WO1998031355A2 - Pharmaceutical composition comprising n-propylnorapomorphine and cathecol-o-methyl-transferase inhibitor for treating parkinson's disease - Google Patents
Pharmaceutical composition comprising n-propylnorapomorphine and cathecol-o-methyl-transferase inhibitor for treating parkinson's disease Download PDFInfo
- Publication number
- WO1998031355A2 WO1998031355A2 PCT/GB1998/000105 GB9800105W WO9831355A2 WO 1998031355 A2 WO1998031355 A2 WO 1998031355A2 GB 9800105 W GB9800105 W GB 9800105W WO 9831355 A2 WO9831355 A2 WO 9831355A2
- Authority
- WO
- WIPO (PCT)
- 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.)
- Ceased
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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
- A61K31/435—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
Definitions
- This invention relates to pharmaceutical compositions especially for use in treating Parkinson's disease.
- levodopa a prodrug for dopamine I:
- levodopa is not an ideal medicament and its deficiencies have penetrated as far as popular scientific writing and cinema.
- apomorphine works where other medicaments have failed and can rapidly restore mobility, for example, following subcutaneous injection it too has disadvantages.
- 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.
- NPA N-propyl norapomorphine III
- 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.
- NPA N-propyl norapomorphine
- COMP catechol-O-methyl-transferase
- 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.
- NPA N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-N-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N
- 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 2 ⁇ mol kg "1 ). MDONPA is more potent than NPA and a maximum effect is often reached and a concentration of around 0.3 ⁇ mol kg "1 .
- NPA or prodrugs 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.
- NPA or NPA prodrug could be administered in some form of controlled release.
- examples include transdermal patches, nasal delivery, electrophoretic methods, suppository and oral controlled release forms.
- 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.
- 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.
- the product of the invention may be in the following form.
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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)
- Medicinal Preparation (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
A medicament is disclosed for 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
PHARMACEUTICAL 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.
II
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 III (hereinafter referred to as NPA)
is a better stimulator of dopamine receptors than apomoφhine 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-adimnistration of a catechol-O-methyl-transferase inhibitor with NPA or 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
IV
Suitable dosages are patient dependent but are typically of the order of 60 to 90 mg per day of NPA (which is about 2μmol kg"1).
MDONPA is more potent than NPA and a maximum effect is often reached and a concentration of around 0.3μmol kg"1.
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 prodrug 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.
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.
Claims
1. A pack comprising a dosage of N-propyl norapomoφhine (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.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB9700855A GB2321190B (en) | 1997-01-16 | 1997-01-16 | Pharmaceutical composition |
| GB9700855.1 | 1997-01-16 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| WO1998031355A2 true WO1998031355A2 (en) | 1998-07-23 |
| WO1998031355A3 WO1998031355A3 (en) | 1998-09-11 |
Family
ID=10806094
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/GB1998/000105 Ceased WO1998031355A2 (en) | 1997-01-16 | 1998-01-14 | Pharmaceutical composition comprising n-propylnorapomorphine and cathecol-o-methyl-transferase inhibitor for treating parkinson's disease |
Country Status (2)
| Country | Link |
|---|---|
| GB (1) | GB2321190B (en) |
| WO (1) | WO1998031355A2 (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2001001984A1 (en) * | 1999-06-30 | 2001-01-11 | Orion Corporation | Levodopa / carbidopa / entacapone pharmaceutical preparation |
| WO2003043974A3 (en) * | 2001-11-19 | 2003-07-17 | Orion Corp | New pharmaceutical compounds |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP3947103B2 (en) * | 2000-07-14 | 2007-07-18 | エフ．ホフマン−ラ ロシュ アーゲー | A method to detect a predisposition to hepatotoxicity |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3717643A (en) * | 1967-05-04 | 1973-02-20 | Sterling Drug Inc | N-substituted-norapomorphines |
| 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 |
| EP0828513B1 (en) * | 1995-05-26 | 2004-01-21 | Pfizer Inc. | Combinations for the treatment of parkinsonism containing selective nmda antagonists |
-
1997
- 1997-01-16 GB GB9700855A patent/GB2321190B/en not_active Expired - Fee Related
-
1998
- 1998-01-14 WO PCT/GB1998/000105 patent/WO1998031355A2/en not_active Ceased
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2001001984A1 (en) * | 1999-06-30 | 2001-01-11 | Orion Corporation | Levodopa / carbidopa / entacapone pharmaceutical preparation |
| 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 |
| KR100905428B1 (en) * | 1999-06-30 | 2009-06-30 | 오리온 코포레이션 | Levodopa / carbidopa / entacapone pharmaceutical formulation |
| CZ303010B6 (en) * | 1999-06-30 | 2012-02-29 | Orion Corporation (Bic 1999212-6) | Peroral solid composition comprising entacapone, levodopa and carbidopa, processes for their preparation and use |
| CZ304416B6 (en) * | 1999-06-30 | 2014-04-23 | Orion Corporation | Pharmaceutical composition containing entacapone, levodopa and carbidopa as well as medicament for the treatment of Parkinsonism |
| WO2003043974A3 (en) * | 2001-11-19 | 2003-07-17 | Orion Corp | New pharmaceutical compounds |
Also Published As
| Publication number | Publication date |
|---|---|
| WO1998031355A3 (en) | 1998-09-11 |
| GB2321190A (en) | 1998-07-22 |
| GB9700855D0 (en) | 1997-03-05 |
| GB2321190B (en) | 2000-09-20 |
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