WO2011147471A1 - Solutions pharmaceutiques anti-démence pour administration par voie orale - Google Patents

Solutions pharmaceutiques anti-démence pour administration par voie orale Download PDF

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Publication number
WO2011147471A1
WO2011147471A1 PCT/EP2010/061065 EP2010061065W WO2011147471A1 WO 2011147471 A1 WO2011147471 A1 WO 2011147471A1 EP 2010061065 W EP2010061065 W EP 2010061065W WO 2011147471 A1 WO2011147471 A1 WO 2011147471A1
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WO
WIPO (PCT)
Prior art keywords
donepezil
oral
oral pharmaceutical
compositions
solution according
Prior art date
Application number
PCT/EP2010/061065
Other languages
English (en)
Inventor
Georgios Liolios
Angelos Karatzas
Ilias Kotsianis
Original Assignee
Alapis S.A.
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 Alapis S.A. filed Critical Alapis S.A.
Publication of WO2011147471A1 publication Critical patent/WO2011147471A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—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
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • 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
    • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
    • 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
    • A61K9/08—Solutions
    • 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
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia

Definitions

  • the present invention refers to oral pharmaceutical solutions comprising donepezil or a pharmaceutically acceptable salt thereof.
  • Donepezil (Formula I), is chemically named ((+/-)-2,3-dihydro-5,6-dimethoxy-2-[[1 - (phenylmethyl)-4-piperidinyl]methyl]-1 H-inden-1 -one). It was first disclosed in EP0296560 A2 and it is a known reversible inhibitor of acetyl cholinesterase. Donepezil and its salts have application in the treatment of a variety of disorders, including dementia and attention deficit disorder.
  • donepezil hydrochloride is employed as a pharmaceutically active agent for the treatment of mild to moderate Alzheimer' s dementia and has been marketed as oral solution of 1 mg/ml under the trade name ARICEPT.
  • the commercially available ARICEPT® 1 mg/ml Oral Solution contains the excipients sorbitol solution 70%, povidone K-30, citric acid anhydrous, sodium citrate dihydrate, sodium benzoate, methylparaben, propylene glycol, sodium metabisulfite, strawberry flavor and purified water.
  • EP0296560 A2 discloses liquid compositions in the form of injections comprising donepezil which may contain a pH modifier, a buffer, a suspending agent, a stabilizer, a tonicity agent, a preservative etc.
  • EP131 1272A1 teaches oral compositions of donepezil which may be in the form of pharmaceutically acceptable emulsions, solutions, suspensions and syrups containing inert ingredients commonly used in the art. Such compositions can also comprise adjuvants, such as wetting agents, emulsifying agents, sweeteners, flavoring and perfuming agents.
  • EP1025858 A1 discloses that donepezil hydrochloride and its compositions have an unpleasant taste. According to the said document, a composition comprising polyvinylpyrrolidone and/or copolyvidone alleviates the unpleasant taste of donepezil hydrochloride medicaments.
  • EP1086706 A1 discloses that donepezil becomes unstable to light and/or heat when an antidementia medicament is prepared.
  • stabilized compositions of donepezil may be prepared with the addition of an organic acid selected from tosyllic acid, mesyllic acid, benzoic acid, salicylic acid, tartaric acid and citric acid.
  • Donepezil undergoes extensive degradation in the presence of common excipients and pharmaceutically acceptable salts of donepezil have varying levels of stability under conditions of elevated temperature and humidity.
  • compositions containing donepezil hydrochloride described in the literature contain numerous preservatives, flavoring agents that limit the safety or desirability of the oral liquid dosage form of the drug.
  • compositions containing donepezil hydrochloride described in the literature include one or more preservatives, such as, butylated hydroxy toluene, butylated hydroxyanisole, sodium benzoate or other preservatives commonly used in the art or any combination thereof. Preservatives, however, have been linked to negative health effects, including drug allergies. The preservatives are included to ensure that the liquid dosage forms maintain microbiological stability.
  • Pharmaceutical compositions containing donepezil hydrochloride described in the literature also typically include one or more flavoring agents. These excipients are used to mask or minimize the bitter or unpleasant taste associated with certain drugs, excipients or combination thereof. However, there has been increasing consumer demand for safer pharmaceutical compositions.
  • compositions containing donepezil hydrochloride described in the literature are not suitable for the preparation of liquid pharmaceutical forms for oral use such as highly concentrated aqueous solutions which allow smaller dose quantities to be delivered and mixed with water, fruit juices or soft drinks before administration.
  • liquid pharmaceutical forms for oral use such as, for example, oral drops, must be chemically and physically stable for a long time even after a first use.
  • donepezil undergoes extensive degradation in presence of common excipients and pharmaceutically acceptable salts of donepezil have varying levels of stability under conditions of elevated temperature and humidity, there remains a need in the art for stabilized donepezil hydrochloride oral liquid compositions.
  • the present invention is directed to stable oral pharmaceutical solutions comprising donepezil or a pharmaceutically acceptable salt thereof in association with a pharmaceutically acceptable liquid carrier.
  • oral pharmaceutical solutions and “oral solutions” refer to homogeneous mixtures of one or more solutes, dissolved in a suitable solvent or mixture of mutually miscible solvents.
  • solutions are defined as “liquid preparations that contain one or more soluble chemical substances, usually dissolved in water and they do not, by reasons of their ingredients, method of preparation, or use, fall into another group of products.”
  • Oral pharmaceutical solutions according to the invention preferably include oral solutions characterized by specific physical and rheological properties i.e. viscosity, surface tension and fluid density so as to be readily formulated into the form of oral drops as they are explicitly defined in European pharmacopoeia, namely solutions that are administered in small volumes such as drops by the means of a suitable device.
  • % refers to percentages by weight and means g of active or inactive ingredient per 100 ml of solution.
  • the oral pharmaceutical solutions of the present invention comprise 0.1 % to 10% of donepezil or its pharmaceutically acceptable salts, 1 % to 25% of polyethylene glycol 400, 1 % to 25% of ethanol and 5% to 45% of propylene glycol.
  • the oral pharmaceutical solutions comprise 0.1 % to 10% of donepezil or its pharmaceutically acceptable salts, 5% to 15% of polyethylene glycol 400, 5% to 15% of ethanol and 25% to 35% of propylene glycol.
  • the percentage of 0.1 to 10% according to the present invention refers to the amount of donepezil base.
  • the amount of donepezil present in the compositions of the present invention is from 0.5% to 2%. Most preferably, the amount of donepezil is 1 %.
  • compositions of the present invention may be used in an antidementia therapy.
  • the amount of donepezil administered is from 1 mg to 100 mg per day.
  • the oral solutions of donepezil hydrochloride according to the invention can also optionally contain additional ingredients commonly used in the preparation of oral liquid pharmaceutical compositions, such as, for example chelating agents, buffering agents and the like.
  • the compositions of the present invention have the advantages of providing higher concentrations of donepezil hydrochloride, allowing therefore smaller dose quantities to be delivered. Furthermore, they exhibit improved stability and extended shelf life.
  • the present invention provides a simple and efficient process for producing an oral pharmaceutical solution of donepezil hydrochloride.
  • Manufacturers will appreciate the simplicity and cost-effectiveness of the process while physicians and consumers will appreciate a stable solution which may be administered in the form of oral drops and whose amount is easily adjusted according to the specific needs of each patient.
  • oral pharmaceutical solutions comprising donepezil or a pharmaceutically acceptable salt thereof in association with a pharmaceutically acceptable liquid carrier.
  • oral pharmaceutical solutions and “oral solutions” refer to homogeneous mixtures of one or more solutes, dissolved in a suitable solvent or mixture of mutually miscible solvents.
  • solutions are defined as "liquid preparations that contain one or more soluble chemical substances, usually dissolved in water and they do not, by reasons of their ingredients, method of preparation, or use, fall into another group of products.”
  • % refers to percentages by weight and means g of active or inactive ingredient per 100 ml of solution.
  • the oral pharmaceutical solutions of the present invention comprise 0.1 % to 10% of donepezil or its pharmaceutically acceptable salts, 1 % to 25% of polyethylene glycol 400, 1 % to 25% of ethanol and 5% to 45% of propylene glycol.
  • the oral pharmaceutical solutions comprise 0.1 % to 10% of donepezil or its pharmaceutically acceptable salts, 5% to 15% of polyethylene glycol 400, 5% to 15% of ethanol and 25% to 35% of propylene glycol.
  • the percentage of 0.1 to 10% refers to the amount of donepezil base.
  • Solubilizing agents such as macrogol 400 (Polyethylene glycol 400), ethanol, propylene glycol, 2-pyrrolidone (Soluphor P), polyethylene glycol 660 12-hydroxystearate (Solutol HS 15) and polyoxyl-40-hydrogenated castor oil (Cremophor RH 40) were included in the study.
  • Oral pharmaceutical solutions according to the invention preferably include oral solutions characterized by specific physical and rheological properties i.e. viscosity, surface tension and fluid density so as to be readily formulated into the form of oral drops as they are explicitly defined in European pharmacopoeia namely solutions, that are administered in small volumes such as drops by the means of a suitable device.
  • the pharmaceutical solutions are in the form of oral drops and complies with European pharmacopoeia test for uniformity of dose, providing a steady drop volume of liquid with a dropping speed of maximum 2 drops/sec, providing no single drop mass deviation by more than 10 per cent from the average mass and further proving a total of 10 drop masses that does not differ by more than 15 per cent from the nominal mass of 10 doses.
  • the compositions of the present invention are aimed to be administered mixed with a sufficient amount of tap water, fruit juices or soft drinks.
  • Oral drops of donepezil hydrochloride offer the advantages of ease of administration and increased compliance for patients who have difficulty swallowing solid dosage forms.
  • compositions of the present invention are preferably contained in a amber colored glass vial, equipped with a continuous flow dropper and screw cap closure, holding 10 to 50 ml donepezil solution.
  • the glass vial (type III) is suitable for liquid preparations for parenteral and oral use.
  • the dropper is preferably made of polyethylene low density (PE-LD) material, according to food and pharmaceutical regulations.
  • the screw cap is preferably made of polypropylene, suitable as child proof closure.
  • the oral pharmaceutical solutions of the present invention are distributed in vials containing from 100 mg to 500 mg of donepezil. Dependent on individual patient response the recommended dose may be increased or decreased respectively.
  • the dosage is preferably administered in the form of 10 to 40 drops, to be diluted in the selected liquid media before use. This corresponds to a single dose of donepezil between 100 mg and 400 mg.
  • the oral pharmaceutical solutions of donepezil hydrochloride according to the invention also comprise one or more ingredients commonly used as thickening agents in the preparation of pharmaceutical compositions.
  • the thickening agent may be xanthan gum, acacia, guar gum, locust bean gum, gum tragacanth, starch, carbopols, sodium carboxy methylcellulose, methylcellulose, hydroxy propylcellulose, glycerin or mixtures thereof.
  • the thickening agent may preferably be sodium carboxy methylcellulose, methylcellulose, hydroxy propylcellulose, glycerin or mixtures thereof.
  • the thickening agent is most preferably glycerin.
  • Thickening agents are used in concentrations sufficient to correct or adjust the physical and rheological properties of said compositions. Thickening agents especially provide an appropriate control of viscosity in order to achieve a dropping speed of maximum 2 drops/sec and at the same time, to allow good dosing control. Thickening agents are preferably used in total concentrations of 5 to 30%.
  • the oral pharmaceutical solutions of donepezil hydrochloride according to the invention do not incorporate additional antimicrobial preservatives except ethanol.
  • antimicrobial preservative encompasses all preservatives that function to preserve a pharmaceutical composition, such as inhibit the growth of bacteria, fungi and mold growth in the composition.
  • preservatives which may be used to preserve pharmaceutical compositions are sodium benzoate, paraoxybenzoic acid esters, methyl, ethyl, butyl, and propyl parabens, chlorobutanol, benzyl alcohol, phenylethylalcohol, dehydroacetic acid, sorbic acid, benzalkonium chloride, benzethonium chloride, phenol, thiomersal, and any combination thereof.
  • the oral drop compositions of donepezil hydrochloride according to the invention may also further contain additional ingredients commonly used in the preparation of oral liquid pharmaceutical compositions, such as, for example chelating agents, buffering agents and the like.
  • the amount of donepezil present in the compositions of the present invention is from 0.5% to 2%. Most preferably, the amount of donepezil is 1 %.
  • a method for preparing the composition and a method for providing an antidementia therapy is also disclosed.
  • the amount of donepezil administered according to the present method is 1 mg to 100 mg per day.
  • compositions of the present invention have the advantages of providing higher concentrations of donepezil hydrochloride, allowing therefore smaller dose quantities to be delivered. Furthermore, they exhibit improved stability and extended shelf life.
  • compositions of the present invention are prepared in a simple manufacturing process which comprises mixing successively selected excipients under continuous stirring and dissolving donepezil hydrochloride to form a solution.
  • the manufacturing process is non-dependent on the order of the excipients addition.
  • compositions were evaluated regarding their stability in accelerated stability conditions of 55°C for one month.
  • the amount of the active substance is determined by HPLC method of analysis. All compositions were assayed in triplicate.
  • Example 1 Oral solutions with ethanol and propylene glycol as solubilizing agents.
  • Four alternative oral solutions were prepared in a manufacturing process where purified water, ethanol, propylene glycol and glycerin are added in a vessel under continuous stirring. Donepezil hydrochloride is then added in the above solution under continuous stirring and the final volume of the solution is adjusted by adding purified water.
  • the compositions described above were subjected to a short term stability examination. The solutions were stored at 55°C for one month, after being filled into amber glass vials of III hydrolytic class.
  • Table 1 Oral drop compositions with ethanol and propylene glycol as solubilizing agents
  • compositions which comprise an amount of a thickening agent provide compliance with European pharmacopoeia test for uniformity of dose providing dropping speed of maximum 2 drops/sec and at the same time, allowing good dosing control when delivered by selected commercial continuous flow droppers.
  • a thickening agent glycolin in the present example
  • Compositions with viscosity of about 10 - 40 cps at 25°C were compliant with the above mentioned test.
  • the selected thickening agent is preferably used in concentrations sufficient to adjust the viscosity of the solution to about 10 - 40 cps at 25°C.
  • Example 2 Oral solutions with the use of several stabilizing agents.
  • compositions were prepared in a manufacturing process where purified water, the selected stabilizing agent, ethanol, propylene glycol and glycerin are added in a vessel under continuous stirring. Donepezil hydrochloride is then added in the above solution under continuous stirring and the final volume of the solution is adjusted by adding purified water.
  • the amount of the solubilizing/ stabilizing agent is in the range commonly used in oral human medicines.
  • the solutions described above were subjected to short term stability examination.
  • the solutions were stored at 55°C for one month, after being filled into amber glass vials of III hydrolytic class.
  • Example 3 Oral solutions containing PEG-400, ethanol and propylene glycol in different concentrations.
  • compositions were prepared in a manufacturing process which found to be non-dependent on the order of the addition. According to said process purified water, peg-400, ethanol, propylene glycol and glycerin are added in a vessel under continuous stirring. Donepezil hydrochloride is then added in the above solution under continuous stirring and the final volume of the solution is adjusted by adding purified water.
  • Example 4 Representative oral drop composition (10 mg donepezil hvdrochloride/ml of solution)
  • Table 7 describes a representative composition of an oral drop solution of 10mg donepezil hydrochloride per ml, according to the present invention.
  • the drug product is prepared by adding the appropriate number of drops to water, fruit juice or soft drink before administration.
  • the solution is prepared with the following manufacturing process: purified water, peg-400, ethanol, propylene glycol and glycerin are added in a vessel under continuous stirring. Donepezil hydrochloride is then added in the above solution under continuous stirring and the final volume of the solution is adjusted by adding purified water.
  • Table 7 Representative oral drop composition according to the invention
  • compositions are preferably contained in an amber colored glass vial, equipped with a continuous flow dropper and screw cap closure, holding 10 to 50 ml donepezil hydrochloride solution.
  • the glass vial (type III) is suitable for liquid preparations for parenteral and oral use.
  • the dropper is made of polyethylene low density (PE-LD) material, according to food and pharmaceutical regulations.
  • the screw cap is made of polypropylene, suitable as child proof closure.
  • the present example justifies the absence of additional, antimicrobial preservation in the oral pharmaceutical solutions prepared according to the invention.
  • the reason for this lies in the sufficient amount of alcohol in the composition.
  • compositions according to the inventions tested for anti-microbial effectiveness were tested over time based on the demands of the Pharmacopoeia European (Efficacy of antimicrobial preservation ⁇ 5.1.3.).
  • the compositions were inoculated with microorganisms and incubated at 20-25°C for 14 and 28 days.
  • Table 9 Compositions according to the inventions tested for anti-microbial effectiveness

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Abstract

L'invention concerne des solutions pharmaceutiques stables pour administration par voie orale, qui peuvent être facilement formulées sous la forme de gouttes pour administration par voie orale, comprenant du donépézil, ou ses sels pharmaceutiquement acceptables, comme principe actif, et une combinaison de polyéthylène glycol 400, d'éthanol et de propylène glycol.
PCT/EP2010/061065 2010-05-27 2010-08-06 Solutions pharmaceutiques anti-démence pour administration par voie orale WO2011147471A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GR20100100308A GR1007368B (el) 2010-05-27 2010-05-27 Ποσιμα φαρμακευτικα διαλυματα για τη θεραπεια των συμπτωματων της ανοιας
GR20100100308 2010-05-27

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WO2011147471A1 true WO2011147471A1 (fr) 2011-12-01

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PCT/EP2010/061065 WO2011147471A1 (fr) 2010-05-27 2010-08-06 Solutions pharmaceutiques anti-démence pour administration par voie orale

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104958254A (zh) * 2015-06-27 2015-10-07 万特制药(海南)有限公司 一种盐酸多奈哌齐口服溶液及其制备方法

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
EP1025858A1 (fr) 1998-08-28 2000-08-09 Eisai Co., Ltd. Compositions medicales presentant une amertume, etc., reduite
EP1086706A1 (fr) 1999-03-31 2001-03-28 Eisai Co., Ltd. Compositions stabilisees contenant des medicaments nootropes
EP1311272A1 (fr) 2000-03-03 2003-05-21 Eisai Co., Ltd. Nouvelles methodes reposant sur l'utilisation d'inhibiteurs de cholinesterase
US20050232990A1 (en) * 2003-12-31 2005-10-20 Garth Boehm Donepezil formulations
US20060018839A1 (en) * 2002-05-17 2006-01-26 Eisai Co., Ltd. Methods and compositions using cholinesterase inhibitors
US20080275030A1 (en) * 2007-01-19 2008-11-06 Sveinbjorn Gizurarson Methods and Compositions for the Delivery of a Therapeutic Agent

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
EP1025858A1 (fr) 1998-08-28 2000-08-09 Eisai Co., Ltd. Compositions medicales presentant une amertume, etc., reduite
EP1086706A1 (fr) 1999-03-31 2001-03-28 Eisai Co., Ltd. Compositions stabilisees contenant des medicaments nootropes
EP1311272A1 (fr) 2000-03-03 2003-05-21 Eisai Co., Ltd. Nouvelles methodes reposant sur l'utilisation d'inhibiteurs de cholinesterase
US20060018839A1 (en) * 2002-05-17 2006-01-26 Eisai Co., Ltd. Methods and compositions using cholinesterase inhibitors
US20050232990A1 (en) * 2003-12-31 2005-10-20 Garth Boehm Donepezil formulations
US20080275030A1 (en) * 2007-01-19 2008-11-06 Sveinbjorn Gizurarson Methods and Compositions for the Delivery of a Therapeutic Agent

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104958254A (zh) * 2015-06-27 2015-10-07 万特制药(海南)有限公司 一种盐酸多奈哌齐口服溶液及其制备方法

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