EP1608367A1

EP1608367A1 - Pramipexole for reducing excessive food intake by children

Info

Publication number: EP1608367A1
Application number: EP04721477A
Authority: EP
Inventors: Joachim Mierau; Jürgen REESS; Marion Wienrich
Original assignee: Boehringer Ingelheim International GmbH; Boehringer Ingelheim Pharma GmbH and Co KG
Current assignee: Boehringer Ingelheim International GmbH; Boehringer Ingelheim Pharma GmbH and Co KG
Priority date: 2003-03-21
Filing date: 2004-03-18
Publication date: 2005-12-28
Also published as: DE10312809A1; CA2519584A1; JP2006520764A; WO2004082680A1

Abstract

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

Description

Pramipexole to reduce excessive food intake in children

The invention relates to the use of pramipexole for the manufacture of a medicament for reducing excessive food intake in children.

Background of the Invention

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.

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.

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.

Description of the invention

Surprisingly, it can now be shown that pramipexole can be used in therapeutically well tolerated effective doses to reduce excessive food intake in children.

Accordingly, the present invention aims to use pramipexole for the manufacture of a medicament for reducing excessive food intake in children.

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.

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.

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.

The use of pramipexole for the manufacture of a medicament for continuous application in children is particularly preferred.

Also particularly preferred is the use of pramipexole for the manufacture of a medicament for transdermal application in children.

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.

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.

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.

Reference to 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. 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.

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:

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.

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.

Effect of pramipexole on feed intake in mice

Explanations of the pictures:

Figure 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 pump NaCI 0.9% s.c.

B: Alzet pump PPX 2.5mg / 24h s.c. C: NaCI 0.9% s.c.

Single application on 4 consecutive days D: PPX 2.5 mg / kg s.c.

Single application on 4 consecutive days.

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

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).

Furthermore, a permanent weight reduction was observed with the permanent application, which - even after the end of the

10 Pramipexole treatment - was statistically highly significant (Figure 2).

Execution of the test, single application:

10 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

Execution of the test continuous application:

10 mice (strain: C57BL / 6) were deprived of their food for 24 h

Access to drinking water.

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.

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.

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.

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.

1st week: 1 tablet containing 0.088 mg pramipexole 3 times a day;

Week 2: 1 tablet containing 0.18 mg pramipexole 3 times a day

3rd week and following: 1/2 tablet containing 0.7 mg 3 times a day; Pramipexole.

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.

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:

Components: mg

Pramipexole dihydrochloride monohydrate 1, 00 mannitol 121, 50

Corn starch 79.85

Highly disperse silicon dioxide, anhydrous 2.30

Polyvidon K25 2.35

Magnesium stearate 3.00 total 210.00

Tablet 2:

Components: mg

Pramipexole 0.5

Mannitol 122.0

Corn starch, dried 61, 8

Corn starch 18.0 Highly disperse silicon dioxide, anhydrous 2.4

Polyvidon K25 2.3

Magnesium stearate 3.0

Total 210.0

Tablet 3:

Components: mg

Pramipexole 0.25 mannitol 61.00

Corn starch 39.90

Highly disperse silicon dioxide, anhydrous 1, 20

Polyvidon K25 1, 15

Magnesium stearate 1,5 total 105.00

Tablet 4: Components: mg

Pramipexole 0.125

Mannitol 49,455 corn starch dried 25,010

Corn starch 7,300

Highly disperse silicon dioxide, anhydrous 0.940

Polyvidon K25 0.940

Magnesium stearate 1,230 total 85,000

Solution for injection:

Pramipexole dihydrochloride monohydrate 0.3 mg sodium chloride 0.8 mg benzalkonium chloride 0.01 mg agua ad injectionem ad 100 ml

Claims

claims

1) Use of pramipexole for the manufacture of a medication to reduce excessive food intake in children.

2) Use according to claim 1, characterized in that the children have an age of 6 to 18 years.

3) Use according to claim 1 or 2, characterized in that the children have a BMI above the 90th percentile.

, 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) 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) Use according to one of claims 1 to 5 for the manufacture of a medicament for continuous application.

7) Use according to one of claims 1 to 6 for the manufacture of a medicament for transdermal application.

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) 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.