WO2000023057A2 - Atypical antiphsychotic in combination with acetylcholinesterase inhibitor for improving cognition - Google Patents

Atypical antiphsychotic in combination with acetylcholinesterase inhibitor for improving cognition Download PDF

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Publication number
WO2000023057A2
WO2000023057A2 PCT/EP1999/007804 EP9907804W WO0023057A2 WO 2000023057 A2 WO2000023057 A2 WO 2000023057A2 EP 9907804 W EP9907804 W EP 9907804W WO 0023057 A2 WO0023057 A2 WO 0023057A2
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WO
WIPO (PCT)
Prior art keywords
atypical antipsychotic
acetylcholinesterase inhibitor
patients suffering
alzheimer
disease
Prior art date
Application number
PCT/EP1999/007804
Other languages
French (fr)
Other versions
WO2000023057A3 (en
Inventor
Paul Leonce Irma De Nijs
Wim Louis Julien Parys
Original Assignee
Janssen Pharmaceutica N.V.
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
Priority to IL14258899A priority Critical patent/IL142588A0/en
Priority to AU64727/99A priority patent/AU6472799A/en
Priority to HU0103781A priority patent/HUP0103781A3/en
Priority to EP99952580A priority patent/EP1121131A2/en
Priority to BR9914419-0A priority patent/BR9914419A/en
Priority to EEP200100136A priority patent/EE200100136A/en
Priority to KR1020017002286A priority patent/KR20010072878A/en
Priority to SK459-2001A priority patent/SK4592001A3/en
Application filed by Janssen Pharmaceutica N.V. filed Critical Janssen Pharmaceutica N.V.
Priority to JP2000576832A priority patent/JP2002527469A/en
Priority to CA002345767A priority patent/CA2345767A1/en
Priority to PL99348107A priority patent/PL348107A1/en
Publication of WO2000023057A2 publication Critical patent/WO2000023057A2/en
Publication of WO2000023057A3 publication Critical patent/WO2000023057A3/en
Priority to BG105302A priority patent/BG105302A/en
Priority to NO20011403A priority patent/NO20011403L/en
Priority to HR20010262A priority patent/HRP20010262A2/en
Priority to HK02100158.6A priority patent/HK1039745A1/en

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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
    • A61K31/395—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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention is concerned with pharmaceutical compositions comprising a carrier and as first active ingredient an atypical antipsychotic agent (I) and as second active ingredient an acetylcholinesterase inhibitor (H), each in an amount producing a therapeutically beneficial effect in patients suffering from psychosis, or Alzheimer's disease or related dementias.
  • Said therapeutically beneficial effect can be a synergistic effect on the cognitive functioning of patients suffering from Alzheimer's disease or related dementias, or the prevention of the further deterioration of cognition in said patients, or the reduction of adverse effects associated with the one of the active ingredients by the other of the active ingredients.
  • an atypical antipsychotic agent (I) for the preparation of a medicament for reducing adverse effects associated with acetylcholinesterase inhibitors (LI) in patients suffering from Alzheimer's disease or related dementias, such as nausea, vomiting, sweating, restlessness and insomnia.
  • an atypical antipsychotic agent (I) for the preparation of a medicament for improving sleep in patients suffering from Alzheimer's disease or related dementias while being treated with acetylcholinesterase inhibitors (II).
  • the present invention is concerned with a pharmaceutical composition
  • a pharmaceutical composition comprising a carrier and as first active ingredient an atypical antipsychotic agent (I) and as second active ingredient an acetylcholinesterase inhibitor (II), each in an amount producing a therapeutically beneficial effect in patients suffering from psychosis, or Alzheimer's disease or related dementias.
  • Said therapeutically beneficial effect can be a synergistic effect on the cognitive functioning of patients suffering from Alzheimer's disease or related dementias, or the prevention of the further deterioration of cognition in said patients, or the reduction of adverse effects associated with the one of the active ingredients by the other of the active ingredients.
  • the atypical antipsychotic (I) is selected from risperidone, 9-hydroxyrisperidone or a o- 20 alkanoic acid ester thereof, olanzapine, quetiapine, iloperidone or ziprasidone, and the acetylcholinesterase inhibitor (II) is selected from galantamine, rivastigmine or donepezil, or therapeutically active acid addition salt form of any of the foregoing.
  • Said salts comprise salt forms which the active ingredients (I) and (H) are able to form with appropriate acids, such as, for example, inorganic acids such as hydrohalic acids, e.g.
  • hydrochloric or hydrobromic acid sulfuric; nitric; phosphoric and the like acids; or organic acids such as, for example, acetic, propanoic, hydroxyacetic, lactic, pyruvic, oxalic, malonic, succinic, maleic, fumaric, malic, tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, -toluenesulfonic, cyclamic, salicylic, p-amino- salicylic, pamoic and the like acids.
  • galantamine may conveniently be used as the ( 1 : 1 ) hydrobromide salt.
  • a lkanoic acids are selected from the group consisting of decanoic (capric), undecanoic, dodecanoic (lauric), tridecanoic, tetradecanoic (myristic), pentadecanoic, hexadecanoic (palmitic), heptadecanoic, octadecanoic (stearic), nonadecanoic and eicosanoic acid. Due to their limited aqueous solubility, it was generally believed that the esters had to be suspended into oils.
  • the ester having a C15 (pentadecyl) chain and the active ingredient corresponding thereto being the 9-hydroxyrisperidone palmitate ester was found to be the superior ester from a pharmacokinetic, as well as from a tolerance point of view.
  • the amount of each of the active ingredients is equal to or less than that which is approved in monotherapy with said active ingredient.
  • compositions wherein the atypical antipsychotic (I) is risperidone and the acetylcholinesterase inhibitor (II) is galantamine, in particular as galantamine hydrobromide are particularly preferred.
  • the amount of risperidone is 0.5, 1, 2, 4, or 6 mg and that of galantamine (as base) is 8, 16, 24 or 32 mg per dosage form.
  • the present invention also relates to products containing as first active ingredient an atypical antipsychotic agent (I) and as second active ingredient an acetylcholinesterase inhibitor (II), as combined preparations for simultaneous, separate or sequential use in the treatment of patients suffering from psychosis, Alzheimer's disease or related dementias.
  • an atypical antipsychotic agent I
  • an acetylcholinesterase inhibitor II
  • the present invention also concerns the use of an acetylcholinesterase inhibitor (II) for the preparation of a medicament for enhancing the effect of an atypical antipsychotic agent (I) on cognition in patients suffering from psychosis.
  • II acetylcholinesterase inhibitor
  • the present invention also concerns the use of an atypical antipsychotic agent (I) for the preparation of a medicament for enhancing the effect of an acetylcholinesterase inhibitor (II) on cognition in patients suffering from Alzheimer's disease or related dementias. Additionally, the present invention concerns the use of an atypical antipsychotic agent
  • acetylcholinesterase inhibitors H
  • Said adverse effect can be nausea, vomiting, sweating, restlessness or insomnia.
  • an atypical antipsychotic agent (I) for the preparation of a medicament for improving sleep in patients suffering from Alzheimer's disease or related dementias while being treated with acetylcholinesterase inhibitors (II).
  • the present invention also concerns the use of an acetylcholinesterase inhibitor
  • the atypical antipsychotic (I) is preferably risperidone and the acetylcholinesterase inhibitor (II) is preferably galantamine, in particular the (1:1) hydrobromide.

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  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Engineering & Computer Science (AREA)
  • Medicinal Chemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Biomedical Technology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Epidemiology (AREA)
  • Psychiatry (AREA)
  • Hospice & Palliative Care (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Medicines Containing Plant Substances (AREA)

Abstract

The present invention is concerned with pharmaceutical compositions comprising a carrier and as first active ingredient an atypical antipsychotic agent (I) and as second active ingredient an acetylcholinesterase inhibitor (II), each in an amount producing a therapeutically beneficial effect in patients suffering from psychosis, or Alzheimer's disease or related dementias. Said therapeutically beneficial effect can be a synergistic effect on the cognitive functioning of patients suffering from Alzheimer's disease or related dementias or the prevention of the further deterioration of cognition in said patients, or the reduction of adverse effects associated with the one of the active ingredients by the other of the active ingredients.

Description

THERAPY FOR IMPROVING COGNITION
The present invention is concerned with pharmaceutical compositions comprising a carrier and as first active ingredient an atypical antipsychotic agent (I) and as second active ingredient an acetylcholinesterase inhibitor (H), each in an amount producing a therapeutically beneficial effect in patients suffering from psychosis, or Alzheimer's disease or related dementias. Said therapeutically beneficial effect can be a synergistic effect on the cognitive functioning of patients suffering from Alzheimer's disease or related dementias, or the prevention of the further deterioration of cognition in said patients, or the reduction of adverse effects associated with the one of the active ingredients by the other of the active ingredients.
Of particular interest is the use of an atypical antipsychotic agent (I) for the preparation of a medicament for reducing adverse effects associated with acetylcholinesterase inhibitors (LI) in patients suffering from Alzheimer's disease or related dementias, such as nausea, vomiting, sweating, restlessness and insomnia. Especially interesting is the use of an atypical antipsychotic agent (I) for the preparation of a medicament for improving sleep in patients suffering from Alzheimer's disease or related dementias while being treated with acetylcholinesterase inhibitors (II).
The present invention is concerned with a pharmaceutical composition comprising a carrier and as first active ingredient an atypical antipsychotic agent (I) and as second active ingredient an acetylcholinesterase inhibitor (II), each in an amount producing a therapeutically beneficial effect in patients suffering from psychosis, or Alzheimer's disease or related dementias. Said therapeutically beneficial effect can be a synergistic effect on the cognitive functioning of patients suffering from Alzheimer's disease or related dementias, or the prevention of the further deterioration of cognition in said patients, or the reduction of adverse effects associated with the one of the active ingredients by the other of the active ingredients.
The atypical antipsychotic (I) is selected from risperidone, 9-hydroxyrisperidone or a o-20 alkanoic acid ester thereof, olanzapine, quetiapine, iloperidone or ziprasidone, and the acetylcholinesterase inhibitor (II) is selected from galantamine, rivastigmine or donepezil, or therapeutically active acid addition salt form of any of the foregoing. Said salts comprise salt forms which the active ingredients (I) and (H) are able to form with appropriate acids, such as, for example, inorganic acids such as hydrohalic acids, e.g. hydrochloric or hydrobromic acid; sulfuric; nitric; phosphoric and the like acids; or organic acids such as, for example, acetic, propanoic, hydroxyacetic, lactic, pyruvic, oxalic, malonic, succinic, maleic, fumaric, malic, tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, -toluenesulfonic, cyclamic, salicylic, p-amino- salicylic, pamoic and the like acids. For example, galantamine may conveniently be used as the ( 1 : 1 ) hydrobromide salt.
Cl0-20alkanoic acids are selected from the group consisting of decanoic (capric), undecanoic, dodecanoic (lauric), tridecanoic, tetradecanoic (myristic), pentadecanoic, hexadecanoic (palmitic), heptadecanoic, octadecanoic (stearic), nonadecanoic and eicosanoic acid. Due to their limited aqueous solubility, it was generally believed that the esters had to be suspended into oils. The ester having a C15 (pentadecyl) chain and the active ingredient corresponding thereto being the 9-hydroxyrisperidone palmitate ester was found to be the superior ester from a pharmacokinetic, as well as from a tolerance point of view.
Preferably, the amount of each of the active ingredients is equal to or less than that which is approved in monotherapy with said active ingredient.
Most preferred are compositions wherein the atypical antipsychotic (I) is risperidone and the acetylcholinesterase inhibitor (II) is galantamine, in particular as galantamine hydrobromide. In said compositions, the amount of risperidone is 0.5, 1, 2, 4, or 6 mg and that of galantamine (as base) is 8, 16, 24 or 32 mg per dosage form.
The present invention also relates to products containing as first active ingredient an atypical antipsychotic agent (I) and as second active ingredient an acetylcholinesterase inhibitor (II), as combined preparations for simultaneous, separate or sequential use in the treatment of patients suffering from psychosis, Alzheimer's disease or related dementias.
The present invention also concerns the use of an acetylcholinesterase inhibitor (II) for the preparation of a medicament for enhancing the effect of an atypical antipsychotic agent (I) on cognition in patients suffering from psychosis.
Conversely, the present invention also concerns the use of an atypical antipsychotic agent (I) for the preparation of a medicament for enhancing the effect of an acetylcholinesterase inhibitor (II) on cognition in patients suffering from Alzheimer's disease or related dementias. Additionally, the present invention concerns the use of an atypical antipsychotic agent
(I) for the preparation of a medicament for reducing adverse effects associated with acetylcholinesterase inhibitors (H) in patients suffering from Alzheimer's disease or related dementias. Said adverse effect can be nausea, vomiting, sweating, restlessness or insomnia. Especially interesting is the use of an atypical antipsychotic agent (I) for the preparation of a medicament for improving sleep in patients suffering from Alzheimer's disease or related dementias while being treated with acetylcholinesterase inhibitors (II).
Finally, the present invention also concerns the use of an acetylcholinesterase inhibitor
(II) for the preparation of a medicament for reducing adverse effects associated with atypical antipsychotic agents (I) in patients suffering from psychoses. Said the adverse effect can be extrapyramidal syndrome or tardive dyskinesia.
In all the preceding uses the atypical antipsychotic (I) is preferably risperidone and the acetylcholinesterase inhibitor (II) is preferably galantamine, in particular the (1:1) hydrobromide.

Claims

Claims
1. A pharmaceutical composition comprising a carrier and as first active ingredient an atypical antipsychotic agent (I) and as second active ingredient an acetylcholinesterase inhibitor (II), each in an amount producing a therapeutically beneficial effect in patients suffering from psychosis, Alzheimer's disease or related dementias.
2. A composition according to claim 1 wherein said therapeutically beneficial effect is a synergistic effect on the cognitive functioning of patients suffering from
Alzheimer's disease or related dementias, or the prevention of the further deterioration of cognition in said patients, or the reduction of adverse effects associated with the one of the active ingredients by the other of the active ingredients.
3. A composition according to claim 1 wherein the atypical antipsychotic (I) is selected from risperidone, 9-hydroxyrisperidone or a C10-2o alkanoic acid ester thereof, olanzapine, quetiapine, iloperidone or ziprasidone, and the acetylcholinesterase inhibitor (II) is selected from galantamine, rivastigmine or donepezil.
4. A composition according to claim 3 wherein the amount of each of the active ingredients is equal to or less than that which is approved in monotherapy with said active ingredient.
5. A composition according to claim 3 wherein the atypical antipsychotic (I) is risperidone and the acetylcholinesterase inhibitor (II) is galantamine.
6. A composition according to claim 5 wherein the amount of risperidone is 0.5, 1, 2, 4, or 6 mg and that of galantamine (as base) is 8, 16, 24 or 32 mg per dosage form.
7. A product containing as first active ingredient an atypical antipsychotic agent (I) and as second active ingredient an acetylcholinesterase inhibitor (II), as a combined preparation for simultaneous, separate or sequential use in the treatment of patients suffering from psychosis, Alzheimer's disease or related dementias.
8. The use of an acetylcholinesterase inhibitor (II) for the preparation of a medicament for enhancing the effect of an atypical antipsychotic agent (I) on cognition in patients suffering from psychosis.
9. The use of an atypical antipsychotic agent (I) for the preparation of a medicament for enhancing the effect of an acetylcholinesterase inhibitor (LI) on cognition in patients suffering from Alzheimer's disease or related dementias.
10. The use of an atypical antipsychotic agent (I) for the preparation of a medicament for reducing adverse effects associated with acetylcholinesterase inhibitors (II) in patients suffering from Alzheimer's disease or related dementias.
11. Use according to claim 10 wherein the adverse effect is nausea, vomiting, sweating, restlessness or insomnia.
12. The use of an acetylcholinesterase inhibitor (II) for the preparation of a medicament for reducing adverse effects associated with atypical antipsychotic agents (I) in patients suffering from psychoses.
13. Use according to claim 12 wherein the adverse effect is extrapyramidal syndrome or tardive dyskinesia.
14. Use according to any one of claims 8 to 13 wherein the atypical antipsychotic (I) is risperidone and the acetylcholinesterase inhibitor (LI) is galantamine.
PCT/EP1999/007804 1998-10-16 1999-10-12 Atypical antiphsychotic in combination with acetylcholinesterase inhibitor for improving cognition WO2000023057A2 (en)

Priority Applications (15)

Application Number Priority Date Filing Date Title
JP2000576832A JP2002527469A (en) 1998-10-16 1999-10-12 Therapy to improve cognition
AU64727/99A AU6472799A (en) 1998-10-16 1999-10-12 Therapy for improving cognition
CA002345767A CA2345767A1 (en) 1998-10-16 1999-10-12 Therapy for improving cognition
BR9914419-0A BR9914419A (en) 1998-10-16 1999-10-12 Perception improvement therapy
EEP200100136A EE200100136A (en) 1998-10-16 1999-10-12 Use of an acetylcholine esterase inhibitor and an antipsychotic agent in the manufacture of a medicament for the treatment of cognitive and psychotic disorders, and a pharmaceutical composition containing these agents
KR1020017002286A KR20010072878A (en) 1998-10-16 1999-10-12 Atypical antiphsychotic in combination with acetylcholinesterase inhibitor for improving cognition
SK459-2001A SK4592001A3 (en) 1998-10-16 1999-10-12 Atypical antipsychotic in combination with acetylcholinesterase inhibitor for improving cognition
IL14258899A IL142588A0 (en) 1998-10-16 1999-10-12 Therapy for improving cognition
HU0103781A HUP0103781A3 (en) 1998-10-16 1999-10-12 Pharmaceutical compositions comprising atypical antiphsychotic agent in combination with acetylcholinesterase inhibitor for improving cognition
EP99952580A EP1121131A2 (en) 1998-10-16 1999-10-12 Atypical antipsychotic in combination with acetylcholinesterase inhibitor for improving cognition
PL99348107A PL348107A1 (en) 1998-10-16 1999-10-12 Therapy for improving cognition
BG105302A BG105302A (en) 1998-10-16 2001-03-01 Means for improving cognition
NO20011403A NO20011403L (en) 1998-10-16 2001-03-20 Therapy to improve congestion
HR20010262A HRP20010262A2 (en) 1998-10-16 2001-04-10 Therapy for improving cognition
HK02100158.6A HK1039745A1 (en) 1998-10-16 2002-01-10 Atypical antipsychotic in combination with acetylcholinesterase inhibitor for improving cognition

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP98203454 1998-10-16
EP98203454.8 1998-10-16

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WO2000023057A2 true WO2000023057A2 (en) 2000-04-27
WO2000023057A3 WO2000023057A3 (en) 2000-07-27

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EP (1) EP1121131A2 (en)
JP (1) JP2002527469A (en)
KR (1) KR20010072878A (en)
CN (1) CN1367697A (en)
AU (1) AU6472799A (en)
BG (1) BG105302A (en)
BR (1) BR9914419A (en)
CA (1) CA2345767A1 (en)
EE (1) EE200100136A (en)
HK (1) HK1039745A1 (en)
HR (1) HRP20010262A2 (en)
HU (1) HUP0103781A3 (en)
ID (1) ID28441A (en)
IL (1) IL142588A0 (en)
NO (1) NO20011403L (en)
PL (1) PL348107A1 (en)
SK (1) SK4592001A3 (en)
TR (1) TR200101082T2 (en)
WO (1) WO2000023057A2 (en)
ZA (1) ZA200103081B (en)

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