WO2020121027A1

WO2020121027A1 - Amorphous alprazolam compositions with anxiolytic activity with ethyl cellulose and crospovidone and corresponding methods

Info

Publication number: WO2020121027A1
Application number: PCT/IB2018/059911
Authority: WO
Inventors: Mario Atilio Los
Original assignee: Laboratorios Bagó S.A.; Eastbrand Holding Gmbh
Priority date: 2018-12-12
Filing date: 2018-12-12
Publication date: 2020-06-18

Abstract

The invention relates to an amorphous alprazolam composition with anxiolytic activity, which comprises: a) a premixture containing: 0.33-0.66% w/w alprazolam; 0.07-0.2% w/w ethyl cellulose as a binding agent; a disintegrating agent, a diluting agent, aspartame and a flavour masking agent; and b) the premixture combined with: 4-6% w/w water-insoluble crospovidone as a disintegrating agent; a lubricating agent; flavouring agents, sweetening agents and q.s. 100% granular mannitol as a diluent, wherein: the ratio of alprazolam to ethyl cellulose in the premixture is in the range of 2.5:1 to 5:1; the ratio of alprazolam to water-insoluble crospovidone is in the range of 0.06:1 to 0.13:1; and the degree of crystallinity of alprazolam is less than 10%.

Description

ALPRAZOLAM AMORFO COMPOSITIONS WITH ANSIOLYTIC ACTIVITY

WITH ETICELLULOSE AND CROSPOVIDONE AND PROCEDURES

CORRESPONDING

FIELD OF THE INVENTION

The present invention relates to a process for the production of a granule in common use formed from a specific premix containing the active ingredient alprazolam previously dissolved and subsequently distributed homogeneously to the mostly amorphous physical state throughout the mass of excipients and, where the granulate is optionally compressed or fractionated and packed as a powder to prepare suspensions. Pharmaceutical compositions containing the granulate and processes for preparing the premix, granules and pharmaceutical compositions are also described.

The alprazolam contained in the composition is mostly in an amorphous physical state. In this sense, in general, when in the present description and claims reference is made to "amorphous alprazolam" or "mostly amorphous alprazolam" it should be understood that it refers to an alprazolam that has less than 10% in crystalline state.

The composition is presented indistinctly in the form of orally disintegrating scored tablets (ODT) made by simple compression of the granules, or in powder form to form the suspension for administration to the patient with water or another drink. In the latter case, the product is made by simple fractionation and conditioning of said commonly used granules.

The scored tablets have an in vitro disintegration time of less than 20 seconds and preferably less than 15 seconds according to the test described in USP 37. In the oral cavity, disintegration begins before 5 seconds and is complete before 8 seconds. The tablets do not require the use of water for administration. Optionally, they can also be administered in the form of a suspension with a pleasant taste, after breaking up into a small volume of water.

In addition to the significant disintegration rate, the dissolution rate of alprazolam containing the composition. Thus, for example, compared to commercial products used as benchmarks, the dissolution rate of alprazolam was greater than 70% after 30 seconds, according to the dissolution test described in USP 37, in buffer medium at pH 6.0. Novel feature not previously described, which contributes to initiating the oropharyngeal absorption of alprazolam before swallowing the suspension formed by the tablets with saliva in the oral cavity

The composition in the form of powder to form a suspension with water determines the immediate availability of the alprazolam it contains when entering the oral cavity

During administration, the absence of nuisance particles in the oral cavity from the composition and its pleasant taste contribute to patient acceptability. In particular, the acceptability of the composition is greater and more prominent in geriatric, pediatric or neurological situations that determine swallowing problems.

The composition due to the unexpected disintegration speed together with the remarkable dissolution speed of the active ingredient it contains presents a faster therapeutic effect than traditional oral tablets containing alprazolam.

The composition also has convenient flexibility due to its easy dosage fractionation during administration.

BACKGROUND OF THE INVENTION

Tablets for oral use are the most preferred dosage form among all dosage forms available for human use.

However, oral tablets frequently present administration difficulties associated with inconveniences during swallowing the tablet. Such swallowing difficulty is even observed in patients who do not have feeding problems and is a consequence of the size of the tablet, surface or taste.

In general, swallowing difficulty is observed more frequently in geriatric patients, children and patients with neurological problems. In patients with dysphagia, liquid dosage forms are an interesting option. But its elaboration is not always possible. In some cases, the unpleasant taste of the active ingredients they contain practically inhibits their application in human therapeutics, since it is very difficult or impossible to prepare them with an acceptable taste for the patient, and in other cases, the degradation of the active ingredient in solution also makes it difficult or impossible. the elaboration of liquid pharmaceutical forms with acceptable stability.

In recent years, interest in so-called oral disintegration or orodispersible tablets known by the acronym ODT (Oral Disintegration Tablets) by FDA has been growing and widespread.

Its advantages include:

1) They are easy to administer in geriatric patients and children.

2) They are particularly useful for administering to uncooperative, disabled, mentally ill, or dysphagia patients.

3) They do not require water for administration.

4) The disintegration of ODT tablets is fast. In contact with saliva they disintegrate forming a suspension that can be easily ingested by the patient.

5) They improve the bioavailability of the active ingredient they contain.

In many cases these pharmaceutical forms for oral use can improve the absorption of the active ingredient they contain and offer greater bioavailability than conventional tablets and capsules.

ODT tablets, also called "orodispersible", allow in certain cases, in addition to gastrointestinal absorption, to oropharyngeal or pre-gastric absorption and a faster therapeutic effect.

Pregastric or oropharyngeal absorption involves absorption through the sublingual and buccal mucosa. The active ingredient fraction of the pharmaceutical composition absorbed by this route prevents the enterohepatic passage and contributes to achieving the presence of the active ingredient in blood in less time than absorption through the gastrointestinal tract, generating a faster therapeutic effect. In some cases the difference in the release rate of the active ingredient in rapidly disintegrating tablets (ODT) has been up to five times greater than the release rate in conventional tablets. This is highlighted for clonazepam Shirsand SB and colab. (Indian J. Pharm. Sci. 2009; 71, 567-572).

Among the ideal characteristics of the active ingredient so that it has, in addition to gastrointestinal absorption, also oropharyngeal absorption and convenient patient acceptability, the following may be mentioned:

1) Molecular weight of the medium or low active ingredient.

2) Preferably, with an active ingredient content of less than 20 mg.

3) Not have a bitter taste.

Various technologies were developed for the production of orodispersible tablets.

Between them:

1} FLASHTAB technology

The tablets are obtained by direct compression from crystals of the active ingredient coated to taste masking and micro granules containing disintegrating agents with high swelling capacity.

2) WOWTAB technology

It uses a mixture of sugars that is made by granulation and where the sugars with little plastic characteristics (mannitol, lactose, glucose, sucrose or erythritol) but more soluble are covered by another sugar with greater plasticity (maltose, sorbitol, trehalose). The active ingredient is added during granulation or at a later stage.

3) ORASOLV technology

It performs direct compression using effervescent excipients (citric, fumaric or malic acid and bicarbonate as the base) and agents to mask the taste of the active ingredient.

To mask the taste of the active ingredient, they prepare microparticles of polymers (airborne, methacrylic, methylcellulose, ethylcellulose resins) that also contain mannitol and oxide of magnesium to facilitate the release of the active ingredient from the polymer.

The pressure applied during compression is generally low to avoid the breakdown of the microparticles that worsens the flavor of the product.

The tablets have very little hardness and are packed in an aluminum blister using a special filling machine.

4) DURASOLV technology

It is subsequent to Orasolv and allows to obtain tablets with greater hardness and its conditioning is simpler and cheaper, being possible to do it with the usual filling machines to condition traditional pharmaceutical forms.

They use water-soluble excipients in the form of small particles with a large surface area. The presence of these particles in a large proportion causes the tablet to disintegrate due to the dissolution of its components by saliva.

Among the drawbacks of this technology are mentioned: a) It does not allow the incorporation of high doses of active ingredient, since it could form a less soluble structure that would delay the disintegration of the tablet; b) The high pressure of compression can affect the structural integrity of the coated granules that contain the active ingredient and mask their taste.

5) Technologies BY LYOPHILIZATION

It has been one of the most widely used methods. Among others, they were applied to: piroxicam, diazepam, desloratadine, loperamide, enalapril, clonazepam, domperidone, chlorpheniramine, ondasetron and others.

The tablets obtained have a high degree of porosity and dissolve rapidly in contact with saliva.

Among the limitations of this technology, the following are mentioned: High cost of equipment and procedure. ¿I The active ingredients should preferably be insoluble, with a small particle size of less than 50 microns to avoid sedimentation during lyophilization.

To form a tablet "by lyophilization" the active ingredient is in suspension with other substances (gelatin, dextrans, etc.) and the suspension they form must be stable throughout the process. 1 Freeze drying of soluble active ingredients is not simple. In some cases it requires the incorporation of ion exchange resins and particular technical considerations. e The tablets made by lyophilization are characterized by their brittleness that requires specific conditioning conditions to avoid breakage. } Avoid contact with moisture as much as possible.

6) ZYDIS technology

It is the best known method of making orodispersible tablets. Among the active ingredients included are: oxacepam, lorazepam, loperamide and enalapril. They are made by lyophilizing a matrix that contains the drug. The matrix is usually made of a combination of water-soluble polymers (gelatin) and a polyol. This technology has some drawbacks. Among them: a) the lyophilization process is expensive; b) the tablets are fragile and photosensitive and require packaging in a special aluminum blister; c) the tablets removed from the blister show low stability at temperature and humidity. They absorb water quickly and are altered with humidity above 65%; d) for this reason, patients should ingest the tablet immediately after its extraction from the blister.

7) Via P PLISA CROSS-LINKED CARIDS

Method known as FLASH DOSE. It is based on the previous formation of a matrix of threads of interlaced sugars called "Floss", generally of sucrose, dextrose, fructose, or lactose by rapid heating and subjected to a centrifugal force that generates a physical appearance similar to the so-called cotton candy. Thus, for example, for sucrose the heating temperature is mentioned to be between 82 and 130 ° C. The active ingredient and excipients are incorporated into these fibers and the obtained mixture is finally compressed.

It is not a simple procedure and for what is described it is limited to active ingredients in the solid state.

The technologies described and others mentioned in the literature are numerous, heterogeneous and have the following general characteristics:

- They are not simple application technologies. They demand very specific operating conditions.

- They require the use of specific industrial equipment (lyophilizers, heating systems, centrifugation, etc.).

- The fat-soluble active ingredients are preferably for your application and when they use water-soluble active ingredients, special operating conditions are necessary.

- Sedimentation of the active ingredient is a problem that must be solved in all cases. Otherwise, the elaboration procedure is not applicable.

- The fragility of the tablets obtained and the taste masking of the active ingredient are other aspects that each technology tends to solve in a particular way.

- The bibliography also highlights the disadvantages of traditional direct compression for the manufacture of orally disintegrating tablets. Different factors are mentioned, such as: segregation of the active ingredient, particle size, limited content of the active ingredient to less than 30% of the weight of the tablet, etc. (Priyanka Nagar et al. Journal of Applied Pharmaceutical Science 01 (04), 2011: 35-45).

Although it was possible to make clonazepam orally disintegrating tablets by direct compression that release the active ingredient up to five times faster than the conventional tablets used as reference, the authors observed that 90% of the active ingredient they contain dissolves only at 22.5 minutes. Obviously prolonged time and incompatible with the absorption of the active ingredient through the mucosa of the oral cavity and in competition with the normal rhythm of swallowing. These are tablets of oral disintegration whose active ingredient is absorbed through the gastrointestinal tract (SB Shirsand et al - Indian Journal of Pharmaceutical Sciences-Sept.-Oct. 2009).

Limitations of the manufacturing process, disintegration time and percentage of dissolution of the active principle that the present invention solves through the preparation of a specific premix to form a granulate that allows the oral disintegration tablets (ODT) to be made by simple compression of the granulate. in common use. Where the tablets obtained are characterized by a disintegration time of 15 seconds and more than 40% of the alprazolam they contain and preferably more than 50% is dissolved in only 30 seconds, as mentioned in the Experimental Part applying the described dissolution test at USP 37.

So far, the recommendations of the regulatory authorities when defining orally disintegrating tablets (ODT) at the international level are also heterogeneous. Thus, it is observed for example:

- In the US, the Food and Drug Administration defines orally disintegrating tablets (ODT) as: "A solid dosage form containing medicinal substances which disintegrates rapidly, usually within a matter of seconds, when placed upon tongue" (FDA - Guidance for Industry : Orally Disintegrating Tablets— Dec. 2008). ODTs should have an in vitro disintegration time of approximately 30 seconds by applying the disintegration test indicated in the United States Pharmacopeia (USP 29, Disintegration, pp. 2670-2672). It also highlights that the tablets should not exceed a weight of 500 mg.

- In Europe, the EUROPEAN PHARMACOPEIA (Version 6.5, 2009) stresses that orodispersible pharmaceutical forms must have a disintegration time of less than 360 seconds.

The decay time limits defined by the FDA and by EUROPEAN PHARMACOPEIA are totally remote from each other. Such discrepancy is a consequence of the heterogeneity of the manufacturing procedures and the particular behavior of the ODT tablets that each technology allows to manufacture.

Consequently, even though the number of technologies developed has been very important; it also follows that regulatory entities like FDA and EMEA indirectly They acknowledge that there is a technical gap that allows solving all the necessary aspects to develop oral disintegration tablets that can be defined as "optimal or ideal".

The technology for making ODT tablets that can be defined as "optimal or ideal" must include, among others, the following characteristics:

- be of simple industrial application,

- allow the production of ODT tablets with a high disintegration rate.

- that the ODT tablets have the lowest possible weight,

- that they do not leave significant residue in the oral cavity,

- which determine a therapeutic effect faster than conventional oral tablets with the same active ingredient,

- and that contribute to the best acceptability for normal, geriatric or pediatric patients with swallowing difficulties.

Aspects that the present invention understands and describes.

Faced with the heterogeneity of technologies and the scope of the characteristics of oral disintegration tablets (ODT) that each technology allows to make, it is clear that all entities (official, academic and industrial) recognize and highlight the importance of disintegration tablets oral compared to conventional oral capsules and tablets for the advantages they offer to all patients and in particular to patients with swallowing problems.

Oral disintegration tablets (ODT) located in the oral cavity have the advantage of forming a suspension with saliva. The drug they contain is partially or completely dispersed or dissolved and can be partially absorbed through the sublingual, buccal, pharyngeal or esophageal mucosa. The fraction absorbed through the aforementioned mucosa does not undergo enterohepatic circulation; also not likely classical enzymatic or chemical degradations of conventional oral tablets containing the same active ingredient and where the active ingredient is absorbed exclusively through the gastrointestinal tract. Consequently, it determines that the bioavailability of the active ingredient in ODT tablets is eventually greater than that observed from conventional oral tablets. This is also highlighted by several authors. Among them: Priyanka Nagar et al. In Journal of Applied Pharmaceutical Science 01 (04), 2011, 35-45.

The disintegration time of ODT tablets in the oral cavity and the frequency of swallowing of the suspension formed by the particles with the saliva that is produced automatically and little controlled by the will, obviously compete with each other and negatively affect the level absorption of the active ingredient through the sublingual and oropharyngeal mucosa. The longer the disintegration time of the ODT tablets, there is naturally less possibility of absorption through the aforementioned mucosa compared to the natural and involuntary rate of swallowing.

These aspects are not considered by the FDA and EMEA in their recommendations for ODT tablets, since tablets with a disintegration time of between 30 and 360 seconds according to the respective specifications of both entities, are not the most suitable for promoting sublingual or oropharyngeal absorption.

Such FDA and EMEA recommendations on disintegration time are preferably limited to highlighting the advantages offered by ODT tablets over conventional oral tablets. This is; facilitate the swallowing of the suspension formed by the ODT tablets with the saliva of the oral cavity, optimize the administration in patients with dysphagia and also avoid the disintegration time in the stomach characteristic of oral tablets. Together, they promote patient acceptability and improve the bioavailability of the active ingredient compared to conventional oral tablets. They do not consider the practical importance of oropharyngeal absorption that only occurs for a short period of time before swallowing. But it has the advantage of minimizing the enterohepatic circulation of the active ingredient or its partial enzymatic or chemical degradation that frequently occurs when the active ingredient enters the gastrointestinal tract.

Thus, for example, USP 37 describes disintegration and dissolution tests previously harmonized with the European Pharmacopoeia and the Japanese Pharmacopoeia. In his chapter "Alprazolam Disintegration Tablets" (pages 1660-1661) he describes that the disintegration time must be 30 seconds and the dissolution time of the active ingredient they contain must be 10 minutes. Conditions only compatible with the following objectives: a) promote swallowing of the suspension formed by the tablets in the oral cavity, and b) ensure the best conditions for gastrointestinal absorption of the active ingredient. The 10-minute dissolution time mentioned in the USP does not expressly consider the possibility of absorption through the oropharyngeal mucosa.

The oropharyngeal absorption requires a higher dissolution rate, -as it refers to the fraction of the pharmaceutical composition that is absorbed in the short period of time between the entry of the composition into the oral cavity and the swallowing of the suspension that forms with saliva.

The active ingredient fraction with oropharyngeal absorption helps to initiate the therapeutic effect, minimize enterohepatic circulation, and the chemical or enzymatic degradation characteristic of the ingredient fraction that enters the gastrointestinal tract directly.

To ensure better gastrointestinal absorption, the USP defines a dissolution time of 10 minutes, a naturally long period of time for oropharyngeal absorption, since swallowing takes less time. But absolutely suitable for the active ingredient that after swallowing enters the gastrointestinal tract.

STATEMENT OF THE INVENTION

A subject of the invention is an amorphous alprazolam composition with anxiety-lithic activity CHARACTERIZED in that it comprises:

a) a premix containing:

- between 0.33 and 0.66% w / w of alprazolam; - between 0.07 and 0.2% w / w of ethylcellulose as a binding agent;

- between 0.15 and 0.3% w / w of a disintegrating agent selected from cross-linked carboxymethyl cellulose, modified starch, croscarmellose sodium, sodium glycollate starch, carboxymethyl hydroxypropyl starch, starch and mixtures of the foregoing;

- between 15 and 20% of a diluting agent selected from microcrystalline cellulose, lactose, sucralose, dextrose, sorbitol, mannitol and mixtures of the above; preferably a mixture of microcrystalline cellulose and lactose;

- between 10 and 15% aspartame and

- between 0.05 and 0.2% of taste masking agent, preferably debitter;

b) said premix combined with:

- between 4 and 6% w / w of water-insoluble crospovidone, preferably crospovidone CL grade as a disintegrating agent,

- between 1 and 2% of a lubricating agent selected from sodium stearyl fumarate, magnesium stearate, zinc stearate, stearic acid and talc;

- flavoring agents, sweetening agents; and

- c.s. p. 100% granular mannitol as a diluent;

where:

- the ratio of alprazolam to ethylcellulose in the premix is in the range of 2.5: 1 to 5: 1; and

- the ratio of alprazolam to water-insoluble crospovidone is in the range of 0.06: 1 to 0.13: 1; and

- the degree of crystallinity of alprazolam is less than 10%.

All the indicated percentages are by weight and with respect to the total weight of the composition.

Preferably the composition comprises:

a) a premix containing:

- between 0.33 and 0.66% w / w of alprazolam;

- 0.13% w / w of ethyl cellulose;

- 0.23% w / w of said disintegrating agent;

- 17.3% w / w of said diluting agent - 13.33% aspartame and

- 0.13% flavor masking agent;

b) said premix combined with:

- 5% w / w of water insoluble crospovidone, preferably crospovidone CL grade,

- 1.5% of said lubricating agent;

- flavoring agents, sweetening agents; and

- c.s. p. 100% granular mannitol as a diluent.

Advantageously the composition comprises:

a) a premix containing:

- between 0.33 and 0.66% w / w of alprazolam;

- 0.13% w / w of ethyl cellulose;

- 0.23% w / w of crosslinked carboxymethyl cellulose,

- 17.3% w / w of a mixture of microcrystalline cellulose and lactose,

- 13.33% aspartame; and

- 0.13% flavor masking agent;

b) said premix combined with:

- 5% w / w of water insoluble crospovidone, preferably crospovidone CL grade,

- 1,5% sodium stearyl fumarate,

- flavoring agents, sweetening agents; and

- c.s. p. 100% granular mannitol as a diluent.

Preferably the composition is supplied in dosage units and advantageously each dosage unit comprises between 0.25 and 2.00 milligrams of alprazolam, and preferably each dosage unit comprises 0.25, 0.5, 1.0 or 2.0 milligrams of alprazolam.

Preferably the dissolution of the amorphous alprazolam present in the premix of the composition at the first minute is greater than 20 percent with respect to the dissolution of crystalline alprazolam present in a physical mixture with the same components, according to USP 35 test in buffer medium.

A preferred form of presentation of the composition is in the form of rapidly orally disintegrating tablets. In these cases, it is advantageous that each tablet has a disintegration time of less than 20 seconds and preferably less than 15 seconds, measured by in vitro determination according to USP 37 in aqueous medium without disc and / or that the disintegration of the tablet located in the oral cavity begins. at 5 seconds and is total at 8 seconds. It is also advantageous if the suspension formed by the tablet with the saliva is free of nuisance particles or agglomerates and the suspension formed has a pleasant taste.

Preferably dissolution of alprazolam in buffer medium, at pH 6.0, volume 900 ml, temperature 37 ° C, speed 50 rpm. in apparatus 2 according to USP 37 at 30 seconds it is greater than 45%, and at 60 seconds it is greater than 65% of the alprazolam content of the composition.

Advantageously, the composition according to the invention is for oral administration to the patient by direct incorporation of the tablet into the oral cavity or after disintegration in a small volume of water and direct administration of the suspension formed and optionally through the Type K-10 enteral probe. 8 or similar.

Another preferred form of presentation of the composition is in the form of a powder for the extemporaneous preparation of a suspension. In this case, the administration of the previously formed suspension with water or other beverages is advantageously carried out by incorporation of the suspension in the oral cavity or by Type K-108 enteral tube or the like.

Another object of the invention is a process for preparing an amorphous alprazolam orally disintegrating composition, CHARACTERIZED BECAUSE it comprises preparing a premix according to the following sequence:

a) prepare a solution by dissolving alprazolam in ethanol, at a temperature between 35 ° C and 45 ° C, and subsequently incorporating ethyl cellulose with stirring until complete dissolution;

b) prepare a mixture incorporating in a solid state, in a high-speed granulator: - a disintegrating agent selected from cross-linked carboxymethyl cellulose, modified starch, croscarmellose sodium, sodium glycollate starch, hydroxypropyl carboxymethyl starch, and starch and mixtures thereof; preferably crosslinked carboxymethyl cellulose;

- ethyl cellulose;

- a diluting agent selected from microcrystalline cellulose, lactose, sucralose, dextrose, sorbitol, mannitol and mixtures of the above, preferably a mixture of microcrystalline cellulose and lactose;

- a flavor masking agent, preferably Debitter;

- aspartame;

c) incorporating the solution obtained in step a) onto the powder mixture obtained in step b) in a mixer;

d) incorporate ethanol into the granulator mixer until obtaining a homogeneous premix; e) drying the formed premix,

and then prepare a commonly used amorphous alprazolam granulate according to the following steps:

i) incorporate into the premix obtained in e);

-crospovidone insoluble in water, preferably crospovidone CL grade;

granular mannitol;

-flavoring agents, preferably cherry essence and / or peppermint essence;

sweetening agents, preferably sucralose and / or aspartame;

ii) mix,

iii) incorporating a lubricating agent selected from sodium stearyl fumarate, magnesium stearate, zinc stearate, stearic acid and talc, preferably sodium stearyl fumarate; and

iv) mixing to obtain the commonly used amorphous alprazolam granules; and optionally v) transforming the granules obtained in step iv) into orally disintegrating scored tablets or powder for extemporaneous preparation of a suspension.

Preferably step v) comprises subjecting the granules to direct compression to obtain tablets, and advantageously scored tablets.

Advantageously step v) comprises the simple fractionation of the granulate and subsequent conditioning in single-dose or multi-dose units to obtain a powder for extemporaneous preparation of a suspension.

Preferably the content of alprazolam dissolved in ethanol is between 5 and 10% by weight with respect to the weight of ethanol.

The content of ethyl cellulose dissolved in ethanol is advantageously between 0.5 and 2.0% by weight with respect to the weight of ethanol.

Preferably the ratio of ethyl cellulose from step a) to ethyl cellulose from step b) is between 60:40 and 30:70, most preferably between 60:40 and 40:60, and particularly preferably is 60:40.

Advantageously, the ethyl cellulose fraction dissolved in ethanol in step a) inhibits, at least partially, the subsequent recrystallization of alprazolam.

Preferably the solid-state incorporated ethylcellulose fraction in step b) acts as a binding agent.

Advantageously, the dissolution of the amorphous alprazolam present in the premix of the composition at the first minute is greater than 20 percent with respect to the solution of crystalline alprazolam present in a physical mixture with the same components, according to the USP 35 test in buffer medium.

Preferably the tablets that are obtained contain between 0.25 and 2.00 milligrams of alprazolam, and preferably contain 0.25, 0.5, 1.0 or 2.0 milligrams of alprazolam.

The tablets advantageously have a disintegration time of less than 20 seconds and preferably less than 15 seconds by in vitro determination according to USP 37 in aqueous medium without disc.

Preferably the disintegration of the tablet, located in the oral cavity, begins at 5 seconds and is complete at 8 seconds.

Advantageously, the suspension formed by the tablet with saliva is free of particles or troublesome agglomerates and the suspension formed has a pleasant taste.

Preferably the alprazolam solution of the composition obtained in step iv) in buffer medium, at pH 6.0, volume 900 ml and temperature 37 ° C, speed 50 R.P.M. in apparatus 2 according to USP 37 at 30 seconds it is greater than 45%, and at 60 seconds it is greater than 65%, of the alprazolam content of the composition.

Advantageously, the tablet is for direct administration to the patient in the oral cavity or after disintegration in a small volume of water and direct administration of the suspension formed and optionally through the Type K-108 enteral probe or similar.

Preferably the powder for extemporaneous preparation of a suspension is suspended with water or other beverages and is for administration by incorporation of the suspension into the oral cavity or by Type K-108 enteral tube or the like.

Advantageously the powder for the extemporaneous preparation of a suspension is presented in single-dose or multi-dose units that contain indistinctly between 0.25 and 2.00 milligrams of alprazolam in the mostly amorphous state and quickly form by simple agitation a suspension with water or another drink.

Preferably the alprazolar ethylcellulose ratio in the composition is between 2.5: 1 and 5: 1.

Advantageously the alprazolar ratio crospovidone in the composition is comprised between 0.06: 1 and 0.13: 1.

The tablet preferably has an alprazolam content of less than 0.5 mg, preferably 0.25 mg.

Advantageously, the compounds incorporated in said step b) have a humidity of less than 1.5%, preferably less than 0.5%.

Preferably in said step e) said premix is dried at less than 50 ° C. Advantageously in said stage e) said premix is dried until reaching a humidity lower than 1%.

The present invention provides innovative elements. Thus, for example: through the novel premix and subsequent granules in common use for the pharmaceutical composition, it contemplates and resolves an unexpected and significant behavior that favors prior oropharyngeal absorption through the following properties not previously described. They are: a) Unexpected rate of disintegration of the tablets:

In the oral cavity, disintegration begins at 5 seconds and is total at 8 seconds, and according to the USP 37 test it is less than 20 seconds and preferably 15 seconds.

b) Immediate availability of alprazolam in the oral cavity when administering the composition as a suspension:

That is, the suspension is formed with the "powder for suspension" described in the Experimental Part, by incorporation of water before administration. C) Surprising dissolution rate of alprazolam containing the composition:

- The oral disintegration tablets of the present invention demonstrated that the dissolution of alprazolam in buffer medium, at pH 6.0, volume 900 ml and temperature 37 ° C, speed 50 rpm. in apparatus 2 according to USP 37 at 30 seconds it is greater than 45%, and at 60 seconds it is greater than 65% of the alprazolam content of the composition.

- For the composition in the form of powder that is described and that is obtained with the same granules in common use, the behavior is similar and does not require the compression step necessary to make the previous tablets.

The pharmaceutical composition in both mentioned cases (orally disintegrating tablets (ODT) and powder for suspension) showed immediate availability of the alprazolam they contain and particularly unexpected and previously not described fast speed of dissolution of the alprazolam they contain.

Both compositions, due to their novel characteristics, contribute to: a) Initiating the oropharyngeal absorption of alprazolam before swallowing with direct entry into the blood and a faster therapeutic effect than conventional oral compositions. b) and continue after swallowing the gastrointestinal absorption of the fraction not previously absorbed through the oropharyngeal mucosa.

As it is known in the art, alprazolam is present in numerous compositions for oral use. Each composition with its own characteristics, advantages and limitations. Among them are:

11 In traditional oral tablets:

For example, Xanax from Pfizer Laboratories and others, with excellent therapeutic applications. All of them used as anxiolytics and with the characteristic drawbacks of conventional tablets: That is, disintegration in the stomach, enterohepatic circulation and activity always after 30 minutes of administration to the patient.

2) In orally disintegrating tablets

Niravan (from Schwartz Laboratories - Pharma) is the first described and marketed ODT-type tablet containing alprazolam.

Compared to conventional oral tablets, the only advantage is that they do not require the use of water for administration in all cases, and as indicated also in the product information, the peak plasma concentration of alprazolam is reached at approximately 1.5 to 2.0 hours after administration (with or without water).

Therapeutic behavior similar to that described for traditional oral tablets containing alprazolam.

The only practical advantage they offer the patient is that they do not require the use of water to facilitate administration.

3) In sublingual or oral tablets:

Sublingual Tranquinal of Laboratorios Bagó S.A. It is the first sublingual-type tablet commercialized internationally.

Sublingual tablets were shown to allow the presence of alprazolam to be determined in the blood after 4 minutes of sublingual administration, reaching the maximum concentration at 2 hours (Héctor Arenoso et al. - International Journal of Pharmaceutical Medicine; 2002; 16: 215 -218).

They also demonstrated significant efficacy in the treatment of panic disorders in the acute phase (Miguel Márquez et al. - Acta Esp. Psiatr. 201 1; 39 (2): 88-94) and in the treatment of primary insomnia (European Patent N 2087893B) and in sleep disorders associated with anxiety states (N. Gargiulo et al.— "Sublingual alprazolam efficacy in primary insomnia and in sleep disorders associated with anxiety disorders" presented at the World Psychiatric Association International Congress, Nov. 10 -13, 2004, Florence, Italy - N. Gargiulo et al— "Sublingual Alprazolam and Sleep Disorder" - Alcmeon Re ^and . Arg. Clin. Neuropsychiatric Clinic 2008,14 (3): 42-27).

Behavior with a rapid therapeutic response that demonstrated a remarkable absorption rate of the active ingredient contained in the sublingual tablets.

The present invention provides for its pharmaceutical compositions innovative elements and characteristics not previously described.

Thus, for example, it describes a novel and simple technology for the preparation of orally disintegrating tablets and powder for suspension in water or other drink through the preparation of the aforementioned premix with the active ingredient (alprazolam), mainly to the amorphous state, and its transformation with other excipients for pharmaceutical use in a specific granule and in common use with which the pharmaceutical composition of choice.

Such technology, which is described in the Detailed Description of the Invention and in the Experimental Part, includes in the compositions described the following novel features: ai It allows the composition to be made in the form of ODT tablets or powder for oral administration in a simple and economic way. . b) It does not require complex and high cost equipment for the elaboration. The necessary equipment is all commonly used in the pharmaceutical industry. c] The active principle (alprazolam) is present in the composition mainly in the amorphous state. Characteristic that contributes to increasing its solubility in water or saliva. Particularly useful for increasing oropharyngeal absorption and minimizing enterohepatic circulation. d] In the form of a powder to form the suspension before administration to the patient, 100% of the alprazolam containing the composition is immediately available in the oral cavity to initiate its absorption through the sublingual and oropharyngeal mucosa, competing with normal swallowing speed and helping to initiate the therapeutic effect of alprazolam. The unabsorbed remainder continues its journey to be absorbed in the gastrointestinal tract. e] In the form of orally disintegrating tablets (ODT) the innovative technology described contributes the following advantages:

1) High speed of disintegration of the tablet and particularly high speed of dissolution of alprazolam that contain unexpected characteristics and not previously described

2) The alprazolam they contain is mainly in the amorphous state, helping to promote its solubility in an aqueous medium.

3) The tablets have, according to the USP test, a disintegration time "in vitro" of about 15 seconds. But, in the oral cavity "in vivo" as it was experimentally determined that the disintegration of the tablet begins at 5 seconds and is total at 8 seconds. Behavior that contributes significantly to patient acceptability.

4) The dissolution rate of alprazolam containing ODT tablets according to the USP test is unexpectedly higher than 40% in only 30 seconds. Behavior that contributes to transmucosal absorption prior to swallowing and gastrointestinal absorption.

5) The disintegration of the tablets in the oral cavity did not present bothersome particles and the taste of the suspension that they form in the presence of saliva is pleasant.

6) Surprisingly the ODT tablets of the present invention demonstrated: Í Achieve similar therapeutic result with lower unit dose of alprazolam than the alprazolam composition in sublingual tablets chosen as a reference. The sublingual composition of administration was chosen as the comparison term for its high bioavailability of alprazolam and rapid therapeutic effect previously described. -Specifically, the composition of the present invention determines saving of active ingredient to achieve similar therapeutic effect

¿I Fast therapeutic effect.

7) It was observed that the acceptability of the patients was greater with the ODT tablets of the present invention compared to conventional oral tablets, and even compared to the sublingual tablets mentioned and taken as benchmarks for their rapid therapeutic effectiveness.

8) Both compositions (ODT tablets and powder) suspended in water due to the absence of particles or agglomerates of significant size, are optionally for administration by enteral feeding tube type K-108 or similar in patients fed exclusively by enteral feeding tube.

- Invalid alternative for conventional oral tablets Therefore, previously ground and suspended in water due to the size of the particles obtained in most In some cases, they obstruct enteral feeding tubes and do not allow this route of administration, particularly useful and necessary in geriatrics.

The novel properties and practical advantages of the compositions as a whole were confirmed through the acceptability of volunteers and patients

Without being limiting, the manufacturing process, properties and uses are mentioned in Detailed description of the invention and in corresponding Examples.

BRIEF DESCRIPTION OF THE FIGURES

Fig. 1: X-ray Diffraction graph expanded in position 9— 9.5 (2 theta) of the active ingredient pure alprazolam and to the crystalline physical state.

Fig. 2: X-ray Diffraction graph expanded at position 9— 9.5 (2 theta) of Niravam 0.25 Disintegrating Tablets

Fig. 3: X-ray Diffraction graph expanded at position 9— 9.5 (2 theta) of the premix for making orally disintegrating tablets, and powder for suspension as described in Experimental Part.

Fig. 4: X-ray Diffraction graph expanded at position 9— 9.5 (2 theta) of orally disintegrating tablets (ODT) containing 2 mg of alprazolam made according to the present invention.

DETAILED DESCRIPTION OF SOME WAYS TO CARRY OUT THE

INVENTION

The present invention relates to a pharmaceutical composition for oral use that offers rapid or immediate availability of alprazolam in the oral cavity. The suspension formed with water or another drink before administration or with saliva in the oral cavity presents the active ingredient mainly in the non-crystalline physical form.

COMMON USE GRANULATE FOR THE COMPOSITION ELABORATION

PHARMACEUTICAL. The composition elaboration procedure comprises the preparation of a premix that determines the homogeneous distribution of alprazolam throughout the mass together with its transformation from the crystalline state to the mostly amorphous physical state. Subsequently, together with other pharmaceutical excipients, it allows the preparation of a specific granule useful for preparing the composition of choice. The commonly used granules have a pleasant taste and are free of annoying particles when placed in the oral cavity.

ORAL DISINTEGRATION TABLETS tQDTl

A pharmaceutical composition of choice comprises orally rapidly disintegrating (ODT) tablets and scored tablets. The disintegration of the tablets in vitro (using the method described in USP 37) takes less than 20 seconds and preferably 15 seconds.

In the oral cavity, disintegration begins before 5 seconds and is complete before 8 seconds, favoring the contact of the active principle of the suspension that forms with saliva with the mucosa of the oral and sublingual cavity. Furthermore, the dissolution of alprazolam containing the composition is significant. Specifically, it is over 40% in just 30 seconds.

POWDER FOR SUSPENSION IN WATER OR BEVERAGES

Surprisingly, said granules (formed from the premix together with other excipients for pharmaceutical use) showed that due to its characteristics (immediate availability of mostly amorphous alprazolam and convenient flavor) it also constitutes another novel pharmaceutical composition not previously described of the powder type to form a suspension with water or another drink. For its elaboration it is only necessary to fractionate the granules of common use and subsequent conditioning in sachets or sachets, or in single-dose or multi-dose containers.

The powder for suspension allows different forms of administration to the patient. For example; suspend in water and administer to the patient or incorporate the suspension formed into food or directly incorporate the powder into food. The choice of alprazolam administration form in the form of a powder for suspension is wide, novel and it is only conditioned on the condition of the patient.

Forms or modalities of administration of alprazolam to the patient, not described to date and also not mentioned for commercial compositions containing alprazolam.

Although there are commercially available orally disintegrating tablets (ODT) (eg Niravan from Schwartz Pharma) the only advantage described for these tablets over conventional oral tablets is the possibility of administration without the aid of water.

So far, no compositions have been described that determine the rapid presence of alprazolam in the oral cavity at the largely amorphous state and a high percentage of this active ingredient dissolved in a few seconds after its administration.

The present invention solves through the commonly used premix and granules the mentioned technological absences and offers the patient significant practical advantages not previously described.

The following are features of the present invention:

1) The pharmaceutical composition quickly releases the active ingredient it contains and with a high dissolution rate. Specifically:

When the oral disintegration tablet (ODT) is placed in the oral cavity, disintegration begins before 5 seconds and is complete before 8 seconds, releasing the alprazolam they contain with a significant increase in dissolution rate. Experimentally it was shown that after 30 seconds according to USP 37 test, 49% of the alprazolam present in the orally disintegrating tablets dissolved. Dissolution percentage significantly higher than that found under similar conditions with the following commercial products that also contain alprazolam: Sublingual Tranquinal 22%.

When the composition is presented as a powder, the presence of alprazolam in the oral cavity is immediate due to the suspension that is formed prior to administration with water. or another drink.

In both cases, the oropharyngeal absorption of the available alprazolam in the oral cavity is encouraged before swallowing and entering the gastrointestinal tract, partially avoiding the enterohepatic circulation of the active ingredient.

2) The pharmaceutical composition presents the active ingredient in the amorphous state.

The loss of the crystalline state of alprazolam present in the premix and in the orally dispersed tablets (ODT) described in the experimental part; It was observed by comparing the X-ray spectra described in Figures I-IV using a Pananalytical kit (2004) (Hardware: X— Per Pro, X Ray Diffraction Systems (Software X-Per Industry, X-Per High Score).

How terms of comparison were used: A) pure alprazolam to the crystalline state and B) Niravan 0.25 Desintegration Tablets

Specifically Figures 1-4 show:

FIGURE 1: Describe the expanded X-ray Diffraction graph at position 9— 9.5 (2 theta) of the active substance pure alprazolam and the crystalline physical state. The signal of crystalline alprazolam is intense and is cut off at the top of the figure.

FIGURE 2: Describe the expanded X-ray Diffraction chart at position 9— 9.5 (2 theta) of Niravam 0.25 Disintegrating Tablets (Lot: 850024 — Schwartz-Pharma). The presence of the characteristic signal of crystalline Alprazolam is observed at position 9—9.5 (2 theta). The signal is naturally weaker than in Figure 1 because the Niravan product contains only 0.25 mg of alprazolam along with the other excipients that make up the tablet.

FIGURE 3: Describe the expanded X-ray Diffraction chart at position 9— 9.5 (2 theta) of the premix for making orally disintegrating tablets, and powder for suspension as described in Experimental Part. No signs of alprazolam in the crystalline state are observed. The way of preparing the premix determines that in said premix, the alprazolam is present as a non-crystalline active ingredient

FIGURE 4: Describes the expanded X-ray Diffraction graph at position 9— 9.5 (2 theta) of orally disintegrating tablets (ODT) containing 2 mg of alprazolam made according to the present invention. The characteristic signal of alprazolam to the crystalline physical state is not observed even when the content of alprazolam in the tablets is 2 mg. That is, 8 times greater than the content in the NIRAVAN tablets used as a comparison term, which only contain 0.25 mg of crystalline alprazolam and whose signal is clearly visible (Fig. 2)

Consequently: a) ODT tablets made according to the present invention are largely free of crystalline alprazolam. b) The powder for suspension formed exclusively by the granules of common use, subsequently fractionated and conditioned, also presents the active ingredient in the most non-crystalline state.

3) The preparation of the pharmaceutical composition of choice is carried out through a simple industrial application procedure. Preparation procedure characterized by using equipment, facilities and excipients commonly used in any pharmaceutical industry.

- The procedure described in the Experimental Part lacks the requirements and limitations described in the Background of the Invention that have historically given rise to a significant number of interesting technologies for making ODT tablets, but not of easy general application. Various elements necessary for the application of such novel technologies have been mentioned in the technical and patent literature. Elements that in many cases become limiting factors. Among them: complex equipment and facilities, complex procedures, the use of special excipients, etc. that even determine high manufacturing cost.

- The procedure described to make the ODT tablets is simple and applicable with the equipment and facilities present throughout the pharmaceutical industry. - In addition, the final granule in common use is itself a novel composition in the form of a powder that only requires, as final stages of preparation of the composition, its fractionation and conditioning in single-dose or multi-dose units. Composition not previously described in the technical or patent literature.

4) Surprisingly it has been found that the premix with which the composition is made allows to increase the dissolution rate of the alprazolam it contains compared to a physical mixture with identical components. With the described premix, a commonly used granulate is subsequently obtained for the preparation of the pharmaceutical composition of choice.

The premix includes:

- alprazolam, active ingredient.

- Crosslinked carboxymethyl cellulose (Ac-Di-Sol or similar) as a disintegrant.

- Microcrystalline cellulose (Avicel PH 101 or similar) and Lactose (DMV 200 or similar), as diluents.

- Ethyl cellulose: successively as a crystallization inhibitor, flavor masker and binder.

- Aspartame: as a sweetener.

- and a flavor masker (Debitter or similar). and where ethylcellulose is incorporated in two stages of the preparation of the premix in a different physical state in each one of them.

The two stages of preparation of the premix are:

In the first stage, up to 60% of the ethylcellulose present in the entire premix dissolves together with the active ingredient in ethanol, forming a solution.

In the second stage of the preparation of the premix with the previous solution, all the other mentioned components are impregnated (cross-linked carboxymethyl cellulose, microcrystalline cellulose, ethyl cellulose, aspartame, taste masker) and includes up to 40% of the total ethyl cellulose in the premix. But in this stage, ethylcellulose is present in the solid state and acts as an agglutinate. The dissolution of ethyl cellulose in the solvent in which alprazolam dissolves unexpectedly determines: a) that this active ingredient is not mostly recrystallized after solvent removal,

b) the homogeneous distribution of the active ingredient over all the components of the premix and contributes to the uniformity of content of the pharmaceutical composition that is made with it.

Unexpectedly, it has been found that there is mostly no recrystallization of alprazolam after the elimination of the solvent and formation of the premix when the following conditions exist: a) that the content of alprazolam dissolved in the solvent in relation to ethanol is between 4.0% to 6.0% with respect to the weight of the solvent, with an alprazolam content of 5% being preferred. (According to Ex. I is 5%). b) the content of ethyl cellulose dissolved in the solvent is comprised between 0.5% and 2.0% by weight with respect to the weight of the solvent, being preferably a content of 1.2%. c) the content of ethyl cellulose by weight in the solution in relation to the active principle corresponds to 20 to 30% of the weight of alprazolam in it and preferably to 24%.

- By light microscopy and X-ray spectroscopy, the presence of alprazolam was observed mainly in the amorphous state.

- During the preparation of the premix, the solvent of choice for the active ingredient and up to 60% of the total ethyl cellulose in the composition is ethanol. Necessary condition for both to be dissolved and subsequently determine the presence of alprazolam mainly in the amorphous state.

It was observed that the presence of ethylcellulose in the solvent is necessary and sufficient to avoid the massive crystallization of the active ingredient and simultaneously contribute to its homogeneous distribution over the entire mass and also to the partial masking of the taste of the active ingredient. The double behavior of ethylcellulose in the premix is practical and novel in that it reduces the number of excipients necessary to fulfill the same functions. That is: a) In solution, it allows to inhibit the recrystallization of alprazolam by eliminating the solvent. b) And the solid state in the same premix acts a posteriori as a binder.

Novel dual behavior of ethyl cellulose and not previously described in the technical and patent literature.

It was also observed that the incorporation of up to an additional 2% of solvent during the preparation of the premix and subsequent agitation contributes to the formation of the premix with homogeneous distribution of the active ingredient throughout the mass.

The premix obtained is dried to final humidity between 0.5 and 1.5% and finally ground and homogenized in the Quadro Comill Mill (sieve: 991 microns - speed: 2400 rpm).

The premix demonstrated a higher dissolution rate of alprazolam contained therein than in the physical mixture with the same components in quality and quantity, which is subsequently transmitted to the pharmaceutical compositions that are made with said premix.

The premix obtained in the subsequent stage is transformed into the commonly used granules that are applicable to the preparation of the pharmaceutical composition of choice (ODT tablets or powder for suspension) as described in the Experimental Part

5) It is a prominent object of the present invention the preparation of a novel granulate and common use for the elaboration of the pharmaceutical composition of choice incorporating the aforementioned excipients for habitual pharmaceutical use into the aforementioned premix and with alprazolam in the amorphous state.

- Crosslinked water-insoluble povidone (also called water-insoluble crospovidone)

- Granular mannitol.

- Cherry essence (Durarome type 860.638). - Piperita peppermint essence or another essence. - Sucralose.

-Aspartame. The incorporation is carried out simply by mixing for 30 minutes and incorporating with stirring sodium stearyl fumarate to obtain the final granulate that contains alprazolam mainly in the amorphous state and necessary to subsequently elaborate the composition.

The dry, described final granulate (formed by the described premix and other carefully selected pharmaceutical excipients) surprisingly proved to determine interesting applications:

A) By simple compression of the granules mentioned, oral disintegration tablets (ODT) are obtained. as described in the Experimental Part, and the tablets have the following general characteristics:

1) In vitro disintegration time according to the USP test: 15 seconds.

2) In the oral cavity, disintegration begins at 5 seconds and is complete at 8 seconds.

3) The dissolution rate of the alprazolam they contain (according to the USP test) was significantly higher than the dissolution rate observed compared to commercially available tablets used as referents and which also contain alprazolam.

- Thus, for example, 30 seconds after the test, the dissolution rate of alprazolam of the orally disintegrating tablets (ODT) described against sublingual Tranquinal was practically 220% higher. Significant advantage that contributes to the oropharyngeal absorption of alprazolam prior to swallowing the suspension that is formed by the disintegration of the ODT tablet with saliva in the oral cavity.

Differential characteristic with commercially available pharmaceutical compositions, whose absorption of the active ingredient begins and takes place in the gastrointestinal tract. The described ODT tablets offer unexpected and rapid availability in the oral cavity of alprazolam that contains the suspension that they form with saliva to initiate their oral, sublingual absorption, prior to swallowing and subsequently to continue the absorption of available alprazolam through the tract. gastrointestinal. 4) The tablets are made by simple compression with simple and inexpensive equipment.

4] After their disintegration in the oral cavity, they do not present annoying particles or agglomerates and due to the pleasant taste of the suspension that they form with the saliva they contribute to the acceptability of the patient. They offer a novel alternative for pediatric patients or patients with swallowing problems.

4) Unexpectedly, they demonstrated a similar therapeutic effect with less administration of alprazolam (0.25 roar per unit dose than the commercially available composition of alprazolam in sublingual tablets (0.50 mg) considered as a comparison term for its bioavailability of alprazolam and rapid therapeutic effect. Confirming similar effect therapeutic with 50% less active ingredient.

B) Surprisingly, the granulate also allows the pharmaceutical composition to be presented directly in the form of a "powder" to prepare a suspension by pouring the powder into water or another drink that is easy to administer to the patient. Due to the characteristics of the granulate, it is only necessary to fractionate and condition it conveniently.

Unexpected, novel composition, practical for the patient and not previously described for alprazolam.

C) Both compositions made with the commonly used granules are useful for the treatment of normal patients, patients with swallowing difficulties or X dysphagia with a faster therapeutic effect than commercially available oral or sublingual tablets.

D) In patients with exclusive enteral tube feeding, both tablet or powder compositions offer a new administration alternative not previously described.

Both compositions (QDT tablets powder) dipped in water were shown to be applicable for administration by enteral tube type K-108 or similar without drawbacks.

The suspension they form in water does not obstruct the probe. Exclusive enteral feeding has been described as practically necessary in 34% of patients hospitalized with cognitive problems and hospitalized in geriatric centers Mitchell St. and others (JAMA 2003, July 2 - 290 (1): 73-80 ).

The frequent practice (hospital or home) of grinding oral tablets for administration by gavage is not advisable due to the frequent obstruction of the probes as a consequence of the size of the particles coming from the grinding or the formation of agglomerates with the water to form the suspension and add to the probe.

Frequent inconvenience and also described that negatively alters the normal administration to the patient.

Negative aspects resolved through the suspensions in water that form the compositions that are described (orally disintegrating tablets and powder for suspension) in the present invention that constitute a novel form of administration of alprazolam not previously described.

From the granules in common use described, the simple fractionation and conditioning in aluminum-aluminum sachets or sachets or other single-dose or multi-dose packaging in a medium with low humidity and at room temperature directly determines the obtaining of the composition in the form of "powder "

The powder contained in each unit subsequently suspended in water forms a suspension characterized by the absence of residue, a pleasant taste and is easy to administer. The powder for the suspension is a novel pharmaceutical composition that offers practical administration in geriatrics, pediatrics and in patients with swallowing problems. Including patients who do not have feeding problems, but who do have difficulty swallowing the usual oral tablets.

6) Another feature of the present invention is the ability to mask the taste of the active ingredient.

The premix and in particular the final granules in common use to optionally elaborate each one of the mentioned compositions ensure the pleasant taste of the composition and facilitate its administration to the patient. Particularly significant property for administration of the composition in pediatrics.

7) With the prepared premix, as described in the present invention, it is only necessary to incorporate other excipients known in the art for the elaboration of the specific granules, in common use and necessary for the pharmaceutical composition of choice.

Optionally, in addition to those indicated and preferably for the present invention, the following are also applicable: a) as disintegrants: cross-linked carboxymethyl cellulose, modified starch, croscarmellose sodium, sodium glycollate starch, carboxymethyl hydroxypropyl starch, starch.

b) as a diluent: microcrystalline cellulose: lactose, sucralose, dextrose, sorbitol, mannitol. c) as flavorings: grapefruit, strawberry, cherry, vanilla essences and others. d) as lubricants: magnesium stearate, zinc stearate, stearic acid and talc.

The necessary condition is that the active ingredient in the premix is practically present in the amorphous state, in order to increase the dissolution rate of the alprazolam it contains and to ensure the characteristics mentioned for the pharmaceutical composition.

8) Another unanticipated aspect indicates that the QDT tablets described in the Experimental Part have therapeutic advantages for the patient over the commercially taxable known tablets.

Thus, for example, they demonstrated:

A) They produce a similar therapeutic effect in less time than other commercial compositions for oral use used as a comparison term.

-_Property particularly useful for patients with anxiety disorders, panic disorders with agoraphobia or panic disorders without agoraphobia.

B) They produce similar anxiolytic activity, administering up to 50% less alprazolam in each dose. - Similar therapeutic effect with less alprazolam is obviously convenient to avoid or minimize side effects associated with the use of high doses of alprazolam.

- The Spanish Medicines Agency, Food and Drug Administration and other medical entities mention contraindications linked to the use of high doses of alprazolam. These include: hypersensitivity to benzodiazepines, myasthemia gravis, respiratory failure, liver failure, acute glaucoma, and others.

- Problem that the oral disintegration tablets (ODT) of the present invention contribute to minimize as mentioned, because they have a similar anxiolytic effect, but with a lower dose.

- Without being limiting, the following examples illustrate how to carry out the present invention

EXPERIMENTAL PART:

EXAMPLE - Procedure for preparing the premix to subsequently prepare a commonly used granule containing alprazolam to the physical state most absent from alprazolam crystals

The described premix contains:

- _. Alprazolam, as the active substance.

- A disintegrant: crosslinked carboxymethyl cellulose.

- Two diluents: Microcrystalline cellulose and Lactose.

Ethyl cellulose: in two different physical forms (dissolved in the solvent and in the solid state).

- A flavor masker (Debitter or similar).

- A sweetener (Aspartame)

The preparation of the premix formed by the active ingredient excipients was carried out according to the following sequence of operations:

STAGE I. a) 250 grams of ethanol, 12.5 grams of alprazolam were incorporated in a stainless steel container successively and with stirring. It was heated to 35 ° C and stirred until alprazolam was completely dissolved. b) 3 grams of ethyl cellulose were incorporated and stirred at room temperature (20-25 ° C) until complete dissolution of the ethyl cellulose.

STAGE II: a] In Collette Type Gral 10 High Speed Granulator Mixer were successively incorporated:

- 8.8 grams of crosslinked carboxymethyl cellulose (Ac-Di-Sol type - FMC Biopolymer). - 2 grams of ethylcellulose (STD 20 PREMIUM type - Dow Chemical). - 275 grams of microcrystalline cellulose (Avicel 101 type - FMC Biopolymer). - 375 grams of lactose (type DMV 200).

- 5 grams of debitter.

- 165 grams of aspartame. all in solid state, previously sieved and with humidity less than 1.0%. b] It was mixed in the High Speed Granulator Mixer with mixing speed and Rotogranulator at maximum speed for 4 minutes. c] The previous powder mixture was slowly incorporated with a Walson Marlow Mod 505 Du Peristaltic Pump armed with a silicone tube of 1/2 inch internal diameter and for 3 minutes the total of the solution obtained in Stage I (b) keeping the mixing speed and Rotogranulator at maximum speed for not less than 3 minutes. d] An additional 50 ml of ethanol were incorporated, maintaining the speed of the mixer-granulator until obtaining a homogeneous granulate. e] The premix formed was dried in a fluid bed dryer at less than 50 ° C until residual humidity less than 1.5% and preferably 0.5%. £ 1 Went through Quadro Cornil Mod 197 S Conical Screen Mill with 991 micron 2A-039R03125 mesh and 2400 rpm speed.

The obtained premix was kept protected from humidity and temperature in a double Polyethylene bag and envelopes containing indicator-activated silicagel until it was transformed into the granules applicable to the preparation of the pharmaceutical composition of choice.

- 830 grams of homogeneous premix were obtained, mostly absent from alprazolam crystals.

Physical behavior of alprazolam during the Pre-Mix Formation Stages

in common use

A) On Stage by light microscopy:

It was observed that the residue from the evaporation of the solution described in Step I (b) lacks mostly crystals. Only irregular clusters are observed (NIKON Mod. YS 100 Microscope with Nikon E4500 camera — 400X magnification objective).

For reference, a solution consisting only of alprazolam in ethanol was prepared under the same conditions and evaporated under vacuum. The residue of the evaporation presented under the microscope and with only magnification of 250 X sharp and needle-shaped crystals of approximately 30 microns.

- Consequently: It was confirmed that the presence of ethylcellulose described in Step 1 determines the inhibition of recrystallization of alprazolam after evaporation of the solvent.

B) On Stage by X-ray spectroscopy:

The final premix obtained upon completion of Stage II was confirmed to be substantially free of alprazolam crystals.

Specifically in the attached Description of the Figures it is observed:

- Figure 1: corresponds to the expanded X-ray diffraction graph for the position Delta 9-9.5 (2 theta) of pure alprazolam used as a reference. A characteristic signal of crystalline alprazolam is observed.

Figure 3: corresponds to the X-ray diffraction graph of the premix prepared as described. In this case, in the same position (Delta 9-9.5 -2 theta) no signal of crystalline alprazolam is observed.

O Solubility

The dissolution rate of alprazolam in the premix prepared as described was determined and compared with the dissolution rate of alprazolam from a physical mixture containing the same composition, but in this case alprazolam at the usual or crystalline physical state.

- The purpose of the determination was to specifically observe the difference in solubility during the first minute after the suspension of both samples in water.

- The faster the dissolution rate of alprazolam, the more efficient is the direct contact of the dissolved active ingredient with the mucosa of the buccal and sublingual cavity and, consequently, determines greater ease of absorption through the oropharyngeal mucosa. - The results were as follows:

Dissolution conditions

Apparatus: II (USP 36) (25 rpm)

Medium: 500 ml Buffer pH 6.0

Sampling time: 1 minute

Result: After the first minute, it was observed that: the amount of alprazolam dissolved from the described premix was 23.9% greater than that of a physical mixture containing the same components but in different physical state. - Preparation of the premix with higher concentration of alprazolam

The procedure described in Example I was applied using 25.0 grams of alprazolam together with the other excipients in equal amount to Example I.

The premix obtained with double concentration of alprazolam showed similar physical characteristics to the premix obtained in Example I

EXAMPLE TTT - Granules for common use and the same qualitative and quantitative composition as the pharmaceutical form of choice - Its preparation:

It was made from the premix obtained in Example I and according to the following sequence of operations:

a) The Erweka AMD Motor Type 5VIM Double Cone Mixer was incorporated successively, previously sieved by a 1 mm sieve:

- 60 grams of the premix obtained according to Example I.

- 15 grams of crospovidone (Kollidon CL-Basf type).

- 166 grams of granular mannitol (type Mannogen 2080- SPI Pharma). - 12 grams of cherry essence (type durarome 860.638 -Firmenich). - 3 grams of peppermint essence (Firmenich).

- 5 grams of sucralose.

- 27 grams of aspartame.

and mixed for 30 minutes at 80 rpm. b) Sieves (per 1 mm sieve) 4.5 grams of sodium stearyl fumarate (type Pruv-FMC Biopolymer) were incorporated into the mixer and the whole was mixed for 5 minutes.

The final granules obtained were kept protected from humidity and temperature in a double polyethylene bag and envelopes containing indicator-activated silica gel until their application to the preparation of the corresponding composition.

EXAMPLE IV— Preparation of orally disintegrating scored tablets (ODT) containing 0.5 mg alprazolam Tablets mostly absent from crystals of the active substance

The granules obtained in Example III were compressed to a theoretical weight of 150 mg in

Compressor

rotary punch 6 Riva Piccola Mod. B-2 with Autoset HI TECH armed with round punch, concave, 7 mm. Approximately 1800 tablets were obtained.

The orally disintegrating tablets obtained had the following characteristics:

- Average weight: 150 mg (146-154 mg) (Mettler Toledo AB 204 -S Balance with LC P45 Printer).

- Hardness: 4-6 SC (ERWEKA Type TBC 30 MD Durometer).

- Maximum height: 3.4 mm

- Friability: less than 1% (Pharmaceutical Equipment Friability Equipment).

- Disintegration time ration.: Less than 15 seconds (AVIC Disintegration Equipment with CITIZEN printer, medium: Water without discs, according to USP 37.

Subsequently, they were incorporated into Bifolia PVC 250 micron / PVDC 60 g / m blisters - Printed aluminum.

The orally disintegrating tablets had the following properties:

A) Disintegration time in the oral cavity:

In 10 healthy volunteers, it was determined that the described oral disintegration tablets containing 0.5 milligrams of alprazolam were located, the disintegration begins before 5 seconds and is total before 8 seconds. The suspension that forms with saliva does not contain annoying particles or aggregates and lacks the flavor of alprazolam.

B) Dissolution rate of the active ingredient:

The dissolution rate of alprazolam from the described orally disintegrating tablets was determined and compared to the dissolution rate in commercially available tablets that also contain alprazolam.

The reference product was: Tranquinal sublingual, sublingual tablets of 0.50 mg (Laboratorios Bagó S.A. - Lot: Al 8 H). Orally disintegrating tablets according to the present invention are identified as ODT 0.50-E 011.

The conditions for carrying out the determinations correspond to those described in USP 37 in the monograph for alprazolam orally disintegrating tablets.

They were: Buffer medium: pH 6.0. Volume: 900 mi. Temperature: 37 ° C. Speed: 50 rpm. Apparatus 2: paddle.

Sampling time: 30. 60, 90 and 120 seconds.

The results were the following:

TABLE 1:

The alprazolam contained in the oral disintegration tablet object of the present invention demonstrated the highest dissolution rate.

For example: at 30 seconds a dissolution rate much higher than the commercially available and used as benchmarks. Specifically at 30 seconds it was 120% higher than the dissolution rate of alprazolam present in the sublingual Tranquinal product

Dissolution rate that helps to initiate oropharyngeal absorption before swallowing

of the suspension formed by the tablets with the saliva in the oral cavity.

C) Tests on administration forms:

The tablets due to their fast disintegration speed, absence of annoying residue in the oral cavity and their pleasant taste confirmed the following administration modalities in 10 healthy volunteers: a) direct ingestion.

b) after disintegration in a small volume of water (10 ml) and subsequent administration of the suspension formed.

c) by incorporation into food after disintegration in a small volume of water. The three forms of administration of the described tablets received excellent acceptability by the volunteers. d) by previous disintegration in a small volume of water (5 to 10 ml) and administration by tube type K-108 to patients who are only fed by enteral tube.

No obstruction of the probe was observed, due to the small size of the particles and in suspension.

The administration forms mentioned under letters b), c) and d) do not apply with traditional commercially available oral tablets.

Preparation of scored orally disintegrating tablets containing 0.25 mg of alprazolam which are largely absent from crystals of the active substance.

Starting from the granules obtained in Example III, oral disintegration scored tablets containing 0.25 milligrams of alprazolam per unit were also prepared according to the present Example IV but at half weight.

EXAMPLE V - Preparation of orally disintegrating scored tablets (QDT) containing LO or 2.0 mg. of alprazolam practically absent from crystals of the active substance

They were respectively made from a premix with the highest alprazolam content (25.0 grams) prepared according to Example II, subsequent preparation of granules according to Example III and finally according to the procedure described in Example IV for the preparation of oral disintegration tablets.

In each case, the weight difference selected during the compression operation of the commonly used granules determined in the orally disintegrating tablets (ODT) respectively the presence of 1.0 or 2.0 mg of mostly non-crystalline alprazolam

EXAMPLE VI- Characteristics of the oral disintegration tablets made according to the previous Examples IV vV.

A) By X-ray spectroscopy it was shown that the tablets made are largely free of alprazolam crystals.

In the attached Description of the Figures for such ODT tablets it is observed:

Figure IV describes the X-ray diffraction graph expanded in the Delta 9-9.5 position (2 theta) for the tablets obtained and previously ground to perform the physical determination.

- The characteristic signal of alprazolam to the crystalline physical state is not observed even when the content of alprazolam in the tablets is high (2 mg per tablet)

B) PHARMACOLOGICAL STUDY:

Balance and motor coordination were evaluated in the animal model (rat) according to the Rotarod test described by Monville Christelle et al (Journal of Neuroscience Methods 158 (2006) 219-223) in a comparative way between oral disintegrating tablets containing 0.25 mg of alprazolam made according to Example IV of the present invention and other commercial compositions containing respectively 0.25 and 0.50 mg of alprazolam.

The latency time or time during which the animal maintains its position in the rotarod without falling was determined. The rotation movement was fixed and the speed was 16 rpm.

The objective of the study was to evaluate the time in which each composition begins to exert its pharmacological action and as a consequence of the absorption rate of the alprazolam they contain.

Animals used: female Sprague Dawley rats.

Selection of the animals: before the experience the rats were tested three times at the mentioned rotation speed (16 rpm) and the animals were selected for the test

They remain in the rotating cylinder without falling for at least 1 minute.

Dose: 0.23 mg / rat (0.9 mg / kg).

Samples, preparation and route of administration:

MI) Orally disintegrating tablets (QDT) containing 0.25 mg alprazolam:

The tablet suspended in 0.3 ml of water in a syringe was administered into the oral cavity using a probe.

M21 _ Oral tablets (brand oral Tranquinal - Lot 4C80) containing 0.25 mg alprazolam:

- The tablet was ground in mortar and suspended in 0.3 ml of water and was also incorporated by probe in the oral cavity. M31 _ Oral tablets (brand Xanax 0.5 mg— Lot D 104— Vto. 03 (2015)):

- Tablets containing 0.50 mg of alprazolam were used due to the absence of such brand-name tablets on the market, containing only 0.25 mg.

- Half of the scored tablet was ground, placed in a syringe, 0.3 ml of water were incorporated and it was administered by gavage in the oral cavity.

Two comparative experiences were carried out evaluating the responses after 10 minutes by self-administration.

Experience I: The orally disintegrating tablets (MI) were compared with the oral tablets (M2) mentioned. The total number of animals incorporated in each case was 11. The number of animals that fell from the rotarod in the indicated time (10 minutes) was determined in relation to the total number of animals involved.

The results were:

At 10 minutes 91% of the animals treated with the orally disintegrating tablet (QDT) dug from the rotarod. while at the same time only 45% of the rats treated with the oral M2 tablet used as reference fell. Confirmed the increased absorption rate of alprazolam present in the orally disintegrating tablet.

Experience II: The effect on balance and motor coordination in rats provoking orally disintegrating (MI) tablets was compared to other commercial oral tablets (M3). Their incorporation in each case was 17 Sprague Dawley rats.

The results were:

At 10 minutes after administration, 82% of the animals treated with the oral disintegration tablet fell from the rotarod, while only 29% of the animals treated with the oral tablet (M3) fell from it.

Both experiences demonstrated the increased absorption rate of alprazolam from the orally disintegrating tablets of the present invention.

C) METHODS OF ADMINISTRATION AND CLINICAL TRIAL

a) In 10 volunteers it was shown that the oral disintegration tablets of the present The invention can be administered interchangeably in the following ways.

1) by direct incorporation into the oral cavity

1) by previous disintegration in a small volume of water (5 ml) and administration of the suspension formed or incorporation of the suspension into food. b) In "in vitro" test it was demonstrated that the suspension formed by the disintegration of the tablets of the present invention in a small volume of water (5 to 10 ml) does not obstruct the nasogastric or nasoenteric feeding probes type K108 or Similary. c) In 21 elderly patients with orally disintegrating tablets containing 0.25 or 0.50 mg alprazolam, the following conclusions were reached in a short clinical experience.

1) The tablets disintegrate in the oral cavity in a few seconds. After disintegration in the oral cavity, there are no nuisance particles and the taste of the suspension formed was considered optimal.

2) In the case of patients with swallowing problems the administration of the orally disintegrating tablets of the present invention was more convenient and practical than the administration of previously administered commercially available oral tablets used as a comparison term.

3) The anxiolytic or hypnotic effect was clearly superior when administered on an empty stomach.

4) Unexpectedly; A similar therapeutic effect was demonstrated in 14 of 19 patients with the QDT tablets of the present invention that only contain 0.25 mg of alprazo lam compared to commercial references that contain twice the concentration of active ingredient. The referents were: the commercial products Tranquinal sublingual and Xanax oral tablets Both contain 0.50 mg alprazolam per tablet.

-A similar therapeutic effect was observed by administering 50% less alprazolam through orally disintegrating tablets.

5) After disintegration in 10 ml of water, the suspension formed could be administered by nasogastric or nasoenteric feeding probes type K 108 or similar.

6) Tablets with only 0.25 mg of alprazolam were used on demand instead of the conventional tablets with 0.50 mg previously used

The oral disintegration tablets of the present invention, as they are in all cases scored tablets, offer convenient logical flexibility, helping to administer to the patient the smallest but necessary amount of alprazolam to achieve similar therapeutic effect.

EXAMPLE VII - Preparation of powder for suspension containing alprazolam

It was prepared according to the granules described in Example III. Dosage in single-dose sachets containing 0.5 mg. of alprazolam and final packaging was carried out in a Rovena brand equipment using Triple Folia (Bioxide + aluminum + polyethylene paper). Obtained: 1800 units containing 0.5 mg of alprazolam.

- Weight contained per envelope: 150 mg. - Humidity: 0.5 to 1.5%

- Water activity: 0.54 (t = 21.2 ° C).

CHARACTERISTICS a) The dispersion of an envelope (150 mg) in 10 ml of water was fast, homogeneous and did not require more than 10 seconds. The suspension formed had a pleasant taste and its ingestion practically left no troublesome particles in the oral cavity.

b) Optionally, the suspension, due to the aforementioned characteristics, was also administered by prior incorporation into food.

c) The above suspension proved to be useful for administration by a K-180 type probe in that due to the small size of the particles it does not obstruct the probe.

In all cases, the powder to prepare the suspension before administration showed excellent acceptability.

EXAMPLE VTTT-Single-dose compositions in powder form to prepare the suspension to be administered a posteriori

-_ Similarly, and as described in Example IV, other single-dose powder compositions for suspension containing respectively 0.25, 1.0 or 2.0 mg were prepared.

(with the active principle practically free of crystals).

EXAMPLE IX-Multidose compositions in powder form to prepare a posteriori the suspension to be administered.

By fractionation of the granules obtained according to Example III and subsequent conditioning, multidose compositions were prepared under two presentations. a) in fractional aluminum-aluminum sachets. b) in a multidose High Density polyethylene bottle with a Polypropylene Cap with an insert for an oral dispenser to reconstitute with water accompanied by a measure for the fractionation of the suspension formed and administration. The suspension formed must be kept at a low temperature.

Claims

CLAIMS.

1) Composition of amorphous alprazolam with anxiolytic activity CHARACTERIZED because it comprises:

a) a premix containing:

- between 0.33 and 0.66% w / w of alprazolam;

- between 0.07 and 0.2% w / w of ethylcellulose as a binding agent;

- between 10 and 15% aspartame and

- between 0.05 and 0.2% of taste masking agent, preferably debitter;

b) said premix combined with:

- flavoring agents, sweetening agents; and

- c.s. p. 100% granular mannitol as a diluent;

where:

- the degree of crystallinity of alprazolam is less than 10%.

2) Composition according to claim 1, CHARACTERIZED in that it comprises: a) a premix containing:

- between 0.33 and 0.66% w / w of alprazolam;

- 0.13% w / w of ethyl cellulose;

- 0.23% w / w of said disintegrating agent;

- 17.3% w / w of said diluting agent

- 13.33% aspartame and

- 0.13% flavor masking agent;

b) said premix combined with:

- 5% w / w of water insoluble crospovidone, preferably crospovidone CL grade,

- 1.5% of said lubricating agent;

- flavoring agents, sweetening agents; and

- c.s. p. 100% granular mannitol as a diluent.

3) Composition according to one of Claims 1 or 2, CHARACTERIZED in that it comprises:

a) a premix containing:

- between 0.33 and 0.66% w / w of alprazolam;

- 0.13% w / w of ethyl cellulose;

- 0.23% w / w of crosslinked carboxymethyl cellulose,

- 17.3% w / w of a mixture of microcrystalline cellulose and lactose,

- 13.33% aspartame; and

- 0.13% flavor masking agent;

b) said premix combined with:

- 5% w / w of water insoluble crospovidone, preferably crospovidone CL grade,

- 1,5% sodium stearyl fumarate,

- flavoring agents, sweetening agents; and

- c.s. p. 100% granular mannitol as a diluent.

4) Composition according to any of claims 1 to 3, CHARACTERIZED in that each dose unit comprises between 0.25 and 2.00 milligrams of alprazolam, and preferably each dose unit comprises 0.25, 0.5, 1.0 or 2.0 milligrams of alprazolam. 5) Composition according to any of claims 1 to 4, CHARACTERIZED in that the dissolution of the amorphous alprazolam present in the premix of the composition in the first minute is greater than 20 percent with respect to the solution of crystalline alprazolam present in a physical mixture with the same components , according to USP 35 test in buffer medium.

6) Composition according to any of claims 1 to 5, CHARACTERIZED in that it is presented in the form of rapidly orally disintegrating tablets.

7) Composition according to claim 6, CHARACTERIZED in that each tablet has a disintegration time of less than 20 seconds and preferably less than 15 seconds, measured by in vitro determination according to USP 37 in aqueous medium without disc.

8) Composition according to one of claims 6 or 7, CHARACTERIZED in that the disintegration of the tablet located in the oral cavity begins at 5 seconds and is total at 8 seconds.

9) Composition according to any of claims 6 to 8, CHARACTERIZED in that the suspension formed by the tablet with the saliva lacks bothersome particles or agglomerates and the suspension formed has a pleasant taste.

10) Composition according to any of claims 6 to 9, CHARACTERIZED in that it is for oral administration to the patient by direct incorporation of the tablet into the oral cavity or after disintegration in a small volume of water and direct administration of the suspension formed and optionally through Enteral tube Type K-10 8 or similar.

11) Composition according to any of claims 1 to 10, CHARACTERIZED in that the solution of alprazolam in buffer medium, at pH 6.0, volume 900 ml and temperature 37 ° C, speed 50 rpm. in apparatus 2 according to USP 37 at 30 seconds it is greater than 45%, and at 60 seconds it is greater than 65% of the alprazolam content of the composition.

12) Composition according to any of claims 1 to 5 or claim 11 when it depends on claims 1 to 5, CHARACTERIZED because it is presented in the form of a powder for the extemporaneous preparation of a suspension. 13) Composition according to claim 12, CHARACTERIZED in that the administration of the previously formed suspension with water or other beverages is carried out by incorporation of the suspension into the oral cavity or by Type K-108 enteral tube or the like.

14) Procedure to prepare an oral disintegration composition of amorphous alprazolam, CHARACTERIZED BECAUSE it comprises preparing a premix according to the following sequence:

b) prepare a mixture incorporating in a solid state, in a high-speed granulator:

- a disintegrating agent selected from cross-linked carboxymethyl cellulose, modified starch, croscarmellose sodium, sodium glycollate starch, hydroxypropyl carboxymethyl starch, and starch and mixtures thereof; preferably crosslinked carboxymethyl cellulose;

- ethyl cellulose;

- a flavor masking agent, preferably Debitter;

- aspartame;

i) incorporate into the premix obtained in e);

-crospovidone insoluble in water, preferably crospovidone CL grade;

granular mannitol;

-flavoring agents, preferably cherry essence and / or peppermint essence;

sweetening agents, preferably sucralose and / or aspartame;

ii) mix, iii) incorporating a lubricating agent selected from sodium stearyl fumarate, magnesium stearate, zinc stearate, stearic acid and talc, preferably sodium stearyl fumarate; and

15) Method according to claim 14, CHARACTERIZED in that step v) comprises subjecting the granules to direct compression with pharmaceutically acceptable excipients to obtain tablets, preferably scored tablets.

16) Procedure according to claim 14, CHARACTERIZED in that step v) comprises the simple fractionation of the granulate and subsequent conditioning in single-dose or multi-dose units to obtain a powder for the extemporaneous preparation of a suspension.

17) Process according to any of claims 14 to 16, CHARACTERIZED in that the content of alprazolam dissolved in ethanol is comprised between 5 and 10% by weight with respect to the weight of the ethanol.

18) Process according to any of claims 14 to 17, CHARACTERIZED in that the content of ethyl cellulose dissolved in ethanol is comprised between 0.5 and 2.0% by weight with respect to the weight of ethanol.

19) Process according to any of claims 14 to 18, CHARACTERIZED in that the ratio between the ethyl cellulose of stage a) and the ethyl cellulose of stage b) is between 60:40 and 30:70, preferably between 60:40 and 40 : 60, and most preferably it's 60:40.

20) Process according to any of claims 14 to 19, CHARACTERIZED in that the fraction of ethyl cellulose dissolved in ethanol in step a) inhibits, at least partially, the subsequent recrystallization of alprazolam.

21) Method according to any of claims 14 to 20, CHARACTERIZED because the ethylcellulose fraction incorporated in the solid state in step b) acts as a binding agent.

22) Method according to any of claims 14 to 21, CHARACTERIZED in that the dissolution of the amorphous alprazolam present in the premix of the composition at the first minute is greater than 20 percent with respect to the solution of crystalline alprazolam present in a physical mixture with the same components , according to USP 35 test in buffer medium.

23) Procedure according to any of claims 15 or 17 to 22 when they depend on claim 15, CHARACTERIZED in that the tablets obtained contain between 0.25 and 2.00 milligrams of alprazolam, and preferably contain 0.25, 0.5 , 1.0 or 2.0 milligrams of alprazolam.

24) Method according to any of claims 15 or 17 to 23 when they depend on claim 15, CHARACTERIZED because the tablets have a disintegration time of less than 20 seconds and preferably less than 15 seconds by in vitro determination according to USP 37 in aqueous medium without disk.

25) Procedure according to any of claims 15 or 17 to 24 when they depend on claim 15, CHARACTERIZED because the disintegration of the tablet, located in the oral cavity, begins at 5 seconds and is total at 8 seconds.

26) Method according to any of claims 15 or 17 to 25 when they depend on claim 15, CHARACTERIZED in that the suspension that forms the tablet with the saliva lacks particles or agglomerates and the suspension has a pleasant taste.

27) Procedure according to any of claims 14 to 26, CHARACTERIZED in that the dissolution of alprazolam of the composition obtained in step iv) in buffer medium, at pH 6.0, volume 900 ml and temperature 37 ° C, speed 50 RPM in apparatus 2 according to USP 37 at 30 seconds is greater than 45%, and at 60 seconds is greater than 65%, of the alprazolam content of the composition. 28) Procedure according to any of claims 15 or 17 to 27 when they depend on claim 15, CHARACTERIZED because the tablet is for direct administration to the patient in the oral cavity or after disintegration in a small volume of water and direct administration of the suspension formed and optionally through Type K-108 enteral probe or the like.

29) Procedure according to any of claims 16 to 22, CHARACTERIZED in that the powder for the extemporaneous preparation of a suspension is suspended with water or other beverages and is for administration by incorporation of the suspension in the oral cavity or by Type K enteral tube. -108 or similar.

30) Procedure according to any of claims 16 to 22 or 29, CHARACTERIZED in that the powder for the extemporaneous preparation of a suspension is presented in single-dose or multi-dose units that contain indistinctly between 0.25 and 2.00 milligrams of alprazolam at the mostly amorphous state and They quickly form by simple agitation a suspension with water or another drink.

31) Process according to any of claims 14 to 30, CHARACTERIZED in that the alprazolam: ethylcellulose ratio in the composition is between 2.5: 1 and 5: 1.

32) Method according to any of claims 14 to 31, CHARACTERIZED in that the proportion at 1 to 1 in: c ro s p o v i do n a in the composition is between 0.06: 1 and 0.13: 1.

33) Method according to any of claims 15 or 17 to 28 when they depend on claim 15 or 31 or 32 when they depend on claim 15, CHARACTERIZED because the tablet has an alprazolam content of less than 0.5 mg, preferably 0, 25 mg.

34) Process according to any of claims 14 to 33, CHARACTERIZED in that the compounds incorporated in said step b) have a humidity of less than 1.5%, preferably less than 0.5%. 35) Process according to any of claims 14 to 34, CHARACTERIZED in that in said step e) said premix is dried at less than 50 ° C.

36) Process according to any of claims 14 to 35, CHARACTERIZED in that in said step e) said premix is dried until reaching a humidity lower than 1%.