WO2014055047A1 - Combinaison d'un agent actif dérivé de la quinone et d'une cholinestérase - Google Patents

Combinaison d'un agent actif dérivé de la quinone et d'une cholinestérase Download PDF

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Publication number
WO2014055047A1
WO2014055047A1 PCT/TR2013/000281 TR2013000281W WO2014055047A1 WO 2014055047 A1 WO2014055047 A1 WO 2014055047A1 TR 2013000281 W TR2013000281 W TR 2013000281W WO 2014055047 A1 WO2014055047 A1 WO 2014055047A1
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WO
WIPO (PCT)
Prior art keywords
donepezil
idebenone
pharmaceutical compositions
compositions
range
Prior art date
Application number
PCT/TR2013/000281
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English (en)
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 WO2014055047A1 publication Critical patent/WO2014055047A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • 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
    • 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

Definitions

  • 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.
  • 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.
  • Acetylcholinesterase inhibitors 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.
  • 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.
  • 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.
  • the patients were administered only idebenone, only donepezil, donepezil and idebenone together and the results were evaluated versus placebo.
  • 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.
  • 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.
  • 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.
  • the present invention is related to pharmaceutical compositions comprising pharmaceutically effective amounts of idebenone and donepezil and at least one pharmaceutically acceptable excipient.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • compositions of the present invention are preferably in film coated tablet dosage form.
  • compositions of the present invention comprising idebenone and donepezil can comprise various excipients in addition to the active agents.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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, psychoan
  • 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.
  • 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 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.
  • 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.
  • 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.
  • 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 S, ethyl acrylate methyl methacrylate copolymer emulsion or combinations thereof.
  • 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.
  • 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.
  • 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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  • Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Epidemiology (AREA)
  • Neurosurgery (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Neurology (AREA)
  • Biomedical Technology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

La présente invention concerne de nouvelles compositions pharmaceutiques destinées à être utilisées dans le traitement symptomatique de l'artériosclérose cérébrale, de symptômes consécutifs à un accident vasculaire cérébral et à une hémorragie cérébrale, du déclin cognitif lié à l'âge, de la maladie cérébrovasculaire chronique, de la démence vasculaire et de la démence légère et modérée de type Alzheimer.
PCT/TR2013/000281 2012-08-31 2013-08-29 Combinaison d'un agent actif dérivé de la quinone et d'une cholinestérase WO2014055047A1 (fr)

Applications Claiming Priority (2)

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TR2012/09945 2012-08-31
TR201209945 2012-08-31

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WO2014055047A1 true WO2014055047A1 (fr) 2014-04-10

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Cited By (2)

* Cited by examiner, † Cited by third party
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
EP3520792A4 (fr) * 2016-09-30 2020-06-03 Bio Pharmartis Co., Ltd. Composition pharmaceutique pour la prévention ou le traitement d'une démence et d'un dysfonctionnement cognitif, contenant du donépézil ou un sel de qualité pharmaceutique de celui-ci et de la mémantine ou un sel de qualité pharmaceutique de celle-ci, et son procédé de préparation

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5962535A (en) * 1997-01-17 1999-10-05 Takeda Chemical Industries, Ltd. Composition for alzheimer's disease
WO2003101458A1 (fr) * 2002-05-31 2003-12-11 H. Lundbeck A/S Combinaison d'un antagoniste de n-methyl d-aspartate et d'inhibiteurs de l'esterase d'acetylcholine pour le traitement de la maladie d'alzheimer
WO2012026902A1 (fr) * 2010-08-25 2012-03-01 Mahmut Bilgic Combinaisons comprenant du donépézil, de la mémantine et de l'extrait de gingko biloba

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5962535A (en) * 1997-01-17 1999-10-05 Takeda Chemical Industries, Ltd. Composition for alzheimer's disease
WO2003101458A1 (fr) * 2002-05-31 2003-12-11 H. Lundbeck A/S Combinaison d'un antagoniste de n-methyl d-aspartate et d'inhibiteurs de l'esterase d'acetylcholine pour le traitement de la maladie d'alzheimer
WO2012026902A1 (fr) * 2010-08-25 2012-03-01 Mahmut Bilgic Combinaisons comprenant du donépézil, de la mémantine et de l'extrait de gingko biloba

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
DEARY I ET AL: "Idebenone: A guide to its use in Alzheimers disease, other age-related cognitive disorders and Friedreichs ataxia", DRUGS AND THERAPY PERSPECTIVES, ADIS INTERNATIONAL, AUCKLAND, NZ, vol. 26, no. 2, January 2010 (2010-01-01), pages 1 - 5, XP009175499, ISSN: 1172-0360, DOI: 10.2165/11203510-000000000-00000 *
RIVEROL M ET AL: "Efficacy and tolerability of a combination treatment of memantine and donepezil for alzheimer's disease: A literature review evidence", EUROPEAN NEUROLOGICAL JOURNAL 2011 SAN LUCAS MEDICAL LTD GBR, vol. 3, no. 1, 2011, pages 15 - 19, XP002718911, ISSN: 2041-8000 *
SELTZER B: "Donepezil: An update", EXPERT OPINION ON PHARMACOTHERAPY 200705 GB, vol. 8, no. 7, May 2007 (2007-05-01), pages 1011 - 1023, XP009175600, ISSN: 1465-6566 *

Cited By (2)

* Cited by examiner, † Cited by third party
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
EP3520792A4 (fr) * 2016-09-30 2020-06-03 Bio Pharmartis Co., Ltd. Composition pharmaceutique pour la prévention ou le traitement d'une démence et d'un dysfonctionnement cognitif, contenant du donépézil ou un sel de qualité pharmaceutique de celui-ci et de la mémantine ou un sel de qualité pharmaceutique de celle-ci, et son procédé de préparation

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