ITMI20120448A1 - LIOFILIZED COMPOSITION OF ESCITALOPRAM OXALATE FOR SUBLINGUAL ADMINISTRATION - Google Patents

Description

LYOPHYLIZED COMPOSITION OF OXALATED ESCITALOPRAM FOR SUBLINGUAL ADMINISTRATION

FIELD OF THE INVENTION

The present invention relates to a lyophilized composition of escitalopram oxalate, in particular to lyophilized tablets of escitalopram oxalate, to a process for their preparation, to the use of said lyophilized tablets for sublingual administration, containing escitalopram oxalate as one of their active ingredients.

BACKGROUND OF THE INVENTION

Escitalopram is the international non-proprietary name of (S) -1- [3- (dimethylamino) propyl] -1- (4-fluorophenyl) -1,3-dihydro-5-isobenzofurancarbonitrile.

The (1: 1) oxalate of (S) -1- [3- (dimethylamino) propyl] -1- (4-fluorophenyl) -1,3-dihydro-5-isobenzofurancarbonitrile, hereinafter referred to as escitalopram oxalate, is a selective serotonin reuptake inhibitor with central antidepressant activity. This product and its preparation are described in US Re. 34,712 and other methods for its preparation, by chemical or chemical-enzymatic way, have been described for example in US 7,834,201, US 2007/0129561 and US 2011/0238887. Escitalopram oxalate is moderately soluble in water and in ethanol. It is used in tablets and drops.

STATE OF THE ART

To facilitate the absorption of escitalopram by the body in the best possible way, technologies for the micronization of particles and / or improvement of the breakdown of escitalopram granules and particles have been developed.

The aforementioned document US 7,834,201 (Lundbeck & Co. A / S) describes orodispersible tablets having a hardness of at least 22 N (Newtons) and a gold-dispersibility time of less than 120 seconds, comprising an active pharmaceutical ingredient, escitalopram, absorbed on a water-soluble support, and one or more disintegrating agents.

Similarly, WO 2009/150665 (Lupine Ltd. And Velhal Avinash Krishnaji) discloses an orodispersible pharmaceutical composition comprising escitalopram or its salts as an active ingredient, excipients selected from the group consisting of cellulose derivatives, such as microcrystalline cellulose and the like, D-mannitol, lactose , dextrose, sorbitol, starch, xylitol, maltitol, maltose, di-calcium phosphate and similar compounds; disintegrating agents and suitable pharmaceutical excipients.

WO 2009/135649 (Hexal) describes a granulate comprising escitalopram oxalate having a particle size of less than 100 μm and at least one support, preferably including disintegrants or disintegration accelerators usually used in the pharmaceutical field.

IN 2006DE00964 (Jubilant Organosys Ltd.) discloses a solid dosage form of escitalopram comprising escitalopram or its pharmaceutically acceptable salts or solvates having an average particle size of less than 20 μ in admixture with one or more pharmaceutically acceptable excipients. Said solid dosage form is prepared by a process comprising mixing said escitalopram and said excipients ensuring a uniform distribution of escitalopram. Furthermore, this solid dosage form is preferably prepared by a direct compression technique.

IN 2007MU00470 (Torrent Pharm. Ltd) discloses a pharmaceutical composition comprising particles of escitalopram oxalate with a specific particle size distribution. In particular, this document describes a tablet composition containing escitalopram oxalate, microcrystalline cellulose, croscarmellose sodium, colloidal silica, talc and magnesium stearate in the main formulation.

US 2009/0048336 («olla et al., IN) describes the preparation of escitalopram oxalate powders having defined parameters in the particle size distribution. In particular, the document describes processes for the preparation of escitalopram oxalate in powder comprising (1) obtaining a solution of escitalopram in an organic solvent; (2) the reaction with oxalic acid to give escitalopram oxalate favoring precipitation in the solid state; (3) the insulation of the solid; and (4) micronization of the solid to obtain escitalopram oxalate with defined particle size parameters. This document also describes the preparation of compositions in which the micronized particles are mixed with disintegrating agents.

WO 2008/046617 (Ratiopharm) describes escitalopram or its pharmaceutically acceptable salts and / or solvates, including oxalate in the form of particles with an average size of less than 40 μm and in which the ratio of the average particle size to the particle size is 95% quantile is equal to or greater than 0.42. According to this document, said escitalopram can be in amorphous or crystalline form, preferably it is in the form of crystalline particles used by direct compression and is included in pharmaceutical compositions which can comprise excipients.

WO 2006/123243 (Aurobindo) discloses the preparation of a pharmaceutical dosage form comprising the steps: (i) mixing of escitalopram oxalate with one or more excipients, (ii) granulating the mixture obtained in step (i) using solvent and optionally a binder, (iii) drying of the granules obtained in step (ii), (iv) mixing of the granules of step (iii) with one or more pharmaceutically acceptable excipients, (v) lubrication of the mixture of step (iv) and (vi) compression of the mixture of step (v) in tablets. The excipients include disintegrating agents.

The literature does not disclose lyophilized tablets based on escitalopram oxalate obtainable from aqueous solutions of escitalopram oxalate in which said escitalopram oxalate is dissolved at concentrations of at least 30 mg / ml and in which common excipients are also dissolved.

SUMMARY OF THE INVENTION

A method has now been found which makes it possible to provide a novel lyophilized tablet obtainable from a relatively high concentration escitalopram oxalate solution. In particular, it has been found that escitalopram oxalate can be dissolved in water at a concentration of at least 30 mg / ml up to 115 mg / ml.

It has also been found that escitalopram oxalate dissolves in water at the above concentrations in a mixture with common excipients. In particular, escitalopram oxalate was dissolved by mixing said escitalopram oxalate with two common excipients, D-mannitol and gelatin in appropriate proportions. In the mixture of escitalopram oxalate, D-mannitol and gelatin, escitalopram oxalate is present from 30% to 50% by weight, D-mannitol from 45% to 75% by weight and gelatin from 4% to 19% by weight. Other agents are generally not required to dissolve escitalopram oxalate, although a small amount of pure ethanol can be used. In addition, said solution can contain ethanol and / or a salt selected from the group comprising sodium chloride and magnesium chloride. Said solution may also contain other excipients selected from the group consisting of preservative, antioxidant, flavoring and coloring agents.

The importance of having a solution of escitalopram oxalate in which said escitalopram oxalate is present in relatively high concentrations is due to the fact that, in the lyophilization process, substrate concentrations are required which, in the case of escitalopram oxalate, were not known. before now.

Thus, the invention provides lyophilized tablets comprising escitalopram oxalate, D-mannitol, gelatin and, optionally, a salt selected from the group formed by sodium chloride and magnesium chloride. Said freeze-dried tablets can also contain one or more additives selected from the group consisting of preservatives, antioxidants, flavors and dyes.

They can be used for sublingual administration in the treatment of depression.

DETAILED DESCRIPTION

Thus, the present invention provides a lyophilized pharmaceutical composition comprising an effective amount of escitalopram oxalate in admixture with a pharmaceutical excipient.

In particular, according to the present invention, said composition is in the form of a dosage unit consisting of a lyophilized tablet (tablet) for sublingual use comprising escitalopram oxalate in an amount equivalent to from 5 mg to 20 mg of escitalopram base, in a mixture with a pharmaceutical excipient.

More particularly, the invention provides lyophilized tablets of escitalopram oxalate comprising escitalopram oxalate, D-mannitol and gelatin.

Said lyophilized tablets can also comprise a salt selected from the group formed by sodium chloride and magnesium chloride.

The present invention also provides a process for the preparation of the aforementioned lyophilized tablets of escitalopram oxalate, which comprises:

(a) suspending a quantity by weight of said escitalopram oxalate in a volume of water to obtain a suspension containing said escitalopram oxalate in an amount from 40 mg / ml to 150 mg / ml;

(b) treating the suspension thus obtained with D-mannitol, in an amount by weight from 90% to 210% of the amount of said escitalopram oxalate; and gelatin, in an amount by weight of from 10% to 45% of the amount of said escitalopram oxalate;

(c) add water or ethanol to the mixture obtained to obtain a suspension containing said escitalopram oxalate in an amount from 30 mg / ml to 115 mg / ml and heat the mixture at a temperature from 20 ° C to 30 ° C until a clear solution; And

(d) pouring a volume of the solution from step (c), containing a calculated amount of escitalopram oxalate into each of the alveoli of a multi-alveolar blister and subjecting said blister to lyophilization.

According to a procedure, the water used in step (a) may contain a salt chosen from the group consisting of sodium chloride and magnesium chloride, dissolved in it at a concentration of 0.9% to 1%.

According to a preferential procedure, in step (a) the content of escitalopram oxalate ranges from 125 mg / ml to 135 mg / ml. In practice, a calculated quantity of escitalopram oxalate is suspended in a volume of water, possibly containing 0.9% -1% sodium or magnesium chloride, sufficient for the desired concentration.

In step (b), D-mannitol is added to the suspension obtained at the end of step (a), in an amount from 90% to 210% of said amount of escitalopram oxalate and gelatin, in an amount from 10% to 45% of said amount of escitalopram oxalate.

In step (c), distilled water is added to the suspension of step (b), possibly containing 0.9% -1% sodium or magnesium chloride, or ethanol to obtain a concentration of escitalopram oxalate from 30 mg / ml to 115 mg / ml, preferably from 30 mg / ml to 95 mg / ml and the temperature of the mixture is brought to 20-30 ° C, preferably 23-27 ° C, with which a clear solution is obtained. In practice, distilled water or a 0.9-1% aqueous solution of a salt selected from the group consisting of sodium chloride and magnesium chloride, or ethanol, is added to the suspension obtained at the end of step (b).

The solution may contain one or more additives chosen from the group consisting of preservative agents in order to improve the stability of the composition, antioxidants, flavors and dyes in view of the pharmaceutical use of the final product.

Preservatives, such as methyl paraben, ethyl paraben, sodium benzoate, sorbic acid and its salts, in particular potassium sorbate, EDTA or its salts, can be present in an overall quantity from 0.01% to 0.3% w / v.

Flavoring agents are pharmaceutically acceptable flavors, synthetic flavors and natural oils, the latest extracts from plants, leaves, flowers, fruits and their combinations, such as cinnamon, peppermint, anise and cedar leaves, bitter almond, citrus fruits, especially oils of orange and / or lemon, lime and Pompeii. Aromas of chocolate, vanilla or eucalyptol and fruit essences, in particular apple, pear, peach, strawberry, cherry, apricot, orange, lemon and grape, can also be used advantageously. A flavoring agent can generally be present at a concentration of 0.1% to 0.25%.

The dyes can be present in amounts of 0.01% -0.02%.

Preferably, the additives indicated above are added in step (b) or (c).

In step (d), the solution obtained at the end of step (c) is lyophilized in order to directly obtain tablets for sublingual administration.

An aqueous solution of escitalopram oxalate for pharmaceutical use comprising said escitalopram oxalate at a concentration of from 30 mg / ml to 115 mg / ml is a useful starting material for step (d). An aqueous solution containing escitalopram oxalate at such high concentrations allows the preparation of lyophilized pharmaceutical compositions containing an effective amount of said escitalopram oxalate, in particular in an amount corresponding to 10 mg or 20 mg of escitalopram base per dosage unit.

Advantageously, said solution comprises escitalopram oxalate, D-mannitol and gelatin, said escitalopram oxalate being dissolved at a concentration of at least 25 mg / ml, advantageously from 30 mg / ml to 95 mg / ml, preferably from 35 mg / ml to 95 mg / ml.

According to this aspect of the invention, escitalopram oxalate, D-mannitol and gelatin are present in the solution in quantities by weight in the ratios 1 / from 0.9 to 2.2 / from 0.04 to 0.1.

More particularly, advantageous starting aqueous solutions comprise, as an active ingredient thereof, an effective amount of escitalopram oxalate at a concentration of at least 25 mg / ml, advantageously from 30 mg / ml to 95 mg / ml, preferably from 35 mg / ml. at 95 mg / ml and furthermore comprise D-mannitol and gelatin, in the aforementioned respective ratios with respect to escitalopram oxalate; and, optionally, ethanol, sodium chloride at a concentration of 0.9 to 1% or magnesium chloride at a concentration of 0.9 to 1%.

As mentioned above, the quantity of D-mannitol is from 90% to 210% of that of escitalopram oxalate, while the quantity of gelatin can vary from 10 to 45% of said quantity of escitalopram oxalate.

Thus, the ingredients dissolved in the solution of the present invention are present in the following percentages: escitalopram oxalate, from 20% to 50% by weight; D-mannitol, from 45% to 70% by weight and gelatin, from 4% to 10% by weight. Advantageous aqueous solutions include, by weight, from 20% to 40% of escitalopram oxalate, from 50% to 70% of D-mannitol and from 7% to 10% of gelatin. Preferred solutions comprise, in weight percentage, from 20% to 50%, preferably from 30% to 50%, of escitalopram oxalate; from 45% to 75%, preferably from 45% to 50%, of D-mannitol and from 4% to 10%, preferably from 5% to 8%, of gelatin.

More particularly, the content by weight of escitalopram oxalate, D-mannitol and gelatin in the starting solution of the present invention is from 20% to 50%, from 45% to 70% and from 4% to 10%, respectively.

Aliquots of the solution obtained at the end of step (c), as illustrated above, containing a calculated quantity of escitalopram oxalate, in particular the quantity chosen for the final lyophilized tablets, are introduced into the open cell of a multialveolar blister and said blister is subjected to freeze-drying under conventional conditions.

At the end of the lyophilization, each blister cell contains a lyophilized tablet comprising, as one of its active ingredients, an effective amount of escitalopram oxalate, said effective amount being, preferably, 6.375 mg, 9.56 mg, 12.75 mg, 19.125 mg, 22.3 mg or 25.5 mg, corresponding respectively to 5 mg, 7.5 mg, 10 mg, 15 mg, 17.5 mg or 20 mg of escitalopram base, in mixture with D-mannitol, gelatin and, possibly sodium chloride or magnesium chloride. If one or more of the above additives was present in the solution obtained at the end of step (c), these additives are also present in the lyophilized tablet.

Said possible additives are selected from the group consisting of preservatives to improve the stability of the composition, antioxidants, flavors and dyes.

Using, as advantageous solutions obtained at the end of step (c), those comprising, in weight percentage from 20% to 50%, from 45% to 70% and from 4% to 10%, respectively of escitalopram oxalate, of D-mannitol and of gelatin, said escitalopram oxalate being in a quantity of 12.75 mg, corresponding to 10 mg of escitalopram base, at the end of lyophilization freeze-dried tablets are obtained comprising 12.75 mg of escitalopram oxalate, from 36 mg to 40 mg of D -mannitol and 3.8 to 5.6 mg of gelatin. Said lyophilized tablets constitute a preferential aspect of the present invention.

Similarly, using as advantageous solutions obtained at the end of step (c) those comprising, in weight percentage from 30% to 50%, from 45% to 50% and from 4% to 8%, respectively of escitalopram oxalate, of D-mannitol and of gelatin, said escitalopram oxalate being in an amount of 25.5 mg, corresponding to 20 mg of escitalopram base, at the end of lyophilization freeze-dried tablets are obtained comprising 25.5 mg of escitalopram oxalate, from 24 mg to 26 mg of D -mannitol and 2.17 to 3.34 mg of gelatin. These freeze-dried tablets also constitute a preferential aspect of the present invention.

Tablets in which escitalopram oxalate is present in a quantity of 12.75 mg; D-mannitol is present in an amount from 36 to 40 mg; and gelatin is present in an amount of 3.8 and 5.6 mg and tablets in which escitalopram oxalate is present in an amount of 25.5 mg; D-mannitol is present in an amount from 24 to 26 mg; and gelatin present in an amount of 2.17 mg to 3.34 mg are particularly preferred. They may also contain a salt selected from the group consisting of sodium chloride and magnesium chloride, each in an amount from 0.01 mg to 0.03 mg.

The tablets of the present invention, when placed on or under the tongue, dissolve instantly and the escitalopram oxalate is absorbed without the aid of disintegrating agents.

The following examples illustrate the invention.

Example 1

(a) 2.55 g of escitalopram oxalate are suspended in 20 ml of distilled water.

(b) 2.55 g of D-mannitol and 0.32 g of gelatin are added to the suspension thus obtained.

(c) Distilled water up to a weight of 38.4 g is added to the suspension obtained, then the temperature of the mixture is brought to 25 ° C, obtaining a clear solution, in which the concentration of escitalopram oxalate is 69.30 mg / ml, having the following composition:

escitalopram oxalate 2550 mg

D-mannitol 2550 mg

gelatin 320 mg

distilled water up to 36.8 ml

(d) From 5.15 ml of the solution obtained at the end of step (c), 0.368 ml of said solution are introduced into each cell of a 14 cell blister and said blister is placed in a lyophilizer. At the end of lyophilization, each blister cell contains a tablet having the following composition:

escitalopram oxalate 25.5 mg

D-mannitol 25.5 mg

gelatin 3.2 mg

Total weight: 54.2 mg

Each lyophilized tablet contains escitalopram oxalate corresponding to 20.0 mg of escitalopram base.

Example 2

(a) In 20 ml of distilled water, 1,275 g of escitalopram oxalate are suspended.

(b) 3.682 g of D-mannitol and 0.463 g of gelatin are added to the suspension thus obtained.

(c) Distilled water up to a weight of 38.4 g is added to the mixture obtained, then the temperature of the mixture is brought to 25 ° C, thus obtaining a clear solution, in which the concentration of escitalopram oxalate is 34.65 mg / ml, having the following composition: escitalopram oxalate 1275 mg

D-mannitol 3682 mg

gelatin 463 mg

distilled water up to 36.8 ml

(d) From 5.15 ml of the solution obtained at the end of step (c), 0.368 ml of said solution are introduced into each cell of a 14 cell blister and said blister is placed in a lyophilizer. At the end of lyophilization, each blister cell contains a tablet having the following composition:

escitalopram oxalate 12.75 mg

D-mannitol 36.82 mg

gelatin 4.63 mg

Total weight: 54.20 mg

Each lyophilized tablet contains escitalopram oxalate corresponding to 10.0 mg of escitalopram base.

Example 3

(a) In 30 ml of 0.9% aqueous sodium chloride solution, 4.00 g of escitalopram oxalate are suspended, corresponding to 3.13 g of escitalopram base (escitalopram oxalate concentration: 133.333 mg / ml).

(b) To the suspension thus obtained are added 4 g of D-mannitol and 0.5 g of gelatin and subsequently a 0.9% aqueous solution of sodium chloride up to a weight of 42.2 g.

(c) 4.5 ml of 96% pure ethanol are added to the obtained mixture and the temperature is brought to 25 ° C, thus obtaining 44.89 ml of clear solution, in which the concentration of escitalopram oxalate is 89.686 mg / ml , having the following composition:

escitalopram oxalate 4000 mg

D-mannitol 4000 mg

gelatin 500 mg

Na <+> 145 mg

cr 230 mg

96% ethanol 4.5 ml

distilled water up to 44.8 ml

(d) From 3.99 ml of the solution obtained at the end of step (c), 0.285 ml of said solution are introduced into each cell of a 14-cell blister and said blister is placed in a lyophilizer. At the end of lyophilization, each blister cell contains a tablet having the following composition:

escitalopram oxalate 25.50 mg

D-mannitol 25.50 mg

gelatin 3.18 mg

NaCI 0.02 mg

Total weight: 54.20 mg

Each lyophilized tablet contains escitalopram oxalate corresponding to 20.0 mg of escitalopram base.

Example 4

(a) In 20 ml of 1.0% aqueous solution of magnesium chloride, 2.55 g of escitalopram oxalate are suspended (escitalopram oxalate concentration: 127.5 mg / ml).

(b) 3.8 g of D-mannitol and 0.48 g of gelatin and subsequently a 1.0% aqueous solution of magnesium chloride are added to the suspension thus obtained up to a volume of 27.2 ml.

(c) 4.5 ml of 96% pure ethanol are added to the mixture obtained and the temperature of the mixture is brought to 25 ° C, thus obtaining a clear solution, in which the concentration of escitalopram oxalate is 80.442 mg / ml, having the following composition: escitalopram oxalate 2550 mg

D-mannitol 3800 mg

gelatin 480 mg

Mg <++> 64 mg

CI 185 mg

96% ethanol 4.5 ml

distilled water up to 31.6 ml

(d) From 4.42 ml of the solution obtained at the end of step (c), 0.316 ml of said solution are introduced into each cell of a 14-cell blister and said blister is placed in a lyophilizer. At the end of lyophilization, each blister cell contains a tablet having the following composition:

escitalopram oxalate 25.50 mg

D-mannitol 38.00 mg

gelatin 4.42 mg

MgCl 20.02 mg

Total weight: 67.94 mg

Each lyophilized tablet contains escitalopram oxalate corresponding to 20.0 mg of escitalopram base.

Example 5

(a) 2.55 g of escitalopram oxalate are suspended in 20 ml of 1.0% aqueous solution of magnesium chloride (concentration of escitalopram oxalate: 127.5 mg / ml).

(b) To the suspension thus obtained are added 3.8 g of D-mannitol and 0.48 g of gelatin and subsequently a 1.0% aqueous solution of magnesium chloride up to a volume of 31.75 ml.

(c) The temperature of the mixture is brought to 25 ° C, thus obtaining a clear solution, in which the concentration of escitalopram oxalate is 80.315 mg / ml, having the following composition:

escitalopram oxalate 2550 mg

D-mannitol 3800 mg

gelatin 480 mg

Mg <++> 64 mg

cI 185 mg

distilled water up to 31.75 ml

(d) From 4.44 ml of the solution obtained at the end of step (c), 0.317 ml of said solution are introduced into each cell of a 14-cell blister and said blister is placed in a lyophilizer. At the end of lyophilization, each blister cell contains a tablet having the following composition:

escitalopram oxalate 25.50 mg

D-mannitol 38.00 mg

gelatin 4.42 mg

MgCl 20.02 mg

Total weight: 67.94 mg

Each lyophilized tablet contains escitalopram oxalate corresponding to 20.0 mg of escitalopram base.

Example 6

(a) In 20 ml of 1.0% aqueous solution of magnesium chloride, 2.55 g of escitalopram oxalate are suspended (escitalopram oxalate concentration: 127.5 mg / ml).

(b) To the suspension thus obtained are added 2.55 g of D-mannitol, 0.32 g of gelatin and 0.001 g of black cherry flavoring and subsequently an aqueous solution of 1.0% of magnesium chloride up to a volume of 31 , 92 mi.

(c) The temperature of the mixture is brought to 25 ° C, thus obtaining a clear solution, in which the concentration of escitalopram oxalate is 79.887 mg / ml, having the following composition:

escitalopram oxalate 2550 mg

D-mannitol 2550 mg

gelatin 320 mg

Mg <++> 64 mg

cI 185 mg

black cherry flavor <'> 1 mg

distilled water up to 31.92 ml

(d) From 4.47 ml of the solution obtained at the end of step (c), 0.319 ml of said solution are introduced into each cell of a 14-cell blister and said blister is placed in a lyophilizer. At the end of lyophilization, each blister cell contains a tablet having the following composition:

escitalopram oxalate 25.50 mg

D-mannitol 25.50 mg

gelatin 3.20 mg

MgCl 20.02 mg

black cherry flavoring 0.01 mg

Total weight: 54.23 mg

Each lyophilized tablet contains escitalopram oxalate corresponding to 20.0 mg of escitalopram base.

Example 7

(a) In 20 ml of 1.0% aqueous solution of magnesium chloride, 2.55 g of escitalopram oxalate are suspended (escitalopram oxalate concentration: 127.5 mg / ml).

(b) To the suspension thus obtained are added 2.55 g of D-mannitol and 0.32 g of gelatin and subsequently a 1.0% aqueous solution of magnesium chloride up to a volume of 31.92 ml.

(c) The temperature of the mixture is brought to 25 ° C, thus obtaining a clear solution, in which the concentration of escitalopram oxalate is 79.887 mg / ml, having the following composition:

escitalopram oxalate 2550 mg

D-mannitol 2550 mg

gelatin 320 mg

Mg <++> 64 mg

CI 185 mg

distilled water up to 31.92 ml

(d) From 4.47 ml of the solution obtained at the end of step (c), 0.319 ml of said solution are introduced into each cell of a 14-cell blister and said blister is placed in a lyophilizer. At the end of lyophilization, each blister cell contains a tablet having the following composition:

escitalopram oxalate 25.50 mg

D-mannitol 25.50 mg

gelatin 3.20 mg

MgCl 20.02 mg

Total weight: 54.22 mg

Each lyophilized tablet contains escitalopram oxalate corresponding to 20.0 mg of escitalopram base.

Claims (4)

CLAIMS 1. A lyophilized pharmaceutical composition comprising an effective amount of escitalopram oxalate in admixture with a pharmaceutical excipient. The composition of claim 1 consisting of a lyophilized tablet for sublingual use comprising an amount of escitalopram oxalate equivalent to an amount of escitalopram base from 5 mg to 20 mg. A composition according to any one of claims 1 and 2, wherein the excipients are D-mannitol and gelatin. 4. A composition according to any one of claims 1 to 3 also comprising sodium chloride or magnesium chloride.