US 20060204486A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2006/0204486A1 Pyke et al. (43) Pub. Date: Sep. 14, 2006

(54) PHARMACEUTICAL COMPOSITIONS FOR Publication Classification THE TREATMENT AND/OR PREVENTION OF SCHIZOPHRENA AND RELATED (51) Int. Cl. DISEASES A6II 38/54 (2006.01) A6II 3/55 (2006.01) (75) Inventors: Robert Pyke, New Fairfield, CT (US); A61K 3.1/5415 (2006.01) Angelo Ceci, Mittlebiberach (DE) A 6LX 3/59 (2006.01) A6II 3L/496 (2006.01) Correspondence Address: A6II 3/445 (2006.01) MICHAEL P. MORRIS A6II 3/405 (2006.01) BOEHRINGERINGELHEM CORPORATION A6II 3L/98 (2006.01) 900 RIDGEBURY ROAD (52) U.S. Cl...... 424/94.2: 514/254.06; 514/220; P. O. BOX 368 514/259.41: 514/419; 514/317; RIDGEFIELD, CT 06877-0368 (US) 514/561; 514/225.8 (73) Assignee: Boehringer Ingelheim International GmbH, Ingelheim (DE) (57) ABSTRACT (21) Appl. No.: 11/364,306 The invention relates to new pharmaceutical compositions for the treatment and/or prevention of schizophrenia and (22) Filed: Feb. 28, 2006 methods for the preparation thereof. In a preferred embodi ment, the instant invention is directed to pharmaceutical Related U.S. Application Data combinations comprising flibanserin as one active ingredi ent in combination with at least one additional active ingre (60) Provisional application No. 60/658,566, filed on Mar. dient for the treatment and/or prevention of schizophrenia 4, 2005. and methods for the preparation thereof. US 2006/0204486 A1 Sep. 14, 2006

PHARMACEUTICAL COMPOSITIONS FOR THE antagonists, alpha 2 adrenoreceptor antagonists, AMPA TREATMENT AND/OR PREVENTION OF modulators and NK 3 antagonists. SCHIZOPHRENA AND RELATED DISEASES 0007 Especially preferred are pharmaceutical composi 0001. The invention relates to new pharmaceutical com tions comprising a therapeutically effective amount of fli positions for the treatment and/or prevention of Schizophre banserin 1 in combination with a therapeutically effective nia and related diseases and methods for the preparation amount of one or more, preferably one antipsychotic drug 2 thereof. In a preferred embodiment, the instant invention is selected from the group consisting of D2 antagonists. directed to pharmaceutical combinations comprising fli banserin as one active ingredient in combination with at 0008. The compositions according to the invention may least one additional active ingredient for the treatment contain flibanserin 1 and the one or more additional antip and/or prevention of Schizophrenia and related diseases and sychotic drugs 2 in a single formulation or in separate methods for the preparation thereof. formulations. If flibanserin and the one or more additional antipsychotic drugs are present in separate formulations BACKGROUND OF THE INVENTION these separate formulations may be administered simulta neously or sequentially. 0002 The invention relates to new pharmaceutical com positions for the treatment and/or prevention of Schizophre 0009. A preferred embodiment according to the invention nia and related diseases and methods for the preparation is directed to pharmaceutical compositions comprising a thereof. In one embodiment, the instant invention is directed therapeutically effective amount of flibanserin 1 and a to pharmaceutical combinations comprising a therapeuti therapeutically effective amount of one or more, preferably cally effective amount of flibanserin 1 as one active ingre one additional antipsychotic drug. 2, optionally in combina dient of combination with a therapeutically effective amount tion with a pharmaceutically acceptable excipient. of at one or more, preferably one additional antipsychotic 00.10 Examples of suitable additional antipsychotic drug 2 for the treatment and/or prevention of Schizophrenia drugs include Chlorpromazine. Thioridazine, Haloperidol, and related diseases and methods for the preparation thereof. Perphenazine. Thiothixene, Trifluoperazine, Fluphenazine, 0003. The compound 1—2–(4 (3 trifluoromethyl Clozapine, Risperidone, Olanzapine, Quetiapine, Pimozide, phenyl)ethyl-2,3-dihydro-1H-benzimidazol-2-one (fli Aripiprazole, Ziprasidone, Perospirone, Nemonapride, banserin) is disclosed in form of its hydrochloride in Euro Sertindole, Levosulpiride, Tandospirone, Bifeprunox, pean Patent Application EP-A-526434 and has the following Asenapine, Paliperidone, Mifepristone, Lamotrigine, Ilo chemical structure: peridone, Blonanserin, DU-125530, Lurasidone, ACP-103. Idazoxan, Org-24448, CX-516, Aplindore, SLV-313, SLV 310, Ocaperidone, PNU-170413, POL-255, ABT-089 Taln O etant, NE-100, LAX-101, LAX-111, RG-1068 (Secretin), Dexefraoxan, Dihydrexidine, SM-13496, D-Serine, Osanet is-( ant, EMR-62218, SB-399885, TC-1698, SR-147778, SLV 319, SSR-181507, AVE-5997, PNU-177864, Abaperidone, SSR-146977, Neboglamine, Lamictal XT, N-Desmethyl \-O-(S\ / clozapine, Topiramate and cycloserine, optionally in form of 1 x HC the pharmaceutically acceptable acid addition salts, in form of the hydrates and/or solvates and optionally in the form of the individual optical isomers, mixtures of the individual 0004 Flibanserin shows affinity for the 5-HT5-HT enantiomers or racemates thereof. and D-receptor. It is therefore a promising thereapeutic 0011 Flibansering 1 may be used inform of the free base, agent for the treatment of a variety of diseases, for instance optionally in form of its pharmaceutically acceptable acid depression, Schizophrenia, Parkinson, anxiety, sleep distur addition salts and/or optionally in form of the hydrates bances, sexual and mental disorders and age associated memory impairment. and/or solvates thereof. Suitable acid addition salts include for example those of the acids selected from, Succinic acid, 0005 One embodiment of the invention is directed to hydrobromic acid, acetic acid, fumaric acid, maleic acid, pharmaceutical compositions comparing a therapeutically methaneSulphonic acid, lactic acid, phosphoric acid, hydro effective amount of flibanserin 1 in combination with a chloric acid, Sulphuric acid, tartaric acid and citric acid. therapeutically effective amount of one or more additional Mixtures of the abovementioned acid addition salts may also antipsychotic drugs 2. be used. From the aforementioned acid addition salts the hydrochloride and the hydrobromide, particularly the hydro 0006 Another embodiment of the invention is directed to pharmaceutical compositions comprising a therapeutically chloride, are preferred. If flibanserin1 is used in form of the effective amount of flibanserin 1 in composition with a free base, it is preferably used in form of flibanserin poly therapeutically effective amount of one or more, preferably morph A as disclosed in WO 03/014079. one antipsychotic drug 2 selected from the group consisting 0012. The antipsychotic drugs 2 which are suitable to be of 5-HT1A agnostics, dopamine modulators, sodium channel combined with flibanserin within the teaching of the instant blockers, 5-HT uptake inhibitors, D3 antagonists, D2 invention and which are mentioned hereinbefore may also antagonists, D1 antagonists, D1 agonists, secretin agonist, be capable of forming acid addition salts with pharmaceu phospholipase A2 inhibitors, 5-HT2 antagonists, 5HT6 tically acceptable acids. Representative salts include the antagonists, COX 2 inhibitors, 5-HT2A antagonists, 5HT following: Acetate, Benzenesulfonate, Benzoate, Bicarbon modulators, NK3 antagonists, alpha 1 adrenoreceptor ate, Bisulfate, Bitartrate, Borate, Bromide, Camsylate, Car US 2006/0204486 A1 Sep. 14, 2006 bonate, Chloride, Clavulanate, Citrate, Dihydrochoride, together in one pharmaceutical composition. In addition, the Edetate, Edisylate, Estolate, Esylate, Fumarate, Gluceptate, administration of one element of the combination of the Glyconate, Glutamate, Glycolylarsanilate, Hexylresorci present invention may be prior to, concurrent to, or Subse nate, Hydrabamine, Hydrobromide, Hydrochloride, quent to the administration of the other element of the Hydroxynaphthoate, Iodide, Isothionate, Lactate, Lacto combination. bionate, Luarate, Malate, Maleate, Mandelate, Mesylate, Methylbromide, Methylnitrate, Methylsulfate. Mucate, 0022. The elements of the combination of 1 and 2 may be Napsylate, Nitrate, N-methylglucamine ammonium salt, administered by oral, parenteral (e.g., intramuscular, intra Oleate, Oxalate, Pamoate (Embonate), Palmitate, Pantoth peritoneal, intravenous or Subcutaneous injection or enate, Phosphate/diphosphate, Polygalacturonate, Salicy implant), buccal, nasal, vaginal, rectal, Sublingual, or topical (e..a... ocular eyedrop) routes of administration and may be late, Stearate, Sulfate, Subacetate, Succinate, Tannate, Tar formulated, alone or together, in Suitable dosage unit for trate, Teoclate, Tosylate, Triethiodide and Valerate. mulations containing conventional non-toxic pharmaceuti 0013 Furthermore, where the compounds 2 carry an cally acceptable carriers, adjuvants and vehicles appropriate acidic moiety, Suitable pharmaceutically acceptable salts for each route of administration. thereof may include alkali metal salts, e.g., Sodium or potassium salts; alkaline earth metal salts, e.g., calcium or 0023 The pharmaceutical compositions for the adminis magnesium salts; and salts formed with Suitable organic tration of the components 1 and 2 of this invention may ligands, e.g., quaternary ammonium salts. conveniently be presented in dosage unit form and may be prepared by any of the methods well known in the art of 0014. The compounds 2 may have chiral centers and pharmacy. All methods include the step of bringing the occur as racemates, racemic mixtures and as individual active ingredient into association with the carrier which is diastermers, or enantiomers with all isomeric forms being constituted of one or more accessory ingredients. In general, included in the present invention. Therefore, where a com the pharmaceutical compositions are prepared by uniformily pound is chiral, the separate enantiomers, Substantially free and intimately bringing the active ingredients into associa of the other, are included within the scope of the invention. tion with a liquid carrier or a finely divided solid carrier or Further included are all mixtures of the two enantiomers. both, and then, if necessary, shaping the product into the Also included within the scope of the invention are poly desired dosage form. In the pharmaceutical compositions the morphs and hydrates of the compounds of the instant active compounds are included in an amount Sufficient to invention. produce the desired pharmacologic effect. 0.015 The present invention includes within its scope 0024. The pharmaceutical compositions containing the prodrugs of the compounds 1 and 2. In general. Such active ingredients 1 and 2, separately or together, that are prodrugs will be functional derivatives of the compounds of suitable for oral administration may be in the form of this invention which are readily convertible in vivo into the discrete units such as hard or soft capsules, tablets, troches required compound. or lozenges, each containing a predetermined amount of the 0016. The term “therapeutically effective amount” shall active ingredients; in the form of a dispersible powder or mean that amount of a drug or pharmaceutical agent that will granules; in the form of a solution or a Suspension in an elicit the biological or medical response of a tissue system aqueous liquid or non-aqueous liquid; in the form of syrups animal or human that is being sought by a researcher or or elixirs; or in the form of an oil-in-water emulsion or a clinician. water-in-oil emulsion. 0017. As used herein, the term “composition' is intended 0025 Dosage forms intended for oral use may be pre to encompass a product comprising the specified ingredients pared according to any method known to the art for the in the specified amounts, as well as any product which manufacture of pharmaceutical formulations and Such com results, directly or indirectly, from combination of the speci positions. fied ingredients in the specified amounts. 0026. The excipients used may be for example, 0018. As used herein, the term antipsychotic drug includes all agents that control agitated psychotic behavior, 0027 (a) inert diluents such as mannitol, sorbitol, cal alleviate acute psychotic states, reduce psychotic symptoms, cium carbonate, pregenatinized starch, lactose, calcium and exert a quieting effect. phosphate or sodium phosphate: 0019. In the present invention the term “modulator 0028 (b) granulating and disintegrating agents, such as means compounds that produce tissue specific effects that povidone, copovidone, hydroxypropylmethylcellulose, can be agonistic or antagonistic. corn starch, alginic acid, crospovidone, Sodiumstarchgly 0020. As used herein, the term "schizophrenia' includes colate, croScarmellose, or polacrilin potassium; but is not limited to the disorganized type, the catatonic type, 0029 (c) binding agents such as microcrystalline cellu the paranoid type, the undifferentiated type, the residual type lose or acacia; and of schizophrenia, schizoaffective disorder, schizophreniform disorder, delusional disorder, brief psychotic disorder, 0030 (d) lubricating agents such as magnesium Stearate, shared psychotic disorder, psychotic disorder due to a gen Stearic acid, fumaric acid or talc. eral medical condition, Substance-induced psychotic disor 0031. In some cases, formulations for oral use may be in der, and psychotic disorder not otherwise specified. the form of hardgelatin or HPMC capsules wherein the 0021. In the combination of the present invention, the active ingredient 1 or 2, separately or together, is mixed with components 1 and 2 may be administered separately or an inter Solid diluent, for example pregenatinized starch, US 2006/0204486 A1 Sep. 14, 2006

calcium carbonate, calcium phosphate, or kaolin, or dis palatable oral preparation. These compositions may be pre pensed via a pellet formulation. pared by the addition of an antioxidant Such as ascorbic acid. 0032. They may also be in the form of soft gelatin 0045 Dispersible powders and granules are suitable for capsules wherein the active ingredient is mixed with water the preparation of an aqueous Suspension. They provide the or an oil medium, for example peanut oil, liquid paraffin, active ingredients 1 and 2, separately or together, in admix medium chain triglycerides or olive oil. ture with a dispersing or wetting agent, a suspending agent and one or more preservatives. Suitable dispersing or wet 0033. The tablets, capsules or pellets may be uncoated or ting agents and Suspending agents are exemplified by those they may be coated by known techniques to delay disinte already mentioned above. Additional excipients, for gration and absorption in the gastrointestinal tract and example, those Sweetening, flavoring and coloring agents thereby provide a delayed action or Sustained action over a longer period. For example, a time delay material Such as described above may also be present. celluloseacetate phtalate or hydroxypropylcellulose acetate 0046) The pharmaceutical compositions of the invention Succinate or Sustained release material Such as ethylcellulose may also be in the form of oil-in-water emulsions. The oily or ammoniomethacrylate copolymer (type B) may be phase may be a Vegtable oil Such as olive oil or arachis oils, employed. or a mineral oil Such as liquid paraffin or a mixture thereof. 0034 Liquid dosage forms for oral administration 0047 Suitable emulsifying agents may be include pharmaceutically acceptable emulsions, Solutions, 0048 (a) naturally-occuring gums such as gum acacia Suspensions, syrups, and elixirs containing inert diluents and gum tragacanth, commonly used in the art, such as water. Besides such inert diluents, compositions can also include adjuvents, such as 0049 (b) naturally-occuring phosphatides such as soy Wetting agents, emulsifying and Suspending agents, and bean and lecithin, Sweetening, flavoring, perfuming and preserving agents. 0050 (c) esters or partial esters derived from fatty acids 0035 Aqueous suspensions normally contain the active and hexitol anhydrides, for example, Sorbitan monooleate, materials 1 and 2, separately or together, in admixture with 0051 (d) condensation products of said partial esters with excipients suitable for the manufacture of aqueous Suspen ethylene oxide, for example polyoxyethylene sorbitan sions. Such excipients may be monooleate. The emulsions may also contain Sweetening 0.036 (a) suspending agents such as hydroxyethylcellu and flavoring agents. lose, Sodium carboxymethylcellulose, methylcellulose, 0052 Syrups and elixirs may be formulated with Sweet hydroxypropylmethylcellulose, Sodium alginate, polyvi ening agents, for example, glycerol, propylene glycol, Sor nylpyrrolidone, gum tragacanth and gum acacia: bitol or Sucrose. Such formulations may also contain a 0037 (b) dispersing or wetting agents which may be preservative and flavoring and coloring agents. 0053. The pharmaceutical compositions containing 1 and 0038 (b.1) a naturally-occuring phosphatide such as leci 2, separately or together, may be in the form of a sterile thin, injectable aqueous or oleagenous Suspension or solution. 0.039 (b.2) a condensation product of an alkylene oxide The Suspension may be formulated according to known with a fatt acid, for example, polyoxyethylene Stearate, methods using those Suitable dispersing or wetting agents and Suspending agents which have been mentioned above. 0040 (b. 3)a condensation product of ethylene oxide with The sterile injectable preparation may also be a sterile a long chain aliphatic alcohol, for example heptadecaethyl injectable solution or Suspension in a non toxic parenterally eneoxycetanol, acceptable diluent or solvent, for example as a solution in 0041) (b.4) a condensation product of ethylene oxide with 1,3-butane-diol. Among the acceptable vehicles and solvents a partial ester derived from a fatty acid and a hexitol Such as that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed polyoxyethylene Sorbitol monooleate, or oils are conventionally employed as a solvent or Suspending 0.042 (b.5) a condensation product of ethylene oxide with medium. For this purpose any bland fixed oil may be a partial ester derived from a fatty acide and a hexitol employed including synthetic mono-or diglycerides. In addi anhyrdride, for example polyoxyethylene Sorbitan tion, fatty acids such as oleic acid find use in the preparation monooleate. of injectables. 0043. The aqueous suspensions may also contain one or 0054 Preparations according to this invention containing more preservatives, for example, ethyl or n-propyl p-hy 1 and 2, separately or together, for parenteral administration droxybenzoate; one or more coloring agents; one or more include sterile aqueous or non-aqueous Solutions, Suspen flavoring agents; and one or more Sweetening agents, such Sion, or emulsions. as Sucrose or saccharin. 0055 Examples of non-aqueous solvents or vehicles are 0044 Oily suspensions may be formulated by suspending propylene glycol, polyethylene glycol, vegetable oils, such the active ingredients 1 and 2, separately or together, in a as olive oil and corn oil, gelatin, and injectable organic esters Vegtable oil, for example arachis oil, olive oil, sesame oil or Such as ethyl oleate. Such dosage forms may also contain coconut oil, or in a mineral oil such as liquid paraffin. The adjuvants such as preserving, wetting, emulsifying, and oily Suspensions may contain a thickening agent, for dispersing agents. They may be sterilized by, for example, example beeswax, hard paraffin or cetyl alcohol. Sweetening filtration through a bacteria-retaining filter, by incorporating agents and flavoring agents may be added to provide a sterilizing agents into the compositions, by irradiating the US 2006/0204486 A1 Sep. 14, 2006

compositions, or by heating the compositions. They can also 445, or 450, 475,500, 520, 550, 575, 600, 625, 650, 675, be manufactured in the form of sterile solid compositions 700, 725, 750, 800, 825, 850, 875, 900, 925, 950, 975, or which can be reconstitured in sterile water, or some other 1,000 mg or 2. Advantageously, the compounds 2 of the sterile injectable medium immediately before use. The com present invention may be administered in a single daily dose, bination of this invention may also be administered in the or the total daily dosage may be administered in divided form of Suppositories for rectal administration. This com doses of two, three or four times daily. position can be prepared by mixing the drugs with a suitable non-irritating exipient which is solidat ordinary tempera 0061. In another preferred embodiment the invention tures but liquid at the rectal temperature and will therefore related to a method for the treatment and/or prevention of melt in the rectum to release the drug. Such materials are Schizophrenia, comprising the administration of a therapeu cocoa butter, hard fat, and polyethylene glycols. Composi tically effective amount of 1 optionally in form of the free tions for buccal, nasal or Sublingual administration are also base, the pharmacologically acceptable acid addition salts prepared with Standard excipients well known in the art. and/or optionally in form of the hydrates and/or solvates thereof, in combination with a therapeutically effective 0056. For topical administration the combinations of this amount of 2, optionally in form of the pharmaceutically invention containing 1 and 2, separately or together, may be acceptable acid addition salts, in form of the hydrates and/or formulated in liquid or semi-liquid preparations such as solvates and optionally in the form of the individual optical miniments, lotions, applications; oil-in-water or water-in-oil isomers, mixtures of the individual enantiomers or race emulsions such as creams, ointments, jellies or pastes, mates thereof, separeately or together within one pharma including tooth-pastes; or solutions or Suspensions such as ceutical composition. drops, and the like. 0062. In another preferred embodiment the invention 0057 The dosage of the active ingredients in the com relates to a method for the treatment and/or prevention of positions of this invention may be varied. However, it is Schizophrenia and related disorders selected from the group necessary that the amount of the active ingredients 1 and 2 consisting of the disorganized type, the catatonic type, the be such that a suitable dosage form is obtained. The selected paranoid type, the undifferentiated type, the residual type of dosage and the dosage form depend upon the desired thera Schizophrenia, Schizoaffective disorder, Schizophreniform peutic effect, on the route of administration and on the disorder, delusional disorder, brief psychotic disorder, duration of the treatment. Dosage ranges in the combination shared psychotic disorder, psychotic disorder due to a gen are approximately one tenth to one times the clinically eral medical condition, substance-induced psychotic disor effective ranges required to induce the desired therapeutic der, and psychotic disorder not otherwise specified, com effect, respecitvely when the compounds are used singly. prising the administration of a therapeutically effective 0.058 Within the instant invention flibanserin 1 is pref amount of 1 optionally in form of the free base, the phar erably administered in Such an amount that per single dosage macologically acceptable acid addition salts and/or option between 5 to 200 mg of flibanserin 1 are applied. Preferred ally in form of the hydrates and/or solvates thereof, in are ranges of between 10 to 150 mg, particular preferred 20 combination with a therapeutically effective amount of 2. to 100 mg of flibanserin 1. Suitable dosage forms may optionally in form of the pharmaceutically acceptable acid contain for instance 20, 25, 30, 35, 40, 45, 50, 55, 60, 65,70, addition salts, in form of the hydrates and/or solvates and 75, 80, 85, 90, 95 or 100 mg of flibanserin 1. The afore optionally in the form of the individual optical isomers, mentioned values are based on flibanserin 1 in form of the mixtures of the individual enantiomers or racemates thereof, free base. If flibanserin1 is applied in form of one of its acid separately or together within one pharmaceutical composi addition salts, the corresponding values are readily calcu tion. lable from the aforementioned values. 0063. In another preferred embodiment the invention 0059. Within the instant invention the additional antip relates to a method for the treatment and/or prevention of the sychotic drug. 2 is preferably administered in Such an amount disorganied type of Schizophrenia, comprising the adminis that per day between 0.1 to 2,500 mg of 2 are applied. tration of a therapeutically effective amount of 1 optionally Preferred are ranges of between 0.5 to 2,000 mg, in particu in form of the free base, the pharmacologically acceptable lar between 1 to 1,000mg. acid addition salts and/or optionally in form of the hydrates and/or solvates thereof, in combination with a therapeuti 0060 Suitable dosage forms may contain for instance cally effective amount of 2, optionally in form of the 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 0.55, 0.6,0.65, pharmaceutically acceptable acid addition salts, in form of 0.7, 0.75, 0.8, 0.85, 0.9, 0.95, 1, 1.05, 1.1, 1.15, 1.2, 1.25, the hydrates and/or solvates and optionally in the form of the 1.3, 1.35, 1.4, 1.45, 1.5, 1.55, 1.6, 1.65, 1.7, 1.75, 1.8, 1.85, individual optical isomers, mixtures of the individual enan 1.9, 1.95, 2, 2.05, 2.1, 2.15, 2.2, 2.25, 2.3, 2.35, 2.4, 2.45, tiomers or racemates thereof, separately or together within 2.5, 2.55, 2.6, 2.65, 2.7, 2.75, 2.8, 2.85, 2.9, 2.95, 3, 3.05, one pharmaceutical composition. 3.1, 3.15, 3.2, 3.25, 3.3, 3.45, 3.4, 3.45, 3.5, 3.55, 3.6, 3.65, 3.7, 3.75, 3.8, 3.85, 3.9, 3.95, 4, 4.1, 4.15, 4.2, 4.25, 4.3, 0064. In another preferred embodiment the invention 4.35, 4.4, 4.45, 4.5, 4.55, 4.6, 4.65, 4.7, 4.75, 4.8, 4.85, 4.9, relates to a method for the treatment and/or prevention of the 4.95, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65,70, 76, catatonic type of Schizophrenia, comprising the administra 80, 85,90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, tion of a therapeutically effective amount of 1 optionally in 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200, form of the free base, the pharmacologically acceptable acid 205, 210, 215, 220, 225, 230, 235, 240, 245, 250, 255, 260, addition salts and/or optionally in form of the hydrates 265, 270,275, 280, 285,290, 295,300, 305,310,315, 320, and/or solvates thereof, in combination with a therapeuti 325, 330, 335,340, 345, 350,355, 360, 365, 370, 375, 380, cally effective amount of 2, optionally in form of the 385, 390, 395, 400, 405, 410, 415, 420, 425, 430, 435, 440, pharmaceutically acceptable acid addition salts, in form of US 2006/0204486 A1 Sep. 14, 2006

the hydrates and/or solvates and optionally in the form of the solvates thereof, in combination with a therapeutically effec individual optical isomers, mixtures of the individual enan tive amount of 2, optionally in form of the pharmaceutically tiomers or racemates thereof, separately or together within acceptable acid addition salts, in form of the hydrates and/or one pharmaceutial composition. solvates and optionally in the form of the individual optical 0065. In another preferred embodiment the invention isomers, mixtures of the individual enentiomers or race relates to a method for the treatment and/or prevention of the mates thereof, separately or together within one pharmaceu paranoid type of Schizophrenia, comprising the administra tical composition. tion of a therapeutically effective amount of 1 optionally in 0070. In another preferred embodiment the invention form of the free base, the pharmacologically acceptable acid relates to a method for the treatment and/or prevention of addition salts and/or optionally in form of the hydrates delusional disorder, comprising the administration of a and/or solvates thereof, in combination with a therapeuti therapeutically effective amount of 1 optionally in form of cally effective amount of 2, optionally in form of the the free base, the pharmacologically acceptable acid addi pharmaceutically acceptable acid addition salts, in form of tion salts and/or optionally in form of the hydrates and/or the hydrates and/or solvates and optionally in the form of the solvates thereof, in combination with a therapeutically effec individual optical isomers, mixtures of the individual enan tive amount of 2, optionally in form of the pharmaceutically tiomers or racemates thereof, separately or together within acceptable acid addition salts, in form of the hydrates and/or one pharmaceutical composition. solvates and optionally in the form of the individual optical 0066. In another preferred embodiment the invention isomers, mixtures of the individual enantiomers or race relates to a method for the treatment and/or prevention of the mates thereof, separately or together within one pharmaceu undifferentiated type of Schizophrenia, comprising the tical composition. administration of a therapeutically effective amount of 1 0071. In another preferred embodiment the invention optionally in form of the free base, the pharmacologically relates to a method for the treatment and/or prevention of acceptable acid addition salts and/or optionally in form of brief psychotic disorder, comprising the administration of a the hydrates and/or solvates thereof, in combination with a therapeutically effective amount of 1 optionally in form of therapeutically effective amount of 2, optionally in form of the free base, the pharmacologically acceptable acid addi the pharmaceutically acceptable acid addition salts, in form tion salts and/or optionally in form of the hydrates and/or of the hydrates and/or solvates and optionally in the form of solvates thereof, in combination with a therapeutically effec the individual optical isomers, mixtures of the individual tive amount of 2, optionally in form of the pharmaceutically enantiomers or racemates thereof, separately or together acceptable acid addition salts, in form of the hydrates and/or within one pharmaceutical composition. solvates and optionally in the form of the individual optical 0067. In another preferred embodiment the invention isomers, mixtures of the individual enantiomers or race relates to a method for the treatment and/or prevention of the mates thereof, separately or together within one pharmaceu residual type of schizophrenia, comprising the administra tical composition. tion of a therapeutically effective amount of 1 optionally in 0072. In another preferred embodiment the invention form of the free base, the pharmacologically acceptable acid relates to a method for the treatment and/or prevention of addition salts and/or optionally in form of the hydrates shared psychotic disorder, comprising the administration of and/or solvates thereof, in combination with a therapeuti a therapeutically effective amount of 1 optionally in form of cally effective amount of 2, optionally in form of the the free base, the pharmacologically acceptable acid addi pharmaceutically acceptable acid addition salts, in form of tion salts and/or optionally in form of the hydrates and/or the hydrates and/or solvates and optionally in the form of the solvates thereof, in combination with a therapeutically effec individual optical isomers, mixtures of the individual enan tive amount of 2, optionally in form of the pharmaceutically tiomers or racemates thereof, separately or together within acceptable acid addition salts, in form of the hydrates and/or one pharmaceutical composition. solvates and optionally in the form of the individual optical isomers, mixtures of the individual enantiomers or race 0068. In another preferred embodiment the invention mates thereof, separately or together within one pharmaceu relates to a method for the treatment and/or prevention of tical composition. Schizoaffective disorder, comprising the administration of a therapeutically effective amount of 1 optionally in form of 0073. In another preferred embodiment the invention the free base, the pharmacologically acceptable acid addi relates to a method for the treatment and/or prevention of tion salts and/or optionally in form of the hydrates and/or psychotic disorder due to a general medical condition, solvates thereof, in combination with a therapeutically effec comprising the administration of a therapeutically effective tive amount of 2, optionally in form of the pharmaceutically amount of 1 optionally in form of the free base, the phar acceptable acid addition salts, in form of the hydrates and/or macologically acceptable acid addition salts and/or option solvates and optionally in the form of the individual optical ally in form of the hydrates and/or solvates thereof, in isomers, mixtures of the individual enantiomers or race combination with a therapeutically effective amount of 2, mates thereof, separately or together within one pharmaceu optionally in form of the pharmaceutically acceptable acid tical composition. addition salts, in form of the hydrates and/or solvates and 0069. In another preferred embodiment the invention optionally in the form of the individual optical isomers, relates to a method for the treatment and/or prevention of mixtures of the individual enantiomers or racemates thereof, Schizophreniform disorder, comprising the administration of separately or together within one pharmaceutical composi a therapeutically effective amount of 1 optionally in form of tion. the free base, the pharmacologically acceptable acid addi 0074. In another preferred embodiment the invention tion salts and/or optionally in form of the hydrates and/or relates to a method for the treatment and/or prevention of the US 2006/0204486 A1 Sep. 14, 2006

Substance-induced psychotic disorder, comprising the ceutically acceptable acid addition salts, in form of the administration of a therapeutically effective amount of 1 hydrates and/or solvates and optionally in the form of the optionally in form of the free base, the pharmacologically individual optical isomers, mixtures of the individual enan acceptable acid addition salts and/or optionally in form of tiomers or racemates thereof. the hydrates and/or solvates thereof, in combination with a therapeutically effective amount of 2, optionally in form of 0080. Another embodiment of the invention relates to the the pharmaceutically acceptable acid addition salts, in form use of the combinations of 1, optionally in form the free of the hydrates and/or solvates and optionally in the form of base, the pharmacologically acceptable acid addition salts the individual optical isomers, mixtures of the individual and/or optionally in form of the hydrates and/or solvates enantiomers or racemates thereof, separately or together thereof, and one or more additional antipsychotic drugs 2. within one pharmaceutical composition. optionally in form of the pharmaceutically acceptable salts, in form of the hydrates and/or solvates and optionally in the 0075. In another preferred embodiment the invention form of the individual optical isomers, mixtures of the relates to a method for the treatment and/or prevention of individual enantiomers or racemates thereof, for the prepa psychotic disorder not otherwise specified, comprising the ration of a medicament for the treatment and/or prevention administration of a therapeutically effective amount of 1 of the aforementioned disorders. optionally in form of the free base, the pharmacologically acceptable acid addition salts and/or optionally in form of 0081. Another embodiment of the invention relates to the the hydrates and/or solvates thereof, in combination with a use of the combinations of 1, optionally in form the free therapeutically effective amount of 2, optionally in form of base, the pharmacologically acceptable acid addition salts the pharmaceutically acceptable acid addition salts, in form and/or optionally in form of the hydrates and/or solvates of the hydrates and/or solvates and optionally in the form of thereof, and 2, optionally in form of their pharmaceutically the individual optical isomers, mixtures of the individual acceptable acid addition salts for the preparation of a medi enantiomers or racemates thereof, separately or together cament for the treatment and/or prevention of the aforemen within one pharmaceutical composition. tioned disorders, wherein 260 is selected from the group consisting of 5HTA agnostics, dopamine modulators, 0.076 The beneficial effects of the compositions accord sodium channel blockers, 5-HT uptake inhibitors, D3 ing to the invention can be observed regardless of whether antagonists, D2 antagonists, D1 antagonists, D1 agonists, the disturbance existed lifelong or was acquired, and inde secretin agonist, phospholipase A2 inhibitors, 5-HT2 pendent of etiologic origin (organic—both, physically and antagonists, 5HT6 antagonists, COX 2 inhibitors, 5-HT2A drug induced , psychogen, a combination of organic— antagonists, 5HT modulators, NK3 antagonists, alpha 1 both, physically and drug induced , and psychogen, or adrenoreceptor antagonists, alpha 2 adrenoreceptor antago unknown). nists, AMPA modulators and NK 3 antagonists. 0.077 Another embodiment of the invention is directed to 0082 Another embodiment of the invention relates to the the aforementioned methods wherein 2 is selected from the use of the combinations of 1, optionally in form of the free group consisting of 5HTA agnostics, dopamine modulators, base, the pharmacologically acceptable acid addition salts sodium channel blockers, 5-HT uptake inhibitors, D3 and/or optionally in form of the hydrates and/or solvates antagonists, D2 antagonists, D1 antagonists, D1 agonists, thereof, and 2, optionally in form of their pharmaceutically secretin agonist, phospholipase A2 inhibitors, 5-HT2 acceptable acid addition salts for the preparation of a medi antagonists, 5HT6 antagonists, COX 2 inhibitors, 5-HT, cament for the treatment and/or prevention of the aforemen antagonists, 5HT modulators, NK3 antagonists, alpha 1 tioned disorders, wherein 2 is selected from the group adrenoreceptor antagonists, alpha 2 adrenoreceptor antago consisting of Clorpromazine. Thioridazine, Haloperidol. nists, AMPA modulators and NK 3 antagonists. Perphenazine. Thiothixene, Trifluoperazine, Fluphenazine, 0078. Another embodiment of the invention is directed to Clozapine, Risperidone, Olanzapine, Quetiapine, Pimozide, the aforementioned methods wherein 2 is selected from the Aripiprazole, Ziprasidone, Perospirone, Nemonapride, group consisting of D2 antagonists. Sertindole, Levosulpiride, Tandospirone, Bifeprunox, Asenapine, Paliperidone, Mifepristone, Lamotrigine, Ilo 0079 Another preferred embodiment of the invention is peridone, Blonanserin, DU-125530, Lurasidone, ACP-103. directed to the aforementioned methods wherein 2 is Idazoxan, Org-24448, CX-516, Aplindore, SLV-313, SLV selected from the group consisting of include Chlorprom 310, Ocaperidone, PNU-170413, POL-255, ABT-089 Taln azine. Thioridazine, Haloperidol, Perphenazine. Thiothix etant, NE-100, LAX-101, LAX-111, RG-1068 (Secretin), ene, Trifluoperazine, Fluphenazine, Clozapine, Risperidone, Dexefaroxan, Dihydrexidine, SM-13496, D-Serine, Osanet Olanzapine, Quetiapine, Pimozide, Aripiprazole, Ziprasi ant, EMR-62218, SB-399885, TC-1698, SR-1447778, SLV done, Perospirone, Nemonapride, Sertindole, Levosulpiride, 319, SSR-181507, AVE-5997, PNU-177864, Abaperidone, Tandospirone, Bifeprunox, Asenapine, Paliperidone, Mife SSR-146977, Neboglamine, Lamictal XR, N-Desmethyl pristone, Lamotrigine, Iloperidone, Blonanserin, clozapine, Topiramate and cycloserine, optionally in form of DU-125530, Lurasidone, ACP-103, Idazoxan, Org-24448, the pharmaceutically acceptable acid addition salts, in form CX-516, Aplindore, SLV-313, SLV-310, Ocaperidone, PNU of the hydrates and/or solvates and optionally in the form of 170413, POL-255, ABT-089 Talnetant, NE-100, LAX-101, the individual optical isomers, mixtures of the individual LAX-111, RG-1068 (Secretin), Dexefraoxan, Dihydrexi enantiomers or racemates thereof. dine, SM-13496, D-Serine, Osanetant, EMR-62218, SB-399885, TC-1698, SR-147778, SLV-319, SSR-181507, 0083. The following examples demonstrate possible AVE-5997, PNU-177864, Abaperidone, SSR-146977, pharmaceutical compositions comprising flibanserin in com Neboglamine, Lamictal XT, N-Desmethylclozapine, Topi bination with one of the aforementioned combination part ramate and cycloserine, optionally in form of the pharma ners 2. US 2006/0204486 A1 Sep. 14, 2006

-continued

EXAMPLE N1 - Combination 1 with chlorpromazine EXAMPLE N3 - Combination 1 with alprazolam Constituents mg tablet Constituents mg tablet Core Coating Flibanserin (free base) SO.OOO Chlorpromazine hydrochloride 2O.OOO Anhydrous dibasic calcium phosphate 1OOOOO HPMC (e.g. Methocel E5) 3.360 Microcrystalline cellulose 2O3.090 Polyethylene Glycol 6000 O.980 HPMC (Methocel E5) 6.615 CroScarmellose sodium 8.82O Titanium dioxide 1400 Magnesium Stearate 2.2SO Talc 1200 Coating Iron oxide red O.O60 HPMC (Methocel E5) 4.32O Polyethylene Glycol 6000 1.260 Total Film coated bilayer tablet 362.OOO Titanium dioxide 1800 Talc 1542 Iron oxide red O.078 0086) Total Film coated tablet 399.775

0084) EXAMPLE N4 - Combination of 1 with citalopran Constituents mg tablet Final Mixture EXAMPLE N2 - Combination 1 with clozapine Flibanserin (free base) SO.OOO Constituents mg tablet Haloperidol 2O.OOO Lactose monohydrate 2OO.OOO Core Pregelatinized starch 108.OOO Magnesium Stearate 2.OOO Flibanserin (free base) SO.OOO Capsule Clozapine 1OO.OOO Lactose monohydrate 133.750 Final Mixture 38O.OOO Microcrystalline cellulose 40.OOO Capsule (size 1) 82.OOO Hydroxypropylcellulose 2. SOO Corn starch 12.SOO Total weight of Capsule 462.OOO Magnesium Stearate 1.2SO Coating HPMC (e.g. Pharmacoat 606) 2.400 The following examples show preferred pharma Polyethylene Glycol 6000 O.7OO 0087 Titanium dioxide 1.OOO ceutical compositions of flibanserin, if the combinations Talc 0.857 according to the invention are administered in separate Iron oxide yellow O.043 dosage units. Total Film coated tablet 345.000

EXAMPLE N'S - Composition 0085 Constituents mg tablet Core EXAMPLE N3 - Combination 1 with alprazolan Flibanserin (free base) 2S.OOO Lactose monohydrate 71.720 Constituents mg tablet Microcrystalline cellulose 23.905 HPMC (Methocel E5) 1.2SO Core Carboxymethylcellulose sodium 2. SOO Magnesium Stearate O.625 Flibanserin (free base) SO.OOO Coating Fluphenazine hydrochloride S.OOO Lactose monohydrate 143.490 HPMC (Methocel E5) 1.440 Microcrystalline cellulose 47.810 Polyethylene Glycol 6000 O42O HPMC (e.g. Pharmacoat 606) 2. SOO Titanium dioxide O.6OO Carboxymethylcellulose sodium S.OOO Talc O.514 Mannitol 6O.OOO Iron oxide red O.O26 Corn starch 36.500 Povidone 1.OOO Total Film coated tablet 128.OOO Colloidal silicon dioxide 1.OOO Magnesium Stearate 1.700 US 2006/0204486 A1 Sep. 14, 2006

0088) -continued EXAMPLE N8 - Composition EXAMPLE N'6 - Composition Constituents mg tablet Constituents mg tablet Talc O.514 Core Iron oxide red O.O26 Flibanserin (free base) SO.OOO Total Film coated tablet 133.OOO Lactose monohydrate 143.440 Microcrystalline cellulose 47.810 HPMC (e.g. Pharmacoat 606) 2. SOO Carboxymethylcellulose sodium S.OOO 0091) Magnesium Stearate 1.2SO Coating HPMC (e.g. Pharmacoat 606) 2.400 EXAMPLE N9 - Composition Polyethylene Glycol 6000 O.7OO Titanium dioxide 1.OOO Constituents mg tablet Talc 0.857 Iron oxide red O.043 Core

Total Film coated tablet 2SS.OOO Flibanserin (free base) 1OO.OOO Dibasic Calciumphosphate, anhydrous 69.750 Microcrystalline cellulose 69.750 HPMC (e.g. Methocel E5) 2.750 0089) Carboxymethylcellulose sodium S.OOO Colloidal silicon dioxide 1.2SO Magnesium Stearate 1. SOO Coating Example N7 - Composition HPMC (e.g. Methocel E5) 2.400 Polyethylene Glycol 6000 O.7OO Constituents mg tablet Titanium dioxide 1.043 Talc 0.857 Core Total Film coated tablet 2SS.OOO Flibanserin (free base) 1OO.OOO Lactose monohydrate 171.08O Microcrystalline cellulose 57.02O HPMC (e.g. Methocel E5) 3.400 0092) Carboxymethylcellulose sodium 6.8OO Magnesium Stearate 1.700 Coating HPMC (e.g. Methocel E5) 3.360 EXAMPLE N10 - Composition Polyethylene Glycol 6000 O.980 Titanium dioxide 1400 Constituents mg tablet Talc 1200 Iron oxide red O.O60 Core

Total Film coated tablet 347.OOO Flibanserin (free base) 2O.OOO Lactose monohydrate 130.OOO Microcrystalline cellulose 43.1OO Hydroxypropyl Cellulose (e.g. Klucel LF) 1.900 Sodium Starch Glycolate 4.OOO 0090) Magnesium Stearate 1.OOO Coating HPMC (e.g. Methocel E5) 2.400 EXAMPLE N8 - Composition Polyethylene Glycol 6000 O.7OO Titanium dioxide 1.043 Constituents mg tablet Talc 0.857

Core Total Film coated tablet 2OS.OOO Flibanserin (free base) 2.OOO Dibasic Calciumphosphate, anhydrous 61010 Microcrystalline cellulose 61010 What is claimed is: HPMC (Methocel E5) 1.9SO Carboxymethylcellulose sodium 2.600 1. A pharmaceutical composition comprising a therapeu Colloidal silicon dioxide O.6SO tically effective amount of flibanserin, in the form of a free Magnesium Stearate O.78O base or a pharmacologically acceptable acid addition salt, in Coating combination with a therapeutically effective amount of an HPMC (Methocel E5) 1.440 additional antipsychotic drug. Polyethylene Glycol 6000 O42O 2. The pharmaceutical composition according to claim 1, Titanium dioxide O.6OO wherein the additional antipsychotic drug is selected from the group consisting of 5HTA agnostics, dopamine modu US 2006/0204486 A1 Sep. 14, 2006

lators, sodium channel blockers, 5-HT uptake inhibitors, D3 acid addition salt, in combination with a therapeutically antagonists, D2 antagonists, D1 antagonists, D1 agonists, effective amount of an additional antipsychotic drug. secretin agonist, phospholipase A2 inhibitors, 5-HT2 12. A method according to claim 11 wherein the schizo antagonists, 5HT6 antagonists, COX 2 inhibitors, 5-HT, phrenia and related diseases are selected from the group antagonists, 5HT modulators, NK3 antagonists, alpha 1 consisting of the disorganized type of the catatonic type of adrenoreceptor antagonists, alpha 2 adrenoreceptor antago Schizophrenia, the paranoid type of schizophrenia, the undif nists, AMPA modulators and NK 3 antagonists. ferentiated type of schizophrenia, the residual type of 3. The pharmaceutical composition according to claim 1, Schizophrenia, Schizoaffective disorder, Schizophreniform wherein the additional antipsychotic drug is a D2 antagonist. disorder, delusional disorder, brief psychotic disorder, 4. The pharmaceutical composition according to claim 1, shared psychotic disorder, psychotic disorder due to a gen wherein the additional antipsychotic drug is selected from eral medical condition, Substance-induced psychotic disor the group consisting of Chlorpromazine. Thioridazine, der, and other psychotic disorders. Haloperidol, Perphenazine. Thiothixene, Trifluoperazine, 13. A method according to claim 11 or 12, wherein the Fluphenazine, Clozapine, Risperidone, Olanzapine, Que additional antipsychotic drug is selected from the group tiapine, Pimozide, Aripiprazole, Ziprasidone, Perospirone, consisting of 5HTA agnostics, dopamine modulators, Nemonapride, Sertindole, Levosulpiride, Tandospirone, sodium channel blockers, 5-HT uptake inhibitors, D3 Bifeprunox, Asenapine, Paliperidone, Mifepristone, Lamot antagonists, D2 antagonists, D1 antagonists, D1 agonists, rigine, Iloperidone, Blonanserin, DU-125530, Lurasidone, secretin agonist, phospholipase A2 inhibitors, 5-HT2 ACP-103, Idazoxan, Org-24448, CX-516, Aplindore, SLV antagonists, 5HT6 antagonists, COX 2 inhibitors, 5-HT2A 313, SLV-310, Ocaperidone, PNU-170413, POL-255, ABT antagonists, 5HT modulators, NK3 antagonists, alpha 1 089 Talnetant, NE-100, LAX-101, LAX-111, RG-1068 adrenoreceptor antagonists, alpha 2 adrenoreceptor antago (Secretin), Dexefraoxan, Dihydrexidine, SM-13496, nists, AMPA modulators and NK 3 antagonists. D-Serine, Osanetant, EMR-62218, SB-399885, TC-1698, 14. A method according to claim 11 or 12, wherein the SR-147778, SLV-319, SSR-181507, AVE-5997, PNU additional antipsychotic drug is a D2 antagonist. 177864, Abaperidone, SSR-146977, Neboglamine, Lamictal 15. A method according to claim 11 or 12, wherein the XT, N-Desmethylclozapine, Topiramate and cycloserine. additional antipsychotic drug is selected from the group 5. The pharmaceutical composition according to claim 1, consisting of Chlorpromazine. Thioridazine, Haloperidol. wherein flibanerin, in the form of a free base or a pharma Perphenazine. Thiothixene, Trifluoperazine, Fluphenazine, cologically acceptable acid addition salt, and the additional Clozapine, Risperidone, Olanzapine, Quetiapine, Pimozide, antipsychotic drug are together in one dosage form. Aripiprazole, Ziprasidone, Perospirone, Nemonapride, 6. The pharmaceutical composition according to claim 1, Sertindole, Levosulpiride, Tandospirone, Bifeprunox, wherein flibanerin, in the form of a free base or a pharma Asenapine, Paliperidone, Mifepristone, Lamotrigine, Ilo cologically acceptable acid addition salt, and the additional peridone, Blonanserin, DU-125530, Lurasidone, ACP-103. antipsychotic drug are separate in one dosage form. Idazoxan, Org-24448, CX-516, Aplindore, SLV-313, SLV 7. The pharmaceutical composition of claim 1, wherein 310, Ocaperidone, PNU-170413, POL-255, ABT-089 Taln flibanserin, in the form of a free base or a pharmacologically etant, NE-100, LAX-101, LAX-111, RG-1068 (Secretin), acceptable acid addition salt, is a hydrate and/or a solvate. Dexefraoxan, Dihydrexidine, SM-13496, D-Serine, Osanet 8. The pharmaceutical composition of claim 1, wherein ant, EMR-62218, SB-399885, TC-1698, SR-147778, SLV the additional antipsychotic drug is in the form of a phar 319, SSR-181507, AVE-5997, PNU-177864, Abaperidone, maceutically acceptable acid addition salt. SSR-146977, Neboglamine, Lamictal XT, N-Desmethyl 9. The pharmaceutical composition of claim 1, wherein clozapine, Topiramate and cycloserine. the additional antipsychotic drug is a hydrate and/or a 16. The method of claim 11, wherein flibanserin, in the Solvate. form of a free base or a pharmacologically acceptable acid 10. The pharmaceutical composition of claim 1, wherein addition salt, and the additional antipsychotic drug are the additional antipsychotic drug is an individual optical administered separately, each in one dosage form. isomer, a mixture of individual enantiomers or racemates 17. The method of claim 11, wherein flibanserin, in the thereof. form of a free base or a pharmacologically acceptable acid 11. A method for the treatment and/or prevention of addition salt, and the additional antipsychotic drug are Schizophrenia and related diseases, comprising the admin administered together within one dosage form. istration of a therapeutically effective amount of flibanserin, in the form of a free base or a pharmacologically acceptable k k k k k