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    • 专利摘要:
    An orodispersible formulation is described, free of polyalcohols and containing vardenafil or a pharmaceutically acceptable salt thereof as an active ingredient, comprising at least one filler, at least one buffering agent, at least one lubricant, at least one sweetener, at least one flavor and possibly further pharmaceutically acceptable excipients.
    公开号:CH716794A2
    申请号:CH01325/20
    申请日:2020-10-16
    公开日:2021-05-14
    发明作者:Stroppolo Federico；Granata Gabriele
    申请人:Alpex Pharma Sa；
    IPC主号:
    专利说明:

    [0001] The present invention relates to an orodispersible formulation (ODT) and more particularly an orodispersible formulation containing vardenafil or a pharmaceutically acceptable salt thereof as an active principle.
    [0002] Vardenafil, whose chemical name is 2- [2-ethoxy-5- (4-ethylpiperazin-1-yl) sulfonylphenyl] -5-methyl-7-propyl-1H-imidazo [5,1-f] [ 1,2,4] triazin-4-one, is a known active ingredient with PDE5 inhibitory activity used for the treatment of erectile dysfunction.
    [0003] ODT formulations of vardenafil are already known in the literature and available on the market. In particular, an ODT formulation containing vardenafil hydrochloride is marketed under the trade name of Staxyn <®> and Levitra <®> Soft.
    [0004] This formulation is described in US patent 8,613,950 (Bayer) and is particularly advantageous because, in addition to the known advantages of administration linked to the ODT formulations (such as ease of administration even for patients with swallowing difficulties, greater compliance, etc.), shows increased bioavailability of the active ingredient and a plateau-like plasma concentration profile.
    [0005] To obtain these advantageous characteristics it is however essential, as reported in US 8,613,950, that the formulation contains at least one polyalcohol, in particular mannitol, sorbitol or their mixtures. In fact, the commercial formulation contains a mixture of mannitol and sorbitol.
    [0006] We have now surprisingly found that the same advantageous bioavailability and plasma profile characteristics of vardenafil of the ODT formulations described in US 8,613,950, can be obtained with a polyalcohol-free ODT formulation.
    [0007] The object of the present invention is therefore an orodispersible formulation (ODT), free of polyalcohols and containing vardenafil or a pharmaceutically acceptable salt thereof as an active ingredient, comprising at least one filler, at least one buffering agent, at least one lubricant, at least one sweetener at least a flavor and optionally further pharmaceutically acceptable excipients.
    [0008] The formulations object of the present invention are herein defined as "orodispersible" in accordance with the European Pharmacopoeia (disintegration time <3 minutes). FDA guidelines, on the other hand, indicate the definition of "orally disintegrating tablet" (ODT) for solid oral formulations with a disintegration time of approximately 30 seconds or less. The formulations of the present invention can be indicated both as orodispersible formulations and as ODT formulations.
    [0009] Various salts of vardenafil are known in the literature both with inorganic acids (eg hydrochloride) and with organic acids (eg citrate). The formulations object of the present invention preferably contain vardenafil hydrochloride, even more preferably vardenafil monohydrochloride, generally used in its trihydrate form.
    [0010] Vardenafil or a pharmaceutically acceptable salt thereof is present in an amount ranging from 2% to 20% by weight, preferably from 5% to 10%.
    [0011] The quantity by weight of the active ingredient generally corresponds to a dose of free vardenafil base of 10 mg per dosage unit (tablet).
    [0012] The characteristic of the formulations object of the present invention is that of being free of sugar alcohols.
    [0013] In the present context, the term "sugar alcohols" is used in its definition commonly known to those skilled in the art, ie as referring to compounds of general formula HOCH2 (CHOH) nCH2OH derived from sugars. Among the most common sugar alcohols used as pharmaceutical excipients we can mention mannitol, sorbitol, inositol, xylitol, maltitol and lactitol.
    [0014] The formulation object of the present invention contains at least one filler, at least one buffering agent, at least one lubricant, at least one sweetener, at least one flavor and possibly further pharmaceutically acceptable excipients.
    Fillers are excipients used to increase the weight of the formulation so as to improve its workability. They are generally present in quantities greater than 50% by weight. The filler preferably used in the object formulation is trisodium citrate but other common fillers such as monosodium phosphate, disodium phosphate, trisodium phosphate, monosodium citrate and disodium citrate can also be used.
    [0016] Trisodium citrate is generally used in a weight ratio with respect to the active ingredient which varies between 1:10 and 1: 3 (ratio of active ingredient: trisodium citrate).
    [0017] Buffering agents are generally pairs of an organic or inorganic acid and a salt thereof which allow the pH to be kept within a certain range. Citric acid and its salts are among the most commonly used buffering agents in the pharmaceutical technique. In the present invention the citric acid / trisodium citrate mixture is preferably used.
    [0018] Trisodium citrate is used in large excess with respect to citric acid, thereby exercising both the function of filler and the function of basic component of the buffering agent.
    [0019] Preferably the weight ratio between citric acid and trisodium citrate varies in the range between 1: 3 and 1:15 (preferably 1: 7)
    [0020] Lubricants are excipients used to improve the workability of the formulations as they reduce the friction of the powder or granulate in the tablet press machines and therefore prevent their adhesion to the punches and to the walls of the mold.
    [0021] Common lubricants used in pharmaceutical technique are stearic acid and magnesium or calcium stearates, talc, paraffin, sodium lauryl sulfate, PEG of various molecular weight (PEG 300, 400, 600, 6000, 8000, etc.) and sodium benzoate .
    In the present context, soluble lubricants such as sodium lauryl sulfate, PEG and sodium benzoate are preferably used. Even more preferably sodium benzoate, PEG 6000 or mixtures thereof are used.
    [0023] Particularly preferred is a mixture of sodium benzoate and PEG 6000.
    In the formulation of the present invention the preferred amount of PEG 6000 is 3-20% by weight and the amount of sodium benzoate is 5-15% by weight.
    [0025] In the formulation object of the present invention there are also present small quantities of sweetener and aroma to improve the organoleptic characteristics.
    [0026] Preferred sweeteners are artificial sweeteners such as acesulfame potassium, aspartame, cyclamate, saccharin, sucralose, preferably sucralose.
    The amount of artificial sweetener is preferably in the range of 1% to 5% by weight of the formulation.
    Preferred flavors are mint flavor, aniseed flavor, licorice flavor, vanilla flavor and mixtures thereof. The flavors are used in an amount which is preferably in the range of 3% to 8% by weight of the formulation.
    The preferred flavor is the mint flavor in an amount of 4% to 5% by weight.
    [0030] In the formulation object of the present invention further excipients among those commonly used in the preparation of orodispersible formulations can be optionally added. By way of non-limiting example, such further excipients can be dyes, anti-adhesives, disintegrants, etc.
    [0031] The formulations object of the present invention are prepared according to conventional techniques such as dry mixing, wet granulation, dry granulation, etc.
    [0032] The formulations of the present invention are solid oral formulations, preferably tablets, which disintegrate rapidly in the mouth and ensure a bioavailability of the active ingredient equivalent to that of the reference product on the market (Staxyn <®> / Levitra <®>).
    [0033] In order to better illustrate the present invention, without however limiting it, the following examples are now given.
    EXAMPLE 1
    [0034] A formulation was prepared having the following composition: Vardenafil hydrochloride trihydrate (equivalent to 10 mg of vardenafil) 11.85 8.46 1.185 Trisodium citrate anhydrous 87.15 62.25 8.715 Citric acid 13.00 9.29 1.300 PEG 6000 8.5 6.07 0.850 Sodium benzoate powder 8.5 6.07 0.850 Sucralose 4.00 2.86 0.400 Peppermint flavor 7.00 5.00 0.700 TOTAL 140 100 14
    Anhydrous trisodium citrate, citric acid, PEG 6000, flavor and sucralose were placed in a cubic mixer and the mixture was mixed for about 10 minutes.
    Vardenafil hydrochloride trihydrate and sodium benzoate were then added and the mixture was mixed for an additional 10 minutes.
    [0037] The obtained mixture was then compressed in a rotary tablet press equipped with 7 mm diameter punches to prepare tablets weighing 140 mg.
    The tablets were chemically and physically analyzed and then individually packaged in an aluminum / aluminum blister.
    EXAMPLE 2
    A batch having the same composition as the batch described in Example 1 was prepared according to the following procedure.
    Anhydrous trisodium citrate, citric acid, PEG 6000, aroma and sucralose were placed in a fluidized bed ganulator. The mixture was granulated using about 1000 g of purified water and dried to a residual moisture content below 5%.
    The obtained granulate was then placed in a cubic mixer and vardenafil hydrochloride trihydrate and sodium benzoate were added. The mixture was mixed for 10 minutes.
    [0042] The obtained mixture was then compressed in a rotary tablet press equipped with 7 mm diameter punches to prepare tablets weighing 140 mg.
    The tablets were chemically and physically analyzed and then individually packaged in an aluminum / aluminum blister.
    EXAMPLE 3
    A batch having the same composition as the batch described in Example 1 was prepared according to the following procedure.
    Anhydrous trisodium citrate, citric acid, PEG 6000, flavor and sucralose were placed in a cubic mixer and the mixture was mixed for about 10 minutes.
    The mixture was then compacted into blocks of about 5 g each using a rotary tablet press. The blocks were crushed by means of an oscillating granulator equipped with a net with a net opening of about 1 mm in diameter and loaded into a cubic mixer.
    Vardenafil hydrochloride trihydrate and sodium benzoate were then added and the mixture was mixed for 10 minutes.
    [0048] The obtained mixture was then compressed in a rotary tablet press equipped with 7 mm diameter punches to prepare tablets weighing 140 mg.
    The tablets were chemically and physically analyzed and then individually packaged in an aluminum / aluminum blister.
    EXAMPLE 4
    [0050] Operating according to a procedure similar to that described in Example 1, a 20 kg lot and 200 mg tablets were prepared having the following composition: Vardenafil hydrochloride trihydrate (equivalent to 10 mg of vardenafil) 11.85 5.925 1.185 Trisodium anhydrous citrate 110.00 55.000 11.000 Citric acid 25.15 12.575 2.515 PEG 6000 30.0 15.000 3.000 Sodium benzoate powder 10.0 5.000 1.000 Sucralose 5.00 2.500 0.500 Peppermint flavor 8.00 4.000 0.800 TOTAL 200 100 20
    EXAMPLE 5
    [0051] Operating according to a procedure similar to that described in Example 2, a batch of 20 kg and tablets of 200 mg having the composition reported in Example 4 was prepared.
    EXAMPLE 6
    [0052] Operating according to a procedure similar to that described in Example 2, but compacting the mixture with a roller compactor, a batch of 20 kg and tablets of 200 mg having the composition reported in Example 4 were prepared.
    EXAMPLE 7
    [0053] The physical characteristics of the tablets according to the present invention were compared with those of the tablets marketed under the trade name Staxyn <®>, ie with the tablets described in US 8,613,950 (reference product). The values of the parameters measured and compared are shown in the following table: Diameter- mm 7 7 7 10 10 10 9 Weight - mg 140 140 140 200 200 200 180 Hardness - KP 2 3 2 2 3 2 2.6 Friability-% 1 1 1 1 1 1 1 Breakdown time - seconds 30 "30" 30 "30" 30 "30" 30 "
    [0054] The tablets of the invention have chemical-physical characteristics similar to those of the reference product.
    Furthermore, the tablets of the invention also show a bioavailability profile of the active ingredient equivalent to that of the reference product.
    权利要求:
    Claims (10)
    [1]
    1. An orodispersible formulation, free of polyalcohols and containing vardenafil or a pharmaceutically acceptable salt thereof as an active ingredient, comprising at least one filler, at least one buffering agent, at least one lubricant, at least one sweetener, at least one flavor and possibly further pharmaceutically acceptable excipients.
    [2]
    A formulation according to claim 1 wherein the active ingredient is vardenafil hydrochloride, preferably vardenafil monohydrochloride trihydrate.
    [3]
    A formulation according to claim 1 or 2 wherein vardenafil or a pharmaceutically acceptable salt thereof is present in an amount ranging from 2% to 20% by weight, preferably from 5% to 10%.
    [4]
    4. A formulation according to claim 1 wherein the filler is trisodium citrate, preferably used in a weight ratio with respect to the active ingredient ranging from 1:10 and 1: 3.
    [5]
    A formulation according to claim 1 wherein the buffering agent is a citric acid / trisodium citrate mixture used in a citric acid: trisodium citrate weight ratio of 1: 3 to 1:15.
    [6]
    A formulation according to claim 1 wherein the lubricant is sodium benzoate, PEG 6000 or mixtures thereof.
    [7]
    7. A formulation according to claim 6 wherein the lubricant is a mixture of sodium benzoate and PEG 6000, preferably a mixture of sodium benzoate and PEG 6000 in which the amount of PEG 6000 is 3-20% by weight of the formulation and the amount sodium benzoate is 5-15% by weight of the formulation.
    [8]
    A formulation according to claim 1 wherein the sweetener is sucralose, preferably in an amount in the range of 1% to 5% by weight of the formulation.
    [9]
    A formulation according to claim 1 wherein the aroma is selected from mint aroma, anise aroma, licorice aroma, vanilla aroma and mixtures thereof, preferably mint aroma in an amount in the range of 3% to 8% by weight of the formulation . The preferred flavor is the mint flavor in an amount of 4% to 5% by weight.
    [10]
    10. A formulation according to any one of the preceding claims in the form of a tablet.
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    IT201900020350|2019-11-05|
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