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WO2011101799A1 - Pharmaceutical compositions for use in therapies for psychiatric disorders - Google Patents

Pharmaceutical compositions for use in therapies for psychiatric disorders Download PDF

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WO2011101799A1
WO2011101799A1 PCT/IB2011/050660 IB2011050660W WO2011101799A1 WO 2011101799 A1 WO2011101799 A1 WO 2011101799A1 IB 2011050660 W IB2011050660 W IB 2011050660W WO 2011101799 A1 WO2011101799 A1 WO 2011101799A1
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drug
pharmaceutical composition
precursor
levodopa
receptors
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Giulio Scigliano
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
    • A—HUMAN NECESSITIES
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4515—Non condensed piperidines, e.g. piperocaine having a butyrophenone group in position 1, e.g. haloperidol
    • A—HUMAN NECESSITIES
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • A—HUMAN NECESSITIES
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/5415—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A61K31/5513—1,4-Benzodiazepines, e.g. diazepam or clozapine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/554—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one sulfur as ring hetero atoms, e.g. clothiapine, diltiazem
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner

Definitions

  • the present invention relates to a drug, use of a drug and a pharmaceutical composition according to the appended independent claims.
  • the present invention applies to treatments/therapies for psychic or mental disorders in schizophrenia, cerebropathies, dementias, mood disturbances and psychotic disorders due to particular clinical conditions.
  • the antipsychotic drugs are used in therapies for mental disorders present in schizophrenia, cerebropathies, dementias, psychosis of the bipolar type and other mood disturbances, and in psychotic disorders due to particular clinical conditions.
  • the antipsychotic drugs are divided into two classes: conventional and atypical antipsychotics or antipsychotics of the new generation.
  • the class of the conventional antipsychotics comprises (although it is not limited thereto) chlorpromazine, haloperidol, flupentixol, perphenazine.
  • the class of the atypical antipsychotics comprises (although it is not limited thereto) 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 the psychotic symptoms are essentially linked to the blockade of the dopamine D2 brain receptors.
  • the atypical antipsychotics offer some advantages relative to the conventional antipsychotics, such as improvement of the adverse symptoms (social isolation, depression) and reduced risk of side effects of the motor type (symptoms of Parkinson's disease, and tardive dyskinesias).
  • the therapeutic action of the antipsychotics is in fact mainly due to the blockade of the dopamine D2 receptors in the mesolimbic system, but since it is not possible to make them act on the desired target only, they will also act on the D2 receptors present in other cerebral and extra-cerebral structures, which will possibly give rise to undesirable effects.
  • the side effects of the motor type are due to the blockade of the 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).
  • the atypical antipsychotic drugs also block the peripheral D2 receptors and thus counteract the modulating effect of the endogenous dopamine on the sympathetic-adrenal system and can induce side effects mainly of two types:
  • the M3 receptor-selective antagonist drugs used for treating patients with urinary incontinence do not cause an increase of risks for diabetes; in addition, the vagotomized subjects who therefore are devoid of the vagal stimulation of the M3 receptors show normal plasmatic insulin values and normal metabolism of sugars (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), Therefore it is possible that the blockade of the M3 receptors only represents a precipitating factor in the development of diabetes in patients treated with antipsychotic drugs.
  • the technical task of the present invention is to remedy the drawbacks of the known art.
  • the present invention starts from the assumption that the atypical antipsychotic drugs presently on the market induce metabolic and cardiovascular side effects altering the functions of the autonomous nervous system.
  • the dopamine receptors are present in the heart, the kidneys, the adrenal glands, the liver, the endocrine pancreas (a and ⁇ -cells of the Langerhans islets producing 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 D2 dopamine receptors in the cardiovascular system. J. Cardiovasc. Pharmacol. 1988; 11 :643-650). Stimulation of the D1 receptors, localised after junction, causes vasodilatation with a reduction in the peripheral resistances and the arterial pressure.
  • the D2 receptors are localised, before junction, on the sympathetic neuron terminations and the adrenal chromaffin cells. Their activation inhibits noradrenaline release from the sympathetic terminals and adrenaline secretion from the adrenal glands, causing indirect vasodilatation, reduced contractility and cardiac excitability, and reduction in the noradrenaline- and adrenaline-induced metabolic effects (inhibition of the 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, lanni L, Bellini F, Sergio M.
  • the actions of the sympathetic nervous system on the endocrine and cardiovascular apparatuses are mediated by Adrenaline and Noradrenaline and result in a diabetogenic, dyslipidemia-inducing effects and in an increase of the arterial pressure, heart rate and possible appearance of arrhythmias.
  • the endogenous dopamine is secreted (in addition to noradrenaline and adrenaline) in order to modulate the activity thereof: the greater the sympathetic activity is, the greater the dopamine release (Langer SZ. Presynaptic regulation of the release of catecholamines. Pharmacol rev 1981 ;32:337-358).
  • Parkinson's disease Studies carried out by the Applicant on Parkinson's disease have proved that the reduced sympathetic activity causes in Parkinson's disease patents, a low frequency of hypertension and diabetes and low plasma levels of cholesterol, triglycerides and total lipids and that dopamine derived from a Levodopa therapy further reduces the sympathetic activity, helping in still more lowering the frequency of hypertension, diabetes and dislypidemia 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).
  • All antipsychotics block the brain D2 receptors with a dose-dependent effect and various power, and their antipsychotic action is ascribed to this effect. However, they also block the peripheral D2 receptors, thus counteracting the endogenous dopamine modulating effect on the sympathetic-adrenal system.
  • This blockade eliminates the peripheral modulating function of the D2 receptors on the sympathetic tone which is thus increased in a chronic manner. Resulting therefrom is an altered control of the lipid and glucide metabolism, an increase in the arterial pressure and arising of arrhythmias.
  • Blockade of the extra-brain D2 receptors causes an increased secretion of adrenaline and noradrenaline (sympathetic hypertone), which however can only exercise their effects if:
  • the increase in the sympathetic tone is not counterbalanced by an equivalent increase in the parasympathetic tone, that usually counters its effects on the pancreatic islets (insulin production) and the cardiovascular apparatus acting on the muscarinic cholinergic receptors. If the latter are free the parasympathetic tone can increase in proportion to the sympathetic one, and counter the effects thereof. If, vice versa, the muscarinic receptors are blocked by the antipsychotic drugs, the increased sympathetic activity is no longer counterbalanced by an increase in the parasympathetic tone and can therefore exercise its effects.
  • haloperidol has a very high affinity for the D2 receptors, but a very low one for the M3 muscarinic receptors, so that the parasympathetic system is completely free to counter the increased sympathetic activity resulting from its administration.
  • clozapine while having a low binding capability for D2 receptors, has a high affinity for M3 receptors, so that the increase in the sympathetic activity although lower than that induced by haloperidol, is not counterbalanced by an appropriate increase in the parasympathetic tone and can exercise its effects.
  • 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.
  • antipsychotic drugs having a low binding capability with the D2 receptors associating them with drugs stimulating the D2 receptors (dopaminoagonists) that have proved to be effective in reducing the arterial pressure, glycaemia 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, Frolich M, et al.
  • the therapeutic effects of the antipsychotic drugs are mainly linked to their blocking action on the brain D2 receptors, and the metabolic and cardiovascular side effects are mainly due to the blockade of the extracerebral peripheral D2 receptors and the consequent sympathetic hypertone, through the present invention it has been surprisingly found how to counteract arising of these side effects (without losing the therapeutic effect) by resorting to a dopaminergic drug mainly acting on the peripheral regions for placing out the antipsychotics only from the D2 receptors present in the peripheral regions and not from those present in the brain.
  • preferably used is Levodopa.
  • Levodopa has been used for many years for treatment of Parkinson's disease. Levodopa is inactive by itself, but once ingested it is decarboxylated to its active metabolite that is dopamine.
  • Levodopa is capable of reaching the cerebral tissue, its conversion into dopamine takes place for more than 95% thereof in the peripheral regions, out of the cerebral circle and the generated dopamine remains out of the brain, being unable to cross the blood-brain barrier.
  • Levodopa gives rise to high dopamine levels circulating in the peripheral regions, and to low brain dopamine levels.
  • the atypical antipsychotic drugs are administered in association with Levodopa, and therefore their bond 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 the dopamine derived from Levodopa inhibits noradrenaline release from the sympathetic nervous terminals and adrenaline secretion from the adrenal medulla, reducing the sympathetic tone.
  • the amount of Levodopa converted to dopamine in the brain is negligible, and therefore a strong competitive antagonism is obtained on the peripheral effects of the antipsychotics, and a weak antagonism on their cerebral effects.
  • composition of the present invention enables:
  • the pharmaceutical composition contains a suitable excipient, vehicle or diluent.
  • excipients are absorbents, lubricants, binders, disgregating and colouring agents, sweeteners, antioxidants, polymers, preservatives or stabilisers.
  • the antipsychotic drug is atypical. It preferably consists of clozapine, risperidone, olanzapine, quetiapine, aripiprazole, ziprasidone, amisulpride, sulpiride, zotepine, sertindole, paliperidone, bifeprunox or asenapine and other possible atypical antipsychotics to be put on the market in the near future.
  • the pharmaceutical composition preferably is a controlled-release formulation or a composition for oral, intravenous, intradermal, intramuscular, subcutaneous or intraperitoneal administration, or it is in a solid or liquid state or a dry product to be reconstituted, or yet it is in the form of tablets, pills, capsules, powder or the like, and also in the form of aqueous or oily suspensions, syrups, solutions, emulsions, drops or the like.
  • composition consists of the combination of:
  • a first therapeutic agent that is an atypical antipsychotic drug (including, although not limited thereto, clozapine, olanzapine, quetiapine, risperidone, ziprasidone, sulpiride, amisulpride, aripripazole zotepine, sertindole, paliperidone, bifeprunox and asenapine) and
  • an atypical antipsychotic drug including, although not limited thereto, clozapine, olanzapine, quetiapine, risperidone, ziprasidone, sulpiride, amisulpride, aripripazole zotepine, sertindole, paliperidone, bifeprunox and asenapine
  • a second therapeutic agent that is a dopaminergic drug mainly acting in the peripheral regions, such as Levodopa, or L-dopa, or dihydroxyphenylalanine, for example.
  • the latter is an aromatic amino acid of 197.2 molecular weight, chemically identified as L-(-)-2-amino-3-(3,4-dihydroxyphenyl-propanoic acid, of empirical formula C9H11 N04.
  • Levodopa an appropriate precursor thereof can be used, such as Ethylvodopa (L-dopa ethyl ester) or Melevodopa (L-dopa methyl ester) and the like.
  • the antipsychotic drug a metabolite or a pro-drug thereof can be used.
  • precursor or "pro-drug” means a derivative of the active molecule requiring a conversion inside the organism for releasing the active drug.
  • the pharmaceutical composition takes the form of tablets, pills, capsules, powder, etc., with various excipients, prepared following the traditional methods.
  • the excipients include although not limited thereto, cornflour, pre-gelatinised starch, anhydrous dibasic calcium phosphate, microcristalline cellulose, crospovidone, E132, lactose monohydrate, methylcellulose, yellow iron oxide, black iron oxide (E172), red iron oxide (E172), gelatin, hydroxypropylcellulose, hypromellose, magnesium stearate, Mannitole E421 , hydrogenated castor oil, polyvinylpyrrolidone, anhydrous colloidal silica, sodium docusate, talc or titanium dioxide.
  • composition is incorporated into oral liquid formulations, such as aqueous or oily suspensions, solutions, emulsions, syrups or the like.
  • liquid formulations contain conventional additives such as sorbitol, methylcellulose, gelatin, glucose, emulsifying agents, colouring agents, sweeteners and preservatives having an antibacterial action or a chelating- antioxidant action such as ascorbic acid, sodium metabisulphite, citrate.
  • the dry formulations to be reconstituted with water or other suitable excipients before use contain excipients such as anhydrous citric acid, pregelatinized cornflour, microcristalline cellulose, magnesium stearate and the like.
  • the pharmaceutical composition is also prepared as a controlled-release formulation such as a slow-release or quick-release formulation.
  • the two therapeutic agents previously described are also administered differently, for example providing preparation of Levodopa in tablets to be administered daily, and preparation of the antipsychotic as "Depot formula".
  • This long-term effect formulation is administered as a subcutaneous or intramuscular implant, or by intramuscular injection.
  • One or both of the therapeutic agents are also administered in orodispersible tablets to be placed under the tongue, with the addition of excipients such as aspartame, gelatin, mannitole, sodium methylparahydroxybenzoate, sodium propylparahydroxybenzoate.
  • the pharmaceutical composition is preferably supplied to the consumer in the form of a kit comprising a first unit dose of the antipsychotic drug and a second unit dose of Levodopa.
  • said pharmaceutical composition can be used in the treatment of psychiatric disorders.
  • psychiatric disorders In particular, schizophrenia, psychotic disorders, schizophrenic form disorders, emotional schizophrenic disorders, short- term psychotic disorders, treatment-resistant psychotic mood disorders, strong depression, generalised anxiety disorders, bipolar disorders, psychotic disorders due to other pathologies or to particular clinical situations, psychotic disorders not otherwise specified.
  • the psychotic disorders due to other pathologies include, although not limited thereto, the Alzheimer's disease and dementias in general, mild cognitive impairment, Huntington's disease, corticobasal degeneration, progressive subnuclear palsy, Down's syndrome.
  • Example 1 A composition containing 5 to 2000 milligrams per unit-dose of Levodopa or a precursor thereof as the first active ingredient, and Quetiapine in a ratio included between 1 :200 and 200:1.
  • Example 1 A composition containing 5 to 2000 milligrams per unit-dose of Levodopa or a precursor thereof as the first active ingredient, and Olanzapine in a ratio included between 1 :10 and 400: 1.
  • Example 3 A composition containing 5 to 2000 milligrams per unit-dose of Levodopa or a precursor thereof as the first active ingredient, and Clozapine in a ratio included between 1 :100 and 100:1.
  • Example 4 A composition containing 5 to 2000 milligrams per unit-dose of Levodopa or a precursor thereof as the first active ingredient and Risperidone in a ratio included between 1 :3 and 1000:1.
  • Example 5 A composition containing 5 to 2000 milligrams per unit-dose of Levodopa or a precursor thereof as the first active ingredient and Aripiprazole in a ratio included between 1 :10 and 500:1.
  • Example 6 A composition containing 5 to 2000 milligrams per unit-dose of Levodopa or a precursor thereof as the first active ingredient and Ziprasidone in a ratio included between 1 :100 and 100:1.
  • Example 7 A composition containing 5 to 2000 milligrams per unit-dose of Levodopa or a precursor thereof as the first active ingredient and Amisulpride in a ratio included between 1 :200 and 200: 1.
  • Example 8 A composition containing 5 to 2000 milligrams per unit-dose of Levodopa or a precursor thereof as the first active ingredient and Sulpiride in a ratio included between 1 :200 and 200:1.
  • Example 9 A composition containing 5 to 2000 milligrams per unit-dose of Levodopa or a precursor thereof as the first active ingredient and Zotepine in a ratio included between 1 :100 and 200:1.
  • Example 10 A composition containing 5 to 2000 milligrams per unit-dose of Levodopa or a precursor thereof as the first active ingredient and Sertindole in a ratio included between 1 :10 and 500:1.
  • Example 1 1 - A composition containing 5 to 2000 milligrams per unit-dose of Levodopa or a precursor thereof as the first active ingredient and Paliperidone in a ratio included between 1 :30 and 500:1.
  • Example 12 A composition containing 5 to 2000 milligrams per unit-dose of Levodopa or a precursor thereof as the first active ingredient and Asenapine in a ratio included between 1 :10 and 500: 1.
  • the Levodopa doses to be associated depend on the affinity degree and dissociation constant of the individual antipsychotics for the D2 receptors.
  • the effective doses consisting of a combination of an antipsychotic and Levodopa according to the present invention, vary as a function of factors such as the patient's state, type of illness, seriousness of symptoms, power of the antipsychotic, administration mode, the patient's age and weight.
  • the appropriate dosage of the pharmaceutical composition can be determined based on studies on animals or humans.
  • Example 14 the daily administration of Levodopa is included between 10 milligrams and 3000 milligrams, in a single or fractionated dose.
  • Example 15 - the daily administration of Quetiapine is included between 10 mg and 1200 mg.
  • Example 16 the daily administration of Olanzapine is included between 10 mg and 50 mg.
  • Example 17 the daily administration of Clozapine is included between 10 mg and 900 mg.
  • Example 18 the daily administration of Risperidone is included between 0.5 mg and 16 mg.
  • Example 19 the daily administration of Aripripazole is included between 2 mg and 50 mg.
  • Example 20 the daily administration of Ziprasidone is included between 5 mg and 400 mg.
  • Example 21 the daily administration of Amisulpride is included between 10 mg and 1500 mg.
  • Example 22 the daily administration of Sulpiride is included between 10 mg and 1200 mg.
  • Example 23 the daily administration of Zotepine is included between 10 mg and 600 mg.
  • Example 24 the daily administration of Sertindole is included between 2 mg and 50 mg.
  • Example 25 the daily administration of Paliperidone is included between 1 mg and 30 mg.
  • Example 26 the daily administration of Asenapine is included between 1 mg and 50 mg.
  • Example 27 the daily administration of all other, conventional and atypical, antipsychotics, is included in the range specified in their dose-rate as monotherapy.
  • Example 28 In case of use of pro-drugs as an alternative to Levodopa, the daily administrations are determined in such a manner that the amount of Levodopa deriving from their metabolisation is equal to 10-3000 mg.

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Abstract

A pharmaceutical composition for use in therapies for psychiatric disorders comprising an atypical antipsychotic drug or a metabolite or a precursor thereof, and further comprising a dopaminergic drug mainly acting on peripheral regions or a precursor thereof adapted to prevent, eliminate or reduce the side effects of said atypical antipsychotic drug.

Description

PHARMACEUTICAL COMPOSITIONS FOR USE IN THERAPIES FOR PSYCHIATRIC DISORDERS
The present invention relates to a drug, use of a drug and a pharmaceutical composition according to the appended independent claims.
The present invention applies to treatments/therapies for psychic or mental disorders in schizophrenia, cerebropathies, dementias, mood disturbances and psychotic disorders due to particular clinical conditions.
The antipsychotic drugs are used in therapies for mental disorders present in schizophrenia, cerebropathies, dementias, psychosis of the bipolar type and other mood disturbances, and in psychotic disorders due to particular clinical conditions.
The antipsychotic drugs are divided into two classes: conventional and atypical antipsychotics or antipsychotics of the new generation. The class of the conventional antipsychotics comprises (although it is not limited thereto) chlorpromazine, haloperidol, flupentixol, perphenazine. The class of the atypical antipsychotics comprises (although it is not limited thereto) 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 the psychotic symptoms are essentially linked to the blockade of the dopamine D2 brain receptors. The atypical antipsychotics offer some advantages relative to the conventional antipsychotics, such as improvement of the adverse symptoms (social isolation, depression) and reduced risk of side effects of the motor type (symptoms of Parkinson's disease, and tardive dyskinesias). The therapeutic action of the antipsychotics is in fact mainly due to the blockade of the dopamine D2 receptors in the mesolimbic system, but since it is not possible to make them act on the desired target only, they will also act on the D2 receptors present in other cerebral and extra-cerebral structures, which will possibly give rise to undesirable effects. The side effects of the motor type are due to the blockade of the 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).
The atypical antipsychotic drugs also block the peripheral D2 receptors and thus counteract the modulating effect of the endogenous dopamine on the sympathetic-adrenal system and can induce side effects mainly of two types:
- effects of the metabolic type (weight increase, insulin resistance, diabetes, dislipidemies);
- effects of the cardio-circulatory type (arterial hypertension, cardiac arrhythmias). These side effects cause an increase in the number of deaths due to cardio and cerebrovascular causes in patients making use of 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 the antipsychotic-induced prolactin and in particular in the benzamide-induced prolactin (galactorrhea, amenorrhoea, gynaecomastia and sexual impotence).
The pathogenic mechanism of the metabolic and cardiovascular side effects of the antipsychotic drugs has not been identified (Ryan MC, Thakore JH. Physical consequences of schizophrenia and its treatment. The metabolic syndrome. Life Sciences 2002; 71 :239-257). It has been suggested that the appearance of side effects is the result of the action of the antipsychotics on a multitude of receptors, so that weight increase is ascribed to the blockade of the histamine receptors, arising of diabetes to the blockade of the serotonin receptors, histamine receptors and muscarinic acetylcholine M3 receptors, while the appearance of dislipidemies finds no explanation (Nasrallah HA, Atypicall antipsychotic-induced metabolic side effects: insights from receptor-binding profiles. Mol Psychiatry 2008; 13:27-35). Some authors have assumed that diabetes induction is due to the blockade of the muscarinic M3 receptors present in the β-cells of the pancreatic islets with consequent inhibition of the 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 hyperglycaemia. Diabetes 2005; 54:1552-1558).
However, the M3 receptor-selective antagonist drugs used for treating patients with urinary incontinence do not cause an increase of risks for diabetes; in addition, the vagotomized subjects who therefore are devoid of the vagal stimulation of the M3 receptors show normal plasmatic insulin values and normal metabolism of sugars (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), Therefore it is possible that the blockade of the M3 receptors only represents a precipitating factor in the development of diabetes in patients treated with antipsychotic drugs.
Accordingly, the technical task of the present invention is to remedy the drawbacks of the known art.
Within the scope of this technical task, it is an important aim of the invention to provide a pharmaceutical composition capable of reducing or eliminating the side effects caused by the atypical antipsychotic drugs commonly present on the market.
Said technical task and the intended aims are achieved by a drug according to one of the appended independent claims.
The present invention starts from the assumption that the atypical antipsychotic drugs presently on the market induce metabolic and cardiovascular side effects altering the functions of the autonomous nervous system.
Out of the central nervous system the dopamine has been always seen as an inactive precursor of noradrenaline and adrenaline.
However the dopamine receptors are present in the heart, the kidneys, the adrenal glands, the liver, the endocrine pancreas (a and β -cells of the Langerhans islets producing 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 D2 dopamine receptors in the cardiovascular system. J. Cardiovasc. Pharmacol. 1988; 11 :643-650). Stimulation of the D1 receptors, localised after junction, causes vasodilatation with a reduction in the peripheral resistances and the arterial pressure. The D2 receptors are localised, before junction, on the sympathetic neuron terminations and the adrenal chromaffin cells. Their activation inhibits noradrenaline release from the sympathetic terminals and adrenaline secretion from the adrenal glands, causing indirect vasodilatation, reduced contractility and cardiac excitability, and reduction in the noradrenaline- and adrenaline-induced metabolic effects (inhibition of the 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, lanni L, Bellini F, Sergio M. Role for endogenous dopamine in modulating sympatheticadrenal activity in humans. Hypertens Res. 1995;1 :S79-86). On the contrary, administration of domperidone, a peripheral D2 receptor-selective antagonist, that does not cross the hemato- encephalic barrier and therefore does not act on the brain, greatly increases adrenaline and noradrenaline release and neutralises the antihypertensive effects of dopaminergic drugs (Luchsinger A, Grilli M, Velasco . Metoclopramide and domperidone block the antihypertensive effect of bromocriptine in hypertensive patients. Am J Ther 1998;5:81-88).
These remarks lead us to consider the peripheral dopaminergic system as an important modulator of the actions that the sympathetic nervous system exercises on the endocrine and cardiovascular apparatuses (Mannelli M, Delitala M, De Feo L, et al. Effects of different dopaminergic antagonists on bromocriptine-induced 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).
The actions of the sympathetic nervous system on the endocrine and cardiovascular apparatuses are mediated by Adrenaline and Noradrenaline and result in a diabetogenic, dyslipidemia-inducing effects and in an increase of the arterial pressure, heart rate and possible appearance of arrhythmias.
Each time the sympathetic system is activated, for instance under a situation of stress, the endogenous dopamine is secreted (in addition to noradrenaline and adrenaline) in order to modulate the activity thereof: the greater the sympathetic activity is, the greater the dopamine release (Langer SZ. Presynaptic regulation of the release of catecholamines. Pharmacol rev 1981 ;32:337-358).
Abolition of this modulating activity of the dopamine is probably responsible for deaths due to cardiac arrhythmias resulting from intravenous administration of domperidone, a peripheral D2 receptor selective antagonist (Roussak JB, Carey P, Harry H. Cardiac arrest after treatment with intravenous domperidone. BMJ 1984;289:1579).
Studies carried out by the Applicant on Parkinson's disease have proved that the reduced sympathetic activity causes in Parkinson's disease patents, a low frequency of hypertension and diabetes and low plasma levels of cholesterol, triglycerides and total lipids and that dopamine derived from a Levodopa therapy further reduces the sympathetic activity, helping in still more lowering the frequency of hypertension, diabetes and dislypidemia 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 prove the importance of the autonomous nervous system in controlling the heart activity and that of the glucide and lipid metabolism and the importance of the peripheral dopaminergic system in modulating the sympathetic activity.
All antipsychotics block the brain D2 receptors with a dose-dependent effect and various power, and their antipsychotic action is ascribed to this effect. However, they also block the peripheral D2 receptors, thus counteracting the endogenous dopamine modulating effect on the sympathetic-adrenal system.
This blockade eliminates the peripheral modulating function of the D2 receptors on the sympathetic tone which is thus increased in a chronic manner. Resulting therefrom is an altered control of the lipid and glucide metabolism, an increase in the arterial pressure and arising of arrhythmias.
Blockade of the extra-brain D2 receptors causes an increased secretion of adrenaline and noradrenaline (sympathetic hypertone), which however can only exercise their effects if:
a) their receptors (a and β adrenergic receptors) are free. It is in fact known that some atypical antipsychotics cause hypotension, above all when they are used in high doses, and this effect is due to the blockade of the a and β adrenergic receptors. In this case the adrenergic activity is reduced in spite of an increased availability of neurotransmitters;
b) the increase in the sympathetic tone is not counterbalanced by an equivalent increase in the parasympathetic tone, that usually counters its effects on the pancreatic islets (insulin production) and the cardiovascular apparatus acting on the muscarinic cholinergic receptors. If the latter are free the parasympathetic tone can increase in proportion to the sympathetic one, and counter the effects thereof. If, vice versa, the muscarinic receptors are blocked by the antipsychotic drugs, the increased sympathetic activity is no longer counterbalanced by an increase in the parasympathetic tone and can therefore exercise its effects.
The two conditions illustrated at points a) and b) explain why haloperidol and ziprasidone, while being the most powerful 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 viewed from Table 1 , haloperidol has a very high affinity for the D2 receptors, but a very low one for the M3 muscarinic receptors, so that the parasympathetic system is completely free to counter the increased sympathetic activity resulting from its administration. On the contrary, clozapine while having a low binding capability for D2 receptors, has a high affinity for M3 receptors, so that the increase in the sympathetic activity although lower than that induced by haloperidol, is not counterbalanced by an appropriate increase in the parasympathetic tone and can exercise its effects.
In the last column of the table it is possible to notice how the ratio between the dissociation constants D2/M3 grows in the order: risperidone, haloperidol, ziprasidone, quetiapine, olanzapine, clozapine, which is the same increasing order by 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 ).
Figure imgf000010_0001
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 powerful competitive bond on the D2 receptors compared with the reference radiobinder spiperone, the most powerful antipsychotic drug (Kd = 0.28+0.02 nM; n= 19). Quetiapine appeared to be the less powerful drug among the studied ones (Kd = 770 nM).
a1 : ziprasidone and risperidone have the most powerful competitive bond on a1 receptors, compared with the radiobinder [3H] prazosin (Kd =0.28+0.01 nM, n=36); olanzapine appeared to be the less powerful drug.
2: risperidone has the most powerful competitive bond on the a2 receptors as compared with the radiobinder rauwolschine (Kd = 2,5+0.1 nM; n = 19); haloperidol appeared to be the less powerful drug.
M3: clozapine has the most powerful bond on the muscarinic receptors, and risperidone the less powerful bond, compared with the radiobinder [3H] quinuclidinyl benzilate (Kd 0.17 nM, n = 18) that has the same affinity for the 5 subtypes of muscarinic receptors.
Since the metabolic and cardiovascular side effects of the antipsychotics are mainly due to the blockade of the extra-cerebral peripheral D2 receptors and the consequent sympathetic hypertone, in order to reduce these effects it would be possible to use antipsychotic drugs having a low binding capability with the D2 receptors associating them with drugs stimulating the D2 receptors (dopaminoagonists) that have proved to be effective in reducing the arterial pressure, glycaemia 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, Frolich M, et al. Activation of dopamine D2 receptors 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, as regards brain, such an action involves cancellation of the desired antipsychotic effect, as the dopaminoagonists are active both on the cerebral and extracerebral regions.
Since the therapeutic effects of the antipsychotic drugs are mainly linked to their blocking action on the brain D2 receptors, and the metabolic and cardiovascular side effects are mainly due to the blockade of the extracerebral peripheral D2 receptors and the consequent sympathetic hypertone, through the present invention it has been surprisingly found how to counteract arising of these side effects (without losing the therapeutic effect) by resorting to a dopaminergic drug mainly acting on the peripheral regions for placing out the antipsychotics only from the D2 receptors present in the peripheral regions and not from those present in the brain.
In particular, preferably used is Levodopa.
Levodopa has been used for many years for treatment of Parkinson's disease. Levodopa is inactive by itself, but once ingested it is decarboxylated to its active metabolite that is dopamine.
Although Levodopa is capable of reaching the cerebral tissue, its conversion into dopamine takes place for more than 95% thereof in the peripheral regions, out of the cerebral circle and the generated dopamine remains out of the brain, being unable to cross the blood-brain barrier.
Therefore administration of Levodopa gives rise to high dopamine levels circulating in the peripheral regions, and to low brain dopamine levels.
In the present invention the atypical antipsychotic drugs are administered in association with Levodopa, and therefore their bond 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 the dopamine derived from Levodopa inhibits noradrenaline release from the sympathetic nervous terminals and adrenaline secretion from the adrenal medulla, reducing the sympathetic tone. The amount of Levodopa converted to dopamine in the brain is negligible, and therefore a strong competitive antagonism is obtained on the peripheral effects of the antipsychotics, and a weak antagonism on their cerebral effects.
In particular, the pharmaceutical composition of the present invention enables:
- the metabolic side effects of antipsychotics to be reduced, such as hyperglycaemia and diabetes, hypercholesteremia and dyslipidemias in general;
- the cardio and cerebrovascular side effects of the antipsychotics to be reduced;
- the antipsychotic-induced and in particular the benzamide-induced hyperprolactinemia to be reduced;
- an advantageously greater tolerability of the antipsychotic drugs in treating the neuropsychiatric disorders to be achieved.
The clinical experiments on patients treated with antipsychotics to whom Levodopa has been administered have confirmed the expected benefits. A pilot study on psychiatric patients suffering from metabolic syndrome induced by the chronic treatment with clozapine and olanzapine has proved that the additional administration of Levodopa is able to reduce the arterial pressure and the plasma levels of glucose, glycated haemoglobin and triglycerides in few weeks.
Preferably, the pharmaceutical composition contains a suitable excipient, vehicle or diluent.
Preferably said excipients are absorbents, lubricants, binders, disgregating and colouring agents, sweeteners, antioxidants, polymers, preservatives or stabilisers.
The antipsychotic drug is atypical. It preferably consists of clozapine, risperidone, olanzapine, quetiapine, aripiprazole, ziprasidone, amisulpride, sulpiride, zotepine, sertindole, paliperidone, bifeprunox or asenapine and other possible atypical antipsychotics to be put on the market in the near future.
The pharmaceutical composition preferably is a controlled-release formulation or a composition for oral, intravenous, intradermal, intramuscular, subcutaneous or intraperitoneal administration, or it is in a solid or liquid state or a dry product to be reconstituted, or yet it is in the form of tablets, pills, capsules, powder or the like, and also in the form of aqueous or oily suspensions, syrups, solutions, emulsions, drops or the like.
The pharmaceutical composition in accordance with the present invention will be described in the following in some of the preferred embodiments thereof.
It is used in drugs for treating psychiatric disorders.
The composition consists of the combination of:
(a) a first therapeutic agent that is an atypical antipsychotic drug (including, although not limited thereto, clozapine, olanzapine, quetiapine, risperidone, ziprasidone, sulpiride, amisulpride, aripripazole zotepine, sertindole, paliperidone, bifeprunox and asenapine) and
(b) a second therapeutic agent that is a dopaminergic drug mainly acting in the peripheral regions, such as Levodopa, or L-dopa, or dihydroxyphenylalanine, for example. The latter is an aromatic amino acid of 197.2 molecular weight, chemically identified as L-(-)-2-amino-3-(3,4-dihydroxyphenyl-propanoic acid, of empirical formula C9H11 N04. As an alternative to Levodopa, an appropriate precursor thereof can be used, such as Ethylvodopa (L-dopa ethyl ester) or Melevodopa (L-dopa methyl ester) and the like. As an alternative to the antipsychotic drug a metabolite or a pro-drug thereof can be used.
The term "precursor" or "pro-drug" means a derivative of the active molecule requiring a conversion inside the organism for releasing the active drug.
For oral administration the pharmaceutical composition takes the form of tablets, pills, capsules, powder, etc., with various excipients, prepared following the traditional methods. The excipients include although not limited thereto, cornflour, pre-gelatinised starch, anhydrous dibasic calcium phosphate, microcristalline cellulose, crospovidone, E132, lactose monohydrate, methylcellulose, yellow iron oxide, black iron oxide (E172), red iron oxide (E172), gelatin, hydroxypropylcellulose, hypromellose, magnesium stearate, Mannitole E421 , hydrogenated castor oil, polyvinylpyrrolidone, anhydrous colloidal 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.
Otherwise it appears in the form of a dry product to be reconstituted with water or other excipients suitable for use.
These liquid formulations contain conventional additives such as sorbitol, methylcellulose, gelatin, glucose, emulsifying agents, colouring agents, sweeteners and preservatives having an antibacterial action or a chelating- antioxidant action such as ascorbic acid, sodium metabisulphite, citrate. The dry formulations to be reconstituted with water or other suitable excipients before use contain excipients such as anhydrous citric acid, pregelatinized cornflour, microcristalline cellulose, magnesium stearate and the like. The pharmaceutical composition is also prepared as a controlled-release formulation such as a slow-release or quick-release formulation.
The two therapeutic agents previously described are also administered differently, for example providing preparation of Levodopa in tablets to be administered daily, and preparation of the antipsychotic as "Depot formula". This long-term effect formulation is administered as a subcutaneous or intramuscular implant, or by intramuscular injection. One or both of the therapeutic agents are also administered in orodispersible tablets to be placed under the tongue, with the addition of excipients such as aspartame, gelatin, mannitole, sodium methylparahydroxybenzoate, sodium propylparahydroxybenzoate.
The pharmaceutical composition is preferably supplied to the consumer in the form of a kit comprising a first unit dose of the antipsychotic drug and a second unit dose of Levodopa.
Examples of therapeutic instructions
According to the present invention, said pharmaceutical composition can be used in the treatment of psychiatric disorders. In particular, schizophrenia, psychotic disorders, schizophrenic form disorders, emotional schizophrenic disorders, short- term psychotic disorders, treatment-resistant psychotic mood disorders, strong depression, generalised anxiety disorders, bipolar disorders, psychotic disorders due to other pathologies or to particular clinical situations, psychotic disorders not otherwise specified. The psychotic disorders due to other pathologies include, although not limited thereto, the Alzheimer's disease and dementias in general, mild cognitive impairment, Huntington's disease, corticobasal degeneration, progressive subnuclear palsy, Down's syndrome.
Treatment of attention deficit disorders, hyperactivity disorders, and emotional disorders, irritability associated with autistic disorders.
Composition examples
The most desirable pharmaceutical compositions according to the present invention are described herebelow:
Example 1 - A composition containing 5 to 2000 milligrams per unit-dose of Levodopa or a precursor thereof as the first active ingredient, and Quetiapine in a ratio included between 1 :200 and 200:1.
Example 1 - A composition containing 5 to 2000 milligrams per unit-dose of Levodopa or a precursor thereof as the first active ingredient, and Olanzapine in a ratio included between 1 :10 and 400: 1.
Example 3 - A composition containing 5 to 2000 milligrams per unit-dose of Levodopa or a precursor thereof as the first active ingredient, and Clozapine in a ratio included between 1 :100 and 100:1.
Example 4 - A composition containing 5 to 2000 milligrams per unit-dose of Levodopa or a precursor thereof as the first active ingredient and Risperidone in a ratio included between 1 :3 and 1000:1.
Example 5 - A composition containing 5 to 2000 milligrams per unit-dose of Levodopa or a precursor thereof as the first active ingredient and Aripiprazole in a ratio included between 1 :10 and 500:1.
Example 6 - A composition containing 5 to 2000 milligrams per unit-dose of Levodopa or a precursor thereof as the first active ingredient and Ziprasidone in a ratio included between 1 :100 and 100:1.
Example 7 - A composition containing 5 to 2000 milligrams per unit-dose of Levodopa or a precursor thereof as the first active ingredient and Amisulpride in a ratio included between 1 :200 and 200: 1. Example 8 - A composition containing 5 to 2000 milligrams per unit-dose of Levodopa or a precursor thereof as the first active ingredient and Sulpiride in a ratio included between 1 :200 and 200:1.
Example 9 - A composition containing 5 to 2000 milligrams per unit-dose of Levodopa or a precursor thereof as the first active ingredient and Zotepine in a ratio included between 1 :100 and 200:1.
Example 10 - A composition containing 5 to 2000 milligrams per unit-dose of Levodopa or a precursor thereof as the first active ingredient and Sertindole in a ratio included between 1 :10 and 500:1.
Example 1 1 - A composition containing 5 to 2000 milligrams per unit-dose of Levodopa or a precursor thereof as the first active ingredient and Paliperidone in a ratio included between 1 :30 and 500:1.
Example 12 - A composition containing 5 to 2000 milligrams per unit-dose of Levodopa or a precursor thereof as the first active ingredient and Asenapine in a ratio included between 1 :10 and 500: 1.
Example 13 - Kit containing 5 to 2000 milligrams per unit-dose of Levodopa or a precursor thereof for oral administration, and an antipsychotic in an injectable delayed-release suspension, Risperidone for example, from 10 to 100 milligrams. Dosage examples
According to the present invention, the Levodopa doses to be associated depend on the affinity degree and dissociation constant of the individual antipsychotics for the D2 receptors.
The effective doses consisting of a combination of an antipsychotic and Levodopa according to the present invention, vary as a function of factors such as the patient's state, type of illness, seriousness of symptoms, power of the antipsychotic, administration mode, the patient's age and weight. The appropriate dosage of the pharmaceutical composition can be determined based on studies on animals or humans.
For instance, according to the invention:
Example 14 - the daily administration of Levodopa is included between 10 milligrams and 3000 milligrams, in a single or fractionated dose.
Example 15 - the daily administration of Quetiapine is included between 10 mg and 1200 mg.
Example 16 - the daily administration of Olanzapine is included between 10 mg and 50 mg.
Example 17 - the daily administration of Clozapine is included between 10 mg and 900 mg.
Example 18 - the daily administration of Risperidone is included between 0.5 mg and 16 mg.
Example 19 - the daily administration of Aripripazole is included between 2 mg and 50 mg.
Example 20 - the daily administration of Ziprasidone is included between 5 mg and 400 mg.
Example 21 - the daily administration of Amisulpride is included between 10 mg and 1500 mg.
Example 22 - the daily administration of Sulpiride is included between 10 mg and 1200 mg.
Example 23 - the daily administration of Zotepine is included between 10 mg and 600 mg.
Example 24 - the daily administration of Sertindole is included between 2 mg and 50 mg.
Example 25 - the daily administration of Paliperidone is included between 1 mg and 30 mg.
Example 26 - the daily administration of Asenapine is included between 1 mg and 50 mg.
Example 27 - the daily administration of all other, conventional and atypical, antipsychotics, is included in the range specified in their dose-rate as monotherapy.
Example 28 - In case of use of pro-drugs as an alternative to Levodopa, the daily administrations are determined in such a manner that the amount of Levodopa deriving from their metabolisation is equal to 10-3000 mg.

Claims

1. A dopaminergic drug exercising its main action on the peripheral regions or a precursor thereof for preventing, eliminating or reducing the side effects arising in patients with psychic disorders treated with atypical antipsychotics.
2. A drug as claimed in claim 1 , consisting of Levodopa.
3. A drug as claimed in claim 1 , consisting of L-dopa.
4. A drug as claimed in claim 1 , consisting of dihydroxyphenylalanine.
5. A dopaminergic drug as claimed in one or more of claims 1-4, wherein said side effects are of the metabolic type, the cardiocirculatory type and due to the prolactin increase.
6. Use of a dopaminergic drug exercising its main action on the peripheral regions or use of a precursor thereof for the preparation of a pharmaceutical composition for preventing, eliminating or reducing the side effects arising in patients with psychic disorders treated with atypical antipsychotics.
7. Use as claimed in claim 6, wherein said dopaminergic drug consists of
Levodopa.
8. A pharmaceutical composition for use in therapies for psychiatric disorders comprising an atypical antipsychotic drug or a metabolite or a precursor thereof, characterised in that it further comprises a dopaminergic drug mainly acting on the peripheral regions or a precursor thereof adapted to prevent, eliminate or reduce the side effects of said atypical antipsychotic drug.
9. A pharmaceutical composition as claimed in claim 8, comprising a suitable excipient, vehicle or diluent.
10. A pharmaceutical composition as claimed in one or more of claims 8-9, wherein said dopaminergic drug is Levodopa or a precursor thereof.
11. A pharmaceutical composition as claimed in one or more of claims 8-
10, wherein said atypical antipsychotic drug is clozapine, risperidone, olanzapine, quetiapine, aripiprazole, ziprasidone, amisulpride, sulpiride, zotepine, sertindole, paliperidone, bifeprunox or asenapine.
12. A pharmaceutical composition as claimed in one or more of claims 8-
11 , consisting of a controlled-release formulation.
13. A pharmaceutical composition as claimed in one or more of claims 8-
12, whose formulation is for oral, intravenous, intradermal, intramuscular, subcutaneous or intraperitoneal administration.
14. A pharmaceutical composition as claimed in one or more of claims 8-13, wherein said excipients are absorbents, lubricants, binders, disgregating and colouring agents, sweeteners, antioxidants, polymers, preservatives or stabilisers.
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