WO2012026902A1 - Combinaisons comprenant du donépézil, de la mémantine et de l'extrait de gingko biloba - Google Patents

Combinaisons comprenant du donépézil, de la mémantine et de l'extrait de gingko biloba Download PDF

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Publication number
WO2012026902A1
WO2012026902A1 PCT/TR2011/000190 TR2011000190W WO2012026902A1 WO 2012026902 A1 WO2012026902 A1 WO 2012026902A1 TR 2011000190 W TR2011000190 W TR 2011000190W WO 2012026902 A1 WO2012026902 A1 WO 2012026902A1
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Prior art keywords
combination
comprised
combination according
donepezil
memantine
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PCT/TR2011/000190
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English (en)
Inventor
Mahmut Bilgic
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Mahmut Bilgic
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Publication of WO2012026902A1 publication Critical patent/WO2012026902A1/fr

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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
    • A61K31/13—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
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/16—Ginkgophyta, e.g. Ginkgoaceae (Ginkgo family)
    • 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
    • A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
    • A61K9/0007—Effervescent
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • 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 relates to combinations comprising donepezil, memantine and ginkgo biloba extract or any pharmaceutically acceptable derivative thereof; and use of this type of dosage forms in the treatment of Alzheimer's disease.
  • Alzheimer's disease is a slow progressing neurodegenerative disease which is characterized by declined vital activities and degenerated cognitive abilities accompanied by behavior changes. Frequency of the disease is 2% among individuals aged 65-70 while this percentage reaches up to 20% among individuals aged 80 or over.
  • the drug group commonly used in the treatment of Alzheimer's disease is acetylcholinesterase inhibitors.
  • Donepezil ⁇ formula I which is an acetylcholinesterase, was first disclosed in the patent numbered EP0296560 and its use in Alzheimer type dementia was referred in that patent document.
  • Donepezil inhibits acetylcholinesterase enzyme which is responsible for destruction of acetylcholine and enables acetylcholine levels to increase. Increase of acetylcholine levels in cerebral cortex is considered responsible for improvements in thinking, learning and memory. However, functionality of this mechanism requires existence of strong cholinergic neurons. As progression of Alzheimer's disease leads to decrease in the number of strong cholinergic neurons, activity of donepezil is lower in such cases.
  • Memantine (formula 2), which is another molecule used in the treatment of Alzheimer's disease, is a non-competitive N-methyl-D-aspartate receptor antagonist neuroprotective drug effective on dementia. It is alleged that neurodegeneration seen in acute and chronic diseases such as hypoxia, ischemia, paralysis and Alzheimer's disease is related with excessively released glutamate. Memantine blocks effects of pathologically increased tonic glutamate levels which cause neural dysfunction.
  • Ginkgo biloba extract that is another substance used in improving cognitive skills in dementia and Alzheimer's disease is an extract obtained from leaves of ginkgo biloba tree which comprises (according to German pharmacopeia) 5-7% of terpene trilactone, 22-27% of ginkgo flavones glycoside and ginkgolic acid less than 5 ppm.
  • Ginkgo biloba extract that has neuroprotective activity is recommended for use in individuals who have busy, stressful professions requiring attention in order to increase attention, energy and performance. It is a natural solution for those who have problem of forgetfulness resulting from stress and intense work pressure. It provides energy support while reinforcing memory and concentration.
  • EP 1509232 discloses that use of acetylcholinesterase inhibitors such as donepezil, galanthamine, rivastigmine and tacrine in combination with memantine is a more effective method in the treatment of Alzheimer's disease in comparison with present monotherapies. However, said combined therapy remains insufficient for many patients.
  • the present invention relates to combinations comprising donepezil, memantine and ginkgo biloba extract or any pharmaceutically acceptable derivative thereof.
  • the present invention relates to use of combinations comprising donepezil, memantine and ginkgo biloba extract in the treatment of Alzheimer's disease.
  • Donepezil comprised in the combination of the present invention can be in the form of its pharmaceutically acceptable hydrates, solvates, esters, enantiomers, polymorphs, crystalline forms, amorphous forms, salts or in free base form and/or combinations thereof.
  • Donepezil comprised in the combination of the present invention is in salt form.
  • Said salts can be selected from a group comprising organic acid salts such as hydrochloride, hydrobromide, sulfate, phosphate, formate, acetate, trifluoroacetate, methanesulphonate, benzenesulphonate, toluenesulphonate; alkali metal salts such as sodium, potassium; alkaline earth metal salts such as calcium, magnesium; organic amine salts such as trimethylamine, triethylamine, pyridine, picoline, dicyclohexylamine or a combination thereof.
  • organic acid salts such as hydrochloride, hydrobromide, sulfate, phosphate, formate, acetate, trifluoroacetate, methanesulphonate, benzenesulphonate, toluenesulphonate
  • alkali metal salts such as sodium, potassium
  • alkaline earth metal salts such as calcium, magnesium
  • organic amine salts such as trimethylamine, tri
  • Donepezil comprised in the formulation of the present invention is in donepezil hydrochloride form.
  • the amount of donepezil comprised in the combination of the present invention is in the range of 0,1-500 mg, preferably in the range of 1-100 mg, more preferably in the range of 2- 50 mg.
  • Memantine comprised in the combination of the present invention can be in the form of its pharmaceutically acceptable hydrates, solvates, esters, enantiomers, polymorphs, crystalline forms, amorphous forms, salts or in free base form and/or combinations thereof.
  • Memantine comprised in the combination of the present invention is in salt form.
  • Said salts are hydrochloride, hydrobromide, hydroiodide, perchloride, sulfate, malate, tartrate, citrate, benzoate, carbonate, cinnamate, mandelate, methyl sulfonate, methanesulphonate, ethanesulphonate, hydroxyethanesullphonate, benzene sulphonate, p-toluene sulphonate, cyclohexane sulphonate, salicylate, p-amino salicylate, phenoxybenzoate or acetoxybenzoate salt.
  • Memantine comprised in the formulation of the present invention is preferably memantine hydrochloride.
  • the amount of memantine comprised in the combination of the present invention is in the range of 0,1-500 mg, preferably in the range of 1-100 mg, more preferably in the range of 2- 50 mg.
  • the amount of ginkgo biloba extract comprised in the combination of the present invention is in the range of 1-1000 mg, preferably in the range of 10-200 mg, more preferably in the range of 20- 100 mg.
  • the present invention discloses a combination comprising memantine, donepezil and ginkgo biloba extract.
  • a feature of this combination is that the ratio of memantine to ginkgo biloba extract is 0.01 to 1, preferably 0.01 to 0.5.
  • the ratio of donepezil to ginkgo biloba extract is 0.01 to 1, preferably 0.01 to 0.25.
  • the present invention discloses a combination comprising memantine, donepezil and ginkgo biloba extract wherein the ratio of memantine to ginkgo biloba extract is 0.01 to 1 and the ratio of donepezil to ginkgo biloba extract is 0.01 to 1.
  • the present invention discloses a combination comprising memantine, donepezil and ginkgo biloba extract wherein the ratio of memantine to ginkgo biloba extract is 0.01 to 0.5 and the ratio of donepezil to ginkgo biloba extract is 0.01 to 0.25.
  • Amount of the active agent to be used in the combination of the present invention is determined according to the age, gender, weight and state of health of the patient.
  • the active agents comprised in the combination of the present invention can be administered simultaneously, sequentially or separately though they are preferably administered simultaneously.
  • the active agents comprised in the combination of the present invention can be formulated in the same dosage form or in separate dosage forms though they are preferably formulated in the same dosage form.
  • Formulating the formulation of the present invention in the same dosage form has provided a more effective and easy use.
  • the combination of the present invention can be administered by the oral or parenteral route.
  • the dosage forms that can be administered by the oral route in scope of the present invention are in solid dosage forms such as pill, tablet, capsule, film tablet, orally disintegrated tablet, enterically coated tablet, modified release tablet, prolonged release tablet, delayed release tablet, effervescent powder, effervescent granule, effervescent tablet, sachet, dragee, pastil or in liquid form such as suspension, emulsion, syrup, drop, solution; preferably in solid form.
  • solid dosage forms such as pill, tablet, capsule, film tablet, orally disintegrated tablet, enterically coated tablet, modified release tablet, prolonged release tablet, delayed release tablet, effervescent powder, effervescent granule, effervescent tablet, sachet, dragee, pastil or in liquid form such as suspension, emulsion, syrup, drop, solution; preferably in solid form.
  • Dosage forms preferred in the present invention are water soluble, preferably effervescent forms due to the reasons such as high bioavailability and ease of use they provide.
  • this problem has been suprisingly solved by adjusting the particle size of the active agents. It has also been suprisingly observed that the solubility of these new formulations is improved and hence the dissolution time is decreased.
  • a characteristic feature of the formulations according to the invention is that D(90) particle sizes of donepezil, memantine and ginkgo biloba extract are lower than 150 ⁇ , preferably lower than 90 ⁇ , more preferably between 1 and 70 ⁇ .
  • a characteristic feature of the formulations according to the invention is that D(10) particle size of donepezil is lower than 30 ⁇ , preferably lower than 20 ⁇ , more preferably between 1 and 10 ⁇ ,
  • a characteristic feature of the formulations according to the invention is that D(50) particle size of donepezil is lower than 60 ⁇ , preferably lower than 50 ⁇ , more preferably between 1 and 40 ⁇ .
  • a characteristic feature of the formulations according to the invention is that D(10) particle size of memantine is lower than 40 ⁇ , preferably lower than 30 ⁇ , more preferably between 1 and 20 ⁇ .
  • a characteristic feature of the formulations according to the invention is that D(50) particle size of memantine is lower than 50 ⁇ , preferably lower than 40 ⁇ , more preferably between 1 and 40 ⁇ .
  • D(10) particle size of ginkgo biloba extract is lower than 50 ⁇ , preferably lower than 30 ⁇ , more preferably between 1 and 20 ⁇ .
  • D(50) particle size of ginkgo biloba extract is lower than 50 ⁇ , preferably lower than 40 ⁇ , more preferably between 1 and 40 ⁇ .
  • compositions prepared by using the active agents which have the particle sizes disclosed above are able to dissolve without the need of any disintegrant.
  • a characteristic feature of the formulations according to the invention is that the formulations do not comprise any disintegrant.
  • Another characteristic feature of the formulations according to the invention is that the formulations can optionally comprise one or more excipients selected from a group comprising effervescent couple, binder, glidant, lubricant, diluent, filler, flavoring agent, sweetener, coloring agent, surfactant, anti-foam agent, viscosity agent, stabilizing agent.
  • effervescent couple refers to use of an effervescent acid and an effervescent base together.
  • the acidic agent mentioned here can be selected from a group comprising acetic acid, citric acid, lactic acid, malic acid, phosphoric acid, propionic acid, tartaric acid and/or hydrates or anhydrates or a combination thereof.
  • the basic agent mentioned here can be selected from a group comprising potassium carbonate, potassium bicarbonate, potassium citrate, potassium hydroxide, sodium carbonate, sodium hydrogen carbonate, sodium hydrogen citrate or a combination thereof.
  • Said binder can be selected from a group comprising starches such as potato starch, corn starch, wheat starch; sugars such as sucrose, glucose, dextrose, lactose, maltodextrin; natural and synthetic gums; gelatin; cellulose derivatives such as microcrystalline cellulose, HPC, HEC, HPMC, carboxymethyl cellulose, methyl cellulose, ethyl cellulose; polyvinylpyrrolidone (povidone), polyethylene glycol (PEG); waxes; calcium carbonate; calcium phosphate; alcohols such as sorbitol, xylitol, mannitol, and water or a combination thereof.
  • starches such as potato starch, corn starch, wheat starch
  • sugars such as sucrose, glucose, dextrose, lactose, maltodextrin
  • natural and synthetic gums such as cellulose derivatives such as microcrystalline cellulose, HPC, HEC, HPMC, carboxymethyl cellulose, methyl cellulose,
  • Said glidant can be selected from a group comprising sodium lauryl sulfate, sodium benzoate, sodium chloride, sodium acetate, sodium fumarate, carbowax 4000, L-leucine(17), polyethylene glycol, silicon dioxide or a combination thereof.
  • Said lubricant can be selected from a group comprising talc, magnesium stearate, stearic acid, sodium stearyl fumarate, polyoxyethylene glycol, polyethylene glycol, silicon dioxide, leucine, alanine, glycine, sodium benzoate, sodium acetate, fumaric acid or a combination thereof.
  • the formulations according to the invention comprise at least one pharmaceutically acceptable glidant and at least one pharmaceutically acceptable lubricant.
  • the inventors have found that the use of the glidant or lubricant more than 5% by weight causes a negative effect on the solubility of the formulations.
  • the formulations according to the invention comprise at least one glidant up to 5 %, preferably in the range of 1-5 % by weight.
  • the formulations according to the invention comprise at least one lubricant up to 5 %, preferably in the range of 1 -4 %, more preferably in the range of 1 -3 % by weight.
  • the ratio of glidant / lubricant in the formulations according to the invention is 1 to 10, preferably 1 to 8, more preferably 1 to 6.
  • Said diluent can be selected from a group comprising lactose, maltose, dextrin, maltodextrin, mannitol, sorbitol, starch or a combination thereof.
  • Said filler can be selected from a group comprising lactose, maltodextrin, sugar, starch, modified starch, mannitol, sorbitol, inorganic salts, microcrystalline cellulose, cellulose, calcium sulphate, xylitol and lactitol or a combination thereof.
  • Said flavoring agent can be selected from a group comprising natural aroma oils (peppermint oil, wintergreen oil, clove bud oil, parsley oil, eucalyptus oil, lemon oil, orange oil), menthol, menthane, anethole, methyl salicylate, eucalyptol, cinnamon, 1 -methyl acetate, sage, eugenol, oxanone, alpha irisone, marjoram, lemon, orange, blackberry, propenyl guaetol acetyl, cinnamon, vanilla, thymol, linalol, cinnamaldehyde glycerol acetal, N-substituted p- menthane-3-carboxamide, 3,1-methoxy propane 1,2-diol or a combination thereof.
  • natural aroma oils peppermint oil, wintergreen oil, clove bud oil, parsley oil, eucalyptus oil, lemon oil, orange oil
  • Said sweetener can be selected from a group comprising sucralose, sucrose, fructose, glucose, galactose, xylose, dextrose, laevulose, lactose, maltose, maltodextrin, mannitol, maltitol, maltol, sorbitol, xylitol, erythritol, lactitol, isomalt, corn syrup, saccharine, saccharine salts, acesulfame potassium, aspartame, D-tryptophane, monoammonium glycyrrhizinate, neohesperidin dihydrochalcone, thaumatin, neotame, alitame, stevioside and cyclamates or a combination thereof.
  • Said coloring agent can be selected from a group comprising carotenoids and chlorophyl or a combination thereof.
  • Said surfactant can be selected from a group comprising sodium lauryl sulfate and magnesium lauryl sulfate or a combination thereof.
  • Said antifoam agent can be selected from a group comprising simethicone emulsion and dimethyl siloxane, silicon oil or a combination thereof.
  • Said viscosity agent can be selected from a group comprising carboxy methyl cellulose, methyl cellulose, xanthan gum, gummi tragacanthae, gum arabic, aerosil 200, kollidon, agar- agar, bentonite, hydroxyl ethyl cellulose or a combination thereof.
  • Said stabilizing agent and/or agents can be selected from a group comprising antioxidants, chelating agents, alkalinizing agents and photoprotective agents.
  • Antioxidants can be selected from substances including butylated hydroxyanisole (BHA), sodium ascorbate, butylhydroxytoluene (BHT), sodium sulphite, gallates (such as propyl gallate), tocoferole, citric acid, malic acid, ascorbic acid, acetylcysteine, fumaric acid, lecithin, ascorbyl palmitate, ethylenediamine tetraacetate or a combination thereof.
  • the chelating agents can be selected from a group comprising disodium EDTA, edetic acid, citric acid, sodium citrate, potassium citrate or a combination thereof.
  • Alkalinizing agents can be selected from alkali metal salts such as sodium carbonate, sodium hydrogen carbonate, sodium hydroxide, sodium silicate, disodium hydrogen orthophosphate, sodium aluminate; alkaline earth metal salts such as calcium carbonate, calcium hydroxide, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulphate, calcium acetate, calcium gluconate, calcium glycerophospate, magnesium carbonate, magnesium hydroxide, magnesium sulphate, magnesium acetate, magnesium silicate, magnesium aluminate; and primary, secondary and tertiary amines, cyclic amines; ⁇ , ⁇ '-dibenzyl ethylenediamine, dietanolamine, ethylenediamine, meglumine, monosodium glutamate, polacrilin sodium, sodium alginate or a combination thereof.
  • alkali metal salts such as sodium carbonate, sodium hydrogen carbonate, sodium hydroxide, sodium silicate, disodium
  • Photoprotective agents can be selected from metal oxides such as titanium oxide, iron oxide and zinc oxide or a combination thereof.
  • the combination of the present invention basically comprises; - Donepezil in the range of 0,01-30% by weight
  • the formulations of the present invention can optionally comprise at least one other antidementia agent.
  • Said antidementia agents can be galanthamine, rivastigmine and/or tacrine and/or pharmaceutically acceptable salts and/or derivatives thereof.
  • the present invention relates to use of combinations comprising donepezil, memantine and ginkgo biloba extract in the treatment of Alzheimer's disease.
  • compositions used in scope of the present invention are pharmaceutically acceptable.
  • pharmaceutically acceptable refers to the component's suitability for use in people; its having few or no side effects (toxicity, irritation, allergic response) and its providing the user an evident benefit.
  • formulations of the present invention can be produced according to any production method existing in the prior art, for instance dry blending, dry granulation and wet granulation. Active agents can be produced separately and combined afterwards or they can be produced together.
  • One of the methods preferred for production of the formulations of the present invention is wet granulation.
  • the wet granulation method to be used for production of the formulations of the present invention comprises the following steps:
  • Ginkgo biloba extract and at least one glidant are blended,
  • step 2 The mixture in step 2 is granulated wet by the granulation solution wherein the solution is preferably composed of at least one pharmaceutically acceptable binder and filler. Examples required for better understanding of the formulation of the present invention are given below, yet the invention should not be restricted to them.
  • the components in the given amounts are prepared as a mixture by one of the methods in the prior art such as wet granulation, dry granulation or dry blending.
  • the final mixture is loaded to tablet compression machine and tablet compression is completed.
  • the components in the given amounts are prepared as a mixture by one of the methods in the prior art such as wet granulation, dry granulation or dry blending, and packed in capsules.
  • the components in the given amounts are prepared by the wet granulation method explained in the description part.

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Abstract

La présente invention concerne des combinaisons comprenant du donépézil, de la mémantine et de l'extrait de ginkgo biloba ou tout dérivés pharmaceutiquement acceptable de ceux-ci; ainsi que l'utilisation de ce type de forme galénique pour le traitement de la maladie d'Alzheimer.
PCT/TR2011/000190 2010-08-25 2011-08-19 Combinaisons comprenant du donépézil, de la mémantine et de l'extrait de gingko biloba WO2012026902A1 (fr)

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TR2010/07110A TR201007110A2 (tr) 2010-08-25 2010-08-25 Sinerjik etki gösteren kombinasyonlar
TR2010/7110 2010-08-25

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014007775A1 (fr) * 2012-07-02 2014-01-09 Mahmut Bilgic Nouvelle formulation à dissolution rapide
WO2014035355A1 (fr) * 2012-08-31 2014-03-06 Mahmut Bilgic Combinaisons pharmaceutiques comprenant un agent actif dérivé de la quinone
WO2014055047A1 (fr) * 2012-08-31 2014-04-10 Mahmut Bilgic Combinaison d'un agent actif dérivé de la quinone et d'une cholinestérase
WO2015120013A1 (fr) 2014-02-04 2015-08-13 Forest Laboratories Holdings Limited Compositions de donépézil et procédé de traitement de la maladie d'alzheimer
CN110573156A (zh) * 2016-09-30 2019-12-13 比奥生物有限公司 用于预防或治疗痴呆和认知功能障碍、含有多奈哌齐或其药学上可接受的盐和美金刚或其药学上可接受的盐的药物组合物，及其制备方法

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EP1509232A1 (fr) 2002-05-31 2005-03-02 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
WO2006089095A2 (fr) * 2005-02-17 2006-08-24 Biogen Idec Ma Inc. Traitement de troubles neurologiques

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EP0296560A2 (fr) 1987-06-22 1988-12-28 Eisai Co., Ltd. Pipéridines 1,4-substituées comme inhibiteurs de l'acétylcholinestérase et leur utilisation dans le traitement de la maladie d'Alzheimer
EP1509232A1 (fr) 2002-05-31 2005-03-02 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
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Title
GRIFFITH P ET AL: "Safety and efficacy of donepezil in a 12-week, open-label trial in African Americans with mild to moderate Alzheimer's disease", ALZHEIMER'S & DEMENTIA: THE JOURNAL OF THE ALZHEIMER'SASSOCIATION, ELSEVIER, NEW YORK, NY, US, vol. 1, no. 1, 1 July 2005 (2005-07-01), pages 73, XP027823405, ISSN: 1552-5260, [retrieved on 20050701] *
JONSSON ET AL: "Cost-effectiveness of memantine for moderate to severe Alzheimer's disease in Sweden", THE AMERICAN JOURNAL OF GERIATRIC PHARMACOTHERAPY, EXCERPTA MEDICA, vol. 3, no. 2, 1 June 2005 (2005-06-01), pages 77 - 86, XP027678082, ISSN: 1543-5946, [retrieved on 20050601] *
LUO Y ET AL: "Therapeutic effects of Ginkgo biloba extract EGB 761 in animal models of Alzheimer's disease", ALZHEIMER'S & DEMENTIA: THE JOURNAL OF THE ALZHEIMER'SASSOCIATION, ELSEVIER, NEW YORK, NY, US, vol. 1, no. 1, 1 July 2005 (2005-07-01), pages 72, XP027823401, ISSN: 1552-5260, [retrieved on 20050701] *

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014007775A1 (fr) * 2012-07-02 2014-01-09 Mahmut Bilgic Nouvelle formulation à dissolution rapide
WO2014035355A1 (fr) * 2012-08-31 2014-03-06 Mahmut Bilgic Combinaisons pharmaceutiques comprenant un agent actif dérivé de la quinone
WO2014055047A1 (fr) * 2012-08-31 2014-04-10 Mahmut Bilgic Combinaison d'un agent actif dérivé de la quinone et d'une cholinestérase
WO2015120013A1 (fr) 2014-02-04 2015-08-13 Forest Laboratories Holdings Limited Compositions de donépézil et procédé de traitement de la maladie d'alzheimer
EP3102186A4 (fr) * 2014-02-04 2017-06-28 Forest Laboratories Holdings Limited Compositions de donépézil et procédé de traitement de la maladie d'alzheimer
EP3102186B1 (fr) 2014-02-04 2021-01-27 Forest Laboratories Holdings Limited Compositions de donépézil et procédé de traitement de la maladie d'alzheimer
CN110573156A (zh) * 2016-09-30 2019-12-13 比奥生物有限公司 用于预防或治疗痴呆和认知功能障碍、含有多奈哌齐或其药学上可接受的盐和美金刚或其药学上可接受的盐的药物组合物，及其制备方法
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
CN110573156B (zh) * 2016-09-30 2023-12-08 现代药品株式会社 用于预防或治疗痴呆和认知功能障碍、含有多奈哌齐或其药学上可接受的盐和美金刚或其药学上可接受的盐的药物组合物，及其制备方法

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