WO2010010138A1

WO2010010138A1 - Pharmaceutical composition comprising pramipexole and a calcium channel blocker for the treatment of parkinson's disease

Info

Publication number: WO2010010138A1
Application number: PCT/EP2009/059468
Authority: WO
Inventors: Erich Buerger; Boris Ferger; Frank Rohde
Original assignee: Boehringer Ingelheim International Gmbh
Priority date: 2008-07-24
Filing date: 2009-07-23
Publication date: 2010-01-28

Abstract

The invention relates to a new medication for the treatment of the cardinal symptoms of Parkinson's disease. The medication comprises the administration of pramipexole or a pharmaceutically acceptable salt thereof and a calcium channel blocker or a pharmaceutically acceptable salt thereof. The medication is a combination of pramipexole or a pharmaceutically acceptable salt thereof and said calcium channel blocker or a pharmaceutically acceptable salt thereof which may be used in a fixed-dose combination as well as in a free-dose combination.

Description

PHARMACEUTICAL COMPOSITION COMPRISING PRAMIPEXOLE AND A CALCIUM CHANNEL BLOCKER FOR THE TREATMENT OF PARKINSON' S DISEASE

Field of the Invention

The invention relates to a new medication for the treatment of Parkinson's disease, preferably at least for the treatment of the cardinal symptoms of Parkinson's disease. The medication comprises the administration of pramipexole or a pharmaceutically acceptable salt thereof and a calcium channel blocker or a pharmaceutically acceptable salt thereof. The medication is a combination of pramipexole or a pharmaceutically acceptable salt thereof and said calcium channel blocker or a pharmaceutically acceptable salt thereof. The combination may be in form of a fixed-dose combination as well as in form of a free-dose combination, the latter being preferred. Furthermore, the invention is related to the use of a pharmaceutical composition for the preparation of a medicament for the treatment of Parkinson's disease comprising said medication and a method of treatment of Parkinson's disease comprising said medication.

Background Art

Calcium channel blockers are a known class of drugs and natural substances of which the main action is to decrease the blood pressure and which are therefore used as antihypertensiva. Most calcium channel blockers decrease the force of contraction of the myocardium (muscle of the heart) known as the negative inotropic effect of calcium channel blockers. It is also known a negative chronotropic effect wherein the calcium channel blockers slow down the conduction of electrical activity within the heart, by blocking the calcium channel during the plateau phase of the action potential of the heart, i.e. they cause a lowering of the heart rate. Calcium channel blockers result in a decrease in cardiac contractility and in less contraction of the vascular smooth muscle and therefore an increase in blood vessel diameter, called vasodilation. Calcium channel blockers are also known to ameliorate symptoms of ischemic heart disease such as angina pectoris.

Pramipexole (INN, trade names Mirapex® and Sifrol®) or pharmaceutically acceptable salts thereof, has a known medication primarily indicated for treating Parkinson's disease and restless legs syndrome (RLS). It is also sometimes used off-label as a treatment for cluster headache. Pramipexole is a known dopamine D2 receptor agonist. It is pharmacologically unique in that it is a full agonist and has receptor selectivity for the dopamine D2 family of dopamine receptors. Pramipexole is chemically designated as (S)-2-amino-4,5,6,7-tetrahydro- 6-(propylamino)benzothiazole and has the molecular formula C10H17N3S and a relative molecular mass of 211.33. The chemical formula (formula 1) is as follows:

formula 1

The salt form commonly used is pramipexole dihydrochloride monohydrate (molecular formula C10H21CI2N3OS; relative molecular mass 302.27). Pramipexole dihydrochloride monohydrate is a white to off-white, tasteless, crystalline powder. Melting occurs in the range of 296°C to 301⁰C, with decomposition. The substance is more than 20% soluble in water, about 8% in methanol, about 0.5% in ethanol, and practically insoluble in dichloromethane.

Pramipexole is a chiral compound with one chiral centre. The pure (S)- or (-)-enantiomer is the pharmaceutically active substance of particular interest.

The main indication of pramipexole as mentioned above is the treatment of Parkinson's disease. Parkinson's disease (hereinafter also abbreviated as "PD") is a degenerative disorder of the central nervous system that often impairs the sufferer's motor skills and speech. Parkinson disease affects movement (motor symptoms). Typical other symptoms include disorders of mood, behavior, thinking, and sensation (non-motor symptoms). Patients' individual symptoms may be quite dissimilar and progression of the disease is also distinctly individual. The symptoms of Parkinson's disease result from the loss of pigmented dopamine- secreting (dopaminergic) cells in the pars compacta region of the substantia nigra (literally "black substance"). The lack of dopamine results in increased inhibition of the ventral anterior nucleus of the thalamus, which sends excitatory projections to the motor cortex, thus leading to hypokinesia. Parkinson's disease is a chronic disorder that requires broad-based management including patient and family education, support group services, general wellness maintenance, physiotherapy, exercise, and nutrition. At present, there is no cure for PD, but medications or surgery can provide relief from the symptoms. WO 2006/091544 discloses a composition comprising a calcium channel Ca_v1.3 blocker, particularly selected from the dihydropyridine calcium channel blockers nifedipine, nimodipine and isradipine and an additional therapeutic agent useful in treating dopaminergic disorders. Among the list of examples of the latter is also mentioned pramipexole.

One objective of the present invention is to provide an improved, more flexible adjustable pharmaceutical composition for the treatment of Parkinson's disease, which may be tailor- made for each individual patient in need thereof.

Summary of the Invention

The present invention is directed to a medication and / or pharmaceutical composition for the treatment of Parkinson's disease in a patient in need of such treatment, whereby the medication and / or pharmaceutical composition comprises as a first active ingredient pramipexole or a pharmaceutically acceptable salt thereof and as a second active ingredient a calcium channel blocker, preferably a selective calcium channel blocker (inclusively the pharmaceutically acceptable salt thereof). Such medication includes simultaneous, separate or sequential administration of the two active ingredients. Subject of the present invention is also the use of pramipexole or a pharmaceutically acceptable salt thereof in combination with a calcium channel blocker or a pharmaceutically acceptable salt thereof for the manufacture of a pharmaceutical composition for the treatment of Parkinson's disease. The use may be either a free-dose combination or a fixed-dose combination, whereby a free-dose combination is particularly preferred.

Description of the Invention

The present invention is based on the concept of a combined application of pramipexole and a calcium channel blocker in order to treat Parkinson's disease. In fact, dopamine depletion is one of the hallmarks of Parkinson's disease due to the loss of dopaminergic neurons which innervate the striatum. Dopamine depletion alters also striatopallidal neurons and leads to a reduction of dendritic spines and glutamatergic synapses. The reduction of spines and synapses on striatal projection neurons is triggered by the dysregulation of calcium channels which leads to uncontrolled movements and an impairment of motor function. Therefore, a combination of the dopamine receptor agonist pramipexole and said calcium channel blockers will prevent the loss of spines and compensate for the dopamine loss which will improve uncontrolled movements and reverse the motor deficits. Pramipexole has been developed for symptomatic treatment of Parkinson's disease and the restless legs syndrome and a complete dataset of pharmacokinetic and pharmacodynamic data are available. Thus, the inventors established the present invention to use the dopamine receptor agonist pramipexole in combination with a calcium channel blocker for the treatment of at least the cardinal symptoms of Parkinson's disease.

The expression "Parkinson's disease" comprises any type of Parkinson's disease as well as Parkinson-like disorders such as juvenile Parkinsonism and Ramsey-Hunt paralysis syndrome and related disorders and afflictions.

The effective amount or dose of the selective calcium channel blocker for treating Parkinsons' s disease is advantageously in the range from about 1 mg/day to about 50 mg/day. The preferred adult dose is in the range from about 2 to about 30 mg/day, and a more highly preferred adult dose is from about 5 to about 20 mg/day. The optimum dose for each patient, as always, must be set by the physician in charge of the case, taking into account the chosen calcium channel blocker, the patient's size, other medications which the patient requires, severity and course of the Parkinson's disease and all of the other circumstances of the patient.

In the context of the present invention the term "therapeutically effective amount" or "effective amount" means that the amount of the corresponding active ingredient that is administered to a patient will be sufficient to provide its therapeutic effect in the brain and thus to support alleviation or elimination of the symptoms of the Parkinson's disease in a patient. It will be acknowledged that the total of the administered amount of the corresponding active ingredient will be sufficiently safe for the patient from a regulatory perspective.

As mentioned before, the inventions comprises a second active ingredient, namely a calcium channel blocker. Preferably the same is a selective calcium channel blocker. A "selective calcium channel blocker" according to the invention is a compound the most significant pharmacological effect it develops in the human body is blocking a calcium channel. Even if such a compound may interact with other targets, the calcium channel blocking effect has the most significant pharmacological impact.

Preferred calcium channel blockers are selected from the calcium channel families Ca_vl.l, Ca_v1.2, Ca_v1.4, Ca_v2.1, Ca_v2.2, Ca_v2.3, Ca_v3.1, Ca_v3.2, Ca_v3.3 (all calcium channel family members except Ca_v1.3).

For a comprehensive summary of the functions of these family members it6 is referred to: Parmaco logical Reviews, Vol. 57 84) (2005) 411.

Preferred calcium channel blockers are selected from dihydropyridines, phenylalkylamines, benzothiazepines, whereby among these compounds representatives of the aforementioned preferred family groups are preferred.

Dihydropyridine calcium channel blockers are known and often used to reduce systemic vascular resistance and arterial pressure. This class of calcium channel blockers (hereinafter also abbreviated as "CCB") is easily identified by the suffix "-dipine".

The group of phenylalkylamine calcium channel blockers is known for being relatively selective for myocardium, reduce myocardial oxygen demand and reverse coronary vasospasm, and are often used to treat angina. They have minimal vasodilatory effects compared with dihydropyridines.

Benzothiazepine calcium channel blockers are an intermediate class between phenylalkylamines and dihydropyridines in their selectivity for vascular calcium channels. By having both cardiac depressant and vasodilator actions, benzothiazepines are able to reduce arterial pressure without producing the same degree of reflex cardiac stimulation caused by dihydropyridines .

Exemplary dihydropyridine calcium channel blockers preferably used according to the concept of the present invention comprise, but are not limited to amlodipine, benidipine, felodipine, isradipine, madipine, nicardipine, nifedipine, nilvadipine, nimodipine, nisoldipine, nitrendipine, lacidipine and lercandipine. Preferred are amlodipine, benidipine, felodipine, madipine, nicardipine, nilvadipine, nisoldipine, nitrendipine, lacidipine and lercandipine.

Most preferred of this group are representatives of the Ca_v1.2, Ca_v1.4, Ca_v2.1, Ca_v2.2, Ca_v2.3, Ca_v3.1, Ca_v3.2, Ca_v3.3 families.

Some exemplary representatives of the group of dihydropyridine calcium channel blockers and their indications will be described in detail in the following for illustrative purposes only.

Amlodipine is a long-acting calcium channel blocker marketed as Norvasc in North America and as Istin in the United Kingdom by Pfizer as well as under various other names. The tablets of amlodipine from different suppliers may contain different salts, such as besylate, mesylate or maleate. The strength of the tablets is expressed in terms of amlodipine base, i.e. without the salt. Tablets containing different salts are therefore considered interchangeable. The application is essential hypertension and prophylaxis of angina, particularly treatment of chronic stable and vasospastic angina pectoris.

Benidipine, also known as Benidipinum or benidipine hydrochloride, is a dihydropyridine calcium channel blocker known for the treatment of hypertension. Benidipine is sold as Coniel^® by Kyowa Hakko Kogyo.

Felodipine is a known drug used to control high blood pressure. It is marketed with the brand name Plendil by AstraZeneca.

Nicardipine hydrochloride (Cardene) is a medication used to treat high blood pressure and angina, particularly essential hypertension and prophylaxis and treatment of angina, particularly chronic stable angina pectoris, and Raynaud's syndrome. It is available in oral and intravenous formulations. Its mechanism of action and clinical effects closely resemble those of nifedipine and the other dihydropyridines (amlodipine, felodipine), except that nicardipine is more selective for cerebral and coronary blood vessels. Furthermore, nicardipine does not intrinsically decrease myocardial contractility and may be also useful in the management of congestive heart failure. Nicardipine also has a longer half-life than nifedipine. Nifedipine, a representative of the Ca_v1.3 family, (brand names: Adalat, Nifedical, and

Procardia) is another dyhyropyridine calcium channel blocker. Its main uses are as an antianginal and antihypertensive, although a large number of other uses have been found for this agent recently, such as Raynaud's syndrome, premature labour and painful spasms of the esophagus in cancer and tetanus patients. It is also used to block pre-term contractions in pregnant women.

Nimodipine, a representative of the Ca_v1.3 family, marketed by Bayer as Nimotop is originally developed for the treatment of high blood pressure but the main use is in preventing a major complication of subarachnoid hemorrhage (a form of cerebral hemorrhage) termed vasospasme. It may be administred orally or via intravenous infusion.

Nilvadipine marketed as Nivadil is known for the treatment of essential hypertension.

Nisoldipine also known under the brand name Sular is used for the treatment of essential hypertension and chronic stable angina and angina pectoris.

Nitrendipine (Cardif, Nitrepin), Lacidipine (Motens), Lercandipine (Zanidip) and Isradipine are also known calcium channel blockers, for example, for the treatment of essential hypertension.

Exemplary phenylalkylamine calcium channel blockers preferably used according to the concept of the present invention comprise, but are not limited to verapamil and gallopamil.

Verapamil (brand names: Isoptin, Verelan, Calan, Bosoptin) is a L-type calcium channel blocker which belongs to the class of phenylalkylamines. It has been used in the treatment of hypertension, angina pectoris, cardiac arrythmia, and most recently cluster headaches. Verapamil has also been used as a vasodilator during cryopreservation of blood vessels. Indications are chronic stable angina of effort, angina resulting from coronary artery spasm, obstructive hypertrophic cardiomyopathy, where surgery is not otherwise indicated, atrial fibrillation or flutter with rapid ventricular response not otherwise controllable with digitalis preparations, and follow-up treatment to the use of injectable verapamil in paroxysmal supraventricular tachycardia. Verapamil is also indicated in the treatment of mild to moderate essential hypertension.

Gallopamil (D600) is indicated for the treatment of coronary heart disease (CHD), particularly chronic stable angina pectoris (exercise-induced angina), instable angina pectoris (crescendo angina, rest angina), vasospastic angina (Prinzmetal's or Variant angina), atrial fibrillation/atrial flatter, disorder of the beating of the heart in association with paroxysmal supraventricular tachycardia, and hypertension.

An exemplary dihydropyridine calcium channel blocker preferably used according to the concept of the present invention is Diltiazem (Cardizem). The same is a member of the group of benzothiazepines used in the treatment of hypertension, the treatment of coronary heart disease (CHD), particularly chronic stable angina pectoris (exercise-induced angina), instable angina pectoris (crescendo angina, rest angina), vasospastic angina (Prinzmetal's or Variant angina), angina pectoris, and some types of arrhythmia, especially temporary control of rapid ventricular rate in atrial fibrillation or atrial flutter (excluded for Wolff-Parkinson- White (WPW) syndrome or short PR syndrome) and rapid conversion of paroxysmal supraventricular tachycardias (PSVT) to sinus rhythm. Diltiazem is a potent vasodilator, increasing blood flow and variably decreasing the heart rate via strong depression of A-V node conduction. The application is recommended for patients for whom low single or daily dosage is not sufficient in therapy. Its pharmacolgical activity is somewhat similar to verapamil.

Preferred calcium channel blockers are selected from the group consisting of amlodipine, benidipine, felodipine, nicardipine, nilvadipine, nisoldipine, nitrendipine, lacidipine, lercandipine, verapamil, gallopamil, diltiazem, especially preferred are amlodipine, felodipine, nicardipine, nitrendipine, lercandipine, verapamil, gallopamil, diltiazem.

The calcium channel blocker according to the invention may be easily formulated in the usual pharmaceutical forms, preferably oral pharmaceutical forms such as tablets, capsules, suspensions, and the like. The usual methods of pharmaceutical scientists are applicable. It may usefully be administered, if there is any reason to do so in a particular circumstance, in other pharmaceutical forms, such as, but not limited to, injectable solutions, depot injections, suppositories and the like, which are well known to and understood by pharmaceutical scientists. It will substantially always be preferred, however, to administer the calcium channel blocker as a tablet or capsule and such pharmaceutical forms are recommended.

The currently broadly accepted effective amount or dose of pramipexole, in particular in form of a pharmaceutically acceptable salt such as the dihydrochloride monohydrate, for treating Parkinson's disease is in the range from about 0.1 mg/day to about 10 mg/day. The preferred adult dose is in the range from about 0.2 to about 6 mg/day, and a more highly preferred adult dose is from about 0.4 to about 5 mg/day. The optimum dose for each patient must be set by the physician in charge of the case, taking into account the patient's size, other medications which the patient requires, severity and course of the Parkinson's disease or condition and all of the other circumstances of the patient.

Also pramipexole may be easily formulated in the usual pharmaceutical forms, preferably oral pharmaceutical forms such as tablets, capsules, suspensions, and the like. The usual methods of pharmaceutical scientists are applicable. It may usefully be administered, if there is any reason to do so in a particular circumstance, in other pharmaceutical forms, such as, but not limited to, injectable solutions, depot injections, suppositories and the like, which are well known to and understood by pharmaceutical scientists. It will substantially always be preferred, however, to administer pramipexole as a tablet or capsule and such pharmaceutical forms are recommended.

Both compounds, pramipexole and the CCB, independently of each other may be administered as instant release (i.r.) formulation(s) and/or extended release (e.r.) formulation(s) in a combined preparation. Such a combined preparation includes the simultaneous, separate or sequential (time-staggered) administration of the active substances. The active substances are therefore each individually or together mixed with additives, carriers and/or excipients into a suitable galenic form for administration.

In the treatment of Parkinsons 's disease, it may be recommendable to apply pramipexole in an extended release form, a suitable one of which is disclosed in WO 2006/015942 or WO 2006/015943, each of which is hereby incorporated by reference (for each patent application the disclosure of the whole document). An extended release tablet according to WO 2006/015942 and applicable in the context of the invention is characterised in that the extended release formulation comprises pramipexole or a pharmaceutically acceptable salt thereof in a matrix comprising at least one water swelling polymer, preferably other than pregelatinized starch. The matrix preferably comprises at least two water swelling polymers preferably other than pregelatinized starch, and wherein at least one of the at least two polymers is an anionic polymer.

The anionic polymer preferably is selected from the group of optionally crosslinked acrylic acid polymers, methacrylic acid polymers, alginates and carboxymethylcellulose. The anionic polymer is an optionally crosslinked acrylic acid polymer, wherein the content of the optionally crosslinked acrylic acid polymer in the matrix is from about 0.25 wt.-% to about 25 wt.-%, and preferably from about 0.5 wt.-% to about 15 wt.-%, and preferably from about 1 wt.-% to about 10 wt.-%. Preferably, such acrylic acid polymer is a carbomer.

In case of tablets that comprise at least two polymers, one them is the aforementioned anionic polymer and the other one is a substantially neutral polymer, preferably other than pregelatinized starch. Preferably, the substantially neutral polymer is selected from hydroxypropyl cellulose and hydroxypropylmethyl cellulose. More preferably the substantially neutral polymer is hydroxypropyl methylcellulose, and wherein the content of hydroxypropyl methylcellulose in the matrix is from about 10 wt.-% to about 75 wt.-%, and preferably from about 25 wt.-% to about 65 wt.-%.

In one embodiment the matrix comprises about:

(a) pramipexole or a salt thereof 0.05 to 5 wt.-% (b) anionic water swelling polymer(s) 0.25 to 25 wt.-%

(c) neutral water swelling polymer(s) 10 to 75 wt.-%

(d) further pharmaceutically acceptable excipients ad 100 wt.-%

Further excipients include, but are not limited to magnesium stearate, microcrystaline cellulose, lactose, silicon dioxide, starch, preferably corn starch.

In one embodiment the matrix comprises (a) at least one water swelling polymer other than pregelatinized starch and optionally excipients, the resulting tablet providing a pH-independent in vitro release characteristic in the range from pH 1 to 7.5, or

(b) at least one water swelling anionic polymer and optionally excipients, the resulting tablet providing a pH-dependent release characteristic with a preferably faster release characteristic in the range of pH < 4.5, and a slower and further on pH-independent release characteristic in the range from pH 4.5 to 7.5.

Such an extended release tablet may have a non- functional coating. Preferably, such tablet is for a once daily application.

An extended release pellet formulation according to WO 2006/015943 and applicable in the context of the present invention is characterised in that it comprises an active ingredient selected from pramipexole and the pharmaceutically acceptable salts thereof, and at least one release-modifying excipient. Preferably, the active ingredient is embedded within a matrix formed by the at least one release-modifying excipient, which is preferably selected from the group of lipids, waxes, and water-insoluble polymers. Preferably, it comprises a core and a coating, wherein at least one release-modifying excipient is incorporated in the coating and optionally the active ingredient is incorporated in the core. Such a coating may comprise at least a first layer and a second layer surrounding the first layer, wherein the first layer comprises the active ingredient, and wherein the second layer comprises at least one release- modifying excipient, preferably selected from ethylcellulose, cellulose acetate, polyvinylacetate, polyacrylates, polymethacrylates, and ammonio methacrylate copolymer. The second layer further may comprise at least one water-soluble excipient, preferably selected from hydroxypropylcellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone and polyethylene glycol. The second layer may further comprise an enteric coating polymer, preferably selected from methacrylic acid copolymers type A and B.

In one embodiment, the second layer comprises from about 10 to about 85 wt.-% of the enteric coating polymer and from about 15 to about 75 wt.-% of the water-insoluble polymer. The core may comprise a saccharide, such as saccharose, starch, cellulose and a cellulose derivative, preferably microcrystalline cellulose. In one embodiment, the extended release pellet formulation comprises an inert pellet core; a first layer being an active ingredient layer comprising pramipexole or a pharmaceutically acceptable salt thereof and optionally one or more wet binders and further excipients; and a second layer provided on the first layer, the second layer being an extended release coating comprising

(a) at least one water-insoluble polymer and optionally a pore former, the resulting pellet having a pH-independent in vitro release characteristic or (b) a mixture of a pH-dependent enteric-coating polymer and a pH- independently water swelling polymer, the resulting pellet having a close to zero order in vitro release characteristic at acidic pH values up to pH 6.8, an accelerated release above pH 6.8 and a more accelerated release above pH 7.3.

The inert pellet core may comprise polysaccharides, cellulose, a cellulose derivative, starch and/or waxes. The inert pellet core further may comprise saccharose and/or microcrystalline cellulose, preferably microcrystalline cellulose.

Such an extended release pellet formulation using active pellets containing pramipexole or a pharmaceutically acceptable salt thereof may be prepared by wet or melt extrusion or melt granulation instead of pellets prepared by drug substance layering onto inert pellet cores.

The water- insoluble polymer of the extended release pellets may be selected from the group consisting of ethylcellulose, cellulose acetate, polyvinylacetate, polyacrylates and derivatives, such as quaternary ammonium substituted acrylic polymer, preferably ammonio methacrylate copolymer, type B, and ethylcellulose, most preferably ethylcellulose.

The pH-dependent enteric-coating polymer may be an anionic carboxylic acrylic polymer, preferably a partly methyl esterified methacrylic acid polymer, soluble above a pH value of 5.5, preferably above a pH value of 7.0. The pH-independently water swelling polymer also may be a quaternary ammonium substituted acrylic polymer, preferably having an ammonium substitution of about 5 to about 10 % by weight.

The pH-dependent enteric-coating polymer may be present in an amount of 10 to 85 % by weight of the coating and the pH-independently water swelling polymer is present in an amount of 15 to 75 % by weight of the coating.

The extended release coating may additionally contain a pore-forming component.

The pore-forming component may be selected from the group consisting of hydroxypropylcellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone and polyethylen glycol, preferably selected hydroxypropylcellulose from the Klucel series.

The extended release pellet formulation containing an active ingredient selected from pramipexole and the pharmaceutically acceptable salts thereof may be prepared by wet or melt extrusion or melt granulation using excipients achieving extended release without a further diffusion membrane.

The pellets may be applied in form of a capsule, which comprises a sufficient number of pellets to provide a daily dose administered at one time.

To the extent that any pharmaceutically active compound is disclosed or claimed in the present invention, it is expressly intended that all active metabolites which are produced in vzVo are included, and it is expressly intended that all enantiomers, diastereomers or tautomers are included, if the compound is capable of occurring in its enantiomeric, diastereomeric or tautomeric form. Obviously, the isomer which is pharmacologically most effective and most free from side effects is preferred.

Both compounds, pramipexole and the CCB, can be administered in form of a pharmaceutically acceptable salt. The term "pharmaceutically acceptable salt" means a salt of pramipexole or a salt of a calcium channel blocker which is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, generally water or oil-soluble or dispersible, and effective for the intended use. The term includes pharmaceutically acceptable acid addition salts and pharmaceutically-acceptable base addition salts. Lists of suitable salts are found in, e.g., S. M. Birget al, J. Pharm. Sci., 1977, 66, pp. 1-19, which is hereby incorporated by reference in its entirety.

Examples of pharmaceutically active salts for each of the compounds which are the subject of this description include, without being restricted thereto, salts which are prepared from pharmaceutically acceptable acids or bases, including organic and inorganic acids and bases. The calcium channel blocker and pramipexole both may be used in form of a salt which may be prepared from pharmaceutically acceptable acids. When selecting the most preferred salt, or to clarify whether a salt or the neutral compound is used, properties such as bioavailability, ease of manufacture, workability and shelf life are taken into consideration, inter alia. Suitable pharmaceutically acceptable acids include acetic acid, benzenesulphonic acid (besylate), benzoic acid, p-bromophenylsulphonic acid, camphorsulphonic acid, carbonic acid, citric acid, ethanesulphonic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, hydriodic acid, isethionic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulphonic acid (mesylate), mucinic acid, nitric acid, oxalic acid, pamoic acid, pantothenic acid, phosphoric acid, succinic acid, sulphuric acid, tartaric acid, p-toluenesulphonic acid and the like. Examples of pharmaceutically acceptable salts include, without being restricted thereto, acetate, benzoate, hydroxybutyrate, bisulphate, bisulphite, bromide, butyne-l,4-dioate, caproate, chloride, chlorobenzoate, citrate, dihydrogenphosphate, dinitrobenzoate, fumarate, glycollate, heptanoate, hexyne-l,6-dioate, hydroxybenzoate, iodide, lactate, maleate, malonate, mandelate, metaphosphate, methanesulphonate, methoxybenzoate, methylbenzoate, monohydrogenphosphate, naphthalene- 1-sulphonate, naphthalene-2-sulphonate, oxalate, phenylbutyrate, phenylpro- prionate, phosphate, phthalate, phenylacetate, propanesulphonate, propiolate, propionate, pyrophosphate, pyrosulphate, sebacate, suberate, succinate, sulphate, sulphite, sulphonate, tartrate, xylenesulphonate and the like.

The two active compounds, the calcium channel blocker and pramipexole, may be subject to one single pharmaceutical formulation or they may be applied as discrete separate pharmaceutical formulations. The advantage of the first variant is that the doses are fixed in this pharmaceutical formulation. In such a case the pharmaceutical formulation is called a "fixed-dose combination". The advantage of the second variation is that each compound can be applied in free eligible dosage form. Such a "free-dose combination" allows for to better titrate a patient if the dosage of one of the two components of the combination therapy should be lowered or raised in relation to the other one in order to increase efficacy. In case of free- dose combinations, the two application forms, (pramipexole application form and calcium channel blocker application form), may be applied together, within a short period of time (within 60 minutes, more preferably 30 minutes, more preferably 10 minutes) or within a long period of time (within 24 hours, more preferably 12 hours, more preferably 6 hours and more preferably 1 hour). Preferably the two kinds of drugs are taken within 5 minutes. According to the present invention a free-dose combination is preferably used.

In the case of a fixed dose combination in form of an extended release formulation, the same may be prepared on basis of the aforementioned pramipexole comprising extended release formulations, in particular the ones according to WO 2006/015942 or WO 2006/015943, the characteristics of which have been outlined above, the calcium channel blocker may be added to the same in the appropriate dosage as outlined in this description.

In case of fixed dose combination in form of an immediate release formulation, the same may be prepared on basis of the immediate formulations as outlined in this description for each of the two combination partners.

The two active ingredients also may be applied in form of pharmaceutical compositions that allow different form of releases, e.g. an extended release of pramipexole or its salt form and an immediate release of the calcium channel blocker.

In case of a free-dose combination it is also provided a kit of parts comprising

(a) a first containment containing a pharmaceutical formulation comprising a therapeutically effective amount of pramipexole or a pharmaceutically acceptable salt thereof and (b) a second containment containing a pharmaceutical formulation comprising a therapeutically effective amount of a calcium channel blocker or a pharmaceutically acceptable salt thereof.

Subject of the present invention is also the pharmaceutical composition provided as a kit of parts, one part being a pharmaceutical formulation comprising pramipexole or a pharmaceutically acceptable salt thereof and another part being a leaflet directed to a Parkinson's disease indication, an instruction for the application of the pharmaceutical formulation comprising pramipexole or a pharmaceutically acceptable salt thereof and the advice to take a pharmaceutical formulation comprising a calcium channel blocker or a pharmaceutically acceptable salt thereof timely related to the intake of the formulation comprising pramipexole or a pharmaceutically acceptable salt thereof.

The pharmaceutical composition is also provided as a kit of parts, one part being a pharmaceutical formulation comprising pramipexole or a pharmaceutically acceptable salt thereof, one part being a pharmaceutical formulation comprising a calcium channel blocker or a pharmaceutically acceptable salt thereof and another part being a leaflet directed to a

Parkinson's disease indication, an instruction for the application of the formulation comprising pramipexole or a pharmaceutically acceptable salt thereof and an instruction for the application of the pharmaceutical formulation comprising a calcium channel blocker or a pharmaceutically acceptable salt thereof.

In the following the invention shall be illustrated in form of formulations which may be freely combined. However, the present invention is not limited to the described formulations and active substances, but other dosage forms and active ingredients and additives are possible.

Examples

Formulations concerning pramipexole

a.) immediate release formulations: Tablet comprising 0.125 mg pramipexole-dihydrochloride-monohydrate or 0.25 mg thereof, or 0.5 mg thereof, or 1 mg thereof in combination with mannitol, corn starch, highly dispersed silicon dioxide, povidon, magnesium stearate. This formulation is known in the market as Sifrol^® or Mirapex^® (immediate release formulation).

b.) extended release formulations:

ba. pramipexole extended release tablets ba.l

ba.2

For any of the above mentioned examples the weight relations between the ingredients may vary within the range outlined in the description, in particular the amount of pramipexole, pramipexole dichloride monohydrate respectively, may vary, preferably between 0.01 and 7 mg, more preferably between 0.5 and 5 mg. General scope of the composition:

(a) pramipexole or a salt thereof 0.05 to 5 wt.-%

(b) anionic water swelling polymer(s) 0.25 to 25 wt.-%

(c) neutral water swelling polymer(s) 10 to 75 wt.-%

(d) further pharmaceutically acceptable excipients ad l00 wt.-%

bb. pramipexole extended release capsules bb.l

removed during processing, does not appear in the final product

bb.2

removed during processing, does not appear in the final product bb.3

* removed during processing, does not appear in the final product bb.4

* removed during processing, does not appear in the final product bb.5

* removed during processing, does not appear in the final product bb.6

bb.7

Pellets prepared by melt extrusion with hydrophilic excipients

In order to achieve adequate content uniformity, 9 g polyethylene glycol 6000 (PEG) is mixed with 1 g of pramipexole. Then this mixture is mixed with 50 g PEG 6000 and 40 g poloxamer 188. The mixture is extruded in a twin screw extruder at 54°C, diameter of dye is 0.7 mm using a face cut granulator to achieve pieces of about 1 mm. These are rounded in a spheronizer at 400 rpm and 41°C. The pellets are sieved, the fraction of 0.8 - 1.1 mm is used for retardation as described in the previous examples.

Examples for melt extrusion:

bb.8 Pellets prepared by melt extrusion

In order to achieve adequate content uniformity, 9 g stearyl alcohol is mixed with 1 g of pramipexole. Then this mixture is mixed with 90 g stearyl alcohol. The mixture is extruded in a twin screw extruder at 51⁰C, diameter of dye is 0.7 mm using a face cut granulator to achieve pieces of about 1 mm. These are rounded in a spheronizer at 400 rpm and 41⁰C. The pellets are sieved, the fraction of 0.8 - 1.1 mm is used for retardation as described in the previous examples. The following table provides some further examples of melt extrusion.

Examples for melt extrusion:

bb.9

Extended release pellets prepared by wet extrusion

In order to achieve adequate content uniformity, 9 g microcrystalline cellulose is mixed with 1 g of pramipexole. Then this mixture is mixed with 60 g microcrystalline cellulose and 30 g carbomer 97 IP. The mixture is extruded in a twin screw extruder with an adequate amount of water (or binder solution), diameter of dye is 0.7 mm. The resulting extrudates are rounded in a spheronizer at 400 rpm. After drying, pellets are sieved, the fraction of 0.8 - 1.1 mm is filled into capsules.

bb.lO

Extended release pellets prepared by melt extrusion

In order to achieve adequate content uniformity, 9 g hydrogenated castor oil is mixed with 1 g of pramipexole. Then this mixture is mixed with 60 g hydrogenated castor oil and 30 g carnauba wax. The mixture is extruded in a twin screw extruder with an adequate amount of water (or binder solution), diameter of dye is 0.7 mm. The resulting extrudates are rounded in a spheronizer at 400 rpm. Pellets are sieved, the fraction of 0.8 - 1.1 mm is filled into capsules.

bb.ll

Extended release pellets prepared by hot melt granulation/melt peptization

In this process agglomeration of active ingredient with excipients is promoted by the addition of low melting point, lipophilic binders, such as waxes, fats, fatty acids, fatty acid alcohols, and more water soluble polymers, such as poloxamers or polyethylene glycols. The binder is usually added to the other components as a powder. The binder is liquefied by heat generated either by friction during the mixing phase or by a heating jacket. Excipients suitable are e.g. lactose, microcrystalline cellulose, and dibasic calcium phosphate. After melting and granulation of the mass, the resulting mass is either cooled down, screened and processed into tablets together with further excipients or, spheronized into pellets, which can be coated in addition, and filled into capsules.

For any of the above mentioned examples the weight relations between the ingredients may vary within the range outlined in the description, in particular the amount of pramipexole, pramipexole dichloride monohydrate respectively, may vary within the formulation of one capsule, preferably between 0.01 and 7 mg, more preferably between 0.5 and 5 mg. Formulations concerning the calcium channel blocker

bc.l tablets

active substance: amlodipine 5 mg/7,5 mg/10 mg (as amlodipine besylate). additives: calcium hydrogenphosphate, carboxymethyl starch-sodium (type A), microcrystalline cellulose, magnesium stearate

active substance: nisoldipine 5 mg/10 mg additives: corn starch, microcrystalline cellulose, lactose IH₂O, povidone 25, sodium dodecylsulfate, magnesium stearate, hypromellose, macrogol 4000, titan dioxide (E 171), iron oxide red (E 172)

active substance: lercanidipine-HCl 10 mg/20 mg (corr. 9.4 mg/18.8 mg lercanidipine) additives: lactose IH₂O, microcrystalline cellulose, poly(O-carboxymethyl)starch, sodium salt, povidone K 30, magnesium stearate (vegetable), hypromellose, talcum, dyestuffs: titan dioxide (E 171), iron (III) oxide (E 172), macrogol 6000

active substance: gallopamil-HCl 25 mg/50 mg additives: hypromellose, lactose IH₂O, magnesium stearate, corn starch, highly dispersed silica, talcum, dyestuff: titan dioxide (E 171), optional additionally: dyestuff E 172

active substance: verapamil-HCl 80 mg, chinidin 160 mg (corr. about 250 mg chinidin hydrogensulfate 4H₂O) additives: iron oxide and hydroxide, gelatine, highly dispersed silica, magnesium stearate, corn starch, hypromellose, microcrystalline cellulose, macrogol 400, macrogol 6000, talcum, titan dioxide

bc.2 retard tablets active substance: felodipine 2,5 mg/5 mg additives: microcrystalline cellulose, hyprolose, hypromellose, iron oxide hydrate (E 172), iron (III) oxide (E 172), lactose, macrogol 6000, macrogol glycerol hydroxystearate, corn starch, hard paraffine, propylgallate, sodium aluminum silicate, sodium stearyl fumarate, titan dioxide (E 171)

active substance: ramipril 2,5 mg/5 mg additives: microcrystalline cellulose, hyprolose, hypromellose, iron oxide hydrate (E 172), iron (III) oxide (E 172), lactose, macrogol 6000, macrogol glycerol hydroxystearate, corn starch, hard paraffine, propylgallate, sodium aluminum silicate, sodium stearyl fumarate, titan dioxide (E 171)

bc.3 capsules

active substance: nicardipine-HCl 20 mg/30 mg additives: corn starch, magnesium stearate, gelatine, purified water, titan dioxide (E 171), indigocarmine (E 132), optional additionally: iron oxide (E 172)

active substance: nifedipine 5 mg/10 mg additives: gelatine, yelloworange S (E 110), purified water, glycerol, macrogol

400, peppermint oil, titan dioxide (E 171), saccharin-sodium 2H₂O

active substance: diltiazem-HCl 90 mg/120 mg/180 mg additives: corn starch, sucrose, povidone K 30, ethyl cellulose, talcum, dodecylsulfate sodium, cetylalcohol, dibutyldecandioate, gelatine, dyestuffs: titan dioxide (E 171), additionally: erythrosine (E 127), indigocarmine (E 132)

bc.4 retard capsules active substance: isradipine 2,5 mg/5 mg additives: gelatine, hexadecylpalmitate, highly dispersed silica, magnesium stearate, micro crystalline cellulose, hypromellose, (3-sn- phosphatidyl)choline, shellack, titan dioxide (E 171), iron (11,111) oxide (E 172, red), iron (11,111) hydroxide oxide (E 172, yellow)

active substance: nilvadipine 8 mg/16 mg additives: corn starch, microcrystalline cellulose, povidone, croscarmellose- sodium, gelatine, titan dioxide (E 171), iron (11,111) oxide, iron (III) oxide, iron oxide hydrate (E 172).

bc.5 injcetion solution

active substance: liquid solution (50 ml), nimodipine 10 mg additives: ethanol 96%, macrogol 400, trometamole, maleic acid, sodium hydroxide, water for infusion or injection application

active substance: 1 ml solution, nitrendipine 5 mg additives: ethanol 96%, polysorbate 20, propylene glycole, peppermint oil, purified water, α-tocopherole, palmitoyl ascorbic acid

Claims

1. Use of a.) pramipexole or a pharmaceutically acceptable salt thereof in form of an extended release formulation as a first ingredient in combination with b.) a calcium channel blocker as a second ingredient for the manufacture of a medication for the treatment of Parkinson's disease.

2. The use according to claim 1, whereby each ingredient may be provided in form of a separate individual pharmaceutical composition or both together may be provided in form of one fixed dose composition, preferably in form of the separate individual pharmaceutical compositions and for each case preferably in form of a composition that is to be taken orally.

3. The use according to claim 1 or 2, whereby the calcium channel blocker is selected from the group consisting of amlodipine, benidipine, felodipine, nicardipine, nilvadipine, nisoldipine, nitrendipine, lacidipine, lercandipine, verapamil, gallopamil, diltiazem, preferably from the group of amlodipine, felodipine, nicardipine, nitrendipine, lercandipine, verapamil, gallopamil, diltiazem.

4. The use according to claim 1, 2 or 3, whereby the calcium channel is selected from the calcium channel family members of Ca_v1.2, Ca_v1.4, Ca_v2.1, Ca_v2.2, Ca_v2.3, Ca_v3.1,

Ca_v3.2, Ca_v3.3.

5. The use according to claim 1 or 2, whereby the calcium channel blocker is safinamide or ralfinamide.

6. The use according to any of the previous claims, whereby the extended release formulation of pramipexole is a matrix tablet comprising:

(c) neutral water swelling polymer(s) 10 to 75 wt.-%

(d) further pharmaceutically acceptable excipients ad 100 wt.-% with preferably the pramipexole being in form of its hydrochloride monohydrate, the anionic water selling polymer (b) preferably being an acrylic acid polymer, preferably from the carbomer group, more preferably carbopol 941, the neutral water swelling polymer (c) preferably being hydroxypropylmethylcellulose and the further pharmaceutical acceptable excipients being selected from the group of magnesium stearate, silicon dioxide, corn starch, lactose, microcrystalline cellulose.

7. The use according to any of the previous claims, whereby the extended release formulation of pramipexole is a pellet formulation comprising: - an inert pellet core; a first layer being an active ingredient layer comprising pramipexole or a pharmaceutically acceptable salt thereof and optionally one or more wet binders and further excipients; and a second layer provided on the first layer, the second layer being an extended release coating comprising a) at least one water-insoluble polymer and optionally a pore former, the resulting pellet having a pH-independent in vitro release characteristic or b) a mixture a pH-dependent enteric-coating polymer, preferably in an amount of 10 to 85 % by weight, and a pH-independently water swelling polymer, preferably in an amount of 15 to 75 % by weight, the resulting pellet having a close to zero order in vitro release characteristic at acidic pH values up to pH 6.8, an accelerated release above pH 6.8 and a more accelerated release above pH 7.3.

8. A medication or a pharmaceutical composition for the treatment of Parkinson's disease comprising as a first active ingredient pramipexole or a pharmaceutically acceptable salt thereof and as a second active ingredient a selective calcium channel blocker or a pharmaceutically acceptable salt thereof, whereby the calcium channel is selected from the calcium channel family of the group of Ca_v1.2, Ca_v1.4, Ca_v2.1, Ca_v2.2, Ca_v2.3, Ca_v3.1, Ca_v3.2, Ca_v3.3.

9. The medication or pharmaceutical composition according to claim 8, whereby each ingredient may be provided in form of a separate individual pharmaceutical composition or both together may be provided in form of one fixed dose composition, preferably in form of the separate individual pharmaceutical compositions and for each case preferably in form of a composition that is to be taken orally.

10. A medication or a pharmaceutical composition for the treatment of Parkinson's disease comprising as a first active ingredient pramipexole or a pharmaceutically acceptable salt thereof and as a second active ingredient a selective calcium channel blocker or a pharmaceutically acceptable salt thereof, whereby the calcium channel blocker is selected from the group of amlodipine, felodipine, nicardipine, nitrendipine, lercandipine, verapamil, gallopamil, diltiazem.

11. A medication as defined in any of the previous claims 1 to 10 in form of a kit of parts comprising

(a) a first containment containing a pharmaceutical formulation comprising a therapeutically effective amount of pramipexole or a pharmaceutically acceptable salt thereof and

(b) a second containment containing a pharmaceutical formulation comprising a therapeutically effective amount of the calcium channel blocker or a pharmaceutically acceptable salt thereof.

12. A medication as defined in any of the previous claims 1 to 10 in form of a kit of parts comprising one part in form of a pharmaceutical composition comprising pramipexole or a pharmaceutically acceptable salt thereof and another part being a leaflet with the instruction for a patient suffering from Parkinson's disease to take the pharmaceutical formulation comprising pramipexole or a pharmaceutically acceptable salt thereof together with a pharmaceutical formulation comprising the calcium blocker or a pharmaceutically acceptable salt thereof timely related to the intake of the formulation comprising pramipexole or a pharmaceutically acceptable salt thereof.

13. A medication according to any one of claims 8 to 12, wherein the pramipexole or pharmaceutically acceptable salt thereof is formulated for immediate release.

14. The medication as defined in any one of claims 1 to 13, wherein the calcium channel blocker or pharmaceutically acceptable salt thereof is formulated for immediate release formulation or for extended release.

15. A medication as defined in any of the previous claims 1 to 14, whereby the medication is for oral administration.