The present invention is related to new pharmaceutical compositions for use in the treatment of cerebral arteriosclerosis, symptoms following stroke and cerebral hemorrhage, age- associated cognitive decline, chronic cerebrovascular disease, multi-infarct dementia and mild and moderate Alzheimer's type dementia and frailty, speech disorders, memory loss, short attention span associated with these diseases, symptoms of vascular and degenerative cerebral pathologies such as psychomotor activity and depression. Idebenone is a quinone derivative drug which has the chemical formula of 2-(10- hydroxydecyl)-5,6-dimethoxy-3-methyl- cyclohexa-2,5-diene-l,4-dione and was disclosed by the firm Takeda in the patent DE 2519730 for the first time.

Formula I: Idebenone The active agent is marketed in 45 mg oral tablet form (Mnesis®) in the treatment of central nervous system disorders in Europe and in 150 mg oral tablet form ( Catena®) in the treatment of Friedreich's ataxia in Canada. In addition to the indications given, effective use of the active agent in other indications (such as neuromuscular diseases, MELAS syndrome, primary MS, Leber 's Hereditary Optic Neuropathy and DMD-Duchenne muscular dystrophy) is also being investigated.

Donepezil (Formula 2), which has the chemical name (+/-) 2,3-Dihydro-5,6-dimethoxy-2-[(l- (phenylmethyl)-4-piperidinyl]methyl]-lH-inden-l -one, is a cholinesterase inhibitor and said molecule was first disclosed in the patent application US4895481.

Formula II. Donepezil

Acetylcholinesterase inhibitors (AChEI) are the most potent agents attested in the treatment of Alzheimer's disease and its related symptoms. AChEIs inhibit breaking down of acetylcholine with cholinesterase and protract biochemical and functional effect of acetylcholine in the brain by increasing the amount of acetylcholine in neural synapse. In comparison to butyrylcholinesterase which is an enzyme primarily found out of central neural system, donepezil hydrochloride is a 1000 times more potent inhibitor of acetylcholinesterase. With this effect of its, donepezil can be effective in symptoms caused by deficit of cholinergic transmission in Alzheimer's disease.

When commonness of Alzheimer's disease and similar neurological diseases is taken into consideration, it is observed that this is an increasing problem for community health. It is obvious that it would be a very significant contribution to economy in addition to protection of human health to treat these diseases or alleviate their symptoms.

As a result of various studies they conducted in this direction, the inventors have surprisingly discovered that combinations wherein idebenone and donepezil are used together induce synergistic effect in the treatment of cerebral arteriosclerosis, symptoms following stroke and cerebral hemorrhage, age-associated cognitive decline, chronic cerebrovascular disease, multi-infarct dementia and mild and moderate Alzheimer's type dementia and frailty, speech disorders, memory loss, short attention span associated with these diseases, symptoms of vascular and degenerative cerebral pathologies such as psychomotor activity and depression.

Said synergistic effect could be in form of;

• Reducing the doses needed to obtain the required therapeutic effect in the case that said combination is used in comparison to the amount needed when only idebenone or only donepezil is used in the treatment and/or

• Reducing the adverse effects and/or

• Observing the therapeutic effect in a shorter amount of time and/or • Observing the therapeutic effect for a longer period of time and/or

• Providing a more efficient treatment.

The inventors have shown the synergistic effect of the combination of the present invention with a multicenter, double-blind clinical study conducted on 102 elderly patients having mild or moderate Alzheimer's type dementia. For said study, the patients were administered only idebenone, only donepezil, donepezil and idebenone together and the results were evaluated versus placebo.

Clinical evaluation was conducted in the beginning of the study, in later months (30 ^th , 60 ^th , 90 ^th and 120 ^th months) and in a following month (150 ^th month). At the end of the study, the inventors observed that formulations in which donepezil and idebenone were used together provided statistically significant improvement memory, concentration and behaviors in comparison to the treatment method in which the two active agents were used separately. These positive cognitive and behavioral findings were started to be observed in the first week of the treatment and continued increasingly in the following treatment periods. In conclusion, the present invention indicates that pharmaceutical compositions where idebenone and donepezil are used together or simultaneously provide higher therapeutic benefit than compositions where these two agents are used separately.

In another aspect, combined use of idebenone and donepezil enables the therapeutic effect to be observed sooner and be stronger in comparison to use of these two active agents alone. It is possible to provide a more efficient treatment to patients this way.

Surprisingly, all these positive effects are seen when the two active agents are given at the same time in a single dosage form or simultaneously in separate dosage forms as well as seen in combinations where the two active agents are given sequentially. High therapeutic benefit can be observed as longer duration of time. According to this, the present invention is related to pharmaceutical compositions comprising idebenone and donepezil in separate dosage forms for sequential use, in separate dosage forms for simultaneous use or in the same dosage form to be administered at the same time.

In another aspect, the present invention provides a method used in the symptomatic treatment of cerebral arteriosclerosis, symptoms following stroke and cerebral hemorrhage, age- associated cognitive decline, chronic cerebrovascular disease, multi-infarct dementia and mild emu moderate Alzheimer's type dementia by administering effective amounts of idebenone and donepezil.

In an aspect, the present invention is related to pharmaceutical compositions comprising pharmaceutically effective amounts of idebenone and donepezil and at least one pharmaceutically acceptable excipient.

In said pharmaceutical compositions, idebenone and donepezil can be comprised in a single formulation with at least one pharmaceutically acceptable excipient while idebenone and donepezil can also be formulated separately with at least one pharmaceutically acceptable excipient. The separate formulations obtained can be combined in a single dosage form or can be prepared to be in separate dosage forms. In the case that the formulations are in separate dosage forms, said dosage forms can be the same or different.

At the same time, the present invention is related to use of idebenone and donepezil in accordance with the invention for preparation of a drug so as to be used in the combination therapy by simultaneous, sequential or separate administration in the treatment of cerebral arteriosclerosis, symptoms following stroke and cerebral hemorrhage, age-associated cognitive decline, chronic cerebrovascular disease, multi-infarct dementia and mild and moderate Alzheimer's type dementia and frailty, speech disorders, memory loss, short attention span associated with these diseases, symptoms of vascular and degenerative cerebral pathologies such as psychomotor activity and depression. Idebenone comprised in the pharmaceutical compositions of the present invention can be in the form of its pharmaceutically acceptable salts, hydrates, solvates, esters, enantiomers, diastereomers and/or in any of polymorphic forms such as amorphous, crystalline form or combinations thereof.

Donepezil comprised in the pharmaceutical compositions of the present invention can be in the form of its pharmaceutically acceptable salts, hydrates, solvates, esters, enantiomers, diastereomers and/or in any of polymorphic forms such as amorphous, crystalline form or combinations thereof. Donepezil is preferably in donepezil hydrochloride form.

The pharmaceutical compositions of the present invention can be prepared in any of the dosage forms of tablet, effervescent tablet, effervescent granule, effervescent dry powder, film coated tablet, enteric-coated tablet, dry powder, granule, capsule, prolonged release tablet, modified release tablet, delayed release tablet, orodispersible tablet, chewing tablet. ι iioimaceutical compositions comprising idebenone and donepezil can be in form of any of these dosage forms in combination, while idebenone and donepezil can also be in form of any of these dosage forms in the case that they are stored in separate dosage forms. In other terms, the compositions comprising the combination of the present invention can be in form of any of these dosage forms or combination of these dosage forms or a treatment pack composed of this combination.

In the case that idebenone and donepezil are in the same dosage form, the pharmaceutical compositions of the present invention are preferably in film coated tablet dosage form.

The pharmaceutical compositions of the present invention comprising idebenone and donepezil can comprise various excipients in addition to the active agents.

The pharmaceutical compositions of the present invention comprising idebenone and donepezil comprise at least one excipient in addition to the active agents selected from a group comprising disintegrant, diluent, lubricant, glidant, filling agents, binder, effervescent couple composed of at least one effervescent acid and at least one effervescent base, coloring agent, pH regulating agent, surfactant, stabilizing agent, sweetener and/or taste regulating agent, flavoring agent.

The filling agents that can be used in the pharmaceutical compositions of the present invention can be selected from a group comprising lactose,, lactose anhydrate, lactose monohydrate, maltodextrin, sugar, starch, modified starch, mannitol, sorbitol, inorganic salts, microcrystalline cellulose, cellulose, calcium sulfate, xylitol and lactitol or combinations thereof.

The disintegrant that can be used in the pharmaceutical compositions of the present invention can be selected from a group comprising carboxymethyl cellulose, carboxymethyl cellulose calcium, carboxymethyl cellulose sodium, croscarmellose sodium, crospovidone, hydroxypropyl cellulose, microcrystalline cellulose, methyl cellulose, chitosan, starch, sodium starch glycolate.

The diluent that can be used in the pharmaceutical compositions of the present invention can be selected from a group comprising calcium carbonate, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulfate, microcrystalline cellulose, dextrose, fructose, lactitol, lactose, magnesium carbonate, magnesium oxide, maltitol, maltodextrin, maltose, mannitol, simethicone, sorbitol, starch, sodium chloride, sucrose, talc, xylitol. i uc lubricant that can be used in the pharmaceutical compositions of the present invention can be selected from a group comprising calcium stearate, magnesium stearate, polyethylene glycol, sodium benzoate, potassium benzoate, sodium lauryl sulfate, talc, stearic acid, zinc stearate. The glidant that can be used in the pharmaceutical compositions of the present invention can be selected from a group comprising tribasic calcium phosphate, colloidal silicon dioxide, magnesium silicate, magnesium trisilicate, talc.

The binder that can be used in the pharmaceutical compositions of the present invention can be selected from a group comprising carboxymethyl cellulose sodium, ethyl cellulose, gelatin, hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, magnesium aluminum silicate, maltodextrin, methyl cellulose, povidone, starch.

The acidic agent composing the effervescent couple comprising at least one acidic agent and at least one basic agent that can be used in the pharmaceutical compositions of the present invention can be selected from a group comprising organic acids such as malic acid, citric acid, tartaric acid, fumaric acid or pharmaceutically acceptable salts of these acids; and the basic agents can be selected from a group comprising agents such as sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate.

The pH regulating agent that can be used in the pharmaceutical compositions of the invention can be selected from citrate, phosphate, carbonate, tartrate, fumarate, acetate and amino acid salts.

The surfactant that can be used in the pharmaceutical compositions of the invention can be selected from sodium lauryl sulphate, polysorbate, polyoxyethylene, polyoxypropylene glycol and similar agents. The stabilizing agent that can be used in the pharmaceutical compositions of the invention can be selected from a group comprising tocopherol, tetrasodium edetate, nicotinamide, cyclodextrin.

The sweetener and/or taste regulating agent that can be used in the pharmaceutical compositions of the invention can be selected from a group comprising acesulfame, dextrose, fructose, maltitol, maltose, mannitol, saccharine, saccharine sodium, sodium cyclamate, sorbitol, sucralose, sucrose, xylitol, sodium chloride.

The flavoring agent that can be used in the pharmaceutical compositions of the invention can be selected from flavors such as menthol, lemon, orange, vanilla, strawberry, raspberry, caramel and the like.

The pharmaceutical compositions of the present invention comprise idebenone in the range of 1% and 50%, preferably in the range of 1% and 45%, more preferably in the range of 1% and 40% by weight.

The pharmaceutical compositions of the present invention comprise donepezil in the range of 0.1%) and 30%, preferably in the range of 0.1% arid 25%, more preferably in the ^" range of 0.1% and 20% by weight.

The amount of idebenone comprised in the pharmaceutical compositions of the present invention is in the range of 10 mg and 300 mg, preferably in the range of 10 mg and 250 mg, more preferably in the range of 10 mg and 200 mg. The amount of donepezil comprised in the pharmaceutical compositions of the. present invention is in the range of 1 mg and 100 mg, preferably in the range of 1 mg and 75 mg, more preferably in the range of 1 mg and 50 mg.

The ratio of idebenone and donepezil in the pharmaceutical compositions of the present invention to each other is in the range of 1 :20 and 20: L preferably in the range of 1 : 10 and 18:1 , more preferably in the range of 1 : 5 and 15: 1 by weight respectively.

In other terms, the present invention discloses pharmaceutical compositions comprising idebenone and donepezil whose ratio to each other is in the range of 1 :20 and 20: 1, preferably in the range of 1 : 10 and 18: 1, more preferably in the range o 1 :5 and 15: 1 by weight respectively. In other terms, for the therapeutic effect provided by the present invention to be observed, the ratio of idebenone and donepezil to each other should be in the range of 1 :20 and 20: 1 , preferably in the range of 1 : 10 and 18: 1 , more preferably in the range of 1 :5 and 15: 1 by weight respectively. nit pharmaceutical compositions of the present invention comprising idebenone and donepezil can optionally comprise a third active agent in addition to the active agents, -

The third active agent that can be comprised in the pharmaceutical compositions can be selected from a group comprising antacid, anticholinergic, antispasmodic, antiemetic, antibiotic, antipropulsive, antiallergic, antidiarrheal, antiobesity, antithrombotic, antifibrinolytic, antianemic, antihypertensive, antifungal, anti-dementia, antipruritic, antipsoriatic, antibiotic, antiseptic, antiacne, antibacterial, antimycotic, antiviral, antineoplastic, antiarrhythmic, antiadrenergic, antiepileptic, anti-parkinson, antiprotozoal, anthelmintic, anti-inflammatory, diuretic, laxative, sulphonamide, imidazole, corticosteroid, thiazolidinedione, biguanide, immunostimulant, immunosuppressant, myorelaxant, analgesic, psycholeptic, psychoanaleptic peripheral vasodilator, beta blocker, calcium channel blocker and lipid modifying agents; alpha-glucosidase inhibitors, aldose fedueta ^{^} se inhibitors, ACE inhibitors; multivitamin and minerals, vitamin A, vitamin D and its analogues, vitamin vitamin C, vitamin E, vitamin B _6; vitamin B _2> vitamin K, calcium, potassium, sodium, zinc, magnesium, fluoride, selenium. ^{" * " "" "" ' "}

Optionally, the pharmaceutical compositions of the present invention comprising idebenone and donepezil preferably comprise an anti-dementia agent as the third active agent.

The anti-dementia agents that can be comprised in the pharmaceutical compositions of the present invention can be selected from a group comprising donepezil, galantamine, rivastigmine, ginkgo biloba extract, tacrine and/or their pharmaceutically acceptable salts, enantiomers, hydrates, anhydrates etc. derivatives thereof.

The pharmaceutical composition of the present invention is obtained by a method composed of the steps of;

• Mixing the active agents idebenone and donepezil homogeneously and adding at least one of the excipients given above if required or

• Granulating the active agents idebenone and- donepezil with a granulation solution comprising at least one of the excipients and then mixing it with the other excipients homogeneously or

• Granulating the mixture comprising the active agents idebenone and donepezil, at least one of the excipients given above with a granulation solution and then mixing it with the other excipients homogeneously or -» Mixing the active agents idebenone and donepezil with at least one of the excipients given above and granulating it with a granulation solution comprising at least one excipient or

• Using any of the methods mentioned above for the active agent compositions separately and combining the obtained formulations or storing them in different dosage forms in the case that idebenone and donepezil in two different formulations.

In the case that the pharmaceutical compositions comprise a third active agent in addition to idebenone and donepezil, the third active agent is added to the formulations by any of the production methods given above and in any step of said production method.

The pharmaceutical composition or compositions obtained can be formed into any of -the dosage forms mentioned above. In the case that they ;are in tablet form, the obtained tablets can be treated with film coating agents, for instance with sugar based coating agents, water soluble film coating agents, enteric coating agents, delayed release coating agents or coating formulations comprising any combination thereof. . ^ .

Saccharose can be used singly or optionally with any of the agents such as talcy ^" calcium ^*" carbonate, calcium phosphate, gelatine, gum arable; polyvinylpyrrolidone and pullulan or an combination thereof as the sugar based coating agent. - ^■ ·

The water-soluble film coating agent can be selected from cellulose derivatives such as hydroxypropyl cellulose, hydroxypropyl methylcellulose, ⁷ hyUfoxyethy! cellulose, ^' methyl hydroxyethyl cellulose and sodium carboxymethyl cellulose: synthetic polymers such as polyvinyl acetal diethyl aminoacetate, aminoalkyl methacrylate copolymers and polyvinylpyrrolidone and polysaccharides such as pullulan or combinations thereof.

The enteric coating agents can be selected from cellulose derivatives such as hydroxypropyl methyl cellulose phthalate, hydroxypropyl methylcellulose acetate succinate, carboxymethyl ethyl cellulose, cellulose acetate phthalate; acrylic acid derivatives such as methacrylic acid copolymer L, methacrylic acid copolymer LD and methacrylic acid copolymer S and natural substances such as shellac or combinations thereof.

The delayed-release coating agent can be selected from a group comprising cellulose derivatives such as ethyl cellulose; acrylic acid derivatives such as aminoalkyl methacrylate copolymer S, ethyl acrylate methyl methacrylate copolymer emulsion or combinations thereof. ny. pharmaceutical compositions of the present invention can be used in symptomatic treatment of cerebral arteriosclerosis, symptoms following stroke and cerebral- hemorrhage, age-associated cognitive decline, chronic cerebrovascular disease, multi-infarct dementia and mild and moderate Alzheimer's type dementia. The examples below are given in order to explain the formulations of the present invention; yet, the invention cannot be limited to these examples.

EXAMPLE 1:

Production Method:

Idebenone, donepezil hydrochloride, diluent and the filling agent are mixed. The mixture is wet-granulated with a granulation solution comprising the binder and at least one solvent. The granules are dried and sieved. The disintegrant is added to the obtained dry granules. The mixture is treated with the lubricant. The final mixture is compressed in tablet form and the tablets are coated with film. L^. PLE 2:

Production Method:

Idebenone, memantine hydrochloride, donepezil hydrochloride; diluent and the filling agent are mixed. The mixture is wet-granulated with a granulation solution. comprising the binder and at least one solvent. The granules are dried and sieved. The disintegrant is added to the obtained dry granules. The mixture is treated with the lubricant. The final mixture is compressed in tablet form and the tablets are coated with film.