EP2429528A2

EP2429528A2 - Orodispersible tablet containing a vardenafil salt

Info

Publication number: EP2429528A2
Application number: EP10721683A
Authority: EP
Inventors: Ralph Stefan; Sandra Brueck
Original assignee: Ratiopharm GmbH
Current assignee: Ratiopharm GmbH
Priority date: 2009-05-12
Filing date: 2010-05-10
Publication date: 2012-03-21
Also published as: WO2010130393A3; DE102009020888A1; WO2010130393A2

Abstract

The invention relates to a method for producing orodispersible tablets containing a pharmaceutically acceptable salt of vardenafil, said method comprising the following steps: (i) production of a mixture containing a pharmaceutically acceptable vardenafil salt, a mucilaginous substance, a sweetener and a flavouring; and (ii) direct compression of the mixture to form orodispersible tablets. The invention also relates to tablets that can be obtained according to said method.

Description

Orodispersible tablet containing a vardenafil salt

The invention relates to a method of producing orodispersible tablets containing a pharmaceutically acceptable salt of vardenafil comprising the steps of (i) preparing a mixture containing pharmaceutically acceptable vardenafil salt, mucilage, sweetening, flavoring agents, and (U) directly compressing the mixture into orodispersible tablets. The invention likewise relates to tablets obtainable by the process according to the invention.

The IUPAC name of vardenafil [INN] is 2-ethoxy-5 - [(4-ethyl-1-piperazinyl) sulfonyl] phenyl} -5-methyl-7-propylimidazo [5, l -f] [l, 2, 4] triazin-4 (3H) -one. The chemical structure of vardenafil is shown in formula (1) below:

(1) Vardenafil

Vardenafil is a potent selective inhibitor of cGMP-specific phosphodiesterase type 5 (PDE-5), which is responsible for the reduction of cGMP in the corpus cavernosum. Vardenafil is sold under the trade name Levitra ^® for the treatment of erectile dysfunction. The production of vardenafil has been described in WO 99/24433.

Various formulations for PDE-5 inhibitors are proposed in the prior art. WO 2007/02125 describes sublingual tablets containing PDE-5 inhibitors, such as vardenafil or vardenafil salts. However, the tablets prepared in the examples have a bitter taste which is unacceptable to the patient.

In addition, in WO 2006/092222, orally disintegrating tablets containing vardenafil or salts thereof with low bioavailability have been proposed. To achieve this low bioavailability, had to be incorporated by means of elaborate compacting into the tablet in the case of vardenafil salts large amounts of Eudragit ^®. The resulting tablets therefore showed an undesirable Size. In addition, it has been found that with regard to the desired pharmacokinetic properties (eg avoidance of too rapid a drop in the plasma concentration after administration) administration forms with low bioavailability are undesirable, see page 1 of WO 2006/92207. Therefore, in WO 2006/092207, orally disintegrating tablets having high bioavailability are proposed. However, it has been found that formulations according to WO 2006/092207, in particular when using vardenafil salts, have an undesirably unpleasant taste. Furthermore, it has been found that the formulations proposed in WO 2006/092207 and WO 2006/092222 are problematic in terms of storage stability.

In summary, it should be noted that the formulations proposed in the prior art have disadvantages. The object of the invention was therefore to overcome these disadvantages.

In particular, it was an object of the present invention to provide an oral dosage form with a short disintegration time in the mouth and a process for its preparation. The oral dosage form should be producible with variable active ingredient content. The total weight of the tablets should be low. The use of the free vardenafil base should be avoided.

In particular, it was an object of the present invention to provide an oral dosage form which results in an advantageous pharmacokinetic profile in vivo.

Further, it was an object of the invention to provide an oral dosage form which is pleasant to the patient, e.g. a dosage form that achieves acceptable taste in the patient (i.e., the patient should not experience a bitter taste). The patient should not feel the dosage form unpleasantly in the mouth.

The acceptable taste should also be made possible with a sugar-free formulation.

Furthermore, it was an object of the invention to provide the oral dosage form in a form that ensures an advantageous storage stability.

Finally, the abovementioned objects are to be achieved in a high space-time yield by means of a technically simple (and thus cost-effective) process. The objects could be achieved by producing a orodispersible tablet containing a pharmaceutically acceptable salt of vardenafil, a mucilage and other pharmaceutical excipients by direct compression.

The invention therefore relates to a process for the preparation of orodispersible tablets containing a pharmaceutically acceptable salt of vardenafil comprising the steps

(i) preparing a mixture comprising (a) pharmaceutically acceptable vardenafil salt,

(b) optionally mucilage,

(c) sweeteners,

(d) flavoring agents, and

(ii) direct compression of the mixture into orodispersible tablets.

The invention further relates to tablets obtainable by the process according to the invention.

Finally, the invention relates to the use of a film which has a water vapor permeability of less than 0.50 g / m ² d, for packaging a fused tablet containing a medicament for the treatment of erectile dysfunction, in particular for packaging the fused tablet according to the invention.

As explained above, the present invention relates to a fused tablet. In the context of this invention, the term "orodispersible tablet" is understood to mean an orodispersible tablet as defined in the European Pharmacopoeia, 6th edition, Grundwerk 2008. Thus, an orodispersible tablet is an oral tablet disintegrating in the oral cavity. The orodispersible tablet is an uncoated tablet, ie the tablet is uncoated or unfilmed.

According to Ph. Eur. 6th edition, orodispersible tablets must disintegrate within 3 minutes. In the context of this invention it is preferred that the orodispersible tablets according to the invention have a disintegration time of less than 60 seconds, more preferably less than 30 seconds, in particular of less than 20 seconds in the mouth.

The disintegration time is determined in accordance with Ph. Eur. 6th edition of Chapter 2.9.1 Test A. If the average disintegration time is referred to in this application, this is to be understood as the average of the disintegration time determination of 10 tablets. The orodispersible tablets according to the invention usually have a total weight of less than 750 mg, more preferably less than 500 mg, in particular less than 300 mg. Usually, the orodispersible tablets according to the invention have a weight of more than 50 mg, preferably 100 mg or more, in particular more than 150 mg.

The weight ratio of active ingredient to excipients in the melt tablets according to the invention is usually 4: 1 to 1: 5, preferably from 2: 1 to 1: 3, in particular 1: 1 to 1: 2.

The orodispersible tablets according to the invention are therefore clearly distinguishable from so-called "chewable tablets", since these usually have a higher weight (about 1.5 to 3 g) and a longer disintegration time.

The orodispersible tablets according to the invention usually have a hardness of from 25 to 80 N, preferably from 35 to 70 N, more preferably from 40 to 65 N, in particular from 45 to 60 N, on. The hardness is usually determined according to Ph. Eur., 6th edition, chapter 2.9.8. If reference is made in this application to the average hardness, this is to be understood as the mean value from the hardness determination of 10 tablets.

In addition, the resulting tablets preferably have a friability of less than 5%, particularly preferably less than 3%, in particular less than 1%. The friability is determined according to Ph. Eur. 6.0, section 2.9.7.

The orodispersible tablet according to the invention contains as component (a) a pharmaceutically acceptable vardenafil salt.

Examples of pharmaceutically acceptable salts are ammonium salts, hydrochlorides, carbonates, bicarbonates, acetates, lac tates, butyrates, propionates, sulfates, methanesulfonates, citrates, tartrates, nitrates, sulfonates, oxalates and / or succinates. In addition, solvates or hydrates of the abovementioned salts can be used as component (a).

Preferably used is vardenafil hydrochloride. In particular, vardenafil hydrochloride is used in the form of the trihydrate. Vardenafil hydrochloride in the form of the trihydrate is preferably prepared according to WO 2008/15181 1 A2.

The orodispersible tablets according to the invention usually comprise component (a) in a proportion of from 1 to 60% by weight, preferably from 2 to 25% by weight, in particular from 5 to

20 wt .-%, based on the total weight of the orodispersible tablet. Furthermore, the orodispersible tablets according to the invention usually contain component (a) in an amount from 2 to 50 mg, more preferably from 5 to 20 mg. In particular, the orodispersible tablets according to the invention contain 5 mg, 10 mg or 20 mg of component (a), based on the content of vardenafil base. For example, 11, 85 mg vardenafil hydrochloride trihydrate corresponds to 10 mg vardenafil base.

The orodispersible tablets according to the invention preferably comprise one (or more) mucilages as component (b). In the context of this invention, mucilages are usually understood to mean substances which are e.g. reduce the contact of drugs with the papillae by increasing the viscosity or by wrapping. This usually achieves a reduction in the intensity of the taste sensation.

In one possible embodiment, as component (b), substances are selected which are in the form of a 2% by weight solution or mixture in distilled water to a viscosity of more than 2 mPa / s, preferably more than 4 mPa / s, in particular more as 6 mPa / s, measured at 25 ⁰ C, determined according to Ph. Eur., 6th edition, chapter 2.2.10.

As mucilages (b), natural substances or synthetic substances (e.g., swellable polymers) can be used.

Examples of (natural) mucilages (b) are agar, alginic acid, alginate, chicle, carrageenan, dammar, marshmallow extracts, gellan (E 418), guar gum (E 412), gum arabic (E 414), maple gum gum, spruce sap , Locust bean gum E 410), karaya (E 416), konjac flour (E 425), extracted from the konjac root, tara gum (E 417), tragacanth (E 413), xanthan gum (E 415), preferably produced by bacterial fermentation, guar gum, starch, in particular gelatinized maize starch (eg available as starch 1500 ^®) and / or lecithin.

In addition to the natural mucilages mentioned above, synthetic mucilage may also be used. Preferably, polymeric synthetic gums are used. Polymer here is to be understood as meaning a substance having two or more repeating monomer units.

The polymeric mucilages optionally have hydrophilic groups. Examples of suitable hydrophilic groups are hydroxy, amino, ester, carboxylic acid or carboxylate. The polymers used as slurries (b) preferably have ester groups or ester and amino groups. Further, the polymeric gums (b) preferably have a weight average molecular weight of from 1000 to 10 ⁸ g / mol, more preferably from 10,000 to 10 ⁶ g / mol.

The polymeric gums (b) are preferably crosslinked. The polymer (b) in this case preferably has a crosslinking degree of from 0.01 to 10%, especially from 0.1 to 5%. (Degree of crosslinking = number of carbon atoms that are more than one chain / total number of carbon atoms in the polymer chain).

In a preferred embodiment, a "water-swellable polymer" is used as the gum (b). By "swellable" it is meant here that the polymer is capable of accumulating or storing water molecules on contact with water, preferably the weight ratio of polymer dehydrated to polymer swollen at 1: 1, 1 to 1: 100, more preferably 1: 2 to 1: 20.

An example of a preferred polymeric mucilage is polyvinylpyrrolidone, insbesonderes crosslinked polyvinylpyrrolidone (for example available as Kollidon ^® CL).

In a preferred embodiment, a polymer having a pH-dependent solubility is used as the gum (b). Preferably, the polymer (b) is not water-soluble in an aqueous solution having a pH of greater than 4.5, 5.0 or 5.5. Preferably, the polymer (b) is water-soluble in an aqueous solution having a pH of less than 4.5, 5.0 or 5.5. "Non-water-soluble" here means a solubility of 10 mg / 1 or less (determined according to column elution method according to EU Directive RL67-548-EEC, Annex V, Chapter A6).

Carrageenan (especially according to Ph.Eur.) Or an acrylic polymer is particularly preferably used as component (b).

Preferred acrylic polymers are e.g. Polyacrylates, polymethacrylates and their derivatives and mixtures or copolymers thereof. The polyacrylates used preferably have the aforementioned parameters (e.g., Mw, solubility, etc.).

In a preferred embodiment, the acrylic polymer (b) is a polymer composed of structures represented by the general formulas (2) and (3).

In the formulas (2) and (3), R _{1 represents} a hydrogen atom or an alkyl group, preferably a hydrogen atom or a

Methyl radical, in particular a methyl radical;

R _{2 is} a hydrogen atom or an alkyl radical, preferably a hydrogen atom or a C ₁ to C ₄ alkyl radical, in particular a methyl radical, ethyl radical or butyl;

R _{3 is} a hydrogen atom or an alkyl radical, preferably a hydrogen atom or a methyl radical;

R _{4 is} an organic radical, preferably a carboxylic acid group or a derivative thereof, more preferably a group of the formula -COOH, -COOR ₅ ,

R _{5 is} an alkyl radical or a substituted alkyl radical, preferably methyl, ethyl, propyl or

Butyl as an alkyl radical or -CH ₂ -CH ₂ -N (CH ₃ J ₂ or -CH ₂ -CH ₂ -N (CH ₃ J ₃ ⁺ halogen ^" (in particular Cl ^" ) as a substituted alkyl radical.

The acrylic polymer (b) contains structures according to the formulas (2) and (3) usually in molar ratios of 1:40 to 40: 1. The ratio of structures according to formula (2) to structures according to formula (3) 2 is preferably: 1 to 1: 1, in particular 1: 1. If R _{4 is} -COO-CH ₂ -CH ₂ -N (CH ₃ J ₃ ⁺ Cr, the ratio of structures of the formula (2) to structures of the formula (3) is preferred 20: 1 to 40: 1.

If an alternating polymerization in the ratio of 1 1, preferably results in a polymer according to the formula (2 + 3)

Particular preference is given to polyacrylates according to the above formulas (2) and (3), where R ₁ and R _{3 are} alkyl, in particular methyl, R _{2 is} methyl and / or butyl, and R _{4 is} -COO-CH ₂ -CH ₂ -N (CH ₃ J ₂ is in this case, preferably, the ratio of structures of the formula (2) to structures of the formula (3). 1: 1. a suitable polymer has in particular a weight average molecular weight of from 50,000 to 250,000 g / mol, more preferably from 120,000 to 180,000 g / mol, up.

In a preferred embodiment, in the above formula (2) (or in formula (2 + 3) the radical R _{2 represents} both a methyl and a butyl group, wherein the ratio of methyl to butyl groups is preferably 1: 1.

In this case, it is preferably a ternary polymer containing the structures according to the general formulas (2a), (2b) and (3)

(2a) (2b) (3)

where R ₁ and R _{3 are} alkyl, in particular methyl, R _{2 is} methyl, R ₂ . Butyl, and R _{4 is} -COO-CH ₂ -CH ₂ -N (CH ₃ J ₂₎ In this case, the structures in formula (2a): (2b): (3) are preferably in the ratio 1: 1: 2 , In the melt tablet according to the invention, component (b) is usually used in an amount of 0.1 to 30% by weight, preferably 1 to 0 to 25% by weight, more preferably 1 to 5 to 20% by weight. even more preferably from 2.0 to 15% by weight, more preferably from 2.5 to 10% by weight, especially from 3.0 to 8% by weight, based on the total weight of the tablet.

In one possible embodiment, the orodispersible tablet according to the invention contains a plurality of different mucilages, for example the tablet according to the invention may contain 2 or 3 different mucilages.

The orodispersible tablets according to the invention contain as component (c) one or more sweeteners. Sweeteners are generally referred to as substances which usually produce a sweet taste impression on the patient when taken.

Preferably, sweeteners are used which have a sweetening power of 0.2 to 13,000, preferably from> 1 to 4000, in particular from 10 to 3000, based on the sweetening power of cane sugar (= 1, 0).

Examples are lactose (0.27-0.3), glycerol (0.5-0.8), D-glucose (0.5-0.6), maltose (0.6), galactose (0.6) , Invert sugar (0.8-0.9), cane sugar (1, 0), xylitol (1, 0), D-fructose (1, 0-1, 5), sodium cyclamate (30), D-tryptophan (35) , chloroform (40), glycyrrhizin (50), acesulfame (130), aspartame (180-200), dulcin (200), suosan ^® (350), saccharin (sodium salt) (400-500), saccharin (ammonium salt) (600 ), 1-bromo-5-nitroaniline (700), naringinedehydrochalcone (1000-1500), thaumatin, monellin (peptides) (3000), P-4000, n-propoxy-2-amino-4-nitrobenzene (4000), alitame (3000) and / or Neotam (13,000). The numerical value in brackets indicates the sweetening power relative to raw sugar. Also, thaumatin and / or neohesperidin DC can be used.

In the orodispersible tablet according to the invention, component (c) is usually used in an amount of from 0.01 to 10% by weight, more preferably from 0.1 to 5% by weight, in particular from 0.5 to 2% by weight, based on the total weight of the tablet used.

In a preferred embodiment, the orodispersible tablet according to the invention contains a plurality of different sweeteners, more preferably the tablet according to the invention contains 2, 3 or 4 different sweeteners.

In a more preferred embodiment, component (c) (C-1) contains an immediate sweet sweetener and (c-2) a sweet sweetener. The components (c-1) and (c-2) may usually be used in a weight ratio of 5: 1 to 1: 5, preferably 3: 1 to 1: 3.

Examples of an instant sweetener (c-1) are saccharin sodium salt, saccharin ammonium salt, sucralose, neotame, alitame, aspartame, cyclamate, thaumatin and / or acesulfame.

Examples of sweeteners with delayed sweetness (c-2) are glycyrrhizin or derivatives thereof, especially glycyrrhizin in the form of the mono-ammonium salt, thaumatin and neohesperidin DC.

The orodispersible tablets according to the invention contain as component (d) one or more flavoring agents. For the purposes of this application, the term "flavoring agent" is to be understood as defined in Council Directive 88/388 / EEC "flavoring substances" of 22 June 1988.

Flavoring agents (d) can be obtained as follows:

(i) by appropriate physical processes (including distillation and solvent extraction) or enzymatic or microbiological processes of substances of plant or animal origin used as such or processed for human consumption by conventional food preparation processes (including drying, roasting and fermentation);

(ii) by chemical synthesis or by isolation by chemical processes, the chemical nature of which is identical to that of a substance naturally occurring in a substance of plant or animal origin referred to in (i);

(ii) by chemical synthesis, but their chemical nature is not identical with a substance naturally occurring in a substance of plant or animal origin as defined in (i).

A flavoring agent may in this case consist of one or preferably of several chemical compounds. For example, peppermint flavor may contain a collective of more than 10 chemical compounds.

In the melt tablet of the present invention, component (d) is usually contained in an amount of 0.001 to 5% by weight, more preferably 0.1 to 4% by weight, especially 0.2 to 2% by weight, based on the total weight of the tablet used. It should be noted in these quantities that component (d) is optionally used in a "supported form". In this case, the above statement refers to flavoring agents including carriers. In a preferred embodiment, the orodispersible tablet according to the invention contains several different flavoring agents (ie several different aroma directions), more preferably the tablet according to the invention contains 2, 3 or 4 different flavoring agents.

Preferred combinations of flavoring agents are e.g. Aroma Peppermint with Aroma Menthol, Aroma Peppermint Aroma Lemon, Aroma Peppermint Aroma Menthol and Aroma Lemon, Aroma Garden Mint Aroma Lemon, Aroma Garden Mint Aroma Menthol, Aroma Garden Mint Aroma Lemon and Aroma Menthol, Aroma Grapefruit Aroma Peppermint, Aroma Grapefruit with aroma menthol and aroma peppermint, aroma grapefruit with aroma garden mint, aroma grapefruit with aroma garden mint and aroma menthol.

In a preferred embodiment, the orodispersible tablet according to the invention further contains one or more mouthfeel improving agents (as component (e)).

The term "mouthfeel" describes the physical and chemical interactions of a substance or a substance mixture (in the present case, in particular, the orodispersible tablet according to the invention) in the mouth. This includes the impressions from the first palate contact on the chewing to the swallowing and the aftertaste.

The mouthfeel can be described by the following criteria, for example:

o Lining of the mouth: type and extent of coating of teeth and mucous membrane of the oral cavity. Of interest is usually the lining after chewing or disintegration of the sample, so just before swallowing; o density: density of the cut surface in terms of a density of the package, after a sample has been completely severed with the molars; o elasticity: ability of the sample to return to its original shape after the application of force; o hardness: measure of the subjectively perceived force to deform the sample by a defined distance; o Moisture: amount of perceived on the surface of the sample

Liquid; o Moisture absorption: amount of absorbed by the sample

saliva; o Uniformity: Describes the uniformity of a sample (taste, texture, color, etc.); o Granularity: the degree of granularity felt during the chewing process; o Adhesion: The force needed to remove the material being tested from a specific surface (lips, teeth, palate, etc.); roughness: the degree of felt that the sample leaves on the tongue; Slipperiness: the extent to which the sample slides over the tongue; o Heavy: At the first contact on the tongue felt weight of the sample; o Shredding: The force needed to break up the sample.

In one possible embodiment, substances which are water-soluble are selected as component (e). These are preferably water-soluble polymers or sugar alcohols.

Preferably, the water-soluble polymer has a solubility of more than 10 mg / l, more preferably more than 30 mg / l, in particular more than 250 mg / l. In the context of this invention, the water solubility according to column elution method according to EU Directive RL67-548-EEC, Annex V, Chap. A6, certainly.

As described above, hydrophilic polymers are preferably used as the water-soluble component (b). These are polymers which have hydrophilic groups. Examples of suitable hydrophilic groups are hydroxy, alkoxy, acrylate, methacrylate, sulfonate, carboxylate and quaternary ammonium groups.

The water-soluble polymer (s) may comprise, for example, the following polymers: starch, in particular pregelatized starch, carboxymethylcellulose (CMC, in particular sodium and calcium salts), crospovidone, polyvinylpyrrolidone (povidone), polyvinyl acetate (PVAC), polyvinyl alcohol (PVA), vinylpyrrolidone-vinyl acetate copolymers (for example Kollidon ^® VA64, BASF), polyalkylene glycols such as polypropylene glycol or, preferably, polyethylene glycol, co-block polymers of the polyethylene glycol, in particular co-block polymers of polyethylene glycol and polypropylene glycol (Pluronic ^®, BASF), and mixtures of said polymers. The water-soluble polymer preferably has a weight-average molecular weight (determined by light scattering method) of 1,000 to 100,000 g / mol, more preferably 4,000 to 70,000 g / mol, especially 5,000 to 50,000 g / mol. In the case of the polyalkylene glycols, the weight-average molecular weight is preferably 2,000 to 10,000 g / mol.

Examples of suitable sugar alcohols (e) are mannitol, sorbitol, xylitol, isomalt, glucose, fructose, maltose and mixtures thereof.

Component (e) particularly preferably contains one or more compounds from the group consisting of sugar alcohols (in particular mannitol), polyvinyl acetate, Vinylpyrrolidone-vinyl acetate copolymers, polyvinylpyrrolidone and starch (especially pregelatized starch).

In the melt tablet of the present invention, the component (e) is usually used in an amount of from 0 to 50% by weight, more preferably from 1 to 35% by weight, especially from 5 to 25% by weight, based on the total weight of Tablet.

In one possible embodiment, the orodispersible tablet according to the invention contains several different substances for improving the mouthfeel, more preferably the tablet according to the invention contains 2 to 5 different substances for improving the mouthfeel.

In a preferred embodiment, the orodispersible tablet according to the invention also contains a lubricant (as component (f)). Lubricants serve as a means for improving the powder flowability (= flow regulator) and / or as a lubricant.

Flow regulators (f) have the task of reducing the interparticle friction (cohesion) between the individual particles as well as the adhesion of these to the wall surfaces of the mold (adhesion) in a tabletting mixture. An example of an additive for improving powder flowability is disperse silica. Preference is given to using silica having a specific surface area of from 50 to 400 m ² / g, determined by gas adsorption in accordance with Ph. Eur., 6th edition, Sept. 2, 1966. In this connection, it was unexpectedly found that by using silica having a specific surface area of 50 to 400 m ² / g, the amount of filler can be advantageously reduced.

Further, as component (f), lubricants can be used. Lubricants are generally used to reduce sliding friction. In particular, the sliding friction is to be reduced, which consists during tabletting on the one hand between the up and down in the die bore moving punches and the die wall and on the other hand between the tablet web and die wall. Suitable lubricants are for example stearic acid, adipic acid, sodium stearyl fumarate represents (eg Pruv ^®), sodium stearyl sulfate, sodium lauryl sulfate, magnesium stearate and / or calcium stearate.

In the melt tablet of the present invention, the component (f) is usually used in an amount of 0 to 5% by weight, more preferably 0 to 1 to 3% by weight, especially 0.3 to 2% by weight on the total weight of the tablet. The fused tablet according to the invention can consist of components (a) to (d) and optionally (e) and (f). Optionally, however, the tablet of the invention may contain other conventional pharmaceutical excipients.

Examples are disintegrants, fillers and acidulants.

As disintegrants are generally referred to substances that accelerate the disintegration of a dosage form, in particular a tablet, after being introduced into water. Suitable disintegrants are e.g. organic disintegrants such as microcrystalline cellulose, starch, pregelatinized starch, sodium carboxymethyl starch, sodium carboxymethyl cellulose and crospovidone. Preferably, microcrystalline cellulose is used as the disintegrant. In one possible embodiment, it is preferred that so-called "super-blasting agents", in particular croscarmellose and crospovidone, be dispensed with.

The orodispersible tablets according to the invention contain disintegrants, in particular superdisintegrants (eg croscarmellose and crospovidone), usually in an amount of from 0 to 25% by weight, more preferably from 1 to 15% by weight, in particular from 2 to 10% by weight, based on the total weight of the tablet. Alternatively, in the case of microcrystalline cellulose as disintegrant, the orodispersible tablets according to the invention contain these in an amount of from 1 to 50% by weight, more preferably from 5 to 35% by weight, in particular from 10 to 25% by weight. Larger amounts of microcrystalline cellulose should be avoided, otherwise the mouthfeel will be adversely affected.

Fillers are generally to be understood as meaning substances which serve to form the tablet body in the case of tablets with small amounts of active ingredient (for example less than 30% by weight). That is, fillers produce by "stretching" of the active ingredients sufficient Tablettiermasse. So fillers are usually used to obtain a suitable tablet size.

Examples of preferred fillers are lactose, calcium phosphate, sucrose, calcium carbonate, calcium silicate, magnesium carbonate, magnesium oxide, maltodextrin, calcium sulfate, dextrate, dextrin, dextrose, hydrogenated vegetable oil and / or cellulose derivatives.

The orodispersible tablets according to the invention usually contain fillers in an amount of from 0 to 30% by weight, more preferably from 1 to 20% by weight, in particular from 2 to 10% by weight, based on the total weight of the tablet.

Acid agents are used to achieve an acidic flavor component. Examples of acidic agents are citric acid, tartaric acid and salts thereof. The orodispersible tablets according to the invention usually contain acidifying agents in an amount of from 0 to 15% by weight, more preferably from 1 to 10% by weight, in particular from 2 to 5% by weight, based on the total weight of the tablet.

It is in the nature of pharmaceutical excipients that they partially perform multiple functions in a pharmaceutical formulation. For the purposes of this invention, the unambiguous delimitation is therefore preferably based on the fiction that a substance which is used as a specific excipient is not simultaneously used as a further pharmaceutical excipient. For example, mannitol, if used as a filler, is not also used as a sweetener. Also microcrystalline cellulose - if used as a disintegrant - not additionally used as a filler (although microcrystalline cellulose also has filler properties). Similarly, if used as a mouthfeel enhancer (s), crospovidone is not also used as a disintegrants (although crospovidone has a strong blast effect).

In a preferred embodiment, the adjuvants are selected in the melt tablet according to the invention so that the fused tablet according to the invention is free of saccharides.

The ingredients described above are processed in the inventive method for orodispersible tablets. The method according to the invention is a "direct compression" (also known as direct compression).

The invention therefore provides a process for producing a orodispersible tablet comprising a pharmaceutically acceptable salt of vardenafil, comprising the steps:

(i) mixing a pharmaceutically acceptable vardenafil salt with the pharmaceutical excipients (described above), and (ii) directly compressing the mixture into orodispersible tablets,

wherein the process is preferably carried out in the absence of solvents.

In step (i) of the process according to the invention, the components are preferred

(a) pharmaceutically acceptable vardenafil salt;

(b) optionally mucilage;

(c) sweeteners; (d) flavoring agents;

(e) optionally, mouthfeel improvers; and

(f) optionally mixed with lubricant. In principle, all the above explanations of preferred embodiments of the individual constituents of the mixture apply to the process according to the invention, for example with regard to the type and amount of components (a) to (f) and the possible addition of further auxiliaries, such as disintegrants, fillers and acidifiers.

In step (i) of the process according to the invention, vardenafil salt (a) and pharmaceutical excipients are mixed. The mixing can be done in conventional mixers. For example, the mixing in positive mixers or gravity mixers can be done, for example by Turbula ^® T 1Ob (Bachofen AG, Switzerland).

In a preferred embodiment of the process according to the invention, components (a) and (b) are mixed with one another before the implementation of step (i). This premixing takes place, for example, in compulsory mixers or in free-fall mixers. When mixed in compulsory mixers usually times of 3 to 15 minutes are needed to achieve a homogeneous mixture. When using free-fall mixers for example by means of Turbula ^® T 1OB (Bachofen AG, Switzerland) or container mixers such as CM 500 (J. Engelsmann AG, Germany) or drum mixers such as type Rhönradmischer (J. Engelsmann AG, Germany) are usually times of 10 to 20 Minutes needed to produce the homogeneous mixture.

The blending conditions of "pre-blending" (components (a) and (b)) are usually selected so that at least 10% of the number of vardenafil salt particles used is bound to the mucilage (preferably cohesively), more preferably at least 30% of the Particles, more preferably at least 50% of the particles, in particular at least 90% of the particles.

In step (ii), the mixture is compressed (from step (i)), i. a compression to tablets. The compression can be done with tableting machines known in the art. The compression takes place in the absence of solvents.

Examples of suitable tableting machines are eccentric presses or concentric presses. For example, a Fette 102i (Fette GmbH, Germany) can be used. In the case of rotary presses, a pressing force of 3 to 50 kN, preferably 7.5 to 45 kN, is usually used.

Optionally, the mixture of step (i) may be compacted and granulated prior to compression. The granulation is preferably carried out as a dry granulation. Alternatively, a wet granulation can be done. Ingredients (a) to (d) and optionally (e) and (f) and the compression conditions may be selected such that the resulting orodispersible tablet has a drug release in physiological saline greater than 50% to less than 70% at 5.0 minutes , more preferably from 52% to 68%, especially from 55% to 65%.

The drug release is determined here in vitro at 37 ⁰ C in 900 ml of physiological saline according to US Pharmacopeia (USP), wherein the measurement is carried out in the Blattrührerapparatur at 50 revolutions per minute.

It has been found in the context of this invention that the above-mentioned drug release is advantageous both in terms of bioavailability as well as in terms of taste and Mündgefühl.

In a preferred embodiment, the method according to the invention comprises a further step (iii). In this step, the resulting orodispersible tablets are packaged by means of a film which has a water vapor permeability of less than 0.50 g / m ² d, preferably 0.001 to 0.4 g / m ² d, more preferably from 0.01 to 0.3 g / m ² . The parameter "d" hereby means "day." The packaging is preferably carried out in blister packs, in particular in mono blister packs.

The water vapor permeability is determined according to Kassis et al., Pharm. Ind. 43, 1036 (1981).

Examples of suitable films are aluminum, PET; PVC-CTFE (chlorotrifluoroethylene = polyvinyl chloride, marketed as Aclar ^®), biaxially oriented polyamide and composite films of the mentioned materials.

Not suitable as films in step (iii) of the process according to the invention are PVC, PP (= polypropylene) or PVDC (polyvinylidene chloride).

It has been shown that step (iii) of the method according to the invention is advantageous, in particular for increasing the storage stability of the orodispersible tablets according to the invention. The same applies to orodispersible tablets containing alternative active ingredients for the treatment of erectile dysfunction. The invention therefore also relates to the use of a film which has a water vapor permeability of less than 0.50 g / m ² d for packaging a fused tablet containing a medicament for the treatment of erectile dysfunction.

The inventive method ensures a technically advantageous manufacturing method. Compared with the wet granulation proposed in the prior art, it is technically less expensive and the space-time yield can be increased. Besides the method according to the invention are also

Orodispersible tablets obtainable by the process according to the invention are the subject of this invention.

The inventors have also found that an acrylic polymer or carrageenan is useful for taste masking medicaments for the treatment of erectile dysfunction (which usually have a bitter taste).

The invention therefore furthermore relates to the use of an acrylic polymer or of carrageenan for taste masking of orodispersible tablets which contain an active substance for the treatment of erectile dysfunction and are preferably produced by means of direct compression.

Finally, it has been found that the tablets according to the invention are advantageously suitable for the treatment of patients with intolerance to sildenafil. The term "intolerance" here means that the intake of sildenafil is contraindicated for this patient group for medical reasons.

The invention will be illustrated by the following examples.

EXAMPLES

Examples 1 to 3: fused tablets according to the invention by means of direct compression

There were inventive orodispersible tablets by means of the invention

Process produced. The formulations used (per tablet) and the

Properties of the resulting orodispersible tablets are shown in Table 1 below.

TabeUe 1

*: Polyacrylate according to general formula 2 and 3 (in the ratio 1: 1), wherein R ₁ to R ₃

Methyl, and R _{4 is} -COO-CH ₂ -CH ₂ -N (CH ₃ ) ₂ ;

**: comprising in form of a mixture of carrageenan and MCC, commercially available as Lustreclear ^®

***: Sodium starch glycolate

****: Mixture of Crospovidone, Kollidone, Povidone and Polyvinyl Acetate: Supported

******: determined at 37 ^° C. in 900 ml of physiological saline according to US Pharmacopeia (USP), the measurement being carried out in the paddle stirrer apparatus at 50 revolutions per minute. Vardenafil salt was added together with MCC, starch, silica and polyacrylate or carrageenan 15 min pre-mixed in the free fall mixer (Turbula ^®). Subsequently, the remaining substances were supplemented and mixed for a further 15 minutes. The finished mixture was pressed on a rotary press with biconvex punches.

Since taste sensations can be individually different, 10 subjects were used for the taste test of the above examples and the average taste perception was determined. Degustation took place 1 hour after the last meal. The subjects were all non-smokers. The test room was of a neutral odor, the temperature was 20 ^° C. The assessment of the sensation of irritation and the training of the test persons was carried out in accordance with DIN 10950.

Comparative Example 1

Tablets were prepared according to Example 6 of WO 2 006/092207.

These showed an unpleasant bitter apricot taste and no creamy mouthfeel.

Example 4: Storage stability

Tablets prepared according to Examples 1 to 3 were packed in blister packs. The following table shows the different storage stabilities when using different films:

Table 2: Results of the stability test

The stability tests were carried out by storage in climate cabinets (main criterion 40 ⁰ C / 75% relative humidity, control at deviations at 25 ⁰ C / 60% relative humidity). Examples 5 and 6: Melt tablets according to the invention by means of direct compression

*****: Supported

******: determined at 37 ^° C. in 900 ml of physiological saline according to US Pharmacopeia (USP), the measurement being carried out in the paddle stirrer apparatus at 50 revolutions per minute.

Vardenafil salt was added together with all excipients - mixed for 15 minutes in free fall mixer (Turbula ^®) - up to Pruv ^®. Then Pruv ^® was added and mixed for a further 5 minutes. The finished mixture was pressed on a rotary press with biconvex punches (8 mm).

Claims

claims

A process for the preparation of orodispersible tablets comprising a pharmaceutically acceptable salt of vardenafil, comprising the steps

(i) preparing a mixture comprising (a) pharmaceutically acceptable vardenafil salt, (b) mucilage,

(c) sweeteners,

(d) flavoring agents, and

(ii) direct compression of the mixture into orodispersible tablets.

2. The method according to claim 1, additionally containing the component

(e) Mouth-feeling improving agent.

3. The method according to claim 1 or 2, wherein pharmaceutically acceptable vardenafil salt (a) in an amount of 2 to 25 wt .-%, based on the

Total weight of the orodispersible tablet is included.

4. The method according to any one of claims 1 to 3, wherein the mucilage (b) in an amount of 1 to 25 wt .-%, based on the total weight of the orodispersible tablet is included.

5. The method according to any one of claims 1 to 4, wherein the mucilage is a water-swellable polymer with pH-dependent solubility.

6. The method according to any one of claims 1 to 5, wherein the mucilage is carrageenan.

A method according to any one of claims 2 to 6, wherein the mouthfeel improving agent is a sugar alcohol and / or a water-soluble polymer.

8. The method according to any one of claims 1 to 7, wherein the components (a) to (d) and optionally (e) and the compression conditions are chosen so that the resulting orodispersible tablet release in physiological saline after 5.0 minutes of more than 50% to less than 70%.

9. The method according to any one of claims 1 to 8, comprising the step

(iii) packaging the resulting orodispersible tablets by means of a film containing a

Has water vapor permeability of less than 0.50 g / m ² d.

10. The method according to claim 9, wherein the film contains aluminum, polyethylene terephthalate, chlorotrifluoroethylene and / or biaxially oriented polyamide.

1 1. orodispersible tablet, obtainable by a method according to any one of claims 1 to 10.

The orodispersible tablet according to claim 11, wherein the orodispersible tablet has a disintegration time of less than 30 seconds and a hardness of 30 to 70 Newton.

13. Use of a film having a water vapor permeability of less than 0.50 g / m ² d, for packaging a fused tablet containing a medicament for the treatment of erectile dysfunction.

14. Use of an acrylic polymer or of carrageenan for taste masking of orodispersible tablets which contain an active substance for the treatment of erectile dysfunction and are preferably produced by means of direct compression.

15. orodispersible tablet according to claim 11 or 12 for the treatment of patients with an intolerance to sildenafil.