MX2007008323A - Pharmaceutical composition comprising the combination of a benzisoxazolic derived agent and a benzodiazepinic agent. - Google Patents

Abstract

The present invention concerns a pharmaceutical composition formed by the synergistic combination of a benzisoxazolic derived agent, such as the active principle: Risperidone and a benzodiazepinic agent, such as the active principle: Clonazepam, which are formulated in a single dosing unit to be administered by oral means in the form of capsules or tablets, the former being prescribed for the control and treatment of diseases such as: psychotic disorders and related pathologies.

Description

PHARMACEUTICAL COMPOSITION COMPRISING THE COMBINATION OF A BENZISOXAZOLIC DERIVATIVE AGENT AND AN AGENT BENZODIAZEPINICO.

FIELD OF THE INVENTION The present invention is applied in the pharmaceutical industry and describes a pharmaceutical composition composed of the synergistic combination of a benzisoxazole derivative agent, such as the active substance: Risperidone and a benzodiazepine agent, as is the active principle: Clonazepam, which They are formulated in a single dosage unit, which is indicated for the control and treatment of psychotic disorders that are accompanied by anxiety. The combination of the active principles mentioned above produces a greater synergistic effect when they are administered together in a single dose unit as opposed to when they are administered independently, generating benefits such as: lower concentrations of the active ingredients formulated, lower administered doses, faster action, greater efficacy of the therapeutic effect, satisfactory control of the symptoms manifested by patients suffering from psychotic disorders, lower risks of interactions between drugs at the liver level and lower risks of adverse effects.

BACKGROUND OF THE INVENTION The causes of psychotic disorders are varied, hence the deep understanding of these is necessary to make a correct diagnosis and offer the indicated treatment. Psychoses are a group of mental illnesses characterized by the loss of contact with reality. The most known and studied psychotic disorder to date is schizophrenia, but it should be clarified that not all psychotic disorders are due or are related to this disease. The term schizophrenia translates directly from the Greek schizo = division, brakes = mind, that is, the division of the thoughts of the mind. Schizophrenia is a mental disorder that is found in varying degrees, but has a chronic course throughout life. Unlike this one, other psychotic disorders are of acute or sub-acute course and tend to have variable degrees in recovery of mental function.

Schizophrenia typically begins late in adolescence or early in adulthood and is characterized by specific changes in the patient's thinking and perception of the outside world. Other psychoses can occur at any other stage of life. Two types of schizophrenia have been considered: 1) schizophrenia with positive signs or type 1: delirium, hallucinations, agitation, emotional decontrol. It has been associated with hyperactivity of the dopaminergic system; and 2) schizophrenia with negative signs or type 2: lack of emotional reactions (the so-called affective flattening), detachment of the subject from their environment, anhedonia (inability to experience pleasure), lack of energy, psychomotor retardation, etc., but without hallucinations or serious delusions. The type 2 syndrome tends to appear at an early age and insidiously. Schizophrenia is a neurodegenerative disorder, because they have been found in these patients smaller brain size, greater ventricular volume, anatomical alterations in the frontal and temporal lobes, particularly in the left cerebral hemisphere, as well as decrease of markers to various neurotransmitters. Psychotic disorders, whether or not they are schizophrenic, are characterized by short or prolonged periods during the which the patient suffers from hallucinations and delusions, thought and behavior become disorganized. The noticeable difference between schizophrenia and other psychoses unrelated to it comes after these acute episodes; in the first, there is a progressive tendency to isolation, to disheveling, to talk very little to not express emotions; On the other hand, in other psychoses that are not related to schizophrenia, these last symptoms are not observed. The causes of schizophrenia and other psychoses are not known for sure, but there are likely to be genetic and environmental components involved. Psychotic disorders not only include schizophrenia in all its clinical forms, it also includes: affective psychoses, psychotic depressions; schizoaffective psychoses; acute or chronic delirious psychosis, paranoia; paranoid reactions; puerperal psychoses; epileptic psychoses; toxic psychoses (amphetamines, cocaine, alcohol); Gilles de la Tourette syndrome; Delirium tremens; decompensation in psychopaths; agitation-senile confusion and arteriosclerotic; psycho-organic syndromes and dementias (Huntington's disease). Treatment schemes include the use of a typical antipsychotic often associated with anticholinergic antiparkinsonians such as trihexyphenidyl. Generally they should be associated with anxiolytic and hypnotic drugs, these can be benzodiazepines such as: Clonazepam. A classic scheme that has had excellent results orally, has been the administration of the antipsychotic Haloperidol (typical) that has an excellent acute antipsychotic profile, but is not sedative, for this reason anxiolytics are used concomitantly as chlorpromazine and levomepromazine (neuroleptics). However, being these dopaminergic blockers will add extrapyramidal effects. The current and modern treatment regimen is the use of atypical antipsychotics such as Risperidone and concomitantly the use of anxiolytic and hypnotic drugs; however, the interactions of these can cause hepatic alterations, due to the administration of frequent and prolonged doses. In order to offer a pharmaceutical alternative that achieves a better quality of life in patients suffering from diseases such as: psychotic disorders and related pathologies, the development of the pharmaceutical composition described below was carried out. At present, most of the medicines found in the market for the treatment of psychotic disorders are composed of active ingredients that are formulated in a independent, which comply with a specific therapeutic activity; However, when these drugs are administered concomitantly and in the doses that are usually used, there are interaction effects between drugs that cause alterations at the liver level with elevation of transaminases, due to their high doses, the frequency of doses and its long-term use.

SUMMARY OF THE INVENTION For this reason and in order to eliminate all the disadvantages that arise when the active ingredients are administered independently, is that the development of the pharmaceutical composition object of the present invention, which is composed of the combination, was carried out. synergistic of a benzisoxazole derivative and a benzodiazepine agent; which produce a satisfactory therapeutic effect when administered together in a single oral dosage unit, unlike when they are administered independently, generating benefits such as: lower concentrations of the active ingredients formulated, lower doses administered, faster action, greater efficacy of the therapeutic effect, satisfactory control of the symptoms manifested by patients suffering from psychotic disorders, lower risks of interactions between drugs at the liver level and lower risks of adverse effects.

BRIEF DESCRIPTION OF THE FIGURES Figure 1 shows the acute and baseline acute agitation scale in the two study groups to which the risperidone / clonazepam combination was administered. Figure 2 shows the evaluation of the severity of the disease on the PANSS scale (Positive and Negative Syndrome Scale) after the administration of the risperidone / clonazepam combination that was similarly distributed between two study groups. Figure 3 shows the evaluation of the severity of the disease on the CGI-S scale (Clinical Global Disease Severity Impression Scale) after the administration of the risperidone / clonazepam combination that was similarly distributed between two groups study.

DETAILED DESCRIPTION OF THE INVENTION The benzisoxazole derivative agents are also referred to as new antipsychotics or atypical antipsychotics because their pharmacodynamic profiles differ from conventional antipsychotics. The generation or classic antipsychotics act by blocking the dopamine D2 receptors in the limbic and striated system. It is considered that the blockade on the limbic system is the basis of its antipsychotic action, the action on the striatum contributes to the appearance of extrapyramidal symptoms (including tardive dyskinesia) and the blockade of the D2 receptors in the hypothalamic-pituitary axis to its action on prolactin. Most of the new antipsychotics are differentiated by their low affinity on the D2 receptors and their greater selectivity on other neuroreceptors for serotonin and noradrenaline, as well as for their modulating action on the functions mediated by the glutamate receptor. The relationship between the activity on the D2 and 5HT2 receptors is typically low in the new antipsychotics. Even so, to have antipsychotic activity it must have some degree of affinity over the D2 receptors. The new antipsychotics are pharmacologically diverse and with different mechanisms of action in some cases.

There are two groups of clearly differentiated antipsychotics: - ATYPICS: They have antipsychotic action without producing extrapyramidal reactions (motor disorders), in addition they block simultaneously D2 dopamine receptors and 5HT2 serotonergic receptors and of these we can expect: a) Extrapyramidal effects, minimal or null, b) Action on the negative symptoms of schizophrenia (in addition to positive ones), c) A significant degree of efficacy in refractory cases to typical antipsychotics. TYPICAL: They have mainly two effects, extrapyramidal reactions and sedation. All antipsychotic agents are equally effective in reducing symptoms. According to their chemical structure they have been grouped into families: phenothiazines, with thioxanthenes, dibenzodiazepines (such as clozapine) and dibenzoxazepines (such as loxapine) as related agents; butyrophenones (such as haloperidol), diphenylbutylpiperidines; the indolones (such as molindone) and other agents called heterocyclics, and finally, the alkaloids of the rauwolfia. The main challenges in research on antipsychotics have been to define their mechanism of action, increase efficacy in patients with resistant schizophrenia (about one third of patients do not respond to classical antipsychotics) and in the so-called negative symptoms of the disease (affective dullness, apathy, anhedonia, isolation, attention deficit and allopathy ), as well as increasing the therapeutic index with respect to extrapyramidal symptoms (SEP). The antipsychotic effects appear slowly as the treatment progresses: agitation and restlessness diminish, communication with others and with the environment increases, impulsive or aggressive behaviors disappear; the same tendency is observed in the case of hallucinations, delusions and disorganization of thought. As can be seen, positive symptoms respond better to pharmacological therapy than negative symptoms. A wide variety of electrophysiological and neurochemical techniques have shown that antipsychotics are blockers of dopaminergic receptors; given the wide distribution of these receptors in the central and peripheral nervous system; these substances show effects at various levels: they act on the group of neurons responsible for the vomiting reflex, the antipsychotics exert powerful antiemetic actions (against vomiting); Due to its effects in the endocrine system, these substances increase the secretion of prolactin, which can produce galactorrhea (milk secretion by the mammary glands), gynecomastia (exaggeration of secondary sexual characteristics, such as breast growth), amenorrhea (interruption) of menstrual cycles), aggravation of tumors sensitive to hormones (such as breast cancer), etc. With regard to the pharmacokinetics and metabolism of antipsychotics, although there are differences between them, some generalizations can be made: given their high solubility in fats, they easily cross all types of biological barriers (including the placenta), and its distribution is largely determined by blood flow, so richly irrigated organs, such as the brain, receive a large amount of the drug. On the other hand, parenteral administration is much more effective than oral administration to produce higher and more stable blood concentrations: the tranquilizing effect appears approximately 60 minutes after ingestion and 10 minutes after intramuscular injection. The antipsychotic effect, however, requires several weeks or months to manifest.

In the central nervous system, adverse reactions of antipsychotics include: akatisia, is the most frequent; it can be defined as the impossibility of remaining calm; dystonia, are involuntary muscle contractions that can manifest as gestures, grimaces, torticollis or exaggerated eye movements; parkinsonian syndrome, these drugs frequently produce slowness of movement (bradykinesia), certain muscular rigidity (hypertonia) that includes the muscles of the face producing an expressionless face ("stick face") and tremor; late dyskinesia, is a serious syndrome that can occur after prolonged administration (months or years) of these drugs and results in involuntary, stereotyped and repetitive movements of the mouth, lips and tongue, of the extremities and the adoption of strange positions, with prolonged muscular contractures; neuroleptic malignant syndrome, this is a rare disorder with severe crisis of parkinsonism, catatonia, tremor, alterations in heart rate and blood pressure, increase in body temperature; and seizures. At the level of the peripheral nervous system, antipsychotics can produce constipation, dry mouth, nasal congestion, blurred vision, pupillary dilation, photophobia (fear of light), tachycardia, retention urinary, increased body weight and blood disorders. Risperidone is an antipsychotic agent belonging to a new class of antipsychotics, the benzisoxazole derivatives. It is a selective monoaminergic antagonist that has a high affinity for the serotonergic receptors 5-HT2 and dopaminergic D2; it also binds to alpha adrenergic receptors, and with lower affinity, to histaminergic receptors Hl and alpha2 adrenergic receptors. It has no affinity for cholinergic receptors. Although Risperidone is a potent D2 antagonist, which is considered to improve the positive symptoms of schizophrenia, it produces less depression of motor activity and induction of catalepsy than classical neuroleptics. The balanced serotoninergic and dopaminergic central antagonism manages to reduce the lability of extrapyramidal side effects and extend the therapeutic activity towards the negative and affective symptoms of schizophrenia. Risperidone is completely absorbed after oral administration, reaching peak plasma concentrations within 1 to 2 hours after administration. Its absorption is not affected by meals, therefore, it can be administered with or without the presence of food.

Risperidone is metabolized to 9-hydroxy-risperidone by cytochrome P450 2D6; said metabolite has a pharmacological action similar to that of Risperidone. Risperidone and its metabolite 9-hydroxy-risperidone form the active antipsychotic fraction. Another metabolic step of Risperidone is N-dealkylation. After oral administration to psychotic patients, Risperidone is eliminated with a half-life of approximately 3 hours. The elimination half-life of the metabolite 9-hydroxy-risperidone and of the active antipsychotic fraction is 24 hours. Stable levels of Risperidone are reached in 1 day in most patients. Stable levels of the 9-hydroxy-risperidone metabolite are reached after 4 to 5 days of the administration of Risperidone. The plasma concentrations of Risperidone are proportional to the dose within the range of therapeutic doses. Risperidone is rapidly distributed. In plasma, it binds to albumin and alphax acid glycoprotein. The binding of Risperidone to plasma proteins is 88%, that of the metabolite 9-hydroxy-risperidone is 77%. One week after administration, 70% of the dose is excreted in the urine and 14% in the stool. In urine, Risperidone and its metabolite 9-hydroxy-risperidone they represent between 35 and 45% of the total dose administered, the rest are inactive metabolites. A single-dose study showed higher active plasma concentrations and a slower elimination of Risperidone in the elderly and in patients with renal insufficiency. Plasma concentrations of Risperidone were normal in patients with hepatic impairment. Risperidone can alter hepatic transaminase values. Risperidone is recommended for the treatment of patients with schizophrenia, including first psychotic episode, acute exacerbations, chronic schizophrenia, and other psychotic conditions, in which positive symptoms (such as hallucinations, delusions, thinking disorders, hostility, suspicion) and / or the negative symptoms (such as affective flattening, emotional and social withdrawal, language poverty) are notorious. Risperidone also relieves affective symptoms (such as depression, guilt, anxiety) associated with schizophrenia. In addition, Risperidone is recommended long-term for the prevention of relapse (acute exacerbations) in chronic schizophrenic patients. Likewise, Risperidone is also indicated for the treatment of remarkable behavioral disorders in patients with dementia in whom the symptoms, such as aggressiveness (explosion of verbal anger, physical violence), disturbances in their activity (agitation, loitering) or psychotic symptoms are notorious. Risperidone is generally well tolerated by patients suffering from such diseases or pathologies. In many circumstances it has been difficult to differentiate collateral effects from the symptoms of underlying diseases. Some side effects associated with the use of Risperidone are: insomnia, agitation, anxiety, headaches. Risperidone is less prone to induce extrapyramidal symptoms than those caused by classical neuroleptics. However, in some cases the following extrapyramidal symptoms may occur: tremor, rigidity, excessive salivation, bradykinesia, akatisia, acute dystonia. These are generally mild and reversible with dose reduction and / or administration of an antiparkinsonian medication, if necessary. Benzodiazepines (BZD) are a class of drugs with anxiolytic, hypnotic, anticonvulsant, sedative, amnestic and muscle relaxant (muscle relaxants) effects. BZDs are more selective depressants of the nervous system than other drugs, such as barbiturates They act, in particular, on the limbic, thalamic and hypothalamic systems of the central nervous system, producing a depression of their activity. BZDs share a similar chemical structure and have a high affinity for the complex of benzodiazepine receptors found in the central nervous system. Structurally, the BZDs present a benzene ring with six elements, joined to another ring of diazepine with seven elements. Each specific BZD will arise by substitution of radicals in different positions. The specific receptors found in the CNS through which the BZDs exert their effect are part of the benzodiazepine-GABA receptor complex. The α-aminobutyric acid (GABA) is a neurotransmitter with inhibitory action and its receptors are part of an inhibitory bidirectional system connected between different areas of the CNS. The BZD potentiate the inhibitory action mediated by GABA. GABA acts on several subtypes of receptors called: GABA-A and GABA-B. GABA-A is the subtype of primary receptor found in the CNS through which anxiolytics and sedatives act. Some subtypes of benzodiazepine receptors appear to be coupled to GABA-A receptors. Three subtypes of benzodiazepine receptors are known: those located in the cerebellum and cerebral cortex called BNZ1, the located in the cerebral cortex and spinal cord called BNZ2 and those located in peripheral tissues (such as adrenal glands, kidneys, pineal gland and platelets) called BNZ3. Activation of BNZl induces sleep, while drugs that bind to BNZ2 cause muscle relaxation, anticonvulsant activity and affect memory. Benzodiazepines bind non-specifically to BNZ1 and BNZ2 receptors, which exalts the effects of GABA. Unlike barbiturates that increase GABA responses by keeping the chlorine channel (C1-) open for longer, benzodiazepines increase the effects of GABA, which allows the chlorine channel to be opened in hyperpolarized cells and prevent further excitation of the same. BZDs can be differentiated according to their time of action, being able to be: short-acting (between 2 and 10 hours) and long-acting (from 12 to 100 hours) in relation to their effect. To carry out the administration of BZD, it is important to know if the patient suffers from or has symptoms related to: liver diseases, alcoholism, brain diseases, poor salivation (in children), glaucoma, hyperactivity, renal or lung, myasthenia gravis, porphyrias, pregnancy or sleep apnea. During treatment seizures, fever, tremors, muscle weakness, loss of reflexes, intense asthenia, involuntary movements, shortness of breath, dry mucous membranes (oral, conjunctival, nasal), erythematous skin, arterial hypotension, slow pulse, mild mental disorders may occur. or, even, confusion and coma. The benzodiazepinas cause dependency reason why they must be used in short treatments of time. When you stop a treatment with benzodiazepines, it takes approximately three weeks for the body to de-habit. Clonazepam is a drug that belongs to the group of benzodiazepines (BZD) with depressant action on the central nervous system. It has several common pharmacological properties with the rest of the BZD, such as: anxiolytic, sedative, hypnotic, miorrelaj before, amnestic and anticonvulsant; being useful in pre-anesthetic medication and, in larger doses, as inducers of general anesthesia and maintenance thereof. These benzodiazepine agents can also produce orexigenic effect (increased appetite), dysarthria (difficulty speaking) and ataxia (difficulty walking) with the administration of high doses. He Clonazepam, like the rest of the BZD, is metabolized primarily by hepatic microsomal enzymes, undergoing microsomal oxidation (phase I) and then glucuronoconjugation (phase II). Most BZDs must first be oxidized (active metabolites, phase I) and then conjugated (inactive metabolites, phase II). The metabolic transformation of Clonazepam is produced by oxidative hydroxylation and reduction of the 7-nitro group, with formation of 7-amino or 7-acetylamino compounds, which can be conjugated to form new metabolites. The main metabolite is 7-amino-clonazepam, with little anticonvulsant activity. Four other metabolites have also been identified, but to a lesser extent. Clonazepam is absorbed quickly and completely in the gastrointestinal tract after oral administration. The maximum plasma concentrations of Clonazepam are recorded in most cases after 1 to 4 hrs. after the administration of the drug. The bioavailability of Clonazepam orally is 90%. The optimal effect is obtained with Clonazepam plasma concentrations of 20-70 ng./mL. (average: 55 ng./mL., approximately). Clonazepam has an intermediate half-life, fluctuating between 30 and 40 hrs. Its degree of binding to plasma proteins is 85%; is metabolized in the liver and is excreted through the kidneys. Clonazepam crosses the placental barrier and its presence in breast milk has been detected. The elimination of Clonazepam is slow since the active metabolites can remain in the blood several days or even weeks, with persistent effects. Within 4 to 10 days, 50 to 70% of an oral dose of Clonazepam is eliminated in the urine and 10 to 30% in the faeces, almost exclusively in the form of free or conjugated metabolites. Less than 0.5% is recovered in the urine in the form of unaltered Clonazepam. The elimination half-life ranges between 20 and 60 hours (average: 30 hours). Because Clonazepam is metabolized in the liver, it is possible that liver diseases impair its elimination. Therefore, precautions should be taken before administering Clonazepam to these groups of patients. It has been observed that the concomitant administration and individually with therapeutic doses of an antipsychotic such as Risperidone and a benzodiazepine such as Clonazepam, produce an increase and prolongation of plasma concentrations by competitive inhibition of Risperidone metabolism.

The benzisoxazole-derived antipsychotic agent used in the pharmaceutical composition object of the present invention is the active ingredient: Risperidone, which is present in the formulation in a concentration range of 1.0 mg. to 10.0 mg, with a concentration of about 1.0 mg being preferably used. to 2.0 mg., per dose unit. The benzodiazepone agent used in the pharmaceutical composition object of the present invention is the active principle: Clonazepam, which is present in the formulation in a concentration range of 0.5 mg. to 6.0 mg, with a concentration of about 0.5 mg being preferably used. to 2.0 mg. , per dose unit. The pharmaceutical composition protected by the present invention is formulated to be administered orally in a single dosage unit in the form of a capsule or tablet, in which the synergistic combination of the active principles: Risperidone and Clonazepam, as well as excipients, is contained. pharmaceutically acceptable Said pharmaceutical composition has been developed with the purpose of providing a pharmaceutical alternative for the control and treatment of diseases such as: psychotic disorders and related pathologies, which offers significant advantages such as: concentrations of the active principles contained in the formulation, lower doses administered, greater speed of action, greater efficacy of the therapeutic effect, satisfactory control of the symptoms suffered by patients with psychotic disorders, lower risk of interaction between drugs at the liver level and lower risks of adverse effects. To evaluate the efficacy and tolerance of the pharmaceutical composition of the present invention, as well as the synergistic effect of the active principles Risperidone and Clonazepam combined in a single dosage unit, a comparative clinical study was conducted in which the active principles were administered previously mentioned separately, as well as the combination thereof. COMPARATIVE CLINICAL STUDY OF THE COMBINATION RISPERIDONA / CLONAZEPAM. This study compared the efficacy and safety of an oral treatment composed of the combination of an atypical antipsychotic agent benzisoxazole derivative, such as the active principle: Risperidone and a benzodiazepine agent, as is the active principle: Clonazepam, against the administration of Risperidone and Clonazepam independently and with the commonly used doses.

Patients with psychotic disorder accompanied by anxiety were included, which required pharmacological treatment. The duration of the study was three months of follow-up. The inclusion criteria were: Patients with a diagnosis of psychotic disorder (schizoaffective disorder, mania with psychotic findings, paranoid reaction, delusional disorder). - Men or women. - Ages between 18 and 65 years old. - A rating of >; 14 on the PANSS scale (Positive and Negative Syndrome Scale). - A rating of > 3 on the CGI-S scale (Clinical Global Impression Scale of Disease Severity). - It was evaluated that women had a safe method of contraception. Patients were assigned to two treatment groups: Group 1 received: Risperidone (1 mg.) And Clonazepam (2 mg.), Three times a day. Group 2 received: the combination Risperidone 1 mg. / Clonazepam 2 mg., Once a day. Evaluations were made with physical and mental history, the PANSS scale was applied, which evaluates: excitability, hostility, non-cooperation, hallucinations and poor impulse control; each of them rated 7 points (1 = absent to 7 = extreme); In addition, the PANSS included the evaluation of: positive symptoms, negative symptoms, disorganized thoughts, uncontrolled excitability / hostility and anxiety / depression. The improvement was evaluated with the CGI-S scale (range of 1 = No symptoms a? - Extremely severe symptoms). The OAS (Aggression Scale) scale was applied with its 16 points that are grouped into 4 categories: verbal aggression (rated from 1 to 4), physical aggression against objects (rated from 2 to 5), physical aggression against oneself (qualified from 3 to 6) and physical aggression against others (rated from 3 to 6). The aggression score is the sum of all the grades for the most severe behavior in each of the 4 categories (maximum score of 21). Blood tests of liver function tests were performed. Spontaneous reports of adverse events were evaluated and monitored and the severity and relationship with the study drugs were evaluated. Physical and neurological exams were performed and evaluated at the beginning or as soon as possible within the first 24 hours. Movement disorders were evaluated with the BAS scale (Scale of Acatisia de Barnes) and the SAS scale (Simpson - Angus Scale) for patients with Parkinson's symptoms. Sedation was evaluated by means of a 4-point scale (0 = No signs, 1 = Discreetly sedated, 2 = Moderately sedated and 3 = No sleep). The following medications were not allowed for concomitant administration: another antipsychotic, another benzodiazepine (except for Clonazepam), psychoactive medications and the use of anticholinergics. Antiparkinson medications could be administered at effective doses if movement disorders or extrapyramidal effects were present during the study. RESULTS We included 80 patients who met the inclusion criteria and were randomly assigned to one of the two groups: Group 1 = 40, Group 2 = 40. The average age was 39 years. The most frequent diagnosis was Paranoid Schizophrenia in 60% of patients and Affective Disorder in 40% of patients. There were no statistically significant differences between groups in their baseline characteristics. The 80 patients completed the study (Table 1). Study patients experienced behavioral emergencies upon entering the study, which is reflected in the Acute Agitation (PA SS) rating of > twenty; Sixty-six patients showed a CGI-S scale rating of > 5 (marked symptoms). The baseline average for the OAS scale was > 19 and aggressive incidents were observed in 100% of the patients on the day of enrollment.

Table 1. Baseline characteristics of patients. Variable Group 1 Group 2 Patients (n = 40) (n = 40) Average age 39.0 39.7 Men / Women 25/15 27/13 Diagnosis (n = 80). Paranoid schizophrenia 18 30 Schizoaffective disorder 12 10 Bipolar disorder severe mania 3 2 Psychotic disorder 3 2 Efficacy (n = 40) (n = 40) Qualification Acute agitation PANSS 20 20 OAS score Aggression score 19 20 CGI-S Severity of the disease ( n = 80) Soft 1 1 Moderate 10 12 Marked 23 20 Severe 7 6 Hepatic functional tests SA S.A. S. A. (without alteration).

Twenty-three patients (57.5%) of Group 1 received medication for the control of extrapyramidal symptoms. Sixty-eight patients completed the study, twelve of them (15%) discontinued the treatment, 11 of Group 1 and 1 of Group 2, the reasons were extrapyramidal effects in 10 Group 1 patients; as well as 1 patient for non-compliance with treatment; the Group 2 patient was suspended from the study due to non-compliance (Table 2).

Table 2. Patients who completed the study and reasons for discontinuation, N (%).

Group 1 Group 2 patient's position (n = 40) (n = 40) Study completed 29 (72.5%) 39 (97.5%) Reason for discontinuation Adverse events 11 (27.5%) 1 (2.5%) Non-compliance 1 ( 2.5%) 1 (2.5%) Insufficient response Loss of follow-up Alterations of PFH 13 Liver function tests performed on the last day of the study showed transaminase alterations in 13 patients in Group 1. For Group 1, there was a significant improvement in the Agitation Scale 30 minutes after the administration of the first dose and this continued during 120 minutes For Group 2 there was significant improvement in the Agitation Agitation Scale 20 minutes after the administration of the first dose and this continued for 120 minutes.

The results showed a significant change in the Acute Agitation Scale from the baseline to the end P = 0.001. The results of the PANSS scale showed that both treatments were equivalently effective in reducing agitation scores in the groups with lower severity of aggression.

Both groups were shown to reduce physical and verbal aggression (OAS), without differences between the groups. The evaluation of the severity of the CGI-S disease of the baseline until 24 hours after the administration of the first dose was similarly distributed between both groups. The proportions of patients with severity of the disease were averaged as marked to severe, decreasing at 24, 36, 48 and 72 hours after dose administration.

CONCLUSIONS As we can see, there was an improvement in the symptomatology in the two groups of patients, with the exception of the adverse events shown; It is of vital importance to point out to doctors that the increase in concentrations and dosages will eventually lead to adverse events such as: Extrapyramidal drugs and when administered concomitantly, medications can bring adverse effects such as: liver disorders in your case, or elevation of transaminases. Therefore, the importance of conducting research that leads us to develop drugs combined with the use of lower concentrations and lower doses administered to avoid or reduce the risk of adverse events.

Claims (5)

1. NOVELTY OF THE INVENTION
2. Having described the present invention, it is considered as a novelty and, therefore, the content of the following is claimed as property
3. CLAIMS 1. Pharmaceutical composition composed of the synergistic combination of a benzisoxazolic derivative and a benzodiazepine agent, characterized in that the benzisoxazole derivative is the active substance: Risperidone and the benzodiazepine agent is the active substance: Clonazepam, in addition to pharmaceutically acceptable excipients; wherein said active principles are present in the formulation in a concentration range of 1.0 mg. to 10.0 mg. for Risperidone and 0.5 mg. to 6.0 mg. for Clonazepam; which are formulated in a single dosage unit to be administered orally, which is indicated for the control and treatment of psychotic disorders and related diseases. 2. Pharmaceutical composition according to claim 1, characterized in that the benzisoxazole derivative agent, such as the active ingredient: Risperidone, is present in the formulation in a concentration range of 1.0 mg. to 10.0 mg., a concentration of 1.0 mg being preferably used in the formulation. to 2.0 mg., per dose unit. 3. Pharmaceutical composition according to claims 1 and 2, characterized in that the benzodiazepine agent, such as the active principle: Clonazepam, is present in the formulation in a concentration range of 0.5 mg. to 6.0 mg. , a concentration of 0.5 mg being preferably used in the formulation. to 2.0 mg. , per dose unit.
4. 4. Pharmaceutical composition according to claims 1 to 3, characterized in that it is formulated in a single dosage unit to be administered orally in the form of capsules or tablets.
5. 5. The use of the pharmaceutical composition according to claims 1 to 4, characterized in that it is indicated for the control and treatment of diseases such as: psychotic disorders and related pathologies.