WO2002007713A2 - Medicaments containing cilansetron for treating non-obstipated male ibs patients - Google Patents
Medicaments containing cilansetron for treating non-obstipated male ibs patients Download PDFInfo
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- WO2002007713A2 WO2002007713A2 PCT/EP2001/008260 EP0108260W WO0207713A2 WO 2002007713 A2 WO2002007713 A2 WO 2002007713A2 EP 0108260 W EP0108260 W EP 0108260W WO 0207713 A2 WO0207713 A2 WO 0207713A2
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—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
- A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/439—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom the ring forming part of a bridged ring system, e.g. quinuclidine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—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
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/538—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with carbocyclic ring systems
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- 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
-
- 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
- A61P1/06—Anti-spasmodics, e.g. drugs for colics, esophagic dyskinesia
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- 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 a new medical use of cilansetron or its acid addition salts.
- Cilansetron is a 5HT 3 receptor antagonist, which falls under the scope of the European patent EP 0 297 651 Bl and which has the chemical name (R) - (-) -4, 5, 6, 8, 9, 10- hexahydro- 10- [(2-methyl-lH-imidazol-l-yl) methyl] -llH-pyrido- [3, 2, 1-j] -carbazol-11-one carries.
- European patent EP 0 601 345 B1 already discloses the use of, inter alia, cilansetron for the production of pharmaceutical preparations for the treatment of functional disorders of the lower intestinal tract associated with increased sensitivity to pain and / or abnormally accelerated stool passage in the colon area in larger mammals and humans.
- non-constipative diarrhea-predominant IBS patient group
- WO 99/17755 mentions alosetron, which in clinical trials showed significantly better efficacy in female IBS patients compared to efficacy in male IBS patients. In these clinical trials, male test subjects treated with alosetron did not find any significant improvement in their condition compared to the placebo group.
- cilansetron is stated to be within the scope of the disclosure.
- IBS irritable bowel syndrome
- IBS refers to a group of symptoms associated with pain and / or a feeling of discomfort in the lower abdomen and changed bowel activities such as diarrhea, constipation (constipation) or alternating diarrhea and constipation. Since no clearly definable physiological or other organic findings can be cited as the cause of IBS, the medical diagnosis of this disease is usually based on the absence or presence of a number of symptoms which are generally regarded as typical for IBS and, for example, in the " Ro e Criteria "(cf. WG Thompson et al., Gastroent. Int. 2 (1989) 92-95; WG Thompson et al., Gut 45/11 (1999) II 43 - II 47; WG Thompson, Lancet 341 ( 1993) 1569 - 1572).
- cilansetron can preferably be used in the form of the cilansetron hydrochloride.
- the cilansetron hydrochloride monohydrate is usually used.
- Further pharmacologically acceptable acid addition salts of cilansetron are known from EP 0 297 651 B1.
- BID dosage a dosage of 5HT 3 receptor antagonists
- TID dosage a dosage of IBS patients of both sexes.
- Examples of 5HT 3 receptor antagonists which can be administered more advantageously in triple daily doses include alosetron, azasetron, dolasetron, granisetron, indisetron, itasetron, lerisetron, ondansetron, ramosetron, tropisetron and (R) -zacoprid. It has proven to be particularly advantageous for the treatment of IBS patients of both sexes to administer cilansetron or its pharmacologically acceptable acid addition salts and / or solvates to the patients three times a day, for example in doses between 1 mg and 16 mg per administration.
- cilansetron or a pharmacologically acceptable acid addition salt of cilansetron can be contained according to the invention in solid or liquid pharmaceutical preparations together with customary pharmaceutical auxiliaries and / or carriers.
- solid preparations are orally administrable preparations such as tablets, dragees, capsules, powders or granules or suppositories.
- These preparations can pharmaceutically customary inorganic and / or organic carriers, such as. B. talc, milk sugar or starch in addition to pharmaceutically customary auxiliaries, for example lubricants or tablet disintegrants.
- Liquid preparations such as suspensions or emulsions of cilansetron can contain the usual diluents such as water, oils and / or suspending agents such as polyethylene glycols and the like. Additional auxiliaries can also be added, e.g. B. preservatives, flavor corrections and the like.
- Cilansetron or a pharmacologically acceptable acid addition salt of cilansetron can be mixed and formulated with the pharmaceutical auxiliaries and / or carriers in a manner known per se.
- cilansetron or an acid addition salt can be mixed, for example, with the auxiliaries and / or excipients in a conventional manner and granulated wet or dry. The granules or powder can be filled directly into capsules or pressed into tablet cores in the usual way. If desired, these can be dragged in a known manner.
- the active ingredient is mixed with cornstarch and fine powdered lactose in a mixer.
- the resulting mixture is moistened with a 20% solution of polyvinylpyrolidone (Kollidon 25 R from BASF) in demineralized water. If necessary, further demineralized water is added.
- the moist granulate is passed through a 2 mm sieve. , dried on trays at 40 ° C and then passed through a 1 mm sieve (Frewitt machine). After mixing the granules with magnesium stearate and talc, tablets with a weight of 114 mg are pressed therefrom, so that each tablet contains 4 mg of active ingredient.
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- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
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Abstract
Description
Cilansetron enthaltende Arzneimittel zur Behandlung nicht-obstipativer männlicher IBS-Patienten Medicines containing cilansetron for the treatment of non-constipative male IBS patients
Beschreibungdescription
Die vorliegende Erfindung betrifft eine neue medizinische Verwendung von Cilansetron oder dessen Säureadditions- salzen.The present invention relates to a new medical use of cilansetron or its acid addition salts.
Cilansetron ist ein 5HT3-Rezeptor-Antagonist, welcher unter den Umfang des europäischen Patentes EP 0 297 651 Bl fällt und welcher den chemischen Namen (R) - (-) -4, 5 , 6, 8, 9, 10- Hexahydro-10- [ (2-methyl-lH-imidazol-l-yl)methyl] -llH-pyrido- [3 , 2 , 1-j ] -carbazol-11-on trägt.Cilansetron is a 5HT 3 receptor antagonist, which falls under the scope of the European patent EP 0 297 651 Bl and which has the chemical name (R) - (-) -4, 5, 6, 8, 9, 10- hexahydro- 10- [(2-methyl-lH-imidazol-l-yl) methyl] -llH-pyrido- [3, 2, 1-j] -carbazol-11-one carries.
Aus dem europäischen Patent EP 0 601 345 Bl ist bereits die Verwendung von unter anderem Cilansetron zur Herstellung von pharmazeutischen Zubereitungen zur Behandlung von mit erhöhter Schmerzempfindlichkeit und/oder anomal beschleunigter Stuhlpassage im Colonbereich verbundenen funktioneilen Störungen der unteren Darmwege in größeren Säugetieren und Menschen bekannt. Zu den funktioneilen Störungen, welche durch u. a. Cilansetron behandelbar sind, zählt beispielsweise auch das "Irritable Bowel Syndrome" (= IBS, Reizdarm- syndrom) , insbesondere in Verbindung mit einer anomal beschleunigten Stuhlpassage durch das Colon.European patent EP 0 601 345 B1 already discloses the use of, inter alia, cilansetron for the production of pharmaceutical preparations for the treatment of functional disorders of the lower intestinal tract associated with increased sensitivity to pain and / or abnormally accelerated stool passage in the colon area in larger mammals and humans. To the functional disorders caused by u. a. Cilansetron are treatable, for example the "Irritable Bowel Syndrome" (= IBS, irritable bowel syndrome), in particular in connection with an abnormally accelerated bowel passage through the colon.
In der internationalen Patentanmeldung, Veröffentli- chungs-Nr. WO 99/17755, werden 5HT3-Rezeptor-Antagonisten beschrieben, welche sich besonders gut zur Behandlung von nicht-obstipativen (= Diarrhoe-prädominante IBS-Patienten- gruppe; im Gegensatz zu der Obstipations-prädominanten IBS- Patientengruppe) weiblichen IBS-Patienten eignen. Als Beispiel wird in der WO 99/17755 Alosetron genannt, welches in klinischen Versuchen eine deutlich bessere Wirksamkeit an weiblichen IBS-Patienten zeigte, verglichen mit der Wirksamkeit an männlichen IBS-Patienten. An mit Alosetron behandelten männlichen Testpersonen wurde in diesen klinischen Versuchen keine aussagekräftige Verbesserung des Befindens gegenüber der Placebo-Gruppe festgestellt. In einer Ausführungsform des Anmeldungsgegenstandes der WO 99/17755 wird u„ a. auch Cilansetron als unter den Umfang der Offenbarung fallend angegeben.In the international patent application, publication no. WO 99/17755 describes 5HT 3 receptor antagonists which are particularly good for the treatment of non-constipative (= diarrhea-predominant IBS patient group; in contrast to the constipation-predominant IBS patient group) female IBS patients suitable. As an example, WO 99/17755 mentions alosetron, which in clinical trials showed significantly better efficacy in female IBS patients compared to efficacy in male IBS patients. In these clinical trials, male test subjects treated with alosetron did not find any significant improvement in their condition compared to the placebo group. In one embodiment of the subject matter of WO 99/17755, inter alia. also cilansetron is stated to be within the scope of the disclosure.
Es wurde nun überraschend gefunden, daß Cilansetron gleichermaßen zur Behandlung von nicht-obstipativen männlichen und weiblichen Patienten, welche am Reizdarmsyndrom (= IBS) leiden, geeignet ist.It has now surprisingly been found that cilansetron is equally suitable for the treatment of non-constipative male and female patients who suffer from irritable bowel syndrome (= IBS).
Gegenstand der Erfindung ist daher die Verwendung von Cilansetron oder dessen pharmakologisch verträglichen Säureadditionssalzen und/oder Solvaten zur Herstellung von pharmazeutischen Zubereitungen für die Behandlung und/oder Prophylaxe des Reizdarmsyndroms (= IBS) bei nicht-obstipativen männlichen Patienten.The invention therefore relates to the use of cilansetron or its pharmacologically acceptable acid addition salts and / or solvates for the production of pharmaceutical preparations for the treatment and / or prophylaxis of irritable bowel syndrome (= IBS) in non-constipative male patients.
IBS bezeichnet eine Gruppe von mit Schmerzen und/oder einem Gefühl des Unwohlseins im Unterleib sowie veränderten Darmaktivitäten einhergehenden Symptomen wie Diarrhöe, Obstipation (= Konstipation) oder wechselweise Diarrhöe und Obstipation. Da bislang noch keine eindeutig faßbaren physiologischen oder anderen organischen Befunde als Ursache für IBS angegeben werden können, stützt sich die ärztliche Diagnose dieser Krankheit üblicherweise auf das Fehlen oder Vorhandensein einer Reihe von Symptomen, welche allgemein als typisch für IBS angesehen werden und beispielsweise in den "Ro e Criteria" (vgl. W. G. Thompson et al . , Gastroent. Int. 2 (1989) 92 - 95; W. G. Thompson et al . , Gut 45/11 (1999) II 43 - II 47; W. G. Thompson, Lancet 341 (1993) 1569 - 1572) festgehalten sind. Erfindungsgemäß kann Cilansetron vorzugsweise in Form des Cilansetron-Hydrochlorids eingesetzt werden. Üblicherweise wird das Cilansetron-Hydrochlorid-Monohydrat eingesetzt. Weitere pharmakologisch verträgliche Säureadditions- salze von Cilansetron sind aus der EP 0 297 651 Bl bekannt.IBS refers to a group of symptoms associated with pain and / or a feeling of discomfort in the lower abdomen and changed bowel activities such as diarrhea, constipation (constipation) or alternating diarrhea and constipation. Since no clearly definable physiological or other organic findings can be cited as the cause of IBS, the medical diagnosis of this disease is usually based on the absence or presence of a number of symptoms which are generally regarded as typical for IBS and, for example, in the " Ro e Criteria "(cf. WG Thompson et al., Gastroent. Int. 2 (1989) 92-95; WG Thompson et al., Gut 45/11 (1999) II 43 - II 47; WG Thompson, Lancet 341 ( 1993) 1569 - 1572). According to the invention, cilansetron can preferably be used in the form of the cilansetron hydrochloride. The cilansetron hydrochloride monohydrate is usually used. Further pharmacologically acceptable acid addition salts of cilansetron are known from EP 0 297 651 B1.
Klinische Untersuchungsdaten belegen die überraschende Eignung von Cilansetron zur Behandlung von nicht-obstipativen IBS-Patienten von gleichermaßen männlichem wie weiblichem Geschlecht :Clinical examination data confirm the surprising suitability of cilansetron for the treatment of non-constipative IBS patients of both male and female sex:
In einer 12-wöchigen Placebo-kontrollierten klinischen Doppelblindstudie mit Zufallsauswahl ( "rando ized" ) und parallelen Versuchsgruppen wurde die Wirkung von Cilansetron auf nicht-obstipative IBS-Patienten beiderlei Geschlechts untersucht. Als nicht-obstipative Patienten wurden im Rahmen der Studie IBS-Patienten angesehen, deren KrankheitsSymptome den "Rome Criteria" (s. o.) entsprachen und deren Stuhlbeschaffenheit und Stuhlhäufigkeit die folgenden Kriterien erfüllte:The effect of cilansetron on non-constipative IBS patients of both sexes was investigated in a 12-week, double-blind, placebo-controlled clinical trial with random selection ("rando ized") and parallel test groups. In the study, IBS patients were considered non-constipative patients whose disease symptoms corresponded to the "Rome Criteria" (see above) and whose stool quality and frequency met the following criteria:
i) <25 % durch Obstipation beeinträchtigte IBS-Ereignisse.i) <25% IBS events affected by constipation.
ii) Als nicht-obstipativ charakterisiert entsprechend denii) Characterized as non-constipative according to
"Rome criteria" (s. o., Personen, welche nicht <3 Darmbewegungen (= "bowel movements") pro Woche und/oder harte/klumpige Stuhlbeschaffenheit aufweisen) ."Rome criteria" (see above, persons who do not have <3 bowel movements per week and / or have hard / lumpy stools).
iii) <4 Tage (aufeinanderfolgend oder nicht aufeinanderfolgend) ohne Darmbewegung während einer zweiwöchigen Beobachtungsperiode (= "run-in period") .iii) <4 days (consecutive or not consecutive) without bowel movement during a two-week observation period (= "run-in period").
iv) Durchschnittliche Stuhlbeschaffenheit >4 (entsprechend der "Bristol-Stuhlskala" ) während einer zweiwöchigen Beobachtungsperiode . Ebenfalls wurden solche Patienten in die Studie einbezogen, sofern sie die Frage nach Schmerzen/Gefühl des Unwohlseins im Unterleib nur in <50 % der Fälle mit "Nein" beantworteten oder welche ihre Schmerzen/ihr Gefühl des Unwohlseins im Unterleib für <2 mal während einer zweiwöchigen Beobachtungsperiode als "einschränkend" beurteilten.iv) Average stool quality> 4 (corresponding to the "Bristol stool scale") during a two-week observation period. Such patients were also included in the study, provided that they answered "No" to the question of pain / discomfort in the abdomen only <50% of the time, or who answered their pain / feeling of discomfort in the abdomen for <2 times during one two-week observation period as "restrictive".
Es wurde Cilansetron in Dosierungen von 1, 2, 8 und 16 mg eingesetzt. Wöchentlich wurden die Patienten auf "angemessene Linderung" (= Primärer Wirksamkeits-Parameter) ihrer IBS-Symptome hin überprüft (Bauchschmerzen wie Schmerzen im Abdomen, anomale Darmtätigkeit) . Bauchschmerzen wie Schmerzen im Abdomen, Stuhlbeschaffenheit und Stuhlhäufigkeit wurden täglich von den Patienten bewertet (= Sekundäre Wirksamkeits- Parameter) .Cilansetron was used in doses of 1, 2, 8 and 16 mg. The patients were checked weekly for "adequate relief" (= primary efficacy parameter) of their IBS symptoms (abdominal pain such as pain in the abdomen, abnormal bowel activity). Abdominal pain such as abdominal pain, stool quality and frequency of stools were assessed daily by the patients (= secondary efficacy parameters).
In einem vorläufigen Ergebnis der Doppelbindstudie wurden die Daten von insgesamt 454 Patienten (297 weibliche Patienten und 157 männliche Patienten) ausgewertet und in der nachfolgenden Tabelle aufgetragen. Entsprechend den der klinischen Doppelblindstudie zugrundeliegenden Kriterien wurden in den beiden Patienten-Untergruppen der männlichen IBS- Patienten und der weiblichen IBS-Patienten die in der nachfolgenden Tabelle angegebenen Erfolgsquoten betreffend die "angemessene Linderung" der IBS-Symptome festgestellt:In a preliminary result of the double-tie study, the data from a total of 454 patients (297 female patients and 157 male patients) were evaluated and entered in the table below. According to the criteria on which the clinical double-blind study is based, the success rates given in the table below regarding the "adequate relief" of IBS symptoms were determined in the two patient subgroups of male IBS patients and female IBS patients:
Tabelletable
Der "primäre Wirksamkeits-Parameter" entspricht der Erfolgsquote (= "responder rate") auf die den Patienten wöchentlich gestellte Frage, ob sie im Verlauf der jeweils vorangegangenen Woche eine "angemessene Linderung" ihrer IBS- Symptome (Schmerzen/Gefühl des Unwohlseins im Unterleib; anomale Darmaktivitäten) erfahren hätten. Als "Erfolgsperson" (= "responder") wird ein Patient oder eine Patientin angesehen, welcher/welche wenigstens vier Wochen lang behandelt wurde und welcher/welche die ihm/ihr gestellte Frage ob eine "angemessene Linderung" seiner/ihrer IBS-Symptome eingetreten sei, wenigstens für die Hälfte seiner/ihrer Behandlungsperiode mit "Ja" beantwortet hat.The "primary efficacy parameter" corresponds to the success rate (= "responder rate") to the weekly question asked of the patients whether they "adequately alleviated" their IBS in the course of the previous week. Symptoms (pain / feeling of discomfort in the abdomen; abnormal bowel activity). A "responder" is considered to be a patient who has been treated for at least four weeks and who has been asked the question whether "adequate relief" of his / her IBS symptoms has occurred has answered "yes" for at least half of his / her treatment period.
Nach dem Abschluß der Doppelblindstudie konnten die Daten von insgesamt 471 Patienten (308 weibliche Patienten und 163 männliche Patienten) ausgewertet werden. Die abschließenden Erfolgsquoten wurden zu 40 % für die Placebo- gruppe, 62 % für die Dosis 1 mg Cilansetron (TID) , 53 % für die Dosis 2 mg Cilansetron (TID) , 55 % für die Dosis 8 mg Cilansetron (TID) und 63 % für die Dosis 16 mg Cilansetron (TID) bestimmt. Die Erfolgsquoten waren bei der männlichen Patientengruppe und bei der weiblichen Patientengruppe sehr ähnlich. Die größten Unterschiede wurden bei der Dosierung 1 mg Cilansetron (TID) beobachtet.After completing the double-blind study, data from a total of 471 patients (308 female patients and 163 male patients) could be evaluated. Final success rates were 40% for the placebo group, 62% for the 1 mg cilansetron (TID) dose, 53% for the 2 mg cilansetron (TID) dose, 55% for the 8 mg cilansetron (TID) dose and 63 % for the 16 mg dose of cilansetron (TID). The success rates were very similar in the male patient group and in the female patient group. The greatest differences were observed with the 1 mg cilansetron (TID) dose.
Aus den vorstehend angegebenen Daten ist ersichtlich, daß die nicht-obstipativen IBS-Patienten beiderlei Geschlechts auf die Behandlung mit Cilansetron in allen untersuchten Dosierungen ansprechen.From the data presented above, it can be seen that the non-constipative IBS patients of both sexes responded to treatment with cilansetron in all doses examined.
Besonders überraschend ist die durch die vorgenannten Untersuchungsergebnisse belegte Wirksamkeit von Cilansetron bei der Behandlung nicht-obstipativer (= Diarrhoe-prädominan- ter) männlicher IBS-Patienten, da der Fachmann aus dem Inhalt der WO 99/17755 den Schluß ziehen mußte, Cilansetron sei - ebenso wie Alosetron - vorzugsweise nur zur Behandlung nicht-obstipativer weiblicher IBS-Patienten geeignet.The effectiveness of cilansetron in the treatment of non-obstipative (= diarrhea-dominant) male IBS patients, as evidenced by the aforementioned test results, is particularly surprising since the expert had to conclude from the content of WO 99/17755 that cilansetron is - as well as alosetron - preferably only suitable for the treatment of non-constipative female IBS patients.
Vorbekannte 5HT3-Rezeptor-Antagonisten werden zur Behandlung von IBS üblicherweise zweimal täglich (= "BID-Dosie- rung") verabreicht. Als vorteilhafter zur Behandlung von IBS-Patienten beiderlei Geschlechts erweist es sich jedoch, 5HT3-Rezeptor-Antagonisten statt dessen dreimal täglich, beispielsweise in Dosierungen von jeweils 1 mg bis 16 mg an IBS- Patienten beiderlei Geschlechts zu verabreichen (= "TID- Dosierung"). Besonders bevorzugt ist es, die dreimal tägliche Einnahme von 5HT3-Antagonisten über den Tag zu verteilen und insbesondere nach den Hauptmahlzeiten (morgens, mittags und abends) zu verordnen. Beispiele für 5HT3-Rezeptor-Antagonis- ten, welche vorteilhafter in dreifach täglicher Dosierung verabreicht werden können, umfassen Alosetron, Azasetron, Dolasetron, Granisetron, Indisetron, Itasetron, Lerisetron, Ondansetron, Ramosetron, Tropisetron und (R) -Zacoprid. Als besonders vorteilhaft zur Behandlung von IBS-Patienten beiderlei Geschlechts erweist es sich, Cilansetron oder dessen pharmakologisch verträgliche Säureadditionssalze und/oder Solvate dreimal täglich an die Patienten zu verabreichen, beispielsweise jeweils in Dosierungen zwischen 1 mg und 16 mg pro Verabreichung.Known 5HT 3 receptor antagonists are usually administered twice a day (= “BID dosage”) for the treatment of IBS. As more beneficial for the treatment of However, IBS patients of both sexes have been found to instead administer 5HT 3 receptor antagonists three times a day, for example in doses of 1 mg to 16 mg, to IBS patients of both sexes (= "TID dosage"). It is particularly preferred to distribute the 5HT 3 antagonists three times a day over the day and in particular to prescribe them after the main meals (morning, noon and evening). Examples of 5HT 3 receptor antagonists which can be administered more advantageously in triple daily doses include alosetron, azasetron, dolasetron, granisetron, indisetron, itasetron, lerisetron, ondansetron, ramosetron, tropisetron and (R) -zacoprid. It has proven to be particularly advantageous for the treatment of IBS patients of both sexes to administer cilansetron or its pharmacologically acceptable acid addition salts and / or solvates to the patients three times a day, for example in doses between 1 mg and 16 mg per administration.
Als Heilmittel kann Cilansetron oder ein pharmakologisch verträgliches Säureadditionssalz von Cilansetron erfindungsgemäß zusammen mit üblichen pharmazeutischen Hilfs- und/oder Trägerstoffen in festen oder flüssigen pharmazeutischen Zubereitungen enthalten sein. Als Beispiele fester Präparate seien oral applizierbare Präparate wie Tabletten, Dragees, Kapseln, Pulver oder Granulate genannt oder auch Supposito- rien. Diese Präparate können pharmazeutisch übliche anorganische und/oder organische Trägerstoffe, wie z. B. Talkum, Milchzucker oder Stärke neben pharmazeutisch üblichen Hilfsmitteln, beispielsweise Gleitmitteln oder Tablettensprengmit- teln, enthalten. Flüssige Präparate wie Suspensionen oder Emulsionen von Cilansetron können die üblichen Verdünnungsmittel wie Wasser, Öle und/oder Suspensionsmittel wie Poly- ethylenglykole und dergleichen enthalten. Es können zusätzlich weitere Hilfsstoffe zugegeben werden wie z. B. Konservierungsmittel, Geschmackskorrigenzien und dergleichen. Cilansetron oder ein pharmakologisch verträgliches Säureadditionssalz von Cilansetron kann mit den pharmazeutischen Hilfs- und/oder Trägerstoffen in an sich bekannter Weise gemischt und formuliert werden. Zur Herstellung fester Arzneiformen kann Cilansetron oder ein Säureadditionssalz beispielsweise mit den Hilfs- und/oder Trägerstoffen in üblicher Weise gemischt und naß oder trocken granuliert werden. Das Granulat oder Pulver kann direkt in Kapseln abgefüllt oder in üblicher Weise zu Tablettenkernen verpreßt werden. Diese können gewünschtenfalls in bekannter Weise dragiert werden.As a remedy, cilansetron or a pharmacologically acceptable acid addition salt of cilansetron can be contained according to the invention in solid or liquid pharmaceutical preparations together with customary pharmaceutical auxiliaries and / or carriers. Examples of solid preparations are orally administrable preparations such as tablets, dragees, capsules, powders or granules or suppositories. These preparations can pharmaceutically customary inorganic and / or organic carriers, such as. B. talc, milk sugar or starch in addition to pharmaceutically customary auxiliaries, for example lubricants or tablet disintegrants. Liquid preparations such as suspensions or emulsions of cilansetron can contain the usual diluents such as water, oils and / or suspending agents such as polyethylene glycols and the like. Additional auxiliaries can also be added, e.g. B. preservatives, flavor corrections and the like. Cilansetron or a pharmacologically acceptable acid addition salt of cilansetron can be mixed and formulated with the pharmaceutical auxiliaries and / or carriers in a manner known per se. To prepare solid pharmaceutical forms, cilansetron or an acid addition salt can be mixed, for example, with the auxiliaries and / or excipients in a conventional manner and granulated wet or dry. The granules or powder can be filled directly into capsules or pressed into tablet cores in the usual way. If desired, these can be dragged in a known manner.
Das folgende Beispiel soll die Herstellung von Cilanse- tron-Hydrochlorid enthaltenden pharmazeutischen Zubereitungen erläutern.The following example is intended to explain the preparation of pharmaceutical preparations containing cilansetron hydrochloride.
Beispiel 1; TablettenExample 1; tablets
Zusammensetzung :Composition:
Cilansetron-Hydrochlorid-Monohydrat 4 TeileCilansetron hydrochloride monohydrate 4 parts
Maisstärke 30 TeileCorn starch 30 parts
Lactose 70 TeileLactose 70 parts
Kollidon 25R 5 TeileKollidon 25 R 5 parts
Magnesiumstearat 2 TeileMagnesium stearate 2 parts
Talkum 3 TeileTalc 3 parts
Gesamt: 114 TeileTotal: 114 parts
Herstellungsvorschrift :Manufacturing instructions:
Der Wirkstoff wird mit Maisstärke und feinpulveriger Lactose in einem Mischer vermischt. Die entstandene Mischung wird mit einer 20%igen Lösung von Polyvinylpyrolidon (Kollidon 25R der Fa. BASF) in entmineralisiertem Wasser durchfeuchtet. Falls erforderlich, wird weiteres ent ineralisiertes Wasser hinzugefügt. Das feuchte Granulat wird durch ein 2 mm-Sieb pas- siert, bei 40 °C auf Horden getrocknet und anschließend durch ein 1 mm-Sieb (Frewitt-Maschine) passiert. Nach dem Vermischen des Granulates mit Magnesiumstearat und Talkum werden daraus Tabletten mit einem Gewicht von 114 mg gepreßt, so daß jede Tablette 4 mg Wirkstoff enthält.The active ingredient is mixed with cornstarch and fine powdered lactose in a mixer. The resulting mixture is moistened with a 20% solution of polyvinylpyrolidone (Kollidon 25 R from BASF) in demineralized water. If necessary, further demineralized water is added. The moist granulate is passed through a 2 mm sieve. , dried on trays at 40 ° C and then passed through a 1 mm sieve (Frewitt machine). After mixing the granules with magnesium stearate and talc, tablets with a weight of 114 mg are pressed therefrom, so that each tablet contains 4 mg of active ingredient.
Ebenso können andere, beispielsweise aus der EP 0 895 782 A2 bekannte pharmazeutische Zubereitungen von Cilansetron verwendet werden. Other pharmaceutical preparations of cilansetron known for example from EP 0 895 782 A2 can also be used.
Claims
Priority Applications (11)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| HU0301479A HUP0301479A2 (en) | 2000-07-26 | 2001-07-18 | Use of cilansetron for producing pharmaceutical compositions for treating non-obstipated male ibs patients |
| AU2001276409A AU2001276409A1 (en) | 2000-07-26 | 2001-07-18 | Medicaments containing cilansetron for treating non-obstipated male ibs patients |
| BR0112690-3A BR0112690A (en) | 2000-07-26 | 2001-07-18 | Cilansetron-containing drug for the treatment of non-constipative male ibs patients |
| KR10-2003-7000038A KR20030019951A (en) | 2000-07-26 | 2001-07-18 | Medicaments containing cilansetron for treating non-obstipated male ibs patients |
| MXPA02012917A MXPA02012917A (en) | 2000-07-26 | 2001-07-18 | Medicaments containing cilansetron for treating non-obstipated male ibs patients. |
| IL15397201A IL153972A0 (en) | 2000-07-26 | 2001-07-18 | Medicaments containing cilansetron for treating non-obstipated male ibs patients |
| JP2002513449A JP2004504343A (en) | 2000-07-26 | 2001-07-18 | Silanesetron-containing drugs for the treatment of non-constipated male IBS patients |
| EP01954044A EP1307195A2 (en) | 2000-07-26 | 2001-07-18 | Medicaments containing cilansetron for treating non-obstipated male ibs patients |
| CA002417677A CA2417677A1 (en) | 2000-07-26 | 2001-07-18 | Medicaments containing cilansetron for treating non-obstipated male ibs patients |
| SK127-2003A SK1272003A3 (en) | 2000-07-26 | 2001-07-18 | Medicaments containing cilansetron for treating non-obstipated male IBS patients |
| NO20030373A NO20030373D0 (en) | 2000-07-26 | 2003-01-24 | Medicines containing cilantrone for the treatment of non-constipated male IBS patients |
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE10036645.7 | 2000-07-26 | ||
| DE10036645 | 2000-07-26 | ||
| DE10123447A DE10123447A1 (en) | 2000-07-26 | 2001-05-14 | Cilansetron-containing medicines for the treatment of non-obstipative male IBS patients |
| DE10123447.3 | 2001-05-14 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| WO2002007713A2 true WO2002007713A2 (en) | 2002-01-31 |
| WO2002007713A3 WO2002007713A3 (en) | 2002-11-14 |
Family
ID=26006529
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/EP2001/008260 Ceased WO2002007713A2 (en) | 2000-07-26 | 2001-07-18 | Medicaments containing cilansetron for treating non-obstipated male ibs patients |
Country Status (16)
| Country | Link |
|---|---|
| EP (1) | EP1307195A2 (en) |
| JP (1) | JP2004504343A (en) |
| CN (1) | CN1444479A (en) |
| AR (1) | AR028970A1 (en) |
| AU (1) | AU2001276409A1 (en) |
| BR (1) | BR0112690A (en) |
| CA (1) | CA2417677A1 (en) |
| CZ (1) | CZ2003158A3 (en) |
| HU (1) | HUP0301479A2 (en) |
| IL (1) | IL153972A0 (en) |
| MX (1) | MXPA02012917A (en) |
| NO (1) | NO20030373D0 (en) |
| PL (1) | PL363517A1 (en) |
| RU (1) | RU2003104798A (en) |
| SK (1) | SK1272003A3 (en) |
| WO (1) | WO2002007713A2 (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005072730A1 (en) * | 2004-01-30 | 2005-08-11 | Astellas Pharma Inc. | Therapeutic agent for diarrhea-type irritable bowel syndrome |
| WO2005073220A1 (en) * | 2004-01-30 | 2005-08-11 | Yamanouchi Pharmaceutical Co., Ltd. | Remedy for irritable bowel syndrome with diarrhea |
| JP2006008707A (en) * | 2005-09-21 | 2006-01-12 | Astellas Pharma Inc | Antidiarrheal irritable bowel syndrome treatment |
| US7470690B2 (en) | 2002-07-10 | 2008-12-30 | Dynogen Pharmaceuticals, Inc. | 4-(2-Fluorophenyl)-6-methyl-2-(1-piperazinyl)thieno[2,3-D)pyrimidine in the treatment of functional bowel disorder |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7601856B2 (en) | 2006-07-27 | 2009-10-13 | Wyeth | Benzofurans as potassium ion channel modulators |
| US7662831B2 (en) | 2006-07-27 | 2010-02-16 | Wyeth Llc | Tetracyclic indoles as potassium channel modulators |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB9721139D0 (en) * | 1997-10-07 | 1997-12-03 | Glaxo Group Ltd | Medicaments |
| GB9930077D0 (en) * | 1999-12-20 | 2000-02-09 | Glaxo Group Ltd | Medicaments |
-
2001
- 2001-06-21 AR ARP010102958A patent/AR028970A1/en unknown
- 2001-07-18 EP EP01954044A patent/EP1307195A2/en not_active Withdrawn
- 2001-07-18 CA CA002417677A patent/CA2417677A1/en not_active Abandoned
- 2001-07-18 JP JP2002513449A patent/JP2004504343A/en active Pending
- 2001-07-18 CZ CZ2003158A patent/CZ2003158A3/en unknown
- 2001-07-18 MX MXPA02012917A patent/MXPA02012917A/en unknown
- 2001-07-18 RU RU2003104798/15A patent/RU2003104798A/en not_active Application Discontinuation
- 2001-07-18 PL PL01363517A patent/PL363517A1/en not_active Application Discontinuation
- 2001-07-18 AU AU2001276409A patent/AU2001276409A1/en not_active Abandoned
- 2001-07-18 CN CN01813307A patent/CN1444479A/en active Pending
- 2001-07-18 HU HU0301479A patent/HUP0301479A2/en unknown
- 2001-07-18 WO PCT/EP2001/008260 patent/WO2002007713A2/en not_active Ceased
- 2001-07-18 IL IL15397201A patent/IL153972A0/en unknown
- 2001-07-18 SK SK127-2003A patent/SK1272003A3/en unknown
- 2001-07-18 BR BR0112690-3A patent/BR0112690A/en not_active Application Discontinuation
-
2003
- 2003-01-24 NO NO20030373A patent/NO20030373D0/en not_active Application Discontinuation
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7470690B2 (en) | 2002-07-10 | 2008-12-30 | Dynogen Pharmaceuticals, Inc. | 4-(2-Fluorophenyl)-6-methyl-2-(1-piperazinyl)thieno[2,3-D)pyrimidine in the treatment of functional bowel disorder |
| WO2005072730A1 (en) * | 2004-01-30 | 2005-08-11 | Astellas Pharma Inc. | Therapeutic agent for diarrhea-type irritable bowel syndrome |
| WO2005073220A1 (en) * | 2004-01-30 | 2005-08-11 | Yamanouchi Pharmaceutical Co., Ltd. | Remedy for irritable bowel syndrome with diarrhea |
| JP2006008707A (en) * | 2005-09-21 | 2006-01-12 | Astellas Pharma Inc | Antidiarrheal irritable bowel syndrome treatment |
Also Published As
| Publication number | Publication date |
|---|---|
| AU2001276409A1 (en) | 2002-02-05 |
| CA2417677A1 (en) | 2003-01-27 |
| AR028970A1 (en) | 2003-05-28 |
| RU2003104798A (en) | 2004-06-27 |
| CN1444479A (en) | 2003-09-24 |
| HUP0301479A2 (en) | 2003-09-29 |
| IL153972A0 (en) | 2003-07-31 |
| PL363517A1 (en) | 2004-11-29 |
| CZ2003158A3 (en) | 2003-08-13 |
| NO20030373L (en) | 2003-01-24 |
| BR0112690A (en) | 2003-06-24 |
| NO20030373D0 (en) | 2003-01-24 |
| MXPA02012917A (en) | 2003-05-14 |
| SK1272003A3 (en) | 2003-07-01 |
| EP1307195A2 (en) | 2003-05-07 |
| WO2002007713A3 (en) | 2002-11-14 |
| JP2004504343A (en) | 2004-02-12 |
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