HK1100765B - Use of rotigotine for treating and preventing parkinson's plus syndrome - Google Patents

Description

Parkinson's syndrome plus is a term used to describe a number of idiopathic diseases that are associated with the appearance of Parkinson's-like symptoms but which can be distinguished from Parkinson's disease in terms of diagnosis and clinical/pathophysiology.

The disease complex of Parkinson' s plus syndrome (PPS) is associated with multisystem atrophy (MSA), progressive supranuclear visual paresis (PSP), cortico-basal ganglion degeneration (CBGD) and dementia with Lewy bodies (DLB).

The most common types of systemic atrophy are the sky-carrier syndrome, the olivo-pontocerebellar atrophy (OPCA) and striatonigraine degeneration (SND) (Mark et al, Neurol Cl. 2001, 19(3): 607).

The classification of Pick's disease, hemiparkinsonism and parkinsonism in Alzheimer's and ALS patients and the Westphalian variant of Huntington's disease is not uniform in the literature, but these diseases are to be subsumed under PPS in the present patent application in accordance with the classification of Hobson et al. (Hobson et al., Can J Neurol Sci. 2003 Mar; 30 Suppl 1: S2).

The disorders subsumed under Parkinson's plus syndrome are characterised by the absence or rapid decline of response to L-dopa and dopamine agonists respectively, as well as additional symptoms such as cerebellar or pyramidal signs, early or severe dementia and early-stage speech and swallowing disorders (Mark 2001, supra; Gerlach et al, Die Parkinson's Disease, Springer, Vienna New York, 2003).

A summary of differential diagnostic criteria for some Parkinson's plus syndromes and Parkinson's disease (also known as idiopathic Parkinson's syndrome, IPS) is given in Table 1. Übersicht über die Klassifizierung einiger Krankheitssymptome parkinsonähnlicher Bewegungsstörungen und differentialdiagnostische Charakteristika

Rigor /Akinese	++	+	++/+++	++/+++	++/+++
Zerebellare Zeichen	+	++	-	-	-
Pyramidenbahnzeichen	-	++	++	+	-
Posturale Instabilität	+	+	+	+++	+
Demenz	-	-	+	+	+
Okulomotorische Störungen	+	(+)	+	+++	+
Dysphagie	-	+	++	++	+
Retrocollies	-	-	-	++	-
Sphinkter-Störungen	+	+	-	-	-
Impotenz	+	+	++	+	+

Übersicht über die Klassifizierung einiger Krankheitssymptome parkinsonähnlicher Bewegungsstörungen und differentialdiagnostische Charakteristika

An important differentiator between IPS and PPS is computed tomography. Patients with IPS have a normal dopamine receptor pool in SPECT until late in life, whereas PPS patients have an early loss of pre- and postsynaptic dopaminergic neurons, which is accompanied by a demonstrable reduction in dopamine receptor density. PET analyses show reduced L-DOPA levels and L-DOPA metabolism in IPS patients (Gerlach et al., 2003, supra).

Medication therapy for PPS is difficult due to the frequent absence or poor response to L-dopa and generally consists of symptomatic therapy of certain individual symptoms, e. g. therapy of hypotension.

For example, Wenning et al (Lancet, 2004, 3, 93) report therapeutic effects of bromocriptine in a study involving six patients, whereas a controlled trial with lisurid showed no effectiveness. Since most dopamine agonists are known to have a complex receptor profile, rather than acting on a single dopamine receptor (Newman-Tancredi, J Pharmacol 2002, 303, 805), the reason for bromocriptine's effectiveness may be due to other receptor characteristics or non-substance specific characteristics.

Parkinson's syndrome plus is usually associated with dopaminergic neurodegeneration in the substantia nigra (Mark, 2001, supra). Successful therapy can therefore be expected from the use of effective neuroprotective agents that inhibit the progressive degradation of dopaminergic neurons (Dawson and Dawson VL, Nat Neurosci. 2002 Nov: 5 Suppl:1.058).

Rotigotine [(-) -5,6,7,8-tetrahydro-6-[propyl[2-(2-thienyl) ethyl]amino]-1-naphthole] is known as a dopamine agonist and symptomatic Parkinson's disease therapeutic.

For example, WO 02/089777 describes the transdermal administration of rotigotine to Parkinson' s patients and the associated improvement in the UPDRS (Unified Parkinson' s Disease Rating Scale) scores as well as various other authors (Metman et al, Clin Neuropharmacol. 2001,243) (163; Mucke HA, Rotigotin Schwarz Pharma.

The UPDRS score is an important tool for the diagnosis and treatment of Parkinson's disease (Fahn S, Elton RL, Members of the UPDRS Development Committee (1987) Unified Parkinson's Disease Rating Scale. In: Fahn S, CD Marsden, DB Calne, M Goldstein (eds) Recent Devlopments in Parkinson's Disease. Vol. 11 Macmillan Healthcare Information, Florham Park (NJ), pp. 153-163, 293-304). However, the UPDRS score only records the effect of a drug on the symptoms of Parkinson's disease. It does not allow direct statements about whether a drug affects the underlying dopamine-induced decline of the symptoms.

However, apoptotic processes play an important role in the pathogenesis of Parkinson's disease, especially in the destruction of dopaminergic neurons (Lev et al, Prog Neuropsychopharmacol Biol Psychiatry, 2003;27(2):245; Michel et al, Rev Neurol (Paris, 2002;158 Spec no 1: S24).

The neuroprotective substances that can stop or even reverse dopaminergic cell death are therefore desired (Vila et al, Nat Rev Neurosci. 2003; 4(5): 365). The MTPT model is used as a predictor of the required neuroprotective properties (Dawson, 2002, supra; Eberhardt O, Schulz JB, Toxicol Lett. 2003, 139(2-3):135).

Experimental studies have now shown surprisingly that rotigotine, which has so far been used only for the symptomatic treatment of idiopathic Parkinson' s disease, has neuroprotective properties, surprisingly showing the desired pharmacological profile in both an acute and a sub-acute MTPT model (Table 2, Figures 1 and 2).

For example, rotigtin shows neuroprotective effects in a Parkinson model of the mouse: after acute administration of MPTP, which produced Parkinson' s symptoms in humans as well as in monkeys, the number of neurons degenerating in the acute phase was measured and the functional integrity of the striatum was recorded in the subacute phase by determining the density of the dopamine transporter in the terminal nerve endings. Anzahl akut degenerierender Neurone im MPTP-Maus-Modell dargestellt mit FluoroJade Färbung mit und ohne Behandlung mit einer Einmalgabe von Rotigotin

Gruppe	Anzahl degen. Neurone	Stndrtabw
1: Vehikel-behandelte Kontrolle	2.0	2.4
2: MPTP Intoxikation	73.5	34.0
3: MPTP Intoxikation + Rotigotin 0.3 mg/kg	66.7	30.5
4: MPTP Intoxikation + Rotigotin 1.0 mg/kg	76.8	41.6
5: MPTP Intoxikation + Rotigotin 3.0 mg/kg	34.9	31.9
5: MPTP -Vehikel + Rotigotin 3.0 mg/kg	3.8	4.3

A pilot study also investigated the neuroprotective effects of rotigotine in monkeys.

In the model used, which reflects the progressive course of dopaminergic cell death in primates, monkeys (macaques) were injected with subcutaneous doses of MPTP over several days. The Parkinsonism symptoms developed in the model over a period of about 2 weeks. Once a certain degree of damage was reached, daily injections of rotigotine were made in a formulation that produced a continuous plasma level over 24 h. The injections of MPTP were stopped as soon as the motor activity in the controls was reduced to a certain degree (about 5 days later). The animals' behaviour was assessed daily. Six weeks after the start of the application of MPTP, the injections of additional rotigotine were stopped for two weeks without treatment. It was observed that the motor activity was significantly improved in the following treatment phase.

At the end of rotigotine administration and at the end of the wash-out phase, one group of animals was killed and the basal ganglia were histologically and biochemically examined. The density of nerve endings in the striatum was significantly increased compared to untreated animals. The levels of pre-pro-encephalin, an indicator of intact networking in the basal ganglia indirect pathway, showed a tendency to normalize after treatment and after the wash-out phase.

The results show that the neuroprotective potential of rotigotine can also be demonstrated in a primate model of dopaminergic cell death, suggesting an antiapoptotic neuroprotective effect in humans.

Rotigotine thus provided an active substance that is ideally suited to the development of a drug or prophylactic to treat and/ or prevent dopaminergic neuronal loss in patients with Parkinson' s plus syndrome, as the neuroprotective effect of rotigotine may be complemented by the dopaminergic effect.

Compared to the previous use of rotigotine, which was limited to the purely symptomatic dopaminergic treatment of Parkinson' s disease patients, this opens up a new area of application for the treatment of patients with Parkinson' s plus syndrome, including those who do not respond or do not respond adequately to L-dopa or dopamine agonists without neuroprotective effects.

The invention is therefore intended to be used with rotigotine, its salts and prodrugs as a medicinal product for the prevention and/or treatment of Parkinson's syndrome plus, whereby the term Parkinson's syndrome plus covers the following diseases: multisystem atrophy, progressive supranuclear optic paresis, corticobasal degeneration, dementia with Lewy bodies, Pick's disease, hemiparkinsonism, Parkinsonism in patients with Alzheimer's disease and ALS and the Westphalian variant of Huntington's chorea.

Another subject matter of the invention is a method of treating a patient with Parkinson's plus syndrome by administering a therapeutically sufficient amount of rotigotine, its salts and/or prodrugs, or by administering a medicinal product containing rotigotine or one of its salts and/or prodrugs as claimed 1.

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Roottig has the formula Other

Derivatives of the phenolic hydroxy group are therefore suitable as prodrugs of rotigotine, namely esters, i.e. arylcarbon esters, alkylcarbon esters or cycloalkylcarbon esters, in particular alkylcarbon esters and cycloalkylcarbon esters with up to 6 carbon atoms each; carbonates; carbamates; acetals; ketals; acyl-oxyalkyl ethers; phosphates; phosphates; sulphates; sulphonates; thiocarbonyl esters; oxythiocarbonyl esters; thiocarbamates; ethers and silylethers.

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In the above definitions of prodrugs, R, R1, R2 are independently selected from hydrogen, alkyl, cycloalkyl or aryl, and preferably from group C1-6 alkyl, C3-10 cycloalkyl, and phenyl.

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The production of rotigotine by reaction with corresponding reactive precursors such as acid chlorides, acid anhydrides, carbamyl chlorides, sulfonyl chlorides, etc. is known to the clinical chemist and can be found in the relevant literature.

Various prodrugs of the racemate of rotigotine (N-0437) and their manufacturing instructions and test methods are described, for example, in Den. Haas et al, Naunyn-Schmiedeberg's Arch Pharmacol. 1990, 342.655; Den.

The basic suitability of a rotigotine derivative as a prodrug can be determined by incubating the compound under defined conditions with an enzyme cocktail, cell homogenisate or enzyme-containing cell fraction and demonstrating that rotigotine can be produced in sufficient quantities. For example, a suitable enzyme mixture is contained in S9 liver preparation from the company Gentest, Woburn, Ma, USA (example 5). Alternatively, incubation with fresh blood or plasma or subcutaneous homogenate may be performed to demonstrate liver-independent metabolism of the prodrug to the active trans-component.

The definitive demonstration of suitability and potential efficacy in disease models is by determination of the plasma rotigotine produced from the prodrug: in vivo, a prodrug should release enough rotigotine to achieve a therapeutically effective steady-state concentration of rotigotine in plasma as already known from clinical or preclinical studies.

Rotigotine is the S ((-) enantiomer of 5,6,7,8-tetrahydro-6-[propyl[2-(thienyl) ethyl]amino-1-naphthole. This means that the proportion of the (R) enantiomer in the product is low as per the invention. The (R) enantiomer is preferably < 10%, preferably < 2 mol% and preferably < 1% of the total amount of rotigotine in the product.

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

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There are several routes of administration for rotigotine and its prodrugs, which the practitioner can select and adjust according to the needs, condition and age of the patient, the required dose and the desired application interval.

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

Rotigotine is preferably applied to the patient's skin in a patch form, the active substance being preferably in a matrix of an adhesive polymer, e.g. a self-adhesive polysiloxane. Examples of suitable transdermal formulations are given in WO 99/49852, WO 02/89777, WO 02/89778, WO 04/58247, WO 04/12730, WO 04/12721 or WO 04/50083. Such a dosage form allows for a largely constant plasma level to be maintained and thus a constant dopaminergic stimulation over the entire application range (WO 02/89778; Metman, Clinical Neuropharmacol. 24, 2001, 163).

However, if a subcutaneous or intramuscular depot is desired, rotigotine may be administered, for example, as a salt crystal, e.g. crystalline hydrochloride, suspended in a hydrophobic, anhydrous medium and injected, 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 are transmucosal formulations, e. g. sublingual or nasal sprays, rectal formulations or aerosols for pulmonary administration.

The appropriate doses of rotigotine are between 0.05 and 50 mg/ day, with daily doses between 0.1 and 40 mg and in particular between 0.2 and 20 mg/ day being preferred, and may be administered in a single dose, i. e. treatment may be started at low doses and then increased to the maintenance dose if necessary.

The specialist will be aware that the dosage interval may vary depending on the amount applied, the type of application and the daily requirements 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.

The neuroprotective formulation may contain other active substances in addition to rotigotine that prevent the progression of dopaminergic cell loss.

Examples of these include anti-apoptotic agents (minocyclines, FK-506, cyclosporin A, zVAD) and neurotrophins such as glial cell-derived neurotrophic factor (GDNF).

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The practitioner is aware that in the context of the present invention various dosage forms and application patterns are conceivable.

Examples of implementations: The following is the list of the products covered by the exemption:

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 [DowCorning]) 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 was dried at 50 °C. The final P-weight was 50 g/cm2.

The following is an example of an example of a rotigotine deposit suspension:

(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 Routine HCl were added and homogenised for 10 minutes with an ultrathrax at 10,000 M under nitrogen. The suspension was filled in brown glass bottles at running ultrathrax (2,000 M).

The following is an example of a sub-acute MPTP model:

For intoxication, mice are given 80 mg/kg of the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydro-pyridine (MPTP) (in 20 mg/kg doses given every two hours, group 3-6 in Figures 1 and 2) which causes approximately 50-60% of Substantia nigra neurons to degenerate (maximum degeneration in group 3 in Figures 1 and 2). Rotigotine is given daily at doses of 0.3, 1 or 3 mg/kg for 7 days as a so-called 'slow-release formulation' (see Exemption 2) (groups 4-6 in Group 1 in Figure 2). and A group of MPTP-treated animals (group 3) receive Rotigotine-L-degenerate solution (see Exemption 2) without Rotigotine 1 as the reference and control groups.On day 8, the animals are killed, the brains removed and frozen. Freeze-cutts are incubated with 100 pm [125 μl] PE2 ([125 μl]E) N-iodopropyl-2-enyl) -2-β-carboxymethyl-3β-methylphenyl-norane) in phosphate buffer, pH 7.4, to mark the amount of dopamine transporters still present in the striatum, which is an indication of the amount of functioning neurotransmitters. Routin also improves the neuronal dependence and dose-dependence properties of neurotransmitters.

Example: Acute MPTP model (including apoptosis)

For intoxication, mice are given 80 mg/kg of the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydro-pyridine (MPTP) (in 20 mg/kg doses given every two hours) which causes about 50-60% of the neurons in the substantia nigra to degenerate. About 16 hours before, rotigotine is given in doses of 0.3, 1 or 3 mg/kg in a so-called 'slow-release formulation' (example 2). Diffusion and absorption lattens result in optimal routin availability when MPTP is given. Animals that have received only a liquid solution (see example Routin 2 HCl) are used as controls for 24 hours without any need for rotigotine.The immunohistochemical marking of tyrosine hydroxylase is used to identify dopaminergic neurons. The tyrosine hydroxylase staining does not show any differences between treated and untreated animals; the fluorodegenerative staining shows a large number of degenerating neurons; however, the neurons are not yet completely removed (which explains the lack of difference in tyrosine hydroxylase staining); this suggests that cell death is apoptotic and not yet complete at the time of measurement (the apoptotic cells are not yet fully resolved or phagocytic). The number of degenerating neurons is about 50% lower after routine application, which indicates the neuroprotective property (Table 2).

Example of implementation: In vitro conversion of a prodrug into the active substance

The subcellular fraction is suspended with a buffer to obtain a solution with a defined protein content. After 1 μM of the prodrug to be tested is added, incubation is carried out at 37 °C for 60 min. Then rotigotine is quantified by HPLC/UV or also by HPLC/MS and related to the amount applied. Concentration or time series are examined for more detailed analyses.

Claims (9)

1. Use of rotigotine, its salts and prodrugs for producing a medicament for the prevention and/or treatment of Parkinson's plus syndrome, wherein the prodrugs are selected from the group consisting of alkylcarbonyl esters -C(O)-alkyl; cycloalkylcarbonyl esters -C(O)-cycloalkyl; arylcarbonyl esters -C(O)-aryl; carbonates -C(O)-O-R; carbamates -C(O)-NRR1, -C(O)-NHR1 or -C(O)-NH₂; acetals -CH(OR)R1; ketals -C(OR)R1R2; acyloxyalkyl ethers -CHR-O-C(O)-R1 or -CH₂-O-C(O)-R1; phosphates -P(O₂H)OR; phosphonates -P(O₂H)R sulphates -S(O)₂OR; sulphonates -S(O)₂R; thiocarbonyl esters -C(=S)-R; oxothiocarbonyl esters -C(=S)-O-R; thiocarbamates -C(=S)-NRR1, -C(=S)-NHR1 or -C(=S)-NH₂; and ethers -R of the phenolic hydroxy group of rotigotine, and wherein R, R1 and R2 are selected in each case independently from hydrogen, alkyl, cycloalkyl or aryl.
2. Use according to claim 1, wherein the Parkinson's plus syndrome is selected from the group of multi-system atrophies, progressive supranuclear palsy, corticobasal degeneration and diffuse Lewy body dementia.
3. Use according to one of the preceding claims, wherein the Parkinson's plus syndrome is characterised by the lack of response by L-dopa.
4. Use according to one of the preceding claims, wherein the medicament is designed for parenteral, transdermal or transmucosal administration.
5. Use according to one of the preceding claims, wherein the rotigotine is to be administered in a dose of 0.05 - 50 mg per day.
6. Use according to one of the preceding claims, wherein the prodrug is an alkylcarbonyl ester having up to 6 carbon atoms.
7. Use according to one of the preceding claims, wherein the medicament is designed for transdermal administration.
8. Use according to claim 7, wherein the form of administration is selected from ointment, paste, spray, film, plaster or an iontophoretic device.
9. Use according to claim 7, wherein the form of administration is a plaster.