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EP1210081A2 - Combinaison d'agents actifs comprenant de la clonidine - Google Patents

Combinaison d'agents actifs comprenant de la clonidine

Info

Publication number
EP1210081A2
EP1210081A2 EP00951485A EP00951485A EP1210081A2 EP 1210081 A2 EP1210081 A2 EP 1210081A2 EP 00951485 A EP00951485 A EP 00951485A EP 00951485 A EP00951485 A EP 00951485A EP 1210081 A2 EP1210081 A2 EP 1210081A2
Authority
EP
European Patent Office
Prior art keywords
active ingredient
combination according
ingredient combination
clonidine
combination
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Withdrawn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
EP00951485A
Other languages
German (de)
English (en)
Inventor
Hans-Michael Brecht
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.)
Boehringer Ingelheim Pharma GmbH and Co KG
Boehringer Ingelheim Pharmaceuticals Inc
Original Assignee
Boehringer Ingelheim Pharma GmbH and Co KG
Boehringer Ingelheim Pharmaceuticals Inc
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 Pharma GmbH and Co KG, Boehringer Ingelheim Pharmaceuticals Inc filed Critical Boehringer Ingelheim Pharma GmbH and Co KG
Publication of EP1210081A2 publication Critical patent/EP1210081A2/fr
Withdrawn legal-status Critical Current

Links

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
    • A61K31/41—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
    • A61K31/4164—1,3-Diazoles
    • A61K31/4168—1,3-Diazoles having a nitrogen attached in position 2, e.g. clonidine
    • 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
    • A61K31/415—1,2-Diazoles
    • 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
    • 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
    • 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
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia

Definitions

  • the invention relates to a new active ingredient combination of pramipexole and clonidine for the more effective treatment of restless leg syndrome (RLS).
  • RLS restless leg syndrome
  • Restless Leg Syndrome is a neurological disorder that mainly manifests itself in leg disorders such as tingling, pulling, tearing, itching, burning, cramps or pain and triggers the irresistible urge to move. These disorders frequently occur when the person concerned is resting. Especially at night when sleeping, these emotional disorders and the consequent urge to move lead to restlessness and sleep disorders.
  • the RLS occurs at all ages, with the frequency increasing in older age. The prevalence in the general population is around 5%. Because of the characteristics of the symptoms, RLS is one of the most common causes of sleep disorders. In 20-40 year olds, the RLS in 7%, in 40-60 year olds in 18% and in those over 60 in 33% cause sleep-wax disorders.
  • L-DOPA levodopa
  • the dopamine agonists examined include: bromocriptine, cabergoline, alpha-dihydroergocryptine, lisuride, pergolide, pramipexole and ropinirole. All of these dopamine agonists were found to be effective. There are no study results on long-term therapy with dopamine agonists, so that the question of the loss of effectiveness after long-term use (tachyphylaxis) cannot yet be answered.
  • the disadvantage of dopamine agonists is the occurrence of side effects such as nausea, vomiting, dizziness, hypotension, constipation, insomnia, which usually occur initially and depending on the dose.
  • Benzodiazepines and opiates are also effective in RLS. However, due to the risk of dependency and the development of tolerance, these substances are only available for therapy to a limited extent.
  • Carbamazepine has only been tested in a few partially open studies in the indication RLS. It only leads to partial freedom from symptoms and is currently not considered a suitable means of treating the RLS.
  • the present invention therefore relates to a combination of active substances for the treatment of restless leg syndrome, which contains clonidine or one of its pharmacologically acceptable salts and pramipexole or a corresponding pharmacologically acceptable salt thereof and overcomes the disadvantages of the monotherapies known from the prior art.
  • the advantage of the invention is, inter alia, that the combined administration of clonidine influences the action of the dopamine agonist pramipexole synergistically (or vice versa) in the sense of an increase in activity, so that even low doses of both active ingredients are sufficient to improve the patient's condition without that intolerable side effects occur.
  • the combined administration of pramipexole with clonidine also leads to better responsiveness and a higher responder rate in patients with RLS.
  • the extent to which the additional administration of clonidine can cancel out any tachyphylaxis that may occur with dopaminergic therapeutic agents is not yet known, but is suspected.
  • the two active ingredients clonidine and pramipexole are preferably used as the hydrochloride.
  • other pharmacologically acceptable salts or the neutral compounds can also be used.
  • the active ingredient combination according to the invention it is not necessary for both active ingredients to be in the form of a salt, especially same salt (for example as hydrochloride) can be used.
  • the two active ingredients can be used both as neutral compounds, as two different salts or as a combination of a salt of one active ingredient and the neutral other
  • Active ingredient can be used.
  • the active substance combination according to the invention can be formulated in accordance with the conventional pharmaceutical processes known from the prior art so that it can be administered orally, spinally, anal, intravenously, by inhalation, subcutaneously or transdermally. Oral and transdermal application forms are preferred.
  • Oral administration can take the form of a tablet, powder, powder in a capsule (e.g. hard gelatin capsule), solution or suspension.
  • the active substance combination according to the invention is given as a solution.
  • the anal application takes place via suppositories.
  • the active ingredient combination can be in the form of a powder, as an aqueous or aqueous-ethanolic solution or by means of a propellant gas formulation.
  • the active ingredient can be applied to the skin either as an ointment or cream, but is preferably administered via a plaster.
  • the active ingredient or combination of active ingredients can either be delivered directly to the outer skin layer or it can be embedded as a solution or as a gel, e.g. in a polymer matrix, using a transdermal patch, via microneedles or microcuts that penetrate the stratum corneum of the skin released directly into the deeper layers of skin.
  • a transdermal patch with micro-cutting edges or micro-spikes is disclosed, for example, in patent application WO 97/03718.
  • Patent application WO 91/07998 describes a method by means of which active ingredients can be applied transdermally in an improved manner by adjusting a certain pH of the skin.
  • the delivery is controlled electronically, possibly under the control of the blood plasma level by sensors or microsensors, which can be integrated in the plaster or are communicatively connected to it, so that the blood plasma level can be set in a targeted manner according to the individual need and consequently a constant delivery is not mandatory is required.
  • the two active ingredients can be present in a separate formulation (for example, each in a capsule or in each case as a tablet), in a single formulation, but separated from one another (for example in a capsule with two chambers), or they are in a single formulation mixed before (eg in the form of a tablet or in a capsule with only one chamber).
  • the two active ingredients are each formulated independently of one another, the two formulations can be offered in the form of a combination pack (kit).
  • the two substances are administered via the same route of administration, but combinations of formulations in which the two active compounds are administered via separate routes of administration can also be used.
  • clonidine can be administered orally while pramipexole is transdermal, e.g. is applied over the transdermal patch described above.
  • preferred formulations are those in which the two active compounds are administered via the same route of administration.
  • the two active ingredients are advantageously formulated together in one application form.
  • the two active substances can either be given in a separate patch, in a common patch, but both active substances are stored separately within the patch, or they are present as a mixture in one patch.
  • the active substance formulation according to the invention is prepared in accordance with the methods known from the prior art and can accordingly contain the formulation constituents which are known in the relevant field.
  • it can contain other pharmacologically active substances or cosmetic additives.
  • an almost simultaneous or overlapping intake or administration is preferred.
  • oral administration for example, within 1 hour, preferably within 15 minutes.
  • the amount of the clonidine or the pharmacologically acceptable salt of the formulation according to the invention per single dose, based on clonidine, corresponds to an oral administration of 0.01 to 1.0 mg, preferably 0.05 to 0.5 mg and very particularly preferably 0.075 to 0 , 3 mg.
  • the amount of pramipexole or its pharmacologically acceptable salt corresponds to an oral dose of 0.05-2 mg, preferably 0.08-1.0 mg, particularly preferably 0.088-0.7 mg, per single dose, based on the neutral compound.
  • the exact amount of the active ingredients can be determined simply
  • both patients were treated with pramipexole, namely 0.088 mg two hours before bedtime.
  • the daily dose had to be increased to 0.36 mg at weekly intervals, in the patient to 0.27 mg.
  • the symptoms had improved in both patients, but there was no difference between the two patients and the previous therapy.
  • both patients were treated with a combination of 0.088 mg pramipexole and 0.075 mg clonidine. After the first night, both patients reported a clear alleviation of the symptoms. After 7 days, the
  • Pramipexole and clonidine showed in both patients by the end of the

Landscapes

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

Abstract

La présente invention concerne une combinaison d'agents actifs constituée de clonidine et de pramipexole qui permet de traiter le syndrome des jambes sans repos.
EP00951485A 1999-08-19 2000-08-09 Combinaison d'agents actifs comprenant de la clonidine Withdrawn EP1210081A2 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE19938825A DE19938825A1 (de) 1999-08-19 1999-08-19 Wirkstoffkombination mit Clonidin
DE19938825 1999-08-19
PCT/EP2000/007718 WO2001013902A2 (fr) 1999-08-19 2000-08-09 Combinaison d'agents actifs comprenant de la clonidine

Publications (1)

Publication Number Publication Date
EP1210081A2 true EP1210081A2 (fr) 2002-06-05

Family

ID=7918574

Family Applications (1)

Application Number Title Priority Date Filing Date
EP00951485A Withdrawn EP1210081A2 (fr) 1999-08-19 2000-08-09 Combinaison d'agents actifs comprenant de la clonidine

Country Status (19)

Country Link
US (1) US20020010201A1 (fr)
EP (1) EP1210081A2 (fr)
JP (1) JP2003507420A (fr)
KR (1) KR20020060163A (fr)
AR (1) AR025330A1 (fr)
AU (1) AU6440600A (fr)
BR (1) BR0013353A (fr)
CA (1) CA2376606A1 (fr)
CO (1) CO5200840A1 (fr)
CZ (1) CZ2002515A3 (fr)
DE (1) DE19938825A1 (fr)
IL (1) IL147741A0 (fr)
MX (1) MXPA02001138A (fr)
NO (1) NO20020793L (fr)
PE (1) PE20010642A1 (fr)
PL (1) PL353358A1 (fr)
TR (1) TR200200449T2 (fr)
UY (1) UY26293A1 (fr)
WO (1) WO2001013902A2 (fr)

Families Citing this family (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE10041478A1 (de) 2000-08-24 2002-03-14 Sanol Arznei Schwarz Gmbh Neue pharmazeutische Zusammensetzung
ATE480235T1 (de) 2001-12-11 2010-09-15 Univ Virginia Verwendung von pramipexol zur behandlung von amyotrophischer lateralsklerose
US20040048779A1 (en) * 2002-05-06 2004-03-11 Erwin Schollmayer Use of rotigotine for treating the restless leg syndrome
DE10220230A1 (de) * 2002-05-06 2003-11-27 Sanol Arznei Schwarz Gmbh Verwendung von Rotigotine zur Behandlung des Restless Leg Syndroms
CA2496920A1 (fr) 2002-08-30 2004-03-11 Kyowa Hakko Kogyo Co., Ltd. Antagonistes du recepteur a2a de l'adenosine destines au traitement du syndrome des jambes sans repos ou de troubles associes
PT1426049E (pt) * 2002-12-02 2005-09-30 Sanol Arznei Schwarz Gmbh Administracao iontoforetica de rotigotina para o tratamento da doenca de parkinson
US8518926B2 (en) 2006-04-10 2013-08-27 Knopp Neurosciences, Inc. Compositions and methods of using (R)-pramipexole
CN102160865A (zh) 2006-05-16 2011-08-24 诺普神经科学股份有限公司 R(+)和s(-)普拉克索的组合物以及使用该组合物的方法
WO2008009664A2 (fr) * 2006-07-19 2008-01-24 Boehringer Ingelheim International Gmbh Traitement de la douleur
US8524695B2 (en) 2006-12-14 2013-09-03 Knopp Neurosciences, Inc. Modified release formulations of (6R)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine and methods of using the same
JP2010521496A (ja) 2007-03-14 2010-06-24 ノップ ニューロサイエンシーズ、インク． キラル精製置換ベンゾチアゾールジアミンの合成
EP1987815A1 (fr) * 2007-05-04 2008-11-05 Schwarz Pharma Ag Compositions pharmaceutiques à base d'agonistes dopaminergiques administrables par voie oro-naso-pharyngale pour la prévention et/ou le traitement de membres sans repos
EP2334185A4 (fr) 2008-08-19 2011-09-21 Knopp Neurosciences Inc Compositions et procédés employant du (r)-pramipexole
US9512096B2 (en) 2011-12-22 2016-12-06 Knopp Biosciences, LLP Synthesis of amine substituted 4,5,6,7-tetrahydrobenzothiazole compounds
WO2014105783A1 (fr) * 2012-12-28 2014-07-03 Noven Pharmaceuticals, Inc. Compositions et procédés pour l'administration transdermique d'amphétamine et de clonidine
US9662313B2 (en) 2013-02-28 2017-05-30 Knopp Biosciences Llc Compositions and methods for treating amyotrophic lateral sclerosis in responders
SMT202100119T1 (it) 2013-07-12 2021-05-07 Knopp Biosciences Llc Trattamento dei livelli elevati di eosinofili e/o basofili
US9468630B2 (en) 2013-07-12 2016-10-18 Knopp Biosciences Llc Compositions and methods for treating conditions related to increased eosinophils
ES2813674T3 (es) 2013-08-13 2021-03-24 Knopp Biosciences Llc Composiciones y métodos para el tratamiento de trastornos de células plasmáticas y trastornos prolinfocíticos de células b
EP3033081B1 (fr) 2013-08-13 2021-05-12 Knopp Biosciences LLC Compositions et méthodes pour le traitement de l'urticaire chronique

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3937271A1 (de) * 1989-11-09 1991-05-16 Boehringer Ingelheim Kg Transdermale applikation von 2-amino-6-n-propylamino-4,5,6,7-tetrahydrobenzothiazol
DE4325491A1 (de) * 1993-07-29 1995-02-02 Boehringer Ingelheim Kg Verwendung von zentral wirksamen alpha-2-Agonisten zur Hemmung des Postaggressionsstoffwechsels
US6001861A (en) * 1998-01-16 1999-12-14 Pharmacia & Upjohn Company Use of pramipexole in the treatment of restless legs syndrome
DE19701619B4 (de) * 1997-01-17 2007-10-11 Boehringer Ingelheim Pharma Gmbh & Co. Kg Verwendung von Pramipexol zur Behandlung des restless legs syndroms
WO2000054773A1 (fr) * 1999-03-12 2000-09-21 Nitromed, Inc. Agonistes dopaminergiques en combinaison avec des donneurs d'oxyde nitrique, compositions et methodes d'utilisation

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO0113902A2 *

Also Published As

Publication number Publication date
PL353358A1 (en) 2003-11-17
IL147741A0 (en) 2002-08-14
JP2003507420A (ja) 2003-02-25
DE19938825A1 (de) 2001-04-26
BR0013353A (pt) 2002-04-23
KR20020060163A (ko) 2002-07-16
PE20010642A1 (es) 2001-06-08
MXPA02001138A (es) 2002-10-31
NO20020793D0 (no) 2002-02-18
CA2376606A1 (fr) 2001-03-01
CO5200840A1 (es) 2002-09-27
NO20020793L (no) 2002-02-18
CZ2002515A3 (cs) 2002-05-15
TR200200449T2 (tr) 2002-08-21
AU6440600A (en) 2001-03-19
WO2001013902A3 (fr) 2001-08-23
AR025330A1 (es) 2002-11-20
WO2001013902A2 (fr) 2001-03-01
US20020010201A1 (en) 2002-01-24
UY26293A1 (es) 2001-04-30

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