Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/12—Ketones
  • A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/13—Amines
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/2004—Excipients; Inactive ingredients

Definitions

• the present invention is related to pharmaceutical compositions used 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.
• Memantine is a non-competitive N-methyl-D-aspartate(NMDA) receptor antagonist neuroprotective drug having the chemical name 3,5-dimethyladamantan-l -amine which is effective against dementia (Formula II).
• the active agent was first approved in Germany in 1982 for use in the treatment of various neurological diseases; and by US Food and Drug Administration (FDA) in 2003 for use in the treatment of mild and moderate Alzheimer's disease.
• FDA Food and Drug Administration
• Nervous system diseases having genetic etiology can generally present symptoms in neonatal and early childhood years as well as at later ages. Especially in western societies where the population over middle-age is increasing; Alzheimer's disease, ALs and many similar neurological diseases come into prominence as affecting morbidity and mortality to a considerable extent. According to 2011 's data, 16.9% of the drug consumption in the world belongs to central nervous system drug group.
• Said therapeutic effect could be in form of
• compositions wherein idebenpne and memantine are used together or simultaneously provides higher therapeutic benefit in comparison to compositions wherein these two agents are used separately.
• the present invention is related to pharmaceutical compositions comprising idebenone and memantine so as to be administered in separate dosage forms for sequential use; in separate dosage forms for simultaneous use or in the same dosage form for use at the same time.
• the present invention provides a method treating cerebral arteriosclerosis, jsymptoms 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 by administering effective amounts of idebenone and memantine.
• the present invention is related to pharmaceutical compositions comprising pharmaceutically effective amounts of idebenone and memantine and at least one pharmaceutically acceptable excipient.
• idebenone and memantine can be comprised in a single formulation with at least one pharmaceutically acceptable excipient while idebenone and memantine 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.
• the present invention is related to use of idebenone and memantine 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.
• Memantine 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.
• Memantine is preferably in memantine hydrochloride form.
• 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.
• compositions comprising idebenone and memantine can be in form of any of these dosage forms in combination, while idebenone and memantine can also be in form of any of these dosage forms in the case that they are stored in separate dosage forms.
• 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.
• the active agents are preferably in the same dosage form.
• the dosage form of the present invention is preferably film coated tablet dosage form.
• compositions of the present invention comprising idebenone and memantine can comprise various excipients in addition to the active agents.
• compositions of the present invention comprising idebenone and memantine comprise at least one excipient in addition to the active agents selected from a group comprising disintegrant, diluent, lubricant, glidant, filling agent, 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.
• active agents selected from a group comprising disintegrant, diluent, lubricant, glidant, filling agent, 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 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 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 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.
• the 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 cellulos_e ? , 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 orga ⁇
• 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 he nvention-can be selected from sodium lauryl sulphate, polysorbatc, polyoxyethylene, polyoxypropylcne 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, aspartame, 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 preferabl in the range of 1% and 40% by weight.
• compositions of the present invention comprise memantine in the range of 0.1% and 20%, preferably in the range of 0.1% and 15%, more preferably in the range of 0.1 % and 10% 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 memantine comprised in the pharmaceutical compositions of the present invention is in the range of 1 mg and 50 mg, preferably in the range of 1 mg and 45 mg, more preferably in the range of 1 mg and 40 mg.
• the ratio of idebenone and memantine in the pharmaceutical compositions of the present invention to each other is in the range of 1 :10 and 30: 1, preferably in the range of 1 :7 and 28: 1 , more preferably in the range of 1 :5 and 25 : 1 by weight respectively.
• compositions of the present invention comprising idebenone and memantine 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,
• 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.
• composition of the present invention is obtained by a method composed of the steps of;
• compositions comprise a third active agent in addition to idebenone and memantine
• 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.
• 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 talc, calcium, carbonate, calcium phosphate, gelatine, gum arabic, polyvinylpyrrolidone and pullulan or any 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, hydroxyethyl cellulose, methyl hydroxyethyl cellulose and sodium carboxymethyl .
• cell-uLose ⁇ -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.
• 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 RS, ethyl acrylate methyl methacrylate copolymer emulsion or combinations thereof.
• the pharmaceutical composition of the present invention can be used in prophylaxis and 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, memantine 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.
• 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.

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Cited By (4)

Citations (3)

• 2013
  • 2013-08-29 WO PCT/TR2013/000282 patent/WO2014035355A1/fr not_active Ceased

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