WO1995003796A1 - New combination of active substances containing esupron and levodopa - Google Patents

New combination of active substances containing esupron and levodopa Download PDF

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Publication number
WO1995003796A1
WO1995003796A1 PCT/EP1994/002196 EP9402196W WO9503796A1 WO 1995003796 A1 WO1995003796 A1 WO 1995003796A1 EP 9402196 W EP9402196 W EP 9402196W WO 9503796 A1 WO9503796 A1 WO 9503796A1
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WO
WIPO (PCT)
Prior art keywords
esupron
levodopa
active substances
combination
new combination
Prior art date
Application number
PCT/EP1994/002196
Other languages
German (de)
French (fr)
Inventor
Rainer Schlecker
Hans-Juergen Teschendorf
Original Assignee
Basf Aktiengesellschaft
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 Basf Aktiengesellschaft filed Critical Basf Aktiengesellschaft
Priority to AU74575/94A priority Critical patent/AU7457594A/en
Publication of WO1995003796A1 publication Critical patent/WO1995003796A1/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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A61K31/366—Lactones having six-membered rings, e.g. delta-lactones
    • A61K31/37—Coumarins, e.g. psoralen

Definitions

  • the present invention relates to a new combination of active ingredients for the treatment of disorders of the extrapyramidal motor system.
  • Esupron is the ethanesulfonic acid ester of 7-hydroxy-3,4-dimethyl-coumarin:
  • the substance is known as an active ingredient for the pharmacotherapy of mental disorders, in particular as an antidepressant (EP-PS 111 746, Example 39).
  • Levodopa is a long-known substance (Merck Index, 11th edition, No. 5344), which is used as an anti-Parkinson agent:
  • the invention relates to medicaments which contain Esupron and Levodopa.
  • the medicaments can be in the form of combination preparations for simultaneous use in a fixed combination or separately for simultaneous or time-graded use.
  • the combination is well suited for the treatment of disorders of the extrapyramidal motor system, in particular Parkinson's disease.
  • the Esupron and levodopa are given in combination in amounts that are below the lower limits of the doses at d en substances in the sole application.
  • the daily dose of Esupron is usually 100 to 200 mg per patient and is administered by a single dose.
  • the daily dose of levodopa is usually 25 to 200 mg per patient. It can be given together with the Esupron or can also be delayed.
  • the daily dose of levodopa can also be divided into 2 to 3 individual doses per day.
  • the combination can be in the usual way, e.g. orally or intravenously.
  • the active substances can be used in the usual galenical forms of application in solid or liquid form, such as tablets,
  • the active ingredients can be combined with the usual pharmaceutical auxiliaries (mainly carriers and diluents) such as talc, gum arabic, sucrose, lactose, cereal or corn starch, potato flour, magnesium stearate, alginates, gum tragacanth, carraghenates, polyvinyl alcohol, polyvinyl pyrrolidone, aqueous or non-aqueous carriers, wetting agents, dispersants, emulsifiers and / or preservatives are processed (cf. H. Sucker et al., Pharmaceutical Technology, Thieme-Verlag, Stuttgart 1978).
  • the preparations thus obtained normally contain the active ingredient in an amount of 10 to 93% by weight.
  • Anesthetized rats male, 180-200 g were injected unilaterally with 6-OH-dopamine (8 ⁇ g in 4 ⁇ l in 4 min) into the substantia nigra.
  • Post-synaptic dopaminergic stimulation e.g. by apomorphine or L-dopa, contralateral rotational movements (Brain Research ___., 485 (1970)).
  • the rotational frequency is a measure of the extent of the stimulation.
  • L-DOPA triggers ip contralateral rotary movements in doses of approx. 200 to 300 mg / kg, which can be seen as an equivalent to the clinically known effect of L-DOPA in Parkinson's disease.
  • the dose of 21.5 mg / kg is ineffective (see table).
  • Esupron makes it possible to potentiate the effect of L-DOPA. 2.15 and 4.64 mg / kg p.o.
  • Esupron doses which are likewise ineffective when given alone
  • Tablets of the following composition are pressed in a conventional manner on a tablet press:
  • the core composition consists of 9 parts of corn starch, 3 parts Milch ⁇ sugar and 1 part Luviskol ® VA 64 (vinylpyrrolidone-vinyl acetate copolymer 60:40; see. Pharm. Ind. 1962, 586).
  • the film coating layer consists of 5
  • 14 tablets 5 with 100 mg Espuron and 14 tablets with 100 mg Levodopa each are arranged in rows so that one Espuron tablet is next to a Levodopa tablet.

Abstract

A combination of esupron and levodopa is suitable for treating extrapyramidal-motor disorders.

Description

Neue Wirkstoffkombination,"die Esupron und Levodopa enthält.New combination of active ingredients " containing Esupron and Levodopa.
Beschreibungdescription
Die vorliegende Erfindung betrifft eine neue Wirkstoffkombination zur Behandlung von Störungen des extrapyramidal-motorischen Systems.The present invention relates to a new combination of active ingredients for the treatment of disorders of the extrapyramidal motor system.
Esupron ist der Ethansulfonsäureester des 7-Hydroxy-3,4-dimethyl- cumarins:Esupron is the ethanesulfonic acid ester of 7-hydroxy-3,4-dimethyl-coumarin:
Figure imgf000003_0001
Figure imgf000003_0001
Die Substanz ist als Wirkstoff zur Pharmakotherapie von psychi¬ schen Störungen, insbesondere als Antidepressivum bekannt (EP-PS 111 746, Beispiel 39).The substance is known as an active ingredient for the pharmacotherapy of mental disorders, in particular as an antidepressant (EP-PS 111 746, Example 39).
Levodopa ist lange bekannte Substanz (Merck Index, 11. Auflage, Nr. 5344), die als Antiparkinsonmittel verwendet wird:Levodopa is a long-known substance (Merck Index, 11th edition, No. 5344), which is used as an anti-Parkinson agent:
Figure imgf000003_0002
Figure imgf000003_0002
Es wurde nun gefunden, daß sich durch die Kombination beider Substanzen eine Wirkung erzielen läßt, die nicht durch die Addi¬ tion der Einzeleffekte zu erklären ist.It has now been found that the combination of the two substances can achieve an effect which cannot be explained by the addition of the individual effects.
Gegenstand der Erfindung sind Arzneimittel, die Esupron und Levo¬ dopa enthalten.The invention relates to medicaments which contain Esupron and Levodopa.
Die Arzneimittel können als Kombinationspräparate zur gleichzei- tigen Anwendung in fixer Kombination oder getrennt zur gleichzei¬ tigen oder zeitlich abgestuften Anwendung vorliegen.The medicaments can be in the form of combination preparations for simultaneous use in a fixed combination or separately for simultaneous or time-graded use.
Die Kombination eignet sich gut zur Behandlung von Störungen des extrapyramidal-motorischen Systems, insbesondere des Morbus Par- kinson. Das Esupron und das Levodopa werden in der Kombination in Mengen gegeben, die unter der unteren Grenze der Dosierungen der beiden Substanzen bei deren alleiniger Applikation liegen. Die Tagesdo¬ sis von Esupron liegt in der Regel bei 100 bis 200 mg pro Patient und wird durch eine einmalige Gabe verabfolgt. Die Tagesdosis an Levodopa beträgt in der Regel 25 bis 200 mg pro Patient. Sie kann zusammen mit dem Esupron gegeben werden oder auch zeitlich ver¬ setzt. Die Tagesdosis an Levodopa kann auch auf 2 bis 3 Einzel¬ gaben pro Tag verteilt werden.The combination is well suited for the treatment of disorders of the extrapyramidal motor system, in particular Parkinson's disease. The Esupron and levodopa are given in combination in amounts that are below the lower limits of the doses at d en substances in the sole application. The daily dose of Esupron is usually 100 to 200 mg per patient and is administered by a single dose. The daily dose of levodopa is usually 25 to 200 mg per patient. It can be given together with the Esupron or can also be delayed. The daily dose of levodopa can also be divided into 2 to 3 individual doses per day.
Die Kombination kann in üblicher Weise, z.B. oral oder intra¬ venös, verabfolgt werden.The combination can be in the usual way, e.g. orally or intravenously.
Die Wirkstoffe können in den üblichen galenischen Applikations- formen fest oder flüssig angewendet werden, wie Tabletten,The active substances can be used in the usual galenical forms of application in solid or liquid form, such as tablets,
Kapseln, Pulver, Granulate, Dragees oder Lösungen. Diese werden in üblicher Weise hergestellt. Die Wirkstoffe können dabei mit den gebräuchlichen galenischen Hilfsmitteln (hauptsächliche Träger- und Verdünnungsmitteln) wie Talkum, Gummiarabikum, Saccharose, Lactose, Getreide- oder Maisstärke, Kartoffelmehl, Magnesiumstearat, Alginaten, Gummi-Tragacanth, Carraghenaten, Polyvinyl.alkohol, Polyvinylpyrrolidon, wäßrigen oder nicht¬ wäßrigen Trägern, Netzmitteln, Dispergiermitteln, Emulgatoren und/oder Konservierungsmitteln verarbeitet werden (vgl. H. Sucker et al., Pharmazeutische Technologie, Thieme-Verlag, Stuttgart 1978) . Die so erhaltenen Präparate enthalten den Wirkstoff normalerweise in einer Menge von 10 bis 93 Gew.-%.Capsules, powders, granules, coated tablets or solutions. These are manufactured in the usual way. The active ingredients can be combined with the usual pharmaceutical auxiliaries (mainly carriers and diluents) such as talc, gum arabic, sucrose, lactose, cereal or corn starch, potato flour, magnesium stearate, alginates, gum tragacanth, carraghenates, polyvinyl alcohol, polyvinyl pyrrolidone, aqueous or non-aqueous carriers, wetting agents, dispersants, emulsifiers and / or preservatives are processed (cf. H. Sucker et al., Pharmaceutical Technology, Thieme-Verlag, Stuttgart 1978). The preparations thus obtained normally contain the active ingredient in an amount of 10 to 93% by weight.
Es ist auch möglich, die Einzelbestandteile der Kombination zu Applikationsformen zu verarbeiten und diese zusammen zu ver¬ packen, z.B. in einer -Durchdrückpackung.It is also possible to process the individual components of the combination into application forms and to package them together, e.g. in a blister pack.
Die therapeutische und prophylaktische Wirkung der Kombination bei Störungen des extrapyramidal-motorischen Systems wird durch die nachfolgenden Versuche belegt:The therapeutic and prophylactic effects of the combination for disorders of the extrapyramidal-motor system are demonstrated by the following experiments:
Narkotisierten Ratten (männlich, 180 - 200 g) wurde unilateral 6-OH-Dopamin (8 μg in 4 μl in 4 min) in die Substantia Nigra injiziert.Anesthetized rats (male, 180-200 g) were injected unilaterally with 6-OH-dopamine (8 μg in 4 μl in 4 min) into the substantia nigra.
In diesen so geschädigten Tieren induziert eine postsynaptische dopmaminerge Stimulation, z.B. durch Apomorphin oder L-Dopa, kontralaterale Drehbewegungen (Brain Research ___., 485 (1970)).Post-synaptic dopaminergic stimulation, e.g. by apomorphine or L-dopa, contralateral rotational movements (Brain Research ___., 485 (1970)).
Die Drehfrequenz ist ein Maß für das Ausmaß der Stimulation.The rotational frequency is a measure of the extent of the stimulation.
10 Tage nach der Operation werden die Tiere zwei- bis dreimal mit 0,5 mg/ks s.c. Apomorphin getestet. Tiere, die mit 70 oder mehr Drehungen in 15 Minuten reagieren, werden zur Substanzprüfung eingesetzt.10 days after the operation, the animals are tested two to three times with 0.5 mg / ks sc apomorphine. Animals with 70 or more Reactions of rotations in 15 minutes are used for substance testing.
Die einseitige Applikation von 6-OH-Dopamin in die Substantia Nigra an Ratten führt zu einer Degeneration der dort gelegenen dopaminergen Neurone und deren Projektion in das Striatum. Diese Veränderungen entsprechen den pathologisch-anatomischen Befunden wie sie bei der Parkinson'sehen Erkrankung beim Menschen gesehen werden. Man erhält also auf diese Weise ein Tiermodell für den Morbus Parkinson. Die nur einseitige Läsion im Tiermodell führt zu Bewegungsasymmetrien (Drehbewegungen) , die eine Quantifizie¬ rung der Schädigung bzw. einer SubstanzWirkung erlauben.The one-sided application of 6-OH-dopamine in the substantia nigra on rats leads to a degeneration of the dopaminergic neurons located there and their projection into the striatum. These changes correspond to the pathological-anatomical findings as seen in Parkinson's disease in humans. An animal model for Parkinson's disease is thus obtained. The only one-sided lesion in the animal model leads to movement asymmetries (rotary movements) which allow the damage or a substance effect to be quantified.
L-DOPA löst in diesem Modell in Dosen von ca. 200 bis 300 mg/kg ip contralaterale Drehbewegungen aus, was als Äquivalent zu der klinisch bekannten Wirkung von L-DOPA beim M. Parkinson gesehen werden kann. Die Dosis von 21,5 mg/kg ist unwirksam (s. Tabelle).In this model, L-DOPA triggers ip contralateral rotary movements in doses of approx. 200 to 300 mg / kg, which can be seen as an equivalent to the clinically known effect of L-DOPA in Parkinson's disease. The dose of 21.5 mg / kg is ineffective (see table).
ErgebnisseResults
Substanz Dosis [mg/kg] Drehungen/60 minSubstance dose [mg / kg] rotations / 60 min
L-DOPA 21,5 ip 11L-DOPA 21.5 ip 11
Esupron 4,64 po 8Esupron 4.64 po 8
Esupron + L-DOPA 2,15 po + 21,5 ip 75Esupron + L-DOPA 2.15 po + 21.5 ip 75
Esupron + L-DOPA 4,64 po + 21,5 ip 149Esupron + L-DOPA 4.64 po + 21.5 ip 149
Durch die gleichzeitige Gabe von Esupron gelingt es, die Wirkung von L-DOPA zu potenzieren. 2,15 und 4,64 mg/kg p.o. Esupron (Do¬ sen, die allein gegeben ebenfalls wirkungslos sind) induzieren in der Kombination mit L-DOPA ausgeprägte Drehbewegungen. Diese Zu¬ nahme ist statistisch signifikant.The simultaneous administration of Esupron makes it possible to potentiate the effect of L-DOPA. 2.15 and 4.64 mg / kg p.o. In combination with L-DOPA, Esupron (doses which are likewise ineffective when given alone) induce pronounced rotary movements. This increase is statistically significant.
Beispiel 1example 1
Auf einer Tablettenpresse werden in üblicher Weise Tabletten folgender Zusammensetzung gepreßt:Tablets of the following composition are pressed in a conventional manner on a tablet press:
50 mg Levodopa50 mg levodopa
100 mg Esupron100 mg esupron
160 mg Maisstärke160 mg corn starch
10 mg PVP10 mg PVP
90 mg Milchzucker90 mg milk sugar
2 mg Magnesium-Stearat Beispiel 22 mg magnesium stearate Example 2
Es wurden Filmtabletten folgender Zusammensetzung hergestellt:Film-coated tablets of the following composition were produced:
5 100 mg Substanz Levodopa5 100 mg substance levodopa
100 mg Substanz Esupron100 mg substance esupron
180 mg Kernmasse180 mg core mass
20 mg Filmcoatingschicht.20 mg film coating layer.
0 Die Kernmasse besteht aus 9 Teilen Maisstärke, 3 Teilen Milch¬ zucker und 1 Teil Luviskol® VA 64 (Vinylpyrrolidon-Vinylacetat- Mischpolymerisat 60:40, vgl. Pharm. Ind. 1962, 586).0 The core composition consists of 9 parts of corn starch, 3 parts Milch¬ sugar and 1 part Luviskol ® VA 64 (vinylpyrrolidone-vinyl acetate copolymer 60:40; see. Pharm. Ind. 1962, 586).
Die Filmcoatingschicht besteht aus 5The film coating layer consists of 5
50 % Methylhydroxypropylcellulose50% methyl hydroxypropyl cellulose
10 % PEG 40010% PEG 400
20 % Talkum20% talc
15 % PEG 8000 0 5 % Farbanteil (davon 4 % Ti02)15% PEG 8000 0 5% color (including 4% Ti0 2 )
Beispiel 3Example 3
In einer -Durchdrückpackung für 28 Tabeletten werden 14 Tabletten 5 mit je 100 mg Espuron und 14 Tabletten mit je 100 mg Levodopa in Reihen so angeordnet, daß jeweils eine Espuron-Tablette neben einer Levodopa-Tablette liegt.In a blister pack for 28 tablets, 14 tablets 5 with 100 mg Espuron and 14 tablets with 100 mg Levodopa each are arranged in rows so that one Espuron tablet is next to a Levodopa tablet.
Beispiel 4 0Example 4 0
In einer -Durchdrückpackung für 36 Tabletten werden 12 Tabletten mit je 100 mg Espuron und 50 mg Levodopa sowie 24 Tabletten mit je 50 mg Levodopa so angeordnet, daß jeweils eine Esupron-haltige Tablette neben zwei Ledodopa-Tabletten liegt. 5In a blister pack for 36 tablets, 12 tablets with 100 mg Espuron and 50 mg Levodopa each and 24 tablets with 50 mg Levodopa each are arranged so that one Esupron-containing tablet is next to two Ledodopa tablets. 5
00
5 5

Claims

Patentansprüche claims
1. Arzneimittel, enthaltend Esupron und Levodopa.1. Medicines containing Esupron and Levodopa.
2. Verfahren zur Herstellung eines Arzneimittels, dadurch gekennzeichnet, daß man Esupron und Levodopa zusammen mit galenischen Hilfsstoffen zu einer oval applizierbaren Applikationsform verarbeitet. 2. A process for the preparation of a medicament, characterized in that Esupron and levodopa are processed together with galenic auxiliaries to form an oval application form.
PCT/EP1994/002196 1993-07-29 1994-07-05 New combination of active substances containing esupron and levodopa WO1995003796A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU74575/94A AU7457594A (en) 1993-07-29 1994-07-05 New combination of active substances containing esupron and levodopa

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE4325435A DE4325435A1 (en) 1993-07-29 1993-07-29 New combination of active ingredients
DEP4325435.7 1993-07-29

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DE (1) DE4325435A1 (en)
HR (1) HRP940429A2 (en)
IL (1) IL110336A0 (en)
WO (1) WO1995003796A1 (en)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7819912B2 (en) 1998-03-30 2010-10-26 Innovational Holdings Llc Expandable medical device with beneficial agent delivery mechanism
US7850727B2 (en) 2001-08-20 2010-12-14 Innovational Holdings, Llc Expandable medical device for delivery of beneficial agent
US7850728B2 (en) 2000-10-16 2010-12-14 Innovational Holdings Llc Expandable medical device for delivery of beneficial agent
US8361537B2 (en) 1998-03-30 2013-01-29 Innovational Holdings, Llc Expandable medical device with beneficial agent concentration gradient

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0111746A2 (en) * 1982-11-23 1984-06-27 BASF Aktiengesellschaft Sulfonic-acid esters of hydroxycoumarines, their preparation and medicines containing them
EP0252290A2 (en) * 1986-06-10 1988-01-13 CHIESI FARMACEUTICI S.p.A. Pharmaceutical compositions containing levodopa methyl ester, preparation and therapeutic applications thereof

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0111746A2 (en) * 1982-11-23 1984-06-27 BASF Aktiengesellschaft Sulfonic-acid esters of hydroxycoumarines, their preparation and medicines containing them
EP0252290A2 (en) * 1986-06-10 1988-01-13 CHIESI FARMACEUTICI S.p.A. Pharmaceutical compositions containing levodopa methyl ester, preparation and therapeutic applications thereof

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7819912B2 (en) 1998-03-30 2010-10-26 Innovational Holdings Llc Expandable medical device with beneficial agent delivery mechanism
US7896912B2 (en) 1998-03-30 2011-03-01 Innovational Holdings, Llc Expandable medical device with S-shaped bridging elements
US8052735B2 (en) 1998-03-30 2011-11-08 Innovational Holdings, Llc Expandable medical device with ductile hinges
US8052734B2 (en) 1998-03-30 2011-11-08 Innovational Holdings, Llc Expandable medical device with beneficial agent delivery mechanism
US8206435B2 (en) 1998-03-30 2012-06-26 Conor Medsystems, Inc. Expandable medical device for delivery of beneficial agent
US8361537B2 (en) 1998-03-30 2013-01-29 Innovational Holdings, Llc Expandable medical device with beneficial agent concentration gradient
US8439968B2 (en) 1998-03-30 2013-05-14 Innovational Holdings, Llc Expandable medical device for delivery of beneficial agent
US8623068B2 (en) 1998-03-30 2014-01-07 Conor Medsystems, Inc. Expandable medical device with ductile hinges
US7850728B2 (en) 2000-10-16 2010-12-14 Innovational Holdings Llc Expandable medical device for delivery of beneficial agent
US8187321B2 (en) 2000-10-16 2012-05-29 Innovational Holdings, Llc Expandable medical device for delivery of beneficial agent
US7850727B2 (en) 2001-08-20 2010-12-14 Innovational Holdings, Llc Expandable medical device for delivery of beneficial agent

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Publication number Publication date
AU7457594A (en) 1995-02-28
DE4325435A1 (en) 1995-02-02
HRP940429A2 (en) 1997-08-31
IL110336A0 (en) 1994-10-21

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