WO2020208398A1

WO2020208398A1 - Pharmaceutical composition comprising memantine and donepezil for use in the treatment of alzheimer's disease

Info

Publication number: WO2020208398A1
Application number: PCT/IB2019/052898
Authority: WO
Inventors: Mario Atilio Los; Juan Manuel APELLA
Original assignee: Laboratorios Bagó S.A.; Eastbrand Holding Gmbh
Priority date: 2019-04-09
Filing date: 2019-04-09
Publication date: 2020-10-15

Abstract

The present invention relates to a pharmaceutical composition in the form of powder for the treatment of moderate or advanced Alzheimer's disease-associated cognitive impairment, comprising: I) memantine or a pharmaceutically acceptable salt thereof in the form of prolonged release microgranules with a particle size less than 1000 microns comprising: - cores consisting of inert pellets with a particle size comprised between 500 and 600 microns, - a first hypromellose coating, - a second coating comprising memantine or a pharmaceutically acceptable salt thereof, povidone, and talc, - a third ethylcellulose coating, and - a fourth coating comprising hypromellose and talc; and II) an immediate release granular donepezil preparation with donepezil or a pharmaceutically acceptable salt thereof; a sweetening agent and a diluting agent selected from sugar, sorbitol, mannitol, and xylitol; with a particle size less than 710 microns.

Description

Pharmaceutical powder 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

FIELD OF THE INVENTION

Patients with cognitive impairment associated with moderate or advanced Alzheimer's disease frequently have marked difficulty swallowing or dysphagia. This pathology determines in the patient significant inconveniences during his feeding or ingestion of medicines. In the case of medicines, the administration of tablets for oral use or capsules frequently determines the partial suspension of treatment due to swallowing difficulties of the patient.

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.

The 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. Preferably 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. During the process of making the memantine microgranules and the donepezil granules, 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. Subsequently with the pellets and the aforementioned granules, a commonly used mixture is prepared for the preparation of the final pharmaceutical composition of choice. Optionally for diabetic patients, 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. Optionally, by incorporating the suspension in the oral cavity, or by dumping the suspension on food and in patients fed exclusively by enteral tube, the suspension can also be administered through a K108 tube or similar, offering a novel alternative and not previously described .

STATE OF THE ART

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.

In general, 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.

Several studies highlight the importance of this pathology that directly affects the normal continuity of treatment or patient compliance. Among them:

- During 1995 Anderson O. et al (Tidsskr Ñor Laegerfore 115-947, 949) mention that of 6158 general medicine patients, approximately 26% did not take the prescribed medication due to problems associated with swallowing.

- Bhaty P. Badgujar et al (Acta Pharm. 61 (2011), 117-139) mention that swallowing difficulty or dysphagia can affect 35% of the general non-ill population.

- According to other authors with aging people, swallowing problems can affect between 70 to 90% of the population (J. Hernández Martín et al - Farm. Hosp. 2013; 37 (3); 198-208).

- In patients with Alzheimer's disease, Cook I. L, Kahrillas PJ (Technical Review on Management of Oropharingeal Dysfagia. Gastroenterology 1999; 116; 455-478) highlight that swallowing problems or dysphagia affect 84% of patients with this pathology. 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.

Consequently, patients with dysphagia require novel pharmaceutical compositions that facilitate their administration and ensure continuity of treatment. In particular, that such novel compositions contribute to avoiding the loss of unit doses due to swallowing problems and allow compliance with the recommended daily dosage throughout their treatment.

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.

The simple grinding of tablets containing memantine does not constitute an optimal alternative for administration to patients with dysphagia since, as everyone skilled in the art knows, it destroys the characteristics and pharmaceutical properties of the composition (such as, for example, the prolonged release of the principle asset it contains).

Neither does the grinding and suspension of the particles in water offer a practical solution since it generally determines the formation of agglomerates of significant size and consequently, difficult to swallow.

Similar behavior is shown by tablets containing donepezil.

It should be noted that involuntary chewing is another negative element compared to the therapeutic effectiveness of pharmaceutical products. Thus, for example, 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. Based on this information and on the behavior of the products administered under the "sprinkle" modality, FDA recommends that 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.

b) The taste of the suspension that they form in the oral cavity and its acceptability.

c) The integrity of the specific pharmaceutical properties of the composition.

It is known that enteral feeding is frequent and necessary in patients with cognitive impairment associated with moderate or advanced Alzheimer's disease.

In many cases it is the only alternative to solve their deficient nutritional intake and administration of medications. This is highlighted by numerous authors. Among them:

- Michel St et al (JAMA 2003 - July 2, 290 (1): 73-80) indicate that 34% of the 186,835 patients residing in geriatric centers with advanced cognitive impairment were fed by tube.

- In Nutr. Hosp. 2006: 21 (Suppl. 4) 3-4 experts mention that swallowing difficulty in some patients is so important that enteral nutrition through tube is the most convenient practical alternative for their feeding and administration of medications.

The increased survival age of the population, together with advances in enteral nutrition and tube placement techniques, have facilitated the spread of this type of feeding and administration of medications with enteral tubes.

However, in the particular case of medications, the obstruction of the tube by the medication is a frequent inconvenience. The grinding of oral tablets as it is done in hospitals and at home and subsequent suspension in water is not an optimal alternative in all cases. They frequently cause any of the following problems: a) Obstruction of the enteral tube, due to the size of the particles from the grinding.

b) Obstruction of the probe due to the formation of undesirable aggregates of the particles in the presence of water.

c) Omission of doses due to mechanical problems during administration.

d) Loss of characteristics and properties present in intact tablets (such as sustained release or enteric coating of the active ingredient they contain).

e) Alteration of the usual bioavailability of the drug (increase or decrease) due to the loss of the characteristics and properties of the whole tablet.

The administration of 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. In general, it is suggested to start administering 5 mg / day of memantine and gradually increase the daily dose in the following weeks to 10 mg / day, 15 mg / day and finally increase to the daily maximum of 20 mg. Having reached 20 mg / day of memantine administration only a posteriori, 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.

The general and commonly used scheme mentioned requires two pharmaceutical compositions (one of memantine and the other of donepezil) and several daily administrations.

To advance in simplifying treatment for the patient, different treatments were described. Thus, for example, 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. In both cases, 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.

In recent years specifically, to simplify neuroprotective administration to patients who require both active principles mentioned, two pharmaceutical 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.

In both cases and when the ingestion of the capsules is not easy for the patient with dysphagia, they only suggest as an alternative to open the capsule and dump its content on apple puree to facilitate administration and mask the bitter taste (known administration method as "sprinkle"). They also indicate not to chew so as not to destroy the prolonged effect of the memantine hydrochloride particles contained in the mixture present in the capsules.

Naturally, for patients with Alzheimer's disease and dysphagia, both products have some unwanted characteristics:

1) The presentation in the form of capsules is difficult to ingest in most cases - Cook I. L, Kahrillas P. J. previously mentioned, emphasize that swallowing problems affect 84% of Alzheimer's patients.

2) The powder contained in the capsules does not mask the bitter taste of the active ingredients.

3) When you want to mask the bitter taste with applesauce, it is necessary to make it easy to remove the entire contents of the capsule. Inasmuch as the unwanted retention of part of the content in the capsule determines alteration of the dosage (aspect of not easy compliance in all the capsules).

4) And it is indicated not to chew probably because of the significant size of the particles containing long-acting memantine and donepezil.

To simplify daily administration, a product called 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.

In summary: so far, 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.

b) That it does not leave annoying residue in the oral cavity.

c) That it does not stimulate involuntary chewing.

d) That it is easy to swallow for the patient with habitual dysphagia.

e) That the 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.

Novel properties absent in the compositions in the form of capsules or tablets described and that the present invention comprises in the form of powder to form a suspension with water before administration. 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.

b) The small particle size of prolonged-release memantine (less than 1000 microns) and donepezil (less than 710 microns) does not disturb the oral cavity and does not stimulate involuntary chewing. The prolonged effect of the memantine it contains is not destroyed.

c) In all patients, the suspension formed with water is easy to swallow.

d) Optionally, 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.

e) Optionally, the powder to prepare the suspension with water before administration to the patient is presented in:

single-dose sachets.

multidose vials.

The 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).

Inadvertent chewing of the particles by dusting administration can lead to non-compliance with taking the medication due to taste and decreased drug efficacy.

The preparation of the powder containing prolonged-release memantine and donepezil -as will be explained in the Experimental Part- comprises the following stages:

1) Preparation of small sized sustained release memantine microgranules with fully masked memantine bitter taste.

2) Preparation of granules with donepezil, also with small particles (less than 710 microns) that contain suitable excipients and flavorings that determine, by Incorporation into water, rapid suspensibility, forming by gentle stirring a homogeneous suspension with a pleasant taste.

3) For diabetic patients, the aforementioned donepezil hydrochloride granules are prepared without sugar and with the presence of sorbitol.

4) Incorporate without previously mixing both active ingredients mechanically, simultaneously and separately to form the pharmaceutical composition of choice (single-dose sachets, multi-dose bottles) and avoid the previous segregation of the particles, ensuring the uniformity of the content of the composition.

5) And where the active principles memantine and donepezil are partially or totally dissolved during the mentioned procedures.

EXHIBITION OF THE INVENTION

The object of the invention is to overcome these drawbacks. This purpose is achieved through a composition of the type indicated at the beginning characterized by comprising:

I) 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:

- Inert pellet cores with a particle size between 500 and 600 microns

- a first coating of hypromellose

- a second coating comprising memantine or a pharmaceutically acceptable salt thereof, povidone and talc

- a third coating of ethylcellulose; Y

- a fourth coating comprising hypromellose and talc; Y

II) an immediate release donepezil granulate with donepezil or a pharmaceutically acceptable salt thereof; a sweetening agent and a diluting agent selected from sugar, sorbitol, mannitol and xylitol; with a particle size less than 710 microns.

In the present description and claims, the expression "microns" has been used to refer to "microns" or "microns".

Preferably, 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. Advantageously, 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.

Preferably 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.

In the present description and claims weight values (or weight percentages) of memantine hydrochloride have been indicated. In the present invention, the relevant element is memantine, so in the values indicated what is really relevant is the memantine content of the memantine hydrochloride. For this reason, 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.

Advantageously, the second coating comprises between 27% and 35%, preferably 31.25%, by weight relative to the total weight of the second coating, of povidone.

Preferably 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.

Advantageously, 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.

Preferably 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.

Advantageously the fourth coating additionally comprises triacetin. Triacetin is also known as glycerin triaceate and 1,2,3-triacetoxypropane.

Preferably the fourth coating comprises between 70% and 75% by weight with respect to the total weight of fourth coating, hypromellose.

Advantageously, the fourth coating comprises between 18% and 22% by weight relative to the total weight of the fourth coating, of talc.

Preferably at least 90% of the particles of the donepezil granulate are less than 500 microns in size.

Advantageously, the sweetening agent in the granules is sucralose.

Preferably, 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.

Preferably, 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.

Advantageously, the composition according to the invention forms with water and with gentle agitation a homogeneous suspension without bitter taste, which facilitates administration to a patient.

Preferably the pharmaceutically acceptable salt of memantine is memantine hydrochloride.

Preferably the salt of donepezil is donepezil hydrochloride.

Advantageously, 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.

Preferably, 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. In these cases, it is advantageous that 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.

The composition is also preferably presented as a multidose powder for the preparation of an extemporaneous suspension with water prior to administration to the patient.

Advantageously the composition comprises sucralose as a sweetening agent and sugar as a diluting agent. An advantageous alternative is that it comprises 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:

I. prepare 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;

b) dissolving memantine or a pharmaceutically acceptable salt thereof and preparing a suspension incorporating, under stirring, talc and povidone grade K;

c) coating the inert pellet cores obtained in stage a) by bottom spray with the suspension from stage b) and isolating the microgranules formed;

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;

e) 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;

II. preparing a granulate containing donepezil or a pharmaceutically acceptable salt thereof

III. Dosing and conditioning the microgranules and granules previously prepared through two independent dosing stations, optionally and at choice, in single-dose sachets or multi-dose bottles as the final packaging of the composition.

Preferably stage II comprises one of the following two sequences: a) calibrating sugar by 813 micron mesh;

b) incorporate purified water in a stainless steel container

c) incorporate in a mixer-granulator 25% of the total sugar previously calibrated in a), donepezil or a pharmaceutically acceptable salt thereof, another 25% of previously calibrated sugar and process at maximum speed for 5 to 15 minutes;

d) incorporating into the granulate obtained in c) the rest of the sugar from step a), the water from step b); mix, granulate and dry in a fluid bed at less than 50 ° C until humidity less than 2%;

e) calibrate by 1575 mesh and successively incorporate sucralose, carboxymethylcellulose, citric acid and Durarome essence, and mix for 20 to 30 minutes, or: a) calibrate a polyol selected from sorbitol, mannitol and xylitol by 813 micron mesh;

b) incorporate alcohol into a stainless steel container fitted with a stirrer,

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;

e) incorporating into the granulate obtained in d) the rest of the polyol from step a), the binder liquid from step c); mix, granulate and dry in a fluid bed at less than 50 ° C until humidity less than 2%;

f) calibrate by mesh 1575.

In the latter case, the polyol is preferably sorbitol.

Preferably 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. .

DETAILED DESCRIPTION OF SOME FORMS OF EMBODIMENT OF THE INVENTION

Other advantages and characteristics of the invention can be seen from the following detailed description of specific forms of embodiment of the invention, in which, without any limitation, preferred modes of embodiment of the invention are reported

Patient adherence to treatment adjusted to the daily dosage indicated by their doctor is a necessary condition for obtaining a satisfactory therapeutic result. In particular, you should not miss any of the indicated daily doses.

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.

Patients with cognitive impairment associated with moderate or advanced Alzheimer's disease face several problems that make their full adherence to treatment difficult. Among them, as mentioned in State of the Art: a) The frequent dysphagia associated with age and illness.

b) The size of the pharmaceutical composition (capsules or tablets) that make its normal ingestion difficult.

c) The bitter taste of the active ingredients.

d) The size of the 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. Specifically, 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.

b) 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.

c) The suspension formed with water is easy to swallow.

d) The 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.

e) Once the suspension is prepared, administration to the patient is feasible in three different ways: They are: a) directly, b) by incorporation into food, and c) for special patients fed exclusively by tube through enteral tube type K- 108 or similar.

f) Optionally for diabetic patients, the powder for suspension is also sugar-free.

An advantageous process for preparing the composition comprises the following three steps:

I) Make microgranules with memantine hydrochloride, prolonged release, and fully masked flavor.

It was carried out according to the following stages and operations: a) Apply a base coating formed by a coating suspension of hydroxypropylmethylcellulose (that is, hypromellose) in water (Opadry-YS-1.19044 Clear), on inert nuclei or granules selected from granules of sucrose, microcrystalline cellulose, starch, microcrystalline cellulose-lactose, microcrystalline cellulose-starch and sucrose-starch granules (Sugarsphere 500/600 cores) by bottom spray at 43-45 ° C, under stirring (12- 16 rpm) and with an application rate of 100 grams per minute.

b) Dissolve memantine hydrochloride in water, subsequently form a homogenized suspension under stirring in water containing the previously dissolved memantine hydrochloride together with grade K povidone, preferably K30 povidone, and talc,

c) Cover the previous cores of Sugarsphere 500/600 with the suspension formed in b) coated with hypromellose obtained in a).

c) Carry out a subsequent functional coating, also by bottom spray, of the particles obtained with a suspension of ethylcellulose (Surrelease E-7) in water.

d) Make a final coating or top coat with a suspension formed by hypromellose (Opadry YS-1.19044 Clear) in water.

e) Separate the particles obtained by vibrating sieve of 1 mm and discard the agglomerates.

The particles obtained showed the following characteristics:

1) They present completely masked the bitter taste of memantine.

2) The particles have an average size less than 1000 microns.

II) Preparation of a granulate containing donepezil hydrochloride with masked taste and small particle size.

The sequence includes: a) Incorporate purified water in a stainless steel container

b) Calibrate sugar.

c) Process in a mixer-rotogranulator at maximum speed a mixture formed by 25% sugar, donepezil hydrochloride, another 25% sugar previously calibrated and process at maximum speed for 5 to 15 minutes;

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.

Optionally for diabetic patients, 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;

b) incorporate alcohol into a stainless steel container fitted with a stirrer,

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 sorbitol previously calibrated in (a), donepezil hydrochloride, sucralose, citric acid, another 25% of sorbitol previously calibrated and process at maximum speed for 4 minutes;

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%;

f) calibrate by mesh 1575.

Under the conditions described, the particles of the granulate obtained have an average size of less than 710 microns.

III) Dose and condition the prolonged-release memantine microgranules and the granules with donepezil hydrochloride previously prepared through two independent dosing stations, optionally and of choice, in single-dose sachets or multidose bottles as the final container of the composition.

IV) Dosage and preparation of single-dose sachets containing the prolonged-release memantine microgranules together with the granules containing donepezil hydrochloride.

Every expert in the art knows that content uniformity is a necessary condition for the approval of pharmaceutical compositions by the health authorities of each country, since the content of each dose is an essential quality element to ensure the uniformity of the content of each dose throughout the treatment administered to the patient.

The pre-mixing of the aforementioned microgranules and granules and their subsequent incorporation into envelopes failed on numerous occasions, even modifying the operating conditions in each case. It was not possible to achieve uniformity of content in the envelopes obtained. Surprisingly, it was only possible to prepare sachets with uniform microgranule content with memantine and granulated with donepezil by filling triple-foil sachets with two dosing stations on Rovena equipment. Through the first dosing station, the equivalent of 28 mg or 14 mg of prolonged release memantine was added to each sachet and through the second station, the equivalent of 10 mg of donepezil was incorporated. Only under these operating conditions was the desired content uniformity necessary for the product achieved.

Similarly, and through 2 dosing stations, 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.

For diabetic patients, as observed in the Experimental Part, the sugar in the granules containing donepezil was replaced by other sweeteners accepted for these patients. The result confirmed that also the suspension formed with water keeps completely masked the bitter taste of memantine and donepezil and the particles contained in the suspension formed do not cause involuntary chewing and allow to preserve the prolonged activity of the memantine present in the composition.

Furthermore, all the suspensions that form the compositions described in the Experimental Part with water have shown that they constitute an original and not previously described alternative of administration by type K 108 or similar probe. A particularly useful and necessary alternative for patients who are only fed through an enteral tube.

Without being limiting, 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.

EXPERIMENTAL PART

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:

1) Manufacture of sustained release memantine microgranules free of the bitter taste of memantine and with an average size of less than 1000 microns.

2} Preparation of a granulate containing donepezil hydrochloride together with flavorings and excipients of common pharmaceutical use that determine the formation of homogeneous suspensions by incorporating water and gentle stirring. The maximum size of the particles contained in the granulate is less than 710 microns and where more than 90 percent is less than 500 microns.

3} Optionally for diabetic patients, the granules with donepezil hydrochloride are prepared without sugar and with the presence of sorbitol. In this case, the average size of the particles is also less than 710 microns and 83.5% less than 500 microns.

4) Subsequently, dose separately and without previously mixing the memantine microgranules and the granules containing donepezil in single-dose sachets or multi-dose bottles through two dosing stations to avoid the segregation of the particles and ensure the uniformity of the content of each one of them. The compositions. EXAMPLE 1: Preparation of powder in single-dose sachets containing 28 mg of prolonged-release memantine hydrochloride and 10 mg of donepezil hydrochloride.

It was carried out according to the following sequence of stages and operations:

A) Manufacture of sustained release memantine hydrochloride microgranules and fully masked flavor:

The sequence comprises:

1) Base coat (Seal Coat) by botom sprav:

a) Prepare a suspension formed by Opadry YS-1.19044 Clear (700 grams) in water (9300 grams).

b) Coat 35000 grams of inert cores, Sugarsphere 500/600, with the previous suspension in CHONGQING DPL 60/120 equipment by bottom spray, under the following conditions: temperature between 43-45 ° C, spray speed (spray speed) 12 -16 rpm, and average application rate: 100 gr / minute.

Product: 35700 grams of inert cores coated with Opadry are obtained.

2) Coating with active principle by bottom sprav:

a) 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.

b) the suspension previously formed in this stage, (2a) was applied on the 35700 grams of inert pellet cores (Sugarsphere 500/600 particles) coated, obtained in the previous stage (1), by bottom spray under the following conditions : inlet temperature (Inlet Temp.) 60 ° C, product temperature: 43 ° C, spray speed (Spray Speed): 12.28 rpm, with a suspension application rate of 150-200 grams / minute and maintaining the stirring of the coating suspension throughout the process.

In this stage, the application of suspension is maintained until obtaining a weight of pellet cores coated with memantine between approximately 38,660 and 43,500 grams. 41,190 grams were obtained Coating with functional suspension by bottom sprav:

a) A suspension formed by Surrelease E-7-19040 (20876 grams) in water (31.314 grams) was prepared under stirring.

b) The memantine microgranules obtained in the previous step (2 b) were coated with the suspension formed under the following conditions: Inlet temperature: 60 ° C, product temperature: 43-45 ° C, spray speed: 12-16 rpm, and suspension application rate 100 grams / minute.

In this step, it is sought to obtain a gain in weight of the particles between 11.75 and 13.5%, preferably 12.75%.

46,153 grams of Surrelease-coated memantine microgranule cores are obtained.

3) Final coating (Ton Coat):

a) A suspension formed by Opadry YS-1.19044 Clear (920 grams) and Talc (235 grams) in water (12000 grams) was prepared.

b) The 46153 grams obtained in the previous stage were coated with the previous suspension and by bottom spray under the following conditions: Temperature 43-45 ° C, spray speed 12-16 rpm and application rate of 100 grams /minute. 47,294 grams of memantine granules are obtained.

c) The particles obtained were passed through a 1 mm vibrating sieve and the retained agglomerates were discarded.

Obtained: 46.348grams.

Average particle size: less than 1000 microns.

B) Preparation of the granules containing donepezil hydrochloride:

The sequence includes: a) Calibrate 111,760 grams of sugar per 813 micron mesh and condition in stainless steel containers.

b) In a stainless steel container add 750 grams of purified water

c) In a high-speed mixer-granulator, 27,940 grams of previously calibrated sugar, 500 grams of donepezil hydrochloride, and again another 27,940 grams of sugar previously calibrated in step a) are incorporated and processed at maximum mixing and rotogranulation speed for 5 minutes.

d) The rest of the calibrated sugar in step a) (55,880 grams) was added in the mixer-granulator.

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%.

f) The granulate obtained in e) was calibrated by 1575 mesh and incorporated into a 1000 liter container, incorporating successively: sucralose (500 grams); 4,500 grams of citric acid and 28,000 grams of 7MF carboxymethylcellulose, all previously calibrated by 1575 mesh.

g) 3340 grams of Durarome 860188 type lemon essence was added to the previous container.

h) It was mixed for 20 minutes and conditioned in a stainless steel tank with hermetic closure.

All operations were carried out in an environment with humidity lower than 65% and at a temperature no higher than 25 ° C.

Average particle size is less than 710 microns and where 92.2% of the particles are less than 500 microns in size.

C) Dosing and filling of the sachets:

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.

Through the first dosing station: The equivalent of 28 mg of prolonged-release memantine hydrochloride was added to each sachet and according to its title.

- Theoretical content 28 mg

- Average weight deviation ± 2.5% of theoretical weight

- Individual weight deviation ± 5.0% of theoretical weight

Through the second dosing station: The equivalent of 10 mg of donepezil present in the described granules was added to each sachet and weight corrected by title.

Theoretical filling weight per unit 3000 mg

Minimum tolerated average weight 2925 mg

Average Maximum Tolerated Weight 3075 mg

Maximum tolerated individual weight 3150 mg

Minimum tolerated individual weight 2850 mg Envelopes with the following composition were obtained:

.the envelopes were packed in boxes. FEATURES:

1) Both active principles (memantine hydrochloride and donepezil hydrochloride) during the production of microgranules and during granulation dissolve totally or partially due to the presence of water, reducing the presence of crystals and favoring the masking of the bitter taste of each active principle.

2) Flavor of the suspension formed in water:

5 healthy volunteers each tested the taste of the suspension formed by the content of an envelope incorporated in 5 ml of water followed by gentle shaking (30 seconds) to homogenize the suspension.

All confirmed the absence of the bitter taste and the presence of a pleasant lemon flavor and the absence of annoying particles in the oral cavity.

3) Particle size:

a) Microcapsules with prolonged-release memantine hydrochloride:

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.

b) Granules containing donepezil hydrochloride:

It was made by tower of sieves. The average size was less than 710 microns and where 92.2% of the particles had an average size less than 500 microns.

4) Dissolution tests:

The dissolution of each of the active principles in the powder containing prolonged-release memantine hydrochloride and rapid-release donepezil hydrochloride was determined under the following terms:

4.1) For MEMANTINE HYDROCHLORIDE:

Device: USP N ° 1, baskets.

Speed: 100 rpm.

Dissolution medium: 900 ml of simulated gastric fluid without enzyme.

Temperature: 37 ° C ± 0.5 ° C.

Sampling time: 1, 4, 8 and 12 hours.

Methodology: Memantine HC1 Tablets USP 39 (with FDA 2016 suggested sampling times for Extended Release).

4.2) For DONEPECILO HYDROCHLORIDE:

Device: USP No. 2, paddles.

Speed: 100 rpm.

Dissolution medium: 900 ml of 0.1 N hydrochloric acid.

Temperature: 37 ° C ± 0.5 ° C.

Sampling time: 10, 15, 20, 30 and 40 minutes.

Methodology: Donepezil HC1 Tablets USP 39.

For MEMANTINE HYDROCHLORIDE the results were:

For DONEPECILO CLORHIDRATO the results were:

EXAMPLE 2: Preparation of single-dose sachets containing 14 mg of Memantine Hydrochloride and

10 mg of Donepezil Hydrochloride.

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.

For Namzarix and Alzetix products, it is specifically indicated that the capsules can be opened and their content poured onto applesauce before administration.

Comparatively, the following differences were observed between the mentioned products and the powder of the present invention:

11 FLAVOR: Five volunteers confirmed that the contents of the Namzarix and Alzetix capsules are bitter. The flavor of sustained release memantine and donepezil is not masked and the capsules according to the described formulas of the commercial products are devoid of flavorings. While the powder for suspension of the present invention contains prolonged release memantine microgranules with fully masked flavor and the granule containing donepezil has lemon essence and sugar. Therefore, the powder in sachets allows its content to be dumped directly into water and has an immediate suspension that is easy to administer to the patient due to the absence of a bitter taste and the presence of a pleasant taste.

21 PARTICLE SIZE:

The particle size distribution was determined by Laser Diffraction in Malvem Mastersizer 2000 equipment. The results were:

2.A) ALZETIC 14 / 10— Lot 29667— D (0.9): In two determinations, an average size of 1317.883 and 1199.941 microns was observed.

2.B) In the powders for preparing suspensions in water according to Examples 1 and 2, it was observed that the powder allows a suspension to be easily administered to the patient with water. Contains per unit optionally 28 mg or 14 mg extended release memantine and as previously mentioned, the average particle size was less than 1000 microns.

Both compositions together with the mentioned microgranules (28 or 14 mg) 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.

Consequently, the size of the particles proved to be lower than the average size of the particles contained in the mentioned commercial products.

31 EASE OF ADMINISTRATION UNDER THE "SPRINKLE" MODE FROM

COMMERCIALIZED CAPSULES COMPARED TO THE EASE OF

ADMINISTRATION FROM ENVELOPES CONTAINING DUST FOR SUSPENSION.

It was observed that the opening of the aforementioned commercial capsules is often not easy and it is necessary in all cases to ensure the total extraction of the pellets they contain so as not to alter the indicated daily dosage.

Disadvantages absent in the powder for suspension in sachets described in EXAMPLES 1 and 2 and where, as indicated, the particles of the powder for suspension are smaller, taste completely masked, do not induce involuntary chewing in the oral cavity and the set of advantages simplifies administration to the patient.

41 ADMINISTRATION BY ENTERAL PROBE TYPE K-108 OR SIMILAR.

Once 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 procedure was similar to Example 1, but replacing the Sugar in the granules containing the Donepezil hydrochloride with Sorbitol.

Al Preparation of granules containing donepezil hydrochloride:

The sequence comprises:

a) In a container of adequate capacity, a binder solution was prepared consisting of 4500 grams of Povidone K30 and 8000 grams of Alcohol.

b) In mixer-granulator 27815 grams of Sorbitol, 500 grams of Donepezil hydrochloride were incorporated together with 4500 grams of Citric Acid, 500 grams of Sucralose and 27815 grams of sorbitol. It was mixed at maximum mixing speed and rotogranulate for 4 minutes.

c) Another 55630 grams of sorbitol powder was added and it was processed at maximum mixing speed and rotogranulation for 4 minutes.

d) The binder liquid (a) was added to the powder mixture and it was granulated and dried in a fluid bed dryer at 50 ° C until residual humidity of less than 2%.

e) The granulate obtained was calibrated by 1575 mesh and incorporated into a 1000 liter container incorporating 24000 grams of 7MF Carboxymethylcellulose previously calibrated by 1575 micron mesh.

f) In addition, 3340 grams of Durarome 860,188 lemon essence was added to the container from the previous step and it is packed in a stainless steel tank with hermetic closure.

All operations were carried out in an environment with humidity lower than 65% and at a temperature not higher than 25 ° C. During the mixing operation, the binder solution favors the partial dissolution of donepezil hydrochloride due to its alcohol content. B) Dosage: With the microgranules of Memantine Hydrochloride obtained in Example 1 and the granules described above, sachets are dosed, idem Example 1 C). Sachets with the following composition were obtained.

The sugar-free sachets were also prepared using other polyols, such as mannitol and xylitol.

C) Powder in single-dose sachets containing 14 mg of prolonged-release memantine hydrochloride and 10 mg of sugar-free donepezil hydrochloride.

The procedure was similar to Example 5, but with a smaller quantity of microgranules of memantine hydrochloride.

EXAMPLE 6: Multi-dose pharmaceutical composition in sugar-free powder form.

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.

The composition per bottle is:

Claims

1. Pharmaceutical composition in powder form, for the treatment of cognitive impairment associated with moderate or advanced Alzheimer's disease, CHARACTERIZED because it comprises:

- Inert pellet cores with a particle size between 500 and 600 microns

- a first coating of hypromellose

- a third coating of ethylcellulose; Y

- a fourth coating comprising hypromellose and talc; Y

Composition according to claim 1, characterized in that said first hypromellose coating has a weight comprised between 1.5 and 2.5%, preferably 2%, relative to the total weight of the pellets coated with said first coating.

Composition according to one of claims 1 or 2, characterized in that said second coating has a weight comprised between 7 and 18%, preferably 13%, relative to the total weight of the pellets coated with said second coating.

Composition according to any of claims 1 to 3, characterized in that said second coating comprises an amount of memantine or a pharmaceutically acceptable salt thereof which is equivalent to between 56% and 65% by weight with respect to the total weight of said second coating, of memantine hydrochloride, and preferably comprises an amount of memantine or a pharmaceutically acceptable salt thereof which is equivalent to 62.5% by weight with respect to the total weight of said second coating, of memantine hydrochloride.

Composition according to any one of claims 1 to 4, characterized in that said second coating comprises between 27% and 35%, preferably 31.25%, by weight with respect to the total weight of said second coating, of povidone.

Composition according to any one of claims 1 to 5, characterized in that said second coating comprises between 3% and 11%, preferably 6.24%, by weight relative to the total weight of said second coating, of talc.

Composition according to any of claims 1 to 6, characterized in that said third coating has a weight comprised between 11 and 13%, preferably 12.75%, with respect to the total weight of the pellets coated with said third coating.

Composition according to any of claims 1 to 7, characterized in that said fourth coating has a weight comprised between 2 and 3%, preferably 2.4%, with respect to the total weight of the pellets coated with said fourth coating.

9 - Composition according to any of claims 1 to 8, characterized in that said fourth coating additionally comprises triacetin.

10 - Composition according to any of claims 1 to 9, characterized in that said fourth coating comprises between 70% and 75% by weight with respect to the total weight of said fourth coating, of hypromellose.

11 - Composition according to any of claims 1 to 10, characterized in that said fourth coating comprises between 18% and 22% by weight with respect to the total weight of said fourth coating, of talc.

Composition according to any one of claims 1 to 11, characterized in that at least 90% of the particles of said donepezil granulate have a size less than 500 microns.

Composition according to any of claims 1 to 12, characterized in that said sweetening agent of said granulate is sucralose.

Composition according to any of claims 1 to 13, characterized in that said sustained-release microgranules have a dissolution of memantine or the corresponding pharmaceutically acceptable salt greater than 90% after 8 hours, according to USP 39 test.

Composition according to any of claims 1 to 14, characterized in that said immediate release granules have a dissolution of donepezil or the corresponding pharmaceutically acceptable salt greater than 90% after 10 minutes, according to USP 39 test.

Composition according to any of claims 1 to 15, characterized in that it forms with water and with gentle stirring a homogeneous suspension without bitter taste, which facilitates administration to a patient.

Composition according to any one of Claims 1 to 16, characterized in that the pharmaceutically acceptable salt of memantine is memantine hydrochloride.

Composition according to any one of claims 1 to 17, characterized in that the donepezil salt is donepezil hydrochloride.

Composition according to any one of claims 1 to 18, characterized in that said pellet cores are selected from the group consisting of granules of sucrose, microcrystalline cellulose, starch, microcrystalline cellulose-lactose, microcrystalline cellulose-starch and sucrose-starch.

Composition according to any of claims 1 to 19, characterized in that the powder suspended in water and with gentle stirring in only 30 seconds forms a homogeneous suspension of small particles that do not induce involuntary chewing, ensuring the integrity of the release microgranules prolonged composition.

21. Composition according to any of claims 1 to 20, characterized in that the powder for the preparation of an extemporaneous suspension that forms in water is for direct oral administration, by incorporation into food and / or for administration through enteral tube type K-108 or similar without obstruction thereof.

Composition according to any of claims 1 to 21, characterized in that it is presented in the form of a single-dose powder for the preparation of an extemporaneous suspension with water prior to administration to the patient.

23. Composition according to claim 22, characterized in that it comprises an amount of memantine or of a pharmaceutically acceptable salt thereof which is equivalent to between 10 and 33 mg of memantine hydrochloride.

Composition according to claim 22, characterized in that it comprises an amount of memantine or a pharmaceutically acceptable salt thereof that is equivalent to 14 mg of memantine hydrochloride.

Composition according to claim 22, characterized in that it comprises an amount of memantine or a pharmaceutically acceptable salt thereof that is equivalent to 28 mg of memantine hydrochloride.

Composition according to any of claims 1 to 21, characterized in that it is presented as a multidose powder for the preparation of an extemporaneous suspension with water prior to administration to the patient.

27. Composition according to any one of claims 1 to 26, characterized in that it comprises sucralose as a sweetening agent and sugar as a diluting agent.

28. Composition according to any one of claims 1 to 26, characterized in that it comprises sucralose as a sweetening agent and sorbitol as a diluting agent.

29. Composition according to any of claims 1 to 28, characterized in that said pellet cores are made of sucrose-starch.

30. Process for preparing a composition according to any of claims 1 to 29, characterized in that it comprises the following steps and operations:

I. prepare 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;

e) apply on the microgranules obtained in step d) a final coating consisting of a hypromellose, talc and water suspension;

f) separating the microgranules obtained in e), passing through a 1 mm vibrating sieve and eliminating the retained agglomerates;

31. Process according to claim 30, characterized in that said stage II comprises the following sequence: a) calibrating sugar by 813 micron mesh;

b) incorporate purified water in a stainless steel container

e) calibrate by 1575 mesh and successively incorporate sucralose, carboxymethylcellulose, citric acid and Durarome essence, and mix for 20 to 30 minutes.

32. Process according to claim 30, characterized in that said step II comprises the following sequence: a) calibrating a polyol selected from sorbitol, mannitol and xylitol per 813 micron mesh;

b) incorporate alcohol into a stainless steel container fitted with a stirrer,

f) calibrate by mesh 1575.

33. Process according to claim 32, characterized in that said polyol is sorbitol.

34. Process according to any one of claims 30 to 33, characterized in that the pharmaceutically acceptable salt of memantine is memantine hydrochloride.

35. Process according to any of claims 30 to 34, characterized in that the pharmaceutically acceptable salt of donepezil is donepezil hydrochloride.

36. Use of a composition according to any of claims 1 to 29, 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.