(12) INTERNATIONALAPPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date 28 January 2010 (28.01.2010) WO 2010/010136 Al

(51) International Patent Classification: AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, A61K 31/428 (2006.01) A61P 25/16 (2006.01) CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, (21) International Application Number: HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, PCT/EP2009/059466 KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, (22) International Filing Date: ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, 23 July 2009 (23.07.2009) NO, NZ, OM, PE, PG, PH, PL, PT, RO, RS, RU, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TJ, TM, TN, TR, TT, (25) Filing Language: English TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (26) Publication Language: English (84) Designated States (unless otherwise indicated, for every (30) Priority Data: kind of regional protection available): ARIPO (BW, GH, 0816 1077.6 24 July 2008 (24.07.2008) EP GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, (71) Applicant (for all designated States except US): TM), European (AT, BE, BG, CH, CY, CZ, DE, DK, EE, BOEHRINGER INGELHEIM INTERNATIONAL ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, GMBH [DE/DE]; Binger StraBe 173, 55216 Ingelheim MC, MK, MT, NL, NO, PL, PT, RO, SE, SI, SK, SM, Am Rhein (DE). TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, ML, MR, NE, SN, TD, TG). (72) Inventor; and (75) Inventor/Applicant (for US only): BUERGER, Erich Published: [DE/DE]; Boehringer Ingelheim GmbH, CD Patents, — with international search report (Art. 21(3)) Binger Strasse 173, 55216 Ingelheim Am Rhein (DE). — before the expiration of the time limit for amending the (74) Agents: HAMMANN, Heinz et al; Binger Str. 173, claims and to be republished in the event of receipt of 5521 6 Ingelheim Am Rhein (DE). amendments (Rule 48.2(h)) (81) Designated States (unless otherwise indicated, for every kind of national protection available): AE, AG, AL, AM,

(54) Title: PHARMACEUTICAL COMPOSITION COMPRISING PRAMIPEXOLE AND AN ANTI-INFLAMMATORY AGENT FOR THE TREATMENT OF PARKINSON'S DISEASE (57) Abstract: The invention relates to a new medication for the treatment of Parkinsons's disease. The medication is a combina tion of pramipexole or a pharmaceutically acceptable salt thereof and an anti-inflammatory agent or a pharmaceutically acceptable salt thereof which may be used in a fixed-dose combination as well as in a free-dose combination. The medication comprises the simultaneous, separate or sequential administration of pramipexole or a pharmaceutically acceptable salt thereof and an anti-in flammatory agent or a pharmaceutically acceptable salt thereof. The invention is further related to the use of the pharmaceutical composition and a method of treatment of Parkinson's disease comprising said medication. PHARMACEUTICAL COMPOSITION COMPRISING PRAMIPEXOLE AND AN ANT I - INFLAMMATORY AGENT 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 the cardinal symptoms of Parkinson's disease. The medication comprises the co administration of pramipexole or a pharmaceutically acceptable salt thereof and an anti inflammatory agent or a pharmaceutically acceptable salt thereof, each of which in an amount that provides a brain exposure which is therapeutically effective. Thus, the medication is a combination of pramipexole or a pharmaceutically acceptable salt thereof and an anti inflammatory agent or a pharmaceutically acceptable salt thereof which may be used in a fixed-dose combination as well as in a free-dose combination, a free-dose combination being preferred. Pharmaceutically preparations that are administered orally are preferred. A further aspect of the invention is related to the use of a pharmaceutical composition for the preparation of a medicament for the improved treatment of Parkinson's disease comprising said medication and an improved method of treatment of Parkinson's disease comprising said medication.

Background Art

Inflammation is the complex biological mechanism of tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. It is a protective attempt by the organism to remove the injurious stimuli as well as to initiate the healing process of the tissue. Inflammation is either acute or chronic. Acute inflammation is the initial response of the body to harmful stimuli. Inflammotory process also affect the brain. Since decades anti-inflammatory drugs are known which are based on active substances having the property to reduce inflammation. Anti inflammatory drugs make up about half of analgesic, which remedy pain by reducing inflammation as opposed to opioids which affect the brain.

Pramipexole is a known dopamine D receptor agonist. It is pharmacologically unique in that it is a full agonist and has receptor selectivity for the dopamine D family of dopamine receptors. Further, 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 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 2 11.33. The chemical formula (formula 1) is as follows:

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 301 0C, 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). 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. 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 for the treatment of Parkinson's disease in a patient in need of such treatment, whereby the medication comprises a first active ingredient that is pramipexole or a pharmaceutically acceptable salt thereof and a second active ingredient that is an anti-inflammatory agent or a pharmaceutically acceptable salt thereof, whereby each of the two active ingredients is provided in an amount that is sufficient to provide a brain exposure of said active ingredient that is therapeutically effective. The two active ingredients may be applied simultaneously or separately. In the latter case preferably sequentially. Thus, a further aspect of the present invention is related to the use of the active ingredient pramipexole or a pharmaceutically acceptable salt thereof in combination with a second active ingredient being an anti-inflammatory agent or a pharmaceutically acceptable salt thereof for the manufacture of a mediaction for the treatment of Parkinson's disease, whereby the mediaction comprises each of the two active ingredients in an amount that is sufficient to provide a therapeutically effective brain exposure after administration of said mediaction. This aspect comprises the use of free-dose combinations as well as of fixed-dose combination, a free-dose combination is particularly preferred. Preferred are pharmaceutical compositions for oral administration.

Description of the Invention

The present invention is based on the concept of a combined application of pramipexole and an anti-inflammatory agent in order to treat Parkinson's disease. The current treatment of Parkinson's disease basically provides symptomatic therapy. The mechanisms of the disease process underlying PD, the degeneration of dopaminergic neurons in the substantia nigra are still not understood, although a large variety of possible pathogenic factors, including the production of inflammatory mediators are discussed to contribute to the pathogenic process. Inflammatory events may contribute to the pathogenesis of a variety of neurological disorders, including PD. Activated microglial cells in affected substantia nigra of PD patients could be observed. These observations suggested that immune system mechanisms are involved in the pathogenesis of neuronal damage in PD and also provided evidence for an ongoing active pathologic process. Although the primary cellular mechanisms of injury in PD remain to be elucidated, inflammation initiated by or accompanying neuronal damage in the substantia nigra and possibly other brain areas could aggravate or maintain the disease process in PD. Nonetheless, the presence of soluble factors and enzymes indicates the occurrence of inflammation in the substantia nigra. These include pro-inflammatory cytokines (e.g TNF alpha), interleukin-1 beta (IL-1 13), IL-2, IL-6, and interferon gamma, as well as inducible nitric oxide synthase (INOS).

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. Furthermore, pramipexole shows neuroprotective properties. Thus, the inventors established the present invention to use the dopamine receptor agonist pramipexole in combination with an anti-inflammatory agent for the treatment of Parkinson's disease, in particular the treatment of the cardinal symptoms of Parkinson's disease. A combination of the dopamine agonist pramipexole and an effective anti-inflammatory drug will have a benefit on Parkinson's disease and will reduce the symptoms and/or prevent the progression of the disease. Pramiepxole in form the the dihydrochloride monohydrate is administered in total daily doses of between 0.1 and 10 mg.

According to the present invention 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.

As used herein, the term "treatment" means the administration of a pharmaceutically active compound or a pharmaceutical composition according to the present invention to alleviate or eliminate symptoms of the Parkinson's disease in a patient.

In the context of the present invention the term "therapeutically 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.

According to the present invention the term "anti-inflammatory agent" as used herein means those substances, ingredients or drugs that are effective for diminishing or preventing the progression of inflammatory processes in the brain. Specific examples of anti-inflammatory agents are listed and discussed in detail later in the specification. It will be evident, that such anti-inflammatory agent must be able to pass the blood brain barrier in a therapeutically effective amount; while the total amount adminsterd being safe for the patient.

The effective amount or dose of the anti-inflammatory agent for treating Parkinsons 's disease is advantageously in the range from about 1 mg/day to about 4000 mg/day. The preferred dose is in the range from about 1 to about 300 mg/day, and a more highly preferred dose is from about 2 to about 150 mg/day. The optimum dose for each patient must be set by the physician in charge of the case, taking into account the chosen anti-inflammatory agent, 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.

An anti-inflammatory agent may be easily formulated in the usual pharmaceutical forms, preferably oral pharmaceutical forms such as tablets, capsules, suspensions, liquid form 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 anti inflammatory agent as a tablet or capsule and such pharmaceutical forms are recommended.

Preferred anti-inflammatory agents are selected from non-steroidal anti-inflammatory drugs (NSAIDs), iNOS inhibitors and other agents that suppress the pro-inflammatory pathway. Illustrative examples comprise the classes of • Salicylates; • arylalkanoic acids; • 2-arylpropionic acids; • N-arylanthranilic acids; • pyrazolidine derivatives; • oxicams; coxibs; and • sulphonanilides.

Of these classes particularly preferred representatives are: • salicylates such as aspirin (acetylsalicylic acid), diflunisal and ethenzamide; • arylalkanoic acids such as diclofenac, indometacin and sulindac; • 2-arylpropionic acids ("profens") such as carprofen, flurbiprofen, ibuprofen, ketoprofen, ketorolac, kerotolac tromethamine, loxoprofen, naproxen, and tiaprofenic acid; • N-arylanthranilic acids (fenamic acids) such as mefenamic acid; • pyrazolidine derivatives such as phenylbutazone; • oxicams such as meloxicam, and piroxicam; • coxibs such as celecoxib, etoricoxib, parecoxib, rofecoxib, and valdecoxib as well as sulphonanilides such as nimesulide.

Further anti-inflammatory agents include: • antibiotic tetracycline family: minocycline (derivative of the), minocycline hydrochloride; • vasoactive intestinal peptide (VIP; an effective anti-inflammatory neuropeptide); • peroxisome proliferator-activated receptor-gamma agonist (PPAR gamma), e.g. pioglitazone, naloxone (a nonselective opioid receptor antagonist); • dextromethorphan and • immune suppressive compounds (immunophiline binding drugs like Tacrolimus (also FK-506 or Fujimycin).

Preferred anti-inflammatory agents are selected from the group consisting of salicylates, arylalkanoic acids, 2-arylpropionic acids, N-arylanthranilic acids, pyrazolidine derivatives, coxibs, sulphonanilides, iNOS inhibitors, minocycline, Vasoactive Intestinal Peptide (VIP), peroxisome proliferator-activated receptor-gamma agonists (PPAR gamma), naloxone, dextromethorphan and immune suppressive compounds for which improved results in a therapy of the Parkinson's disease will be achieved due to the spectrum of activity.

The 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.

Pramipexole may be easily formulated in the usual pharmaceutical forms, preferably oral pharmaceutical forms such as tablets, capsules, suspensions, liquid form 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 anti-inflammatory agent, 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 it is 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 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, if not indicated otherwise. Obviously, the isomer which is pharmacologically most effective and most free from side effects is preferred.

Both compounds, i.e. pramipexole and the anti-inflammatory agent, can be administered in form of a pharmaceutically acceptable salt. The term "pharmaceutically acceptable salt" means a salt of pramipexole or a salt of the anti-inflammatory agent 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 anti-inflammatory agent 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 anti-inflammatory agent and pramipexole (or a saltt hereof), 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 anti-inflammatory agent 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 anti-inflammatory agent 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 anti-inflammatory agent.

A preferred pharmaceutical composition is for oral application (swalloable dosage form). In case of free dose combinations, each of the dosage forms, the one comprising pramipexole or a salt therof and the other one comprising the anti-inflammaoty agent, is for oral use.

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 an anti-inflammatory agent 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 an anti-inflammatory agent 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 an anti-inflammatory agent 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 an anti-inflammatory agent 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 Pellets prepared by wet extrusion 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 5 10C, 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. 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 3 O 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 anti-inflammatory agent bc.l tablets active substance: acetylsalicylic acid, 500 mg, tablet additives: microcrystalline cellulose, silica, crospovidone, stearic palmitinic acid active substance: diclofenac, 25 mg/50 mg, tablet, enteric-coated additives: microcrystalline cellulose, hypromellose, poly(O- carboxymethyl)starch-sodium, sodium stearinic fumarate, highly dispersed silica, methacrylic acid ethyl acrylate copolymer (1:1), macrogol 6000, triethylcitrate, talc, titan dioxide, iron oxide hydrate, chinolin yellow aluminum salt active substance: indometacin, 50 mg, tablet additives: microcrystalline cellulose, lactose monohydrate, magnesium stearate, corn starch, sodium edetate, soluble starch, polysorbate 80, highly dispersed silica, talc, iron oxide hydrate (E 172) active substance: ibuprofen, 600 mg, film tablet additives: microcrystalline cellulose, crospovidone, highly dispersed silica, povidone K25, croscarmellose sodium, sodium stearinic fumarate, macrogol 6000, acesulfam potassium (E 950), macrogol 20000, titan dioxide (E 171), macrogol 3000, triacetin, lactose monohydrate, hypromellose active substance: naproxen, 250 mg/500 mg, tablet additives: crospovidone, hyprolose, lactose monohydrate, magnesium stearate, corn starch, iron (III) oxide (E 172) active substance: tiaprofenic acid, 200 mg/300 mg, tablet additives: corn starch, magnesium stearate, talcum, poloxamer 188 active substance: phenylbutazone, 200 mg, tablet additives: cellulose powder, gelatine, highly dispersed silica, croscarmellose sodium, corn starch, lactose, talc, macrogol, magnesium stearate, basic butyl methacrylat copolymer, titan dioxide (E 171) active substance: meloxicam, 7,5 mg/15 mg, tablet additives: microcrystalline cellulose, corn starch, lactose monohydrate, sodium citrate, highly dispersed silica, magnesium stearate active substance: piroxicam, 10 mg/20 mg, tablet additives: lactose, microcrystalline cellulose, silica, corn starch, croscarmellose sodium, copovidone, magnesium stearate active substance: valdecoxib, 10 mg/20 mg/40 mg, film tablet additives: lactose 1 H O, microcrystalline cellulose, pregelatinized corn starch, croscarmellose sodium, magnesium stearate, titan dioxide (E 171), hypromellose (E 464), macrogol 400, polysorbate 80 (E 433), optional additionally iron oxide hydrate (E 172)

active substance: pioglitazone, 15 mg/30 mg/45 mg, tablet additives: carmellose calcium, hyprolose, lactose monohydrate, magnesium stearate active substance: minocycline-HCl, 50 mg, film tablet additives: microcrystalline cellulose, magnesium stearate, carboxymethyl starch sodium (type A), hypromellose, povidone K25, highly dispersed silica, titan dioxide (E 171), E 172 bc.2 retard tablets active substance: ketoprofen 200 mg, retard tablet additives: microcrystalline cellulose, silicon dioxide, hypromellose, lactose, magnesium stearate, macrogol, silicon oil, dimeticon, alpha-hydro- omega(octadecyloxy)po ly(oxyethylene)- 10 bc.3 capsules active substance: mefenamic acid, 250 mg, capsule additives: dimeticon, gelatine, lactose IH O, sodium dodecylsulfate, shellack, sojalecithine, dyestuffs E 132, E 171, E 172 active substance: celecoxib, 100 mg/200 mg, capsule additives: lactose monohydrate, sodium dodecylsulfate, povidon K30, croscarmellose sodium, magnesium stearate, gelatine, titan dioxide (E 171), optional additionally indigocarmin (E 132), iron oxide (E 172)

bc.5 injection solution active substance: parecoxib-sodium, 42,36 mg per bottle (corr. 40 mg parecoxib), injection solution additives: disodiumhydrogenphosphate 7 H2O, phosphoric acid and/or sodium hydroxide, water for injection

active substance: naloxone-HCl, 0.4 mg, injection solution ( 1 ampoule/1 ml) additives: sodium chloride, sodium hydroxide, water for injection bc.6 suppository active substance: ketoprofen, 100 mg, suppository additives: cellulose powder, silicon dioxide, hard fat bc.7 suspension

active substance: dextromethorphan, 11 1 mg, suspension additives: purified water, sorbitol solution, methyl-4-hydroxy benzoate, citric acid, saccharose sodium, propyl-4-hydroxy benzoate, sodium bicarbonate Claims

1. Pharmaceutical composition for the treatment of Parkinson's disease comprising the active ingredient pramipexole or a pharmaceutically acceptable salt thereof and a second active ingredient being an anti-inflammatory agent or a pharmaceutically acceptable salt thereof, whereby each of the two active ingredients is provided in an amount that is sufficient to provide a brain exposure of said active ingredient that is therapeutically effective after administration.

2. The pharmaceutical composition 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 pharmaceutical composition according to claim 1 or claim 2 as 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 an anti-inflammatory agent or a pharmaceutically acceptable salt thereof.

4. The pharmaceutical composition according to any one of claims 1 to 3 for oral administration.

5. The pharmaceutical composition according to any one of claims 1 to 4, wherein the pramipexole or a pharmaceutically acceptable salt thereof comprising pharmaceutical formulation is an immediate release formulation or an extended release formulation, preferably an extended release formulation, each of which preferably for oral administration. 6. The pharmaceutical composition according to any one of claims 1 to 5, wherein the anti-inflammatory agent or a pharmaceutically acceptable salt thereof comprising pharmaceutical formulation is an immediate release formulation or an extended release formulation, preferably an extended release formulation, each of which preferably for oral administration.

7. The pharmaceutical composition according to any one of claims 1 to 6, wherein the anti-inflammatory agent is selected from non-steroidal anti-inflammatory drugs (NSAIDs), particularly salicylates such as aspirin (acetylsalicylic acid), diflunisal and ethenzamide; arylalkanoic acids such as diclofenac, indometacin and sulindac; 2- arylpropionic acids ("profens") such as carprofen, flurbiprofen, ibuprofen, ketoprofen, ketorolac, loxoprofen, naproxen, and tiaprofenic acid; N-arylanthranilic acids (fenamic acids) such as mefenamic acid; pyrazolidine derivatives such as phenylbutazone; piroxicam; coxibs such as celecoxib, etoricoxib, parecoxib, rofecoxib, and valdecoxib as well as sulphonanilides such as nimesulide; iNOS inhibitors and other agents that suppress the pro-inflammatory pathway such as minocycline, vasoactive intestinal peptide (VIP), peroxisome proliferator-activated receptor-gamma agonists (PPAR gamma), particularly pioglitazone; naloxone, dextromethorphan and immune suppressive compounds such as FK-506.

8. The pharmaceutical composition according to any one of claims 1 to 7, wherein the anti-inflammatory agent is not Meloxicam.

9. Use of pramipexole or a pharmaceutically acceptable salt thereof in combination with an anti-inflammatory agent or a pharmaceutically acceptable salt thereof for the preparation of a medication for the treatment of Parkinson's disease, particularly a medication according to any one of the preceding claims 1 to 8.

10. The use according to claim 9, whereby within the medication 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. 11. The use according to claim 9 or claim 10, wherein the pharmaceutical composition is a kit of parts, one part being a pharmaceutical formulation 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 anti-inflammatory agent or a pharmaceutically acceptable salt thereof timely related to the intake of the formulation comprising pramipexole or a pharmaceutically acceptable salt thereof.

12. The use according to claim 9 or claim 10, wherein the pharmaceutical composition is a kit of parts, one part in form of a pharmaceutical composition comprising pramipexole or a pharmaceutically acceptable salt thereof, one part being a pharmaceutical formulation comprising an anti-inflammatory agent 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 an anti-inflammatory agent or a pharmaceutically acceptable salt thereof.

13. The use according to any one of claims 9 to 11, wherein the pharmaceutical composition is for oral administration.

14. The use according to any one of claims 9 to 13, wherein the anti-inflammatory agent is selected from non-steroidal anti-inflammatory drugs (NSAIDs), particularly salicylates such as aspirin (acetylsalicylic acid), diflunisal and ethenzamide; arylalkanoic acids such as diclofenac, indometacin and sulindac; 2-arylpropionic acids such as carprofen, flurbiprofen, ibuprofen, ketoprofen, ketorolac, loxoprofen, naproxen, and tiaprofenic acid; N-arylanthranilic acids (fenamic acids) such as mefenamic acid; pyrazolidine derivatives such as phenylbutazone; oxicams such as meloxicam, and piroxicam; coxibs such as celecoxib, etoricoxib, parecoxib, rofecoxib, and valdecoxib as well as sulphonanilides such as nimesulide; iNOS inhibitors and other agents that suppress the pro-inflammatory pathway such as minocycline, vasoactive intestinal peptide (VIP), peroxisome proliferator-activated receptor-gamma agonists (PPAR gamma), particularly pioglitazone, naloxone, dextromethorphan and immune suppressive compounds such as FK-506.

15. The use according to any of claims 9 to 14, wherein pramipexole or a pharmaceutically acceptable salt thereof is present in an immediate release formulation or an extended release formulation, preferably an extended release formulation each of which preferably for oral administration.

16. The use according to any of claims 9 to 15, wherein the anti-inflammatory agent or a pharmaceutically acceptable salt thereof is present in an immediate release formulation or an extended release formulation, preferably an extended release formulation each of which preferably for oral administration. A. CLASSIFICATION OF SUBJECT MATTER INV. A61K31/428 A61P25/16

According to International Patent Classification (IPC) or to both national classification and IPC

B. FIELDS SEARCHED Minimum documentation searched (classification system followed by classification symbols) A61K

Documentation searched other than minimum documentation to the extent that such documents are included in the fields searched

Electronic data base consulted during the international search (name of data base and where practical search terms used) EPO-Internal , WPI Data, EMBASE, BIOSIS

C. DOCUMENTS CONSIDERED TO BE RELEVANT

Category * Citation of document, with indication, where appropriate, of the relevant passages Relevant to claim No

WO 2004/089375 A (TITAN PHARMACEUTICALS 1-16 INC [US]; PATEL RAJESH A [US]; BUCALO LOUIS R [U) 2 1 October 2004 (2004-10-21) page 4 , paragraph 9 - page 5 , paragraph 10 page 5 , paragraph 14 - page 6 , paragraph 15 page 10, paragraph 26 claims 1,5,11-14,29,34,44 page 16, paragraph 43 - page 17, paragraph 45

-/--

Further documents are listed in the continuation of Box C See patent family annex

* Special categories of cited documents 1T' later document published after the international filing date or priority date and not in conflict with the application but "A" document defining the general state of the art which is not cited to understand the principle or theory underlying the considered to be of particular relevance invention 1 E' earlier document but published on or after the international "X" document of particular relevance, the claimed invention filing date cannot be considered novel or cannot be considered to "L1 document which may throw doubts on pπoπty claιm(s) or involve an inventive step when the document is taken alone which is cited to establish the publication date of another "Y- document of particular relevance the claimed invention citation or other special reason (as specified) cannot be considered to involve an inventive step when the O" document referring to an oral disclosure use exhibition or document is combined with one or more other such docu¬ other means ments such combination being obvious to a person skilled • P" document published prior to the international filing date but in the art later than the priority date claimed "&' document member of the same patent family

Date of the actual completion of the international search Date of mailing of the international search report

29 October 2009 02/12/2009

Name and mailing address of the ISA/ Authorized officer European Patent Office, P B 5818 Patentlaan 2 NL - 2280 HV Rl|SWI|k TeI (+31-70) 340-2040, Fax (+31-70) 340-3016 Nyeki , Agnes

Form PCT/ISA/210 (second sheet) (April 2005) C(Continuation). DOCUMENTS CONSIDERED TO BE RELEVANT

Category* Citation of document, with indication, where appropriate of the relevant passages Relevant to claim No

BIGLAN K M ET AL: "A review of 1-16 pramipexole and its clinical utility in Parkinson's disease" EXPERT OPINION ON PHARMACOTHERAPY, ASHLEY, LONDON, vol. 3 , no. 2 , 1 January 2002 (2002-01-01), pages 197-210, XP008087918 ISSN: 1465-6566 the whole document

ASANUMA M ET AL: "Nonsteroidal 1-16 anti -inflammatory drugs in experimental parkinsonian models and parkinson's disease" CURRENT PHARMACEUTICAL DESIGN 200805 NL, vol. 14, no. 14, May 2008 (2008-05), pages 1428-1434, XP002506340 ISSN: 1381-6128 the whole document page 1431, right-hand column, paragraph 1

P ,X WO 2008/132712 A (SIGMOID PHARMA LTD [IE]; 1-16 COULTER IVAN [IE]) 6 November 2008 (2008-11-06) claims 1,34,35

Form PCT/ISA/210 (continuation ol second sheet) 2005) Patent document Publication Patent family Publication cited in search report date member(s) date

WO 2004089375 21-10-2004 AU 2004228017 A l 21-10- 2004 CA 2520613 A l 21-10- 2004 CN 1777426 A 24-05- 2006 EP 1610791 A l 04-01- 2006 JP 2006522149 T 28-09- 2006 KR 20060015491 A 17-02- 2006 MX PA05010450 A 04-11- 2005 NZ 542548 A 30-04- 2009 ZA 200507877 A 31-01- 2007

WO 2008132712 06-11-2008 EP 2073798 A2 01-07-2009 EP 2063875 A2 03-06-2009 WO 2008132710 A2 06-11-2008

Form PCT/ISA/210 (patent family annex) (April 2005)