Patent Publication Number: US-2006014757-A1

Title: Method for the treatment of anorexia nervosa

Description:
The invention relates to a method for the treatment of anorexia nervosa comprising the administration of a therpeutically effective amount of flibanserin. 
    
    
     DESCRIPTION OF THE INVENTION  
      The compound 1-[2-(4-(3-trifluoromethyl-phenyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H-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-HT 1A  and 5-HT 2 -receptor. It is therefore a promising therapeutic agent for the treatment of a variety of diseases, for instance depression, schizophrenia, and anxiety.  
      The instant invention relates to a method for the treatment of anorexia nervosa comprising the administration of a therapeutically effective amount of flibanserin, optionally in form of the pharmacologically acceptable acid addition salts thereof.  
      Another embodiment of the invention relates to the use of flibanserin, optionally in form of the pharmacologically acceptable acid addition salts thereof for the preparation of a medicament for the treatment of anorexia nervosa.  
      Anorexia nervosa is a disorder usually occurring in teenage girls, characterized by a fear of obesity, a distorted self-image, an aversion to food, and severe weight loss.  
      Sub-indications include the binge-eating/purging type of anorexia nervosa, in which the patient engages in these behaviors regularly, and the restricting type, in which the patient simply restricts intake. Other associated mental disorders include depressive symptoms, obsessive-compulsive features, social anxiety related to eating in public.  
      Accordingly, the instant invention further relates to a method for the treatment of binge-eating/purging type of anorexia nervosa and the restricting type of anorexia nervosa comprising the administration of a therapeutically effective amount of flibanserin, optionally in form of the pharmacologically acceptable acid addition salts thereof. Moreover, the instant invention relates to a method for the treatment of anorexia nervosa accociated with mental disorders, including depressive symptoms, obsessive-compulsive features, social anxiety related to eating in public comprising the administration of a therapeutically effective amount of flibanserin, optionally in form of the pharmacologically acceptable acid addition salts thereof.  
      Another embodiment of the invention relates to the use of flibanserin, optionally in form of the pharmacologically acceptable acid addition salts thereof for the preparation of a medicament for the treatment of binge-eating/purging type of anorexia nervosa and the restricting type of anorexia nervosa. Another embodiment of the invention relates to the use of flibanserin, optionally in form of the pharmacologically acceptable acid addition salts thereof for the preparation of a medicament for the treatment of of anorexia nervosa accociated with mental disorders, including depressive symptoms, obsessive-compulsive features, social anxiety related to eating in public.  
      Flibanserin can optionally 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, particularity the hydrochloride, are preferred.  
      Flibanserin, optionally used in form of its pharmaceutically acceptable acid addition salts, 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 dosis range applicable per day is between 0.1 to 400, preferably between 1.0 to 300, more preferably between 2 to 200 mg.  
      Each dosage unit may conveniently contain from 0.01 mg to 100 mg, preferably from 0.1 to 50 mg.  
      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° 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 instsnt 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                             Constituents   mg/tablet                                             Core                       Flibanserin   25.000               Lactose monohydrate   71.720               Microcrystalline cellulose   23.905               HPMC (Methocel E5)   1.250               Carboxymethylcellulose sodium   2.500               Magnesium stearate   0.625                             Coating                                         HPMC (Methocel E5)   1.440               Polyethylene Glycol 6000   0.420               Titanium dioxide   0.600               Talc   0.514               Iron oxide red   0.026               Total Film coated tablet   128.000                      
 
     
       
         
           
               
            
               
                   
               
               
                   
               
               
                 H) Film coated tablet 
               
            
           
           
               
               
               
            
               
                   
                 Constituents 
                 mg/tablet 
               
               
                   
                   
               
            
           
           
               
               
               
               
            
               
                   
                 Core 
                   
                   
               
               
                   
                   
                 Flibanserin 
                 50.000 
               
               
                   
                   
                 Lactose monohydrate 
                 143.440 
               
               
                   
                   
                 Microcrystalline cellulose 
                 47.810 
               
               
                   
                   
                 HPMC (e.g. Pharmacoat 606) 
                 2.500 
               
               
                   
                   
                 Carboxymethylcellulose sodium 
                 5.000 
               
               
                   
                   
                 Magnesium stearate 
                 1.250 
               
            
           
           
               
               
               
            
               
                   
                 Coating 
                   
               
            
           
           
               
               
               
               
            
               
                   
                   
                 HPMC (e.g. Pharmacoat 606) 
                 2.400 
               
               
                   
                   
                 Polyethylene Glycol 6000 
                 0.700 
               
               
                   
                   
                 Titanium dioxide 
                 1.000 
               
               
                   
                   
                 Talc 
                 0.857 
               
               
                   
                   
                 Iron oxide red 
                 0.043 
               
               
                   
                   
                 Total Film coated tablet 
                 255.000 
               
               
                   
                   
               
            
           
         
       
     
     
       
         
           
               
            
               
                   
               
               
                   
               
               
                 I) Film coated tablet 
               
            
           
           
               
               
               
            
               
                   
                 Constituents 
                 mg/tablet 
               
               
                   
                   
               
            
           
           
               
               
               
               
            
               
                   
                 Core 
                   
                   
               
               
                   
                   
                 Flibanserin 
                 100.000 
               
               
                   
                   
                 Lactose monohydrate 
                 171.080 
               
               
                   
                   
                 Microcrystalline cellulose 
                 57.020 
               
               
                   
                   
                 HPMC (e.g. Methocel E5) 
                 3.400 
               
               
                   
                   
                 Carboxymethylcellulose sodium 
                 6.800 
               
               
                   
                   
                 Magnesium stearate 
                 1.700 
               
               
                   
                 Coating 
               
               
                   
                   
                 HPMC (e.g. Methocel E5) 
                 3.360 
               
               
                   
                   
                 Polyethylene Glycol 6000 
                 0.980 
               
               
                   
                   
                 Titanium dioxide 
                 1.400 
               
               
                   
                   
                 Talc 
                 1.200 
               
               
                   
                   
                 Iron oxide red 
                 0.060 
               
               
                   
                   
                 Total Film coated tablet 
                 347.000 
               
               
                   
                   
               
            
           
         
       
     
     
       
         
           
               
            
               
                   
               
               
                   
               
               
                 J) Film coated tablet 
               
            
           
           
               
               
               
            
               
                   
                 Constituents 
                 mg/tablet 
               
               
                   
                   
               
            
           
           
               
               
               
               
            
               
                   
                 Core 
                   
                   
               
               
                   
                   
                 Flibanserin 
                 2.000 
               
               
                   
                   
                 Dibasic Calciumphosphate, anhydrous 
                 61.010 
               
               
                   
                   
                 Microcrystalline cellulose 
                 61.010 
               
               
                   
                   
                 HPMC (Methocel E5) 
                 1.950 
               
               
                   
                   
                 Carboxymethylcellulose sodium 
                 2.600 
               
               
                   
                   
                 Colloidal silicon dioxide 
                 0.650 
               
               
                   
                   
                 Magnesium stearate 
                 0.780 
               
               
                   
                 Coating 
               
               
                   
                   
                 HPMC (Methocel E5) 
                 1.440 
               
               
                   
                   
                 Polyethylene Glycol 6000 
                 0.420 
               
               
                   
                   
                 Titanium dioxide 
                 0.600 
               
               
                   
                   
                 Talc 
                 0.514 
               
               
                   
                   
                 Iron oxide red 
                 0.026 
               
               
                   
                   
                 Total Film coated tablet 
                 133.000 
               
               
                   
                   
               
            
           
         
       
     
     
       
         
           
               
            
               
                   
               
               
                   
               
               
                 K) Film coated tablet 
               
            
           
           
               
               
               
            
               
                   
                 Constituents 
                 mg/tablet 
               
               
                   
                   
               
            
           
           
               
               
               
               
            
               
                   
                 Core 
                   
                   
               
               
                   
                   
                 Flibanserin 
                 100.000 
               
               
                   
                   
                 Dibasic Calciumphosphate, anhydrous 
                 69.750 
               
               
                   
                   
                 Microcrystalline cellulose 
                 69.750 
               
               
                   
                   
                 HPMC (e.g. Methocel E5) 
                 2.750 
               
               
                   
                   
                 Carboxymethylcellulose sodium 
                 5.000 
               
               
                   
                   
                 Colloidal silicon dioxide 
                 1.250 
               
               
                   
                   
                 Magnesium stearate 
                 1.500 
               
               
                   
                 Coating 
               
               
                   
                   
                 HPMC (e.g. Methocel E5) 
                 2.400 
               
               
                   
                   
                 Polyethylene Glycol 6000 
                 0.700 
               
               
                   
                   
                 Titanium dioxide 
                 1.043 
               
               
                   
                   
                 Talc 
                 0.857 
               
               
                   
                   
                 Total Film coated tablet 
                 255.000 
               
               
                   
                   
               
            
           
         
       
     
     
       
         
           
               
            
               
                   
               
               
                   
               
               
                 L) Film coated tablet 
               
            
           
           
               
               
               
            
               
                   
                 Constituents 
                 mg/tablet 
               
               
                   
                   
               
            
           
           
               
               
               
            
               
                 Core 
                   
                   
               
               
                   
                 Flibanserin 
                 20.000 
               
               
                   
                 Lactose monohydrate 
                 130.000 
               
               
                   
                 Microcrystalline cellulose 
                 43.100 
               
               
                   
                 Hydroxypropyl Cellulose (e.g. Klucel LF) 
                 1.900 
               
               
                   
                 Sodium Starch Glycolate 
                 4.000 
               
               
                   
                 Magnesium stearate 
                 1.000 
               
               
                 Coating 
               
               
                   
                 HPMC (e.g. Methocel E5) 
                 2.400 
               
               
                   
                 Polyethylene Glycol 6000 
                 0.700 
               
               
                   
                 Titanium dioxide 
                 1.043 
               
               
                   
                 Talc 
                 0.857 
               
               
                   
                 Total Film coated tablet 
                 205.000