Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
  • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
  • A61K47/42—Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
  • A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/2004—Excipients; Inactive ingredients
  • A61K9/2013—Organic compounds, e.g. phospholipids, fats
  • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/2004—Excipients; Inactive ingredients
  • A61K9/2022—Organic macromolecular compounds
  • A61K9/2063—Proteins, e.g. gelatin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/2095—Tabletting processes

Definitions

• the present invention relates to lyophilized tablets of escitalopram oxalate for sublingual administration, in particular, to a process for the preparation thereof, to the use of said lyophilized tablets for sublingual administration, or anyway by instantaneous dissolution in the mouth cavity, comprising escitalopram oxalate as an active ingredient thereof.
• Escitalopram is the International Non-Proprietary Name of the (S)-1-[3-(dimethy
• the (S)-1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1 ,3-dihydro-5-isobenzofuran carbonitrile acid oxalate (1 :1 ), herein below referred to as escitalopram oxalate, is a selective serotonin reuptake inhibitor with central antidepressant activity.
• This product is described in US Re. 34,712 and EP 347.066 as crystallized from acetone. Methods for its preparation, by chemical or chemo-enzymatic route, have been described, for example in US 7,834,201 , US 2007/0129561 and US 201 1/0238887.
• Escitalopram oxalate is sparingly soluble in water and in ethanol. It is used in tablets and in drops. When in drops, escitalopram oxalate is dissolved in a water/96% ethanol mixture added with propyl gallate, citric acid, sodium hydroxide, containing escitalopram base in a concentration of 20 mg/ml.
• WO 2009/150665 discloses an oro-dispersible pharmaceutical composition
• escitalopram or salts thereof as active ingredient comprising excipients selected from the group consisting of cellulose derivatives, such as microcrystalline cellulose and the like, D-mannitol, lactose, dextrose, sorbitol, starch, xylitol, maltose, dicalcium phosphate and similar compounds; disintegrating agents and suitable pharmaceutical excipients.
• WO 2009/135649 discloses a granulate comprising escitalopram oxalate having a particle size of less than 100 ⁇ and at least one filler, including preferably disintegrants or disintegration accelerators customary used in the pharmaceutical field.
• IN 2006DE00964 discloses a solid dosage form of escitalopram, comprising escitalopram or pharmaceutically acceptable salts or solvates thereof, having a median particle size less than 20 ⁇ in admixture with one or more pharmaceutically acceptable excipients.
• Said solid dosage form is prepared by a process comprising blending of said escitalopram and said excipients ensuring uniform distribution of escitalopram. Further said solid dosage form is preferably prepared by a direct compression technique.
• IN 2007MU00470 discloses a pharmaceutical composition comprising escitalopram oxalate particles having a specific particle size distribution.
• this document describes a tablet composition containing escitalopram oxalate, microcrystalline cellulose, croscarmellose sodium, colloidal silica, talc, and magnesium stearate in the core formulation.
• US 2009/0048336 discloses the preparation of escitalopram oxalate powders having definite particle size distribution parameters.
• the document describes processes for the preparation of escitalopram oxalate in powder comprising (1 ) the obtainment of a solution of escitalopram base in an organic solvent; (2) the reaction with oxalic acid to produce escitalopram oxalate and cause its precipitation as a solid; (3) the isolation of the solid; and (4) the micronization of the solid to obtain escitalopram oxalate with defined particle size parameters.
• This document also discloses the preparation of compositions wherein the micronized particles are mixed with disintegrating agents.
• US Re 34,712 and EP 347066 disclose the preparation of the (+) isomer of citalopram, i.e. of the (+)-1-(3-dimethylaminopropyl)-1-(4'-fluorophenyl)-1.3-dihydroisobenzofuran-5- carbonitrile (escitalopram base), and points out that its oxalate crystallized from acetone.
• WO 2008/046617 discloses escitalopram or pharmaceutically acceptable salt and/or solvate thereof, including the oxalate, in the form of particles having a median particle size of less than 40 ⁇ and wherein the ratio between the median particle size and the particle size at the 95% quantile is equal to or greater than 0.42.
• said escitalopram may be in amorphous or crystalline form, preferably it is in the form of crystalline particles used for direct compression and is included in pharmaceutical compositions which may comprise excipients.
• WO 2006/123243 discloses the preparation of pharmaceutical dosage form comprising the steps (i) mixing escitalopram oxalate with one or more excipients, (ii) granulating the blend obtained in step (i) using solvent and optionally a binder, (iii) drying the granules obtained in step (ii), (iv) mixing the granules of step (iii) with one or more pharmaceutically acceptable excipients, (v) lubricating the mixture of step (iv) and (vi) compressing the blend of step (v) into tablets.
• the excipients include disintegrating agents.
• the literature does not disclose escitalopram oxalate lyophilized tablets obtainable from escitalopram oxalate aqueous solution wherein said escitalopram oxalate is dissolved at concentrations of at least 30 mg/ml and wherein common carriers are also dissolved.
• escitalopram oxalate may be dissoved in water at a concentration of at least 30 mg/ml up to 1 15 mg/ml, advantageously from 50 mg/ml to 115 mg/ml, preferably from 60 mg/ml to 115 mg/ml.
• escitalopram oxalate dissolves in water at the above concentrations in admixture with common pharmaceutical excipients or carriers.
• escitalopram oxalate has been dissolved in water by mixing said escitalopram oxalate with two common carriers, D-mannitol and gelatin in appropriate proportions, in order to obtain clear aqueous solutions which are sufficiently stable to allow a subsequent freeze drying.
• D-mannitol and gelatin escitalopram oxalate is present from 30% to 50% by weight, D-mannitol is from 45% to 75% by weight and gelatin is from 4% to 10% by weight.
• said solution may contain ethanol and/or a salt selected from the group consisting of sodium chloride and magnesium chloride.
• a salt selected from the group consisting of sodium chloride and magnesium chloride may also be contained in said solution.
• the invention provides orosoluble, lyophilized tablets comprising escitalopram oxalate, D-mannitol, gelatin and, optionally, a salt selected from the group consisting of sodium chloride and magnesium chloride.
• Said lyophilized tablets may also contain one or more adjuvants selected from the group consisting of preservative, flavoring and dying agents.
• the invention also provides an escitalopram oxalate aqueous solution for pharmaceutical use comprising said escitalopram oxalate at a concentration of from 30 mg/ml to 115 mg/ml.
• An aqueous solution containing escitalopram oxalate at so high concentrations allows the preparation of lyophilized compositions containing an effective amount of said escitalopram oxalate per unit form, in particular corresponding to 5 mg to 20 mg of base.
• said solution contains escitalopram oxalate, D-mannitol and gelatin, escitalopram oxalate being dissolved at a concentration of at least 30 mg/ml, advantageously from 50 mg/ml to 1 15 mg/ml, preferably from 60 mg/ml to 1 15 mg/ml.
• the present invention provides escitalopram oxalate lyophilized tablets for pharmaceutical use comprising escitalopram oxalate, D-mannitol, gelatin and, optionally, a salt selected from the group consisting of sodium chloride and magnesium chloride.
• the present invention provides escitalopram oxalate lyophilized tablets comprising from 6 mg to 26 mg of escitalopram oxalate, from 24 mg to 41 mg of D- mannitol and from 2.17 mg to 5.6 mg of gelatin.
• said lyophilized tablets comprise escitalopram oxalate, in an amount of 12.75 mg; D-mannitol, in an amount of from 27 mg to 41 mg; and gelatin, in an amount of from 3.8 mg to 5.6 mg.
• escitalopram oxalate in an amount of 25.5 mg
• D-mannitol in an amount of from 24 mg to 41 mg
• gelatin in an amount of from 2.17 mg to 4.34 mg.
• the present invention also provides a process for the preparation of the aforesaid escitalopram oxalate lyophilized tablets which comprises:
• step (d) pouring a volume of the solution coming from step (c), containing a calculated amount of escitalopram oxalate, into the open cavity of a multi-cavity blister and submitting said blister to freeze drying.
• the water used in step (a) may contain a salt selected from the group consisting of sodium chloride and magnesium chloride, dissolved therein at a concentration of from 0.9% to 1 %.
• the content of escitalopram oxalate is from 30 mg/ml to 115 mg/ml.
• a calculated amount of escitalopram oxalate is suspended in a volume of water, optionally containing 0.9%-1 % of sodium or magnesium chloride, sufficient for the desired concentration.
• step (b) D-mannitol, in an amount of from 90% to 210% of said amount of said escitalopram oxalate, and gelatin, in an amount of from 10% to 45% of said amount of said escitalopram oxalate, are added to the suspension obtained at the end of step (a).
• step (c) distilled water, optionally containing 0.9%-1 % sodium or magnesium chloride, or ethanol is added to the suspension of step (b) in order to obtain an escitalopram oxalate concentration of from 30 mg/ml to 115 mg/ml, preferably more than 30 mg/ml to 115 mg/ml and the temperature of the mixture is set at 20-30'C, preferably at 23-27'C, whereby a clear solution is obtained.
• the suspension obtained at the end of step (b) is added with distilled water, or with a 0.9-1 % aqueous solution of a salt selected from the group consisting of sodium chloride or magnesium chloride, or with ethanol.
• the solution may contain one or more adjuvants selected from the group consisting of preservative agents to improve the stability of the composition, flavoring and dying agents 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 salts thereof, may be present in a total amount of from 0.01 % to 0.3% w/v.
• the flavoring agents are pharmaceutically acceptable flavors, tastes of synthetic and natural oils, the latter extracted from plants, leaves, flowers, fruits and their combinations, such as cinnamon, peppermint, anise and citron leaves, bitter almond, citrus fruits, in particular orange and/or lemon, linden and grapefruit oils.
• chocolate, vanilla or eucalyptus flavor and essences of fruit, in particular apple, pear, peach, strawberry, cherry, apricot, orange, lemon and grapes may be advantageously used.
• a flavoring agent may be generally present at a concentration of from 0.1 % to 0.25%.
• Dyes may be present in an amount of 0.01%-0.02%.
• the above adjuvants are added in step (b) or (c).
• step (d) the solution obtained at the end of step (c) is freeze dried in order to directly obtain tablets for sublingual administration.
• An escitalopram oxalate aqueous solution for pharmaceutical use comprising said escitalopram oxalate at a concentration of from 30 mg/ml to 1 15 mg/ml is a useful starting material for step (d).
• An aqueous solution containing escitalopram oxalate at so high concentrations allows the preparation of pharmaceutical compositions containing an effective amount of said escitalopram oxalate, in particular an amount corresponding to 5 mg, 10 mg or 20 mg of escitalopram base per unit form.
• 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 1 15 mg/ml, preferably from 35 mg/ml to 95 mg/ml.
• escitalopram oxalate, D-mannitol and gelatin are present in the solution in an amount by weight in the ratios 1/from 0.9 to 2.2/from 0.04 to 0.1.
• advantageous starting aqueous solutions comprise, as an active ingredient thereof, an effective amount by weight of escitalopram oxalate at a concentration of at least 25 mg/ml, advantageously from 30 mg/ml to 1 15 mg/ml, preferably from 35 mg/ml to 95 mg/ml, and further comprises D-mannitol, gelatin, in the above respective ratios, in respect of escitalopram oxalate and, optionally, ethanol, sodium chloride at a concentration of 0.9%-1 % or magnesium chloride at a concentration of 0.9%-1 %.
• the amount of D-mannitol is from 90% to 210% the amount of escitalopram oxalate, while the amount of gelatin may vary from 10% to 45% of said amount of escitalopram oxalate.
• the ingredients dissolved in the solution obtained at the end of step (c) are present in the following percentage: escitalopram oxalate, from 30% to 50% by weight; D- mannitol, from 45% to 70% by weight; and gelatin, from 4% to 10% by weight.
• Advantageous aqueous solutions comprise, in percentage by weight, from 30% to 50% escitalopram oxalate, from 50% to 70% D-mannitol, and from 4% to 10% gelatin.
• each cavity of the blister contains a lyophilized tablet comprising as an active ingredient thereof, an effective amount of escitalopram oxalate, said effective amount corresponding to 5 mg to 20 mg of escitalopram base, preferably being 12.75 mg or 25.5 mg, corresponding to 10 mg and 20 mg, respectively, of escitalopram base, in admixture with D-mannitol, gelatin and, optionally, sodium chloride or magnesium chloride. If one or more of the above-mentioned adjuvants were present in the solution obtained at the end of step (c), these adjuvants are also present in the lyophilized tablet.
• Said adjuvant are selected from the group consisting of preservative, flavoring and dying agents.
• the aliquots of the solution obtained at the end of step (c), which are introduced in each open cavity of a multi-cavity blister comprise a therapeutically effective amount of escitalopram oxalate, the calculated amounts of D-mannitol, and gelatin according to the above-mentioned ratios and, optionally, sodium chloride or magnesium chloride in the aforesaid percent range.
• said aliquots of the used solution contain from 6 mg to 26 mg escitalopram oxalate; from 24 mg to 41 mg of D-mannitol; from 2.17 to 5.6 mg of gelatin, and, optionally, a salt selected from the group consisting of sodium chloride and magnesium chloride, in an amount of from 0.01 mg to 0.03 mg.
• a lyophilized tablet comprising escitalopram oxalate, D-mannitol and gelatin in the above amount ranges is obtained.
• escitalopram oxalate being in an amount of 12.75 mg, corresponding to 10 mg of escitalopram base, D- mannitol being in an amount of from 36 to 38 mg, up to 41 mg, and gelatin being in an amount of from 3.8 to 5.6 mg, at the end of the freeze drying lyophilized tablets comprising 12.75 mg of escitalopram oxalate are obtained.
• Said lyophilized tablets which may contain one or more members selected from the group consisting of antioxidant, preservative and flavoring agents, are a preferred embodiment of the present invention.
• step (c) by using, as advantageous solutions obtained at the end of step (c), those comprising, in percentage by weight, from 30% to 50%, from 45% to 70% and from 4% to 10% of escitalopram oxalate, D-mannitol and gelatin respectively, said escitalopram oxalate being in an amount of 25.5 mg, corresponding to 20 mg of escitalopram base, D-mannitol being in an amount of from 24 to 26 mg, up to 41 mg, and gelatin being in an amount of from 2.17 to 3.34 mg, up to 4.5, lyophilized tablets are obtained at the end of the freeze drying. These lyophilized tablets represent another preferred embodiment of the present invention.
• the tablet of the present invention when put on or under the tongue, instantaneously dissolves and the escitalopram oxalate is absorbed without the presence of any disintegrating agent.
• the present invention provides an aqueous solution for pharmaceutical use comprising an effective amount by weight of (S)-1-(4-fluorophenyl)-1 ,3-dihydro-5-isobenzo furancarbonitrile oxalate at a concentration of from 30 mg/ml to 115 mg/ml, advantageously of from 50 mg/ml to 115 mg/ml, preferably from 60 mg/ml to 115 mg/ml; D-mannitol in an amount by weight of from 90% to 210% the amount of escitalopram oxalate; and gelatin in an amount by weight of from 10% to 45% of the amount of escitalopram oxalate; and, optionally, ethanol in un amount by volume of 8-10% of the total volume of the solution.
• the following examples illustrate the invention.
• each cavity of the blister contained a tablet having the following composition:
• Each lyophilized tablet contained an amount of escitalopram oxalate equivalent to 20.0 mg of escitalopram base.
• each cavity of the blister contained a tablet having the following composition:
• Each lyophilized tablet contained an amount of escitalopram oxalate equivalent to 10.0 mg of escitalopram base.
• each cavity of the blister contained a tablet having the following composition:
• Each lyophilized tablet contained an amount of escitalopram oxalate equivalent to
• each cavity of the blister contained a tablet having the following composition:
• Each lyophilized tablet contained an amount of escitalopram oxalate equivalent to 20.0 mg of escitalopram base.
• each cavity of the blister contained a tablet having the following composition:
• Each lyophilized tablet contained an amount of escitalopram oxalate equivalent to 20.0 mg of escitalopram base.
• each cavity of the blister contained a tablet having the following composition:
• Each lyophilized tablet contained an amount of escitalopram oxalate equivalent to 20.0 mg of escitalopram base.
• each cavity of the blister contained a tablet having the following composition:
• Each lyophilized tablet contained an amount of escitalopram oxalate equivalent to 20.0 mg of escitalopram base.

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• 2012
  • 2012-03-22 IT IT000448A patent/ITMI20120448A1/it unknown
• 2013
  • 2013-01-30 WO PCT/IT2013/000028 patent/WO2013114416A1/fr not_active Ceased

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