GB2321190A - Medicament pack for treating Parkinson's Disease - Google Patents

Medicament pack for treating Parkinson's Disease Download PDF

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Publication number
GB2321190A
GB2321190A GB9700855A GB9700855A GB2321190A GB 2321190 A GB2321190 A GB 2321190A GB 9700855 A GB9700855 A GB 9700855A GB 9700855 A GB9700855 A GB 9700855A GB 2321190 A GB2321190 A GB 2321190A
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United Kingdom
Prior art keywords
npa
pack
disease
dosage
physiologically acceptable
Prior art date
Legal status (The legal status 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 status listed.)
Granted
Application number
GB9700855A
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GB2321190B (en
GB9700855D0 (en
Inventor
Derek Alan Woodcock
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Britannia Pharmaceuticals Ltd
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Britannia Pharmaceuticals Ltd
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Publication date
Application filed by Britannia Pharmaceuticals Ltd filed Critical Britannia Pharmaceuticals Ltd
Priority to GB9700855A priority Critical patent/GB2321190B/en
Publication of GB9700855D0 publication Critical patent/GB9700855D0/en
Priority to PCT/GB1998/000105 priority patent/WO1998031355A2/en
Publication of GB2321190A publication Critical patent/GB2321190A/en
Application granted granted Critical
Publication of GB2321190B publication Critical patent/GB2321190B/en
Anticipated expiration legal-status Critical
Expired - Fee Related legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/485—Morphinan derivatives, e.g. morphine, codeine
    • 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
    • A61K31/12—Ketones
    • 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
    • A61K31/275—Nitriles; Isonitriles
    • A61K31/277—Nitriles; Isonitriles having a ring, e.g. verapamil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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

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

Abstract

A medicament treating Parkinson's disease which is in the form of a pack comprising a dosage of N-propyl norapomorphine (NPA) physiologically acceptable salts or prodrugs thereof and a dosage of a catechol-O-methyl-transferase (COMT) inhibitor.

Description

PHARMACE;UTICAL COMPOSITION This invention relates to pharmaceutical compositions especially for use in treating Parkinson's disease.
The primary medicament used in the treatment of Parkinsonism is levodopa either alone or in conjunction with inhibitors. As is well known levodopa is a prodrug for dopamine I:
As is also well known levodopa is not an ideal medicament and its deficiencies have penetrated as far as popular scientific writing and cinema.
Attempts have been made to devise other dopaminergic drugs of which Britaject (TM) (apomorphine II) is an example.
While apomorphine works where other medicaments have failed and can rapidly restore mobility, for example, following subcutaneous injection it too has disadvantages. At one time the commonest medical use for apomorphine was as an emetic for use in case of poisoning.
Apomorphine can also induce azotemia which is a hepatoxic condition.
N-propyl norapomorphine m (hereinafter referred to as NPA)
is a better stimulator of dopamine receptors than apomorphine and additionally causes less emesis and is less likely to produce nephrotoxicity. Unfortunately while initially effective the therapeutic potency of NPA diminishes with time. This diminution is known as tachyphylaxis.
It has now been unexpectedly found that co-adininistration of a catechol-O-methyl-transferase inhibitor with NPA er an NPA prodrug substantially reduces tachyphylaxis.
According to the invention therefore there is provided a pack comprising a dosage of N-propyl norapomorphine (NPA) physiologically acceptable salts or prodrugs thereof and a dosage of a catechol-O-methyl-transferase (COMT) inhibitor.
According to the invention there is further provided a product containing: i. NPA, physiologically acceptable salts thereof or prodrugs thereof, and ii. a COMT inhibitor as a combined preparation for simultaneous, separate or sequential use in treatment of Parkinson's disease.
According to the invention there is yet further provided the use of: a. NPA, physiologically acceptable salts thereof or prodrugs thereof, and b. COMT inhibitors in the manufacture of a medicament for the treatment of Parkinson's disease.
NPA can be used as the free base or as an acid addition salt for example the hydrochloride. Prodrugs can be used. A particularly preferred prodrug is methylene dioxy-N-n-propyl norapomorphine IV (MDONPA) and its salts
Suitable dosages are patient dependent but are typically of the order of 60 to 90 mg per day of NPA (which is about 2pinol keg?1).
MDONPA is more potent than NPA and a maximum effect is often reached and a concentration of around 0.3unol kg-l.
It is preferred to keep the bodily concentration of NPA or prodrugs relatively constant. Thus it may be desired to administer the NPA or NPA prodrug several for example 4 to 6 or 8 times daily if administered orally or subcutaneously.
Alternatively the NPA or NPA pro drug could be administered in some form of controlled release. Examples include transdermal patches, nasal delivery, electrophoretic methods, suppository and oral controlled release forms.
If desired the COMT inhibitor can be administered at the same time as the NPA or NPA prodrug for example by incorporating both NPA and COMT inhibitor in one preparation for subcutaneous administration. It is not essential however and the components could be administered sequentially or separately.
A suitable COMT inhibitor is tolcapone V
Tolcapone can be administered orally. Typical doses of tolcapone are in the range of 100 to 1000 mg per day especially 200 to 800 mg. Entacapone VI is a further COMT inhibitor.
Entacapone too is suitable for administration orally. Typically dosages are in the range 50 to 800 mg especially 100 to 400 mg.
Other usuable COMT inhibitors may include nitecapone VIII and CGP28014 VIII.
VIII This list should not be construed as limiting. Mixtures of COMT inhibitors may be used.
The invention can be used at all stages of the disease's progression from diagnosis onwards. Importantly the invention can have application where dopaminergic therapy has failed.
By way of non-limiting example the product of the invention may be in the following form: EXAMPLE 1 First Component Tolcapone 400 mg Tolcapone 400 mg was tableted in conventional manner.
Second Component NPA 40 mg NPA 40 mg was made up into capsules in known manner.
Administration One each of the first and second component were administered orally twice sequentially.
EXAMPLE 2 MDONPA 10 mg Entacapone 200 mg The active ingredients were incorporated in a capsule in conventional way. One capsule per day was administered orally.

Claims (11)

Claims
1. A pack comprising a dosage of N-propyl norapomorphine (NPA) physiologically acceptable salts or prodrugs thereof and a dosage of a catechol-O-methyl-transferase (COMT) inhibitor.
2. A pack as claimed in claim 1 wherein the dosage of NPA physiologically acceptable salts or a prodrug thereof is for administration separate from the COMT inhibitor.
3. A pack as claimed in claim 1 or claim 2 for oral delivery, transdermal delivery, nasal delivery or electrophoretic delivery.
4. A pack as claimed in any one of the preceding claims wherein the daily dosage of NPA or salts thereof is 60 to 90 mg per day (calculated as NPA).
5. A pack as claimed in any one of claims 1 to 3 wherein the prodrug of NPA is methylenedioxy-N-n-propyl norapomorphine (MDONPA) or physiologically acceptable salts thereof.
6. A pack as claimed in claim 5 wherein the dosage of MDONPA or physiological salt thereof is 10 to 15 mg per day calculated as MDONPA.
7. A pack as claimed in anyone of the preceding claims wherein the COMT inhibitor is entacapone or tolcapone.
8. A pack as claimed in any one of the preceding claims for use in therapy.
9. A pack as claimed in claim 8 for use in therapy of Parkinson's disease.
10. Product containing: i. NPA, physiologically acceptable salts thereof or prodrugs thereof, and ii. a COMT inhibitor as a combined preparation for simultaneous, separate or sequential use in treatment of Parkinson's disease.
11. The use of: a. NPA, physiologically acceptable salts thereof or prodrugs thereof, and b. COMT inhibitors in the manufacture of a medicament for the treatment of Parkinson's disease.
GB9700855A 1997-01-16 1997-01-16 Pharmaceutical composition Expired - Fee Related GB2321190B (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
GB9700855A GB2321190B (en) 1997-01-16 1997-01-16 Pharmaceutical composition
PCT/GB1998/000105 WO1998031355A2 (en) 1997-01-16 1998-01-14 Pharmaceutical composition comprising n-propylnorapomorphine and cathecol-o-methyl-transferase inhibitor for treating parkinson's disease

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
GB9700855A GB2321190B (en) 1997-01-16 1997-01-16 Pharmaceutical composition

Publications (3)

Publication Number Publication Date
GB9700855D0 GB9700855D0 (en) 1997-03-05
GB2321190A true GB2321190A (en) 1998-07-22
GB2321190B GB2321190B (en) 2000-09-20

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ID=10806094

Family Applications (1)

Application Number Title Priority Date Filing Date
GB9700855A Expired - Fee Related GB2321190B (en) 1997-01-16 1997-01-16 Pharmaceutical composition

Country Status (2)

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GB (1) GB2321190B (en)
WO (1) WO1998031355A2 (en)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6500867B1 (en) * 1999-06-30 2002-12-31 Orion Corporation Pharmaceutical composition comprising entacapone, levodopa, and carbidopa
WO2002006523A3 (en) * 2000-07-14 2003-04-17 Hoffmann La Roche Method for detecting pre-disposition to hepatotoxicity

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FI20012242A0 (en) * 2001-11-19 2001-11-19 Orion Corp New pharmaceutical compounds

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3717643A (en) * 1967-05-04 1973-02-20 Sterling Drug Inc N-substituted-norapomorphines

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU3140577A (en) * 1976-12-13 1979-06-14 Sterling Drug Inc N-propylnorapormorphine diesters
US4469695A (en) * 1980-02-25 1984-09-04 Ayerst, Mckenna & Harrison, Inc. 2-(4-Hydroxyalkyl-1-piperazinyl)-2,4,6-cycloheptatrien-1-one derivatives
US5496836A (en) * 1994-05-05 1996-03-05 Mount Sinai School Of Medicine Of The City University Of New York Use of famotidine and related compounds in the treatment of movement disorders
DK0828513T3 (en) * 1995-05-26 2004-04-13 Pfizer Combination preparations for the treatment of parkinsonism, containing selective NMDA antagonists

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3717643A (en) * 1967-05-04 1973-02-20 Sterling Drug Inc N-substituted-norapomorphines

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
Biosis No: 67062980 & Archives of Neurology 35(12), 1978, pages 787 - 791. *
Chemical Abstract No: 125:48284 & Eur. J. Clin. Pharmacology50(1/2), 1996, pages 47 - 55. *
Chemical Abstract No: 125:49128 & Clin. Neuropharmacology 19(3), 1996, pages 222 - 223. *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6500867B1 (en) * 1999-06-30 2002-12-31 Orion Corporation Pharmaceutical composition comprising entacapone, levodopa, and carbidopa
US6797732B2 (en) 1999-06-30 2004-09-28 Orion Corporation Pharmaceutical composition comprising entracapone, levodopa, and carbidopa
WO2002006523A3 (en) * 2000-07-14 2003-04-17 Hoffmann La Roche Method for detecting pre-disposition to hepatotoxicity

Also Published As

Publication number Publication date
GB2321190B (en) 2000-09-20
WO1998031355A3 (en) 1998-09-11
WO1998031355A2 (en) 1998-07-23
GB9700855D0 (en) 1997-03-05

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PCNP Patent ceased through non-payment of renewal fee

Effective date: 20060116