ITMI20100260A1 - PHARMACEUTICAL COMPOSITION CONTAINING A DRUG TO REDUCE THE SIDE EFFECTS OF ANTIPSYCHOTIC DRUGS - Google Patents

Description

Description of a patent application for an industrial invention

DESCRIPTION

The present invention relates to a pharmaceutical composition, to a dopaminergic drug and to a kit comprising an antipsychotic drug and a dopaminergic drug for the treatment of side effects due to antipsychotic drugs.

The present invention is used in the therapy of psychic disorders in schizophrenia, in cerebropathies, in dementias and mood disorders, and in psychotic disorders secondary to particular clinical conditions.

Antipsychotic drugs are used for the therapy of psychic disorders present in schizophrenia, cerebropathy, dementia, bipolar psychosis and other mood disorders, and in psychotic disorders secondary to particular clinical conditions. Antipsychotic drugs are divided into two classes: conventional and atypical or new generation. The class of conventional antipsychotic drugs includes (but is not limited to) chlorpromazine, haloperidol, flupentixol, perphenazine. The class of atypical antipsychotics includes (but is not limited to) clozapine, risperidone, olanzapine, quetiapine, aripiprazole, ziprasidone, amisulpride, sulpiride, zotepine, sertindole, paliperidone, bifeprunox, asenapine.

All antipsychotic drugs act on various types of brain receptors, with different affinities for the various molecules, but their therapeutic effects on psychotic symptoms are essentially linked to the blocking of the brain D2 receptors for dopamine. Atypical antipsychotics offer some advantages over conventional antipsychotics, such as improvement of negative symptoms (social isolation, depression), and reduced risk of motor side effects (parkinsonian symptoms, and tardive dyskinesias). The therapeutic action of antipsychotics is in fact mainly due to the blocking of dopamine D2 receptors in the mesolimbic system, but since it is not possible to make them act only on the desired target, they also act on the D2 receptors present in other cerebral and extracerebral structures, thus being able to give rise to side effects. Motor side effects are due to blockage of D2 receptors in the striatum (Miyamoto S, Duncan G E, Marx C E, Lieberman J A. Treatments for schizophrenia: a critical review of pharmacology and mechanisms of action of antipsychotic drugs. Molecular Psychiatry 2005; 10 : 79-104).

Antipsychotic drugs also block peripheral D2 receptors and thus counteract the modulating effect of endogenous dopamine on the sympathetic-adrenal system. In fact, all antipsychotic drugs, but especially atypical ones, can induce non-motor side effects of two types:

- metabolic effects (weight gain, insulin resistance, diabetes, dyslipidemia)

- cardiovascular effects (arterial hypertension, cardiac arrhythmias)

These side effects cause increased mortality from cardio and cerebro-vascular causes in patients using these drugs (Osby U, Correia N, Brandt L, Ekbom A, Sparen P. Mortality and causes of death in schizophrenia in Stockholm County, Sweden. Schizophr Res 2000; 45: 21-28).

Other side effects are those due to the increase in prolactin induced by antipsychotics and in particular by benzamides (galactorrhea, amenorrhea, gynecomastia and sexual impotence).

The pathogenic mechanism of the metabolic and cardiovascular side effects of antipsychotic drugs has not been identified, and in most of the studies aimed at detecting their occurrence no explanation is even attempted (Ryan MC, Thakore JH. Physical consequences of schizophrenia and its treatment. metabolic syndrome. Life Sciences 2002; 71: 239-257). It has been proposed that the appearance of side effects is the result of the action of antipsychotics on a myriad of receptors, for which weight gain is attributed to blocking histamine receptors, the onset of diabetes to blocking serotonin receptors , of histamine and muscarinic M3 of acetylcholine, while the onset of dyslipidemias finds no explanation (Nasrallah HA. Atypical antipsychotic-induced metabolic side effects: insights from receptor-binding profiles. Mol Psychiatry 2008; 13: 27-35).

Some authors have hypothesized that the induction of diabetes is due to the blockade of the M3 muscarinic receptors present in the β cells of the pancreatic islets with consequent inhibition of insulin secretion (Johnson DE, Yamazaki H, Ward KM, et al. Inhibitory effects of antipsychotics on carbachol- enhanced insulin secretion from perfused rat islets. Role of muscarinic antagonism in antipsychotic-induced diabetes and hyperglycemia. Diabetes 2005; 54: 1552-1558). However, selective M3 receptor antagonist drugs used to treat patients with urinary incontinence do not cause an increased risk for diabetes; moreover, vagotomized subjects, and therefore deprived of vagal stimulation of M3 receptors, show normal plasma insulin values and normal sugar metabolism (Fabris SE, Thorburn A, Litchfield A, Proietto J. Effect of parasympathetic denervation of liver and pancreas on glucose kinetics in man. Metabolism 1996; 45 (8): 987-91). It is therefore possible that the blocking of M3 receptors is only a precipitating factor for diabetes in patients treated with antipsychotic drugs.

The technical task of the present invention is therefore to provide a pharmaceutical composition which reduces or eliminates the side effects caused by the antipsychotic drugs commonly present on the market.

This technical task is solved with the present invention by a pharmaceutical composition comprising an antipsychotic drug or its metabolite or its precursor and a dopaminergic drug which acts mainly at the peripheral level or a precursor thereof.

The invention also refers to a dopaminergic drug with a prevalent action at the peripheral level or its precursor to prevent, eliminate or reduce the non-motor side effects that arise in patients with mental disorders treated with antipsychotics.

In particular, the dopaminergic drug is levodopa or its precursor.

The present invention starts from the assumption that the antipsychotic drugs on the market today induce metabolic and cardiovascular side effects by altering the functionality of the autonomic nervous system.

The autonomic nervous system maintains body homeostasis by controlling the cardiovascular system and glucose and lipid metabolism through its two branches, sympathetic and parasympathetic, which have different anatomical pathways and often antagonistic actions. The parasympathetic branch reaches the peripheral organs via the vagus nerve, and uses acetylcholine as a neurotransmitter, which stimulates the muscarinic receptors (M1, M2, M3, M4, M5) located in the organs themselves. Its activation causes slow heart rate and stimulates the β-cells of the pancreatic islets to release insulin.

The sympathetic branch uses catecholamines (noradrenaline, adrenaline) as neurotransmitters, which interact with the α and β receptors (with various subtypes) present in the peripheral tissues, causing effects that depend on the type, location, and density of the activated receptors. The activation of the α1 receptors present in the heart and vessels causes increased cardiac activity (positive inotropic, chronotropic and dromotropic action) and vasoconstriction, while the activation of the α1 receptors present in the liver stimulates gluconeogenesis and glycogenolysis. Activation of β1 receptors leads to increased cardiac contractility and renin secretion. The activation of the α2 receptors present in the pancreatic islets inhibits the secretion of insulin. Noradrenaline and adrenaline thus induce hyperglycemia, through the transformation of hepatic and muscle glycogen into free glucose and through the inhibition of insulin release from pancreatic islets (Ahren B, Wierup N, Sundler F. Neuropeptides and the regulation of islet function. Diabetes 2006 ; 55: S98-107). They also cause insulin resistance by reducing glucose uptake in muscle and adipose tissue (Deibert DC, DeFronzo RA. Epinephrineinduced insulin resistance in man. J Clin Invest. 1980; 65 (3): 717-21). The resultant of these actions is a diabetogenic effect.

Noradrenaline and adrenaline also stimulate lipolysis in adipose tissue by promoting the release of glycerol, free fatty acids, leptin, adiponectin and proinflammatory cytokines into the bloodstream (Arner P. Human fat cell lipolysis: biochemistry, regulation and clinical role. Best Pract Res Clin Endocrinol Metab 2005; 19: 471-482). The last three substances favor the onset of obesity (Kahn SE, Hull RL, Utzschneider KM. Mechanism linking obesity to insulin resistance and type 2 diabetes. Nature 2006; 444: 840-846). The increased availability of fatty acids favors hepatic synthesis and the release into the circulation of VLDL and LDL lipoproteins with consequent increase in plasma levels of triglycerides and LDL-cholesterol and reduction of HDL-cholesterol (Ginsberg HN, Zhang YL, Hernandez-Ono A. Regulation of plasma triglycerides in insulin resistance and diabetes. Arch Med Res 2005; 36: 232-240). The resultant of these actions is a lipid-lowering effect.

Finally, norepinephrine and adrenaline play a pathogenetic role in arterial hypertension. In fact, they increase cardiac output, increase peripheral resistance and stimulate renin production (Amerena J, Julius S. The role of the autonomic nervous system in hypertension. Hypertens Res 1995; 18: 99-110). They also increase the electrical excitability of the heart, favoring the onset of arrhythmias (Abildskov JA, Lux RL. Mechanisms in adrenergic dependent onset of torsades de pointes.

Pacing Clin Electrophysiol. 1997; 20 (1 Pt 1): 88-94).

Outside the central nervous system, dopamine has always been seen as an inactive precursor of norepinephrine and adrenaline. However, dopamine receptors are present in the heart, kidneys, adrenal glands, liver, endocrine pancreas (α and β cells of the islets of Langerhans, which produce glucagon and insulin respectively), and in the renal, cerebral and coronary arteries (Missale C , Castelletti L, Mancia M, Carruba MO, Spano PF. Identification of postsynaptic D1 and D2dopamine receptors in the cardiovascular system. J. Cardiovasc. Pharmacol. 1988; 11: 643-650). The stimulation of the D1 receptors, located postjunctionally, causes vasodilation with a reduction in peripheral resistance and arterial pressure. D2 receptors are pre-junctionally located on the endings of sympathetic neurons and on adrenal chromaffin cells. Their activation inhibits the release of norepinephrine from the sympathetic terminals and the secretion of adrenaline from the adrenal glands, causing indirect vasodilation, reduced contractility and cardiac excitability, and reduction of the metabolic effects induced by noradrenaline and adrenaline (inhibition of sympathetic tone) (Missale C, Nash SR, Robinson SW, Jaber M, Caron MG. Dopamine receptors: from structure to function. Physiol Rev 1998; 78: 189-225; Mannelli M, Pupilli C, Lanzillotti R, Ianni L, Bellini F, Sergio M. Role for endogenous dopamine in modulating sympathetic adrenal activity in humans. Hypertens Res. 1995; 1: S79-86). On the contrary, the administration of domperidone, a selective peripheral antagonist of D2 receptors, which does not cross the blood-brain barrier and therefore does not act in the brain, considerably increases the release of adrenaline and noradrenaline and neutralizes the antihypertensive effect of dopaminergic drugs (Luchsinger A, Grilli M, Velasco M. Metoclopramide and domperidone block the antihypertensive effect of bromocriptine in hypertensive patients. Am J Ther 1998; 5: 81-88).

These observations lead to consider the peripheral dopaminergic system as an important modulator of the actions that the sympathetic nervous system exerts on the endocrine and cardiovascular systems (Mannelli M, Delitala M, De Feo L, et al. Effects of different dopaminergic antagonists on bromocriptineinduced inhibition of norepinephrine release . J. Clin. Endocrinol. Metab. 1984; 59: 74-78; Murphy MB. Dopamine: a role in the pathogenesis and treatment of hypertension. J Hum Hypertens 2000; 14: 47-50; Goldstein DS, Mezey E, Yamamoto T, et al. Is there a third peripheral catecholaminergic system? Endogenous dopamine as an autocrine / paracrine substance derived from plasma dopa and inactivated by conjugation. Hypertens Res 1995; 18: S93-99).

Every time the sympathetic system is activated, for example in stressful situations, endogenous dopamine is secreted (in addition to noradrenaline and adrenaline) in order to modulate its activity: the greater the sympathetic activity, the greater the release dopamine (Langer SZ. Presynaptic regulation of the release of catecholamines. Pharmacol Rev 1981; 32: 337-358). The abolition of this dopamine modulating activity is probably responsible for the deaths from cardiac arrhythmia following the intravenous administration of domperidone, a selective peripheral D2 receptor antagonist (Roussak JB, Carey P, Harry H. Cardiac arrest after treatment with intravenous domperidone. BMJ 1984; 289: 1579).

Studies conducted by the applicant himself on Parkinson's disease, have shown how the reduced sympathetic activity causes, in parkinsonian patients, a low frequency of hypertension and diabetes, and low plasma levels of cholesterol, triglycerides and total lipids and that dopamine resulting from therapy with Levodopa further reduces sympathetic activity, helping to further lower the frequency of hypertension, diabetes and dyslipidemia in these patients (Scigliano G, Musicco M, Soliveri P, et al. Reduced risk factors for vascular disorders in Parkinson's disease patients: a case-control study. Stroke 2006; 37: 1184-1188; Scigliano G, Ronchetti G, Girotti F, Musicco M. Sympathetic modulation by levodopa reduces vascular risk factors in Parkinson disease. Parkinsonism Relat Disord 2009; 15: 138-143).

These studies demonstrate the importance of the autonomic nervous system in controlling cardiac activity and glucose and lipid metabolism and the importance of the peripheral dopaminergic system in modulating sympathetic activity.

All antipsychotics block, with a dose-dependent effect and with varying potency, the brain D2 receptors, and their antipsychotic action is attributed to this effect. However, they also block peripheral D2 receptors, thus counteracting the modulating effect of endogenous dopamine on the sympathetic-adrenal system.

This block abolishes the peripheral modulating function of the D2 receptors on sympathetic tone, which is thus chronically increased. From this derives an altered control of lipid and carbohydrate metabolism, an increase in blood pressure and the onset of arrhythmias.

Blockade of extracerebral D2 receptors causes increased secretion of adrenaline and noradrenaline (sympathetic hypertonus), but these can only exert their effects if:

a) Their receptors (α and β adrenergic receptors) are free. In fact, it is known that some antipsychotics cause hypotension, especially when used at high doses, and that this effect is due to the blocking of the α and β adrenergic receptors. In this case, the adrenergic activity is reduced despite an increased availability of neurotransmitters.

b) the increase in sympathetic tone is not counterbalanced by an equivalent increase in parasympathetic tone, which normally counteracts its effects on pancreatic islets (insulin production) and on the cardiovascular system by acting on muscarinic cholinergic receptors. If the latter are free, the parasympathetic tone can increase proportionally to the sympathetic one, and counteract its effects. If, on the other hand, the muscarinic receptors are blocked by antipsychotic drugs, the increased sympathetic activity is no longer counterbalanced by an increase in parasympathetic tone and can exert its effects.

The two conditions illustrated in points a) and b) account for the fact that haloperidol and ziprasidone, despite being the most potent blockers of D2 receptors, cause metabolic side effects less frequently than clozapine, olanzapine and quetiapine (American Diabetes Association, American Psychiatric Association, American Association of Clinical Endocrinologists, North American Association for the Study of Obesity. Consensus development conference on antipsychotic drugs and obesity and diabetes. Diabetes care 2004; 27: 596-601).

As can be seen in Table 1, haloperidol has a very high affinity for D2 receptors, but very low for M3 muscarinic receptors, so the parasympathetic system remains completely free to counteract the increased sympathetic activity resulting from its administration. On the contrary, clozapine, despite having a low binding capacity for D2 receptors, has a high affinity for M3, so that the increase in sympathetic activity, although lower than that induced by haloperidol, is not counterbalanced by an adequate increase parasympathetic tone and can exert its effects. In the last column of the table it is possible to observe how the ratio between the dissociation constants D2 / M3 increases in the order: risperidone, haloperidol, ziprasidone, quetiapine, olanzapine, clozapine, which is the same increasing order with which these drugs are likely to induce metabolic side effects (American Diabetes Association, American Psychiatric Association, American Association of Clinical Endocrinologists, North American Association for the Study of Obesity. Consensus development conference on antipsychotic drugs and obesity and diabetes. Diabetes care 2004; 27: 596-601; Lambert BL , Cunningham FE, Miller DR, Dalack GW, Hur K. Diabetes Risk Associated with Use of Olanzapine, Quetiapine, and Risperidone in Veterans Health Administration Patients with Schizophrenia American Journal of Epidemiology 2006; 164: 672-681).

D2α1α2Cholinergic D2 / α1D2 / α2D2 / M3dissociation dissociation dissociation (muscarinic

constant constant constant M3)

(nM) (nM) (nM) dissociation

constant

(nM)

Haloperidol 2.6 ± 0.5 17 ± 1 600 ± 100 ≥ 10,000 0.153 0.004 0.00026 Ziprasidone 2.6 ± 0.1 2.6 ± 0.3 154 ± 9 2440 ± 80 1.0 0.017 0.001 Risperidone 3.77 ± 0.04 2.7 ± 0.3 8 ± 1 34000 ± 3000 1.396 0.471 0.00011 Olanzapine 20 ± 3 44 ± 4 280 ± 30 36 ± 5 0.455 0.071 0.55 Clozapine 210 ± 30 6.8 ± 0.8 15 ± 0.6 9 ± 1 30.88 14.0 23.33 Quetiapine 770 ± 30 8.1 ± 0.9 80 ± 10 1400 ± 200 95.06 9.625 0.55 Table 1 Dissociation constants for antipsychotic drugs on human brain receptors. From Richelson and Souder (Richelson E, Souder T. Binding of antipsychotic drugs to human brain receptors.

Focus on newer generation compounds. Life Sci 2000; 68: 29-39), modified.

D2: haloperidol and ziprasidone have the most potent competitive binding on D2 receptors compared to the reference radioligand spiperone, the most potent antipsychotic drug (Kd = 0.28 ± 0.02 nM; n = 19). Quetiapine was the least potent of the drugs studied (Kd = 770 nM).

α1: Ziprasidone and risperidone have the most potent competitive binding on α1 receptors, compared to the radioligand [3H] prazosin (Kd = 0.28 ± 0.01 nM, n = 36); olanzapine was the least potent.

α2: Risperidone has the strongest competitive binding on α2 receptors in comparison with the radioligand rauwolscine (Kd = 2.5 ± 0.1 nM; n = 19); haloperidol was the least potent.

M3: Clozapine has the most potent muscarinic receptor binding, and risperidone the least potent, compared to the radioligand [3H] quinuclidinyl benzylate (Kd 0.17 nM, n = 18) which has equal affinity for the 5 muscarinic receptor subtypes

Since the metabolic and cardiovascular side effects of antipsychotics are mainly due to the blockade of extracerebral peripheral D2 receptors and the consequent sympathetic hypertonus, antipsychotic drugs with low D2 binding capacity could be used to reduce these effects by combining them with drugs that stimulate the D2 receptors ( dopamine agonists) which have been shown to be effective in reducing blood pressure, blood sugar and plasma lipids (Murphy MB. Dopamine: a role in the pathogenesis and treatment of hypertension. J Hum Hypertens 2000; 14: 47-50; Kok P, Roelfsema F , Frölich M, et al. Activation of dopamine D2receptors simultaneously ameliorates various metabolic features of obese women Am J Physiol Endocrinol Metab 2006; 291: E1038-1043; Cincotta AH, Meier AH, Cincotta Jr M. Bromocriptine improves glycaemic control and serum lipid profile in obese Type 2 diabetic subjects: a new approach in the treatment of diabetes. Expert Opin Investig Drugs 1999; 8 : 1683-1707).

However, at the cerebral level, such an action involves a cancellation of the desired antipsychotic effect, since dopamine agonists are active both at the cerebral level and at the extracerebral level.

Given that the therapeutic effects of antipsychotic drugs are mainly related to their blocking action on the cerebral D2 receptors and the metabolic and cardiovascular side effects are mainly due to the blocking of the extracerebral peripheral D2 receptors and the consequent sympathetic hypertonus, with the present invention the way to counteract the onset of these side effects (without losing the therapeutic effect) by resorting to a drug, for example Levodopa to displace antipsychotics only from the D2 receptors present in the periphery and not from those present in the brain.

Levodopa has been in use for many years for the treatment of Parkinson's disease.

Levodopa itself is inactive, but once ingested it is decarboxylated to its active metabolite which is dopamine.

Although Levodopa is capable of reaching the brain tissue, more than 95% of its transformation into dopamine occurs in the periphery, outside the cerebral circulation, and the dopamine generated remains outside the brain, being unable to cross the blood barrier. -encephalic.

The administration of Levodopa therefore gives rise to high levels of dopamine circulating in the periphery, and to low levels of cerebral dopamine.

In the present invention the antipsychotic drugs are administered in association with Levodopa, therefore their binding with the peripheral D2 receptors is very reduced, due to the competition of dopamine on the same receptors. Stimulation of the peripheral D2 receptors by dopamine resulting from Levodopa inhibits the release of norepinephrine from sympathetic nerve terminals and the secretion of adrenaline from the adrenal medulla, reducing sympathetic tone. The amount of levodopa transformed into dopamine in the brain is negligible, and therefore a strong competitive antagonism is obtained on the peripheral effects of antipsychotics, and a weak antagonism on their cerebral effects. In particular, the pharmaceutical composition of the present invention allows to:

- reduce the metabolic side effects of antipsychotics, such as hyperglycemia and diabetes, hypercholesterolemia and dyslipidemia in general

- reduce the cardio and cerebrovascular side effects of antipsychotics

- reduce hyperprolactinemia induced by antipsychotics and in particular by benzamides

- offer the advantage of greater tolerability of antipsychotic drugs in the treatment of neuropsychiatric disorders. Preferably the pharmaceutical composition contains a suitable excipient, vehicle or diluent.

Preferably said excipients are absorbents, lubricants, binders, disintegrants, dyes, sweeteners, antioxidants, polymers, presevants or stabilizers.

The antipsychotic drug is of the conventional or atypical type.

The antipsychotic drug, if conventional, is preferably flupentixol, haloperidol, chlorpromazine or perphenazine.

The antipsychotic drug, if atypical, is preferably clozapine, risperidone, olanzapine, quietiapine, aripiprazole, ziprasidone, amisulpride, sulpiride, zotepine, sertindole, paleperidone, bifeprunox or asenapine.

The pharmaceutical composition is preferably a controlled release formulation, or in form for oral, intravenous, intradermal, intramuscular, subcutaneous or intraperitoneal administration, or in solid, liquid form or as a dry product to be reconstituted, or in the form of tablets, pills, capsules, powder, orodispersible tablets or the like, or in the form of aqueous, oily suspensions, syrups, solutions, emulsions, drops or the like.

The invention also refers to a kit or product containing an antipsychotic drug or its metabolite or its precursor and a dopaminergic drug or its precursor which acts mainly at the peripheral level, for simultaneous, separate or sequential use.

Preferably in the kit the antipsychotic drug is conventional or atypical and the dopaminergic drug is Levodopa.

Preferably, said dopaminergic drug is used to prevent, eliminate or reduce side effects of the metabolic type, of the cardiovascular type and those due to the increase in prolactin.

The pharmaceutical composition, according to the present invention, will be described below in some of its preferred embodiments.

The composition provides in combination (a) a first therapeutic agent, which is an atypical antipsychotic drug (which includes, but is not limited to, clozapine, olanzapine, quetiapine, risperidone, ziprasidone, sulpiride, amisulpride, aripiprazole, zotepine, sertindole, paliperidone , bifeprunox and asenapine) or conventional (which includes, but is not limited to, chlorpromazine, haloperidol, flupentixol, perphenazine, etc.) and (b) a second therapeutic agent which is Levodopa, or L-dopa, or dihydroxyphenylalanine. The latter is an aromatic amino acid with molecular weight 197.2, chemically designated as L - (-) - 2-amino-3- (3,4-dihydroxyphenyl) propanoic acid, with the empirical formula C9H11NO4. As an alternative to Levodopa, a suitable precursor can be used, such as for example Ethilevodopa (L-dopa ethyl ester) or Melevodopa (L-dopa methyl ester) and the like. As an alternative to the antipsychotic drug, its metabolite or prodrug can be used instead. By "precursor" or "prodrug" we mean a derivative of the active molecule that requires a transformation within the body to release the active drug.

For oral administration the pharmaceutical composition takes the form of tablets, pills, capsules, powder, etc., with various excipients, prepared according to traditional methods. The other ingredients include, but are not limited to, maize starch, pregelatinised starch, anhydrous dibasic calcium phosphate, microcrystalline cellulose, crospovidone, E132, lactose monohydrate, methylcellulose, yellow iron oxide (E172), black iron oxide (E172), iron oxide red (E172), gelatin, hydroxypropylcellulose, hypromellose, magnesium stearate, Mannitol E421, hydrogenated castor oil, polyvinylpyrrolidone, colloidal anhydrous silica, sodium docusate, talc or titanium dioxide.

Alternatively, the composition is incorporated into oral liquid formulations, such as aqueous or oily suspensions, solutions, emulsions, syrups or the like. Or presented as a dry product to be made up with water or other suitable vehicles before use. Such liquid formulations contain conventional additives such as sorbitol, methylcellulose, gelatin, glucose, emulsifying agents, dyes, sweeteners, and preservatives with antibacterial or chelating-antioxidant action such as ascorbic acid, sodium metabisulphite, citrate or the like. Dry formulations to be made up with water or other suitable vehicles before use contain excipients such as anhydrous citric acid, pregelatinized corn starch, microcrystalline cellulose, magnesium stearate or the like.

The pharmaceutical composition is also prepared as a controlled release formulation, such as slow release or fast release.

The two therapeutic agents described above are also administered by different routes, which include, for example, the preparation of Levodopa tablets, to be administered daily, and the preparation of the antipsychotic as a Depot formula. This long-acting formulation is administered as a subcutaneous or intramuscular implant, or by intramuscular injection. One or both therapeutic agents are also administered in sublingual or orodispersible tablets, with the addition of excipients such as aspartame, gelatin, mannitol, sodium methyl parahydroxybenzoate, sodium propyl parahydroxybenzoate. The pharmaceutical composition is preferably provided to the consumer in the form of a kit comprising a first dose unit of an antipsychotic drug and a second dose unit of Levodopa.

Examples of therapeutic indications

According to the present invention, said pharmaceutical composition can be used in the treatment of psychiatric disorders. In particular schizophrenia, psychotic disorders, schizophreniform disorders, schizoaffective disorders, brief psychotic disorders, treatment-resistant psychotic disorders, major depression, generalized anxiety disorder, bipolar disorders, psychotic disorders secondary to other pathologies or to particular clinical situations, psychotic disorders not otherwise specified. Psychotic disorders secondary to other pathologies include, but are not limited to, Alzheimer's disease and dementia in general, Mild Cognitive Impairment, Huntington's disease, corticobasal degeneration, progressive supranuclear palsy, Down syndrome.

Treatment of attention deficit disorders, hyperactivity disorders, and affective disorders, irritability associated with autistic disorders.

Examples of composition

The preferable pharmaceutical compositions according to the present invention are described below:

Ex 1 - Composition containing from 5 to 2000 milligrams per unit-dose of Levodopa or its precursor as the first active ingredient, and Quetiapine in a ratio between 1: 200 and 200: 1

Ex 2 - Composition containing from 5 to 2000 milligrams per unit-dose of Levodopa or its precursor as the first active ingredient, and Olanzapine in a ratio between 1:10 and 400: 1

Ex 3 - Composition containing from 5 to 2000 milligrams per unit-dose of Levodopa or its precursor as the first active ingredient, and Clozapine in a ratio between 1: 100 and 100: 1

Ex 4 - Composition containing from 5 to 2000 milligrams per unit-dose of Levodopa or one of its precursors as the first active ingredient, and Risperidone in a ratio between 1: 3 and 1000: 1

Ex 5 - Composition containing from 5 to 2000 milligrams per unit-dose of Levodopa or its precursor as the first active ingredient, and Aripiprazole in a ratio between 1:10 and 500: 1

Ex 6 - Composition containing from 5 to 2000 milligrams per unit-dose of Levodopa or its precursor as the first active ingredient, and Ziprasidone in a ratio between 1: 100 and 100: 1

Ex 7 - Composition containing from 5 to 2000 milligrams per unit-dose of Levodopa or its precursor as the first active ingredient, and Amisulpride in a ratio between 1: 200 and 200: 1

Ex 8 - Composition containing from 5 to 2000 milligrams per unit-dose of Levodopa or one of its precursors as the first active ingredient, and Sulpiride in a ratio between 1: 200 and 200: 1

Ex 9 - Composition containing from 5 to 2000 milligrams per unit-dose of Levodopa or its precursor as the first active ingredient, and Zotepine in a ratio between 1: 100 and 200: 1

Ex 10 - Composition containing from 5 to 2000 milligrams per unit-dose of Levodopa or its precursor as the first active ingredient, and Sertindole in a ratio between 1:10 and 500: 1

Ex 11 - Composition containing from 5 to 2000 milligrams per unit-dose of Levodopa or its precursor as the first active ingredient, and Paliperidone in a ratio between 1:30 and 500: 1

Ex 12 - Composition containing from 5 to 2000 milligrams per unit-dose of Levodopa or its precursor as the first active ingredient, and Asenapine in a ratio between 1:10 and 500: 1

Ex 13 - Composition containing from 5 to 2000 milligrams per unit-dose of Levodopa or its precursor as the first active ingredient, and Haloperidol in a ratio between 1: 3 and 1000: 1

Ex 14 - Composition containing from 5 to 2000 milligrams per unit-dose of Levodopa or its precursor as the first active ingredient, and Chloropromazine from 10 to 200 milligrams per unit-dose

Ex 15 - Composition containing from 5 to 2000 milligrams per unit-dose of Levodopa or its precursor as the first active ingredient, and Flupentixol from 0.5 to 10 milligrams per unit-dose

Ex 16 - Composition containing from 5 to 2000 milligrams per unit-dose of Levodopa or its precursor as the first active ingredient, and Perfenazine from 0.5 to 15 milligrams per unit dose

Ex 17 - Composition containing from 5 to 2000 milligrams per unit-dose of Levodopa or its precursor as the first active ingredient, and Clotiapine from 10 to 50 milligrams per unit dose

Ex 18 - Kit containing from 5 to 2000 milligrams per unit-dose of Levodopa or its precursor for oral intake, and an antipsychotic in prolonged-release suspension for injection, for example Risperidone, from 10 to 100 milligrams

Examples of dosages

According to the present invention, the doses of Levodopa to be associated depend on the degree of affinity and the dissociation constant of the individual antipsychotics for the D2 receptors. The effective dose of an antipsychotic and Levodopa in combination, according to the present invention, varies according to factors such as the patient's status, the type of disease, the severity of symptoms, the strength of the antipsychotic, the method of administration, age and weight of the patient. An appropriate dosage of the pharmaceutical composition can be determined in animal or human studies.

For example, according to the invention:

Ex 19 - the daily dose of Levodopa is between 10 milligrams and 3000 milligrams, as a single or divided administration.

Ex 20 - the daily dose of Quetiapine is between 10 mg and 1200 mg

Ex 21 - the daily dose of Olanzapine is between 1 mg and 50 mg

Ex 22 - the daily dose of Clozapine is between 10 mg and 900 mg

Ex 23 - the daily dose of Risperidone is between 0.5 mg and 16 mg

Ex 24 - the daily dose of Aripiprazole is between 2 mg and 50 mg

Ex 25 - the daily dose of Ziprasidone is between 5 mg and 400 mg

Ex 26 - the daily dose of Amisulpride is between 10 and 1500 mg

Ex 27 - the daily dose of Sulpiride is between 10 mg and 1200 mg

Ex 28 - the daily dose of Zotepine is between 10 mg and 600 mg

Ex 29 - the daily dose of Sertindole is between 2mg and 50mg

Ex 30 - the daily dose of Paliperidone is between 1 mg and 30 mg

Ex 31 - the daily dose of Asenapine is between 1mg and 50mg

Ex 32 - the daily dose of all other antipsychotics, conventional and atypical, are included in the range indicated in their administration as monotherapy.

Ex 33 - In the case of using prodrugs as an alternative to Levodopa, the daily doses to be administered are determined in such a way that the amount of levodopa resulting from their metabolization is equal to 10-3000 milligrams.

Claims (16)

CLAIMS 1. Pharmaceutical composition comprising an antipsychotic drug or a metabolite or a precursor thereof, characterized in that it further comprises a dopaminergic drug which acts mainly at the peripheral level or a precursor thereof. 2. Pharmaceutical composition according to claim 1, characterized in that it comprises a suitable excipient, vehicle or diluent. 3. Pharmaceutical composition according to one or more preceding claims, characterized in that said dopaminergic drug is Levodopa or a precursor thereof. 4. Pharmaceutical composition according to one or more claims, characterized in that said antipsychotic drug is of the conventional or atypical type. 5. Pharmaceutical composition according to claim 4, characterized in that said conventional antipsychotic drug is flupentixol, haloperidol, chlorpromazine or perphenazine. 6. Pharmaceutical composition according to claim 4, characterized in that said atypical antipsychotic drug is clozapine, risperidone, olanzapine, quietiapine, aripiprazole, ziprasidone, amisulpride, sulpiride, zotepine, sertindole, paleperidone, bifeprunox or asenapine. 7. Pharmaceutical composition according to one or more preceding claims, characterized in that it is a controlled release formulation. 8. Pharmaceutical composition according to one or more preceding claims, characterized in that it is formulated in form for oral, intravenous, intradermal, intramuscular, subcutaneous or intraperitoneal administration. 9. Pharmaceutical composition according to one or more preceding claims, characterized in that it is formulated in solid, liquid form or as a dry product to be reconstituted. 10. Pharmaceutical composition according to claim 8, characterized in that it is formulated in the form of a tablet, pill, capsule, powder, orodispersible tablet or the like, or in the form of an aqueous, oily suspension, syrup, solution, emulsion, drops or similar. 11. Pharmaceutical composition according to one or more preceding claims characterized in that said excipients are absorbents, lubricants, binders, disintegrants, dyes, sweeteners, antioxidants, polymers, presevants or stabilizers. 12. Kit containing an antipsychotic drug or its metabolite or its precursor and a dopaminergic drug or its precursor which acts predominantly at the peripheral level, for simultaneous, separate or sequential use. The kit according to claim 12 wherein the antipsychotic drug is conventional or atypical and the dopaminergic drug is levodopa. 14. A dopaminergic drug with a predominantly peripheral action or a precursor thereof to prevent, eliminate or reduce the non-motor side effects that arise in patients with psychic disorders treated with antipsychotics. 15. A dopaminergic drug according to claim 14, which is levodopa. 16. A dopaminergic drug according to claim 14 or 15 to prevent, eliminate or reduce side effects of the metabolic type, of the cardiovascular type and those due to the increase in prolactin.