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EP1622622A2 - Compound preparation for dizziness - Google Patents

Compound preparation for dizziness

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Publication number
EP1622622A2
EP1622622A2 EP04701888A EP04701888A EP1622622A2 EP 1622622 A2 EP1622622 A2 EP 1622622A2 EP 04701888 A EP04701888 A EP 04701888A EP 04701888 A EP04701888 A EP 04701888A EP 1622622 A2 EP1622622 A2 EP 1622622A2
Authority
EP
European Patent Office
Prior art keywords
combination
dizziness
vertigo
study
used according
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
Application number
EP04701888A
Other languages
German (de)
French (fr)
Inventor
Helga Schleenhain
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.)
Hennig Arzneimittel GmbH and Co KG
Original Assignee
Hennig Arzneimittel GmbH and Co KG
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 Hennig Arzneimittel GmbH and Co KG filed Critical Hennig Arzneimittel GmbH and Co KG
Priority to EP09177748A priority Critical patent/EP2174690A1/en
Publication of EP1622622A2 publication Critical patent/EP1622622A2/en
Ceased 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
    • 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
    • A61P27/00—Drugs for disorders of the senses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to the use of cinnarizine and dimenhydrinate or their physiologically tolerable salts in combination.
  • Dizziness is often described by the patient as if he is experiencing turning, swaying or lifting movements or the floor is swaying underfoot. Others describe the dizziness as a slight loss of consciousness with confusion and gait uncertainty.
  • Three sensory systems are responsible for orienting people in space: the optical system, the vestibular system and the proprioceptive system.
  • Dizziness is triggered by information conflicts of these three sensory systems, by lesions in peripheral or central equilibrium structures or by ocular or psychogenic disorders. Dizziness can also be an early sign of a serious illness. Dizziness can be caused by vascular diseases, cardiovascular diseases, metabolic diseases and rheology disorders. Because of this multitude of possible causes, an interdisciplinary diagnosis is required. The different vestibular forms of vertigo are usually classified according to their location. A distinction is made between peripheral-vestibular, central-vestibular and combined central / peripheral-vestibular vertigo.
  • the differential diagnosis of vertigo is based above all on the comprehensive medical history.
  • the medical history should include questions about the type of vertigo, accompanying vegetative disorders, vertigo-inducing situations or mechanisms, the duration of the vertigo attacks and underlying or concomitant illnesses.
  • a standardized medical history sheet, in which the course of the disease can also be documented, can be helpful here.
  • Tests to test the vestibulo-ocular system are based on the fact that the balance system responds to a labyrinthine stimulus with reflex eye movements (nystagmas).
  • the patient's eye movements can be observed directly using the Frenzibrille or recorded using electronystagmography (ENG) or video oculography (VOG).
  • the evaluable parameters here are the number of nystagn ⁇ rashes per unit of time (nystagmus frequency), the speed of the slow nystagmus phase (GLP, also: slow phase velocity, SPV) and the nystagmus amplitude.
  • Standard procedures for irritation of the labyrinth are the calorific test with water or air, with which each labyrinth can be stimulated and checked individually, and swivel chair tests. If nystagmas already occur without a stimulus (i.e. there is a so-called spontaneous nystagmus), diagnostic conclusions can be drawn from the direction of the nystagmus beats.
  • the Romberg standing test and the Unterberg pedaling test are particularly suitable for examining the vestibulo-spinal system.
  • the patient's reactions can be observed directly and recorded using posturography or craniocorpography.
  • the choice of the optimal drug therapy depends on the cause of the vertigo.
  • the task is solved by using cinnarizine and dimenhydrinate in combination.
  • the present invention therefore relates to the use of cinnarizine and dimenhydrinate or their physiologically tolerable salts in combination for the treatment of vertigo of any origin.
  • Another object of the present invention is the use of cinnarizine and dimenhydrinate or their physiologically tolerable salts in combination for the manufacture of medicaments for the treatment of vertigo of any origin.
  • the present invention furthermore relates to the use of cinnarizine and dimenhydrinate or their physiologically tolerable salts in combination in addition to pharmaceutically acceptable auxiliaries and / or additives for the manufacture of medicaments for the treatment of vertigo of any origin
  • the invention thus solves the problem of successfully treating all forms of vertigo - in particular also the very frequently occurring forms of vertigo which cannot be clearly diagnosed - without successful therapeutic attempts. Due to the inventive use of the active ingredient combination of cinnarizine and dimenhydrinate, only a single medication is necessary. This represents a major advance in the treatment of vertigo.
  • the individual active ingredients used in combination according to the invention are known per se.
  • Cinnarizine (CAS 298-57-7) is the international free name (INN) for l-benzhydryl-4-trans-cinnamylpiperazine, is an antihistamine and vasodilator and is described, for example, in US Pat. No. 2,882,271.
  • Dimenhydrinate (CAS 523-87-5) is the international free name (INN) for the 8-chlorothheophylline salt of diphenhydramine and is an antihistamine used as an antiemetic and against motion sickness and is described, for example, in US Pat. Nos. 2,499,058 or US-A -2, 534, 813. According to the invention, these active compounds can also be used in the form of their physiologically tolerable salts.
  • Typical physiologically compatible inorganic and organic acids are, for example, hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, oxalic acid, maleic acid, fu aric acid, lactic acid, tartaric acid, malic acid, citric acid, salicylic acid, adipic acid and benzoic acid.
  • suitable acids are also theophylline and its derivatives, such as 8-chlorothheophylline, or other xanthines or caffeine and its derivatives.
  • Other acids that can be used are described, for example, in Advances in Pharmaceutical Research, vol. 10, pages 224-225, Birkhäuser Verlag, Basel and Stuttgart, 1966, and Journal of Pharmaceutical Sciences, vol. 66, pages 1-5 (1977).
  • the acid addition salts are generally in a manner known per se by mixing the free base or its solutions with the corresponding acid or its solutions in an organic solvent, for example a lower alcohol such as methanol, ethanol, n-propanol or isopropanol or a lower ketone such as Acetone, methyl ethyl ketone or methyl isobutyl ketone or an ether such as diethyl ether, tetrahydrofuran or dioxane. Mixtures of the solvents mentioned can also be used for better crystal deposition.
  • physiologically compatible aqueous solutions of acid addition salts of the active ingredients of an aqueous acid solution used according to the invention can be prepared.
  • the acid addition salts used according to the invention of the active ingredients can be in a conventional manner, for. B. with alkalis or ion exchangers, are converted into the free base.
  • the free base can be Settling with inorganic or organic acids, especially those which are suitable for the formation of therapeutically usable salts, win further salts.
  • These or other salts of the new compound, such as. B. the picrate can also be used to purify the free base by converting the free base into a salt, separating it and releasing the base from the salt.
  • the present invention also relates to pharmaceuticals for oral, rectal, subcutaneous, intravenous or intramuscular application which, in addition to conventional carriers and diluents, contain a combination of the active compounds or their acid addition salt as active compound.
  • the medicaments of the invention are produced in a known manner with the customary solid or liquid carriers or diluents and the commonly used pharmaceutical-technical auxiliaries in accordance with the desired type of application with a suitable dosage.
  • the preferred preparations are in a dosage form which is suitable for oral administration. Dosage forms of this type are, for example, tablets, film-coated tablets, coated tablets, capsules, pills, powders, solutions or suspensions or depot forms.
  • parenteral preparations such as injection solutions are also suitable. Suppositories may also be mentioned as preparations.
  • Corresponding tablets can be obtained, for example, by mixing the active ingredient with known auxiliaries, for example inert diluents such as dextrose, sugar, sorbitol, mannitol, polyvinylpyrrolidone, disintegrants such as corn starch or alginic acid, binders such as starch or gelatin, lubricants such as magnesium stearate or talc and / or agents for achieving a depot effect such as carboxylpolymethylene, carboxylmethylcellulose, cellulose acetate phthalate or polyvinyl acetate.
  • auxiliaries for example inert diluents such as dextrose, sugar, sorbitol, mannitol, polyvinylpyrrolidone, disintegrants such as corn starch or alginic acid, binders such as starch or gelatin, lubricants such as magnesium stearate or talc and / or agents for achieving a depot effect such as carboxy
  • Coated tablets can accordingly be produced by coating cores produced analogously to the tablets with agents conventionally used in tablet coatings, for example polyvinylpyrrolidone or shellac, gum arabic, talc, titanium dioxide or sugar.
  • the coated tablet can also consist of several layers, wherein the auxiliaries mentioned above for the tablets can be used.
  • Solutions or suspensions with the active ingredient according to the invention can additionally taste-improving agents such as saccharin, cyclamate or sugar and z.
  • B. contain flavorings such as vanillin or orange extract. They can also contain suspending agents such as sodium carboxymethylcellulose or preservatives such as p-hydroxybenzoates.
  • Capsules containing active ingredients can be produced, for example, by mixing the active ingredient with an inert carrier such as milk sugar or sorbitol and encapsulating it in gelatin capsules.
  • Suitable suppositories can be produced, for example, by mixing them with carriers such as neutral fats or polyethylene glycol or their derivatives.
  • the use of the active ingredient combination according to the invention shows, among other things, the following surprising properties: • With the combination of active substances used according to the invention, the doctor can successfully treat a far larger spectrum of vertigo patients than with the individual substances (widening the therapeutic range, broadening the active profile). Cinnarizine as a single substance only has the indication "dizziness in diagnosed inner ear complaints, ie in peripheral vestibular complaints”.
  • This study is a multicenter study in which the combination of active substances used according to the invention was compared with the individual components cinnarizine (50 mg) and dimenhydrinate (100 mg), which are usually highly dosed in monotherapy, and with placebo.
  • Study centers were 3 ENT university clinics in Hungary (Budapest, Pecs, Debrecen). 246 patients were admitted who suffered from peripheral-vestibular, central-vestibular or the very common combined form of peripheral-central-vestibular dizziness.
  • the combination of active substances used according to the invention proved to be statistically highly significant (p ⁇ 0.001) both compared to placebo and to the high-dose individual components.
  • the active ingredient combination used according to the invention was statistically significantly superior (p ⁇ 0.01) to both individual components.
  • Study IV (3 centers: ENT clinic at the University of Brunn, Neurological University Clinic Sofia, ENT clinic in Pilsen) also compared the active ingredient combination used according to the invention with the individual components in “original concentration” (20 mg cinnarizine or 40 mg dimenhydrinate) patients who suffered from either central-vestibular, peripheral-vestibular or combined peripheral-central-vestibular dizziness. This study also showed that the combination of active substances used according to the invention was statistically significantly superior (p ⁇ 0.01) to the individual components.
  • Study VI was carried out in the ENT clinic, Pilsen. Patients with diagnosed inner ear vertigo were included.
  • the reference substance in this case was betahistine. "The result showed a highly significant (p ⁇ 0.001) statistical superiority of the Active ingredient combination used according to the invention via the substance betahistine, which is the standard for this indication.

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Abstract

The invention relates to the combined use of cinnarizine and dimenhydrinate or the physiologically compatible salts thereof for the treatment of any form of dizziness.

Description

Kombinationspräparat gegen Schwindel Combination preparation for dizziness
Die vorliegende Erfindung betrifft die Verwendung von Cinnarizin und Dimenhydrinat oder deren physiologisch verträgliche Salze in Kombination.The present invention relates to the use of cinnarizine and dimenhydrinate or their physiologically tolerable salts in combination.
Jeder zehnte Patient in der Allgemeinpraxis klagt über Schwindel. Mehr als zwei Millionen Menschen suchen jährlich wegen Gleichgewichtsstörungen und Schwindel ihren Hausarzt auf. Nach Kopfschmerzen ist Vertigo damit das zweithäufigste Krankheitssymptom.Every tenth patient in general practice complains of dizziness. More than two million people visit their family doctor annually for balance problems and dizziness. After headaches, vertigo is the second most common disease symptom.
Schwindel wird vom Patienten häufig so beschrieben, als ob er Dreh-, Schwank- oder Liftbewegungen erlebe oder der Boden unter den Füßen schwanke. Andere beschreiben den Schwindel als leichte Bewusstseinstrübung mit Verwirrung und Gangunsicherheit.Dizziness is often described by the patient as if he is experiencing turning, swaying or lifting movements or the floor is swaying underfoot. Others describe the dizziness as a slight loss of consciousness with confusion and gait uncertainty.
Für die Orientierung des Menschen im Raum sind drei Sinnessysteme zuständig: das optische System, das vestibuläre System und das propriozeptive System.Three sensory systems are responsible for orienting people in space: the optical system, the vestibular system and the proprioceptive system.
Schwindel wird durch Informationskonflikte dieser drei Sinnessysteme, durch Läsionen in peripheren oder zentralen Gleichgewichtsstrukturen bzw. durch okuläre oder psy- chogene Störungen ausgelöst. Schwindel kann auch ein frühes Zeichen für eine schwere Erkrankung sein. Ursachen von Schwindel können vaskuläre Erkrankungen, Herz- Kreislauferkrankungen, Stoffwechselerkrankungen und Störungen der Rheologie sein. Aufgrund dieser Vielzahl an möglichen Ursachen ist eine interdisziplinäre Diagnostik erforderlich. Die Einteilung der verschiedenen vestibulären Schwindelformen wird üblicherweise nach dem Entstehungsort vorgenommen. Man unterscheidet peripher-vestibulären, zentral- vestibulären sowie kombiniert zentral/peripher- vestibulären Schwindel.Dizziness is triggered by information conflicts of these three sensory systems, by lesions in peripheral or central equilibrium structures or by ocular or psychogenic disorders. Dizziness can also be an early sign of a serious illness. Dizziness can be caused by vascular diseases, cardiovascular diseases, metabolic diseases and rheology disorders. Because of this multitude of possible causes, an interdisciplinary diagnosis is required. The different vestibular forms of vertigo are usually classified according to their location. A distinction is made between peripheral-vestibular, central-vestibular and combined central / peripheral-vestibular vertigo.
Aus der Art, wie sich die Schwindelbeschwerden manifestieren, lassen sich bereits Informationen zum Ort der Läsion gewinnen.Information on the location of the lesion can already be obtained from the way the symptoms of dizziness manifest.
Die Differentialdiagnose des Schwindels stützt sich vor allem auf die umfassende Anamnese. Die Anamnese sollte Fragen nach der Art des Schwindels, nach begleitenden vegetativen Störungen, nach schwindelauslösenden Situationen oder Mechanismen, nach Dauer der Schwindelanfälle und nach Grund- oder Begleiterkrankungen enthalten. Ein standardisierter Anamnesebogen, in dem auch der Krankheitsverlauf dokumentiert werden kann, kann hierbei hilfreich sein.The differential diagnosis of vertigo is based above all on the comprehensive medical history. The medical history should include questions about the type of vertigo, accompanying vegetative disorders, vertigo-inducing situations or mechanisms, the duration of the vertigo attacks and underlying or concomitant illnesses. A standardized medical history sheet, in which the course of the disease can also be documented, can be helpful here.
Tests zur Prüfung des vestibulo-okulären Systems beruhen darauf, dass das Gleichgewichtssystem auf einen laby- rinthären Reiz mit reflektorischen Augenbewegungen (Nystagmen) antwortet. Augenbewegungen können beim Patienten direkt mittels der Frenzeibrille beobachtet oder mit Hilfe der Elektronystagmographie (ENG) bzw. Video- Okulographie (VOG) aufgezeichnet werden. Auswertbare Parameter hierbei sind die Anzahl der Nystagnαusschläge pro Zeiteinheit (Nystagmusfrequenz) , die Geschwindigkeit der langsamen Nystagmusphase (GLP, auch: slow phase velocity, SPV) sowie die Nystagmusamplitude . Standardverfahren zur Reizung des Labyrinths sind die kalorische Prüfung mit Wasser oder Luft, mit der jedes Labyrinth einzeln stimuliert und überprüft werden kann, und Drehstuhltests. Treten bereits ohne Stimulus Nystagmen auf (liegt also ein sog. Spontannystagmus vor) , lassen sich aus der Richtung der Nystagmusschläge diagnostische Rückschlüsse ziehen.Tests to test the vestibulo-ocular system are based on the fact that the balance system responds to a labyrinthine stimulus with reflex eye movements (nystagmas). The patient's eye movements can be observed directly using the Frenzibrille or recorded using electronystagmography (ENG) or video oculography (VOG). The evaluable parameters here are the number of nystagnα rashes per unit of time (nystagmus frequency), the speed of the slow nystagmus phase (GLP, also: slow phase velocity, SPV) and the nystagmus amplitude. Standard procedures for irritation of the labyrinth are the calorific test with water or air, with which each labyrinth can be stimulated and checked individually, and swivel chair tests. If nystagmas already occur without a stimulus (i.e. there is a so-called spontaneous nystagmus), diagnostic conclusions can be drawn from the direction of the nystagmus beats.
Zur Untersuchung des vestibulo-spinalen Systems eignen sich besonders der Romberg-Stehversuch und der Unterber- ger-Tretversuch. Die Reaktionen des Patienten können direkt beobachtet werden und mittels Posturographie oder Craniocorpographie aufgezeichnet werden.The Romberg standing test and the Unterberg pedaling test are particularly suitable for examining the vestibulo-spinal system. The patient's reactions can be observed directly and recorded using posturography or craniocorpography.
Je nach Ursache des Schwindels können unterschiedliche therapeutische Ansätze zum Erfolg führen.Depending on the cause of the vertigo, different therapeutic approaches can lead to success.
Zur medikamentösen Vertigo-Therapie stehen u.a. Anti- histaminika, Parasympatholytika, zerebral wirksame Kalzi- umantagonisten, Benzodiazepine, Neuroleptika, durchblu- tungsfördernde Medikamente sowie Homöopathika zur Verfügung.For medicinal Vertigo therapy, i.a. Antihistamines, parasympatholytics, cerebral calcium antagonists, benzodiazepines, neuroleptics, blood circulation medications and homeopathics are available.
Die Auswahl der optimalen medikamentösen Therapie richtet sich nach der Ursache des Schwindels.The choice of the optimal drug therapy depends on the cause of the vertigo.
Aufgabe der vorliegenden Erfindung ist es daher, ein therapeutisches System zur Verfügung zu stellen, das alle Arten des Schwindels, also Schwindel jedweder Genese the- rapierbar macht.It is therefore an object of the present invention to provide a therapeutic system which makes it possible to treat all types of vertigo, ie vertigo of any genesis.
Die Aufgabe wird durch Verwendung von Cinnarizin und Di- menhydrinat in Kombination gelöst.The task is solved by using cinnarizine and dimenhydrinate in combination.
Ein Gegenstand der vorliegenden Erfindung ist daher die Verwendung von Cinnarizin und Dimenhydrinat oder deren physiologisch verträgliche Salze in Kombination zur Behandlung von Schwindel jedweder Genese. Ein weiterer Gegenstand der vorliegenden Erfindung ist die Verwendung von Cinnarizin und Dimenhydrinat oder deren physiologisch verträgliche Salze in Kombination zur Herstellung von Arzneimitteln zur Behandlung von Schwindel jedweder Genese.The present invention therefore relates to the use of cinnarizine and dimenhydrinate or their physiologically tolerable salts in combination for the treatment of vertigo of any origin. Another object of the present invention is the use of cinnarizine and dimenhydrinate or their physiologically tolerable salts in combination for the manufacture of medicaments for the treatment of vertigo of any origin.
Gegenstand der vorliegenden Erfindung ist ferner die Verwendung von Cinnarizin und Dimenhydrinat oder deren physiologisch verträgliche Salze in Kombination neben pharmazeutisch verträglichen Hilfs- und/oder Zusatzstoffen zur Herstellung von Arzneimitteln zur Behandlung von Schwindel jedweder GeneseThe present invention furthermore relates to the use of cinnarizine and dimenhydrinate or their physiologically tolerable salts in combination in addition to pharmaceutically acceptable auxiliaries and / or additives for the manufacture of medicaments for the treatment of vertigo of any origin
Durch die Erfindung wird also das Problem gelöst, alle Schwindelformen - insbesondere auch die sehr häufig auftretenden nicht eindeutig diagnostizierbaren Schwindelformen - ohne therapeutische Fehlversuche erfolgreich zu behandeln. Durch die erfindungsgemäße Verwendung der Wirkstoffkombination aus Cinnarizin und Dimenhydrinat ist nur eine einzige Medikation notwendig. Dies stellt einen großen Fortschritt in der Therapie des Schwindels dar.The invention thus solves the problem of successfully treating all forms of vertigo - in particular also the very frequently occurring forms of vertigo which cannot be clearly diagnosed - without successful therapeutic attempts. Due to the inventive use of the active ingredient combination of cinnarizine and dimenhydrinate, only a single medication is necessary. This represents a major advance in the treatment of vertigo.
Die einzelnen, erfindungsgemäß in Kombination verwendeten Wirkstoffe sind an sich bekannt.The individual active ingredients used in combination according to the invention are known per se.
Cinnarizin (CAS 298-57-7) ist der internationale Freiname (INN) für l-Benzhydryl-4-trans-cinnamylpiperazin, ist ein Antihistaminikum und Vasodilatator und beispielsweise beschrieben in US-A-2, 882,271.Cinnarizine (CAS 298-57-7) is the international free name (INN) for l-benzhydryl-4-trans-cinnamylpiperazine, is an antihistamine and vasodilator and is described, for example, in US Pat. No. 2,882,271.
Dimenhydrinat (CAS 523-87-5) ist der internationale Freiname (INN) für das 8-Chlortheophyllin-Salz des Diphen- hydramins und ist ein als Antiemetikum und gegen Reisekrankheiten eingesetztes Antihistaminikum und ist beispielsweise in US-A-2,499,058 oder US-A-2, 534, 813 beschrieben. Diese Wirkstoffe können erfindungsgemäß auch in Form ihrer physiologisch verträglichen Salze eingesetzt werden. Übliche physiologisch verträgliche anorganische und organische Säuren sind beispielsweise Salzsäure, Bromwasserstoffsäure, Phosphorsäure, Schwefelsäure, Oxalsäure, Maleinsäure, Fu arsäure, Milchsäure, Weinsäure, Äpfelsäure, Citronensäure, Salicylsäure, Adipinsäure und Benzoesäure. Weitere geeignete Säuren sind aber auch Theophyllin und dessen Derivate, wie beispielsweise 8-Chlortheophyllin, oder andere Xanthine oder Coffein und dessen Derivate. Weitere verwendbare Säuren sind beispielweise in Fortschritte der Arzneimittelforschung, Bd. ,10, Seiten 224- 225, Birkhäuser Verlag, Basel und Stuttgart, 1966, und Journal of Pharmaceutical Sciences, Bd. 66, Seiten 1-5 (1977) beschrieben.Dimenhydrinate (CAS 523-87-5) is the international free name (INN) for the 8-chlorothheophylline salt of diphenhydramine and is an antihistamine used as an antiemetic and against motion sickness and is described, for example, in US Pat. Nos. 2,499,058 or US-A -2, 534, 813. According to the invention, these active compounds can also be used in the form of their physiologically tolerable salts. Typical physiologically compatible inorganic and organic acids are, for example, hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, oxalic acid, maleic acid, fu aric acid, lactic acid, tartaric acid, malic acid, citric acid, salicylic acid, adipic acid and benzoic acid. However, other suitable acids are also theophylline and its derivatives, such as 8-chlorothheophylline, or other xanthines or caffeine and its derivatives. Other acids that can be used are described, for example, in Advances in Pharmaceutical Research, vol. 10, pages 224-225, Birkhäuser Verlag, Basel and Stuttgart, 1966, and Journal of Pharmaceutical Sciences, vol. 66, pages 1-5 (1977).
Die Säureadditionssalze werden in der Regel in an sich bekannter Weise durch Mischen der freien Base oder deren Lösungen mit der entsprechenden Säure oder deren Lösungen in einem organischen Lösungsmittel, beispielsweise einem niederen Alkohol wie Methanol, Ethanol, n-Propanol oder Isopropanol oder einem niederen Keton wie Aceton, Methyl- ethylketon oder Methyl-isobutylketon oder einem Ether wie Diethylether,, Tetrahydrofuran oder Dioxan, erhalten. Zur besseren Kristallabscheidung können auch Mischungen der genannten Lösungsmittel verwendet werden. Darüber hinaus können physiologisch verträgliche wässrige Lösungen von Säureadditionssalzen der erfindungsgemäß verwendeten Wirkstoffe einer wässrigen Säurelösung hergestellt werden.The acid addition salts are generally in a manner known per se by mixing the free base or its solutions with the corresponding acid or its solutions in an organic solvent, for example a lower alcohol such as methanol, ethanol, n-propanol or isopropanol or a lower ketone such as Acetone, methyl ethyl ketone or methyl isobutyl ketone or an ether such as diethyl ether, tetrahydrofuran or dioxane. Mixtures of the solvents mentioned can also be used for better crystal deposition. In addition, physiologically compatible aqueous solutions of acid addition salts of the active ingredients of an aqueous acid solution used according to the invention can be prepared.
Die erfindungsgemäß verwendeten Säureadditionssalze der Wirkstoffe können in an sich bekannter Weise, z. B. mit Alkalien oder Ionenaustauschern, in die freie Base überführt werden. Von der freien Base lassen sich durch Um- Setzung mit anorganischen oder organischen Säuren, insbesondere solchen, die zur Bildung von therapeutisch verwendbaren Salzen geeignet sind, weitere Salze gewinnen. Diese oder auch andere Salze der neuen Verbindung, wie z. B. das Pikrat, können auch zur Reinigung der freien Base dienen, indem man die freie Base in ein Salz überführt, dieses abtrennt und aus dem Salz wiederum die Base freisetzt .The acid addition salts used according to the invention of the active ingredients can be in a conventional manner, for. B. with alkalis or ion exchangers, are converted into the free base. The free base can be Settling with inorganic or organic acids, especially those which are suitable for the formation of therapeutically usable salts, win further salts. These or other salts of the new compound, such as. B. the picrate, can also be used to purify the free base by converting the free base into a salt, separating it and releasing the base from the salt.
Gegenstand der vorliegenden Erfindung sind auch Arzneimittel zur oralen, rektalen, subcutanen, intravenösen o- der intramuskulären Applikation, die neben üblichen Träger- und Verdünnungsmitteln eine erfindungsgemäße Kombination der Wirkstoffe oder deren Säureadditionssalz als Wirkstoff enthalten.The present invention also relates to pharmaceuticals for oral, rectal, subcutaneous, intravenous or intramuscular application which, in addition to conventional carriers and diluents, contain a combination of the active compounds or their acid addition salt as active compound.
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Die Arzneimittel der Erfindung werden mit den üblichen festen oder flüssigen Trägerstoffen oder Verdünnungsmitteln und den üblicherweise verwendeten pharmazeutischtechnischen Hilfsstoffen entsprechend der gewünschten Applikationsart mit einer geeigneten Dosierung in bekannter Weise hergestellt. Die bevorzugten Zubereitungen bestehen in einer Darreichungsform, die zur oralen Applikation geeignet ist. Solche Darreichungsformen sind beispielsweise Tabletten, Filmtabletten, Dragees, Kapseln, Pillen, Pulver, Lösungen oder Suspensionen oder Depotformen.The medicaments of the invention are produced in a known manner with the customary solid or liquid carriers or diluents and the commonly used pharmaceutical-technical auxiliaries in accordance with the desired type of application with a suitable dosage. The preferred preparations are in a dosage form which is suitable for oral administration. Dosage forms of this type are, for example, tablets, film-coated tablets, coated tablets, capsules, pills, powders, solutions or suspensions or depot forms.
Selbstverständlich kommen auch parenterale Zubereitungen wie Injektionslösungen in Betracht. Weiterhin seien als Zubereitungen beispielsweise auch Suppositorien genannt.Of course, parenteral preparations such as injection solutions are also suitable. Suppositories may also be mentioned as preparations.
Entsprechende Tabletten können beispielsweise durch Mischen des Wirkstoffs mit bekannten Hilfsstoffen, beispielsweise inerten Verdünnungsmitteln wie Dextrose, Zucker, Sorbit, Mannit, Polyvinylpyrrolidon, Sprengmitteln wie Maisstärke oder Alginsäure, Bindemitteln wie Stärke oder Gelantine, Gleitmitteln wie Magnesiumstearat oder Talk und/oder Mitteln zur Erzielung eines Depoteffektes wie Carboxylpolymethylen, Carboxylmethylcellulose, Cellu- loseacetatphthalat oder Polyvinylacetat, erhalten werden. Die Tabletten können auch aus mehreren Schichten bestehen.Corresponding tablets can be obtained, for example, by mixing the active ingredient with known auxiliaries, for example inert diluents such as dextrose, sugar, sorbitol, mannitol, polyvinylpyrrolidone, disintegrants such as corn starch or alginic acid, binders such as starch or gelatin, lubricants such as magnesium stearate or talc and / or agents for achieving a depot effect such as carboxylpolymethylene, carboxylmethylcellulose, cellulose acetate phthalate or polyvinyl acetate. The tablets can also consist of several layers.
Entsprechend können Dragees durch Überziehen von analog den Tabletten hergestellten Kernen mit üblicherweise in Drageeüberzügen verwendeten Mitteln, beispielsweise Poly- vinylpyrrolidon oder Schellack, Gummiarabicum, Talk, Titandioxid oder Zucker, hergestellt werden. Dabei kann auch die Drageehülle aus mehreren Schichten bestehen, wobei die oben bei den Tabletten erwähnten Hilfsstoffe verwendet werden können.Coated tablets can accordingly be produced by coating cores produced analogously to the tablets with agents conventionally used in tablet coatings, for example polyvinylpyrrolidone or shellac, gum arabic, talc, titanium dioxide or sugar. The coated tablet can also consist of several layers, wherein the auxiliaries mentioned above for the tablets can be used.
Lösungen oder Suspensionen mit dem erfindungsgemäßen Wirkstoff können zusätzlich geschmacksverbessernde Mittel wie Saccharin, Cyclamat oder Zucker sowie z. B. Aromastoffe wie Vanillin oder Orangenextrakt enthalten. Sie können außerdem Suspendierhilfsstoffe wie Natriumcarboxy- methylcellulose oder Konservierungsstoffe wie p-Hydroxy- benzoate enthalten. Wirkstoffe enthaltende Kapseln können beispielsweise hergestellt werden, indem man den Wirkstoff mit einem inerten Träger wie Milchzucker oder Sorbit mischt und in Gelatinekapseln einkapselt.Solutions or suspensions with the active ingredient according to the invention can additionally taste-improving agents such as saccharin, cyclamate or sugar and z. B. contain flavorings such as vanillin or orange extract. They can also contain suspending agents such as sodium carboxymethylcellulose or preservatives such as p-hydroxybenzoates. Capsules containing active ingredients can be produced, for example, by mixing the active ingredient with an inert carrier such as milk sugar or sorbitol and encapsulating it in gelatin capsules.
Geeignete Suppositorien lassen sich beispielsweise durch Vermischen mit dafür vorgesehenen Trägermitteln wie Neutralfetten oder Polyäthylenglykol bzw. deren Derivaten herstellen.Suitable suppositories can be produced, for example, by mixing them with carriers such as neutral fats or polyethylene glycol or their derivatives.
Die erfindungsgemäße Verwendung der Wirkstoffkombination zeigt unter anderem die folgenden überraschenden Eigenschaften: • Mit der erfindungsgemäß verwendeten Wirkstoffkombination kann der Arzt ein weitaus größeres Spektrum von Schwindelpatienten erfolgreich behandeln als mit den Einzelsubstanzen (Ausweitung der therapeutischen Breite, Verbreiterung des Wirkprofils) . Cinnarizin als Monosubstanz hat lediglich die Indikation „Schwindel bei diagnostisch abgeklärten Innenohrbeschwerden, d. h. bei peripher-vestibulären Beschwerden" .The use of the active ingredient combination according to the invention shows, among other things, the following surprising properties: • With the combination of active substances used according to the invention, the doctor can successfully treat a far larger spectrum of vertigo patients than with the individual substances (widening the therapeutic range, broadening the active profile). Cinnarizine as a single substance only has the indication "dizziness in diagnosed inner ear complaints, ie in peripheral vestibular complaints".
• Verringerung der Einnahmefrequenz.• Reduction of the frequency of use.
• Vereinfachung des Dosierungsschemas.• Simplification of the dosing schedule.
• Verbesserung der Co pliance• Improve compliance
• Überraschend ist die Beobachtung, dass bei 2,5fach reduzierter Dosierung der Einzelkomponenten in der erfindungsgemäß verwendeten Wirkstoffkombination im Vergleich zu den entsprechenden Monotherapien die Wirkung statistisch signifikant erhöht war bei nachgewiesener gleichzeitiger Verminderung der Nebenwir- kungsinzidenz .• Surprising is the observation that when the dosage of the individual components in the active ingredient combination used according to the invention was reduced by 2.5 times, the effect was statistically significantly increased in comparison with the corresponding monotherapies with a proven simultaneous reduction in the incidence of side effects.
• Durch den Einsatz der fixen Kombination in der erfindungsgemäß verwendeten Wirkstoffkombination lässt sich der synergistische, therapeutische Effekt optimal ausnutzen.• By using the fixed combination in the active ingredient combination used according to the invention, the synergistic, therapeutic effect can be optimally exploited.
Die folgenden Beispiele erläutern die Erfindung.The following examples illustrate the invention.
Beispiele:Examples:
Wirksamkeitsstudien mit der erfindungsgemäß verwendeten WirkstoffkombinationEfficacy studies with the combination of active ingredients used according to the invention
Es wurden die unten aufgeführten 12 Klinischen Studien durchgeführt, die alle randomisiert und - mit Ausnahme der experimentellen Studie IX - doppelblind nach den Grundsätzen der „Good Clinical Practice", d. h. nach den jeweils neuesten internationalen Bestimmungen durchgeführt wurden.The 12 clinical studies listed below were carried out, all randomized and - with the exception of experimental study IX - double blind according to the principles of "Good Clinical Practice", ie according to the the latest international regulations have been implemented.
Studie IStudy I
Bei dieser Studie handelt es sich um eine multizentrische Studie, in der die erfindungsgemäß verwendete Wirkstoffkombination mit den üblicherweise in der Monotherapie hochdosierten Einzelkomponenten Cinnarizin (50 mg) und Dimenhydrinat (100 mg) sowie mit Plazebo verglichen wurde. Studienzentren waren 3 HNO-Universitätskliniken in Ungarn (Budapest, Pecs, Debrecen) . Aufgenommen wurden 246 Patienten, die an peripher-vestibulärem, zentral- vestibulärem oder an der sehr häufig vorkommenden kombinierten Form von peripher-zentral-vestibulärem Schwindel litten. Im Ergebnis erwies sich die erfindungsgemäß verwendete Wirkstoffkombination sowohl gegenüber Plazebo als auch gegenüber den hochdosierten Einzelkomponenten statistisch hochsignifikant (p < 0,001) überlegen.This study is a multicenter study in which the combination of active substances used according to the invention was compared with the individual components cinnarizine (50 mg) and dimenhydrinate (100 mg), which are usually highly dosed in monotherapy, and with placebo. Study centers were 3 ENT university clinics in Hungary (Budapest, Pecs, Debrecen). 246 patients were admitted who suffered from peripheral-vestibular, central-vestibular or the very common combined form of peripheral-central-vestibular dizziness. As a result, the combination of active substances used according to the invention proved to be statistically highly significant (p <0.001) both compared to placebo and to the high-dose individual components.
Studie IIStudy II
In diese Plazebo-kontrollierte Studie an der HNO-Klinik der Medizinischen Akademie Magdeburg wurden Patienten mit Schwindel in Folge einer diagnostisch gesicherten ver- tebrobasilären Insuffizienz aufgenommen. Die erfindungsgemäß verwendete Wirkstoffkombination erwies sich sowohl gegenüber Betahistin als auch gegenüber Plazebo statistisch signifikant (p < 0,01 bzw. p < 0,001) überlegen.This placebo-controlled study at the ENT clinic of the Magdeburg Medical Academy included patients with dizziness as a result of diagnosed vertebral basilar insufficiency. The combination of active ingredients used according to the invention was statistically significantly superior (p <0.01 and p <0.001) both with betahistine and with placebo.
Studie IIIStudy III
In die Studie an der Hals-Nasen-Ohren-Klinik der Universität Rostock wurden 50 Patienten mit Schwindel infolge einer Neuropathia Vestibularis aufgenommen. Hier wurde die erfindungsgemäß verwendete Wirkstoffkombination mit den Einzelwirkstoffen Cinnarizin (20 mg) und Dimenhydrinat (40 mg) - d. h. mit gleicher Dosierung, wie sie in der erfindungsgemäß verwendeten Wirkstoffkombination vor- liegt - verglichen. Im Ergebnis zeigte sich die erfindungsgemäß verwendete Wirkstoffkombination gegenüber beiden Einzelkomponenten statistisch signifikant (p < 0,01) überlegen.The study at the Otolaryngology Clinic of the University of Rostock included 50 patients with dizziness due to a neuropathy vestibularis. Here, the active ingredient combination used according to the invention with the individual active ingredients cinnarizine (20 mg) and dimenhydrinate (40 mg) - ie with the same dosage as that used in the active ingredient combination used according to the invention lies - compared. As a result, the active ingredient combination used according to the invention was statistically significantly superior (p <0.01) to both individual components.
Studie IVStudy IV
Auch in Studie IV (3-Zentren: HNO-Klinik der Universität Brunn, Neurologische Universitätsklinik Sofia, HNO-Klinik Pilsen) wurde die erfindungsgemäß verwendete Wirkstoffkombination mit den Einzelkomponenten in „Originalkonzentration" (20 mg Cinnarizin bzw. 40 mg Dimenhydrinat) verglichen. Aufgenommen wurden Patienten, die entweder an zentral-vestibulärem, peripher-vestibulärem oder kombiniert peripher-zentral-vestibulärem Schwindel litten. Auch in dieser Studie zeigte sich die erfindungsgemäß verwendete Wirkstoffkombination gegenüber den Einzelkomponenten statistisch signifikant (p < 0,01) überlegen.Study IV (3 centers: ENT clinic at the University of Brunn, Neurological University Clinic Sofia, ENT clinic in Pilsen) also compared the active ingredient combination used according to the invention with the individual components in “original concentration” (20 mg cinnarizine or 40 mg dimenhydrinate) patients who suffered from either central-vestibular, peripheral-vestibular or combined peripheral-central-vestibular dizziness.This study also showed that the combination of active substances used according to the invention was statistically significantly superior (p <0.01) to the individual components.
Studie VStudy V
Diese 2-Zentren-Studie wurde an den HNO-Kliniken der Medizinischen Akademie Dresden und der Martin-Luther- Universität Halle durchgeführt. Aufgenommen wurden Patienten, die an peripherem, zentralem oder kombiniert peri- pher-zentralem Schwindel litten. Vergleichssubstanzen waren die Einzelwirkstoffe in höherer Dosierung, Cinnarizin (50 mg) und Dimenhydrinat (100 mg) . Die erfindungsgemäß verwendete Wirkstoffkombination zeigte sich den Einzelsubstanzen gegenüber statistisch hochsignifikant (p < 0,001) überlegen.This 2-center study was carried out at the ENT clinics of the Dresden Medical Academy and the Martin Luther University in Halle. Patients with peripheral, central or combined peripheral-central dizziness were included. The comparison substances were the individual active substances in higher doses, cinnarizine (50 mg) and dimenhydrinate (100 mg). The active ingredient combination used according to the invention was statistically highly significant (p <0.001) superior to the individual substances.
Studie VIStudy VI
Studie VI wurde in der HNO-Klinik, Pilsen durchgeführt. Eingeschlossen wurden Patienten mit diagnostisch gesichertem Innenohrschwindel. Vergleichssubstanz war in diesem Falle Betahistin. „Als Ergebnis zeigte sich eine hochsignifikante (p < 0,001) statistische Überlegenheit der erfindungsgemäß verwendeten Wirkstoffkombination über die bei dieser Indikation ..als Standard geltende Substanz Betahistin.Study VI was carried out in the ENT clinic, Pilsen. Patients with diagnosed inner ear vertigo were included. The reference substance in this case was betahistine. "The result showed a highly significant (p <0.001) statistical superiority of the Active ingredient combination used according to the invention via the substance betahistine, which is the standard for this indication.
Studie VIIStudy VII
Diese Studie wurde an 3 Studienzentren (HNO-Kliniken in Prag, Pilsen, Budweis) durchgeführt. Hier wurde die erfindungsgemäß verwendete Wirkstoffkombination gegen Betahistin bei Patienten mit akuten Schwindelbeschwerden geprüft. Auch in dieser Studie erwies sich die erfindungsgemäß verwendete Wirkstoffkombination dem Betahistin statistisch signifikant (p < 0,05) überlegen.This study was carried out at 3 study centers (ENT clinics in Prague, Pilsen, Budweis). Here the combination of active substances used according to the invention against betahistine was tested in patients with acute dizziness. In this study too, the active ingredient combination used according to the invention was statistically significantly superior (p <0.05) to betahistine.
Studie VIIIStudy VIII
In Studie VIII wurde in der HNO-Klinik der Universität Olomouc bei Patienten mit diagnostisch gesichertem Morbus Meniere die Wirkung der erfindungsgemäß verwendeten Wirkstoffkombination im Vergleich zu Betahistin überprüft. Im Ergebnis zeigte sich zwischen der erfindungsgemäß verwendeten Wirkstoffkombination und dem bei Morbus Meniere standardmäßig eingesetzten Betahistin kein statistisch signifikanter Unterschied.In study VIII, the effect of the active ingredient combination used according to the invention compared to betahistine was checked in the ENT clinic of the University of Olomouc in patients with diagnosed Meniere's disease. As a result, there was no statistically significant difference between the active ingredient combination used according to the invention and the betahistin used as standard in Meniere's disease.
Studie IX, XStudy IX, X
Schließlich wurden noch 2 experimentelle Studien mit der erfindungsgemäß verwendeten Wirkstoffkombination gegen Plazebo bzw. der erfindungsgemäß verwendeten Wirkstoff- kombination gegen Betahistin von der „Aerospace Medicine Group" der Johannes-Gutenberg-Universität in Mainz durchgeführt. Hier wurde bei gesunden, freiwilligen Probanden mittels eines exzentrischen Drehstuhls - wie er auch beim Gleichgewichtstraining von Astronauten Einsatz findet - Schwindel durch Rotation bei gleichzeitiger Ausführung von Kopfbewegungen induziert und die Wirkung der erfindungsgemäß verwendeten Wirkstoffkombination mit der von Plazebo bzw. mit der von Betahistin verglichen. In beiden Studien war die Wirkung der erfindungsgemäß verwendeten Wirkstoffkombination auf die Zahl der tolerierten Kopfbewegungen der von Plazebo bzw. Betahistin statistisch signifikant (p < 0,01 bzw. p < 0,001) überlegen.Finally, two experimental studies were carried out with the active substance combination against placebo or the active substance combination against betahistine used according to the invention by the "Aerospace Medicine Group" of the Johannes Gutenberg University in Mainz. Here, healthy, voluntary subjects were treated with an eccentric Swivel chair - as it is also used in astronaut balance training - induces dizziness by rotation while simultaneously performing head movements and the effect of the active ingredient combination used according to the invention is compared with that of placebo or with that of betahistine The effect of the active ingredient combination used according to the invention on the number of tolerated head movements was statistically significantly superior to that of placebo or betahistine (p <0.01 or p <0.001).
Studie XI, XIIStudy XI, XII
Ferner wurden zwei Studien zur Ermittlung des Einflusses der erfindungsgemäß verwendeten Wirkstoffkombination auf die Vigilanz durchgeführt (HNO-Klinik der Universität Würzburg; Institut für Hirnforschung, Bulgarische Akademie der Wissenschaften, Sofia) . In beiden Studien zeigte die erfindungsgemäß verwendete Wirkstoffkombination keinen statistisch signifikanten Unterschied auf die Vigilanz sowohl im Vergleich zu Betahistin als auch im Vergleich zu Placebo. Furthermore, two studies were carried out to determine the influence of the active ingredient combination used according to the invention on vigilance (ENT clinic of the University of Würzburg; Institute for Brain Research, Bulgarian Academy of Sciences, Sofia). In both studies, the combination of active substances used according to the invention showed no statistically significant difference on the vigilance both in comparison to betahistine and in comparison to placebo.

Claims

Patentansprüche claims
1. Verwendung von Cinnarizin und Dimenhydrinat oder deren physiologisch verträgliche Salze in Kombination zur Behandlung von Schwindel jedweder Genese.1. Use of cinnarizine and dimenhydrinate or their physiologically tolerable salts in combination for the treatment of vertigo of any origin.
2. Verwendung von Cinnarizin und Dimenhydrinat oder deren physiologisch verträgliche Salze in Kombination zur Herstellung von Arzneimitteln zur Behandlung von Schwindel jedweder Genese.2. Use of cinnarizine and dimenhydrinate or their physiologically tolerable salts in combination for the production of medicaments for the treatment of vertigo of any origin.
3. Verwendung von Cinnarizin und Dimenhydrinat oder deren physiologisch verträgliche Salze in Kombination neben pharmazeutisch verträglichen Hilfs- und/oder Zusatzstoffen zur Herstellung von Arzneimitteln zur Behandlung von Schwindel jedweder Genese 3. Use of cinnarizine and dimenhydrinate or their physiologically tolerable salts in combination in addition to pharmaceutically acceptable auxiliaries and / or additives for the manufacture of medicaments for treating vertigo of any origin
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RU2005125062A (en) 2006-01-27
EP2174690A1 (en) 2010-04-14
DE10301981A1 (en) 2004-07-29
US20060135533A1 (en) 2006-06-22
PL378180A1 (en) 2006-03-06
US20120157475A1 (en) 2012-06-21
CN1738626A (en) 2006-02-22
US20090137602A1 (en) 2009-05-28
JP2006515610A (en) 2006-06-01
WO2004064843A2 (en) 2004-08-05
JP2011140502A (en) 2011-07-21
BRPI0406746A (en) 2005-12-20
WO2004064843A3 (en) 2004-12-23
CA2511948A1 (en) 2004-08-05
KR20050092106A (en) 2005-09-20

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