DE102009058321A1 - Orodispersible tablet containing dapoxetine - Google Patents

Abstract

The invention relates to orodispersible tablets containing dapoxetine, preferably dapoxetine resinate. Furthermore, the invention relates to a process for the preparation of Dapoxetinresinat and a method for producing a orodispersible tablet containing Dapoxetinresinat.

Description

The invention relates to orodispersible tablets containing dapoxetine, preferably dapoxetine resinate. Furthermore, the invention relates to a process for the preparation of Dapoxetinresinat and a method for producing a orodispersible tablet containing Dapoxetinresinat.

Dapoxetine, in a broader sense, belongs to the group of Selective Serotonin Reuetake Inhibitors (SSRIs), in particular it inhibits the transport molecule of serotonin.

The chemical name of dapoxetine [INN] is (S) - (+) - N, N-dimethyl-1-phenyl-3- (1-naphthalenyloxy) -propanamine. The chemical structure of dapoxetine is shown in formula (1) below:

The synthesis of dapoxetine is in EP 0 288 188 B1 described.

EP 1 225 881 B1 concerns the use of dapoxetine for the treatment or management of sexual dysfunction, in particular ejaculatio Praecox. Capsule and tablet formulations with a dapoxetine content of about 2.5 to 10% by weight are proposed for this purpose. The intake of hard gelatin capsules and tablets is usually done with liquid to facilitate the swallowing process.

However, this form of fluid intake requires a certain minimum of organization, which may be problematic given the range of indications of dapoxetine and the associated spontaneity of the patient. Another drawback with the use of conventional capsule and tablet formulations with liquid is that taking it while lying down is extremely difficult and that the patient may want to discretely take the dosage form, which would be much easier to do without liquid.

In addition, the preparation of suitable oral dosage forms of dapoxetine may prove problematic because dapoxetine has a bitter taste and a local anesthetic effect.

It was therefore an object of the present invention to overcome the described disadvantages of the prior art formulations and to provide a dosage form which makes it possible to take ingestion without liquid while lying down and to ensure a particularly rapid onset of action.

It was a further object of the invention to provide oral dosage forms of dapoxetine (and a method for the production thereof) which produce no bitter taste and no local anesthetic effect in the mouth. The advantageous taste or the lack of local anesthetic effect should also be made possible with a sugar-free formulation.

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.

Surprisingly, the above objects could be achieved by providing dapoxetine resinate or orodispersible tablets containing dapoxetine. In particular, it has been found that the preparation of a orodispersible tablet containing dapoxetine resinate provides a formulation which unexpectedly solves the above objects.

The invention therefore relates to a fused tablet containing dapoxetine.

Furthermore, the subject of the invention Dapoxetinresinat.

• (i) Lösen von Dapoxetin (a),
• (ii) Dispergieren eines polymeren Adsorptionsmittel (b),
• (iii) gegebenenfalls Rühren bis ein stabiler pH-Wert erreicht wird,
• (iv) Filtrieren der aus (ii) oder (iii) erhaltenen Dispersion,
• (v) Trocknen des aus (iv) erhaltenen Filterkuchens.

The invention further provides a process for the preparation of dapoxetine resinate, comprising the steps:

• (i) dissolving dapoxetine (a),
• (ii) dispersing a polymeric adsorbent (b),
• (iii) optionally stirring until a stable pH is reached,
• (iv) filtering the dispersion obtained from (ii) or (iii),
• (v) drying the filter cake obtained from (iv).

• (I) Bereitstellen von Dapoxetinresinat,
• (II) Vermischen mit weiteren pharmazeutischen Hilfsstoffen,
• (III) gegebenenfalls Granulieren der aus (II) erhaltenen Mischung,
• (IV) Verpressen der aus (II) erhaltenen Mischung oder des aus (III) erhaltenen Granulats zu einer Schmelztablette.

In addition, the subject matter of the invention is a process for the preparation of an orodispersible tablet containing dapoxetine resinate, comprising the steps:

• (I) providing dapoxetine resinate,
• (II) mixing with other pharmaceutical excipients,
• (III) optionally granulating the mixture obtained from (II),
• (IV) pressing the mixture obtained from (II) or the granule obtained from (III) into an orodispersible tablet.

The invention further relates to dapoxetinresinate for the treatment of sexual dysfunction wherein dapoxetine resinate is taken without liquid.

Finally, the subject of the invention is the use of a cation exchange resin for masking a local anesthetic effect and the bitter taste of a drug, preferably a drug for the treatment of sexual dysfunction, in the mouth.

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 in European Pharmacopoeia, 6th edition, basic text 2008 Are defined. 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 150 seconds, in particular of less than 50 seconds, in the mouth.

The disintegration time is according to Ph. Eur. 6th Edition Chapter 2.9.1 Test A determined. If reference is made to the average disintegration time in the context of this application, this is to be understood as the mean value from the disintegration time determination of 10 tablets.

The orodispersible tablets according to the invention usually have a total weight of less than 1000 mg, more preferably less than 750 mg, in particular less than 500 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 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 breaking strength 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 breaking strength is usually according to Ph. Eur. 6th Edition Chapter 2.9.8 certainly. If reference is made in this application to the average breaking strength, this is to be understood as the mean value from the breaking strength 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%. Friability is determined according to Ph. Eur. 6.0, section 2.9.7 certainly.

The weight ratio of active ingredient (based on dapoxetine in the form of the free base) to excipients in the melt tablets according to the invention is usually 4: 1 to 1: 8, preferably from 2: 1 to 1: 6, in particular 1: 1 to 1: 5.

The orodispersible tablet according to the invention contains dapoxetine as component (a).

In the context of this invention, the term "dapoxetine" comprises (S) - (+) - N, N-dimethyl-1-phenyl-3- (1-naphthalenyloxy) -propanamine according to formula (1) above. In addition, the term "dapoxetine" includes all pharmaceutically acceptable salts as well as hydrates and solvates thereof.

The salts may be acid addition salts. Examples of suitable salts are hydrochlorides, carbonates, bicarbonates, acetates, lactates, butyrates, propionates, sulfates, methanesulfonates, citrates, tartrates, nitrates, sulfonates, oxalates and / or succinates. Dapoxetine (a) is preferably used in the form of the hydrochloride in the context of this invention.

Usually, the dapoxetine (a) in the orodispersible tablet according to the invention in an amount of (a) from 1 to 25 wt .-%, preferably from 2 to 20 wt .-%, more preferably from 5 to 15 wt .-%, based on the Total weight of orodispersible tablet used. Unless otherwise indicated, all weights of component (a) refer to dapoxetine in the form of the (anhydrous) free base.

In a preferred embodiment, the orodispersible tablet according to the invention contains a polymeric adsorbent as component (b). Generally, it refers to one or more polymeric materials (i.e., materials having more than two repeating monomer units) capable of adsorbing component (a).

Preferably, the polymeric adsorbent is a hydrophilic polymer.

These are polymers which have hydrophilic groups. Examples of suitable hydrophilic groups are hydroxy, amino, carboxylic acid or carboxylate (hereinafter also referred to as carboxyl / carboxylate), sulfonic acid or sulfonate (hereinafter also referred to as sulfonic acid / sulfonate).

Further, the polymer (b) preferably has a weight-average molecular weight of more than 900 g / mol, more preferably from 10 ³ to 10 ²⁰ g / mol, even more preferably from 10 ⁴ to 10 ¹⁹ g / mol, especially from 10 ⁶ to 10 ¹⁸ g / mol.

The polymer (b) may be linear or preferably crosslinked. In the latter case, the polymer (b) preferably has a degree of crosslinking of from 0.01 to 10%, in particular from 0.1 to 5%. (Degree of crosslinking = number of carbon atoms which are more than one chain connected / number of carbon atoms in the polymer chain in total).

In a preferred embodiment, the polymeric adsorbent (b) is an ion exchange resin. An ion exchange resin is a polymer that can be used to replace dissolved ions with other ions of the same charge type but with different charges.

More preferably, a cation exchange resin is used as the component (b). By cation exchange resin is meant a polymer containing functional groups with a dissociable cation. Examples of these functional groups are sulfonic acid groups / sulfonate groups or carboxyl groups / carboxylate groups. Thus, as the component (b), a polymer containing carboxyl groups / carboxylate groups and / or sulfonyl groups / sulfonate groups is preferably used. If carboxylate or sulfonate groups are present, for. As ammonium, alkali and alkaline earth metal ions serve as counterions, preferred are sodium and potassium, especially potassium. Sodium starch glycolate is preferably not a polymeric adsorbent (b) for the purposes of this invention.

Alternatively, as the component (b), an anion exchange resin is used. By anion exchange resin is meant a polymer containing functional groups with a dissociable anion. Examples of these functional groups are ammonium groups.

In a further preferred embodiment, the polymeric adsorbent (b) is a copolymer obtainable by copolymerization of styrene and divinylbenzene. Such copolymers are known under the name polystyrene sulfonate.

A preferred polystyrene sulfonate is monographed according to US Pharmacopeia and can be illustrated by the following structural formula.

In a particularly preferred embodiment, the polymeric adsorbent (b) is a copolymer obtainable by copolymerization of methacrylic acid and divinylbenzene. Such a copolymer is known as polacrilin.

In particular, in the context of this invention, polacrilin in the form of the potassium salt (polacrilin potassium, in particular monographed according to US Pharmacopeia) is used.

wobei x und y natürliche Zahlen sind, beispielsweise von 10¹ bis 10²⁰, bevorzugt von 10⁶ bis 10¹⁸. Das Verhältnis von x zu y beträgt üblicherweise 50:1 bis 1:1, bevorzugt 20:1 bis 2:1, besonders bevorzugt 10:1 bis 3:1.Polacrilin potassium can be illustrated by the following structural formula.

where x and y are natural numbers, for example from 10 ¹ to 10 ²⁰ , preferably from 10 ⁶ to 10 ¹⁸ . The ratio of x to y is usually 50: 1 to 1: 1, preferably 20: 1 to 2: 1, more preferably 10: 1 to 3: 1.

Usually, the polymeric adsorbent (b) in the ore tablet according to the invention in an amount (b) of 1 to 60 wt .-%, preferably from 2 to 50 wt .-%, more preferably from 5 to 40 wt .-%, based on the total weight of the orodispersible tablet used.

The orodispersible tablets according to the invention usually have a weight ratio of dapoxetine (a) to polymeric adsorbent (b) of 1:10 to 10: 1, preferably 1: 5 to 5: 1, more preferably 1: 3 to 3: 1, in particular 1: 2 to 2: 1, up.

By combining dapoxetine (a) with polymeric adsorbent (b), dapoxetine may form as a resinate. Thus, another subject of the invention is dapoxetine resinate (also referred to as component (a-b)). Dapoxetinresinate is explained in more detail following the comments on the orodispersible tablet according to the invention.

In a further preferred embodiment, the orodispersible tablet according to the invention contains a breath freshening agent as component (c).

As a breath freshening agent, one or more substances are commonly referred to, which usually generate fresh breath in the patient when ingested.

In the context of this application, the "breath freshening agent" preferably contains flavoring agents as in Council Directive 88/38 / EEC "flavorings" of 22 June 1988 Are defined.

• i) durch geeignete physikalische Verfahren (einschließlich Destillation und Extraktion mit Lösungsmitteln) oder durch enzymatische beziehungsweise mikrobiologische Verfahren aus Stoffen pflanzlichen oder tierischen Ursprungs, die als solche verwendet oder mittels herkömmlicher Lebensmittelzubereitungsverfahren (einschließlich Trocknen, Rösten und Fermentierung) für den menschlichen Verzehr verarbeitet werden;
• ii) durch chemische Synthese oder durch Isolierung mit chemischen Verfahren, wobei ihre chemische Beschaffenheit mit einer Substanz identisch ist, die in einem Stoff pflanzlichen oder tierischen Ursprungs im Sinne von Ziffer i) natürlich vorkommt;
• iii) durch chemische Synthese, wobei jedoch ihre chemische Beschaffenheit nicht mit einer Substanz identisch ist, die in einem Stoff pflanzlichen oder tierischen Ursprungs im Sinne von Ziffer i) natürlich vorkommt.

Breath freshening agents (c) can be obtained as follows:

• (i) by appropriate physical processes (including distillation and solvent extraction) or by 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);
• (iii) by chemical synthesis, but their chemical constitution is not identical to a substance naturally occurring in a substance of plant or animal origin as defined in (i).

A breath freshening agent may consist of one or, preferably, of several chemical compounds. For example, peppermint flavor may contain a collective of more than 10 chemical compounds.

In a preferred embodiment, the orodispersible tablet according to the invention contains several different breath freshening agents (i.e., several different aroma directions), more preferably, the orodispersible tablet according to the invention contains 2, 3 or 4 different breath freshening agents.

Preferred combinations of breath freshening agents are e.g. B. Aroma Peppermint with Aroma Menthol, Aroma Peppermint with Aroma Lemon, Aroma Peppermint with Aroma Menthol and Aroma Lemon, Aroma Garden Mint with Aroma Lemon, Aroma Garden Mint with Aroma Menthol, Aroma Garden Mint with Aroma Lemon and Aroma Menthol, Aroma Grapefruit with Aroma Peppermint, Aroma Aroma Grapefruit with Aroma Menthol and Aroma Peppermint, Aroma Grapefruit Aroma with Garden Mint, Aroma Grapefruit with Aroma Garden Mint and Aroma Menthol.

Examples of commercially available breath freshening agents are xylitol (z. B. Xylisorb ^®, available from Roquette), spray-dried sorbitol (z. B. Merisorb ^®, available from Syral), L-menthol (z. B. available from Caelo).

Typically, the breath freshening agent (c) in the orodispersible tablet according to the invention in an amount (c) of 0.1 to 7 wt .-%, preferably from 0.5 to 5 wt .-%, more preferably from 1 to 3 wt. %, based on the total weight of the orodispersible tablet.

In a further preferred embodiment, the orodispersible tablet according to the invention contains a sweetener as component (d).

As a sweetener, one or more substances are generally referred to, which usually cause a sweet taste sensation in the patient when ingested.

Preferably, sweeteners are used which have a sweetening power of from 0.2 to 13,000, preferably from> 1 to 4,000, in particular from 10 to 3,000, 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), naringin dihydrochalcone (1000-1500), thaumatin, monellin (peptides) (3000), P-4000, n-propoxy-2-amino-4-nitrobenzene (4000), Alitam (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 melt tablet according to the invention, component (d) is usually added 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 2.5% by weight. %, based on the total weight of the orodispersible tablet.

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 (d) contains
(d-1) a sweetener with immediate sweetness, and
(d-2) a sweetener with delayed sweetness.

The components (d-1) and (d-2) can usually be used in a weight ratio of 5: 1 to 1: 5, preferably from 3: 1 to 1: 3.

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

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

In a further possible embodiment, the orodispersible tablet according to the invention contains a mucilage as component (e).

In the context of this invention, a mucilage is understood to mean one or more substances which reduce the contact of drugs with the papillae of the tongue 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 (e), 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 than 6 mPa / s, measured at 25 ° C, according to Ph. Eur. 6th edition, chapter 2.2.10 ,

As gums (e) it is possible to use natural gums, cellulose derivatives, alginates and / or nonionic hydrocolloids.

Examples of mucilage (s) 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 juice gum, 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 and / or lecithin.

As mucilage based on cellulose derivatives z. As carboxymethyl cellulose, hydroxyethyl cellulose and / or methyl cellulose used.

In the melt tablet of the present invention, the component (e) is usually contained in an amount of from 0 to 25% by weight, more preferably from 0.1 to 20% by weight, especially from 0.5 to 20% by weight the total weight of the orodispersible tablet used.

In addition, the orodispersible tablet according to the invention may contain further customary pharmaceutical auxiliaries.

Examples of these are fillers (f), lubricants (g), disintegrants (h), and acid agents (j).

In general, fillers (f) are to be understood as meaning substances which are used to form the tablet body in the case of tablets having low amounts of active ingredient (for example less than 70% 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, starch, starch derivatives, calcium phosphate, sucrose, calcium carbonate, calcium silicate, magnesium carbonate, magnesium oxide, maltodextrin, calcium sulfate, dextrates, dextrin, dextrose, hydrogenated vegetable oil, kaolin and / or preferably sugar alcohols. Examples of suitable sugar alcohols are mannitol, sorbitol, xylitol, isomalt, glucose, fructose, maltose and mixtures thereof. Lactose is particularly preferably used as filler.

The orodispersible tablets according to the invention usually contain fillers in an amount of from 0 to 70% by weight, more preferably from 1 to 60% by weight, in particular from 2 to 55% by weight, based on the total weight of the orodispersible tablet.

Lubricant (g) is generally understood to mean substances which are suitable for improving the powder flowability (= flow regulator (g ₁ )) and / or as lubricant (g ₂ ).

Flow regulators (g ₁ ) 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 silica having a specific surface area of 50 to 400 m ² / g, determined after gas adsorption according to Ph. Eur., 6th edition 2.9.26 ., used. 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 the component (g ₂ ), 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 in the die bore and from moving punches and the die wall and on the other hand between the tablet web and die wall. Suitable lubricants provide z. As stearic acid, adipic acid, sodium stearyl fumarate (z. B. Pruv ^®), magnesium stearate and / or calcium stearate is.

In the melt tablet of the present invention, the component (g) is usually used in an amount of 0 to 10% by weight, more preferably 0.1 to 5% by weight, especially 1.0 to 3% by weight, based on the total weight of the tablet used.

As disintegrants (h) 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 z. Organic disintegrants such as microcrystalline cellulose, starch, pregelatinized starch, sodium carboxymethyl starch, sodium carboxymethyl cellulose, cross-linked polyvinylpyrrolidones, sodium starch glycolate, and crospovidone. Crosslinked polyvinylpyrrolidones and / or sodium starch glycolate are preferably used as disintegrating agents.

The orodispersible tablets according to the invention contain disintegrants (h) usually in an amount of from 0 to 35% by weight, more preferably from 1 to 30% by weight, in particular from 2 to 25% by weight, based on the total weight of the orodispersible tablet.

Acid (j) serve to obtain an acidic flavor component. Examples of acidic agents are citric acid, tartaric acid and salts thereof.

The orodispersible tablets according to the invention usually comprise acidity agent (j) 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 orodispersible 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, polacrilin - if used as a polymeric adsorbent (b) - not additionally used as a disintegrant (although polacrilin also shows a certain explosive effect).

Thus, the orodispersible tablet according to the invention can contain constituents (a) to (h) and (j). As explained above, the combination of dapoxetine (a) with polymeric adsorbent (b) gives dapoxetine in the form of a resinate according to the invention. The dapoxetine resinate (a-b) according to the invention is usually a combination of dapoxetine and a polymeric adsorbent (b). Here, reference is made to all the above explained preferred embodiments of components (a) and (b).

In general, in the combination according to the invention (= dapoxetine resetin), dapoxetine (a) can be bonded to the polymeric adsorbent (b) via chemical and / or physical bonds.

In a preferred embodiment of the combination according to the invention dapoxetine is bound thereto via an ionic bond to the polymeric adsorbent. The combination according to the invention can thus be present at least partially in the form of a salt. It is further possible in one embodiment of the invention for dapoxetine and polymeric adsorbent to form an ion pair. By "ion pair" is hereby preferably understood that dapoxetine and polymeric adsorbent have a common hydrate shell in an aqueous solution.

In an alternative preferred embodiment of the combination according to the invention, dapoxetine is bound to the polymeric adsorbent via van der Waals bonds. In this embodiment, dapoxetine is preferably in amorphous form.

Furthermore, mixed forms of the mentioned preferred embodiments may be present.

In the case of dapoxetine resetin, the type and amount of dapoxetine (a) and polymeric adsorbent (b) are usually chosen so that the resulting combination (i.e., the resulting dapoxetine resetin) exhibits substantially no local anesthetic effect. In addition, the type and amount of dapoxetine (a) and of polymeric adsorbent (b) are preferably chosen so that the resulting combination has substantially no bitter taste. Thus, combinations of z. As dapoxetine with starch, microcrystalline cellulose, lactose and / or polyvinylpyrrolidone not under the term "Dapoxetinresinat" in the context of the present invention.

The water content of Dapoxetinresinat is usually 1 to 12 wt .-%, preferably 2 to 10 wt .-%, particularly preferably 3 to 7 wt .-%, based on the Dapoxetinresinat total weight. The water content is determined by coulometric Karl Fischer measurement with a Karl Fischer titrator AQUA 40.00 (Analytik Jena AG, Germany), wherein a sample of 20 mg is measured.

The invention is not only the Dapoxetinresinat invention but also a process for its preparation.

• (i) Lösen von Dapoxetin (a),
• (ii) Dispergieren eines polymeren Adsorptionsmittel (b),
• (iii) gegebenenfalls Rühren bis ein stabiler pH-Wert erreicht wird,
• (iv) Filtrieren der aus Schritt (ii) oder Schritt (iii) erhaltenen Dispersion,
• (v) Trocknen des aus Schritt (iv) erhaltenen Filterkuchens.

The invention therefore relates to a process for the preparation of dapoxetine resinate, comprising the steps:

• (i) dissolving dapoxetine (a),
• (ii) dispersing a polymeric adsorbent (b),
• (iii) optionally stirring until a stable pH is reached,
• (iv) filtering the dispersion obtained from step (ii) or step (iii),
• (v) drying the filter cake obtained from step (iv).

In step (i), dapoxetine (a) is dissolved in a solvent. The solvents of the invention used in step (i) are generally polar organic solvents. In a preferred embodiment, an organic solvent is used, with a relative permittivity (= ε _r ) of greater than 15 to 85, preferably 20 to 80, measured at 20 ° C.

Suitable solvents are, for. For example, water, alcohol (eg., Methanol, ethanol, isopropanol), dimethyl sulfoxide (DMSO), acetone, butanol, ethyl acetate, heptane, pentanol or mixtures thereof. Preferably, water is used.

As a "dissolution" is generally understood at least a partial dissolution, preferably the dissolution of a major part of dapoxetine, usually greater than 80 wt .-%, preferably greater than 90 wt .-%, particularly preferably greater than 95 wt .-%, in step ( ii) the polymeric adsorbent (b) is dispersed in the solution obtained in step (i), preferably suspended. Optionally, parts of the polymeric adsorbent (b) may also be dissolved. Usually, greater than 10 wt .-%, preferably greater than 80 wt .-%, more preferably greater than 95 wt .-% of the polymeric adsorbent (b) in undissolved (= dispersed) form.

Upon or after contacting dapoxetine and adsorbent, the pH of the resulting composition may change. Optionally, the dispersion obtained in step (ii) is stirred in optional step (iii) until a stable pH is reached. A stable pH is usually a pH that does not or only minimally changes. Minimal means a change of ± 0.2 over a period of one minute.

In step (iv), the dispersion obtained from step (ii) or step (iii) is filtered to obtain a filter cake.

For the purposes of this application, filtration is understood to mean the separation of solid particles from liquids with suitable filters.

In step (v) the drying of the filter cake obtained from step (iv) takes place.

In this application drying is understood to mean the separation of solids adhering to solids. The adhering liquids are preferably water in the form of adhesive water, capillary, hydration, adsorption, hydrate and constitutional water. Drying is generally carried out in conventional drying devices, such as cabinet or tray dryers, vacuum dryers, fluidized bed dryers, spray dryers or freeze dryers. Cabinet or tray dryers are preferably used according to the invention.

Under filter cake are generally understood to be the components remaining on the filter.

The drying time is usually 1 to 20 hours, preferably 2 to 17 hours, more preferably 5 to 15 hours. The drying temperature is usually 40 to 120 ° C, preferably 50 to 100 ° C, especially 60 to 90 ° C. The drying conditions are particularly preferably chosen so that the resulting dapoxetine resinate has the above-described water content.

In principle, all the explanations given above on preferred embodiments of dapoxetine (a) and polymeric adsorbent and all combinations thereof are also used in the process according to the invention. Thus, in a preferred embodiment of the process according to the invention in step (i), a pharmaceutically acceptable salt of dapoxetine (a), preferably dapoxetine HCl, is dissolved in a solvent, preferably in water. In step (ii), a polymeric adsorbent, preferably a cation exchange resin, is dispersed with stirring in the solution obtained in step (i).

In a still more preferred embodiment, in step (i), dapoxetine HCl is used as component (a) and in step (ii) polacrilin potassium is used as component (b). Preferably, in step (iii) is stirred to a pH of at least 7.0. The mixture is then passed through a filter and the filter cake, z. B. at a temperature of 60 to 90 ° C dried.

• (I) Bereitstellen von Dapoxetin, bevorzugt Dapoxetinresinat,
• (II) Vermischen mit weiteren pharmazeutischen Hilfsstoffen,
• (III) gegebenenfalls Granulieren der aus Schritt (II) erhaltenen Mischung,
• (IV) Verpressen der aus (II) erhaltenen Mischung oder des aus (III) erhaltenen Granulats zu einer Schmelztablette.

The dapoxetine resinate obtainable by the process according to the invention is likewise the subject of this invention. It is preferably used for the preparation of the above-described orodispersible tablet. The invention thus also provides a process for the preparation of an orodispersible tablet containing dapoxetine, in particular dapoxetine resinate, comprising the steps:

• (I) providing dapoxetine, preferably dapoxetine resinate,
• (II) mixing with other pharmaceutical excipients,
• (III) optionally granulating the mixture obtained from step (II),
• (IV) pressing the mixture obtained from (II) or the granule obtained from (III) into an orodispersible tablet.

In principle, all the above explanations on preferred embodiments of the orodispersible tablet according to the invention are applicable to the method according to the invention, for example regarding the type and amount of components (a) and (b) and the possible addition of further pharmaceutical excipients such as respirator, sweetener, mucilage. In step (II) of the process according to the invention, dapoxetine, preferably dapoxetine resinate, is mixed with further pharmaceutical excipients. The mixing can be done in conventional mixers. For example, the mixing can be done in compulsory or free-fall mixers, z. Example by means of Turbula ^® T 10B (Bachofen AG, Switzerland).

When mixed in compulsory mixers usually times of 3 to 15 minutes are required to achieve a homogeneous mixture. When using free-fall mixers z. Example by means of Turbula ^® T 10B (Bachofen AG, Switzerland) or container mixers z. B. by CM 500 (J. Engelsmann AG, Germany) or drum mixers z. B. type Rhönradmischer (J. Engelsmann AG, Germany) are usually times of 10 to 20 minutes needed to produce the homogeneous mixture.

Optionally, the mixture obtained in step (II) of the process according to the invention in step (III) is granulated. The granulation can be carried out by methods known in the art. The granulation is preferably carried out as a dry granulation. Alternatively, a wet granulation can be done.

In a preferred embodiment, a melt granulation takes place. In this case, the provided in step (I) dapoxetine, preferably Dapoxetinresinat be embedded in a melt. Usually, the melt is formed from a matrix-forming polymer (= matrix former). In the context of this invention, the "matrix former" is generally a pharmaceutical excipient which, when heated above the melting point, in particular in a melt granulation or melt extrusion process, is deformable and able to embed the dapoxetine resinate according to the invention, i. H. to form a matrix for particulate dapoxetine resinate. The matrix former thus preferably has a thermoplastic behavior, i. H. it is a thermoplastic matrix former.

Polyvinylpyrrolidone, preferably having a weight-average molecular weight of 10,000 to 40,000 g / mol, copolymer of vinylpyrrolidone and vinyl acetate, in particular having a weight-average molecular weight of 40,000 to 75,000 g / mol, of polyethylene glycol, in particular having a weight-average molecular weight of 2,000 to 20,000, is preferably used as matrix former g / mol, polyoxyethylene alkyl ethers and / or polyvinyl alcohol, preferably having a weight-average molecular weight of from 1,000 to 30,000 g / mol. As a matrix former alternatively used are co-block polymers of polyethylene glycol and polypropylene glycol, ie polyoxyethylene polyoxypropylene block polymers. Preferably, these have a weight-average molecular weight of from 1,000 to 20,000 g / mol, more preferably from 1,500 to 12,500 g / mol, in particular from 5,000 to 10,000 g / mol. These block polymers are preferably obtainable by condensation of propylene oxide with propylene glycol and subsequent condensation of the resulting polymer with ethylene oxide. That is, preferably, the ethylene oxide is present as an "end block". Preferably, the block polymers have a weight ratio of propylene oxide to ethylene oxide of from 50:50 to 95: 5, more preferably from 70:30 to 90:10. The block polymers preferably have a viscosity at 25 ° C. of from 200 to 2000 mPas, more preferably from 500 to 1500 mPas, in particular from 800 to 1200 mPas, measured at 25 ° C. and according to Ph. Eur., 6th edition, chapter 2.2.10 certainly.

In step (IV), the compression of the mixture obtained from step (II) or the granulate obtained from step (III) is carried out to form a fused tablet, i. H. a compression to tablets. The compression can be done with tableting machines known in the art. The compression is preferably carried out in the absence of solvents.

Examples of suitable tableting machines are eccentric presses or concentric presses. For example, a Korsch eccentric EKO (Korsch AG, Germany) can be used. In the case of eccentric presses and rotary presses, a pressing force of 3 to 50 kN, preferably 7.5 to 35 kN, is usually used.

In a preferred embodiment of the method according to the invention Dapoxetinresinat is mixed with other pharmaceutical excipients, preferably with the proviso that no lubricant (g) is mixed. The mixture is preferably carried out for 1 to 15 minutes, in particular for 3 to 7 minutes. It can, for. B. a Turbula ^® T 10B can be used. The mixture is then preferably sieved through a sieve, in particular with a mesh size of 500 to 1000 microns, z. B. 800 microns. Preference is mixed for another 1 to 15 minutes. Subsequently, a lubricant (g) is preferably sieved through a sieve, z. B. over a sieve of mesh size 800 microns, and the mixture was added. The mixture now obtained is preferably again for z. B. mixed for 1 to 5 minutes. The resulting mixture is then, z. B. using a Korsch eccentric EKO, pressed.

The invention further relates to dapoxetine resinate for the treatment of sexual dysfunction wherein an oral dosage form containing dapoxetine resetin is taken without liquid.

In this application is meant by "oral dosage forms" all pharmaceutical dosage forms that are taken orally. Examples of oral dosage forms according to the invention are tablets, capsules and granules. Examples of tablets are orodispersible tablets, lozenges, uncoated tablets, coated tablets, effervescent tablets, enteric coated tablets, modified release tablets, oral cavity tablets, suspension tablets. Preference is given thereto orodispersible tablets.

In this application, taking the oral dosage form without liquid, the ingestion of the oral dosage form of the invention without additional fluid intake such. B. understood the ingestion of the oral dosage form with water.

Sexual dysfunction in the context of this invention is usually understood to mean a disorder of sexual functions or reactions, preferably an ejaculation of Praecox.

The inventors have also found that a cation exchange resin is useful in masking a local anesthetic effect of a drug, preferably a drug for the treatment of sexual dysfunction, in the mouth.

In the context of this invention, masking is understood as the weakening or obliterating of a sensation produced by one or more substances in the mouth of the patient.

Under local anesthetic effect in the mouth is understood in the context of this invention, a numbing sensation in the mouth of a patient.

The invention therefore further provides the use of a cation exchange resin for masking a local anesthetic effect of a drug, preferably a drug for the treatment of sexual dysfunction, in the mouth.

The present invention will be illustrated by the following examples.

EXAMPLES

The dapoxetine resinate according to the invention and orodispersible tablets containing dapoxetine resinate were prepared by the methods according to the invention. The formulations used and the physical properties of the resulting orodispersible tablets are shown in the following table.

example 1

Dapoxetinresinate was prepared by the method according to the invention.

To this end, 100 ml of demineralized water were placed in a test tube with stirring fish and 34.02 mg dapoxetine-HCl added. With constant stirring, polacrilin potassium NF was then added to the mixture and the pH was measured continuously. After stirring for 3 h, a constant pH was achieved. The mixture was then passed through a filter paper and dried in an oven at 80 ° C for 14 h.

Example 2

Melt tablets containing Dapoxetinresinat were prepared by the method according to the invention. Example 2.1 Direct tableting material Quantity (in mg) 1. Dapoxetine Resinate 60,00 2. sorbitol (Neosorb ^®) 140.00 3. sodium starch (Explotab ^®) 20.00 4. Cross-linked polyvinylpyrrolidone (Kollidon CL ^®) 40,00 5. Saccharin sodium 5.00 6. Peppermint flavor 3.00 7. Menthol flavor 3.00 8. Sodium stearyl (PRUV ^®) 5.00

For this purpose, the dapoxetine resinate prepared in Example 1 was mixed at position 2-7 for 5 minutes in Turbula T 10B and then comminuted. The mixture was sieved through a sieve of mesh size 800 μm and mixed for a further 10 minutes in Turbula T 10B. Then position 8 was sieved through a sieve of size 300 microns and added to the mixture. The mixture was then mixed for a further 5 minutes in the Turbula T 10B. The resulting mixture was pressed directly using a Korsch eccentric press EKO.

Example 2.2 Tableting of dapoxetine resinate with prior melt embedment

Melt embedding of Dapoxetine Resinate: material Quantity (in mg) Dapoxetinresinat 60,00 PEG 6000 30.00

30.00 mg PEG 6000 was melted on the water bath at 50 ° C. Subsequently, 60.00 mg dapoxetine resinate was granulated into the PEG 6000 melt. material Quantity (in mg) 1. Dapoxetine granules 90.00 2. sorbitol (Neosorb ^®) 140.00 3. sodium starch (Explotab ^®) 20.00 4. Cross-linked polyvinylpyrrolidone (Kollidon CL ^®) 40,00 5. Saccharin sodium 5.00 6. Peppermint flavor 3.00 7. Menthol flavor 3.00 8. Sodium stearyl (PRUV ^®) 5.00

After solidification, the resulting granules were crushed and sieved through a sieve of mesh size 800 microns. Dapoxetine granules were then mixed at position 2 to 7 for 5 minutes in the Turbula T 10B. The mixture was sieved through a sieve of mesh size 800 μm and mixed for a further 10 minutes in Turbula T 10B.

Subsequently, position 8 was screened through a sieve of mesh size 300 microns and added to the mixture. It was then mixed again for 3 minutes in the Turbula T10B. The resulting mixture was then compressed into tablets using the Korsch eccentric press EKO.

Example 3: Tablet properties

Ten of the orodispersible tablets prepared according to Examples 2.1 and 2.2 were tested for the following parameters: Breaking strength, disintegration time, taste and local anesthetic effect. The values of each parameter shown in Table 1 are to be understood as the mean value of 10 tablets. Table 1 parameter Tablet Example 2.1 Tablet Example 2.2 Breaking strength (in N) 50 50 Decay time (in s) 30 120 taste sensation pleasant peppermint flavor pleasant peppermint flavor Local anesthetic effect no local anesthetic effect no local anesthetic effect

The test of the breaking strength was according to Pharm. Eur. 6.0, chapter 2.9.8 determined.

The disintegration time of the orodispersible tablets was determined according to Pharm. Eur. 6.0, chapter 2.9.1 Test A is determined at a temperature of 37 ° C.

The local anesthetic effect was determined with the help of 10 test persons.

On a scale of 1 to 4, the subjects were able to evaluate their perception of the local anesthetic effect in the mouth. The individual stages 1 to 4 were defined as follows: (1) "strong local anesthetic effect", (2) "average local anesthetic effect", (3) "slight local anesthetic effect (4)" no local anesthetic effect ". The evaluation points of the 10 subjects were added together and the sum of all evaluation points classified accordingly: 10 to 15 points: "distinct local anesthetic effect", 16 to 30 points: "moderate local anesthetic effect", 31 to 40 points: "no local anesthetic effect".

Since taste sensations may be individually different, 10 subjects were used to taste test the orodispersible tablets prepared according to Examples 2.1 and 2.2, and the average taste perception was determined.

For tasting and local anesthetic effects, the tasting took place 1 hour after the last meal. The subjects were all male and non-smokers. The test room was of a neutral odor, the temperature was 20 ° C. The assessment of the stimulus sensations and the training of the test persons was carried out according to DIN 10950 ,

QUOTES INCLUDE IN THE DESCRIPTION

This list of the documents listed by the applicant has been generated automatically and is included solely for the better information of the reader. The list is not part of the German patent or utility model application. The DPMA assumes no liability for any errors or omissions.

Cited patent literature

• EP 0288188 B1 [0004]
• EP 1225881 B1 [0005]

Cited non-patent literature

• European Pharmacopoeia, 6th edition, Grundwerk 2008 [0018]
• Ph. Eur. 6th Edition [0019]
• Ph. Eur. 6th Edition Chapter 2.9.1 [0020]
• Ph. Eur. 6th Edition Chapter 2.9.8 [0023]
• Ph. Eur. 6.0, Section 2.9.7 [0024]
• Council Directive 88/38 / EEC " Flavorings " of 22 June 1988 [0048]
• Ph. Eur. 6th Edition Chapter 2.2.10 [0067]
• Ph. Eur., 6th edition 2.9.26 [0078]
• Ph. Eur., 6th Edition, Chapter 2.2.10 [0112]
• Pharm. Eur. 6.0, chapter 2.9.8 [0135]
• Pharm. Eur. 6.0, chapter 2.9.1 [0136]
• DIN 10950 [0140]

Claims (16)

Orodispersible tablet containing dapoxetine. An orodispersible tablet according to claim 1, comprising (a) dapoxetine, and (b) a polymeric adsorbent, preferably a cation exchange resin. The orodispersible tablet according to claim 2, wherein the components (a) and (b) are in the form of dapoxetine resinate (a-b). Orodispersible tablet according to claims 1 to 3, additionally containing a breath freshening agent (c). Melt tablet according to claims 1 to 4, additionally containing a sweetening agent (d). Melt tablet according to claims 1 to 5, additionally containing a gum (e). The orodispersible tablet according to claims 2 to 6, wherein the polymeric adsorbent (b) is polacrilin potassium. The orodispersible tablet according to claims 1 to 7, wherein the weight ratio of dapoxetine (a) to polymeric adsorbent (b) is 1:10 to 10: 1. The orodispersible tablet according to claims 1 to 8, wherein dapoxetine (a) in an amount of 1 to 25 wt .-% and the polymeric adsorbent (b) in an amount of 1 to 60 wt .-%, based on the total weight of the orodispersible tablet are. Process for the preparation of dapoxetine resinate, comprising the steps: (i) dissolving dapoxetine (a), (ii) dispersing a polymeric adsorbent (b), (iii) optionally stirring until a stable pH is reached, (iv) filtering the dispersion obtained from step (ii) or step (iii), (v) drying the filter cake obtained from step (iv). A process according to claim 11 wherein in step (i) dapoxetine HCl is used as component (a) and in step (ii) polacrilin potassium is used as component (b) and preferably in step (iii) up to a pH of is stirred at least 7.0. A process for preparing a orodispersible tablet containing dapoxetine resinate comprising the steps (I) providing dapoxetine resinate, (II) mixing with other pharmaceutical excipients, (III) optionally granulating the mixture obtained from step (II), (IV) pressing the mixture obtained from step (II) or from step (III). obtained granules to an orodispersible tablet. Dapoxetinresinat. Dapoxetine resinate according to claim 13, obtainable by a method according to claim 10 or 11. Dapoxetinresinat for the treatment of sexual dysfunction, wherein an oral dosage form containing Dapoxetinresinat is taken without liquid. Use of a cation exchange resin for masking a local anesthetic effect of a drug, preferably a drug for the treatment of sexual dysfunction, in the mouth.