ITMI20120106A1 - LIOFILIZED PADS OF ESCITALOPRAM OXALATE FOR SUBLINGUAL ADMINISTRATION - Google Patents

Description

LYOPHYLIZED OXALATED ESCITALOPRAM TABLETS FOR SUBLINGUAL ADMINISTRATION

FIELD OF INVENTION

The present invention relates 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 Common Name of (S) -1- [3- (dimethylamino) propyl] -1- (4-fluorophenyl) -1,3-dihydro-5-isobenzofurancarbonitrile.

The acid oxalate (1: 1) of (S) -1- [3- (dimethylamino) propyl] -1- (4-fluorophenyl) -1,3-dihydro-5-iso benzofurancarbonitrile, 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

In order to favor the absorption of escitalopram by the body in the best way, technologies for the micronization of particles and / or improvement of the breakdown of the granules and particles of escitalopram 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, 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.) describes a solid dosage form of escitalopram comprising escitalopram or pharmaceutically acceptable salts or solvates thereof having an average particle size of less than 20 Î1⁄4 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 (Kolla 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 isolation of the solid; and (4) micronization of the solid to obtain escitalopramoxalate 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 below 40 µm and in which the ratio between the average particle size and the particle size 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) described the preparation of a pharmaceutical dosage form comprising the steps: (i) mixing 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) into 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 admixture 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% in weight, D-mannitol from 45% to 75% by weight and gelatin from 4% to 19% by weight. Other agents are generally not needed to dissolve escitalopram oxalate, although a small amount of pure ethanol can be used. In addition, said solution may 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 freeze-drying process, substrate concentrations are required which, in the case of escitalopram oxalate, they were not known before now.

Thus, the invention provides lyophilized tablets comprising escitalopram oxalate, 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, flavorings and dyes.

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

DETAILED DESCRIPTION

Thus, the present invention provides lyophilized tablets of escitalopram oxalate comprising escitalopram oxalate, mannitol, gelatin and, optionally, 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 ossalate in a volume of water to obtain a suspension containing said escitalopram oxalate in a quantity ranging 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 a quantity by weight of from 10% to 45% of the quantity 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 obtaining a clear solution; And

(d) pour a volume of the solution from step (c), containing a calculated amount of escitalopram oxalate into each of the blisters of a multi-cell blister and lyophilize said blister.

According to one way of proceeding, 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 from 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 quantities from 90% to 210% of said quantity of escitalopram oxalate and gelatin, in quantities from 10% to 45% of said amount of escitalopram oxalate.

In step (c), distilled water, possibly containing 0.9% -1% sodium or magnesium chloride, or ethanol is added to the suspension of step (b) 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 formed by preserving agents in order to improve the stability of the composition, flavorings 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 quantities 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 30 mg / ml to 115 mg / ml is a starting material for step (d). An aqueous solution containing escitalopram oxalate at such high concentrations allows the preparation of pharmaceutical compositions comprising 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, 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, 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 also include 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 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, !! content by weight of escitalopram oxalate, 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 freeze-dried tablets, are introduced into the open pocket of a multi-cell blister and said blister à It 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, 12.75 or 25.5 mg corresponding respectively to 10 mg and 20 mg of escitalopram base, mixed with 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, flavorings 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, mannitol and gelatin, called 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 38 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% 8%, respectively of escitalopram oxalate, mannitol and gelatin , said escitalopram oxalate being in a quantity 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 a quantity of 3.8 and 5.6 mg and tablets in which escitalopram oxalate is present in a quantity of 25.5 mg; D-mannitol is present in an amount from 24 to 26 mg; and gelatin is present in an amount from 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 amounts 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) In 20 ml of distilled water, 2.55 g of escitalopram oxalate are suspended.

(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 a volume of 5.15 ml of the solution obtained at the end of step (c), 0.368 ml of said solution was introduced into each cell of a 14 cell blister and said blister was subjected to lyophilization. At the end of the lyophilization, each blister cell contained 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 contained 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 suspension 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 a volume of 5.15 ml of the solution obtained at the end of step (c), 0.368 ml of said solution was introduced into each cell of a 14 cell blister and said blister was subjected to lyophilization. At the end of lyophilization, each blister cell

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 contained escitalopram oxalate corresponding to 10.0 mg of escitalopram base.

Example 3

(a) In 30 ml of 0.9% sodium chloride aqueous 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 mixture obtained 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

ethanol 96% 4.5 ml

distilled water up to 44.8 ml

(d) From a volume of 3.99 ml of the solution obtained at the end of step (c), 0.285 ml of said solution was introduced into each cell of a 14-cell blister and said blister was subjected to lyophilization. At the end of the lyophilization, each blister cell contained 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 contained 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) 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 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 a volume of 4.42 ml of the solution obtained at the end of step (c), 0.357 ml of said solution was introduced into each cell of a 14 cell blister and said blister was subjected to lyophilization. At the end of the lyophilization, each blister cell contained 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 contained escitalopram oxalate corresponding to 20.0 mg of escitalopram base.

Claims (13)

CLAIMS 1. A lyophilized tablet for sublingual administration comprising an effective amount of (S) -1- [3- (dimethylamino) propylJ-1 - (4-fluorophenyl) -1, 3-dihydro-5-isobenzofurancarbonitrile oxalate (escitalopram oxalate), D-mannitol, in an amount by weight from 90% to 210% of the amount of escitalopram oxalate; and gelatin, in a quantity by weight of from 10% to 45% of the quantity of escitalopram oxalate. The tablet of claim 1 wherein the content by weight of escitalopram oxalate, mannitol, and gelatin is respectively from 20% to 50%, from 45% to 70% and from 4% to 10%. The tablet of any one of claims 1 and 2, also comprising a salt selected from the group formed by sodium chloride and magnesium chloride, in an amount from 0.02% to 0.04%. The tablet of any one of claims 1 to 3, also comprising one or more members of the group formed by preserving, antioxidant, flavoring and coloring agents. The tablet of any one of claims 1 to 4, wherein said effective amount of escitalopram oxalate is equivalent to 10 mg or 20 mg of escitalopram base. The tablet of any one of claims 1 to 5, wherein the escitalopram oxalate is in an amount of 12 mg to 26 mg; mannitol is in an amount from 24 mg to 27 mg; and the gelatin is in an amount from 2.17 mg to 5.6 mg. The tablet according to claim 6, wherein the amount of escitalopram oxalate is in an amount of 12.75 mg; mannitol is in an amount from 27 mg to 38 mg; and the gelatin is in an amount from 3.8 mg to 5.6 mg. The tablet according to claim 6, wherein the amount of escitalopram oxalate is in an amount of 25.5 mg; mannitol is in an amount from 24 mg to 26.7 mg; and the gelatin is in an amount from 2.17 mg to 4.34 mg. The tablet of any one of claims 6 to 8, also comprising a salt selected from the group formed by sodium chloride and magnesium chloride, in an amount from 0.01 mg to 0.03 mg. 10. Process for the preparation of lyophilized tablets of escitalopram oxalate, which includes: (a) suspending a quantity by weight of said escitalopram oxalate in a volume of water to obtain a suspension containing said escitalopram oxalate in a quantity ranging 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 a quantity by weight of from 10% to 45% of the quantity 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) pour a volume of the solution from step (c), containing a calculated amount of escitalopram oxalate into each of the alveoli of a multialveolar blister and lyophilize said blister. 11. The process of claim 10 wherein, in step (a) the water used also comprises a salt selected from the group formed by sodium chloride and magnesium chloride, at a concentration of 0.9 to 1%. 12. The process of claim 10 wherein one or more additives selected from the group consisting of preservative, flavoring and coloring agents is added in step (b) or (c). 13. The process of claim 10 wherein the starting concentration of escitalopram oxalate in step (a) is from 30 to 115 mg / ml. Va â € ̃r d