WO2012026904A1 - A single unit dosage form on the basis of a combination comprising donepezil and ginkgo biloba extract - Google Patents

A single unit dosage form on the basis of a combination comprising donepezil and ginkgo biloba extract Download PDF

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Publication number
WO2012026904A1
WO2012026904A1 PCT/TR2011/000192 TR2011000192W WO2012026904A1 WO 2012026904 A1 WO2012026904 A1 WO 2012026904A1 TR 2011000192 W TR2011000192 W TR 2011000192W WO 2012026904 A1 WO2012026904 A1 WO 2012026904A1
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Prior art keywords
combination
combination according
donepezil
tablet
range
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PCT/TR2011/000192
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French (fr)
Inventor
Mahmut Bilgic
Original Assignee
Mahmut Bilgic
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Publication of WO2012026904A1 publication Critical patent/WO2012026904A1/en

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    • 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
    • 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)

Definitions

  • the present invention relates to single unit dosage forms comprising donepezil or any pharmaceutically acceptable derivative thereof and ginkgo biloba extract; 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 ⁇ ), 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.
  • 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.
  • formulations comprising donepezil and ginkgo biloba extract on the market.
  • dose and dosage form adjustment is required before use when two drugs are used separately because formulations comprising donepezil are marketed in oral tablet forms of 5 and 10 mg while formulations comprising ginkgo biloba are present in various doses as 40 mg, 60 mg, 80 mg, 120 mg and 450 mg and in a wide range of dosage forms as oral tablet, capsule, effervescent tablet and oral drop.
  • single unit dosage forms comprising donepezil and ginkgo biloba extract provide ease of use for patients and it is a more effective and reliable treatment method since it does not require dose and dosage form adjustment in advance.
  • the single unit dosage form comprising donepezil and ginkgo biloba extract displays more therapeutic activity compared to combinations comprising donepezil and ginkgo biloba extract separately.
  • the present invention relates to single unit dosage forms comprising donepezil and ginkgo biloba extract.
  • 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 I 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.
  • 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 ratio of ginkgo biloba to donepezil in the formulations of the present invention is 1 to 30, preferably 1 to 20.
  • the single unit dosage form of the present invention can be administered by the oral or I parenteral route though it is preferably administered by the oral route.
  • the single unit dosage form of the present invention can be in solid 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.
  • solid 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.
  • solid dosage forms have appeared more advantageous in scope of the present invention.
  • the formulations of the present invention can also be formulated in solid dosage forms which can be used after watered for patients who have difficulty in swallowing solid dosage forms or do not want to swallow solid dosage forms.
  • dosage forms can either hold effervescent characteristics or not.
  • Effervescent and/or water soluble powder, granule, tablet formulations can be given as examples.
  • 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.
  • the inventors found that, depending on the fact that the amount of ginkgo biloba extract in the formulations is at least 10 times more than the I amount of donepezil, homogeneous distribution of donepezil used in that little amounts cannot be ensured in the formulations and therefore therapeutic dose amount taken by patients decreases.
  • 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;
  • I calcium phosphate ; alcohols such as sorbitol, xylitol, mannitol, and water or a combination thereof.
  • the binder used in the present invention is preferably sorbitol.
  • the amount of sorbitol used in the present invention is less than 5%, preferably less than 3%, more preferably in the range of 0.1% to 3% by weight in total formulation.
  • compositions of the present invention comprise at least one pharmaceutically acceptable > filling agent in addition to the binder.
  • Said filling agents can be selected from a group comprising lactose, maltodextrin, sugar, starch, modified starch, mannitol, sorbitol, organic salts, microcrystalline cellulose, cellulose, calcium sulfate, xylitol and lactitol or a combination thereof.
  • the amount of the filling agent in the formulations is in the range of 0.1-20%, preferably in the range of 0.1-15%, more ' preferably in the range of 0.1-10% by weight.
  • the filling agent preferred in the formulations of the present invention is maltodextrin.
  • the ratio of maltodextrin to sorbitol in the formulations is 1 to 10, preferably 1 to 5.
  • the formulations of the present invention can comprise one or more pharmaceutically acceptable excipients selected from a group comprising effervescent couple, glidant, lubricant, diluent, disintegrant, flavoring agent, sweetener, coloring agent, surfactant, anti- foam agent, viscosity agent, stabilizing agent in addition to the binder and the filling agent.
  • the term "effervescent couple” refers to use of an acidic agent and a basic agent 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, 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 glidant can be selected from a group comprising silicon dioxide, sodium lauryl sulfate, sodium benzoate, sodium chloride, sodium acetate, sodium fumarate, carbowax 4000, L- leucine(17), polyethylene glycol or a combination thereof.
  • Said lubricant can be selected from a group comprising polyethylene glycol, talc, magnesium stearate, stearic acid, sodium stearyl fumarate, polyoxyethylene glycol, silicon dioxide, leucine, alanine, glycine, sodium benzoate, sodium acetate, fumaric acid or a combination thereof.
  • Said diluent can be selected from a group comprising lactose, maltose, dextrin, maltodextrin, mannitol, sorbitol, starch or a combination thereof.
  • Said disintegrant can be selected from a group comprising starches such as potato starch, corn starch, wheat starch, pregelatinized starch, sodium starch glycolate; cellulose derivatives such as croscarmellose sodium or microcrystalline cellulose; polyvinylpyrrolidone; crospovidone; alginic acid and its salts; clays such as xanthan gum or Veegum; ion exchange resins 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, I 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, i 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.
  • BHA butylated hydroxyanisole
  • BHT butylhydroxytoluene
  • 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, pola
  • 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 comprises;
  • the present invention relates to use of single unit dosage forms comprising donepezil and ginkgo biloba extract in the treatment of Alzheimer's disease.
  • the formulations of the present invention can optionally comprise at least one other antidementia agent.
  • Said antidementia agents can be galanthamine, rivastigmine, tacrine, memantine and/or pharmaceutically acceptable salts and/or derivatives thereof.
  • compositions 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 granulation solution used is composed of the binder and the filling agent.
  • Another feature of the wet granulation method to be used for production of the formulations of the present invention is that the granulation solution comprises at least 30% of the binder and 40% of the filling agent in the formulations by weight.
  • the ratio of the filling agent to the binder used in the granulation solution is in the range of 1 to 20, preferably in the range of 1 to 15, more preferably in the range of 1 to 10.
  • the wet granulation method to be used for production of the formulations of the present invention comprises the following steps:
  • the granulation solution is prepared by mixing at least 30% of the binder and at least
  • Ginkgo biloba and at least one pharmaceutically acceptable glidant are blended dry; the dry mixture is prepared by adding donepezil hydrochloride, rest of the binder and the filling agent left from the granulation solution, at least one other excipient into the blend.
  • the dry mixture obtained in the second step is granulated with the granulation solution. 4. Tablet compression
  • the granules prepared are treated with the lubricant.
  • at least one flavoring agent is added into the mixture and the mixture is compressed in tablet form.
  • 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 effervescent formulation given above is produced according to wet granulation method described in the description part in detail and tablets are compressed.

Abstract

The present invention relates to single unit dosage forms comprising donepezil or any pharmaceutically acceptable derivative thereof and ginkgo biloba extract; and use of this type of dosage forms in the treatment of Alzheimer's disease.

Description

A SINGLE UNIT DOSAGE FORM ON THE BASIS OF A COMBINATION COMPRISING DONEPEZIL AND
GINKGO BILOBA EXTRACT
The present invention relates to single unit dosage forms comprising donepezil or any pharmaceutically acceptable derivative thereof and ginkgo biloba extract; 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.
Mechanism of various types of dementia including Alzheimer's disease has not been explained yet. Present drugs decelerates progression of the disease by operating on central nervous system through different ways.
The drug group commonly used in the treatment of Alzheimer's disease is acetylcholinesterase inhibitors. Donepezil (formula Γ), 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.
Figure imgf000002_0001
(formula 1)
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.
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.
As a result of the studies they conducted, Yancheva et. al. (Aging & Mental Health, vol. 13, No. 2, March 2009, 183-190) have indicated that use of donepezil and ginkgo biloba extract in combination is a more effective treatment method compared with monotherapies in which the substances are used separately; and the side effects existing in the treatment in which donepezil is used alone are eliminated.
There exist formulations comprising donepezil and ginkgo biloba extract on the market. However, it poses problems to take two separate drugs when declined vital activities, I degenerated cognitive abilities and behavior changes induced by age of the patients and the disease into consideration. Furthermore, dose and dosage form adjustment is required before use when two drugs are used separately because formulations comprising donepezil are marketed in oral tablet forms of 5 and 10 mg while formulations comprising ginkgo biloba are present in various doses as 40 mg, 60 mg, 80 mg, 120 mg and 450 mg and in a wide range of dosage forms as oral tablet, capsule, effervescent tablet and oral drop. At this point, it poses problems to determine suitable dose and the dosage form combination.
When the prior art is taken into consideration, there is need to develop user-friendly dosage forms comprising donepezil and ginkgo biloba extract for use in the treatment of Alzheimer's disease which ensures an effective and reliable treatment by eliminating the problem of I adjusting dose and dosage form in advance.
The inventors have surprisingly found that single unit dosage forms comprising donepezil and ginkgo biloba extract provide ease of use for patients and it is a more effective and reliable treatment method since it does not require dose and dosage form adjustment in advance. Again surprisingly, it has been seen that the single unit dosage form comprising donepezil and ginkgo biloba extract displays more therapeutic activity compared to combinations comprising donepezil and ginkgo biloba extract separately.
In this aspect, the present invention relates to single unit dosage forms comprising donepezil and ginkgo biloba extract.
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.
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 I 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.
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 ratio of ginkgo biloba to donepezil in the formulations of the present invention is 1 to 30, preferably 1 to 20.
The single unit dosage form of the present invention can be administered by the oral or I parenteral route though it is preferably administered by the oral route.
The single unit dosage form of the present invention can be in solid 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.
In terms of ensuring precise and accurate dose adjustment and having long shelf life, solid dosage forms have appeared more advantageous in scope of the present invention. ' The formulations of the present invention can also be formulated in solid dosage forms which can be used after watered for patients who have difficulty in swallowing solid dosage forms or do not want to swallow solid dosage forms.
These dosage forms can either hold effervescent characteristics or not. Effervescent and/or water soluble powder, granule, tablet formulations can be given as examples.
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.
As a result of the studies they had conducted, the inventors found that, depending on the fact that the amount of ginkgo biloba extract in the formulations is at least 10 times more than the I amount of donepezil, homogeneous distribution of donepezil used in that little amounts cannot be ensured in the formulations and therefore therapeutic dose amount taken by patients decreases.
The inventors have found that this problem can be solved by selection of diluent type and amount. 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;
I calcium phosphate; alcohols such as sorbitol, xylitol, mannitol, and water or a combination thereof.The binder used in the present invention is preferably sorbitol.
The amount of sorbitol used in the present invention is less than 5%, preferably less than 3%, more preferably in the range of 0.1% to 3% by weight in total formulation.
The formulations of the present invention comprise at least one pharmaceutically acceptable > filling agent in addition to the binder.
Said filling agents can be selected from a group comprising lactose, maltodextrin, sugar, starch, modified starch, mannitol, sorbitol, organic salts, microcrystalline cellulose, cellulose, calcium sulfate, xylitol and lactitol or a combination thereof. The amount of the filling agent in the formulations is in the range of 0.1-20%, preferably in the range of 0.1-15%, more ' preferably in the range of 0.1-10% by weight. The filling agent preferred in the formulations of the present invention is maltodextrin.
The ratio of maltodextrin to sorbitol in the formulations is 1 to 10, preferably 1 to 5.
The formulations of the present invention can comprise one or more pharmaceutically acceptable excipients selected from a group comprising effervescent couple, glidant, lubricant, diluent, disintegrant, flavoring agent, sweetener, coloring agent, surfactant, anti- foam agent, viscosity agent, stabilizing agent in addition to the binder and the filling agent.
The term "effervescent couple" refers to use of an acidic agent and a basic agent 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, 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 glidant can be selected from a group comprising silicon dioxide, sodium lauryl sulfate, sodium benzoate, sodium chloride, sodium acetate, sodium fumarate, carbowax 4000, L- leucine(17), polyethylene glycol or a combination thereof.
Said lubricant can be selected from a group comprising polyethylene glycol, talc, magnesium stearate, stearic acid, sodium stearyl fumarate, polyoxyethylene glycol, silicon dioxide, leucine, alanine, glycine, sodium benzoate, sodium acetate, fumaric acid or a combination thereof.
Said diluent can be selected from a group comprising lactose, maltose, dextrin, maltodextrin, mannitol, sorbitol, starch or a combination thereof.
Said disintegrant can be selected from a group comprising starches such as potato starch, corn starch, wheat starch, pregelatinized starch, sodium starch glycolate; cellulose derivatives such as croscarmellose sodium or microcrystalline cellulose; polyvinylpyrrolidone; crospovidone; alginic acid and its salts; clays such as xanthan gum or Veegum; ion exchange resins 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.
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, I 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, i 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; Ν,Ν'-dibenzyl ethylenediamine, dietanolamine, ethylenediamine, meglumine, monosodium glutamate, polacrilin sodium, sodium alginate or a combination thereof.
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 comprises;
- Donepezil or a pharmaceutically acceptable derivative in the range of 0,01-30% by weight,
- Ginkgo biloba extract in the range of 0, 1 -60% by weight,
- Disintegrant in the range of 0-50% by weight,
- Binder in the range of 0, 1 -5% by weight,
- Lubricant in the range of 0, 1 - 10% by weight,
- Filling agent in the range of 0.1 -20% by weight,
- Other excipients in the range of 0-50% by weight.
In another aspect, the present invention relates to use of single unit dosage forms comprising donepezil and ginkgo biloba extract in the treatment of Alzheimer's disease.
The formulations of the present invention can optionally comprise at least one other antidementia agent. Said antidementia agents can be galanthamine, rivastigmine, tacrine, memantine and/or pharmaceutically acceptable salts and/or derivatives thereof.
All the components used in scope of the present invention are pharmaceutically acceptable. The term '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. • The 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.
One of the features of the wet granulation method used for production of the formulations of the present invention is that the granulation solution used is composed of the binder and the filling agent. Another feature of the wet granulation method to be used for production of the formulations of the present invention is that the granulation solution comprises at least 30% of the binder and 40% of the filling agent in the formulations by weight.
Another feature of the wet granulation method to be used for the production of the formulations of the present invention is that the ratio of the filling agent to the binder used in the granulation solution is in the range of 1 to 20, preferably in the range of 1 to 15, more preferably in the range of 1 to 10.
In summary, the wet granulation method to be used for production of the formulations of the present invention comprises the following steps:
1. Preparation of the granulation solution The granulation solution is prepared by mixing at least 30% of the binder and at least
40% of the filling agent used in the formulations by weight.
2. Preparation of the dry mixture
Ginkgo biloba and at least one pharmaceutically acceptable glidant are blended dry; the dry mixture is prepared by adding donepezil hydrochloride, rest of the binder and the filling agent left from the granulation solution, at least one other excipient into the blend.
3. Wet granulation
The dry mixture obtained in the second step is granulated with the granulation solution. 4. Tablet compression
The granules prepared are treated with the lubricant. Optionally, at least one flavoring agent is added into the mixture and the mixture is compressed in tablet form.
Examples required for better understanding of the formulation of the present invention are given below, yet the invention should not be restricted to them.
EXAMPLES
Example 1
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.
Figure imgf000010_0001
Example 2
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.
Figure imgf000011_0001
Example 3. Effervescent Tablet Formulation
Figure imgf000012_0001
The effervescent formulation given above is produced according to wet granulation method described in the description part in detail and tablets are compressed.

Claims

1. A combination comprising donepezil and ginkgo biloba extract characterized in that said combination is formulated in single unit dosage form.
2. The combination according to claim 1 characterized in that donepezil comprised in said combination is in the form of its pharmaceutically acceptable hydrates, solvates, esters, enantiomers, polymorphs, crystalline forms, amorphous forms, salt forms or in free base form and/or a combination thereof.
3. The combination according to claim 2 characterized in that donepezil comprised in said combination is in salt form.
4. The combination according to claim 3 characterized in that donepezil salt comprised in said combination is selected form 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.
5. The combination according to claim 3 or 4 characterized in that donepezil comprised in said combination is donepezil hydrochloride.
6. The combination according to claim 1 characterized in that the amount of donepezil comprised in said combination 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.
7. The combination according to claim 1 characterized in that the amount of ginkgo biloba extract comprised in said combination 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.
8. The combination according to any preceding claims characterized in that the ratio of ginkgo biloba to donepezil comprised in said combination is 1 to 30.
9. The combination according to claim 8 characterized in that the ratio of ginkgo biloba to donepezil comprised in said combination is 1 to 20.
10. The combination according to claim 1 characterized in that said combination is administered by the oral or parenteral route.
11. The combination according to claim 10 characterized in that said combination is administered by the oral route.
12. The combination according to claim 11 characterized in that said combination is formulated in solid 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.
13. The combination according to claim 12 characterized in that said combination is formulated in solid 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.
14. The combination according to any preceding claims characterized in that said combination comprises at least one pharmaceutically acceptable binder.
15. The combination according to claim 14 characterized in that the binder comprised in said combination is 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.
16. The combination according to claim 15 characterized in that the binder comprised in said combination is sorbitol.
17. The combination according to claim 16 characterized in that said combination comprises less than 5% sorbitol by weight.
18. The combination according to claim 17 characterized in that said combination comprises less than 3% sorbitol by weight.
19. The combination according to claim 18 characterized in that said combination comprises 0.1-3% sorbitol by weight.
20. The combination according to any preceding claims characterized in that said combination comprises at least one pharmaceutically acceptable filling agent.
21. The combination according to claim 20 characterized in that said combination comprises at least one filling agent in the range of 0.1-20% by weight.
22. The combination according to claim 21 characterized in that said combination comprises at least one filling agent in the range of 0.1-15% by weight.
23. The combination according to claim 22 characterized in that said combination comprises at least one filling agent in the range of 0.1-10% by weight.
24. The combination according to claim 20 characterized in that the filling agent is selected from a group comprising lactose, maltodextrin, sugar, starch, modified starch, mannitol, sorbitol, inorganic salts, microcrystalline cellulose, cellulose, calcium sulfate, xylitol and lactitol or a combinations thereof.
25. The combination according to claim 24 characterized in that the filling agent is maltodextrin.
26. The combination according to claims 14-25 characterized in that the ratio of maltodextrin to sorbitol is 1 to 10.
27. The combination according to claims 26 characterized in that the ratio of maltodextrin to sorbitol is 1 to 5.
28. The combination according to any preceding claims, wherein said combination comprises one or more excipients selected from a group comprising effervescent couple, binder, glidant, lubricant, diluent, disintegrant, flavoring agent, sweetener, coloring agent, surfactant, anti-foam agent, viscosity agent, stabilizing agent.
29. The combination according to any preceding claims characterized in that said combination is produced by wet granulation, dry granulation and/or dry blending methods.
30. A method according to claim 29 characterized in that said method is wet granulation.
PCT/TR2011/000192 2010-08-25 2011-08-19 A single unit dosage form on the basis of a combination comprising donepezil and ginkgo biloba extract WO2012026904A1 (en)

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