DE19536916A1 - Inhalative application of 2-amino-6n-propyl-amino-4,5,6,7-tetrahydrobenzothiazole, in particular its (-) - enantiomer, and their pharmacologically acceptable acid addition salts - Google Patents

Inhalative application of 2-amino-6n-propyl-amino-4,5,6,7-tetrahydrobenzothiazole, in particular its (-) - enantiomer, and their pharmacologically acceptable acid addition salts

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Publication number
DE19536916A1
DE19536916A1 DE19536916A DE19536916A DE19536916A1 DE 19536916 A1 DE19536916 A1 DE 19536916A1 DE 19536916 A DE19536916 A DE 19536916A DE 19536916 A DE19536916 A DE 19536916A DE 19536916 A1 DE19536916 A1 DE 19536916A1
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DE
Germany
Prior art keywords
amino
tetrahydrobenzothiazole
acid addition
pharmacologically acceptable
acceptable acid
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.)
Withdrawn
Application number
DE19536916A
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German (de)
Inventor
Michael Dr Herschel
Richard Dr Reichl
Volkmar Dr Haeselbarth
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Boehringer Ingelheim GmbH
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Boehringer Ingelheim GmbH
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Boehringer Ingelheim GmbH filed Critical Boehringer Ingelheim GmbH
Priority to DE19536916A priority Critical patent/DE19536916A1/en
Priority to ZA968315A priority patent/ZA968315B/en
Priority to AU72856/96A priority patent/AU7285696A/en
Priority to PCT/EP1996/004327 priority patent/WO1997012614A1/en
Publication of DE19536916A1 publication Critical patent/DE19536916A1/en
Withdrawn legal-status Critical Current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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/428—Thiazoles condensed with carbocyclic rings

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

The administration by inhalation of pramipexols is disclosed.

Description

Die vorliegende Erfindung betrifft die inhalative Applikation von 2-Amino-6n-propyl­ amino-4,5,6,7-tetrahydrobenzothiazol, insbesondere seines (-)-Enantiomeren, sowie deren pharmakologisch verträgliche Säureadditionssalze.The present invention relates to the inhalative application of 2-amino-6n-propyl amino-4,5,6,7-tetrahydrobenzothiazole, in particular its (-) - enantiomer, and their pharmacologically acceptable acid addition salts.

Die genannten Verbindungen sind als Arzneimittel bekannt, wobei die Behandlung der Schizophrenie und die Behandlung der Parkinsonschen Krankheit im Vordergrund stehen. Einzelheiten zur Herstellung dieser Verbindungen - deren (-)- Enantiomeren in der Literatur auch als SND 919 oder Pramipexol bezeichnet wird, können der Europäischen Patentanmeldung EP-A 85 116 016 entnommen werden. Aus dem europäischen Patent 428 038 ist die transdermale Applikation dieser Verbindung bekannt. Überraschenderweise hat sich gezeigt, daß Pramipexol in Form einer inhalativen Gabe besonders vorteilhaft appliziert werden kann, da ein schneller Wirkungseintritt bei gleichzeitig guter Verträglichkeit beobachtet wird.The compounds mentioned are known as medicaments, the treatment schizophrenia and the treatment of Parkinson's disease in the Foreground. Details of the preparation of these compounds - their (-) - Enantiomers in the literature is also referred to as SND 919 or pramipexole, can be found in European Patent Application EP-A 85 116 016. European Patent 428,038 discloses the transdermal application of these Known connection. Surprisingly, it has been shown that pramipexole in Form of an inhaled dose can be applied particularly advantageous, as a rapid onset of action is observed at the same time good tolerability.

Die Behandlung der Parkinsonschen Krankheit erfolgt üblicherweise durch orale Applikation von Arzneimitteln. Die erfindungsgemäß vorgeschlagene inhalative Applikation bringt für den Parkinson-Patienten wesentliche Vorteile mit sich, die seine Lebensumstände verbessern. Die Parkinson′sche Erkrankung ist bei vielen Patienten mit einem Zustand der Bewegungshemmung verbunden. Die erfindungsgemäße inhalative Applikation von Pramipexole führt zu einem außergewöhnlich raschem Anstieg der Blutspiegelwerte innerhalb kürzester Zeit (Minuten) wodurch der Zustand der Bewegungshemmung rasch aufgehoben wird. Bei oraler Applikation kann es bis zu zwei Stunden dauern, bis optimale Blutspiegelwerte erreicht sind.The treatment of Parkinson's disease is usually by oral Application of medicines. The inventively proposed inhalative Application brings significant benefits for the Parkinson's patients who improve his living conditions. Parkinson's disease is present in many Patients associated with a state of motor inhibition. The inhalative administration of pramipexole according to the invention leads to a exceptionally rapid increase in blood levels within a very short time (Minutes) whereby the state of the movement inhibition is rapidly abolished. With oral administration, it can take up to two hours to get optimal Blood levels are reached.

2-Amino-6n-propyl-amino-4,5,6,7-tetrahydrobenzothiazol kann in Form seiner Säureadditionssalze in Form von wässerigen oder ethanolischen Lösungen zur Herstellung eines Aerosols zur erfindungsgemäßen Anwendung verwendet werden. Bevorzugtes Säureadditionssalz ist das Dihydrochlorid.2-amino-6n-propylamino-4,5,6,7-tetrahydrobenzothiazole may be in the form of its Acid addition salts in the form of aqueous or ethanolic solutions for Preparation of an aerosol can be used for the application of the invention. Preferred acid addition salt is the dihydrochloride.

Vorrichtungen zur Erzeugung eines Dosieraerosols sind aus dem Stand der Technik zur Behandlung von Asthmaerkrankungen bekannt. Besonders bevorzugt ist eine Vorrichtung wie sie in der WO 91/14468 - Atomising Devices and Methods - offenbart ist. Der Vorteil der dort beschriebenen Vorrichtung ist es, daß auf die üblicherweise bei metered dose inhalers (MDI′s) erforderlichen Treibgase zur Erzeugung des Aerosols verzichtet werden kann.Devices for generating a metered dose inhaler are known in the art known for the treatment of asthma. Particularly preferred is a Device as described in WO 91/14468 - Atomizing Devices and Methods -  is disclosed. The advantage of the device described therein is that on the Usually with metered dose inhalers (MDI's) required propellant gases Generation of the aerosol can be dispensed with.

Alternativ zu einem Dosieraerosol kann Pramipexol auch mittels eines sogenannten Pulverinhalators appliziert werden, bei dem mikronisierte Teilchen in einem Bereich von 1 bis 15, bevorzugt 4 bis 8 µm des Wirkstoffes direkt als Pulver inhaliert werden.As an alternative to a metered dose inhaler, pramipexole can also be administered by means of a so-called Powder inhaler can be applied to the micronized particles in one area from 1 to 15, preferably 4 to 8 microns of the active ingredient inhaled directly as a powder become.

Erfindungsgemäß wird eine inhalative Einzeldosis zwischen 0.125 und 4,5 mg pro Patient vorgeschlagen.According to the invention, a single inhaled dose is between 0.125 and 4.5 mg per Patient proposed.

Der nachfolgende Versuch belegt, daß durch die inhalative Applikation von Pramipexole im Tierexperiment bereits kurz nach der Inhalation hohe Plasmaspiegel erzielt werden.The following experiment proves that inhalative administration of Pramipexole in animal experiment already high plasma levels shortly after inhalation be achieved.

Inhalative Einzeldosierung von 2 mg Pramipexole in 20 Mikroliter Wasser/Hund Gewicht des Hundes (Beagle) 10.7 kg
Narkosemittel:
Praemedikation: Valium 7.5 mg i.m.
Nembutal: 30 mg/kg i.v.Inhalative single dose of 2 mg pramipexole in 20 microliter water / dog Dog's weight (Beagle) 10.7 kg
Anesthetic:
Pre-medication: Valium 7.5 mg im
Nembutal: 30 mg / kg iv

Die Applikation des Wirkstoffs erfolgte mittels Respimat Blutplasmaspiegel: Inhalation 2 mgThe application of the drug was carried out by means of Respimat Blood plasma level: inhalation 2 mg

Zeit (Min. nach Appl.)Time (min. After appl.) ng/mlng / ml 1.001:00 5.075:07 5.005:00 1.701.70 15.0015:00 1.351:35 45.0045.00 0.970.97 90.0090.00 0.680.68 120.00120.00 0.640.64 180.00180.00 0.660.66

Beispiel für die Herstellung einer InhalationslösungExample of the preparation of an inhalation solution Beispiel 1example 1 10%ige Lösung 2-Amino-6-n-propyl-amino-4,5,6,7-tetrahydro-benzthiazoldihydrochlorid (Pramipexol)10% solution of 2-amino-6-n-propylamino-4,5,6,7-tetrahydrobenzothiazole dihydrochloride (pramipexole) SND 919|10 gSND 919 | 10 g Zitronensäurecitric acid 14 g14 g Natriumphosphat sek. × 2H₂OSodium phosphate sec. × 2H₂O 6 g6 g Natriumpyrosulfitpyrosulfite 2 g2 g Dest. WasserDest. Water ad 100 mlad 100 ml

Herstellungsverfahrenproduction method

In ausgekochtem und unter CO₂-Begasung abgekühltem Wasser werden nacheinander die Puffersubstanzen, die Wirksubstanz sowie Natriumpyrosulfit gelöst. Man füllt mit abgekochtem Wasser auf das gegebene Volumen auf und filtriert pyrogenfrei.In boiled and cooled under CO₂ fumigation water successively the buffer substances, the active substance and sodium pyrosulfite solved. Make up to the given volume with boiled water and filtered pyrogen-free.

Abfüllung: in braune Ampullen unter Schutzgas
Sterilisation: 20 Minuten bei 120°CFilling: in brown ampoules under inert gas
Sterilization: 20 minutes at 120 ° C

Die Herstellung und Abfüllung der Inhalationslösung muß in abgedunkelten Räumen vorgenommen werden.The preparation and filling of the inhalation solution must be carried out in darkened rooms be made.

Claims (10)

1. Verwendung von 2-Amino-6n-propyl-amino-4,5,6,7-tetrahydrobenzothiazol, seines (-)-Enantiomeren sowie deren pharmakologisch verträgliche Säureadditionssalze zur inhalativen Behandlung von Krankheiten.1. Use of 2-amino-6n-propylamino-4,5,6,7-tetrahydrobenzothiazole, its (-) - enantiomer and their pharmacologically acceptable Acid addition salts for the inhalative treatment of diseases. 2. Verwendung von (-)-2-Amino-6n-propyl-amino-4,5,6,7-tetrahydrobenzothiazol sowie deren pharmakologisch verträglichen Säureadditionssalze zur inhalativen Behandlung von Krankheiten.2. Use of (-) - 2-amino-6n-propylamino-4,5,6,7-tetrahydrobenzothiazole and their pharmacologically acceptable acid addition salts for inhalation Treatment of diseases. 3. Verwendung von (-)-2-Amino-6n-propyl-amino-4,5,6,7-tetrahydrobenzothiazol­ dihydrochlorid zur inhalativen Behandlung von Krankheiten.3. Use of (-) - 2-amino-6n-propylamino-4,5,6,7-tetrahydrobenzothiazole dihydrochloride for the inhalative treatment of diseases. 4. Verwendung nach Anspruch 1, 2 oder 3 zur inhalativen Behandlung der Parkinsonschen Erkrankung.4. Use according to claim 1, 2 or 3 for the inhalative treatment of Parkinson's disease. 5. Lösung enthaltend 2-Amino-6n-propyl-amino-4,5,6,7-tetrahydrobenzothiazol, sein (-)-Enantiomer sowie deren pharmakologisch verträgliche Säureadditionsalze für die inhalative Behandlung von Krankheiten.5. solution containing 2-amino-6n-propylamino-4,5,6,7-tetrahydrobenzothiazole, its (-) - enantiomer and its pharmacologically acceptable Acid addition salts for the inhalative treatment of diseases. 6. Dosieraerosol enthaltend einen pharmakologisch aktiven Wirkstoff zur Behandlung der Parkinsonschen Erkrankung.6. metered aerosol containing a pharmacologically active ingredient for Treatment of Parkinson's disease. 7. Dosieraerosol nach Anspruch 6, dadurch gekennzeichnet, daß der Wirkstoff (-)2-Amino-6n-propyl-amino-4,5,6,7-tetrahydrobenzothiazol sowie sein pharmakologisch verträgliches Säureadditionssalz ist.7. metered dose inhaler according to claim 6, characterized in that the active ingredient (-) 2-amino-6n-propylamino-4,5,6,7-tetrahydrobenzothiazole and its pharmacologically acceptable acid addition salt. 8. Mikronisiertes Pulver für die inhalative Behandlung enthaltend einen pharmakologisch aktiven Wirkstoff zur Behandlung der Parkinsonschen Erkrankung.8. Micronized powder for inhalation treatment containing a pharmacologically active ingredient for the treatment of Parkinson's Illness. 9. Mikronisiertes Pulver nach Anspruch 8, dadurch gekennzeichnet, daß der Wirkstoff (-)-2-Amino-6n-propyl-amino-4,5,6,7-tetrahydrobenzothiazol sowie sein pharmakologisch verträgliches Säureadditionssalz ist.9. Micronized powder according to claim 8, characterized in that the Active ingredient (-) - 2-amino-6n-propylamino-4,5,6,7-tetrahydrobenzothiazole and its pharmacologically acceptable acid addition salt is. 10. Lösung enthaltend nach Anspruch 5, dadurch gekennzeichnet, daß sie zwischen 5 und 12 Gew.% (-)2-Amino-6n-propyl-amino-4,5,6,7- tetrahydrobenzothiazol sowie sein pharmakologisch verträgliches Säureadditionssalz enthält.10. A solution containing according to claim 5, characterized in that they between 5 and 12% by weight of (-) 2-amino-6n-propyl-amino-4,5,6,7-  tetrahydrobenzothiazole and its pharmacologically acceptable Contains acid addition salt.
DE19536916A 1995-10-04 1995-10-04 Inhalative application of 2-amino-6n-propyl-amino-4,5,6,7-tetrahydrobenzothiazole, in particular its (-) - enantiomer, and their pharmacologically acceptable acid addition salts Withdrawn DE19536916A1 (en)

Priority Applications (4)

Application Number Priority Date Filing Date Title
DE19536916A DE19536916A1 (en) 1995-10-04 1995-10-04 Inhalative application of 2-amino-6n-propyl-amino-4,5,6,7-tetrahydrobenzothiazole, in particular its (-) - enantiomer, and their pharmacologically acceptable acid addition salts
ZA968315A ZA968315B (en) 1995-10-04 1996-10-03 Administration by inhalation of 2-amino-6n-propyl-amino-4,5,,7-tetrahydrobenzothiazole particularly the (-)-enan-tiomer thereof and the pharmacologically acceptable acid addition salts thereof
AU72856/96A AU7285696A (en) 1995-10-04 1996-10-04 Administration by inhalation of 2-amino-6n-propylamino-4,5,6,7-tetrahydrobenzothiazol, in particular of its (-)enantiomer and its pharmacologically tolerable acid addition salts
PCT/EP1996/004327 WO1997012614A1 (en) 1995-10-04 1996-10-04 Administration by inhalation of 2-amino-6n-propylamino-4,5,6,7-tetrahydrobenzothiazol, in particular of its (-)enantiomer and its pharmacologically tolerable acid addition salts

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
DE19536916A DE19536916A1 (en) 1995-10-04 1995-10-04 Inhalative application of 2-amino-6n-propyl-amino-4,5,6,7-tetrahydrobenzothiazole, in particular its (-) - enantiomer, and their pharmacologically acceptable acid addition salts

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DE19536916A1 true DE19536916A1 (en) 1997-04-10

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DE19536916A Withdrawn DE19536916A1 (en) 1995-10-04 1995-10-04 Inhalative application of 2-amino-6n-propyl-amino-4,5,6,7-tetrahydrobenzothiazole, in particular its (-) - enantiomer, and their pharmacologically acceptable acid addition salts

Country Status (4)

Country Link
AU (1) AU7285696A (en)
DE (1) DE19536916A1 (en)
WO (1) WO1997012614A1 (en)
ZA (1) ZA968315B (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE19653969A1 (en) * 1996-12-20 1998-06-25 Boehringer Ingelheim Kg New aqueous pharmaceutical preparation for the production of propellant-free aerosols

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2839431A1 (en) * 1978-09-11 1980-03-20 Dolorgiet Arzneimittelfabrik Tranquilliser and hypertonic for heart and vascular disease treatment - contg. 1-(2-nitro-5-methylphenoxy)-3-tert.butyl-aminopropan-2-ol
DE3572485D1 (en) * 1984-12-22 1989-09-28 Thomae Gmbh Dr K Tetrahydro-benzothiazoles, their production and their use as intermediates or drugs

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE19653969A1 (en) * 1996-12-20 1998-06-25 Boehringer Ingelheim Kg New aqueous pharmaceutical preparation for the production of propellant-free aerosols

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WO1997012614A1 (en) 1997-04-10
ZA968315B (en) 1997-04-04
AU7285696A (en) 1997-04-28

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