WO2010037398A1 - Oral formulation - Google Patents

Oral formulation Download PDF

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Publication number
WO2010037398A1
WO2010037398A1 PCT/DK2009/050258 DK2009050258W WO2010037398A1 WO 2010037398 A1 WO2010037398 A1 WO 2010037398A1 DK 2009050258 W DK2009050258 W DK 2009050258W WO 2010037398 A1 WO2010037398 A1 WO 2010037398A1
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WO
WIPO (PCT)
Prior art keywords
compound
composition
disorder
formula
abuse
Prior art date
Application number
PCT/DK2009/050258
Other languages
French (fr)
Inventor
René HOLM
Christine Kau
Birgitte Willumsen
Klaus Peter Hertel
Kristina Kurre Olsen
Lone Bruun
KARINA KRøJER SØBY
Original Assignee
H. Lundbeck A/S
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.)
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Publication date
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=41217546&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=WO2010037398(A1) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Priority to EP09776299A priority Critical patent/EP2344163A1/en
Priority to US13/119,846 priority patent/US20110178094A1/en
Priority to CN200980139559XA priority patent/CN102170884A/en
Priority to BRPI0919165A priority patent/BRPI0919165A2/en
Priority to NZ590897A priority patent/NZ590897A/en
Priority to JP2011529448A priority patent/JP2012504560A/en
Priority to EA201170512A priority patent/EA201170512A1/en
Application filed by H. Lundbeck A/S filed Critical H. Lundbeck A/S
Priority to MX2011001044A priority patent/MX2011001044A/en
Priority to UAA201104341A priority patent/UA102403C2/en
Priority to AU2009298264A priority patent/AU2009298264A1/en
Priority to CA2732613A priority patent/CA2732613A1/en
Publication of WO2010037398A1 publication Critical patent/WO2010037398A1/en
Priority to IL210235A priority patent/IL210235A0/en
Priority to ZA2011/02446A priority patent/ZA201102446B/en

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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
    • A61K31/495—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
    • A61K31/4965—Non-condensed pyrazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
    • A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4808—Preparations in capsules, e.g. of gelatin, of chocolate characterised by the form of the capsule or the structure of the filling; Capsules containing small tablets; Capsules with outer layer for immediate drug release
    • 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
    • A61P25/06—Antimigraine agents
    • 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
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • 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
    • A61P25/20—Hypnotics; Sedatives
    • 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
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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
    • 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
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • 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
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/32—Alcohol-abuse
    • 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
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/34—Tobacco-abuse
    • 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
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/36—Opioid-abuse

Definitions

  • WO 2005/016900 discloses the compound of formula I (Compound I) as a free base and its corresponding succinate and malonate salts. The compound is reported to have high affinity for dopamine Dl and D2 receptors (antagonist), for the 5-HT 2 receptor (antagonist) and for oci adrenoceptors. In WO 2005/016900 the compound is suggested to be useful for treatment of several diseases in the central nervous system, including psychosis, in particular schizophrenia (positive, negative, and/or depressive symptoms) or other diseases involving psychotic symptoms, such as, e.g., Schizophrenia,
  • Schizophreniform Disorder Schizoaffective Disorder, Delusional Disorder, Brief Psychotic Disorder, Shared Psychotic Disorder as well other psychotic disorders or diseases associated with psychotic symptoms, e.g. mania in bipolar disorder.
  • WO 2005/016900 also suggests the use of compound of formula I for treatment of anxiety disorders, affective disorders including depression, treatment of bipolar disorders, sleep disturbances, migraine, neuroleptic drug induced parkinsonism, as well as cocaine abuse, nicotine abuse, alcohol abuse and other abuse disorders.
  • Other publications disclosing the compound of formula I and related compounds, having the above pharmacological profile, are EP 638 073; B ⁇ ges ⁇ K.P.et al. J. Med.
  • the compound of formula l is a putative antipsychotic compound with affinity for both dopamine Dl and D2 receptors.
  • C AR condition avoidance response
  • Cortical Dopamine D2/D3 Receptors are a Common Site of Action for Antipsychotic Drugs; An Original Patient Data Meta-analysis of the SPECT and PET In Vivo, Schizophr Bull. 2008 Feb 26. [Epub in advance of print].).
  • the compound of formula I induces a Dl receptor occupancy increase from 32 to 69% in putamen when increasing the dose from 2 to lOmg/day given daily for 18 days.
  • Such high level of Dl occupancy is not generally seen with current used antipsychotic drugs (Farde L, Nordstrom AL, Wiesel FA, Pauli S, Halldin C, Sedvall G.
  • the compound of formula I have clinically significant therapeutic effects in patients with schizophrenia at doses (from 4mg/day to 14mg/day) that induce only a low level of D2 receptor occupancy. This might well be a consequence of the high Dl receptor occupancy and the unique ratio of Dl versus D2 receptor occupancy displayed by the compound of formula I.
  • a low D2 receptor occupancy at therapeutically effective doses will be beneficial in terms of reduced tendency to induce troublesome side effects mediated by D2 receptor blockade, including extrapyramidal side effects and hyperprolactinemia.
  • adjuvants examples include cornstarch, lactose, talcum, magnesium stearate, gelatine, gums, and the like.
  • Typical fillers are selected from lactose, mannitol, sorbitol, cellulose and microcrystalline cellulose. Any other adjuvant or additive such as colourings, aroma, preservatives, etc, may also be used provided that they are compatible with the active ingredient.
  • compound of formula I is intended to designate any form of the compound, such as the free base, pharmaceutically acceptable salts thereof, eg. pharmaceutically acceptable acid addition salts, such as succinate and malonate salts, hydrates or solvates of the free base or salts thereof, as well as anhydrous forms, amorphous forms, or crystalline forms.
  • pharmaceutically acceptable salts thereof eg. pharmaceutically acceptable acid addition salts, such as succinate and malonate salts, hydrates or solvates of the free base or salts thereof, as well as anhydrous forms, amorphous forms, or crystalline forms.
  • suitable organic acids include formic, acetic, trichloroacetic, trifluoroacetic, propionic, benzoic, cinnamic, citric, fumaric, glycolic, itaconic, lactic, methanesulfonic, maleic, malic, malonic, mandelic, oxalic, picric, pyruvic, salicylic, succinic, methane sulfonic, ethanesulfonic, tartaric, ascorbic, pamoic, bismethylene salicylic, ethanedisulfonic, gluconic, citraconic, aspartic, stearic, palmitic, EDTA, glycolic, p-aminobenzoic, glutamic, benzenesulfonic, p-toluenesulfonic acids, theophylline acetic acids, as well as the 8-halotheophyllines, for example 8-bromotheophylline and the
  • the compound of formula I may exist in unsolvated form, as well as in solvated forms with pharmaceutically acceptable solvents such as water, ethanol and the like.
  • solvated forms are considered to be equivalent to unsolvated forms for the purposes of this invention.
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising the compound of formula (I)
  • the composition comprising the compound of formula I is for treatment of cognitive dysfunction, schizophrenia, Schizophreniform Disorder, Schizoaffective Disorder, Delusional Disorder, Brief Psychotic Disorder, Shared Psychotic Disorder, mania in bipolar disorder, anxiety disorders, depression, maintenance of bipolar disorders, sleep disturbances, migraine, neuroleptic-induced parkinsonism, or cocaine abuse, nicotine abuse, or alcohol abuse.
  • Typical use of the composition of the invention is in the treatment of schizophrenia, such as positive symptoms of schizophrenia, or cognitive dysfunction in schizophrenia.
  • the present invention relates to use of a compound of formula (I) for the preparation of a medicament for treatment of cognitive dysfunction, schizophrenia, Schizophreniform Disorder, Schizoaffective Disorder, Delusional Disorder, Brief Psychotic Disorder, Shared Psychotic Disorder, mania in bipolar disorder, anxiety disorders, depression, maintenance of bipolar disorders, sleep disturbances, migraine, neuroleptic-induced parkinsonism, or cocaine abuse, nicotine abuse, or alcohol abuse, wherein the compound of formula I is present in a therapeutically effective amount of from 4-14 mg calculated as the free base.
  • the present invention also relates to a method of treating cognitive dysfunction, schizophrenia, Schizophreniform Disorder, Schizoaffective Disorder, Delusional Disorder, Brief Psychotic Disorder, Shared Psychotic Disorder, mania in bipolar disorder, anxiety disorders, depression, maintenance of bipolar disorders, sleep disturbances, migraine, neuroleptic-induced parkinsonism, or cocaine abuse, nicotine abuse, or alcohol abuse, comprising administering a therapeutically effective amount of from 4-14 mg calculated as the free base of the compound of formula I to a patient in need thereof.
  • the compound of formula I is formulated for oral administration, such as a tablet or capsule, typically a tablet.
  • the composition, such as a tablet, is typically for oral administration once daily.
  • the compound of formula I is in the form of a succinate or malonate salt.
  • the succinate salt typically, the succinate salt.
  • the amount of the compound of formula (I) is from 4-12 mg. In further embodiments of the composition, use, or method of treatment, the amount of the compound of formula (I) is from 5-14 mg.
  • the amount of the compound of formula (I) is from 4-6 mg, such as 5 mg.
  • the amount of the compound of formula (I) is from 6-8 mg, such as 7 mg.
  • the amount of the compound of formula (I) is from 8- 10 mg.
  • the amount of the compound of formula (I) is from 10-12 mg. In further embodiments of the composition, use, or method of treatment, the amount of the compound of formula (I) is from 12-14 mg, such as 14 mg.
  • the amount of the compound of formula (I) is from 7-9 mg.
  • the amount of the compound of formula (I) is from 9-11 mg, such as 10 mg
  • the composition further comprises povidone, such as Kollidone 30 (CAS-No. 94800-10-9), or copovidone, such as Kollidone VA64 (CAS-No. 25086-89-9), as a binder.
  • povidone such as Kollidone 30 (CAS-No. 94800-10-9)
  • copovidone such as Kollidone VA64 (CAS-No. 25086-89-9)
  • the binder is typically present in a concentration range of from 2-10% (w/w), such as 2-4%, 4-6%, 6-8%, 8-10%, 2-8%, 4-8%, 4-10%, or 6-10% (w/w).
  • binder (i) and povidone or copovidone as binder.
  • binder is Kollidone VA64.
  • the binder is present in a concentration range of from 2- 10% (w/w). Typically in a concentration range of from 2-4%, 4-6%, 6-8%, or 8-10% (w/w).
  • typical fillers are selected from calcium hydrogen phosphate lactose, mannitol, sorbitol, cellulose and microcrystalline cellulose, and preferably lactose, mannitol, sorbitol, cellulose and microcrystalline cellulose, such as lactose.
  • the filler such as anyone of the above, is in a concentration range of from 15-50% (w/w).
  • the filler such as anyone of lactose, mannitol, sorbitol, cellulose and microcrystalline cellulose, is in a concentration range of from 15-25 %, 20-50%, 30-45% (w/w).
  • the compound of formula (I) is in the form of the succinate salt.
  • the safety and efficacy of the compound of formula I in schizophrenic patient will be investigated by standard measures of efficacy (including the Positive and Negative Syndrome Scale [PANSS] and the Clinical Global Impressions scale [CGI]) and safety.
  • eligible patients will be randomised in a 2:1 ratio to blinded treatment with either the compound of formula I (e.g. at doses of 5, 7, 10 and 14mg/day) or placebo for 8 weeks.
  • the study includes 5 parts with increasing doses of the compound of formula I and a decision to initiate the next dose level will be based on safety and tolerability assessment based on the previous part of the study.
  • the efficacy and the safety of the compound of formula I will be evaluated in comparison to the pooled placebo group from all parts of the study.
  • the compound of formula I has been shown to possess cognition enhancing properties in preclinical models of cognitive dysfunctions. It is believed that the 5- HT6 receptor affinity of the compound of formula I is involved in the precognitive effects of the compound. Furthermore, it is believed that such pro- cognitive effect of the compound of formula I will be evident at a low level of D2 receptor occupancy, which is beneficial in terms of the side-effect profile.
  • the effect of the compound of formula I on cognitive deficits in schizophrenic patients will be assessed in a clinical trial where eligible patients will be randomised in a 1 : 1 ratio to blinded treatment with flexible doses of either the compound of formula I (5 to 7mg/day) or olanzapine (10 to 15mg/day) for 12 weeks.
  • the efficacy of the compound of formula I on cognitive symptoms will be assessed using the Brief Assessment of Cognition in Schizophrenia (BACS) scale (Keefe RS, Goldberg TE, Harvey PD, Gold JM, Poe MP, Coughenour L.
  • the Brief Assessment of Cognition in Schizophrenia reliability, sensitivity, and comparison with a standard neurocognitive battery. Schizophr Res. 2004;68(2- 3):283-97.i. Schizophr Res. 2004;68(2-3):283-97.).
  • the compound of formula I is formulated as immediate release film-coated tablet intended for oral administration. Tablets containing compound of formula I in this example are made in two strengths, 5 and 7 mg.
  • the product containing compound of formula l is a white film-coated tablet encapsulated in a brownish red hard capsule. Other strengths, such as 4, 6, 8, 9, 10, 1 1, 12, 13, or 14 mg, may be prepared in the same manner.
  • compositions of the tablets 5 mg and 7 mg are given below in Table 1.
  • the method of granulation is a traditional wet granulation process using copovidone (Kollidone VA64) as a dry binder and water as granulation liquid.
  • copovidone Kerdone VA64
  • water granulation liquid
  • Ad magnesium stearate to the mixer and mix.
  • Compress the granulate into tablets on a tablet compressing machine Compress the granulate into tablets on a tablet compressing machine.
  • FIG. 1 A flow diagram of the manufacturing process and process controls is shown in figure 1.
  • copovidone as binder leads to tablets with better pharmaceutical technical properties, e.g. the cabability of producing harder tablets with low loss on friability without compromising the disintegration time, as demonstrated in table 5:
  • Compound I is formulated as immediate release film-coated tablet intended for oral administration. Tablets containing compound of formula I in this example are made in two strengths, 2.5 and 5 mg.
  • the product containing compound of formula I is a white film-coated tablet encapsulated in a brownish red hard capsule.
  • Other strengths, such as 2, 3, 4, 6, 7, 8, 9, 10, 11, 12, 13, or 14 mg, may be prepared in the same manner.
  • compositions of the tablets 2.5 mg and 5 mg are given below in Table
  • Table 7 Composition of tablets 2.5 mg and 5 mg (calcium phosphate form.)
  • the current pharmacopoeia is used 2 Volatile material
  • FIG. 1 A flow diagram of the manufacturing process and process controls is shown in figure 1.
  • copovidone as binder (Formulation No. 6) leads to tablets with good pharmaceutical technical properties, e.g. a relative long disintegration time permitting the tablets to be swallowed as whole tablets (as demonstrated in table 10) and acceptable stability data (as demonstrated in table 11): Table 10. Comparision of pharmaceutical technical data for tablets containing compound of formula I succinate with the composition given in table 9.
  • Compound I is formulated as immediate release film-coated tablet intended for oral administration. Tablets containing compound of formula I in this example are made in two strengths, 2.5 and 5 mg.
  • the product containing compound of formula l is a white film-coated tablet encapsulated in a brownish red hard capsule.
  • Other strengths, such as 2, 3, 4, 6, 7, 8, 9, 10, 11, 12, 13, or 14 mg, may be prepared in the same manner.
  • compositions of the tablets 2.5 mg and 5 mg are given below in Table 12 and Table 13.
  • Manufacturing process and process controls is as in Example 1. A flow diagram of the manufacturing process and process controls is shown in figure 1. Table 12 Composition of tablets 2.5 mg and 5 mg (calcium phosphate formulation)
  • the current pharmacopoeia is used 2 Volatile material

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Abstract

The invention relates to a pharmaceutical composition intended for oral administration comprising low doses of 4-((1R,3S)-6-chloro-3-phenylindan-1-yl)- 1,2,2-trimethylpiperazine and to a composition comprising the compound.

Description

ORAL FORMULATION
The present invention relates to a pharmaceutical composition intended for oral administration comprising low doses of 4-((/Λ,iS)-6-chloro-3-phenylindan-l-yl)- 1 ,2,2-trimethylpiperazine. Moreover the invention relates to an improved binder in a composition comprising 4-((/Λ,35)-6-chloro-3-phenylindan-l-yl)- 1 ,2,2- trimethylpiperazine.
BACKGROUND OF THE INVENTION The compound which is the subject of the present invention (4-((l R,3S)-6-cMoro- 3-phenylindan-l-yl)-l,2,2-trimethylpiperazine) has the formula (I)
Figure imgf000002_0001
(0
International patent publication No WO 2005/016900 discloses the compound of formula I (Compound I) as a free base and its corresponding succinate and malonate salts. The compound is reported to have high affinity for dopamine Dl and D2 receptors (antagonist), for the 5-HT2 receptor (antagonist) and for oci adrenoceptors. In WO 2005/016900 the compound is suggested to be useful for treatment of several diseases in the central nervous system, including psychosis, in particular schizophrenia (positive, negative, and/or depressive symptoms) or other diseases involving psychotic symptoms, such as, e.g., Schizophrenia,
Schizophreniform Disorder, Schizoaffective Disorder, Delusional Disorder, Brief Psychotic Disorder, Shared Psychotic Disorder as well other psychotic disorders or diseases associated with psychotic symptoms, e.g. mania in bipolar disorder. WO 2005/016900 also suggests the use of compound of formula I for treatment of anxiety disorders, affective disorders including depression, treatment of bipolar disorders, sleep disturbances, migraine, neuroleptic drug induced parkinsonism, as well as cocaine abuse, nicotine abuse, alcohol abuse and other abuse disorders. Other publications disclosing the compound of formula I and related compounds, having the above pharmacological profile, are EP 638 073; Bøgesø K.P.et al. J. Med. Chem., 1995, 38, page 4380-4392; and Bøgesø K.P. "Drug Hunting, the Medicinal Chemistry of l-Piperazino-3-phenylindanes and Related Compounds", 1998, ISBN 87-88085-10-4 (cf. e.g. compound 69 in table 3, p 47 and in table 9A, p 101).
DESCRIPTION OF THE INVENTION
The compound of formula l is a putative antipsychotic compound with affinity for both dopamine Dl and D2 receptors. Preclinical experiments in rats using the condition avoidance response (C AR) model (Experimental procedure previously described in: Hertel P, Olsen CK, Arnt J. Repeated administration of the neurotensin analogue NT69L induces tolerance to its suppressant effect on conditioned avoidance behaviour. Eur J Pharmacol. 2002;439(l-3):107-l 1.) have indicated that the compound of formula I possesses antipsychotic activity at very low levels of D2 receptor occupancy.
In a positron emission tomography (PET) study in healthy subjects using 1 IC- SCH23390 and "C-raclopride as Dl and D2 receptor tracers, it was found that the compound of formula I induces a D2 receptor occupancy of from 1 1 to 43% in the putamen when increasing the dose from 2 to 10mg/day given daily for 18 days. Such level of D2 receptor occupancy is low in comparison with that of currently used antipsychotic drugs, which in general requires a D2 receptor occupancy around or exceeding 50% to be therapeutically effective (Stone JM, Davis JM, Leucht S, Pilowsky LS. Cortical Dopamine D2/D3 Receptors Are a Common Site of Action for Antipsychotic Drugs; An Original Patient Data Meta-analysis of the SPECT and PET In Vivo, Schizophr Bull. 2008 Feb 26. [Epub in advance of print].). In the same PET study, it was found that the compound of formula I induces a Dl receptor occupancy increase from 32 to 69% in putamen when increasing the dose from 2 to lOmg/day given daily for 18 days. Such high level of Dl occupancy is not generally seen with current used antipsychotic drugs (Farde L, Nordstrom AL, Wiesel FA, Pauli S, Halldin C, Sedvall G. Positron emission tomographic analysis of central Dl and D2 dopamine receptor occupancy in patients treated with classical neuroleptics and clozapine. Relation to extrapyramidal side effects. Arch Gen Psychiatry. 1992; 49(7):538-44.). Thus, the compound of formula I exhibits a unique ratio of Dl to D2 receptor occupancy at low daily doses.
Based on the above, it is expected that the compound of formula I have clinically significant therapeutic effects in patients with schizophrenia at doses (from 4mg/day to 14mg/day) that induce only a low level of D2 receptor occupancy. This might well be a consequence of the high Dl receptor occupancy and the unique ratio of Dl versus D2 receptor occupancy displayed by the compound of formula I. A low D2 receptor occupancy at therapeutically effective doses will be beneficial in terms of reduced tendency to induce troublesome side effects mediated by D2 receptor blockade, including extrapyramidal side effects and hyperprolactinemia.
The compound of formula I in a therapeutically effective amount of from 4-14 mg calculated as the free base is administered orally, and may be presented in any form suitable for such administration, e.g. in the form of tablets, capsules, powders, syrups or solutions. In one embodiment, a salt of the compound of formula I is administered in the form of a solid pharmaceutical entity, suitably as a tablet or a capsule. Methods for the preparation of solid pharmaceutical compositions or preparations are well known in the art. Thus, tablets may be prepared by mixing the active ingredient with conventional adjuvants, fillers and diluents and subsequently compressing the mixture in a suitable tabletting machine. Examples of adjuvants, fillers and diluents comprise cornstarch, lactose, talcum, magnesium stearate, gelatine, gums, and the like. Typical fillers are selected from lactose, mannitol, sorbitol, cellulose and microcrystalline cellulose. Any other adjuvant or additive such as colourings, aroma, preservatives, etc, may also be used provided that they are compatible with the active ingredient.
As already indicated, the compound 4-((7/?,JS)-6-chloro-3-phenylindan-l-yl)- 1 ,2,2-trimethylpiperazine has the general formula (I)
Figure imgf000005_0001
(0 as used throughout the present description the term "compound of formula I" is intended to designate any form of the compound, such as the free base, pharmaceutically acceptable salts thereof, eg. pharmaceutically acceptable acid addition salts, such as succinate and malonate salts, hydrates or solvates of the free base or salts thereof, as well as anhydrous forms, amorphous forms, or crystalline forms.
The compound of formula I to be comprised in the composition of the present invention also comprises salts thereof, typically, pharmaceutically acceptable salts. Such salts include pharmaceutical acceptable acid addition salts. Acid addition salts include salts of inorganic acids as well as organic acids. Representative examples of suitable inorganic acids include hydrochloric, hydrobromic, hydroiodic, phosphoric, sulfuric, sulfamic, nitric acids and the like. Representative examples of suitable organic acids include formic, acetic, trichloroacetic, trifluoroacetic, propionic, benzoic, cinnamic, citric, fumaric, glycolic, itaconic, lactic, methanesulfonic, maleic, malic, malonic, mandelic, oxalic, picric, pyruvic, salicylic, succinic, methane sulfonic, ethanesulfonic, tartaric, ascorbic, pamoic, bismethylene salicylic, ethanedisulfonic, gluconic, citraconic, aspartic, stearic, palmitic, EDTA, glycolic, p-aminobenzoic, glutamic, benzenesulfonic, p-toluenesulfonic acids, theophylline acetic acids, as well as the 8-halotheophyllines, for example 8-bromotheophylline and the like.
Further, the compound of formula I may exist in unsolvated form, as well as in solvated forms with pharmaceutically acceptable solvents such as water, ethanol and the like. In general, solvated forms are considered to be equivalent to unsolvated forms for the purposes of this invention.
The present invention relates to a pharmaceutical composition comprising the compound of formula (I)
Figure imgf000006_0001
(i) in a therapeutically effective amount of from 4-14 mg calculated as the free base. In a further embodiment, the composition comprising the compound of formula I is for treatment of cognitive dysfunction, schizophrenia, Schizophreniform Disorder, Schizoaffective Disorder, Delusional Disorder, Brief Psychotic Disorder, Shared Psychotic Disorder, mania in bipolar disorder, anxiety disorders, depression, maintenance of bipolar disorders, sleep disturbances, migraine, neuroleptic-induced parkinsonism, or cocaine abuse, nicotine abuse, or alcohol abuse. Typical use of the composition of the invention is in the treatment of schizophrenia, such as positive symptoms of schizophrenia, or cognitive dysfunction in schizophrenia.
In a further aspect the present invention relates to use of a compound of formula (I) for the preparation of a medicament for treatment of cognitive dysfunction, schizophrenia, Schizophreniform Disorder, Schizoaffective Disorder, Delusional Disorder, Brief Psychotic Disorder, Shared Psychotic Disorder, mania in bipolar disorder, anxiety disorders, depression, maintenance of bipolar disorders, sleep disturbances, migraine, neuroleptic-induced parkinsonism, or cocaine abuse, nicotine abuse, or alcohol abuse, wherein the compound of formula I is present in a therapeutically effective amount of from 4-14 mg calculated as the free base.
In a further aspect the present invention also relates to a method of treating cognitive dysfunction, schizophrenia, Schizophreniform Disorder, Schizoaffective Disorder, Delusional Disorder, Brief Psychotic Disorder, Shared Psychotic Disorder, mania in bipolar disorder, anxiety disorders, depression, maintenance of bipolar disorders, sleep disturbances, migraine, neuroleptic-induced parkinsonism, or cocaine abuse, nicotine abuse, or alcohol abuse, comprising administering a therapeutically effective amount of from 4-14 mg calculated as the free base of the compound of formula I to a patient in need thereof.
In an embodiment of the composition, the use, or the method of treatment of the invention, the compound of formula I is formulated for oral administration, such as a tablet or capsule, typically a tablet. The composition, such as a tablet, is typically for oral administration once daily.
In a further embodiment of the composition, the use, or the method of treatment, the compound of formula I is in the form of a succinate or malonate salt. Typically, the succinate salt.
In further embodiments of the composition, use, or method of treatment, the amount of the compound of formula (I) is from 4-12 mg. In further embodiments of the composition, use, or method of treatment, the amount of the compound of formula (I) is from 5-14 mg.
In further embodiments of the composition, use, or method of treatment, the amount of the compound of formula (I) is from 4-6 mg, such as 5 mg.
In further embodiments of the composition, use, or method of treatment, the amount of the compound of formula (I) is from 6-8 mg, such as 7 mg.
In further embodiments of the composition, use, or method of treatment, the amount of the compound of formula (I) is from 8- 10 mg.
In further embodiments of the composition, use, or method of treatment, the amount of the compound of formula (I) is from 10-12 mg. In further embodiments of the composition, use, or method of treatment, the amount of the compound of formula (I) is from 12-14 mg, such as 14 mg.
In further embodiments of the composition, use, or method of treatment, the amount of the compound of formula (I) is from 5-7 mg.
In further embodiments of the composition, use, or method of treatment, the amount of the compound of formula (I) is from 7-9 mg.
In further embodiments of the composition, use, or method of treatment, the amount of the compound of formula (I) is from 9-11 mg, such as 10 mg
In further embodiments of the composition, use, or method of treatment, the amount of the compound of formula (I) is from 11-13 mg. When the invention relates to the use or the method of treatment then the dose indicated above of from 4-14 mg, such as 5 mg, 7 mg, 10 mg, or 14 mg, is on a daily basis.
In a further embodiment of the composition, the use, or the method of treatment, the composition further comprises povidone, such as Kollidone 30 (CAS-No. 94800-10-9), or copovidone, such as Kollidone VA64 (CAS-No. 25086-89-9), as a binder. The binder is typically present in a concentration range of from 2-10% (w/w), such as 2-4%, 4-6%, 6-8%, 8-10%, 2-8%, 4-8%, 4-10%, or 6-10% (w/w).
In a further aspect the present invention also relates to a pharmaceutical composition comprising the compound of formula (I)
Figure imgf000009_0001
(i) and povidone or copovidone as binder. Typically the binder is Kollidone VA64.
In an embodiment the binder is present in a concentration range of from 2- 10% (w/w). Typically in a concentration range of from 2-4%, 4-6%, 6-8%, or 8-10% (w/w). When the binder is povidone or copovidone typical fillers are selected from calcium hydrogen phosphate lactose, mannitol, sorbitol, cellulose and microcrystalline cellulose, and preferably lactose, mannitol, sorbitol, cellulose and microcrystalline cellulose, such as lactose. In an embodiment the filler, such as anyone of the above, is in a concentration range of from 15-50% (w/w). Typically, the filler, such as anyone of lactose, mannitol, sorbitol, cellulose and microcrystalline cellulose, is in a concentration range of from 15-25 %, 20-50%, 30-45% (w/w).
In a further embodiment of the composition the compound of formula (I) is in the form of the succinate salt.
Experimental
The safety and efficacy of the compound of formula I in schizophrenic patient will be investigated by standard measures of efficacy (including the Positive and Negative Syndrome Scale [PANSS] and the Clinical Global Impressions scale [CGI]) and safety. After a screening period, eligible patients will be randomised in a 2:1 ratio to blinded treatment with either the compound of formula I (e.g. at doses of 5, 7, 10 and 14mg/day) or placebo for 8 weeks. The study includes 5 parts with increasing doses of the compound of formula I and a decision to initiate the next dose level will be based on safety and tolerability assessment based on the previous part of the study. The efficacy and the safety of the compound of formula I will be evaluated in comparison to the pooled placebo group from all parts of the study.
Efficacy on cognitive deficits in schizophrenia The compound of formula I has been shown to possess cognition enhancing properties in preclinical models of cognitive dysfunctions. It is believed that the 5- HT6 receptor affinity of the compound of formula I is involved in the precognitive effects of the compound. Furthermore, it is believed that such pro- cognitive effect of the compound of formula I will be evident at a low level of D2 receptor occupancy, which is beneficial in terms of the side-effect profile.
The effect of the compound of formula I on cognitive deficits in schizophrenic patients will be assessed in a clinical trial where eligible patients will be randomised in a 1 : 1 ratio to blinded treatment with flexible doses of either the compound of formula I (5 to 7mg/day) or olanzapine (10 to 15mg/day) for 12 weeks. The efficacy of the compound of formula I on cognitive symptoms will be assessed using the Brief Assessment of Cognition in Schizophrenia (BACS) scale (Keefe RS, Goldberg TE, Harvey PD, Gold JM, Poe MP, Coughenour L. The Brief Assessment of Cognition in Schizophrenia: reliability, sensitivity, and comparison with a standard neurocognitive battery. Schizophr Res. 2004;68(2- 3):283-97.i. Schizophr Res. 2004;68(2-3):283-97.).
Example 1 Preparation of immediate release film-coated tablet intended for oral administration I
Pharmaceutical Development
A study of the compatibility of the excipients and compound of formula I demonstrated that the components used in the tablet formulation were compatible with the compound. Based on this, a traditional wet granulation, tabletting and film-coating process was developed using standard methods and excipients.
Description of Drug product
The compound of formula I is formulated as immediate release film-coated tablet intended for oral administration. Tablets containing compound of formula I in this example are made in two strengths, 5 and 7 mg. The product containing compound of formula l is a white film-coated tablet encapsulated in a brownish red hard capsule. Other strengths, such as 4, 6, 8, 9, 10, 1 1, 12, 13, or 14 mg, may be prepared in the same manner.
Composition
The compositions of the tablets 5 mg and 7 mg are given below in Table 1.
Table 1. Composition of tablets 5 mg and 7 mg
Figure imgf000012_0001
Figure imgf000013_0001
^he current pharmacopoeia is used 2 Volatile material
The batch compositions for a representative batch size of 10,000 tablets are presented in Table 2.
Table 2. Batch composition for film-coated tablets (Batch size 10,000 tablets)
Figure imgf000013_0002
Figure imgf000014_0001
Description of Manufacturing Process and Process Controls The method of granulation is a traditional wet granulation process using copovidone (Kollidone VA64) as a dry binder and water as granulation liquid. In the 10-litre PMAl high shear mixer the process is as follows for a 2 kg batch:
Mix compound of formula I succinate, anhydrous calcium hydrogen phosphate, maize starch and copovidone for 2 minutes at 500 rpm.
Add purified water to initiate agglomeration. Granulate at 800 rpm for approximately 4 minutes, so a suitable granule size is achieved.
Sieve the wet granules.
Dry the granules in a tray dryer at 500C, until the product has a relative humidity
(RH) of 25-55%RH. Sieve the dried granules. Mix the granules with microcrystalline cellulose, croscarmellose sodium and talc in a mixer.
Ad magnesium stearate to the mixer and mix.
Compress the granulate into tablets on a tablet compressing machine.
Film-coat the tablet cores in a film coater, using the process parameters given in table 3.
Table 3. Equipment and process conditions for the coating process.
Figure imgf000015_0001
A flow diagram of the manufacturing process and process controls is shown in figure 1.
Unexpected effects of binder in the tablet formulation
In order to optimise the agglomeration process, two different tablet formulations was produced and their effect on the chemical stability of compound of formula I was evaluated. The composition of these tablets are given in table 4, and the manufacturing process, was similar to the one described above:
Table 4. Batch composition of film-coated tablets with 2 different binders (Batch size 10,000 tablets)
Figure imgf000015_0002
Figure imgf000016_0001
The use of copovidone as binder leads to tablets with better pharmaceutical technical properties, e.g. the cabability of producing harder tablets with low loss on friability without compromising the disintegration time, as demonstrated in table 5:
Table 5. Comparision of pharmaceutical technical data for tablets containing compound of formula I succinate with the composition given in table 4
Figure imgf000016_0002
Figure imgf000017_0001
Furthermore, the difference in binder lead to surprising stability differences as demonstrated in table 6
Table 6. Decomposition of compound of formula I succinate, in formulations where maltodextrin and copovidon are used as binder, composition of tablets given in table 4.
Figure imgf000017_0002
Example 2 Preparation of immediate release film-coated tablet intended for oral administration II
Pharmaceutical Development
A study of the compatibility of the excipients and Compound I demonstrated that the components used in the tablet formulation were compatible with the compound. Based on this, a traditional wet granulation, tabletting and film-coating process was developed using standard methods and excipients. Description of Drug product
Compound I is formulated as immediate release film-coated tablet intended for oral administration. Tablets containing compound of formula I in this example are made in two strengths, 2.5 and 5 mg. The product containing compound of formula I is a white film-coated tablet encapsulated in a brownish red hard capsule. Other strengths, such as 2, 3, 4, 6, 7, 8, 9, 10, 11, 12, 13, or 14 mg, may be prepared in the same manner.
Composition The compositions of the tablets 2.5 mg and 5 mg are given below in Table
7.
Table 7 Composition of tablets 2.5 mg and 5 mg (calcium phosphate form.)
Figure imgf000019_0001
The current pharmacopoeia is used 2 Volatile material
The batch compositions for a representative batch size of 10,000 tablets are presented in Table 8.
Table 8. Batch composition for film-coated tablets (Batch size 10,000 tablets)
Figure imgf000019_0002
Figure imgf000020_0001
Manufacturing process and process controls is as in Example 1.
A flow diagram of the manufacturing process and process controls is shown in figure 1.
Unexpected effects of binder in the tablet formulation II
In order to optimise the agglomeration process, one tablet formulation (2.5 mg) for each binder was produced and the effect of binder on the chemical stability of
Compound I was evaluated. The composition of these tablets is given in table 9, and the manufacturing process, was similar to the one described above. Table 9. Batch composition of film-coated tablets with 7 different binders (Batch size 10,000 tablets)
Figure imgf000021_0001
Table 9 cont. Batch composition of film-coated tablets with 7 different binders (Batch size 10,000 tablets)
Figure imgf000021_0002
Figure imgf000022_0001
The use of copovidone as binder (Formulation No. 6) leads to tablets with good pharmaceutical technical properties, e.g. a relative long disintegration time permitting the tablets to be swallowed as whole tablets (as demonstrated in table 10) and acceptable stability data (as demonstrated in table 11): Table 10. Comparision of pharmaceutical technical data for tablets containing compound of formula I succinate with the composition given in table 9.
Figure imgf000023_0001
Some differences in the stability of the products containing different binders can be seen in table 11 (next page).
Table 11 Decomposition of compound of formulation 1 to 6 - different binders are used, composition of tablets given in table 9
Figure imgf000024_0001
ND = Not detected
Table 1 1 cont., Decomposition of compound of formulation 7, in formulation where maltodextrin is used as binder, composition of tablets given in table 9
Figure imgf000024_0002
Figure imgf000025_0001
Example 3 Preparation of immediate release film-coated tablet intended for oral administration III
Pharmaceutical Development
A study of the compatibility of the excipients and Compound I demonstrated that the components used in the tablet formulation were compatible with the compound. Based on this, a traditional wet granulation, tabletting and film-coating process was developed using standard methods and excipients.
Description of Drug product
Compound I is formulated as immediate release film-coated tablet intended for oral administration. Tablets containing compound of formula I in this example are made in two strengths, 2.5 and 5 mg. The product containing compound of formula l is a white film-coated tablet encapsulated in a brownish red hard capsule. Other strengths, such as 2, 3, 4, 6, 7, 8, 9, 10, 11, 12, 13, or 14 mg, may be prepared in the same manner.
Composition
The compositions of the tablets 2.5 mg and 5 mg are given below in Table 12 and Table 13.
Manufacturing process and process controls is as in Example 1. A flow diagram of the manufacturing process and process controls is shown in figure 1. Table 12 Composition of tablets 2.5 mg and 5 mg (calcium phosphate formulation)
Figure imgf000026_0001
Figure imgf000027_0001
The current pharmacopoeia is used 2 Volatile material
Figure imgf000027_0002
Figure imgf000028_0001
lie current pharmacopoeia is used 2 Volatile material

Claims

We claim:
1. A pharmaceutical composition comprising the compound of formula (I)
Figure imgf000029_0001
(i) in a therapeutically effective amount of from 4-14 mg calculated as the free base.
2. The composition of claim 1 which is formulated for oral administration, such as a tablet or capsule.
3. The composition of any one of claims 1-2 wherein the compound of formula (I) is in the form of a succinate or malonate salt.
4. The composition of any one of claims 1-3 wherein the amount of the compound of formula (I) is 4-12 mg, 5-14 mg, 4-6 mg, 6-8 mg, 8-10 mg, 10-12 mg, 12-14 mg, 5-7 mg, 7-9 mg, 9-11 mg, 11-13 mg, 5 mg, 7 mg, 10 mg, or 14 mg.
5. The composition of any one of claims 1-4 wherein said composition is for oral administration once daily.
6. The composition of any one of claims 1-5 wherein said composition further comprises copovidone, such as Kollidone VA64, as a binder.
7. The composition of any one of claims 1-6 for treatment of cognitive dysfunction, schizophrenia, Schizophreniform Disorder, Schizoaffective Disorder, Delusional Disorder, Brief Psychotic Disorder, Shared Psychotic Disorder, mania in bipolar disorder, anxiety disorders, depression, maintenance of bipolar disorders, sleep disturbances, migraine, neuroleptic-induced parkinsonism, or cocaine abuse, nicotine abuse, or alcohol abuse.
8. Use of a compound of formula (I) for the preparation of a medicament for treatment of cognitive dysfunction, schizophrenia, Schizophreniform Disorder, Schizoaffective Disorder, Delusional Disorder, Brief Psychotic Disorder, Shared Psychotic Disorder, mania in bipolar disorder, anxiety disorders, depression, maintenance of bipolar disorders, sleep disturbances, migraine, neuroleptic- induced parkinsonism, or cocaine abuse, nicotine abuse, or alcohol abuse, wherein the compound of formula I is present in a therapeutically effective amount of from 4-14 mg calculated as the free base.
9. A method of treating cognitive dysfunction, schizophrenia, Schizophreniform Disorder, Schizoaffective Disorder, Delusional Disorder, Brief Psychotic Disorder, Shared Psychotic Disorder, mania in bipolar disorder, anxiety disorders, depression, maintenance of bipolar disorders, sleep disturbances, migraine, neuroleptic-induced parkinsonism, or cocaine abuse, nicotine abuse, or alcohol abuse, comprising administering a therapeutically effective amount of from 4-14 mg calculated as the free base of the compound of formula I to a patient in need thereof.
10. A pharmaceutical composition comprising the compound of formula (I)
Figure imgf000031_0001
(i) and povidone or copovidone as binder.
11. The composition of claim 10 wherein the binder is present in a concentration range of from 2-10% (w/w), such as 2-4%, 4-6%, 6-8%, or 8-10%.
12. The composition of any one of claims 10-11 wherein the binder is Kollidone VA64.
13. The composition of any one of claims 10-12 wherein the compound of formula (I) is in the form of the succinate salt.
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JP2014517050A (en) * 2011-06-20 2014-07-17 ハー・ルンドベック・アクチエゼルスカベット Method of administering 4-((1R, 3S) -6-chloro-3-phenyl-indan-1-yl) -1,2,2-trimethyl-piperazine and salts thereof in the treatment of schizophrenia
AU2012274150B2 (en) * 2011-06-20 2016-10-06 H. Lundbeck A/S Method of administration of 4-((1R,3S)-6-chloro-3-phenyl-indan-1-yl) -1,2,2-trimethyl-piperazine and the salts thereof in the treatment of schizophrenia
RU2613177C2 (en) * 2011-06-20 2017-03-15 Х. Лундбекк А/С Method of using 4-((1r,3s)-6-chloro-3-phenylindane-1-yl)-1,2,2-trimethylpiperazine and salts thereof in treating schizophrenia
US9610287B2 (en) 2011-06-20 2017-04-04 H. Lundbeck A/S Method of administration of 4-((1R,3S)-6-chloro-3-phenyl-indan-1-yl)-1,2,2-trimethyl-piperazine and the salts thereof in the treatment of schizophrenia
KR101900989B1 (en) * 2011-06-20 2018-09-20 하. 룬드벡 아크티에셀스카브 Method of administration of 4-((1r,3s)-6-chloro-3-phenyl-indan-1-yl)-1,2,2-trimethyl-piperazine and the salts thereof in the treatment of schizophrenia

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AU2009298264A1 (en) 2010-04-08
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CA2732613A1 (en) 2010-04-08

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