represents the interplanar spacing and I/I ⁇ represents the typical relative intensities: d ⁇ /i ⁇
  • substantially pure refers to Form II associated with less than about 5% Form I, preferably less than about 2% Form I, and more preferably less than about 1% Form I. Further, “substantially pure” Form II will contain less than about 0.5% related substances, wherein “related substances” refers to undesired chemical impurities or residual solvent or water.
  • the polymorph obtainable by the process taught in the '382 patent will be designated as Form I and has a typical x-ray powder diffraction pattern substantially as follows, obtained using a Siemens D5000 x-ray powder diffractometer, wherein d represents the interplanar spacing:
  • the interplanar spacings in the column marked “d” are in Angstroms.
  • the typical relative intensities are in the column marked "I/Ii”.
  • the term “mammal” shall refer to the Mammalia class of higher vertebrates.
  • the term “mammal” includes, but is not limited to, a human.
  • the term “treating” as used herein includes prophylaxis of the named condition or amelioration or elimination of the condition once it has been established.
  • Bipolar Disorder shall refer to a condition characterized as a Bipolar Disorder, in the DSM-IV-R. Diagnostic and Statistical Manual of Mental Disorders. Revised. 3rd Ed. (1994) as catagory 296.xx. To further clarify. Applicants contemplate the treatment of both Bipolar Disorder I and Bipolar disorder II as described in the DSM-IV-R.
  • the DSM-IV-R was prepared by the Task Force on Nomenclature and Statistics of the American Psychiatric
  • olanzapine has muscarinic cholinergic receptor activity.
  • the compound is active at the dopamine D-l and D-2 receptors as indicated by an IC50 of less than 1 uM in the 3H-SCH233390 (Billard, et al. Life Sciences 35:1885 (1984)) and the 3H spiperone (Seeman et al Nature 216:717 (1976)) binding assays respectively.
  • olanzapine is active at the 5-HT-2 receptor and 5-HTlC receptor.
  • the complex pharmacological profile of the compound provides a medicament which can be useful for the treatment of Bipolar Disorder. The usefulness of the compound for treating a
  • Olanzapine is effective over a wide dosage range, the actual dose administered being dependent on the condition being treated. For example, in the treatment of adult humans, dosages of from about 0.25 to 50 mg, preferably from 1 to 30 mg, and most preferably 1 to 20 mg per day may be used. A once a day dosage is normally sufficient, although divided doses may be administered. For treatment of a Bipolar Disorder, a dose range of from 1 to 30 mg, preferably 1 to 20 mg per day is suitable. Radiolabelled olanzapine, can be detected in the saliva and thus the compound can potentially be monitored in patients to assess compliance.
  • a preferred formulation of the invention is a solid oral formulation comprising from about 1 to about 20 mg or 1 to 10 mg of olanzapine as an effective amount of the active ingredient.
  • the solid oral formulation is contained in packaging materials which protect the formulation from moisture and light.
  • suitable packaging materials include amber colored high density polyethylene bottles, amber colored glass bottles, and other containers made of a material which inhibits the passage of light.
  • the packaging will include a desiccant pack.
  • the container may be sealed with an aluminum foil blister to provide the desired protection and maintain product stability.
  • Olanzapine will normally be administered orally or by injection and, for this purpose, it is usually employed in the form of a pharmaceutical composition.
  • compositions comprising olanzapine, as active ingredient associated with a pharmaceutically acceptable carrier may be prepared.
  • conventional techniques for the preparation of pharmaceutical compositions may be used.
  • the active ingredient will usually be mixed with a carrier, or diluted by a carrier, or enclosed within a carrier which may be in the form of a capsule, sachet, paper or other container.
  • the carrier serves as a diluent, it may be solid, semi-solid or liquid material which acts as a vehicle, excipient or medium for the active ingredient.
  • the active ingredient can be adsorbed on a granular solid container for example in a sachet.
  • compositions of the invention may, if desired, be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient.
  • compositions for the treatment of central nervous system conditions may be formulated as tablets, capsules, injection solutions for parenteral use, gel or suspension for transdermal delivery, suspensions or elixirs for oral use or suppositories.
  • the compositions are formulated in a unit dosage form, each dosage containing from 0.25 to 25 mg, more usually 1 to 20 mg, of the active ingredient .
  • An alternative preferred composition is a unit dosage form containing from 1 to 30 mg.
  • the materials for the present invention can be purchased or prepared by a variety of procedures well known to those of ordinary skill in the art.
  • Olanzapine can be prepared as described by Chakrabarti in U.S. Patent No 5,229,382 ('382), herein incorporated by reference in its entirety. Further, the following preparations illustrate a method for preparing of the especially preferred Form II olanzapine polymorph.
  • Compound characterization methods include, for example, x-ray powder pattern analysis, thermogravimetric analysis (TGA) , differential scanning calorimetery (DSC) , titrametric analysis for water, and H 1 -NMR analysis for solvent content.
  • a sub-surface nitrogen sparge line was added to remove the ammonia formed during the reaction.
  • the reaction was heated to 120°C and maintained at that temperature throughout the duration of the reaction.
  • the reactions were followed by HPLC until ⁇ 5% of the intermediate 1 was left unreacted.
  • reaction mixture was allowed to cool slowly to 20°C (about 2 hours) .
  • the reaction mixture was then transferred to an appropriate three neck round bottom flask and water bath.
  • To this solution with agitation was added 10 volumes reagent grade methanol and the reaction was stirred at 20°C for 30 minutes. Three volumes of water was added slowly over about 30 minutes.
  • the reaction slurry was cooled to zero to 5°C and stirred for 30 minutes.
  • the product was filtered and the wet cake was washed with chilled methanol. The wet cake was dried in vacuo at 45°C overnight.
  • the product was identified as technical olanzapine.
  • hydroxypropyl cellulose was dissolved in purified water to form a solution for granulation.
  • the remaining hydroxypropyl cellulose (total of 4.0% w/w final tablet weight), which was an extra fine grade, was combined with the olanzapine (1.18% w/w), lactose (79.32% w/w) and a portion of the crospovidone (5% w/w) in a high shear granulator. All ingredients were security sieved prior to addition and dry blended in the granulator. This mixture was then granulated with the hydroxypropyl cellulose solution in the high shear granulator. The granulation was wet sized using standard methods. The wet granulation was then dried in a fluidized bed dryer and sized. The material was then added to a tumble bin mixer.
  • the running powders consisting of microcrystalline cellulose (granular) (10% w/w), magnesium stearate (0.5% w/w), and the remainder of the crospovidone were added to the sized granulation. The mixture was blended and compressed with the appropriate tooling on tablet compression equipment.
  • Color Mixture White (hydroxypropyl methylcellulose, polyethylene glycol, polysorbate 80, and titanium dioxide) was mixed with purified water to form the coating suspension. Subcoated tablets were divided into approximately equal sections and spray coated with the coating suspension described above. The operation was performed in a perforated coating pan.
  • the coated tablets were lightly dusted with carnauba wax and imprinted with appropriate identification.

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  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Neurology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Neurosurgery (AREA)
  • Biomedical Technology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Psychiatry (AREA)
  • Pain & Pain Management (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
  • Electrical Discharge Machining, Electrochemical Machining, And Combined Machining (AREA)
PCT/US1996/019575 1996-03-11 1996-12-04 Method for treating bipolar disorder WO1997033577A1 (en)

Priority Applications (10)

Application Number Priority Date Filing Date Title
IL12616296A IL126162A0 (en) 1996-03-11 1996-12-04 Method for treating bipolar disorder
AU13307/97A AU734011B2 (en) 1996-03-11 1996-12-04 Method for treating bipolar disorder
EA199800819A EA000758B1 (ru) 1996-03-11 1996-12-04 Способ лечения биполярного расстройства
CA 2248905 CA2248905A1 (en) 1996-03-11 1996-12-04 Method for treating bipolar disorder
BR9612548A BR9612548A (pt) 1996-03-11 1996-12-04 Método para tratar distúrbio bipolar
PL96328925A PL328925A1 (en) 1996-03-11 1996-12-04 Method of treating bipolar disorders
JP9532570A JP2000506859A (ja) 1996-03-11 1996-12-04 双極性障害の処置方法
EP96944772A EP0889725A4 (en) 1996-03-11 1996-12-04 METHOD FOR TREATING BIPOLAR DISORDERS
NZ326031A NZ326031A (en) 1996-03-11 1996-12-04 Use of olanzapine in the manufacture of a medicament for treating bipolar disorder
NO984189A NO984189D0 (no) 1996-03-11 1998-09-11 Fremgangsmåte for behandling av bipolar forstyrrelse

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US1315996P 1996-03-11 1996-03-11
US60/013,159 1996-03-11

Publications (1)

Publication Number Publication Date
WO1997033577A1 true WO1997033577A1 (en) 1997-09-18

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Application Number Title Priority Date Filing Date
PCT/US1996/019575 WO1997033577A1 (en) 1996-03-11 1996-12-04 Method for treating bipolar disorder

Country Status (15)

Country Link
EP (1) EP0889725A4 (pt)
JP (1) JP2000506859A (pt)
KR (1) KR19990087713A (pt)
CN (1) CN1213966A (pt)
AU (1) AU734011B2 (pt)
BR (1) BR9612548A (pt)
CZ (1) CZ290298A3 (pt)
EA (1) EA000758B1 (pt)
HU (1) HUP9903679A3 (pt)
IL (1) IL126162A0 (pt)
NO (1) NO984189D0 (pt)
NZ (1) NZ326031A (pt)
PL (1) PL328925A1 (pt)
TR (1) TR199801797T2 (pt)
WO (1) WO1997033577A1 (pt)

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0958824A3 (en) * 1998-05-22 1999-12-01 Eli Lilly And Company Olanzapine (zyprexa) in combination with fluoxetine (prozac), lithium or anticonvulsant for therapy of refractory depression
EP0966967A3 (en) * 1998-05-29 2000-05-31 Eli Lilly And Company Combination therapy of olanzapine (zyprexa) and fluoxetine (prozac) for treatment of bipolar disorder
WO2000030650A1 (en) * 1998-11-23 2000-06-02 Sepracor Inc. Desmethylolanzapine compositions and methods
WO2000030648A1 (en) * 1998-11-23 2000-06-02 Sepracor Inc. 2-hydroxymethylolanzapine compositions and methods
WO2000030649A1 (en) * 1998-11-23 2000-06-02 Sepracor Inc. Pharmaceutical compositions containing olanzapine-n-oxide
US6960577B2 (en) 1998-05-22 2005-11-01 Eli Lilly And Company Combination therapy for treatment of refractory depression
US10154988B2 (en) 2012-11-14 2018-12-18 The Johns Hopkins University Methods and compositions for treating schizophrenia

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5229382A (en) * 1990-04-25 1993-07-20 Lilly Industries Limited 2-methyl-thieno-benzodiazepine
US5457101A (en) * 1994-06-03 1995-10-10 Eli Lilly And Company Thieno[1,5]benzoidiazepine use

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5229382A (en) * 1990-04-25 1993-07-20 Lilly Industries Limited 2-methyl-thieno-benzodiazepine
US5457101A (en) * 1994-06-03 1995-10-10 Eli Lilly And Company Thieno[1,5]benzoidiazepine use

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of EP0889725A4 *

Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0958824A3 (en) * 1998-05-22 1999-12-01 Eli Lilly And Company Olanzapine (zyprexa) in combination with fluoxetine (prozac), lithium or anticonvulsant for therapy of refractory depression
US6960577B2 (en) 1998-05-22 2005-11-01 Eli Lilly And Company Combination therapy for treatment of refractory depression
EP0966967A3 (en) * 1998-05-29 2000-05-31 Eli Lilly And Company Combination therapy of olanzapine (zyprexa) and fluoxetine (prozac) for treatment of bipolar disorder
US6174882B1 (en) 1998-11-23 2001-01-16 Sepracor Inc. 2-hydroxymethylolanzapine compositions and methods
WO2000030649A1 (en) * 1998-11-23 2000-06-02 Sepracor Inc. Pharmaceutical compositions containing olanzapine-n-oxide
US6121259A (en) * 1998-11-23 2000-09-19 Sepracor Inc. Olanzapine-N-oxide compositions and methods
WO2000030648A1 (en) * 1998-11-23 2000-06-02 Sepracor Inc. 2-hydroxymethylolanzapine compositions and methods
US6346528B1 (en) 1998-11-23 2002-02-12 Sepracor Inc. 2-Hydroxymethylolanzapine compositions and methods
US6348455B1 (en) 1998-11-23 2002-02-19 Sepracor Inc. Desmetylolanzapine compositions and methods
US6468997B2 (en) 1998-11-23 2002-10-22 Sepracor Inc. Desmethylolanzapine compositions and methods
WO2000030650A1 (en) * 1998-11-23 2000-06-02 Sepracor Inc. Desmethylolanzapine compositions and methods
US10154988B2 (en) 2012-11-14 2018-12-18 The Johns Hopkins University Methods and compositions for treating schizophrenia
EP3610890A1 (en) 2012-11-14 2020-02-19 The Johns Hopkins University Methods and compositions for treating schizophrenia
US10624875B2 (en) 2012-11-14 2020-04-21 The Johns Hopkins University Methods and compositions for treating schizophrenia

Also Published As

Publication number Publication date
AU1330797A (en) 1997-10-01
KR19990087713A (ko) 1999-12-27
JP2000506859A (ja) 2000-06-06
NO984189L (no) 1998-09-11
EA000758B1 (ru) 2000-04-24
TR199801797T2 (xx) 1998-12-21
NO984189D0 (no) 1998-09-11
EP0889725A4 (en) 2000-01-19
CZ290298A3 (cs) 1999-10-13
AU734011B2 (en) 2001-05-31
EP0889725A1 (en) 1999-01-13
HUP9903679A3 (en) 2001-10-29
CN1213966A (zh) 1999-04-14
BR9612548A (pt) 1999-07-20
NZ326031A (en) 2001-05-25
PL328925A1 (en) 1999-03-01
HUP9903679A2 (hu) 2000-04-28
IL126162A0 (en) 1999-05-09
EA199800819A1 (ru) 1999-02-25

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