New Use of flibanserin

The invention relates to the use of flibanserin for preparing a medicament for treating diseases in which the use of therapeutic effective amounts of compounds displaying affinity for the 5-HT _2B -receptor display a therapeutic benefit.

Description of the invention

The compound 1 -[2-(4-(3-trifluoromethyl-phenyl)piperazin-1 -yl)ethyl]-2,3-dihydro-1 H- benzimidazol-2-one (flibanserin) is disclosed in form of its hydrochloride in European Patent Application EP-A-526434 and has the following chemical structure:

Flibanserin shows affinity for the 5-HT1 A and 5-HT2-receptor. It is therefore a promising therapeutic agent for the treatment or prevention of a variety of diseases, for instance depression, schizophrenia, and anxiety.

Surprisingly, it has now been found that flibanserin, optionally in form the free base, the pharmacologically acceptable acid addition salts and/or optionally in form of the hydrates and/or solvates thereof shows affinity for the 5-HT _2B -receptor with antagonistic activity. Accordingly, the instant invention relates to the use of flibanserin, optionally in form the free base, the pharmacologically acceptable acid addition salts and/or optionally in form of the hydrates and/or solvates thereof for the preparation of a medicament for preventing and/or treating diseases in which the use of therapeutic effective amounts of compounds displaying affinity for the 5-HT _2B - receptor display a therapeutic benefit.

In a preferred embodiment the instant invention relates to the use of flibanserin, optionally in form the free base, the pharmacologically acceptable acid addition salts and/or optionally in form of the hydrates and/or solvates thereof for the preparation

of a medicament for preventing and/or treating diseases in which the use of therapeutic effective amounts of compounds displaying antagonistic activity to the 5- HT _2B -receptor display a therapeutic benefit.

Pulmonary arterial hypertension (PAH) is the clinical term used to describe a condition associated with progressive elevation in pulmonary arterial pressure (by 10-15 mmHg). PAH occurs more commonly secondary to collagen vascular disease, congenital systemic to pulmonary shunt, portal hypertension, human immunodeficiency virus infection, chronic obstructive lung diseases, interstitial fibrosis and high left-sided filling pressures.

In the normal lung, low pulmonary vascular tone is regulated by a balance between the effects of vasodilators/antiproliferative agents such as prostacyclin and nitric oxide and vasoconstrictors/co-mitogens such as 5-HT (5-Hydroxytryptamin).

Alterations in 5-HT turnover leading to an increased availability of free 5-HT in the vicinity of the pulmonary artery wall. Under normal conditions, the lung vascular bed is not exposed to excessive 5-HT levels, because of its position as a secondary filter located downstream from the liver and because of the ability of platelets to store large amounts of 5-HT. 5-HT can cause relaxation of pulmonary arteries, an effect that is most likely mediated by 5-HT2B receptors: a similar relaxation is seen with 5- HT2B agonists.

Accordingly, in a further embodiment the invention relates to the use of flibanserin, optionally in form the free base, the pharmacologically acceptable acid addition salts and/or optionally in form of the hydrates and/or solvates thereof for the preparation of a medicament for preventing and/or treating Pulmonary arterial hypertension (PAH).

In a further embodiment the invention relates to the use of flibanserin, optionally in form the free base, the pharmacologically acceptable acid addition salts and/or optionally in form of the hydrates and/or solvates thereof for the preparation of a medicament for preventing and/or treating PAH secondary to collagen vascular disease.

In a further embodiment the invention relates to the use of flibanserin, optionally in form the free base, the pharmacologically acceptable acid addition salts and/or optionally in form of the hydrates and/or solvates thereof for the preparation of a medicament for preventing and/or treating PAH congenital systemic to pulmonary shunt.

In a further embodiment the invention relates to the use of flibanserin, optionally in form the free base, the pharmacologically acceptable acid addition salts and/or optionally in form of the hydrates and/or solvates thereof for the preparation of a medicament for preventing and/or treating PAH secondary to portal hypertension.

In a further embodiment the invention relates to the use of flibanserin, optionally in form the free base, the pharmacologically acceptable acid addition salts and/or optionally in form of the hydrates and/or solvates thereof for the preparation of a medicament for preventing and/or treating PAH secondary to human immunodeficiency virus infection.

In a further embodiment the invention relates to the use of flibanserin, optionally in form the free base, the pharmacologically acceptable acid addition salts and/or optionally in form of the hydrates and/or solvates thereof for the preparation of a medicament for preventing and/or treating PAH secondary to chronic obstructive lung diseases.

In a further embodiment the invention relates to the use of flibanserin, optionally in form the free base, the pharmacologically acceptable acid addition salts and/or optionally in form of the hydrates and/or solvates thereof for the preparation of a medicament for preventing and/or treating PAH secondary to interstitial fibrosis.

In a further embodiment the invention relates to the use of flibanserin, optionally in form the free base, the pharmacologically acceptable acid addition salts and/or optionally in form of the hydrates and/or solvates thereof for the preparation of a

medicament for preventing and/or treating PAH secondary to high left-sided filling pressures.

Another embodiment of the invention relates to a method for preventing and/or treating of any of the aforementioned conditions comprising the administration of a therapeutically effective amount of flibanserin optionally in form the free base, the pharmacologically acceptable acid addition salts and/or optionally in form of the hydrates and/or solvates thereof.

Flibanserin can optionally be used in form of its pharmaceutically acceptable acid addition salts. Suitable acid addition salts include for example those of the acids selected from, succinic acid, hydrobromic acid, acetic acid, fumaric acid, maleic acid, methanesulphonic acid, lactic acid, phosphoric acid, hydrochloric acid, sulphuric acid, tartaric acid and citric acid. Mixtures of the abovementioned acid addition salts may also be used. From the aforementioned acid addition salts the hydrochloride and the hydrobromide, particularly the hydrochloride, are preferred. If flibanserin is used in form of the free base, it is preferably used in form of flibanserin polymorph A as disclosed in WO 03/014079.

Flibanserin, optionally used in form the free base, the pharmacologically acceptable acid addition salts and/or optionally in form of the hydrates and/or solvates thereof, may be incorporated into the conventional pharmaceutical preparation in solid, liquid or spray form. The composition may, for example, be presented in a form suitable for oral, rectal, parenteral administration or for nasal inhalation: preferred forms includes for example, capsules, tablets, coated tablets, ampoules, suppositories and nasal spray.

The active ingredient may be incorporated in excipients or carriers conventionally used in pharmaceutical compositions such as, for example, talc, arabic gum, lactose, gelatine, magnesium stearate, corn starch, acqueous or non acqueous vehicles, polyvynil pyrrolidone, semisynthetic glicerides of fatty acids, benzalconium chloride, sodium phosphate , EDTA, polysorbate 80. The compositions are advantageously

formulated in dosage units, each dosage unit being adapted to supply a single dose of the active ingredient. The dose range applicable per day is between 0.1 to 400, preferably between 1.0 to 300, more preferably between 2 to 200 mg Flibanserin. Each dosage unit may conveniently contain from 0,01 mg to 100 mg Flibanserin, preferably from 0,1 to 50 mg.

The dosage units are administered to the patient 1 , 2, 3, or 4 times daily. It is preferred that flibanserin is administered either three or fewer times, more preferably once or twice daily consecutively over a period of time.

Preferably, the dose is administered to a patient in the morning and the evening, more preferably once in the morning and once in the evening, most preferably once in the evening only consecutively over a period of time.

Suitable tablets may be obtained, for example, by mixing the active substance(s) with known excipients, for example inert diluents such as calcium carbonate, calcium phosphate or lactose, disintegrants such as corn starch or alginic acid, binders such as starch or gelatine, lubricants such as magnesium stearate or talc and/or agents for delaying release, such as carboxymethyl cellulose, cellulose acetate phthalate, or polyvinyl acetate. The tablets may also comprise several layers.

Coated tablets may be prepared accordingly by coating cores produced analogously to the tablets with substances normally used for tablet coatings, for example collidone or shellac, gum arabic, talc, titanium dioxide or sugar. To achieve delayed release or prevent incompatibilities the core may also consist of a number of layers. Similarly the tablet coating may consist of a number or layers to achieve delayed release, possibly using the excipients mentioned above for the tablets.

Syrups or elixirs containing the active substances or combinations thereof according to the invention may additionally contain a sweetener such as saccharine, cyclamate, glycerol or sugar and a flavour enhancer, e.g of. a flavouring such as vanilline or orange extract. They may also contain suspension adjuvants or thickeners such as sodium carboxymethyl cellulose, wetting agents such as, for

example, condensation products of fatty alcohols with ethylene oxide, or preservatives such as p-hydroxybenzoates.

Solutions for injection are prepared in the usual way, e.g of. with the addition of preservatives such as p-hydroxybenzoates, or stabilisers such as alkali metal salts of ethylenediamine tetraacetic acid, and transferred into injection vials or ampoules.

Capsules containing one or more active substances or combinations of active substances may for example be prepared by mixing the active substances with inert carriers such as lactose or sorbitol and packing them into gelatine capsules.

Suitable suppositories may be made for example by mixing with carriers provided for this purpose, such as neutral fats or polyethyleneglycol or the derivatives thereof.

The Examples which follow illustrate the present invention without restricting its scope:

Examples of pharmaceutical formulations

A) Tablets per tablet

flibanserin hydrochloride 100 mg lactose 240 mg corn starch 340 mg polyvinylpyrrolidone 45 mg magnesium stearate 15 mg

740 mg

The finely ground active substance, lactose and some of the corn starch are mixed together. The mixture is screened, then moistened with a solution of Polyvinylpyrrolidone in water, kneaded, wet-granulated and dried. The granules, the

remaining corn starch and the magnesium stearate are screened and mixed together. The mixture is compressed to produce tablets of suitable shape and size.

B) Tablets per tablet

flibanserin hydrochloride 80 mg corn starch 190 mg lactose 55 mg microcrystalline cellulose 35 mg polyvinylpyrrolidone 15 mg sodium-carboxymethyl starch 23 mg magnesium stearate 2 mg

400 mg

The finely ground active substance, some of the corn starch, lactose, microcrystalline cellulose and polyvinylpyrrolidone are mixed together, the mixture is screened and worked with the remaining corn starch and water to form a granulate which is dried and screened. The sodium-carboxymethyl starch and the magnesium stearate are added and mixed in and the mixture is compressed to form tablets of a suitable size.

C) Coated tablets per coated tablet

flibanserin hydrochloride 5 mg corn starch 41.5 mg lactose 30 mg polyvinylpyrrolidone 3 mg magnesium stearate 0.5 mg

80 mg

The active substance, corn starch, lactose and polyvinylpyrrolidone are thoroughly mixed and moistened with water. The moist mass is pushed through a screen with a 1 mm mesh size, dried at about 45°C and the granules are then passed through the same screen. After the magnesium stearate has been mixed in, convex tablet cores with a diameter of 6 mm are compressed in a tablet-making machine . The tablet cores thus produced are coated in known manner with a covering consisting essentially of sugar and talc. The finished coated tablets are polished with wax.

D) Capsules per capsule

Flibanserin hydrochloride 150 mg

Corn starch 268 ■5 mg

Magnesium stearate 1 ■5 mg

420 mg

The substance and corn starch are mixed and moistened with water. The moist mass is screened and dried. The dry granules are screened and mixed with magnesium stearate. The finished mixture is packed into size 1 hard gelatine capsules.

E) Ampoule solution

flibanserin hydrochloride 50 mg sodium chloride 50 mg water for inj. 5 ml

The active substance is dissolved in water at its own pH or optionally at pH 5.5 to 6.5 and sodium chloride is added to make it isotonic. The solution obtained is filtered free from pyrogens and the filtrate is transferred under aseptic conditions into ampoules which are then sterilised and sealed by fusion.

F) Suppositories

flibanserin hydrochloride 50 mg solid fat 1650 mg

1700 mg

The hard fat is melted. At 40 ⁰ C the ground active substance is homogeneously dispersed. It is cooled to 38°C and poured into slightly chilled suppository moulds.

In a particular preferred embodiment of the instant invention, flibanserin is administered in form of specific film coated tablets. Examples of these preferred formulations are listed below. The film coated tablets listed below can be manufactured according to procedures known in the art (see hereto WO 03/097058).

G) Film coated tablet Core

Coating

Iron oxide red 0.026

Total Film coated tablet 128.000

H) Film coated tablet Core

Coating

I) Film coated tablet Core

Coating

J) Film coated tablet Core

Coating

Total Film coated tablet 133.000

K) Film coated tablet

Core

Coating

L) Film coated tablet

Core

Coating