WO2004082680A1 - Pramipexole for reducing excessive food intake by children - Google Patents

Pramipexole for reducing excessive food intake by children Download PDF

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Publication number
WO2004082680A1
WO2004082680A1 PCT/EP2004/002793 EP2004002793W WO2004082680A1 WO 2004082680 A1 WO2004082680 A1 WO 2004082680A1 EP 2004002793 W EP2004002793 W EP 2004002793W WO 2004082680 A1 WO2004082680 A1 WO 2004082680A1
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Prior art keywords
pramipexole
children
optionally
use according
manufacture
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PCT/EP2004/002793
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German (de)
French (fr)
Inventor
Joachim Mierau
Jürgen REESS
Marion Wienrich
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Boehringer Ingelheim International Gmbh
Boehringer Ingelheim Pharma Gmbh & Co Kg
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Application filed by Boehringer Ingelheim International Gmbh, Boehringer Ingelheim Pharma Gmbh & Co Kg filed Critical Boehringer Ingelheim International Gmbh
Priority to EP04721477A priority Critical patent/EP1608367A1/en
Priority to CA002519584A priority patent/CA2519584A1/en
Priority to JP2006504716A priority patent/JP2006520764A/en
Publication of WO2004082680A1 publication Critical patent/WO2004082680A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/428—Thiazoles condensed with carbocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents

Definitions

  • the invention relates to the use of pramipexole for the manufacture of a medicament for reducing excessive food intake in children.
  • the object of the invention is to make it easier for the young patient between the ages of 6 and 18 to reduce the calorie intake and thus to reduce the health risks associated with obesity.
  • pramipexole can be used in therapeutically well tolerated effective doses to reduce excessive food intake in children.
  • the present invention aims to use pramipexole for the manufacture of a medicament for reducing excessive food intake in children.
  • pramipexole for the manufacture of a medicament for reducing excessive food intake in children aged 6 to 18 years, preferably aged 12 to 18 years. Also preferred is use in children whose BMI is above the 90th percentile, preferably above the 97th percentile.
  • the use is particularly preferred, with the children being given a daily dose of approximately 0.005 mg / kg to 0.02 mg / kg body weight, preferably approximately 0.1 mg / kg body weight, of pramipexole.
  • pramipexole for the manufacture of a medicament for the treatment of obesity in type 2 diabetes in children.
  • pramipexole for the manufacture of a medicament for continuous application in children is particularly preferred.
  • pramipexole for the manufacture of a medicament for transdermal application in children.
  • pramipexole is optionally used in the form of its enantiomers, preferably the (-) enantiomer, optionally in the form of the pharmacologically acceptable acid addition salts and optionally in the form of the hydrates and solvates.
  • a pharmaceutical composition containing pramipexole as the active ingredient optionally in the form of its enantiomers, preferably the (-) enantiomer, optionally in the form of the pharmacologically acceptable acid addition salts and optionally in the form of the hydrates and solvates or their physiologically acceptable salts in combination with one or more active ingredients selected from the group of Dopamine-Dr, D 2 -, D 3 - or D 4 - agonists, anorectics, lipase inhibitors and sympathomimetics for the manufacture of a medicament for the treatment of children.
  • Pramipexole has a high selectivity for the dopamine D 3 receptor. It can be shown that this reduces the side effects of pharmacologically influencing food intake.
  • the D 3 receptor is predominantly located in regions of the brain that are associated with emotion.
  • One . Activation of the D 3 receptor by pramipexole can occur via mood enhancement can help reduce excessive food intake or pathologically impaired food intake.
  • the pramipexole used in the context of the present invention can optionally be used in the form of its enantiomers or its racemates, optionally in the form of the pharmacologically acceptable acid addition salts and optionally in the form of the hydrates and solvates.
  • pramipexole includes the (+) enantiomer and the racemate. In the context of the present invention, however, the (-) enantiomer is of particular importance.
  • the pramipexole which can be used according to the invention can optionally be used in the form of its pharmaceutically acceptable acid addition salts and, if appropriate, in the form of its hydrates and / or solvates.
  • pharmaceutically acceptable acid addition salts of pramipexole are understood to be those salts which are selected from the salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, acetic acid, fumaric acid, succinic acid, lactic acid, citric acid, holy acid and maleic acid, the salts of hydrochloric acid, Hydrobromic acid, sulfuric acid, phosphoric acid, and acetic acid are particularly preferred.
  • the salts of hydrochloric acid are of particular importance here.
  • pramipexole dihydrochloride is of particular importance.
  • the base of the pramipexole is preferably used.
  • the pramipexole dihydrochloride monohydrate is particularly preferred:
  • pramipexole can optionally be used in combination with other active ingredients.
  • Preferred combination partners are compounds selected from the classes of dopamine Di, D 2, D 3 or D 4 - receptor agonist selected from the group consisting of Adrogolide, A- 86929, Rotigotine, NeurVex, Nolomirole, talipexol, CHF 1512 ( -) - Stepholidine, DAR-201, Diacrin / Genzyme, Bromocriptine, Bupropion, LEK-8829, BAM- ⁇ 110, AIT-203, NS-2330, Terguride, Aripiprazole, OPC-4392, GMC-1111, PD-148903, Apomorphine HCI, PD-89211, PD-158771, Cabergoline, Sumanirole, PNU- 14277E, POL-255, Dihydrexidine, GBR-12783, Quinagolide HCI, (R) -Bupropion, S-32504, S-3
  • Figure 1 describes the results of a 4-day long application of pramipexole (PPX) compared to the single application on 4 consecutive days.
  • PPX pramipexole
  • Figure 2 describes the reduction in body weight during 14 days of continuous subcutaneous (sc) infusion of pramipexole and 7 days of follow-up.
  • Pramipexole inhibits food intake in mice when administered continuously.
  • the continuous application by means of osmotic pumps led to a permanent, statistically highly significant inhibition of feed intake (Figure 1). in the
  • mice (strain: C57BL / 6) were deprived of their food for 24 h with free access to drinking water. 15 20 min before the end of the fasting period, pramipexole (2.5 mg / kg body weight SC) was applied.
  • the control group also 10 mice, received physiological saline, the solvent used for pramipexole. After that, the animals were offered feed and the feed consumption was measured over a period of 4 days every 30 minutes. 0
  • mice 10 mice (strain: C57BL / 6) were deprived of their food for 24 h
  • the alzet® Mini-osmotic 5 pump (model 2002) was implanted subcutaneously in the animals 20 min before the end of the fasting period with a release dose of 2.5 mg pramipexole / 24 h s.c.
  • the pumping rate was 0.54 ⁇ U.
  • a group of 10 control animals received the solvent, physiological saline solution, applied at the same pumping rate in an analog test.
  • the continuous release of the substance or solvent was measured for 4 days. Feed intake 0 was measured every two hours for the first ten hours, later daily.
  • the change in weight for the long-term application was measured over a period of 22 days, the pramipexole administration being ended after 14 days 5.
  • the change in weight was measured daily.
  • dosages for the administration of pramipexole are included here Children specified. These can be used in doses of about 0.05 to 3 mg, preferably from about 0.1 to 1.5 mg, per day. These dosages are based on pramipexole in the form of its free base. Based on the preferred salt form of pramipexole dihydrochloride monohydrate, the above-mentioned dosages correspond to about 0.07 to 4.26 mg, preferably 0.14 to 2.13 mg, of pramipexole dihydrochloride monohydrate per day.
  • Week 2 1 tablet containing 0.18 mg pramipexole 3 times a day
  • pramipexole can be administered orally, transdermally, intrathecally, by inhalation, nasally or parenterally, preferably transdermally or parenterally, particularly preferably transdermally.
  • Suitable forms of use are, for example, tablets, preferably slow release tablets, capsules, suppositories, solutions, juices, emulsions, dispersible powders, implants or plasters, preferably plasters, particularly preferably micron plasters.
  • Tablets can, for example, by mixing the active ingredient (s) with known auxiliaries, for example inert diluents such as calcium carbonate, calcium phosphate or milk sugar, 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 Achievement of the depot effect, such as carboxymethyl cellulose, cellulose acetate phthalate, or polyvinyl acetate can be obtained.
  • auxiliaries for example inert diluents such as calcium carbonate, calcium phosphate or milk sugar, 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 Achievement of the depot effect, such as carboxymethyl cellulose, cellulose acetate phthalate, or polyvinyl acetate can be obtained.
  • the tablets can also consist of several layers.
  • Pramipexole dihydrochloride monohydrate 0.3 mg sodium chloride 0.8 mg benzalkonium chloride 0.01 mg agua ad injectionem ad 100 ml

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  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Obesity (AREA)
  • Chemical Kinetics & Catalysis (AREA)
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Abstract

The invention relates to the use of dopamine receptor agonists for producing a pharmaceutical for reducing excessive food intake.

Description

Pramipexol zur Reduzierung übermäßiger Nahrungsaufnahme bei Kindern Pramipexole to reduce excessive food intake in children
Die Erfindung betrifft die Verwendung von Pramipexol zur Herstellung eines Arzneimittels zur Reduzierung übermäßiger Nahrungsaufnahme bei Kindern.The invention relates to the use of pramipexole for the manufacture of a medicament for reducing excessive food intake in children.
Hintergrund der ErfindungBackground of the Invention
Übermäßige Nahrungsaufnahme führt in der Regel zu Übergewichtigkeit oder Adipositas, d.h. eine die Normgrenze überschreitende Erhöhung des Normalgewichts. Übergewichtigkeit stellt in der heutigen Zeit nicht nur ein zu hohes Gesundheitsrisiko, sondern auch ein gesellschaftliches Problem, insbesondere bei Kindern, dar. Übergewichtigkeit ist ein Risikofaktor für eine Reihe von späteren Erkrankungen wie Bluthochdruck, Diabetes mellitus, Hyperlipidämie, Arthrose, Gicht und die damit verbundenen Gefäßerkrankungen, vor allem Arteriosklerose. Weiterhin kann, induziert durch eine Übergewichtigkeit schon bei Kindern eine seelische Mißstimmung bis hin zur Depression auftreten.Excessive food intake usually leads to obesity or obesity, i.e. an increase in normal weight that exceeds the normal limit. In today's world, obesity is not only a health risk that is too high, but also a social problem, especially in children. Obesity is a risk factor for a number of later diseases such as high blood pressure, diabetes mellitus, hyperlipidemia, arthrosis, gout and the associated problems Vascular diseases, especially arteriosclerosis. Furthermore, induced by an obesity, even in children, a mental disaffection can lead to depression.
Die Feststellung von Übergewicht und Adipositas kann bei Kindern anhand geschlechtsspezifischer Altersperzentilen für den BMI (body mass index) erfolgen (Leitlinien der DGfKJ, Urban und Fischer, Januar 2002). Die einzige wirksame therapeutische Maßnahme ist die Reduzierung der Kalorienzufuhr. Diese ist bei vielen jungen Patienten trotz Kennfciis der oben aufgeführten Konseguenzen nur schwer zu erreichen.The determination of overweight and obesity in children can be made on the basis of gender-specific age percentiles for the BMI (body mass index) (guidelines of the DGfKJ, Urban and Fischer, January 2002). The only effective therapeutic measure is to reduce calorie intake. This is difficult to achieve in many young patients despite the characteristics of the consensus listed above.
Gegenstand der Erfindung ist es, dem jungen Patienten im Alter von etwa 6 bis 18 Jahren die Reduzierung der Kalorienaufnahme zu erleichtern und somit die mit einer Fettleibigkeit verbundenen Gesundheitsrisiken zu reduzieren.The object of the invention is to make it easier for the young patient between the ages of 6 and 18 to reduce the calorie intake and thus to reduce the health risks associated with obesity.
Beschreibung der ErfindungDescription of the invention
Es kann nun überraschenderweise gezeigt werden, daß Pramipexol zur Reduzierung übermäßiger Nahrungsaufnahme bei Kindern in therapeutisch gut verträglichen wirksamen Dosen sinnvoll zum Einsatz gelangen kann.Surprisingly, it can now be shown that pramipexole can be used in therapeutically well tolerated effective doses to reduce excessive food intake in children.
Dementsprechend zielt die vorliegende Erfindung auf die Verwendung von Pramipexol zur Herstellung eines Arzneimittels zur Reduzierung übermäßiger Nahrungsaufnahme bei Kindern.Accordingly, the present invention aims to use pramipexole for the manufacture of a medicament for reducing excessive food intake in children.
Bevorzugt ist die Verwendung von Pramipexol zur Herstellung eines Arzneimittels zur Reduzierung übermäßiger Nahrungsaufnahme bei Kindern im Alter von 6 bis 18 Jahren, vorzugsweise im Alter von 12 bis 18 Jahren. Weiterhin bevorzugt ist die Verwendung bei Kindern, deren BMI oberhalb des 90. Perzentils, vorzugsweise oberhalb des 97. Perzentils liegt.Preference is given to using pramipexole for the manufacture of a medicament for reducing excessive food intake in children aged 6 to 18 years, preferably aged 12 to 18 years. Also preferred is use in children whose BMI is above the 90th percentile, preferably above the 97th percentile.
Besonders bevorzugt ist die Verwendung, wobei den Kindern eine Tagesdosis von etwa 0,005 mg/kg bis 0,02 mg/kg Körpergewicht, vorzugsweise von etwa 0,1 mg/kg Körpergewicht, Pramipexol verabreicht wird.The use is particularly preferred, with the children being given a daily dose of approximately 0.005 mg / kg to 0.02 mg / kg body weight, preferably approximately 0.1 mg / kg body weight, of pramipexole.
Weiterhin besonders bevorzugt ist die Verwendung von Pramipexol zur Herstellung eines Arzneimittels zur Behandlung von Obesitas in Typ 2-Diabetes bei Kindern.Also particularly preferred is the use of pramipexole for the manufacture of a medicament for the treatment of obesity in type 2 diabetes in children.
Insbesondere bevorzugt ist die Verwendung von Pramipexol zur Herstellung eines Arzneimittels für die kontinuierliche Applikation bei Kindern.The use of pramipexole for the manufacture of a medicament for continuous application in children is particularly preferred.
Weiterhin insbesondere bevorzugt ist die Verwendung von Pramipexol zur Herstellung eines Arzneimittels für die transdermale Applikation bei Kindern.Also particularly preferred is the use of pramipexole for the manufacture of a medicament for transdermal application in children.
Ebenfalls bevorzugt ist die Verwendung, wobei Pramipexol gegebenenfalls in Form seiner Enantiomere, vorzugsweise des (-)-Enantiomeren, gegebenenfalls in Form der pharmakologisch verträglichen Säureadditionssalze sowie gegebenenfalls in Form der Hydrate und Solvate eingesetzt wird.Also preferred is the use, where pramipexole is optionally used in the form of its enantiomers, preferably the (-) enantiomer, optionally in the form of the pharmacologically acceptable acid addition salts and optionally in the form of the hydrates and solvates.
Von besonderer Bedeutung ist die Verwendung einer pharmazeutischen Zusammensetzung, enthaltend als Wirkstoff Pramipexol gegebenenfalls in Form seiner Enantiomere, vorzugsweise des (-)-Enantiomer, gegebenenfalls in Form der pharmakologisch verträglichen Säureadditionssalze sowie gegebenenfalls in Form der Hydrate und Solvate oder deren physiologisch verträgliche Salze in Kombination mit einem oder mehreren Wirkstoffen ausgewählt aus der Gruppe der Dopamin-Dr, D2-, D3- oder D4- Agonisten, Anorektika, Lipasehemmer und Sympathomimetika zur Herstellung eines Arzneimittels zur Behandlung von Kindern.Of particular importance is the use of a pharmaceutical composition containing pramipexole as the active ingredient, optionally in the form of its enantiomers, preferably the (-) enantiomer, optionally in the form of the pharmacologically acceptable acid addition salts and optionally in the form of the hydrates and solvates or their physiologically acceptable salts in combination with one or more active ingredients selected from the group of Dopamine-Dr, D 2 -, D 3 - or D 4 - agonists, anorectics, lipase inhibitors and sympathomimetics for the manufacture of a medicament for the treatment of children.
Pramipexol weist eine hohe Selektivität zum Dopamin-D3-Rezeptor auf. Es kann gezeigt werden, daß dadurch die Nebenwirkungen einer pharmakologischen Beeinflussung der Nahrungsaufnahme reduziert werden. Der D3 Rezeptor ist überwiegend in solchen Regionen des Gehirns lokalisiert, die mit Emotion assoziiert sind. Eine. Aktivierung des D3 Rezeptors durch Pramipexol kann über eine Stimmungsaufhellung zur Reduzierung einer übermäßigen Nahrungsaufnahme oder einer krankhaft gestörten Nahrungsaufnahme beitragen.Pramipexole has a high selectivity for the dopamine D 3 receptor. It can be shown that this reduces the side effects of pharmacologically influencing food intake. The D 3 receptor is predominantly located in regions of the brain that are associated with emotion. One . Activation of the D 3 receptor by pramipexole can occur via mood enhancement can help reduce excessive food intake or pathologically impaired food intake.
Das im Rahmen der vorliegenden Erfindung eingesetzte Pramipexol kann gegebenenfalls in Form seiner Enantiomere oder seiner Racemate, gegebenenfalls in Form der pharmakologisch verträglichen Säureadditionssalze sowie gegebenenfalls in Form der Hydrate und Solvate zur Anwendung gelangen.The pramipexole used in the context of the present invention can optionally be used in the form of its enantiomers or its racemates, optionally in the form of the pharmacologically acceptable acid addition salts and optionally in the form of the hydrates and solvates.
Die Bezugnahme auf Pramipexol schließt das (+)-Enantiomer sowie das Racemat mit ein. Im Rahmen der vorliegenden Erfindung kommt allerdings dem (-)- Enantiomer eine besondere Bedeutung zu.Reference to pramipexole includes the (+) enantiomer and the racemate. In the context of the present invention, however, the (-) enantiomer is of particular importance.
Die erfindungsgemäß einsetzbaren Pramipexol kann gegebenenfalls in Form seiner pharmazeutisch verträglichen Säureadditionssalze sowie gegebenenfalls in Form seiner Hydrate und/oder Solvate verwendet werden. Unter pharmazeutisch verträglichen Säureadditionssalzen des Pramipexols werden erfindungsgemäß solche Salze verstanden, die ausgewählt sind aus den Salzen der Salzsäure, Bromwasserstoff säure, Schwefelsäure, Phosphorsäure, Methansulfonsäure, Essigsäure, Fumarsäure, Bernsteinsäure, Milchsäure, Zitronensäure, Weihsäure und Maleinsäure, wobei die Salze der Salzsäure, Bromwasserstoffsäure, Schwefelsäure, Phosphorsäure, und Essigsäure besonders bevorzugt sind. Eine besondere Bedeutung kommt hierbei den Salzen der Salzsäure zu.The pramipexole which can be used according to the invention can optionally be used in the form of its pharmaceutically acceptable acid addition salts and, if appropriate, in the form of its hydrates and / or solvates. According to the invention, pharmaceutically acceptable acid addition salts of pramipexole are understood to be those salts which are selected from the salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, acetic acid, fumaric acid, succinic acid, lactic acid, citric acid, holy acid and maleic acid, the salts of hydrochloric acid, Hydrobromic acid, sulfuric acid, phosphoric acid, and acetic acid are particularly preferred. The salts of hydrochloric acid are of particular importance here.
Diesbezüglich kommt dem Pramipexoldihydrochlorid eine besondere Bedeutung zu. Im Falle einer transdermalen Applikation wird die Base des Pramipexols bevorzugt eingesetzt. Von den Hydraten des Pramipexols ist das Pramipexoldihydrochlorid-monohydrat besonders bevorzugt:In this regard, pramipexole dihydrochloride is of particular importance. In the case of transdermal application, the base of the pramipexole is preferably used. Of the hydrates of the pramipexole, the pramipexole dihydrochloride monohydrate is particularly preferred:
Erfindungsgemäß kann Pramipexol gegebenenfalls in Kombination mit weiteren Wirkstoffen zur Anwendung gelangen. • Bevorzugte Kombinationspartner sind Verbindungen ausgewählt aus den Klassen der Dopamin-Di, D2, D3, oder D4- Rezeptoragonisten, ausgewählt aus der Gruppe bestehend aus Adrogolide, A- 86929, Rotigotine, NeurVex, Nolomirole, Talipexol, CHF 1512, (-)-Stepholidine, DAR-201 , Diacrin/Genzyme, Bromocriptine, Bupropion, LEK-8829, BAM-Ϊ 110, AIT-203, NS-2330, Terguride, Aripiprazole, OPC-4392, GMC-1111, PD-148903, Apomorphine HCI, PD-89211 , PD-158771 , Cabergoline, Sumanirole, PNU- 14277E, POL-255, Dihydrexidine, GBR-12783, Quinagolide HCI, (R)-Bupropion, S-32504, S-33592, SKF-80723, SKF-83959, Fenoldopam, Ropinirole, SKF-82958, SKF-77434, DU 127090, SLV-308, SLV 318, NeuroCRIB, SP-1037C, Spheramine, Gallotrank, Preclamol, DAB-452, YM-435, BP-897, ProSavin, Etilevodopa, P63, A 68930, A 77636, Alaptide, Alentemol, Cl 1007; PD 143188, BLSI, JA 116a; JA 116, Melevodopa; Levodopa methyl; CHF 1301 ; NSC 295453; Levomet, MR 708, PD 128483, RD 21 1 , SKF 38393, SKF 81297, U 86170F, U 91356A, WAY 124486 und Z 15040, der Antidepressiva, der Anorektika, vorzugsweise Silbutramin, der Lipasehemmer, vorzugsweise Orlistat, und der Sympathomimetika, vorzugsweise Ephedrin. Über synergistische Effekte bei der beabsichtigten Wirkung können im Falle des Einsatzes von Kombinationen enthaltend neben den erfindungsgemäßen Dopamin-Rezeptoragonisten einen der vorstehend genannten weiteren Wirkstoffe die Dosierung der Einzelkomponenten verringert werden.According to the invention, pramipexole can optionally be used in combination with other active ingredients. • Preferred combination partners are compounds selected from the classes of dopamine Di, D 2, D 3 or D 4 - receptor agonist selected from the group consisting of Adrogolide, A- 86929, Rotigotine, NeurVex, Nolomirole, talipexol, CHF 1512 ( -) - Stepholidine, DAR-201, Diacrin / Genzyme, Bromocriptine, Bupropion, LEK-8829, BAM-Ϊ 110, AIT-203, NS-2330, Terguride, Aripiprazole, OPC-4392, GMC-1111, PD-148903, Apomorphine HCI, PD-89211, PD-158771, Cabergoline, Sumanirole, PNU- 14277E, POL-255, Dihydrexidine, GBR-12783, Quinagolide HCI, (R) -Bupropion, S-32504, S-33592, SKF-80723, SKF-83959, Fenoldopam, Ropinirole, SKF-82958, SKF-77434, DU 127090, SLV-308, SLV 318, NeuroCRIB, SP-1037C, Spheramine, Gallotrank, Preclamol, DAB-452, YM-435, BP-897, ProSavin, Etilevodopa, P63, A 68930, A 77636, Alaptide, alentemol, Cl 1007; PD 143188, BLSI, JA 116a; JA 116, Melevodopa; Levodopa methyl; CHF 1301; NSC 295453; Levomet, MR 708, PD 128483, RD 21 1, SKF 38393, SKF 81297, U 86170F, U 91356A, WAY 124486 and Z 15040, the antidepressants, the anorectics, preferably silbutramine, the lipase inhibitors, preferably orlistat, and the sympathomimetics, preferably ephedrine. The dosage of the individual components can be reduced by using synergistic effects in the intended action when using combinations comprising, in addition to the dopamine receptor agonists according to the invention, one of the further active ingredients mentioned above.
Die erfindungsgemäße Wirkung soll durch nachfolgendes Beispiel von Pramipexol erläutert werden. Es dient lediglich zur Veranschaulichung der Erfindung und ist nicht als limitierend anzusehen.The effect according to the invention is to be illustrated by the following example of pramipexole. It only serves to illustrate the invention and is not to be regarded as limiting.
Effekt von Pramipexol auf die Futteraufnahme bei MäusenEffect of pramipexole on feed intake in mice
Erläuterungen der Abbildungen:Explanations of the pictures:
Figur 1 beschreibt die Ergebnisse einer 4-tägigen Dauerapplikation von Pramipexol (PPX) im Vergleich zur Einmalapplikation an 4 aufeinander folgenden Tagen. In Figur 1 bedeutenFigure 1 describes the results of a 4-day long application of pramipexole (PPX) compared to the single application on 4 consecutive days. In Figure 1 mean
A: Alzet Pumpe NaCI 0,9 % s.c.A: Alzet pump NaCI 0.9% s.c.
B: Alzet Pumpe PPX 2.5mg/24h s.c. C: NaCI 0,9 % s.c.B: Alzet pump PPX 2.5mg / 24h s.c. C: NaCI 0.9% s.c.
Einmalapplikation an 4 aufeinanderfolgenden Tagen D: PPX 2.5 mg/kg s.c.Single application on 4 consecutive days D: PPX 2.5 mg / kg s.c.
Einmalapplikation an 4 aufeinanderfolgenden Tagen.Single application on 4 consecutive days.
Figur 2 beschreibt die Reduzierung des Körpergewichts während 14-tägiger kontinuierlicher subkutaner (s.c.) infusion von Pramipexol und 7-tägiger Nachbeobachtung. Pramipexol hemmt bei Dauerapplikation die Futteraufnahme bei Mäusen. Die Dauerapplikation mittels osmotischer Pumpen führte zu einer dauerhaften, statistisch hochsignifikanten Hemmung der Futteraufnahme (Figur 1). ImFigure 2 describes the reduction in body weight during 14 days of continuous subcutaneous (sc) infusion of pramipexole and 7 days of follow-up. Pramipexole inhibits food intake in mice when administered continuously. The continuous application by means of osmotic pumps led to a permanent, statistically highly significant inhibition of feed intake (Figure 1). in the
5 Gegensatz dazu führte eine an aufeinanderfolgenden Tagen durchgeführte Einmalapplikation mit einer der Dauerapplikation vergleichbaren Dosis zu keiner signifikanten Reduzierung der Futteraufnahme (Figur 1).5 In contrast, a single application carried out on consecutive days with a dose comparable to the long-term application did not lead to a significant reduction in feed intake (FIG. 1).
Des weiteren wurde bei der Dauerapplikation bereits eine dauerhafte Gewichtsreduzierung beobachtet, die - selbst noch nach Beendigung derFurthermore, a permanent weight reduction was observed with the permanent application, which - even after the end of the
10 Pramipexol-Behandlung - statistisch hochsignifikant nachweisbar war (Figur 2).10 Pramipexole treatment - was statistically highly significant (Figure 2).
Versuchsdurchführung Einmalapplikation:Execution of the test, single application:
10 Mäusen (Stamm: C57BL/6) wurde für 24 h das Futter entzogen bei freiem Zugang zu Trinkwasser. 15 20 min vor Ablauf der Fastenperiode wurde Pramipexol (2,5 mg/kg Körpergewicht s.c.) appliziert. Die Kontrollgruppe, ebenfalls 10 Mäuse, erhielt physiologische Kochsalzlösung, das für Pramipexol eingesetzte Lösungsmittel. Danach wurde den Tieren Futter angeboten und der Futterverbrauch über 4 Tage im 30 min Rhythmus gemessen. 010 mice (strain: C57BL / 6) were deprived of their food for 24 h with free access to drinking water. 15 20 min before the end of the fasting period, pramipexole (2.5 mg / kg body weight SC) was applied. The control group, also 10 mice, received physiological saline, the solvent used for pramipexole. After that, the animals were offered feed and the feed consumption was measured over a period of 4 days every 30 minutes. 0
Versuchsdurchführung Dauerapplikation:Execution of the test continuous application:
10 Mäusen (Stamm: C57BL/6) wurde für 24 h das Futter entzogen bei freiem10 mice (strain: C57BL / 6) were deprived of their food for 24 h
Zugang zu Trinkwasser.Access to drinking water.
20 min vor Ablauf der Fastenperiode wurde den Tieren die alzet® Mini-osmotic 5 pump (Modell 2002) subkutan implantiert mit einer Freigabe-Dosis von 2,5 mg Pramipexol/24 h s.c. Die Pumprate betrug 0.54 μU . Eine Gruppe von 10 Kontrolltieren erhielten im Analogversuch das Lösungsmittel, physiologische Kochsalzlösung, mit gleicher Pumprate appliziert. Die kontinuierliche Freigabe der Substanz bzw. des Lösungsmittels wurde 4 Tage gemessen. Die Futteraufnahme 0 wurde über die ersten zehn Stunden im 2 Stunden-Rhythmus, später täglich gemessen.The alzet® Mini-osmotic 5 pump (model 2002) was implanted subcutaneously in the animals 20 min before the end of the fasting period with a release dose of 2.5 mg pramipexole / 24 h s.c. The pumping rate was 0.54 μU. A group of 10 control animals received the solvent, physiological saline solution, applied at the same pumping rate in an analog test. The continuous release of the substance or solvent was measured for 4 days. Feed intake 0 was measured every two hours for the first ten hours, later daily.
Die Messung der Gewichtsveränderung für die Dauerapplikation erfolgte über einen Zeitraum von 22 Tagen, wobei die Pramipexol-Gabe nach 14 Tagen 5 beendet wurde. Die Gewichtsveränderung wurde täglich gemessen.The change in weight for the long-term application was measured over a period of 22 days, the pramipexole administration being ended after 14 days 5. The change in weight was measured daily.
Ohne den Gegenstand der vorliegenden Erfindung darauf zu beschränken seien an dieser Stelle mögliche Dosierungen für die Darreichung von Pramipexol bei Kindern angegeben. Pro Tag kann diese in Dosierungen von etwa 0,05 bis 3 mg, bevorzugt von etwa 0,1 bis 1 ,5 mg Verwendung finden. Diese Dosierungen sind bezogen auf Pramipexol in Form seiner freien Base. Bezogen auf die bevorzugt zum Einsatz gelangende Salzform Pramipexoldihydrochlorid-monohydrat entsprechen die vorstehend genannten Dosierungen etwa 0,07 bis 4,26 mg, bevorzugt 0,14 bis 2,13 mg Pramipexoldihydrochlorid-monohydrat pro Tag.Without restricting the subject matter of the present invention to this, possible dosages for the administration of pramipexole are included here Children specified. These can be used in doses of about 0.05 to 3 mg, preferably from about 0.1 to 1.5 mg, per day. These dosages are based on pramipexole in the form of its free base. Based on the preferred salt form of pramipexole dihydrochloride monohydrate, the above-mentioned dosages correspond to about 0.07 to 4.26 mg, preferably 0.14 to 2.13 mg, of pramipexole dihydrochloride monohydrate per day.
Eine mögliche und nur als beispielhaft erläuternd zu verstehende Vorgehensweise zur Dosierung ist nachfolgend ausgeführt (bezogen auf Pramipexol in Form seiner freien Base): Individuelle Dosistitration in wöchentlichen Abständen je nach Wirkung und Verträglichkeit.A possible procedure for dosing, which is only to be understood as an example, is described below (based on pramipexole in the form of its free base): Individual dose titration at weekly intervals depending on the effect and tolerability.
1. Woche: 3mal täglich 1 Tablette enthaltend 0,088 mg Pramipexol;1st week: 1 tablet containing 0.088 mg pramipexole 3 times a day;
2. Woche: 3mal täglich 1 Tablette enthaltend 0,18 mg PramipexolWeek 2: 1 tablet containing 0.18 mg pramipexole 3 times a day
3. Woche und folgende: 3mal täglich 1/2 Tablette enthaltend 0,7 mg ; Pramipexol.3rd week and following: 1/2 tablet containing 0.7 mg 3 times a day; Pramipexole.
Pramipexol kann im Rahmen der erfindungsgemäßen Anwendung oral, transdermal, intrathecal, inhalativ, nasal oder parenteral, bevorzugt transdermal oder parenteral, insbesondere bevorzugt transdermal, verabreicht werden. Geeignete Anwendungsformen sind beispielsweise Tabletten, vorzugsweise Slow Release Tabletten, Kapseln, Zäpfchen, Lösungen, Säfte, Emulsionen, dispersible Pulver, Implantate oder Pflaster, bevorzugt Pflaster, insbesondere bevorzugt mikronale Pflaster. Bezüglich möglicher Ausführungsformen einer erfindungsgemäß einsetzbaren transdermalen Applikationsform wird an dieser Stelle bezüglich Pramipexol auf die Ausführungsbeispiele gemäß US 5112842 verwiesen, auf die hiermit ausdrücklich Bezug genommen wird. Tabletten können beispielsweise durch Mischen des oder der Wirkstoffe mit bekannten Hilfsstoffen, beispielsweise inerten Verdünnungsmitteln, wie Calciumcarbonat, Calciumphosphat oder Milchzucker, Sprengmitteln, wie Maisstärke oder Alginsäure, Bindemitteln, wie Stärke oder Gelatine, Schmiermitteln, wie Magnesiumstearat oder Talk, und/oder Mitteln zur Erzielung des Depoteffektes, wie Carboxymethylcellulose, Celluloseacetatphthalat, oder Polyvinylacetat erhalten werden. Die Tabletten können auch aus mehreren Schichten bestehen.In the context of the use according to the invention, pramipexole can be administered orally, transdermally, intrathecally, by inhalation, nasally or parenterally, preferably transdermally or parenterally, particularly preferably transdermally. Suitable forms of use are, for example, tablets, preferably slow release tablets, capsules, suppositories, solutions, juices, emulsions, dispersible powders, implants or plasters, preferably plasters, particularly preferably micron plasters. With regard to possible embodiments of a transdermal application form that can be used according to the invention, reference is made at this point with regard to pramipexole to the exemplary embodiments according to US 5112842, to which reference is hereby expressly made. Tablets can, for example, by mixing the active ingredient (s) with known auxiliaries, for example inert diluents such as calcium carbonate, calcium phosphate or milk sugar, 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 Achievement of the depot effect, such as carboxymethyl cellulose, cellulose acetate phthalate, or polyvinyl acetate can be obtained. The tablets can also consist of several layers.
Im Folgenden sind einige Beispiele für erfindungsgemäß einsetzbare pharmazeutische Zubereitungen angegeben. Diese dienen lediglich der beispielhaften Erläuterung, ohne den Gegenstand der Erfindung auf selbige zu beschränken. Tablette 1 :Some examples of pharmaceutical preparations which can be used according to the invention are given below. These serve only as an example, without restricting the subject matter of the invention to the same. Tablet 1:
Bestandteile: mgComponents: mg
Pramipexoldihydrochlorid-monohydrat 1 ,00 Mannitol 121 ,50Pramipexole dihydrochloride monohydrate 1, 00 mannitol 121, 50
Maisstärke 79,85Corn starch 79.85
Hochdisperses Siliciumdioxid, wasserfrei 2,30Highly disperse silicon dioxide, anhydrous 2.30
Polyvidon K25 2,35Polyvidon K25 2.35
Magnesiumstearat 3,00 Gesamt 210,00Magnesium stearate 3.00 total 210.00
Tablette 2:Tablet 2:
Bestandteile: mgComponents: mg
Pramipexol 0,5Pramipexole 0.5
Mannitol 122,0Mannitol 122.0
Maisstärke, getrocknet 61 ,8Corn starch, dried 61, 8
Maisstärke 18,0 Hochdisperses Siliciumdioxid, wasserfrei 2,4Corn starch 18.0 Highly disperse silicon dioxide, anhydrous 2.4
Polyvidon K25 2,3Polyvidon K25 2.3
Magnesiumstearat 3,0Magnesium stearate 3.0
Gesamt 210,0Total 210.0
Tablette 3:Tablet 3:
Bestandteile: mgComponents: mg
Pramipexol 0,25 Mannitol 61 ,00Pramipexole 0.25 mannitol 61.00
Maisstärke 39,90Corn starch 39.90
Hochdisperses Siliciumdioxid, wasserfrei 1 ,20Highly disperse silicon dioxide, anhydrous 1, 20
Polyvidon K25 1 ,15Polyvidon K25 1, 15
Magnesiumstearat 1 ,5 Gesamt 105,00Magnesium stearate 1,5 total 105.00
Tablette 4: Bestandteile: mgTablet 4: Components: mg
Pramipexol 0,125Pramipexole 0.125
Mannitol 49,455 Maisstärke getrocknet 25,010Mannitol 49,455 corn starch dried 25,010
Maisstärke 7,300Corn starch 7,300
Hochdisperses Siliciumdioxid, wasserfrei 0,940Highly disperse silicon dioxide, anhydrous 0.940
Polyvidon K25 0,940Polyvidon K25 0.940
Magnesiumstearat 1,230 Gesamt 85,000Magnesium stearate 1,230 total 85,000
Lösung zur Injektion:Solution for injection:
Pramipexoldihydrochlorid-monohydrat 0,3 mg Natriumchlorid 0,8 mg Benzalkoniumchlorid 0,01 mg Agua ad injectionem ad 100 ml Pramipexole dihydrochloride monohydrate 0.3 mg sodium chloride 0.8 mg benzalkonium chloride 0.01 mg agua ad injectionem ad 100 ml

Claims

Patentansprücheclaims
1) Verwendung von Pramipexol zur Herstellung eines Arzneimittels zur Reduzierung übermäßiger Nahrungsaufnahme bei Kindern.1) Use of pramipexole for the manufacture of a medication to reduce excessive food intake in children.
2) Verwendung nach Anspruch 1 , dadurch gekennzeichnet, das die Kinder ein Alter von 6 bis 18 Jahren haben.2) Use according to claim 1, characterized in that the children have an age of 6 to 18 years.
3) Verwendung nach Anspruch 1 oder 2 , dadurch gekennzeichnet, dass die Kinder einen BMI oberhalb des 90. Perzentils aufweisen.3) Use according to claim 1 or 2, characterized in that the children have a BMI above the 90th percentile.
, 4) Verwendung nach einem der Ansprüche 1 bis 3 , dadurch gekennzeichnet, dass den Kindern eine Tagesdosis von 0,005 bis 0,02 mg Pramipexol je kg Körpergewicht verabreicht wird., 4) Use according to one of claims 1 to 3, characterized in that the children are administered a daily dose of 0.005 to 0.02 mg of pramipexole per kg of body weight.
5) Verwendung nach einem der Ansprüche 1 bis 4 zur Herstellung eines Arzneimittels zur Behandlung von Obesitas in Typ 2-Diabetes.5) Use according to one of claims 1 to 4 for the manufacture of a medicament for the treatment of obesity in type 2 diabetes.
6) Verwendung nach einem der Ansprüche 1 bis 5 zur Herstellung eines Arzneimittels für die kontinuierliche Applikation.6) Use according to one of claims 1 to 5 for the manufacture of a medicament for continuous application.
7) Verwendung nach einem der Ansprüche 1 bis 6 zur Herstellung eines Arzneimittels für die transdermale Applikation.7) Use according to one of claims 1 to 6 for the manufacture of a medicament for transdermal application.
8) Verwendung nach einem der Ansprüche 1 bis 7, dadurch gekennzeichnet, daß Pramipexol gegebenenfalls in Form seines Enantiomere, gegebenenfalls in Form der pharmakologisch verträglichen Säureadditionssalze sowie gegebenenfalls in Form der Hydrate und Solvate eingesetzt wird.8) Use according to one of claims 1 to 7, characterized in that pramipexole is optionally used in the form of its enantiomer, optionally in the form of the pharmacologically acceptable acid addition salts and optionally in the form of the hydrates and solvates.
9) Verwendung einer pharmazeutischen Zusammensetzung, enthaltend als Wirkstoff Pramipexol gegebenenfalls in Form seiner Enantiomere, gegebenenfalls in Form der pharmakologisch verträglichen Säureadditionssalze sowie gegebenenfalls in Form der Hydrate und Solvate oder deren physiologisch verträgliche Salze in Kombination mit einem oder mehreren Wirkstoffen ausgewählt aus der Gruppe der Dopamin-D , D2-, D3- oder D4- Agonisten, Anorektika, Lipasehemmer und Sympathomimetika zur Herstellung eines Arzneimittels zur Behandlung von Kindern. 9) Use of a pharmaceutical composition containing as active ingredient pramipexole, optionally in the form of its enantiomers, optionally in the form of the pharmacologically acceptable acid addition salts and optionally in the form of the hydrates and solvates or their physiologically acceptable salts in combination with one or more active ingredients selected from the group of the dopamine -D, D 2 -, D 3 - or D 4 - agonists, anorectics, lipase inhibitors and sympathomimetics for the manufacture of a medicament for the treatment of children.
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