Orally disintegrating pharmaceutical tablet containing cariprazine

Abstract

The present invention relates to an orally disintegrating pharmaceutical tablet comprising between 0.1 and 21% by weight of cariprazine or a pharmaceutically acceptable salt thereof, between 0.1 and 15% by weight of a disintegrating agent, between 0.1 and 5% by weight of colloidal silica, between 0.1 and 10% by weight of a taste masking agent, between 0.1 and 5% by weight of a lubricant, and up to 100% by weight of a diluent, the percentage being expressed relative to the total weight of the pharmaceutical tablet. The present invention relates to a composition for use in the treatment and / or prevention of pathological conditions requiring modulation of dopamine receptors, the composition is selected from the group consisting of psychosis, drug abuse, cognitive impairment associated with schizophrenia, mild to moderate cognitive deficits, dementia, psychotic states associated with dementia, eating disorders, attention deficit disorders, hyperactivity disorders in children, psychotic depression, bipolar disorders, paranotic and delusional disorders, dyskinesia, anxiety, sexual dysfunction, sleep disorders, vomiting, or the like. And attacking behaviors and autism.

Description

Technical Field

[0001] The present invention relates to an orally disintegrating pharmaceutical tablet comprising cariprazine or a pharmaceutically acceptable salt thereof. The present invention also relates to said pharmaceutical tablet for use in the treatment and / or prevention of pathological conditions requiring modulation of dopamine receptors. Background Art

[0002] Cariprazine is a partial agonist of dopamine D3 receptor and D2 receptor, and has high selectivity for D3 receptor. WO 2005 / 012266 A1 discloses cariprazine and its use for treating and / or preventing pathological conditions requiring modulation of dopamine receptors, such as psychosis (e.g., schizophrenia and schizoaffective disorder), drug abuse (e.g., alcohol, cocaine, nicotine and opioids), cognitive impairment associated with schizophrenia (including positive symptoms such as delusions and hallucinations, and negative symptoms such as lack of motivation and social withdrawal, and cognitive symptoms such as attention and memory problems), mild to moderate cognitive deficits, dementia, psychotic states associated with dementia, eating disorders (e.g., bulimia nervosa, etc.), attention deficit disorder, childhood hyperactivity disorder, psychotic depression, bipolar disorder, paranoid and delusional disorders, movement disorders (e.g., Parkinson's disease, neuroleptic-induced parkinsonism, tardive dyskinesia), anxiety, sexual dysfunction, sleep disorders, vomiting, aggressive behavior and autism.

[0003] The current administration form of cariprazine is an immediate release (IR) capsule, which is sold in the United States under the trade name Vraylar for the treatment of adult schizophrenia, acute treatment of manic or mixed episodes associated with adult bipolar disorder type I, and treatment of depressive episodes associated with adult bipolar disorder type I (bipolar depression), and sold in the European Union under the trade name Reagila for the treatment of adult schizophrenia. Due to the rapid release mechanism of the active compound, the capsule must be administered daily to patients in need thereof. For the purpose of producing a therapeutic effect in patients, the total daily dose of cariprazine ranges from about 0.5 mg to about 6 mg. However, inter-individual differences and co-medication may require dose adjustment in patients. The longer the treatment, the easier it is to take in the dosage regimen, because, among other factors, the effectiveness of long-term therapy is closely related to the patient's compliance. The patient's oral administration compliance is even more important in pediatric and elderly populations, where, among other aspects, swallowing drug preparations is often very difficult due to the size and taste of a single dosage form.

[0004] CN 107970217 A discloses an orally disintegrating tablet composition comprising cariprazine hydrochloride, a binder, a disintegrant, a diluent and a lubricant. Based on the total amount of the orally disintegrating tablet, the content of the disintegrant must be between 16% and 48% by weight. The preferred concentration range of the disintegrant is between 18% and 48% by weight, between 20% and 48% by weight, between 22% and 48% by weight, between 22% and 47% by weight, between 24% and 46% by weight, and between 25% and 45% by weight. The mechanical properties of the orally disintegrating tablet disclosed in CN 107970217A, such as friability, are affected by the high concentration of disintegrant in the tablet.

[0005] The taste and tablet texture of orally disintegrating drug formulations containing cariprazine should be considered in clinical practice. It is well known that taste and texture thresholds and perceptions can change significantly under pharmacological conditions. Several studies support this observation, for example, in a survey, participants affected by bipolar disorder experienced highly unstable taste perception, that is, they perceived the same type of food differently during mania and depression (Altered Sensory Phenomena Experienced in Bipolar Disorder (Am J Psychiatry 174:12, December 2017). In another study, the relationship between major depression and changes in smell or taste was studied. It was concluded that in adults, there was a strong association between major depression and olfactory and taste dysfunction (Association of Alterations in Smell and Taste with Depression in Older Adults Laryngoscope Investigative Otolaryngology 33: April 2018).

[0006] In general, the literature defines orally disintegrating tablets (ODT) as solid dosage forms that rapidly disintegrate within a few seconds when placed under the tongue. The official requirement disintegration time of ODT can vary from a few seconds to a few minutes depending on their size and formulation (U.S. FDA, 2003, Hirani et al., 2009, Thakur and Narwal, 2012). An ideal orally disintegrating tablet has the following properties: no water is required for oral administration, good swallowability, rapid disintegration in the mouth, good bioavailability, pleasant taste, and sufficient mechanical strength.

[0007] Therefore, there is a need to provide orally disintegrating cariprazine formulations that improve patient acceptance and compliance while maintaining good manufacturability and bioavailability of the product. Summary of the invention

[0008] The present invention provides an orally disintegrating pharmaceutical tablet comprising:

[0009] between 0.1 and 21% by weight of cariprazine or a pharmaceutically acceptable salt thereof,

[0010] between 0.1 and 15% by weight of a disintegrant,

[0011] between 0.1 and 5% by weight of colloidal silicon dioxide,

[0012] between 0.1 and 10% by weight of a taste masking agent,

[0013] between 0.1 and 5 wt. % lubricant, and

[0014] Up to 100% by weight of diluent,

[0015] The percentages are expressed relative to the total weight of the pharmaceutical tablet.

[0016] The present invention also provides the orally disintegrating pharmaceutical tablet for use in treating and / or preventing pathological conditions requiring modulation of dopamine receptors, such as psychosis (e.g., schizophrenia and schizoaffective disorder), drug abuse (e.g., alcohol, cocaine, nicotine, and opioids), cognitive impairment associated with schizophrenia (including positive symptoms such as delusions and hallucinations, and negative symptoms such as lack of motivation and social withdrawal, and cognitive symptoms such as attention and memory problems), mild to moderate cognitive deficits, dementia, psychotic states associated with dementia, eating disorders (e.g., bulimia nervosa, etc.), attention deficit disorder, childhood hyperactivity disorder, psychotic depression, bipolar disorder, paranoid and delusional disorders, movement disorders (e.g., Parkinson's disease, neuroleptic-induced parkinsonism, tardive dyskinesia), anxiety, sexual dysfunction, sleep disorders, vomiting, aggressive behavior, and autism.

[0017] The present invention also provides the use of the orally disintegrating pharmaceutical tablet in the preparation of a medicament for treating and / or preventing pathological conditions requiring modulation of dopamine receptors, such as psychosis (e.g., schizophrenia and schizoaffective disorder), drug abuse (e.g., alcohol, cocaine, nicotine and opioids), cognitive impairment associated with schizophrenia (including positive symptoms such as delusions and hallucinations, and negative symptoms such as lack of motivation and social withdrawal, and cognitive symptoms such as attention and memory problems), mild to moderate cognitive deficits, dementia, psychotic states associated with dementia, eating disorders (e.g., bulimia nervosa, etc.), attention deficit disorder, childhood hyperactivity disorder, psychotic depression, bipolar disorder, paranoid and delusional disorders, movement disorders (e.g., Parkinson's disease, neuroleptic-induced parkinsonism, tardive dyskinesia), anxiety, sexual dysfunction, sleep disorders, vomiting, aggressive behavior and autism.

[0018] The present invention also provides a method for treating a patient suffering from a pathological condition requiring modulation of dopamine receptors, such as psychosis (e.g., schizophrenia and schizoaffective disorder), drug abuse (e.g., alcohol, cocaine, nicotine, and opioids), cognitive impairment associated with schizophrenia (including positive symptoms such as delusions and hallucinations, and negative symptoms such as lack of motivation and social withdrawal, and cognitive symptoms such as attention and memory problems), mild to moderate cognitive deficits, dementia, psychotic states associated with dementia, eating disorders (e.g., bulimia nervosa, etc.), attention deficit disorder, childhood hyperactivity disorder, psychotic depression, bipolar disorder, paranoid and delusional disorders, movement disorders (e.g., Parkinson's disease, neuroleptic-induced parkinsonism, tardive dyskinesia), anxiety, sexual dysfunction, sleep disorders, vomiting, aggressive behavior, and autism, wherein the method comprises administering the orally disintegrating pharmaceutical tablet to a patient in need thereof.

[0019] The orally disintegrating pharmaceutical tablet of the present invention improves compliance in patients with dysphagia, including pediatric and elderly patients. It can be administered daily in an effective, cost-effective and convenient manner for lifelong treatment and / or prevention of the above-mentioned pathological conditions. DETAILED DESCRIPTION

[0020] The orally disintegrating pharmaceutical tablet of the present invention comprises, based on the total weight of the pharmaceutical tablet, a therapeutically effective amount of cariprazine or a pharmaceutically acceptable salt thereof, a diluent, a disintegrant in an amount between 0.1 and 15 weight %, a colloidal silicon dioxide in an amount between 0.1 and 5 weight %, a taste masking agent in an amount between 0.1 and 10 weight %, and a lubricant in an amount between 0.1 and 5 weight %.

[0021] Typically, orally disintegrating tablets may have the following problems: poor mechanical strength of the tablet, improper disintegration, dissolution problems, degradation and inhomogeneity of the active pharmaceutical ingredient. During the formulation experiments of orally disintegrating tablets containing cariprazine, we encountered several problems. Increasing the amount of cariprazine in the tablet matrix reduced mechanical and degradation problems, but increased dissolution and manufacturability problems. Faced with such a complex effect of the active pharmaceutical ingredient on the final product, it is troublesome to overcome all formulations and quality problems for all desired dosage specifications (i.e., for dosage specifications between 0.01 and 6 mg). The different problems that arise can only be solved in a complex manner by carefully selecting excipients. Due to the fact of dose selectivity problems, a specific formulation solution causes improvements in some tablet parameters of a dosage specification, but increases quality problems in other dosage specifications.

[0022] The directly compressible matrix of ODT mainly contains fillers, which only provide low levels of inter-particle bonding within the tablet matrix. This allows rapid disintegration, but causes poor mechanical strength. Adding disintegrants to ODT further improves disintegration, but makes the tablets even more susceptible to brittleness and cracking or capping / delamination. In addition, the disintegrant component also contributes to the dissolution of cariprazine, especially at higher dosage specifications. On the other hand, the amount of disintegrant must be limited to maintain satisfactory mechanical strength. However, it has been observed that smaller amounts of disintegrants may cause dissolution problems.

[0023] The pharmaceutical tablets of the present invention are primarily designed for orally disintegration in the patient's mouth, or they may be dissolved in a suitable volume of liquid such as water before administration.

[0024] In addition, the pharmaceutical tablet of the present invention is characterized by low friability, high physical stability at high temperature and humidity levels (30 and 40°C / 75% RH), and it meets all measurable quality attributes. The orally disintegrating tablet of the present invention can be stored and used at room temperature for more than two years, and can also be stored and used in a climate zone characterized by high temperature and high humidity (30°C / 75% RH).

[0025] The pharmaceutical tablet of the present invention does not require a special preparation method. It can be prepared by a simple and cost-effective industrial process by mixing and directly compressing the ingredients. Therefore, the total treatment cost that may be incurred during the patient's entire life can be substantially reduced.

[0026] In the context of the present invention, the term "orodisintegrating pharmaceutical tablet" means an uncoated tablet intended to be placed in the mouth, where it rapidly disperses before being swallowed. Orodisintegrating pharmaceutical tablets disintegrate in the mouth within 3 minutes, within 2 minutes, within 1 minute, or within 30 seconds. Recently, the European Pharmacopoeia has used the term "orodispersible tablets" for tablets that disperse easily and within 3 minutes in the mouth before swallowing. The U.S. Food and Drug Administration (FDA) defines an orodisintegrating tablet as a solid dosage form containing a pharmaceutical substance or active ingredient that rapidly disintegrates, typically within a few seconds, when placed on the tongue.

[0027] Unless otherwise specified herein, the term "pharmaceutically acceptable salt" refers to a salt obtained by reacting the main compound as a base with an inorganic or organic acid to form a salt, such as hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, camphorsulfonic acid, oxalic acid, maleic acid, succinic acid, citric acid, formic acid, hydrobromic acid, benzoic acid, tartaric acid, fumaric acid, salicylic acid, mandelic acid and carbonic acid. Pharmaceutically acceptable salts also include those salts in which the main compound is used as an acid and is formed by reacting with an appropriate base, such as sodium, potassium, calcium, magnesium, ammonium and choline salts. Those skilled in the art will additionally appreciate that acid addition salts can be prepared by any of a large number of known methods by reacting a compound with an appropriate inorganic or organic acid. Alternatively, alkali metal and alkaline earth metal salts can be prepared by reacting the compound of the present invention with an appropriate base by various known methods.

[0028] In addition, several acid salts can be obtained by reaction with inorganic or organic acids, namely acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, digluconate, cyclopentanepropionate, dodecylsulfate, ethanesulfonate, glucoheptonate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrobromide, hydroiodide, 2-hydroxy-ethanesulfonate, lactate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, palmitate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, toluenesulfonate, mesylate and undecanoate.

[0029] Disintegrants used according to the present invention are substances or mixtures of substances added to pharmaceutical preparations, which promote the splitting or disintegration of pharmaceutical tablets into smaller particles so that they can be more rapidly dispersed or dissolved in the patient's mouth. Disintegrants can improve the bioavailability of the applied active compound by improving the disintegration and dissolution of solid dosage forms. The main function of disintegrants is to offset the effect of physical forces and / or tablet binders generated during tablet compression. There is a subgroup in the disintegrant family, which is called super disintegrants, which are advantageously used for oral disintegrating preparations due to their high water absorption and swelling capacity. Suitable disintegrants according to the present invention are, for example, starch, modified starch, such as sodium carboxymethyl starch (sodium starch glycolate), cellulose, modified cellulose, such as cross-linked sodium carboxymethyl cellulose, cross-linked polyvinyl pyrrolidone (cross-linked polyvinylpyrrolidone), soybean polysaccharides, cross-linked alginic acid, gellan gum, xanthan gum, calcium silicate and ion exchange resins, such as indion 414.

[0030] As used herein, a "diluent" (also referred to as a "filler" or "diluent") is a diluting agent. Diluents act as fillers in pharmaceutical tablets and capsules to increase weight and improve content uniformity. Diluents also provide better tablet properties, such as improved cohesion or facilitated flow. Diluents themselves and in combination with active pharmaceutical ingredients must be non-toxic, physiologically inert, and physically and chemically stable. They are inactive ingredients added to tablets and capsules in addition to the active drug.

[0031] The diluent used according to the present invention can be any diluent conventionally used for the preparation of orally disintegrating tablets. Suitable diluents include sugars, such as lactose or lactose derivatives, sugar alcohols, such as mannitol, microcrystalline cellulose, starch, starch derivatives or combinations thereof.

[0032] As used herein, a "glidant" is a non-toxic, neutral tasting, pharmacologically inactive substance used to optimize the flow properties of tablet granulation or powder materials by reducing inter-particle friction and cohesion. Typically, a glidant can inhibit the flow properties above a certain concentration. Suitable glidants include corn starch, silicon dioxide derivatives (colloidal silicon dioxide), (micron-sized) silica gel, fumed silica, and hydrated sodium sulfoaluminate.

[0033] "Lubricant" as used herein is an agent added to tablet and capsule formulations in very small amounts (usually between 0.1 and 5% by weight) to improve the powder processing properties of the formulation. Suitable lubricants include metal salts of fatty acids, such as magnesium stearate, and stearic acid, fatty acid esters, inorganic materials and polymers.

[0034] As used herein, a "therapeutically effective amount" of a compound means an amount sufficient to cure, alleviate or partially inhibit the clinical manifestations of a given disease and its complications in a therapeutic intervention comprising the administration of the compound. The therapeutically effective amount will vary depending, inter alia, on the disease and its severity, as well as on the age, weight, physical condition and responsiveness of the patient to be treated.

[0035] As used herein, "treatment" or "treating" refers to the management and care of a patient for the purpose of combating a condition such as a disease or disorder. The term is intended to include the full range of treatments for a given condition suffered by a patient, such as the administration of active compounds to relieve symptoms or complications, delay the progression of a disease, disorder or condition, alleviate or relieve symptoms and complications, and / or cure or eliminate a disease, disorder or condition, as well as prevention of a condition, wherein prevention is understood as the management and care of a patient for the purpose of combating a disease, disorder or disorder, and includes the administration of active compounds to prevent the onset of symptoms or complications.

[0036] Unless otherwise indicated herein, all percentages are by weight based on the total weight of the pharmaceutical tablet.

[0037] The present invention also relates to an orally disintegrating pharmaceutical tablet comprising:

[0038] between 0.1 and 21% by weight of cariprazine or a pharmaceutically acceptable salt thereof,

[0039] between 0.1 and 15% by weight of a disintegrant,

[0040] between 0.1 and 5% by weight of colloidal silicon dioxide,

[0041] between 0.1 and 10% by weight of a taste masking agent,

[0042] between 0.1 and 5 wt. % lubricant, and

[0043] Up to 100 wt.% diluent

[0044] The percentages are expressed relative to the total weight of the drug tablet.

[0045] In one embodiment, cariprazine or a pharmaceutically acceptable salt thereof is present in an amount between 0.1 and 15 weight %, between 0.2 and 12 weight %, between 0.25 and 10 weight %, between 1 and 5 weight %, or between 0.39 and 4.67 weight %, based on the total weight of the pharmaceutical tablet.

[0046] In one embodiment, the pharmaceutically acceptable salt may be a hydrochloride, a hydrobromide or a methanesulfonate. In another embodiment, the pharmaceutically acceptable salt is a hydrochloride.

[0047] In one embodiment, cariprazine hydrochloride is present in an amount between 0.1 and 15 weight %, between 0.2 and 12 weight %, between 0.25 and 10 weight %, between 1 and 5 weight %, or between 0.39 and 4.67 weight %, based on the total weight of the pharmaceutical tablet.

[0048] In one embodiment of the invention, the disintegrant is a super disintegrant. In yet another embodiment, the disintegrant is sodium starch glycolate, crospovidone or croscarmellose sodium.

[0049] In another embodiment, the disintegrant is present in an amount between 0.1 and 12 weight %, between 0.2 and 12 weight %, between 0.1 and 10 weight %, between 1 and 10 weight %, between 1 and 5 weight %, or between 3 and 5 weight %, based on the total weight of the pharmaceutical tablet.

[0050] In another embodiment, the pharmaceutical tablet of the invention has a disintegration time of no more than 30 seconds. The disintegration time is determined according to the European Pharmacopoeia (9th edition, 2.9.1. Disintegration of tablets and capsules Test A).

[0051] In an embodiment of the present invention, the diluent comprises mannitol, dextrates, isomalt, sorbitol, and a mixture thereof with starch. In another embodiment, the diluent is a mixture of mannitol and starch. Such a mixture is available, for example, from Roquette under the trade name Flash is available, which contains 78.0-82.0 wt. % D-mannitol and 15.0-19.0 wt. % corn starch.

[0052] In yet another embodiment, the diluent is present in an amount between 75 wt % and 85 wt % based on the total weight of the pharmaceutical tablet.

[0053] According to an embodiment of the present invention, the taste masking agent is selected from the group consisting of artificial sweeteners, flavoring agents and organic acidic components.

[0054] According to another embodiment, the taste masking agent is present in an amount between 0.1 and 8 weight %, between 0.1 and 5 weight %, or between 0.5 and 1.5 weight %, based on the total weight of the pharmaceutical tablet.

[0055] In another embodiment, the taste masking agent is an organic acid component selected from oxalic acid, maleic acid, succinic acid, citric acid, tartaric acid, malic acid, ascorbic acid, fumaric acid, adipic acid. In another embodiment, the pharmaceutical tablet further comprises an anhydride of the organic acid; or an inorganic acid salt, including but not limited to sodium dihydrogen phosphate, disodium dihydrogen pyrophosphate and sodium bisulfite. In addition, the pharmaceutical tablet may comprise a mixture of the organic acid, and / or the anhydride of the organic acid and / or the inorganic acid salt.

[0056] In one embodiment, the organic acidic component is selected from oxalic acid, maleic acid, succinic acid, citric acid, tartaric acid, malic acid or a combination thereof. In yet another embodiment, the organic acidic component is malic acid.

[0057] According to another embodiment, the organic acidic component is present in an amount between 0.1 and 10 weight %, between 0.1 and 5 weight %, or between 0.5 and 1.5 weight %, based on the total weight of the pharmaceutical tablet.

[0058] In an embodiment of the present invention, the orally disintegrating pharmaceutical tablet of the present invention contains colloidal silicon dioxide as a glidant, such as anhydrous colloidal silicon dioxide, hydrated colloidal silicon dioxide and hydrophobic colloidal silicon dioxide.

[0059] In yet another embodiment, the colloidal silicon dioxide is anhydrous or hydrated colloidal silicon dioxide. In another embodiment, the colloidal silicon dioxide is hydrated colloidal silicon dioxide. According to another embodiment, the colloidal silicon dioxide is present in an amount between 0.1 wt % and 2 wt %, between 0.1 wt % and 1 wt %, or between 0.1 wt % and 0.5 wt %, based on the total weight of the pharmaceutical tablet.

[0060] In a further embodiment of the present invention, the pharmaceutical tablet comprises a lubricant selected from calcium stearate, glyceryl behenate, magnesium stearate, mineral oil, polyethylene glycol, sodium stearyl fumarate, stearic acid, talc, vegetable oil, zinc stearate or a combination thereof.

[0061] In an embodiment of the present invention, the lubricant is selected from metal stearates (such as magnesium stearate), stearic acid, sodium fumarate, talc, or a combination thereof.

[0062] Pharmaceutical tablets may additionally contain one or more additional excipients, such as binders, granulation aids, effervescent agents and film formers. These excipients may be used in a conventional manner, alone or in any combination.

[0063] In a further embodiment, the pharmaceutical tablet of the present invention comprises:

[0064] between 0.1 and 21% by weight of cariprazine or a pharmaceutically acceptable salt thereof,

[0065] between 0.1 and 15% by weight of a disintegrant,

[0066] between 0.1 and 5% by weight of colloidal silicon dioxide,

[0067] between 0.1 and 10% by weight of a taste masking agent,

[0068] between 0.1 and 2.5 wt. % lubricant, and

[0069] Up to 100% by weight of diluent,

[0070] The percentages are expressed relative to the total weight of the pharmaceutical tablet.

[0071] In a further embodiment, the pharmaceutical tablet of the present invention comprises:

[0072] between 0.2 and 12% by weight of cariprazine or a pharmaceutically acceptable salt thereof,

[0073] between 0.1 and 10% by weight of a disintegrant,

[0074] between 0.1 and 2.5 wt. % colloidal silicon dioxide,

[0075] between 0.1 and 5% by weight of a taste masking agent,

[0076] between 0.1 and 2.5 wt. % lubricant, and

[0077] Up to 100% by weight of diluent,

[0078] The percentages are expressed relative to the total weight of the pharmaceutical tablet.

[0079] In a further embodiment, the pharmaceutical tablet of the present invention comprises:

[0080] between 0.25 and 10% by weight of cariprazine or a pharmaceutically acceptable salt thereof,

[0081] between 0.1 and 10% by weight of a disintegrant,

[0082] between 0.1 and 2% by weight of colloidal silicon dioxide,

[0083] between 0.1 and 5% by weight of a taste masking agent,

[0084] between 0.1 and 2.5 wt. % lubricant, and

[0085] Up to 100% by weight of diluent,

[0086] The percentages are expressed relative to the total weight of the pharmaceutical tablet.

[0087] In a further embodiment, the pharmaceutical tablet of the present invention comprises:

[0088] between 0.1 and 21% by weight of cariprazine hydrochloride,

[0089] between 0.1 and 15% by weight of a disintegrant selected from sodium starch glycolate, croscarmellose sodium and crospovidone,

[0090] between 0.1 and 5% by weight of colloidal silicon dioxide,

[0091] between 0.1 and 10% by weight of a taste masking agent selected from oxalic acid, maleic acid, succinic acid, citric acid, tartaric acid and malic acid,

[0092] between 0.1 and 2.5 weight percent of a lubricant selected from sodium stearyl fumarate and magnesium stearate, and

[0093] Up to 100 wt % of a mixture of 78.0-82.0 wt % D-mannitol and 15.0-19.0 wt % corn starch,

[0094] The percentages are expressed relative to the total weight of the pharmaceutical tablet.

[0095] In a further embodiment, the pharmaceutical tablet of the present invention comprises:

[0096] between 0.2 and 12% by weight of cariprazine hydrochloride,

[0097] between 0.1 and 10% by weight of a disintegrant selected from sodium starch glycolate, croscarmellose sodium and crospovidone,

[0098] between 0.1 and 2.5 wt. % colloidal silicon dioxide,

[0099] between 0.1 and 5% by weight of a taste masking agent selected from oxalic acid, maleic acid, succinic acid, citric acid, tartaric acid and malic acid,

[0100] between 0.1 and 2.5 weight percent of a lubricant selected from sodium stearyl fumarate and magnesium stearate, and

[0101] Up to 100 wt % of a mixture of 78.0-82.0 wt % D-mannitol and 15.0-19.0 wt % corn starch,

[0102] The percentages are expressed relative to the total weight of the pharmaceutical tablet.

[0103] In a further embodiment, the pharmaceutical tablet of the present invention comprises:

[0104] between 0.25 and 10% by weight of cariprazine hydrochloride,

[0105] between 0.1 and 10% by weight of a disintegrant selected from sodium starch glycolate, croscarmellose sodium and crospovidone,

[0106] between 0.1 and 2% by weight of colloidal silicon dioxide,

[0107] between 0.1 and 5% by weight of a taste masking agent selected from oxalic acid, maleic acid, succinic acid, citric acid, tartaric acid and malic acid,

[0108] between 0.1 and 2.5 weight percent of a lubricant selected from sodium stearyl fumarate and magnesium stearate, and

[0109] Up to 100 wt % of a mixture of 78.0-82.0 wt % D-mannitol and 15.0-19.0 wt % corn starch,

[0110] The percentages are expressed relative to the total weight of the pharmaceutical tablet.

[0111] In a further embodiment, the pharmaceutical tablet of the present invention comprises:

[0112] between 0.1 and 21% by weight of cariprazine hydrochloride,

[0113] between 0.1 and 15% by weight of a disintegrant selected from sodium starch glycolate, croscarmellose sodium and crospovidone,

[0114] between 0.1 and 5% by weight of colloidal silicon dioxide,

[0115] between 0.1 and 10% by weight of malic acid,

[0116] between 0.1 and 2.5% by weight of sodium stearyl fumarate,

[0117] Up to 100 wt % of a mixture of 78.0-82.0 wt % D-mannitol and 15.0-19.0 wt % corn starch,

[0118] The percentages are expressed relative to the total weight of the pharmaceutical tablet.

[0119] In a further embodiment, the pharmaceutical tablet of the present invention comprises:

[0120] between 0.2 and 12% by weight of cariprazine hydrochloride,

[0121] between 0.1 and 10% by weight of a disintegrant selected from sodium starch glycolate, croscarmellose sodium and crospovidone,

[0122] between 0.1 and 2.5 wt. % colloidal silicon dioxide,

[0123] between 0.1 and 5% by weight of malic acid,

[0124] between 0.1 and 2.5% by weight of sodium stearyl fumarate,

[0125] Up to 100 wt % of a mixture of 78.0-82.0 wt % D-mannitol and 15.0-19.0 wt % corn starch,

[0126] The percentages are expressed relative to the total weight of the pharmaceutical tablet.

[0127] In a further embodiment, the pharmaceutical tablet of the present invention comprises:

[0128] between 0.25 and 10% by weight of cariprazine hydrochloride,

[0129] between 0.1 and 10% by weight of a disintegrant selected from sodium starch glycolate, croscarmellose sodium and crospovidone,

[0130] between 0.1 and 2% by weight of colloidal silicon dioxide,

[0131] between 0.1 and 5% by weight of malic acid,

[0132] between 0.1 and 2.5 wt. % sodium stearyl fumarate, and

[0133] Up to 100 wt % of a mixture of 78.0-82.0 wt % D-mannitol and 15.0-19.0 wt % corn starch,

[0134] The percentages are expressed relative to the total weight of the pharmaceutical tablet.

[0135] In a further embodiment, the pharmaceutical tablet of the present invention comprises:

[0136] between 0.1 and 21% by weight of cariprazine hydrochloride,

[0137] between 0.1 and 15% by weight of a disintegrant selected from sodium starch glycolate, croscarmellose sodium and crospovidone,

[0138] between 0.1 and 5% by weight of anhydrous colloidal silica or hydrated colloidal silica,

[0139] between 0.1 and 10% by weight of malic acid,

[0140] between 0.1 and 2.5 wt. % sodium stearyl fumarate, and

[0141] Up to 100 wt % of a mixture of 78.0-82.0 wt % D-mannitol and 15.0-19.0 wt % corn starch,

[0142] The percentages are expressed relative to the total weight of the pharmaceutical tablet.

[0143] In a further embodiment, the pharmaceutical tablet of the present invention comprises:

[0144] between 0.2 and 12% by weight of cariprazine hydrochloride,

[0145] between 0.1 and 10% by weight of a disintegrant selected from sodium starch glycolate, croscarmellose sodium and crospovidone,

[0146] between 0.1 and 2.5% by weight of anhydrous colloidal silica or hydrated colloidal silica,

[0147] between 0.1 and 5% by weight of malic acid,

[0148] between 0.1 and 2.5 wt. % sodium stearyl fumarate, and

[0149] Up to 100 wt % of a mixture of 78.0-82.0 wt % D-mannitol and 15.0-19.0 wt % corn starch,

[0150] The percentages are expressed relative to the total weight of the pharmaceutical tablet.

[0151] In a further embodiment, the pharmaceutical tablet of the present invention comprises:

[0152] between 0.25 and 10% by weight of cariprazine hydrochloride,

[0153] between 0.1 and 10% by weight of a disintegrant selected from sodium starch glycolate, croscarmellose sodium and crospovidone,

[0154] between 0.1 and 2% by weight of anhydrous colloidal silica or hydrated colloidal silica,

[0155] between 0.1 and 5% by weight of malic acid,

[0156] between 0.1 and 2.5 wt. % sodium stearyl fumarate, and

[0157] Up to 100 wt % of a mixture of 78.0-82.0 wt % D-mannitol and 15.0-19.0 wt % corn starch,

[0158] The percentages are expressed relative to the total weight of the pharmaceutical tablet.

[0159] In another embodiment, the pharmaceutical tablet of the present invention comprises:

[0160] between 0.39 and 4.67% by weight of cariprazine hydrochloride,

[0161] between 1 and 5% by weight of sodium starch glycolate,

[0162] between 0.1 and 0.25% by weight of anhydrous colloidal silica or hydrated colloidal silica,

[0163] between 0.5 and 1 wt. % malic acid,

[0164] between 0.5 and 1 wt. % sodium stearyl fumarate, and

[0165] Up to 100 wt % of a mixture of 78.0-82.0 wt % D-mannitol and 15.0-19.0 wt % corn starch,

[0166] The percentages are expressed relative to the total weight of the pharmaceutical tablet.

[0167] Another aspect of the invention relates to an orally disintegrating pharmaceutical tablet as described above for use in the treatment and / or prevention of pathological conditions requiring modulation of dopamine receptors. In one embodiment, such use comprises the treatment of psychosis, drug abuse, cognitive impairment associated with schizophrenia, mild to moderate cognitive deficits, dementia, psychotic states associated with dementia, eating disorders, attention deficit disorder, childhood hyperactivity disorder, psychotic depression, bipolar disorder, paranoid and delusional disorders, movement disorders, anxiety, sexual dysfunction, sleep disorders, vomiting, aggressive behavior and autism.

[0168] Another aspect of the present invention relates to an orally disintegrating pharmaceutical tablet as described above for use in the treatment and / or prevention of schizophrenia and / or bipolar disorder and / or autism.

[0169] The present invention also provides the use of the orally disintegrating pharmaceutical tablet for the preparation of a medicament for the treatment and / or prevention of pathological conditions requiring modulation of dopamine receptors, such as psychosis (e.g., schizophrenia and schizoaffective disorder), drug abuse (e.g., alcohol, cocaine, nicotine and opioids), cognitive impairment associated with schizophrenia (including positive symptoms such as delusions and hallucinations, and negative symptoms such as lack of motivation and social withdrawal, and cognitive symptoms such as attention and memory problems), mild to moderate cognitive deficits, dementia, psychotic states associated with dementia, eating disorders (e.g., bulimia nervosa, etc.), attention deficit disorder, childhood hyperactivity disorder, psychotic depression, bipolar disorder, paranoid and delusional disorders, movement disorders (e.g., Parkinson's disease, neuroleptic-induced parkinsonism, tardive dyskinesia), anxiety, sexual dysfunction, sleep disorders, vomiting, aggressive behavior and autism.

[0170] Another aspect of the present invention relates to the use of the orally disintegrating pharmaceutical tablet for preparing a medicament for treating and / or preventing schizophrenia and / or bipolar disorder and / or autism.

[0171] The present invention also provides a method for treating a patient suffering from a pathological condition requiring modulation of dopamine receptors, such as psychosis (e.g., schizophrenia and schizoaffective disorder), drug abuse (e.g., alcohol, cocaine, nicotine, and opioids), cognitive impairment associated with schizophrenia (including positive symptoms such as delusions and hallucinations, and negative symptoms such as lack of motivation and social withdrawal, and cognitive symptoms such as attention and memory problems), mild to moderate cognitive deficits, dementia, psychotic states associated with dementia, eating disorders (e.g., bulimia nervosa, etc.), attention deficit disorder, childhood hyperactivity disorder, psychotic depression, bipolar disorder, paranoid and delusional disorders, movement disorders (e.g., Parkinson's disease, neuroleptic-induced parkinsonism, tardive dyskinesia), anxiety, sexual dysfunction, sleep disorders, vomiting, aggressive behavior, and autism, wherein the method comprises administering the orally disintegrating pharmaceutical tablet to a patient in need thereof.

[0172] Another aspect of the present invention relates to a method of treating a patient suffering from schizophrenia and / or bipolar disorder and / or autism, wherein the method comprises administering the orally disintegrating pharmaceutical tablet to a patient in need thereof.

[0173] Yet another aspect of the present invention relates to a method for preparing an orally disintegrating pharmaceutical tablet as described above, comprising the following steps:

[0174] a. mixing a therapeutically effective amount of cariprazine or a pharmaceutically acceptable salt thereof with a diluent and optionally with a disintegrant,

[0175] b. The mixture obtained under a. is compressed into a solid tablet form.

[0176] The following examples are used to illustrate the present invention. However, they should not be construed as limiting the scope of the present invention.

[0177] Example

[0178] Example 1. Preparation of orally disintegrating drug tablets

[0179] All tablets in the following examples were prepared according to the following method:

[0180] 1. Weigh the components of the product, then

[0181] 2. Roto-sieving the components of the product, then

[0182] 3. Blend the components of the product in a container, then

[0183] 4. Compress the powder blend into tablets using a rotary tablet press.

[0184] Example 2. Taste masking test

[0185] Orally disintegrating tablets must have a pleasant taste as they disintegrate in the patient's mouth. Therefore, commonly used taste masking agents were tested in the pharmaceutical tablets according to the present invention. We found that the most common taste masking agents were not very effective in masking the taste of cariprazine.

[0186] A multi-channel taste sensor system or electronic tongue was used to evaluate bitterness inhibition in different formulations. The sensors are cross-selective for the five basic tastes: sour, sweet, bitter, salty and umami. This cross-selectivity is manifested in different response curves for the 5 basic taste components. The sensor can detect taste in a manner similar to human taste perception through the potentiometric response pattern to taste substances. The sensitivity, reproducibility and durability are better than those of humans. For the different concentrations of quinine used in the bitterness test, the response patterns of the seven sensors were similar, while the electrical output of each individual sensor was slightly different.

[0187] In the first set of experiments, different taste masking agents were investigated for their ability to reduce the bitterness of cariprazine. Malic acid, citric acid, tartaric acid, acesulfame potassium and orange flavor (at 1.4 mg / 100 ml; 2.8 mg / 100 ml and 4.2 mg / 100 ml concentrations) were added to a 1.5 mg / ml solution of cariprazine in purified water, and the samples were subjected to electronic tongue measurements. Table 1 summarizes the predicted quinine bitterness of the different samples.

[0188] Table 1: Predicted quinine bitterness of different samples

[0189] coding Element Predicted quinine bitterness AC_14 1.5mg / ml cariprazine + 1.4mg / ml acesulfame potassium 29.57 AC_28 1.5mg / ml cariprazine + 2.8mg / ml acesulfame potassium 29.47 AC_42 1.5mg / ml cariprazine + 4.2mg / ml acesulfame potassium 5.70 AS_14 1.5mg / ml cariprazine + 1.4mg / ml malic acid -11.99 AS_28 1.5mg / ml cariprazine + 2.8mg / ml malic acid -29.34 AS_42 1.5mg / ml cariprazine + 4.2mg / ml malic acid -30.20 BS_14 1.5mg / ml cariprazine + 1.4mg / ml tartaric acid -25.98 BS_28 1.5mg / ml cariprazine + 2.8mg / ml tartaric acid -40.96 BS_42 1.5mg / ml cariprazine + 4.2mg / ml tartaric acid -43.17 CS_14 1.5mg / ml cariprazine + 1.4mg / ml citric acid -23.71 CS_28 1.5mg / ml cariprazine + 2.8mg / ml citric acid -40.25 CS_42 1.5mg / ml cariprazine + 4.2mg / ml citric acid -52.21 NA_14 1.5mg / ml cariprazine + 1.4mg / ml orange flavor 46.90 NA_28 1.5mg / ml cariprazine + 2.8mg / ml orange flavor 22.80 NA_42 1.5mg / ml cariprazine + 4.2mg / ml orange flavor 42.43 HA 1.5mg / ml Cariprazine 51.72 Q1 1.6 μM Quinine Q2 8.3 μM Quinine Q3 83 μM Quinine

[0190] The taste (bitterness) masking effects of the test substances were compared using PLS regression and the results are shown in Figure 1 middle.

[0191] Commonly used taste masking agents, such as orange flavoring and the artificial sweetener acesulfame potassium, were shown to be less effective than organic acidic compounds in reducing the bitterness of cariprazine.

[0192] In a second set of experiments, the taste properties of the placebo formulation were compared with formulations containing different concentrations of malic acid and cariprazine and with quinine solutions of different concentrations (Q1-1.6 μM, Q2-8.3 μM, Q3-83 μM). Table 2 shows the composition of the samples tested.

[0193] Table 2: Composition of different samples

[0194]

[0195] The results of the electronic tongue measurements were evaluated using PLS (partial least squares) regression, showing an estimate of the bitterness of each sample compared to the quinine solution (predicted "quinine bitterness").

[0196] Table 3 and Figure 2 The results of the measurements described above are illustrated, showing that all formulations tested were below the human bitter taste threshold represented by Q2.

[0197] Table 3: Predicted quinine bitterness of different samples

[0198] coding Cariprazine HCl content (wt%) Predicted quinine bitterness A30 0.0 -33.96 A30 0.39 -40.72 A32 0.78 -19.56 A33 1.17 5.82 A34 2.34 6.02 A35 3.50 13.84 A36 4.67 10.48

[0199] Example 3. Disintegration Efficacy, Friability and Crush Resistance Tests

[0200] The disintegration efficiency of pharmaceutical tablets is measured according to the European Pharmacopoeia (9th edition, 2.9.1. Disintegration of tablets and capsules Test A). This test is provided to determine whether a tablet or capsule disintegrates within a specified time when placed in a liquid medium under experimental conditions.

[0201] For the purpose of this test, disintegration does not mean complete dissolution of the unit or its active ingredients. Complete disintegration is defined as the state where any remnants of the unit are a soft mass with no apparent hard core (except for fragments of insoluble coating or capsule shell remaining on the screen of the test apparatus or adhering to the lower surface of the disc (if used)).

[0202] The friability and resistance to crushing of pharmaceutical tablets were measured according to the European Pharmacopoeia (9th edition, 2.9.7. Friability of uncoated tablets; 2.9.8. Resistance to crushing of tablets).

[0203] Table 4: Qualitative and quantitative composition of different exemplary formulations

[0204]

[0205] Table 5: Physical properties of exemplary formulations of Table 4

[0206] F1 F2 F3 F4 F5 F6 F7 F8 F9 F10 Average hardness [N] 67 65 61 62 62 49 56 53 50 52 Disintegration rate[s] 19 15 29 21 18 17 25 11 7 17 Friability % 0.60 0.60 0.40 1.10 0.50 0.90 1.00 0.39 0.31 0.31

[0207] Table 6: Qualitative and quantitative composition of different exemplary formulations

[0208]

[0209] Table 7: Physical properties of exemplary formulations of Table 6 ("nm": not measurable)

[0210] F11 F12 F13 F14 F15 F16 F17 F18 Average hardness [N] 56 29 21 nm 23 nm 21 nm Disintegration rate[s] 27 27 21 39 37 25 48 39 Friability % 0.40 4.12 10.63 18.34 2.70 91.96 1.10 2.25

[0211] Tables 4 to 7 show that concentrations of disintegrant (sodium starch glycolate) below 15 wt % do not negatively affect the disintegration time of the pharmaceutical tablets, whereas concentrations above this value substantially affect friability. According to the literature, such low disintegrant concentrations would not allow acceptable tablet disintegration times.

[0212] Example 4. Dissolution Test

[0213] ODT products are usually developed for a more convenient form of administration or for a more rapid onset of drug action, so they are essentially immediate-release products. EMA (EMA / CHMP / CVMP / QWP / 336031 / 2017) defines immediate-release as a drug product in which at least 75% (Q) of the active substance is dissolved within 45 minutes. The dissolution specification of the product should ensure batch-to-batch consistency and, ideally, foreshadow potential problems with in vivo bioavailability. Therefore, reproducible dissolution behavior with low standard deviation is necessary to ensure consistent quality during shelf life and product life cycle.

[0214] The dissolution behavior of different strengths of the same product should be similar, especially if the dissolution properties of other marketed dosage forms of the same product are similar across strengths.

[0215] During formulation experiments it was found that despite rapid tablet disintegration, the release of cariprazine at the higher dose strength was insufficient, i.e. the mean dissolution was not close to complete and the standard deviation of the dissolution values ​​measured at 15 min was higher compared to the lower dose strength.

[0216] If the dissolution release kinetics are not the same for all dosage strengths, the pharmacokinetic parameters and therapeutic effect of the drug may be subject to uncertainty. Slowed dissolution can alter the onset of drug action, and heterogeneity in dissolution may lead to pharmacokinetic variability.

[0217] It was found that disintegrants neither significantly increased the in vitro disintegration of tablets nor significantly increased the dissolution of cariprazine from tablets. Increasing the amount of superdisintegrant resulted in a powder quality with poorer flow properties and produced more friable tablets without significantly improving the dissolution of cariprazine.

[0218] Several different excipients were tested to improve the dissolution of cariprazine, but most of them were not suitable for palatable orally disintegrating tablets. During formulation experiments, glidants were tested to improve powder and tablet properties, and surprisingly it was found that the use of colloidal silicon dioxide improved the dissolution of cariprazine without interfering with other parameters of the tablet.

[0219] The dissolution of the tablet containing 1.5 mg cariprazine and no colloidal silicon dioxide was almost complete after 15 minutes, and each tablet measured showed similar dissolution, i.e., the minimum-maximum range of the measurement was small (Tables 8 and 9). On the other hand, the dissolution of the tablet containing 6 mg cariprazine and no colloidal silicon dioxide was lower at 15 minutes, and the individual measurement points showed a higher standard deviation, i.e., the minimum-maximum range of the measurement was large (Tables 8 and 9). In clinical practice, when switching to a higher dosage strength, this can cause changes in pharmacokinetic parameters and can increase the variability of blood levels of the drug.

[0220] However, even a smaller amount of colloidal silicon dioxide significantly improved the dissolution of cariprazine at higher dose strengths, and it became more similar to the dissolution of lower dose strengths. Both the mean dissolution and the standard deviation of dissolution were improved (Tables 8 and 9).

[0221] Table 8: Qualitative and quantitative composition of different exemplary formulations

[0222]

[0223] Table 9: Dissolution parameters of different exemplary formulations (*Levels of dissolution acceptance criteria measured from 6 tablets according to Ph. Eur. 2.9.3)

[0224]

[0225] The tablets according to the invention show similar dissolution kinetics for all dosage strengths with low variability, thus meeting therapeutic and safety requirements. Thus, the overall quality of the product is improved.

[0226] Example 5. Stability test

[0227] The stability of pharmaceutical tablets was measured according to CPMP / ICH / 2736 / 99 (Q1A(R2) Stability Testing of New Drug Substances and Products) (EC, Europe - adopted by CPMP in March 2003).

[0228] The samples were packaged in cold stamped aluminum blisters (sample "A") and PVC / PE / PVDC-aluminum packaging materials (sample "B") and stored under accelerated conditions (40°C / 70% RH) as well as long-term conditions (30°C / 65% RH and 25°C / 60% RH). The tablets according to the invention showed good stability over time (up to 6 months) even under high temperature and high humidity conditions.

Claims

1. An orally disintegrating pharmaceutical tablet comprising: between 0.1 and 21% by weight of cariprazine or a pharmaceutically acceptable salt thereof, between 0.1 and 15% by weight of a disintegrant, between 0.1 and 5% by weight of colloidal silicon dioxide, between 0.1 and 10% by weight of a taste masking agent, between 0.1 and 5 wt. % lubricant, and Up to 100% by weight of diluent, The percentages are expressed relative to the total weight of the pharmaceutical tablet.

2. The pharmaceutical tablet according to claim 1, wherein the pharmaceutically acceptable salt of cariprazine is hydrochloride.

3. The pharmaceutical tablet according to claim 1 or 2, wherein the silicon dioxide is anhydrous colloidal silicon dioxide or hydrated colloidal silicon dioxide. The pharmaceutical tablet according to claim 3 , wherein the colloidal silicon dioxide is hydrated colloidal silicon dioxide.

5. The pharmaceutical tablet according to any one of claims 1 to 4, wherein the taste masking agent is an organic acid.

6. The pharmaceutical tablet according to claim 5, wherein the organic acid is selected from the group consisting of oxalic acid, maleic acid, succinic acid, citric acid, tartaric acid, malic acid, and combinations thereof.

7. The pharmaceutical tablet according to any one of claims 1 to 6, wherein the disintegrant is selected from sodium starch glycolate, crospovidone, croscarmellose sodium and combinations thereof.

8. The pharmaceutical tablet according to any one of claims 1 to 7, wherein the diluent comprises mannitol, dextrates, isomalt or sorbitol, or a mixture thereof with starch.

9. The pharmaceutical tablet according to claim 8, wherein the diluent is a mixture of 78.0-82.0 wt% of D-mannitol and 15.0-19.0 wt% of corn starch.

10. The pharmaceutical tablet according to any one of claims 1 to 9, wherein the lubricant is magnesium stearate or sodium stearyl fumarate.

11. The pharmaceutical tablet according to any one of claims 1 to 10, wherein the disintegrant is present in an amount between 0.1 wt% and 10 wt%.

12. The pharmaceutical tablet according to any one of claims 1 to 11, wherein the colloidal silicon dioxide is present in an amount between 0.1 wt% and 2 wt%.

13. A pharmaceutical tablet according to any one of claims 1 to 12, wherein the taste masking agent is present in an amount between 0.1 and 5% by weight.

14. Pharmaceutical tablet according to any one of claims 1 to 13, for use in the treatment and / or prevention of pathological conditions requiring modulation of dopamine receptors, selected from psychosis, substance abuse, cognitive impairment associated with schizophrenia, mild to moderate cognitive deficits, dementia, psychotic states associated with dementia, eating disorders, attention deficit disorder, childhood hyperactivity disorder, psychotic depression, bipolar disorder, paranoid and delusional disorders, movement disorders, anxiety, sexual dysfunction, sleep disorders, vomiting, aggressive behavior and autism.

15. Pharmaceutical tablet for use according to claim 14, wherein the pathological condition is selected from schizophrenia, bipolar disorder and autism.

16. Use of a pharmaceutical tablet according to any one of claims 1 to 13 for the preparation of a medicament for the treatment and / or prevention of pathological conditions requiring modulation of dopamine receptors, selected from psychosis, drug abuse, cognitive impairment associated with schizophrenia, mild to moderate cognitive deficits, dementia, psychotic states associated with dementia, eating disorders, attention deficit disorder, childhood hyperactivity disorder, psychotic depression, bipolar disorder, paranoid and delusional disorders, movement disorders, anxiety, sexual dysfunction, sleep disorders, vomiting, aggressive behavior and autism.

17. Use according to claim 16, wherein the pathological condition is selected from schizophrenia, bipolar disorder and autism.

18. A method for treating a patient suffering from a pathological condition requiring modulation of dopamine receptors, the pathological condition being selected from psychosis, substance abuse, cognitive impairment associated with schizophrenia, mild to moderate cognitive deficits, dementia, psychotic states associated with dementia, eating disorders, attention deficit disorder, childhood hyperactivity disorder, psychotic depression, bipolar disorder, paranoid and delusional disorders, movement disorders, anxiety, sexual dysfunction, sleep disorders, vomiting, aggressive behavior and autism, wherein the method comprises administering a pharmaceutical tablet according to any one of claims 1 to 13 to a patient in need thereof.

19. The method of treating a patient according to claim 18, wherein the patient suffers from schizophrenia, bipolar disorder or autism.

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