HK1091131B - Use of rotigotine for the treatment of depression - Google Patents

Description

The WHO estimates that by 2020, depression will be the second leading cause of disability (Murray, Lancet 349 (1997) 1498). The effectiveness of current pharmacological treatments is limited for various reasons, such as delayed onset, side effects or lack of efficacy of the drugs.

The use of antidepressants has been predominantly in the form of aminoprecipitators or monoamine oxidase inhibitors (Goodman & Gilman's, The pharmacological basis of therapeutics, 9th edition). Recently, the use of agents that affect both serotonergic (5HT1) and adrenergic receptors (a2) has been discussed as a promising therapy concept (Westenberg, J. Clin. Psychiatry 60, Supp. 17, 1999, 4; Schatzberg, Human Psychopharmacology 17, 2002, p. 17).

Dual-acting agents are expected to have a faster onset of action and superior efficacy compared to conventional antidepressants, as the high selectivity of the agents and the associated favorable side effect profile allow for rapid adjustment of the patient to the individual maintenance dose (Deakin, Int. Cl. Psychopharmacology 17, Supplement 1, 2002, p. 13).

Recently, the dopamine agonists pramipexole and ropinirole have also been associated with antidepressant activity and have been shown to have this effect in clinical trials (Ostow, M., Am J Psychiatry, 2002 Feb;159(2):320-1). However, the contribution of dopamine agonism and other possible effects of the dopamine agonists studied is unclear, as they also affect other neurotransmitter systems specifically.

Surprisingly, rotigotine, described as a dopamine agonist and used as a transdermal therapy in the treatment of Parkinson' s disease, was found to bind to both α2 and 5HT1A receptors (US 2003/ 0026830 and Metman et al., Clinical Neuropharmacol. 24, 2001, 163).

With this profile, especially in view of its surprising 5HT1A agonist activity, rotigotine [(-) -5,6,7,8-tetrahydro-6-[propyl[2- (thienyl) ethyl]amino]-1-naphthol] is a candidate for use as an antidepressant.

In three different validated animal models, the efficacy of rotigotine as an antidepressant was demonstrated.

Err1:Expecting ',' delimiter: line 1 column 47 (char 46)

Err1:Expecting ',' delimiter: line 1 column 46 (char 45)

In another animal model (example 3) it was investigated whether the antidepressant effects of rotigotine could be distinguished from general motor stimulation, where rotigotine was administered to rats whose olfactory bulbs were removed on both sides. The removal of the olfactory bulbs led to adaptive hyperactivity in the untreated control group. It is known from the literature that chronically administered antidepressants in this model resulted in a reduction in the animals' motor activity, while stimulants further increased motor activity (van Ronziezen et al, Pharmacol. 604, 1977, JP 521; Kelly et al, Pharmacol. 743, 1997, 299).

This clearly showed that rotigotine, when applied subcutaneously, had a surprisingly significant antidepressant effect in all three trials.

Err1:Expecting ',' delimiter: line 1 column 80 (char 79)

Err1:Expecting ',' delimiter: line 1 column 140 (char 139)

Figure 3 shows that rotigotine at low doses in bulbectomised rats (Example 3) significantly reduces motor hyperactivity and thus has a clear antidepressant effect, whereas at higher doses non-specific activation of locomotor activity is dominant and occurs in both bulbectomised and control animals.

These preclinical data suggest that rotigotine, its biologically active metabolites and associated prodrugs and salts may provide new effective medicinal products for the treatment of depression.

Err1:Expecting ',' delimiter: line 1 column 223 (char 222)

Err1:Expecting ',' delimiter: line 1 column 406 (char 405)

Err1:Expecting ',' delimiter: line 1 column 61 (char 60)

Err1:Expecting ',' delimiter: line 1 column 604 (char 603)Diseases or injuries that often occur with altered brain metabolism include brain tumours, Parkinson's disease, migraines, epilepsy, cerebral palsy, atherosclerosis, brain trauma, encephalitis, stroke and dementia, such as Alzheimer's disease;symptomatic depression, often as a result of or as a side effect of a disease that only indirectly affects brain function.This may include a blood vessel disease, hypothyroidism or other hormone disorder, infectious craneitis, cancer or liver disease; and drug-induced depression, such as drug abuse, alcoholism or psychotropic depression. Other These are often overreactions to one or more traumatic experiences, often divided into exhaustion-depression, neurotic depression, and reactive depression due to current conflicts or events. IV. Depression in special situations Other Examples are weekly bedtime depression,Age-related depression, childhood depression, seasonal depression, and puberty depression.

Routintig and its prodrug as claimed in claim 1 and salts are generally suitable for the development of a medicinal product for the treatment of the various forms of depression mentioned above or for the treatment of mood disorders, in particular depressive episodes, recurrent depressive disorders and depressive phases in bipolar mood disorder, as defined in ICD-10.

Err1:Expecting ',' delimiter: line 1 column 281 (char 280)

Endogenous, unipolar depression is thought to be caused by metabolic disorders of brain cells, i.e. a lack of norepinephrine or serotonin and/or a genetic predisposition.

Err1:Expecting ',' delimiter: line 1 column 61 (char 60)

Err1:Expecting ',' delimiter: line 1 column 389 (char 388)

Err1:Expecting ',' delimiter: line 1 column 126 (char 125)

In the treatment of depression resulting from Parkinson' s disease, the present invention leads to the clinically relevant conclusion that the usual comedication of antidepressants and anti-parkinson agents is not necessary when depressed parkinsonian patients are started on rotigotine.

The invention therefore concerns the use of rotigotine, its prodrugs as claimed in claim 1 and salts, to produce a medicinal product for the treatment of depression associated with Parkinson's disease, with the option of not using comedic drugs with other antidepressants.

Another subject matter of the invention is the use of rotigotine, its prodrugs as claimed in claim 1, and salts, either alone or in combination with other antidepressants, for the treatment of organic depressions not associated with Parkinson's disease, such as those associated with tumours of the pituitary gland, migraines, epilepsy, cerebral palsy, atherosclerosis, traumatic brain injury, meningitis, stroke, dementia, Alzheimer's disease or Parkinson's Plus syndrome.

Err1:Expecting ',' delimiter: line 1 column 201 (char 200)

For the purposes of this patent application, the term 'sub-drug' of claim 1 of rotigotine means in particular twistings which are broken down, transformed or metabolised into rotigotine in the human body, particularly in plasma or when penetrating the skin or mucous membrane in therapeutically effective quantities.

These prodrugs are esters, especially alkane esters and especially preferably alkane esters with up to 6 carbon atoms, carbamate, carbonate, ketal, acetal, phosphate, phosphonate, sulphate and sulphonate.

The production of the prodrugs described in claim 1 by reaction of rotigotine with correspondingly reactive precursors such as acid chlorides, acid anhydrides, carbamoyl chlorides, suphonyl chlorides, etc. is known to the medical chemist and can be found in the relevant literature.

Examples of literature include Bundgaard: Design of Prodrugs, Elsevier, Amsterdam, 1985; Higuchi and Stella: Pro-drugs as novel drug delivery systems in the American Chemical Society, Washington DC, 1975; Sloan: Prodrugs - Topical and Ocular Drug Delivery, Ed: M. Dekker, 1992; Roche: Design of biopharmaceutical properties through prodrugs and analogs, Washington, DC, 1977.

The basic suitability of a rotigotine derivative as a prodrug can be determined by incubating the compound under defined conditions with an enzyme mixture, cell preparation, cell homogenizate or enzyme-containing cell fraction and measuring the resulting rotigotine. A suitable enzyme mixture is, for example, contained in the S9 liver preparation of the company Gentest, Woburn, MA, USA. For measuring particularly rapidly fissionable prodrug, the prodrug to be tested can also be incubated in plasma, e.g. plasma from human blood. The optimal hydrolysis rate of the prodrug depends on the target.

Various prodrugs of the racemate of rotigotine (N-0437) are described, for example, in Den Haas et al., Naunyn-Schmiedeberg's Arch Pharmacol 342, 1990, 655 and Den Haas et al., J. Pharm Pharmacol 43, 1991, 11.

In vivo, a prodrug should release enough rotigotine to achieve a therapeutically effective steady-state rotigotine plasma concentration, whereby generally, rotigotine concentrations between 0.05 and 20 ng/ ml, preferably between 0.1 and 10 ng/ ml, and particularly between 0.2 and 5 ng/ ml plasma are considered therapeutically effective.

However, for the specific treatment of depression, lower rotigotine plasma levels may be sufficient, e. g. below 2 ng/ ml, e. g. between 0.05 and 1 ng/ ml plasma or between 0.1 and 0.5 ng/ ml plasma.

Routin is the S- ((-) enantiomer of 5,6,7,8-tetrahydro-6-[propyl[2-(thienyl) ethyl]amino]-1-naphthal. This means that the proportion of the (R) enantiomer in the product is low as per the invention. The (R) enantiomer is preferably present in the antidepressant with a proportion of < 10 mol%, particularly preferably with a proportion of < 2 mol% and most particularly preferably with a proportion of < 1 mol %, in relation to the total amount of routin.

Rotigotine and its prodrugs as claimed 1 may be present in the medicinal product as free bases or as the physiologically acceptable salts, e.g. in the form of hydrochloride.

Err1:Expecting ',' delimiter: line 1 column 43 (char 42)

There are several routes of administration for rotigotine and its prodrug as claimed 1 which the practitioner can select and adapt according to the needs, condition and age of the patient, the required dosage and the desired application interval.

A preferred route of administration of rotigotine is the transdermal route, which may be e. g. ointment, paste, spray, film, fiaster or an ionophoresis device.

Preferably, rotigotine is applied to the patient's skin in a patch form, with the active substance preferably in a matrix of an adhesive polymer, e.g. a self-adhesive polysiloxane (example 1). Examples of suitable transdermal formulations are given in WO 99/49852, WO 02/89777 and WO 02/89778.

However, if an antidepressant is desired in subcutaneous or intramuscular depot form, rotigotine may be suspended and injected, for example, as a salt crystal, e.g. as crystalline hydrochloride, in a hydrophobic, anhydrous medium, as described in WO 02/15903, or as microcapsules, micro-particles or implants based on biodegradable polymers, as described in WO 02/38646.

Other possible forms of administration of rotigotine and its prodrugs as claimed by claim 1 are transmukous forms, e.g. sublingual sprays, nasal or rectal forms or aerosols for pulmonary administration.

Doses of rotigotine above 0.5 mg/ day are particularly preferred, with rotigotine applications that do not require concomitant treatment of motor disorders in Parkinson' s disease, particularly preferring dosages where the antidepressant effect of rotigotine is pronounced but where the nonspecific stimulatory effect of rotigotine is minimal. Such dosages are generally below 10 mg/ day, e. g. below 7.5 or below 4.5, 3, 2 or 1 mg/ day and particularly between 0.5 and 5 mg/ day.

In Parkinson's disease patients, on the other hand, a dose of sometimes more than 5 mg/day may be required for the concomitant treatment of motor disorders.

Depending on the application method chosen, the desired daily dose can be controlled by the formulation design. For example, the daily dose of rotigotine administered transdermally can be adjusted by setting an appropriate flow rate per unit area and/ or by varying the size of the patch.

The invention therefore concerns a dosage form, e.g. a patch or injectable depot formulation, which releases the corresponding amount of rotigotine required for the treatment of depression, e.g. between 0.5 and 10 mg/day or between 0.5 and 5 mg/day as described above.

The specialist will be aware that the dosage interval may vary depending on the amount applied, the type of application and the daily needs of the patient, for example, a transdermal application may be designed to be administered once a day, three days or seven days, while a subcutaneous or intramuscular depot may allow injections, for example, at a one, two or four weekly rate.

Rotigotine and its prodrugs as described in the first indent may be used as monotherapeutic agents for the treatment of depression.

Examples include other antidepressants that directly or indirectly affect serotonin or norepinephrine metabolism. Examples of this are: Selective serotonin reuptake inhibitors such as sertraline, citalopram, paroxetine or fluoxetine-mixed serotonin, norepinephrine reuptake inhibitors such as venlaxafin, milnacipram, mirtazapine and tricyclic antidepressants such as amitryptiline and imipramine Selective norepinephrine reuptake inhibitors such as reboxetine Monoamine oxidase inhibitors such as tranylcypramine or chlorgyl-alpha 2 receptor and/ or serotonin receptor modulators such as mirtazapine or nefazone.

Other examples of antidepressants are adenosine antagonists such as ST 1535, sigma opioid receptor ligands, NK antagonists such as GW 597599, saredudant or aprepitant, melatonin agonists or modulators of the hypothalamic-pituitary-adrenal axis.

Depending on the cause and symptoms of depression, a combination medicinal product may also contain an additional antipsychotic, sedative, anxiolytic or migraine medicinal product or an active substance that has one or more of the following effects: antidepressant, antipsychotic, sedative, anxiolytic or anti-migraine.

The combination of formula I or II and the additional antidepressant, antipsychotic, sedative, anxiolytic or migraine medicinal product may be in the same pharmaceutical formulation, e.g. a combination tablet, or in different units of application, e.g. two separate tablets.

In a combination preparation, sequential administration may be achieved, for example, by a dosage form, e.g. an oral tablet, having two different layers with differing release profiles for the different pharmaceutically active ingredients.

Examples of antipsychotics include promethazine, fluphenazine, perfenazine, levomepromazine, thioridazine, perazine, promazine, chloroprotexin, zuclopenthixol, prothipendyl, flupentixol, zotepin, benperidol, pipamperon, melperon, haloperidol, bromperidol, sulpiride, clozapine, pimozide, risperidone, quetiapine, amisulpride and olanzapine.

Examples of sedatives include diphenhydramine, doxylamine, nitrazene, midazolam, lormetazepam, flunitrazepam, flurazepam, oxazepam, bromazepam, triazolam, brotizolam, temazepam, chloral hydrate, zopiclone, zolpidem, tryptophan, zaleplon, and other sedatives that are used in the treatment of depression.

Examples of anxiolytics include fluoxetine, thioridazine, oxazepam, alprazolam, bromazepam, lorazepam, prazepam, diazepam, clobazam, medazepam, chloride peroxide, dicalcium chlorasepat, nordazepam, meprobamate, buspirone, kavaine and hydroxyzine.

Examples of medicinal products used for migraines include almotriptan, zolmitriptan, acetylsalicylic acid, ergotamine, dihydroergotamine, methysergid, iprazochrome, ibuprofen, sumatriptan, rizatriptan, naratriptan and paracetamol.

Examples of implementations: The test chemical is used to determine the concentration of the active substance in the test chemical.

1.8 g of rotigotine (free base) is dissolved in 2.4 g of ethanol and added to 0.4 g of collidon 90F (dissolved in 1 g of ethanol). This mixture is added to a 74% solution of silicon polymers (8.9 g BioPSA 7-4201 + 8.9 g BIO-PSA 7-4301 [Dow Corning]) in heptane. After adding 2.65 g of petrolether, the mixture is stirred for 1 hour at 700 UpM to obtain a homogeneous dispersion. After lamination on polyester, it is dried at 50 °C. The final plaster weight is 50 g/cm2.

Example 2: Rotigotine deposit suspensions

(a) 1411,2 g of Miglyol 812 were weighed in a Duran bottle. 14,4 g of Imwitor 312 were added to the miglyol and then heated to 80°C for 30 minutes by stirring. The clear solution was cooled to room temperature and filtered. (b) 1188 g of the solution prepared under (a) were transferred to a glass laboratory reactor, 12 g of routin were added and homogenised for 10 minutes with an ultrasound at UpM under 10,000 nitrogen. The suspension was filled in brown glass bottles at running ultrasound (2,000 UpM).

Example of implementation 3:

The bulbectomy study was performed on Sprague-Dawley rats. A control group was a sham group that underwent surgery without the olfactory bulbs being removed. 14 days after surgery, the rats were treated with vehicles, rotigotine depot suspension (every 2 days) or imipramine. On test days, the rats were placed on a test field and left to fend for themselves for 3 minutes.

Claims (6)

1. Medicament comprising rotigotine [(-)-5,6,7,8-tetrahydro-6-[propyl[2-(2-thienyl)ethyl]amino]-1-naphthol] or a prodrug thereof or physiologically acceptable salts thereof for the treatment of depression, wherein prodrugs of rotigotine are esters, carbamates, carbonates, ketals, acetates, phosphates, phosphonates, sulphates or sulphonates.
2. Medicament according to claim 1, wherein the affective disturbance is selected from depressive episodes, recurring depressive disturbances, depressive phases in bipolar affective disturbances, anxiety disturbances, adaptation disturbances and cerebro-organic disorders which go along in each case with depressive symptoms.
3. Medicament comprising rotigotine [(-)-5,6,7,8-tetrahydro-6-[propyl[2-(2-thienyl)ethyl]amino]-1-naphthol] or a prodrug thereof or physiologically acceptable salts thereof for the treatment of depression, wherein prodrugs of rotigotine are esters, carbamates, carbonates, ketals, acetates, phosphates, phosphonates, sulphates or sulphonates and the depression is a Parkinson's disease-associated depression.
4. Medicament according to one of the preceding claims, wherein the medicament is provided for parenteral, transdermal or mucosal administration.
5. Medicament according to one of the preceding claims, wherein the rotigotine is administered in a dose of 0.5 - 50 mg per day.
6. Medicament according to claim 1 or 3, wherein the medicament is a combination preparation for the treatment of depression comprising a further active ingredient from the group of antidepressants, antipsychotics, sedatives, anxiolytics or anti-migraine preparations.