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WO2014035355A1 - Pharmaceutical combination comprising idebenone and memantine - Google Patents

Pharmaceutical combination comprising idebenone and memantine Download PDF

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Publication number
WO2014035355A1
WO2014035355A1 PCT/TR2013/000282 TR2013000282W WO2014035355A1 WO 2014035355 A1 WO2014035355 A1 WO 2014035355A1 TR 2013000282 W TR2013000282 W TR 2013000282W WO 2014035355 A1 WO2014035355 A1 WO 2014035355A1
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WO
WIPO (PCT)
Prior art keywords
idebenone
memantine
pharmaceutical composition
range
vitamin
Prior art date
Application number
PCT/TR2013/000282
Other languages
French (fr)
Inventor
Mahmut Bilgic
Original Assignee
Mahmut Bilgic
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Mahmut Bilgic filed Critical Mahmut Bilgic
Publication of WO2014035355A1 publication Critical patent/WO2014035355A1/en

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    • 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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Abstract

The present invention is related to pharmaceutical compositions comprising idebenone and memantine in combination which are 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.

Description

DESCRIPTION
PHARMACEUTICAL COMBINATIONS COMPRISING A QUINONE DERIVATIVE ACTIVE AGENT
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.
Figure imgf000002_0001
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.
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).
Figure imgf000003_0001
Formula II: Memantine
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. Today, drugs comprising memantine are marketed in different dosage forms (oral drop, solution, effervescent tablet and film tablet).
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.
Therefore, there is need for new, effective treatments so as to be used particularly in the treatment of central nervous system diseases such as 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. The studies that the inventor conducted in this direction has pointed out that use of idebenone and memantine together provided an unexpected therapeutic benefit.
Said therapeutic 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 memantine 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 f time and or
• Providing a more efficient treatment.
In another aspect, the pharmaceutical composition wherein idebenpne and memantine are used together or simultaneously provides higher therapeutic benefit in comparison to compositions wherein these two agents are used separately.
In another aspect, combined use of idebenone and memantine enables to observe the therapeutic effect in a short time and this effect is stronger compared to use of these two active agents on their own. It is possible to provide a more efficient treatment to patients this way. Surprisingly, all these positive effects can be seen in combinations where the two active agents are given sequentially as well as when the two active agents are given at the same time in a single dosage form or simultaneously in separate dosage forms. High therapeutic benefit can also be observed as long duration of time.
According to this, 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.
In another aspect, 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. In an aspect, the present invention is related to pharmaceutical compositions comprising pharmaceutically effective amounts of idebenone and memantine and at least one pharmaceutically acceptable excipient. in said pharmaceutical composition, 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.
At the same time, 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.
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.
Pharmaceutical 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. 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 pharmaceutical compositions of the present invention comprising idebenone and memantine, the active agents are preferably in the same dosage form. The dosage form of the present invention is preferably film coated tablet dosage form.
The pharmaceutical compositions of the present invention comprising idebenone and memantine can comprise various excipients in addition to the active agents.
The pharmaceutical 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. 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 ^
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 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.
The pharmaceutical 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.
The pharmaceutical 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, psychoanaleptic peripheral vasodilator, beta blocker, calcium channel blocker and lipid modifying agents; alpha-glucosidase inhibitors, aldose reductase inhibitors, ACE inhibitors; multivitamin and minerals, vitamin A, vitamin D and its analogues, vitamin B|, vitamin C, vitamin E, vitamin B6; vitamin B2: vitamin , calcium, potassium, sodium, zinc, magnesium, fluoride, selenium. Optionally, the pharmaceutical compositions of the present invention comprising idebenone and memantine 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 memantine homogeneously and adding at least one of the excipients given above if required or
• Granulating the active agents idebenone and memantine 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 memantine, 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 memantine 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 memantine in two different formulations.
In the case that the pharmaceutical 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. 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 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.
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.
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:
Figure imgf000011_0001
Production Method:
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.
EXAMPLE 2:
Figure imgf000011_0002
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.

Claims

1. A pharmaceutical composition comprising idebenone and memantine combination as the active agent.
2. The pharmaceutical composition comprising idebenone and memantine according to claim 1, characterized in that said composition comprises idebenone in the range of 10 mg and 300 mg.
3. The pharmaceutical composition comprising idebenone and memantine according to claims 1-2, characterized in that said composition comprises idebenone in the range of 10 mg and 250 mg.
4. The pharmaceutical composition comprising idebenone and memantine according to claims 1-3, characterized in that said composition comprises idebenone in the range of 10 mg and 200 mg.
5. The pharmaceutical composition comprising idebenone and memantine according to claims 1-4, characterized in that said composition comprises memantine in the range of 1 mg and 50 mg.
6. The pharmaceutical composition comprising idebenone and memantine according to claims 1-5, characterized in that said composition comprises memantine in the range of 1 mg and 45 mg.
7. The pharmaceutical composition comprising idebenone and memantine according to claims 1-6, characterized in that said composition comprises memantine in the range of 1 mg and 40 mg.
8. The pharmaceutical composition comprising idebenone and memantine according to claims 1-7, characterized in that idebenone in said compositions is 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.
9. The pharmaceutical composition comprising idebenone and memantine according to claims 1-8, characterized in that memantine in said compositions is 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.
10. The pharmaceutical composition comprising idebenone and memantine according to claim 9, characterized in that memantine in said compositions is memantine hydrochloride.
IT . The pharmaceutical composition comprising idebenone and memantine according to claims 1-10, characterized in that idebenone and memantine are in the same pharmaceutical formulation.
12. The pharmaceutical composition comprising idebenone and memantine according to claim 11, characterized in that said composition is in form 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 or combinations thereof.
13. The pharmaceutical composition comprising idebenone and memantine according to claims 11-12, characterized in that said composition Js in_ form of film coated tablet dosage form.
14. The pharmaceutical composition comprising idebenone and" memantine according to any preceding claims, characterized in that said composition comprises at least one pharmaceutically acceptable excipient in addition to the active agents.
15. The pharmaceutical composition comprising idebenone and memantine according to claims 14, characterized in that said composition comprises at least one pharmaceutically acceptable excipient 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 in addition to the active agent.
16. The pharmaceutical composition comprising idebenone and memantine according to any preceding claims, characterized in that said composition comprises idebenone in the range of 1% and 50% by weight.
17. The pharmaceutical composition comprising idebenone and memantine according to any preceding claims, characterized in that said composition comprises memantine in the range of 0.1% and 20% by weight.
18. The pharmaceutical composition comprising idebenone and memantine according to any preceding claims, characterized in that said composition comprises at least a third active agent in addition to the active agents 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 reductase inhibitors, ACE inhibitors; multivitamin and minerals, vitamin A, vitamin D and its analogues, vitamin Bi, vitamin C, vitamin E, vitamin B6, vitamin B2j vitamin K, calcium, potassium, sodium, zinc, magnesium, fluoride, selenium. -
19. A pharmaceutical composition comprising the active agents idebenone and memantine in the same or different dosage forms used sequentially, at the same time or simultaneously.
20. A pharmaceutical composition comprising a combination of idebenone in the range of 10 mg and 300 mg and memantine in the range of 1 mg and 50 mg.
21. A pharmaceutical composition comprising idebenone and memantine and having the ratio of these two active agents to each other in the range of 1 : 10 and 30:1 by weight respectively.
PCT/TR2013/000282 2012-08-31 2013-08-29 Pharmaceutical combination comprising idebenone and memantine WO2014035355A1 (en)

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US12274703B2 (en) 2017-12-21 2025-04-15 Gliapharm Sa Compositions and methods of treatment for neurological disorders comprising a dementia
US12310967B2 (en) 2017-12-21 2025-05-27 Gliapharm Sa Compositions and methods of treatment for neurological disorders comprising motor neuron diseases

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Publication number Priority date Publication date Assignee Title
US9750705B2 (en) 2012-08-31 2017-09-05 The Regents Of The University Of California Agents useful for treating obesity, diabetes and related disorders
US12274703B2 (en) 2017-12-21 2025-04-15 Gliapharm Sa Compositions and methods of treatment for neurological disorders comprising a dementia
US12310967B2 (en) 2017-12-21 2025-05-27 Gliapharm Sa Compositions and methods of treatment for neurological disorders comprising motor neuron diseases

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