WO2020208398A1 - Composition pharmaceutique en poudre avec de la mémantine et du donépézil à utiliser dans le traitement de la maladie d'alzheimer - Google Patents

Composition pharmaceutique en poudre avec de la mémantine et du donépézil à utiliser dans le traitement de la maladie d'alzheimer Download PDF

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WO2020208398A1
WO2020208398A1 PCT/IB2019/052898 IB2019052898W WO2020208398A1 WO 2020208398 A1 WO2020208398 A1 WO 2020208398A1 IB 2019052898 W IB2019052898 W IB 2019052898W WO 2020208398 A1 WO2020208398 A1 WO 2020208398A1
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Prior art keywords
coating
memantine
composition according
pharmaceutically acceptable
donepezil
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PCT/IB2019/052898
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English (en)
Spanish (es)
Inventor
Mario Atilio Los
Juan Manuel APELLA
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Laboratorios Bagó S.A.
Eastbrand Holding Gmbh
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Priority to PCT/IB2019/052898 priority Critical patent/WO2020208398A1/fr
Publication of WO2020208398A1 publication Critical patent/WO2020208398A1/fr

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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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5084—Mixtures of one or more drugs in different galenical forms, at least one of which being granules, microcapsules or (coated) microparticles according to A61K9/16 or A61K9/50, e.g. for obtaining a specific release pattern or for combining different drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—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
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
    • A61K9/1623—Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
    • 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
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
    • A61K9/5042—Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose
    • A61K9/5047—Cellulose ethers containing no ester groups, e.g. hydroxypropyl methylcellulose
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5073—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings
    • A61K9/5078—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings with drug-free core
    • 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

  • composition with memantine and donepezil for the extemporaneous preparation of a homogeneous suspension with water for oral administration for the treatment of cognitive impairment associated with Alzheimer's disease
  • the present invention relates to pharmaceutical compositions that are presented in powder form to be administered to the patient in the form of suspensions prepared after dumping the contents of the pharmaceutical composition in water followed by a little stirring to homogenize the suspension in formation.
  • compositions are presented in the form of a single-dose powder, or as a multi-dose powder in a bottle and in all cases, the suspensions with water are prepared prior to administration to the patient.
  • the composition contained in single-dose sachets or multi-dose powder in a suitable bottle contains a mixture of microgranules of prolonged-release memantine with a granule containing immediate-release donepezil hydrochloride and excipients of common pharmaceutical use.
  • the composition comprises 28 mg of memantine in the form of sustained release memantine microgranules together with 10 mg of rapid release donepezil or 14 mg of prolonged release memantine with 10 mg of rapid release donepezil.
  • both active principles dissolve, and their immediate recrystallization is not favored due to the presence of other substances in the medium.
  • the sustained-release memantine microgranules have an average size of less than 1000 microns and the granules containing donepezil less than 710 microns.
  • the physical size of these particles is convenient, novel and contributes to avoid involuntary chewing in the oral cavity and to preserve the pleasant taste of the composition.
  • a commonly used mixture is prepared for the preparation of the final pharmaceutical composition of choice.
  • the donepezil granules contain sorbitol and sucralose or other sweeteners accepted by these patients, replacing sugar.
  • the suspension in water formed from the content of any of the compositions described is easy to administer to the patient due to the small size of the particles and because of the masking of the bitter taste of the active principles they contain.
  • the suspension can also be administered through a K108 tube or similar, offering a novel alternative and not previously described .
  • Oral administration is the most comfortable and widely spread way for the administration of drugs on an international scale. However, in certain cases the administration of traditional tablets or capsules is not the most practical route of administration.
  • Dysphagia or swallowing difficulty present in patients is one of the factors that inhibits the correct ingestion of medications in the form of tablets or capsules.
  • dysphagia is defined as the difficulty in passing food from the mouth to the stomach. It is caused by different disorders such as: structural alterations, functional disorders that impede the propulsion of the food bolus, oropharyngeal reconfiguration during swallowing or opening of the upper esophageal sphincter.
  • swallowing problems can affect between 70 to 90% of the population (J. Hernández Mart ⁇ n et al - Farm. Hosp. 2013; 37 (3); 198-208).
  • Dysphagia is a pathology that affects the regular feeding and administration of drugs to normal individuals, the elderly and patients with neurological problems, and is much more complex when the patient needs several daily intakes of a drug or different drugs that are presented in tablets or capsules.
  • Memantine hydrochloride is the common name for l-amino-3,4-dimethyl adamatine hydrochloride approved by the FDA for the treatment of Alzheimer's disease with neuroprotective activity. It is soluble in water and has an intense characteristic bitter taste that is very difficult to mask. It comes in the form of tablets, long-acting tablets, or drops. The latter, due to their intense bitter taste, are preferably mixed with jellies or creams to facilitate their administration.
  • involuntary chewing is another negative element compared to the therapeutic effectiveness of pharmaceutical products.
  • several authors Jalabert Malbos ML et al 2007 - Food Quality and Preference, 18-803-812-Peyron, MA et al - 2004 - Journal of Dental Research 83 (7) -578-582 demonstrated that there is involuntary chewing when the size of the particles in the oral cavity is between 0.82 and 3.04 millimeters.
  • the particles that enter the oral cavity should preferably have a size of up to 2.50 millimeters (Guidance for Industry-Size of Beads in Drug Products Labelled for Sprinkle - May 2012). Consequently, the following factors of significant practical importance favor normal swallowing of the patient and the therapeutic effect of the pharmaceutical form: a) The size of the particles.
  • memantine and its subsequent association together with donepezil is recommended to be carried out in a sustained gradual manner and carefully observing the side effects that the patient may experience.
  • the administration of 5 mg / day of donepezil is started and it is slowly increased to a maximum of 10 mg / day according to the receptivity of the patient and the absence of effects. secondary.
  • Forest Pharmaceutical describes (US 8,039,009 B2) a method of treating Alzheimer's that comprises prolonged-release memantine-containing tablets and subsequently Adams Pharmaceutical (US 8,058,291 B2 - US 8,173,708 B) describes the treatment with the association in capsules of prolonged release memantine and donepezil.
  • the number of daily administrations to the patient is reduced, but the bitter taste of the active principles is not considered, nor the difficulties in administering capsules or tablets to patients with dysphagia and Alzheimer's.
  • compositions containing prolonged release memantine together with immediate release donepezil have been described and available. Both pharmaceutical compositions constitute a significant advance. They make it possible to reduce the number of daily administrations to the Alzheimer patient. Specifically, they contribute to reducing the number of daily intakes of compositions with memantine and donepezil and contribute to increasing adherence to treatment. They are: Namzarix from Forest Pharmaceutical Inc. (Ireland) and Alzetix from Laboratorios Gador (Argentina). They are available as capsules containing 28 mg or 14 mg of memantine hydrochloride incorporated in prolonged-release particles together with 10 mg of donepezil.
  • Conexine Combi from Laboratorios Beta has also been marketed as of 2017 in the form of prolonged-release coated tablets that optionally contain 14 or 28 mg of memantine along with 10 mg of donepezil.
  • This product contributes to reducing the number of daily doses to the patient, and simplifying the daily administration of both active principles. But it does not solve or facilitate daily administration to the elderly patient with swallowing problems or dysphagia. It is also not feasible to grind the tablet and suspend it in water before administration, since the prolonged effect characteristic of the composition would be nullified.
  • a pharmaceutical composition formed by the association of prolonged-release memantine and donepezil that facilitates administration to patients with cognitive impairment associated with Alzheimer's disease and dysphagia has not been described, and includes the following properties and advantages: a) That the bitter taste of both active ingredients (memantine and donepezil) is completely masked.
  • composition specifically has the advantage of being administered to patients through tube for enteral nutrition similar to the procedure for your usual feeding, but without the risk of obstruction of the enteral tube.
  • the suspension formed with water has the following properties and advantages: a) The taste of both active principles is totally masked and surprisingly the suspension has a pleasant taste.
  • the suspension with both active principles has the property of being also administered by enteral tube type K-108 to patients fed exclusively by this route.
  • the suspension does not clog the probe and does not form undesirable agglomerates.
  • composition particles have a size that broadly complies with the FDA recommendations (Guidance for Industry Size of Beads in Drug Products Labelled for Sprinkle, May 2012).
  • the aforementioned donepezil hydrochloride granules are prepared without sugar and with the presence of sorbitol.
  • composition of the type indicated at the beginning characterized by comprising:
  • memantine or a pharmaceutically acceptable salt thereof in the form of sustained-release microgranules with a particle size of less than 1,000 microns comprising:
  • the first hypromellose coating has a weight between 1.5 and 2.5%, preferably 2%, relative to the total weight of the pellets coated with the first coating.
  • the second coating has a weight of between 7 and 18%, preferably 13%, relative to the total weight of the pellets coated with the second coating.
  • the second coating comprises an amount of memantine or a pharmaceutically acceptable salt thereof which is equivalent to between 56% and 65% by weight relative to the total weight of the second coating, of memantine hydrochloride, and most preferably it comprises an amount of memantine or of a pharmaceutically acceptable salt thereof which is equivalent to 62.5% by weight with respect to the total weight of the second coating, of memantine hydrochloride.
  • weight values (or weight percentages) of memantine hydrochloride have been indicated.
  • the relevant element is memantine, so in the values indicated what is really relevant is the memantine content of the memantine hydrochloride.
  • expressions such as "an amount of memantine or a pharmaceutically acceptable salt thereof that is equivalent to (indication of a weight or percentage) of memantine hydrochloride" have been used. These expressions are to be understood in the sense that it is possible to use memantine or any pharmaceutically acceptable salt thereof instead of memantine hydrochloride, as long as the same quantity of memantine is supplied as the indicated quantity of memantine hydrochloride.
  • the second coating comprises between 27% and 35%, preferably 31.25%, by weight relative to the total weight of the second coating, of povidone.
  • the second coating comprises between 3% and 11%, most preferably 6.24%, by weight relative to the total weight of the second coating, of talc.
  • the third coating has a weight between 11 and 13%, preferably 12.75%, relative to the total weight of the pellets coated with the third coating.
  • the fourth coating has a weight of between 2 and 3%, most preferably 2.4%, relative to the total weight of the pellets coated with the fourth coating.
  • the fourth coating additionally comprises triacetin.
  • Triacetin is also known as glycerin triaceate and 1,2,3-triacetoxypropane.
  • the fourth coating comprises between 70% and 75% by weight with respect to the total weight of fourth coating, hypromellose.
  • the fourth coating comprises between 18% and 22% by weight relative to the total weight of the fourth coating, of talc.
  • At least 90% of the particles of the donepezil granulate are less than 500 microns in size.
  • the sweetening agent in the granules is sucralose.
  • the sustained-release microgranules have a solution of memantine or the corresponding pharmaceutically acceptable salt greater than 90% after 8 hours, according to USP 39 test.
  • the immediate release granules have a solution of the donepezil or the corresponding pharmaceutically acceptable salt greater than 90% after 10 minutes, according to USP 39 test.
  • composition according to the invention forms with water and with gentle agitation a homogeneous suspension without bitter taste, which facilitates administration to a patient.
  • the pharmaceutically acceptable salt of memantine is memantine hydrochloride.
  • the salt of donepezil is donepezil hydrochloride.
  • the pellet cores are selected from the group formed by granules of sucrose, microcrystalline cellulose, starch, microcrystalline cellulose-lactose, microcrystalline cellulose-starch and sucrose-starch. It is particularly advantageous if the pellet cores are made of sucrose-starch.
  • the powder suspended in water and with gentle agitation forms a homogeneous suspension of small particles that do not induce involuntary chewing in only 30 seconds, ensuring the integrity of the microgranules of prolonged release of the composition.
  • the powder for the preparation of an extemporaneous suspension that forms in water is preferably for direct oral administration, by incorporation into food and / or for administration through an enteral tube type K-108 or similar without obstruction thereof.
  • the composition is preferably presented in the form of a single-dose powder for the preparation of an extemporaneous suspension with water prior to administration to the patient.
  • the composition comprises an amount of memantine or a pharmaceutically acceptable salt thereof which is equivalent to between 10 and 33 mg of memantine hydrochloride. It is particularly advantageous that the composition comprises an amount of memantine or a pharmaceutically acceptable salt thereof that is equivalent to 14 mg of memantine hydrochloride. Another particularly advantageous alternative is that it comprises an amount of memantine or a pharmaceutically acceptable salt thereof that is equivalent to 28 mg of memantine hydrochloride.
  • composition is also preferably presented as a multidose powder for the preparation of an extemporaneous suspension with water prior to administration to the patient.
  • composition comprises sucralose as a sweetening agent and sugar as a diluting agent.
  • sucralose as a sweetening agent and sugar as a diluting agent.
  • sucralose as a sweetening agent and sorbitol as a diluting agent.
  • the invention also has as its object a process for preparing a composition according to the invention, characterized in that it comprises the following steps and operations:
  • microgranules for prolonged release of memantine or a pharmaceutically acceptable salt thereof according to the following sequence and operations: a) coating cores of inert 500/600 pellets selected from the group consisting of granules of sucrose, microcrystalline cellulose, of starch, of microcrystalline cellulose-lactose, of microcrystalline cellulose-starch and of sucrose-starch with a first coating of a suspension of hypromellose in water; in a fluid bed, by bottom spray at a temperature between 43-45 ° C, a spray speed of 12-16 rpm and an average application rate of 100 gr / minute;
  • step d) apply a coating on the microgranules obtained in step c) with a suspension formed by ethylcellulose in water under the following conditions: inlet temperature 60 ° C, product temperature 43-45 ° C, spray speed 12-16 rpm and suspension application rate of 100 grams / minute;
  • step d) applying on the microgranules obtained in step d) a final coating consisting of a suspension of hypromellose, talc and water; f) separating the microgranules obtained in e), passing through a 1 mm vibrating sieve and eliminating the retained agglomerates;
  • stage II comprises one of the following two sequences: a) calibrating sugar by 813 micron mesh;
  • c) incorporate and stir until final dissolution K grade povidone to form a binder liquid
  • d) incorporate in a mixer-granulator 25% of the total polyol previously calibrated in a), donepezil or the pharmaceutically acceptable salt thereof, sucralose, citric acid , another 25% of polyol previously calibrated and process at maximum speed for 4 minutes;
  • the polyol is preferably sorbitol.
  • the pharmaceutically acceptable salt of memantine is memantine hydrochloride and / or the pharmaceutically acceptable salt of donepezil is donepezil hydrochloride.
  • the invention also has for its object a use of a composition according to the invention for the preparation of an extemporaneous suspension in water for direct oral administration, by incorporation into food or for administration through an enteral tube type K-108 or similar. .
  • Adherence to the indicated treatment is an object of special medical concern and has been widely studied, described, and is the consequence of numerous factors.
  • One of the factors that determine adherence to treatment is the ease of administration of the previously indicated pharmaceutical composition.
  • composition particles that frequently stimulate involuntary chewing in the oral cavity and modify the bioavailability of the long-acting active principles contained in the particles and others.
  • the present invention aims to solve frequent problems of commercial pharmaceutical compositions or described in literature that negatively affect patient adherence to the indicated treatment and, consequently, facilitate greater adherence to treatment through the novel compositions that are described to achieve better therapeutic result.
  • it refers to the preparation of a powder to prepare a suspension with water prior to administration.
  • the suspension that is formed by dumping the powder in water after gentle shaking is easy to administer to the patient and has the following novel properties not previously described in the technical literature. They are: a) They contain microgranules with prolonged-release memantine hydrochloride together with a granule containing donepezil hydrochloride and in both cases the bitter taste of the active principles is totally masked.
  • the particles with the active ingredients are small in size and do not induce involuntary chewing. It allows to preserve the prolonged release of the memantine they contain.
  • composition formed by the powder in common use is optionally presented in the form of 1) single-dose sachets, or 2) in multi-dose bottles.
  • the powder for suspension is also sugar-free.
  • hydroxypropylmethylcellulose that is, hypromellose
  • the particles have an average size less than 1000 microns.
  • the sequence includes: a) Incorporate purified water in a stainless steel container
  • step (d) incorporating to the donepezil granulate obtained in (c) the rest of the sugar from step (b), the water from step (a); mix, granulate and dry in a fluid bed at less than 50 ° C until humidity less than 2%; e) calibrate by 1575 mesh, discard the largest particles and successively incorporate sucralose, carboxymethylcellulose, citric acid and Durarome essence, and mix for 20 to 30 minutes.
  • the granules with donepezil hydrochloride are prepared without sugar and with the presence of sorbitol, according to the following sequence: a) calibrate a polyol selected from sorbitol, mannitol and xylitol per 813 micron mesh;
  • step (e) incorporate to the donepezil granules obtained in (d) the rest of the sorbitol from step (a), the liquid binder from step (c); mix, granulate and dry in a fluid bed at less than 50 ° C until humidity less than 2%;
  • the particles of the granulate obtained have an average size of less than 710 microns.
  • the memantine microgranules and the granules with donepezil were dosed in multidose bottles destined to prepare the suspension destined for its fractionation and administration to the patient with water and subsequent shaking.
  • the Experimental Part explains the preparation of the pharmaceutical composition of choice, its properties and advantages for administration to patients with cognitive impairment associated with moderate or advanced Alzheimer's disease.
  • the preparation of the powder in common use, object of this invention contains microgranules with prolonged release memantine and a fast release donepezil granulate.
  • the powder in common use makes it possible to prepare homogeneous suspensions by incorporating water and gentle stirring. Said suspensions have small particles and do not have the bitter taste of the active principles they contain.
  • the preparation of the commonly used powder and compositions comprises the following stages:
  • the granules with donepezil hydrochloride are prepared without sugar and with the presence of sorbitol.
  • the average size of the particles is also less than 710 microns and 83.5% less than 500 microns.
  • EXAMPLE 1 Preparation of powder in single-dose sachets containing 28 mg of prolonged-release memantine hydrochloride and 10 mg of donepezil hydrochloride.
  • the sequence comprises:
  • a coating suspension was prepared by previously dissolving in a reactor and under stirring 3435 grams of memantine hydrochloride in 63 200 grams of water and successively incorporating 343 grams of talc and 1717 grams of povidone K30 under stirring for 15 minutes after each incorporation and at 35 rpm. to homogenize the suspension that is formed.
  • this step it is sought to obtain a gain in weight of the particles between 11.75 and 13.5%, preferably 12.75%.
  • Average particle size less than 1000 microns.
  • the sequence includes: a) Calibrate 111,760 grams of sugar per 813 micron mesh and condition in stainless steel containers.
  • step d) The rest of the calibrated sugar in step a) (55,880 grams) was added in the mixer-granulator.
  • step e) The binder liquid (purified water) from step b) was incorporated, and mixed, granulated and dried in fluid bed at 50 ° C until residual humidity less than 2%.
  • Average particle size is less than 710 microns and where 92.2% of the particles are less than 500 microns in size.
  • the memantine microgranules and the granules containing donepezil were incorporated into triple foil envelopes (Bioxide paper (40 m), aluminum (15 m) and polyethylene (40 m)).
  • the filling of the sachets was carried out in two dosing stations. According to the following specifications in Rovena Brand equipment.
  • the determination of the particle size distribution was performed by Laser Diffraction-Malvem Mastersizer 2000 Equipment.
  • the D (0.90) was less than 1000 microns.
  • the average size was less than 710 microns and where 92.2% of the particles had an average size less than 500 microns.
  • Dissolution medium 900 ml of simulated gastric fluid without enzyme.
  • Dissolution medium 900 ml of 0.1 N hydrochloric acid.
  • Example 2 The procedure was similar to Example 1, but decreasing the amount of memantine hydrochloride and other excipients incorporated during the production of microgranules of memantine hydrochloride.
  • EXAMPLE 3 Comparison between the powder for suspension described in Examples 1 and 2 and the content of capsules of commercial products containing memantine of prolonged release together with donepezil of optional administration under the modality "Sprinkle”.
  • the "sprinkle" mode means extracting and dumping the contents of the capsule containing the active ingredient (s) on jellies or other elements that facilitate administration to the patient.
  • the particle size distribution was determined by Laser Diffraction in Malvem Mastersizer 2000 equipment. The results were:
  • compositions together with the mentioned microgranules contain a granulate with the equivalent of 10 mg of donepezil hydrochloride per unit. Said granulate through two determinations presented an average particle size of less than 710 microns, where 92% was less than 500 microns.
  • the size of the particles proved to be lower than the average size of the particles contained in the mentioned commercial products.
  • the suspension was prepared by incorporating water into the powder and gentle stirring in vitro, it was confirmed that it does not cause obstruction of the enteral catheter type K-108 or similar. Subsequently, the suspension prepared with water was also administered to patients with cognitive impairment associated with Alzheimer's disease and marked dysphagia. There was no obstruction of the probe.
  • EXAMPLE 4 Multi-dose pharmaceutical composition in powder form.
  • the equivalent of 5 days of treatment (approximately 15 grams of powder) formed by the memantine microgranules and the granules with donepezil were dosed in a similar way to Example 1 in a 150 ml bottle to subsequently form the suspension with 100 ml of previous water to the administration. Daily dose of 20 ml.
  • the composition per bottle is:
  • EXAMPLE 5 Sugar-free composition for patients with diabetes in the form of Powder in single-dose sachets containing 28 mg of prolonged-release memantine hydrochloride and 10 mg of sugar-free donepezil hydrochloride.
  • the sequence comprises:
  • a binder solution was prepared consisting of 4500 grams of Povidone K30 and 8000 grams of Alcohol.
  • the sugar-free sachets were also prepared using other polyols, such as mannitol and xylitol.
  • EXAMPLE 6 Multi-dose pharmaceutical composition in sugar-free powder form.
  • Example 1 The equivalent of 5 days of treatment (approximately 15 grams of powder) formed by the memantine microgranules obtained in Example 1 and the granules with donepezil obtained in a similar way to Example 5 were dosed in a 200 ml bottle to subsequently form the suspension with 150 ml of water prior to administration. Daily dose of 20 ml.
  • composition per bottle is:

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne une composition pharmaceutique sous forme de poudre, pour le traitement du déclin cognitif associé à la maladie d'Alzheimer à un stade modéré ou avancé, qui comprend: I) de la mémantine ou un sel pharmaceutiquement acceptable de celle-ci sous forme de microgranules à libération prolongée ayant une granulométrie inférieure à 1 000 microns qui comprennent: - des noyaux de pellets inertes d'une granulométrie comprise entre 500 et 600 microns - un premier revêtement d'hypromellose - un deuxième revêtement qui comprend de la mémantine ou un sel pharmaceutiquement acceptable de celle-ci, de la povidone et du talc - un troisième revêtement d'éthylcellulose; et - un quatrième revêtement qui comprend de l'hypromellose et du talc; et II) une forme granulée de donépézil à libération immédiate avec du donépézil ou un sel pharmaceutiquement acceptable de celui-ci; un agent édulcorant et un agent diluant sélectionné parmi le sucre, le sorbitol, le mannitol et le xylitol; d'une granulométrie inférieure à 710 microns.
PCT/IB2019/052898 2019-04-09 2019-04-09 Composition pharmaceutique en poudre avec de la mémantine et du donépézil à utiliser dans le traitement de la maladie d'alzheimer WO2020208398A1 (fr)

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WO2023128890A1 (fr) * 2021-12-28 2023-07-06 Ilko Ilac Sanayi Ve Ticaret A.S. Composition de gélule à libération prolongée de donépézil-mémantine

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023128890A1 (fr) * 2021-12-28 2023-07-06 Ilko Ilac Sanayi Ve Ticaret A.S. Composition de gélule à libération prolongée de donépézil-mémantine

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