CA2453485A1

CA2453485A1 - Pramipexole for the treatment of adhd

Info

Publication number: CA2453485A1
Application number: CA002453485A
Authority: CA
Inventors: Juergen Reess; Franco Borsini
Original assignee: Individual
Current assignee: Boehringer Ingelheim Pharma GmbH and Co KG
Priority date: 2001-08-03
Filing date: 2002-07-31
Publication date: 2003-02-20
Also published as: WO2003013520A1; EP1416930A1; UY27408A1; JP2005500368A; DE10137633A1; MXPA04001001A; AR035273A1

Abstract

The invention relates to the use of 2-amino-4,5,6,7-tetrahydro-6-n-propylami no- benzothiazole, the (+) or (-) enantiomers thereof, the pharmacologically acceptable acid addition salts of the same, and hydrates and solvates for producing a pharmaceutical for the prevention and/or treatment of ADHD.</SDO AB>

Description

Case 111245-Prio/ff CA 02453485 2004-O1-12 gpEHRINGER INGEIHEIM PHARMA KG
78770tra.206 Pramipexole for the treatment of ADHD
The invention relates to the use of 2-amino-4,5,6,7-tetrahydro-6-n-propylamino-benzothiazole, the (+) or (-) enantiomer thereof, the pharmacologically acceptable acid addition salts thereof as well as hydrates and solvates for preparing a pharmaceutical composition for the prevention and/or treatment of ADHD.
Background to the invention 2-Amino-6-n-propylamino-4,5,6,7-tetrahydrobenzo-thiazole is a dopamine agonist which is also known in the art by the name pramipexole. Pramipexole and processes for preparing it are known for example from EP-A-186 087 and US 4,886,812. It is known in particular for the treatment of schizophrenia and particularly for the treatment of Parkinson's disease. The prior art further discloses for example that ~5 pramipexofe towers the prolactin serum level (DE 38 43 227).
Description of the invention Surprisingly it has been found that pramipexole can be used in therapeutically effective doses for the prevention and/or treatment of ADHD.
Accordingly, the present invention relates to the use of 2-amino-4,5,6,7-tetrahydro-6-n-propylamino-benzothiazole, optionally in the form of its (+) or (-) enantiomer, optionally in the form of the pharmacologically acceptable acid addition salts as well as hydrates and solvates for preparing a pharmaceutical composition for the prevention and/or treatment of ADHD.
The abbreviation ADHD stands for "attention deficit hyperactivity disorder".
It denotes a disorder which affects both children and adults in the form of an attention deficit.
ADHD also refers to a hyperactivity disorder which is also observed both in children 3o and adults. Depending on which of the above disorders predominates, ADHD
may be observed in different degrees. There is the combined type in which both an attention deficit and a hyperactivity disorder can be observed, the predominantly inattentive type and the predominantly hyperactive-impulsive type.
The combined type is present when at least six out of nine symptoms of the attention disorder and hyperactivity/impulsivity persist for at least six months. If at least six symptoms of attention deficit but fewer than six of hyperactivity/impulsivity have persisted for at least six months it is the predominantly inattentive type.
The predominantly hyperactive-impulsive type is present when at least six symptoms of hyperactivity/impulsivity but fewer than six of attention deficit have persisted for a period of at least six months.
The following criteria of assessment are symptoms of inattentiveness and hyperactivity, which form the basis for classifying the abovementioned types of ADHD (according to DSM IV = diagnostic and statistical manual of psychic disorders, Version IV):
Inattentiveness (a) frequently takes no notice of details or makes errors of haste in schoolwork, at to work or in other activities;
(b) often has difficulty maintaining concentration for lengthy periods during tasks or when playing;
(c) frequently appears not to be listening when spoken to by other people;
(d) often does not fully carry out instructions from other people and cannot complete ~5 schoolwork, other work or duties in the workplace;
(e) frequently has problems organising tasks and activities;
(f) frequently avoids, is disinclined to do or often only undertakes under protest tasks which require sustained mental effort;
(g) frequently loses objects that he/she needs for tasks or activities;
20 (h) is often easily distracted by external stimuli;
(i) is often forgetful during everyday activities;
Hvperactivity (a) frequently fidgets with hands or feet or shifts around on the chair;
(b) often stands up in class or in other situations where people are expected to stay 25 seated ;
(c) frequently runs around or climbs up excessively in situations where this is inappropriate (in young people or adults this may be restricted to a subjective feeling of restlessness);
(d) often has trouble playing quietly or occupying him/herself quietly with leisure so activities;
(e) is often "on the go" or frequently acts as if he/she were "driven";
(f) often talks excessively; impulsiveness;
(g) often bursts out with the answers before the question is finished;
(h) has trouble waiting his/her turn;
35 (i) often interrupts and disturbs other people (e.g. interrupts conversations or breaks into other people's games).

Accordingly the present invention relates to the use of 2-amino-4,5,6,7-tetrahydro-6-n-propylamino-benzothiazole, optionally in the form of the (+) or (-) enantiomer thereof, optionally in the form of the pharmacologically acceptable acid addition salts thereof as well as hydrates and solvates for preparing a pharmaceutical composition for the prevention and/or treatment of attention deficits.
Moreover, the present invention relates to the use of 2-amino-4,5,6,7-tetrahydro-6-n-propylamino-benzothiazole, optionally in the form of the (+) or (-) enantiomer thereof, optionally in the form of the pharmacologically acceptable acid addition salts thereof as well as hydrates and solvates for preparing a pharmaceutical composition for the prevention and/or treatment of hyperactivity disorders.
In another aspect the present invention relates to the use of 2-amino-4,5,6,7-tetrahydra-6-n-propylamino-benzothiazole, optionally in the form of the (+) or (-) r5 enantiomer thereof, optionally in the form of the pharmacologically acceptable acid addition salts thereof as well as hydrates and solvates for preparing a pharmaceutical composition for the prevention andlor treatment of hyperactivity disorders accompanied by attention deficit.
2o For treatment and/or prevention of the medical indications described above, in addition to monotherapy using pramipexole it is also possible, as an alternative, to carry out a combined therapy using pramipexole with one or more, preferably one other pharmaceutically active compound. It may prove effective, for example, to use a combination with active substances selected from among the a-sympathomimetics 25 and antidepressants, preferably tricyclic antidepressants, antidepressants of the SSRI or antidepressants of the MAO type.
In the case of a combined therapy pramipexole may preferably be used to treat the abovementioned conditions with one or more, preferably one of the following 3o substances: methylphenidate, amphetamine, amphetaminil, methamphetamine, pemoline, tomoxetin, desipramine, imipramine, bupropion and modafinil, of which methylphenidate, amphetamine, pemoline, tomoxetin and modafinil are particularly preferred.
35 Pramipexole may be used within the scope of the present invention as a racemate, in the form of its (+) or (-) enantiomer. Moreover, pramipexole may be used in the form of the pharmaceutically acceptable acid addition salts thereof as well as optionally in the form of its hydrates and/or solvates. By pharmaceutically acceptable acid addition salts are meant according to the invention the salts selected from the salts of hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, acetic acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid and malefic acid, of which the salts of hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid and acetic acid are particularly preferred. The salts of hydrochloric acid are particularly important. Most preferably, within the scope of the present invention, therefore, the hydrochlorides of pramipexole are used, pramipexole dihydrochloride being of particular significance. Of the hydrates of pramipexole, pramipexole dihydrochloride monohydrate is particularly preferred.
The dosage of pramipexole naturally depends to a great extent on the clinical picture. For example, without restricting the present invention thereto, pramipexole may be used in doses of about 0.05 to 7.5 mg, preferably 0.1 to 5 mg per day.
These doses are based on pramipexole in the form of its free base. Based on the salt form pramipexole dihydrochloride monohydrate which is preferably used, the doses ~5 mentioned above correspond to about 0.07 to 10.65 mg, preferably 0.14 to 7.1 mg of pramipexole dihydrochloride monohydrate per day.
One possible dosing method, which is to be understood as being merely an illustrative example, is described below, based on pramipexole in the form of its free 20 base: individual dosage titration at weekly intervals depending on activity and acceptability.
1 st week: 1 tablet containing 0.088 mg of pramipexole 3 times a day;
2nd week: 1 tablet containing 0.18 mg of pramipexole 3 times a day;
3rd week and thereafter: 1/2 tablet containing 0.7 mg of pramipexole 3 times a day.
Within the scope of the use according to the invention pramipexole may be administered orally, transdermally, intrathecally, by inhalation or parenterally.
Suitable preparations include for example tablets, capsules, suppositories, solutions, syrups, emulsions, dispersible powders or patches. Regarding possible so embodiments of a transdermal preparation which may be used according to the invention we now refer to the embodiments described by way of example in US
5112842, to which reference is hereby expressly made. Suitable tablets may be produced for example by mixing the active substance or substances with known excipients, for example inert diluents, such as calcium carbonate, calcium phosphate or lactose, disintegrants such as corn starch or alginic acid, binders such as starch or gelatine, lubricants such as magnesium stearate or talc, and/or agents for achieving delayed release such as carboxymethyfcellulose, cellulose acetate phthalate, or polyvinyl acetate. The tablets may also consist of several layers.

The following are some examples of pharmaceutical preparations which may be used according to the invention. These are intended solely as an illustration without restricting the subject matter of the invention thereto.

5 Tablet 1:
Ingredients: mg pramipexole dihydrochloride monohydrate 1.00 mannitol 121.50 maize starch 79.85 highly dispersed silicon dioxide, 2.30 anhydrous Polyvidone K25 2.35 magnesium stearate 3.00 Total 210.00 Tablet 2:
Ingredients: mg pramipexole 0.5 2o mannitol 122.0 maize starch. dried 61.8 maize starch 18.0 highly dispersed silicon dioxide, 2.4 anhydrous Polyvidone K25 2.3 magnesium stearate 3.0 Total 210.0 Tablet 3:
Ingredients: mg pramipexole 0.25 mannitol 61.00 maize starch 39.90 highly dispersed silicon dioxide,1.20 anhydrous Polyvidone K25 1.15 magnesium stearate 1.5 Total 105.00 Tablet 4:
Ingredients: mg pramipexole 0.125 s mannitol 49.455 maize starch dried 25.010 maize starch 7.300 highly dispersed silicon dioxide, 0.940 anhydrous Polyvidone K25 0.940 magnesium stearate 1.230 Total 85.000 Solution for infection:
pramipexole dihydrochloride monohydrate 0.3 mg sodium chloride 0.8 mg benzalkonium chloride 0.01 mg water for injections ad 100 ml

Claims

1) Use of 2-amino-4,5,6,7-tetrahydro-6-n-propylamino-benzothiazole, optionally in the form of the pharmacologically acceptable acid addition salts thereof as well as hydrates and solvates for preparing a pharmaceutical composition for the prevention and/or treatment of ADHD.

2) Use according to claim 1, characterised in that 2-amino-4,5,6,7-tetrahydro-6-n-propylamino-benzothiazole is used in the form of the (+) or (-) enantiomer thereof.

3) Use according to claim 1 or 2, for the prevention and/or treatment of attention deficits.

4) Use according to claim 1 or 2, for the prevention and/or treatment of hyperactivity disorders.

5) Use according to claim 1 or 2, for the prevention and/or treatment of hyperactivity disorders accompanied by attention deficits.

6) Use according to one of claims 1 to 5, characterised in that pramipexole is used in combination with one or more other pharmaceutical substances.

7) Use according to claim 6, characterised in that the active substance is selected from among the .alpha.-sympathomimetics and antidepressants.

8) Use according to claim 6 or 7, characterised in that pramipexole is used with one or more active substances selected from among methylphenidate, amphetamine, amphetaminil, methamphetamine, pemoline, tomoxetin, desipramine, imipramine, bupropion and modafinil.

9) Use according to one of claims 1 to 8, characterised in that pramipexole is used in the form of a pharmaceutically acceptable acid addition salt which is selected from the salts of hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, acetic acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid and maleic acid.

10) Use according to one of claims 1 to 9, characterised in that pramipexole is used in doses of about 0.05 to 7.5 mg, preferably about 0.1 to 5 mg per day.