WO2009008695A1 - Pharmaceutical composition comprising the combination of risperidone (benzisoxazolic agent) and clonazepam (benzodiazepinic agent) and use thereof in psychotic disorders and related pathologies - 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 THAT INCLUDES THE COMBINATION OF A BENZISOXAZOLIC DERIVATIVE AGENT AND A BENZODIAZEPINIC AGENT.

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 ingredient: Risperidone and a benzodiazepine agent, as is the active ingredient: 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 aforementioned active ingredients produces a greater synergistic effect when they are administered together in a single dose unit unlike when they are administered independently, generating benefits such as: lower concentrations of the formulated active ingredients, lower administered doses, faster of 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 that are characterized by the loss of contact with reality. The most known and studied psychotic disorder to date is schizophrenia, but it is clear that not all psychotic disorders are due or 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, other psychotic disorders are acute or sub-acute and usually present varying degrees in recovery of mental function.

Schizophrenia typically begins at a late stage of adolescence or at an early stage of 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 lack of control. It has been associated with hyperactivity of the dopaminergic system, - and 2) schizophrenia with negative or type 2 signs: lack of emotional reactions (the so-called affective flattening), detachment of the subject from its environment, anhedonia (inability to experience pleasure), lack of energy, psychomotor retardation, etc., but without hallucinations or serious delusions. Type 2 syndrome It tends to appear at an early age and insidiously.

Schizophrenia is a neurodegenerative disorder, since they have found in these patients smaller brain size, greater ventricular volume, anatomical alterations in the frontal and temporal lobes, particularly of the left cerebral hemisphere, as well as decreased markers to various neurotransmitters. Psychotic disorders, whether or not schizophrenia, are characterized by short or prolonged periods during which the patient suffers from hallucinations and delusions, thinking and behavior are disorganized. The notorious difference between schizophrenia and other psychosis unrelated to it, comes after these acute episodes; in the first, there is a progressive tendency to isolation, to disgust, to speak very little to not express emotions; on the other hand, in other psychoses that are not related to schizophrenia, the latter symptoms are not observed. The causes of schizophrenia and other psychosis are not known for sure, but genetic and environmental components are likely to be involved.

Psychotic disorders not only include schizophrenia in all its clinical forms, it also includes: affective psychosis, psychotic depressions, - schizoaffective psychosis; acute or chronic delusional psychosis, paranoia; paranoid reactions, - puerperal psychosis; epileptic psychosis; toxic psychoses (amphetamines, cocaine, alcohol); Gilíes de la Tourette syndrome, - Delirium tremens; decompensations in psychopaths; agitation-senile and atherosclerotic confusion; psycho-organic syndromes and dementias (Huntington's Korea). Treatment schedules include the use of a typical antipsychotic often associated with anticholinergic antiparkinsonians such as trihexyphenyl. Generally they must be associated with anxiolytic and hypnotic drugs, these can be benzodiazepine 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 antipsychotic profile acute, but not very sedative, for this reason concomitant anxiolytics are used such as chlorpromazine and levomepromazine (neuroleptics). However, being these dopaminergic blockers will add extrapyramidal effects.

The current and modern treatment scheme is the use of atypical antipsychotics such as Risperidone and concomitantly the use of anxiolytic and hypnotic drugs; however, their interactions can cause liver alterations, due to frequent and prolonged dose administration.

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 independently, which comply with an activity specific therapeutics; However, when these medications are administered concomitantly and at the doses that are usually used, interaction effects occur between the drugs that cause liver-level alterations with elevated transaminase levels, due to their high doses, the dose frequency and its long-term use.

SUMMARY OF THE INVENTION

For this reason and in order to eliminate all the inconveniences that arise when the active ingredients are administered independently, it is that the development of the pharmaceutical composition object of the present invention was carried out, which is composed of the combination synergistic of a benzisoxazole derivative agent 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 symptoms manifested by patients suffering from psychotic disorders, lower risks of interactions between drugs at the liver level and lower risks of effects Adverse

BRIEF DESCRIPTION OF THE FIGURES

Figure 1 shows the basal and final 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 (Syndrome Scale

Positive and Negative) after 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 (Scale of

Global Clinical Impression of the Severity of the

Disease) after the administration of the risperidone / clonazepam combination that was similarly distributed between two study groups.

DETAILED DESCRIPTION OF THE INVENTION

The benzisoxazole derivative agents are also referred to as new atypical antipsychotics or antipsychotics because their pharmacodynamic profiles differ from conventional antipsychotics. The antipsychotics of I ^to generation or classics act by blocking dopamine D2 receptors in the limbic and striatum 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 D2 receptors in the hypothalamic-pituitary axis a its action on prolactin.

Most of the new antipsychotics are distinguished by their low affinity for D2 receptors and their greater selectivity over other neuroreceptors for serotonin and norepinephrine, as well as for their modulating action on the functions mediated by the glutamate receptor The relationship between activity on D2 and 5HT2 receptors is typically low in new antipsychotics. Even so, to have antipsychotic activity you must have some degree of affinity for D2 receptors. The new antipsychotics are pharmacologically diverse and with different mechanisms of action in some cases.

There are two clearly differentiated groups of antipsychotics: - ATYPICS: They have antipsychotic action without producing extrapyramidal reactions (motor disorders), they also simultaneously block D2 dopaminergic receptors and 5HT2 serotonergic receptors and from these one can expect: a) minimal or no extrapyramidal effects, b) Action on the negative symptoms of schizophrenia (in addition to the positive ones), c) A significant degree of efficacy in typical antipsychotic refractory conditions. - TYPICAL: They have mainly two effects, extrapyramidal reactions and sedation.

All antipsychotic agents are equally effective in reducing symptoms. According to their Chemical structure has been grouped into families: phenothiazines, with thioxanthenes, dibenzodiazepines (such as clozapine) and dibenzoxazepines (such as loxapine) as related agents; butyrophenones (such as haloperidol), diphenylbutylpiperidines; indolones (such as molindone) and other agents called heterocyclics, and finally, rauwolfia alkaloids.

The main challenges in research on antipsychotics have been to define its 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 disease (affective dullness, apathy, anhedonia, isolation, attention deficit and praise), as well as increasing the therapeutic index with respect to extrapyramidal symptoms (SEP).

Antipsychotic effects appear slowly as the treatment progresses: agitation and restlessness decrease, communication with others and with the environment increases, impulsive or aggressive behaviors increase. disappearing; the same tendency is observed in the case of hallucinations, delusions and disorganization of thought. As can be seen, positive symptoms respond better to drug therapy than negative symptoms.

A wide variety of electrophysiological and neurochemical techniques have shown that antipsychotics are dopamine receptor blockers; 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 vomiting reflex, antipsychotics exert potent antiemetic actions (against vomiting); due to their effects on the endocrine system, these substances increase prolactin secretion, which can cause galactorrhea (secretion of milk by the mammary glands), gynecomastia (exaggeration of secondary sexual characteristics, such as breast growth), amenorrhea (interruption of menstrual cycles), aggravation of hormone-sensitive tumors (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 fat solubility, they easily cross all types of biological barriers (including the placental), 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 calming 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 inability to remain calm; dystonia, are involuntary muscle contractions that can manifest as gesticulation, grimaces, torticollis or exaggerated eye movements; Parkinsonia.no syndrome, these drugs frequently cause slowing of movements (bradykinesia), some muscle stiffness (hypertonia) that includes the muscles of the face producing an inexpressive face ("stick face") and tremor; tardive 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, limbs and the adoption of strange positions, with prolonged muscle contractures; neuroleptic malignant syndrome, this is a rare disorder with severe crises of parkinsonism, catatonia, tremor, changes in heart rate and blood pressure, increased body temperature; and seizures.

At the level of the peripheral nervous system, antipsychotics can cause constipation, dry mouth, nasal congestion, blurred vision, pupil dilation, photophobia (fear of light), tachycardia, urinary retention, increased body weight and blood disorders. Risperidone is an antipsychotic agent belonging to a new class of antipsychotics, benzisoxazole derivatives. It is a selective monoamine antagonist that has a high affinity for serotonergic 5-HT2 and dopamine D2 receptors; it also binds to alphai adrenergic receptors, and with less affinity, to Hl histaminergic and alpha ₂ 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 causes less depression of motor activity and induction of catalepsy than classical neuroleptics. The balanced central serotoninergic and dopaminergic antagonism reduces the lability of extrapyramidal side effects and extends the therapeutic activity towards the negative and affective symptoms of schizophrenia. Risperidone is completely absorbed after oral administration, reaching maximum plasma concentrations in 1 to 2 hours after being administered. Its absorption is not affected by the Meals, therefore, 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 9-hydroxy-risperidone metabolite 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 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. Risperidone plasma concentrations are proportional to the dose within the therapeutic dose range.

Risperidone is rapidly distributed. In plasma, it binds to albumin and acid glycoprotein alpha!. 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 urine and 14% in feces. In urine, Risperidone and its 9-hydroxy-risperidone metabolite 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 impairment. Risperidone plasma concentrations were normal in patients with hepatic impairment. Risperidone may alter liver 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 negative symptoms (such as affective flattening, emotional and social withdrawal, language poverty) are noticeable. Risperidone also relieves the affective symptoms (such as depression, guilt, anxiety) associated with schizophrenia. In addition, Risperidone is recommended in the long term for relapse prevention (acute exacerbations) in chronic schizophrenic patients. Likewise, Risperidone is also indicated for the treatment of notable behavioral disorders in patients with dementia in whom 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 the side effects of the symptoms of underlying diseases. Some side effects associated with the use of Risperidone are: insomnia, agitation, anxiety, headaches. Risperidone has a lower propensity to induce extrapyramidal symptoms unlike those caused by classical neuroleptics. However, in some cases the following extrapyramidal symptoms may occur: tremor, stiffness, 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, amnesic and miorrelaj effects (muscle relaxants).

BZD are more selective nervous system depressants than other drugs, such as barbiturates. They act, in particular, on the limbic, thalamic and hypothalamic system of the central nervous system causing a depression of its activity. BZDs share similar chemical structure and have great affinity with the benzodiazepine receptor complex found in the central nervous system. Structurally, the BZD have a benzene ring with six elements, attached 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 BZD exert their effect form part of the benzodiazepine-GABA receptor complex. D-aminobutyric acid (GABA) is a neurotransmitter with inhibitory action and its receptors are part of an inhibitory bidirectional system connected between various areas of the CNS. BZDs enhance the inhibitory action mediated by GABA. GABA acts on several subtypes of receptors called: GABA-A and GABA-B. GABA-A is the primary receptor subtype 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 BNZl, those 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) denominated BNZ3. The BNZl activation induces sleep, while drugs that bind to BNZ2 cause muscle relaxation, anticonvulsant activity and affect memory. The benzodiazepines bind nonspecifically to the BNZl and BNZ2 receptors, which enhances the effects of GABA.

Unlike barbiturates that increase GABA responses by keeping the chlorine channel (Cl-) open for longer, benzodiazepines increase the effects of GABA, which allows the chlorine channel to be opened in hyperpolarized cells and avoid further excitation of the same.

The BZD can be differentiated according to their time of action, being able to be: of short action (between 2 and 10 hours) and of long action (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 or has symptoms related to: liver diseases, alcoholism, brain diseases, poor salivation (in children), glaucoma, hyperactivity, kidney or lung diseases, myasthenia gravis , porphyrias, pregnancy or sleep apnea. Seizures, fever, tremor, muscle weakness, loss of reflexes, intense asthenia, involuntary movements, shortness of breath, dryness of mucous membranes (oral, conjunctival, nasal), erythematous skin, arterial hypotension, slow pulse, mild mental disorders may occur during treatment. or even confusion and coma. Benzodiazepines cause dependence so they should be used in short time treatments. When a treatment with benzodiazepines is discontinued, it takes approximately three weeks for the body to become uninhabited.

Clonazepam is a drug that belongs to the group of benzodiazepines (BZD) with depressing 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, amnesic and anticonvulsant; being useful in preanesthetic medication and, in larger doses, as inducers of general anesthesia and its maintenance. These benzodiazepine agents can also produce orexigenic effect (increased appetite), dysarthria (difficulty speaking) and ataxia (difficulty walking) with high dose administration. 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 the 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. In addition, four other metabolites have been identified, but to a lesser extent.

Clonazepam is absorbed quickly and completely in the gastrointestinal tract after oral administration. Maximum Clonazepam plasma concentrations are recorded in most cases after 1 to 4 hrs. after drug administration. 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).

The Clonazepam is of intermediate half-life, fluctuating between 30 and 40 hrs. Its degree of fixation to plasma proteins is 85%; It is metabolized in the liver and excreted by 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 and even weeks, with persistent effects. Within a period of 4 to 10 days, 50 to 70% of an oral dose of Clonazepam is eliminated in the urine and feces, 10 to 30%, almost exclusively in the form of free or conjugated metabolites. Less than 0.5% is recovered in the urine in the form of unchanged Clonazepam. The elimination half-life ranges from 20 to 60 hours (average: 30 hours). Because Clonazepam is metabolized in the liver, liver diseases may impair its elimination. Therefore, they should be Take precautions before administering Clonazepam to these patient groups.

It has been observed that 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 derivative 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. at 10.0 mg., a concentration of approximately 1.0 mg being preferably used. at 2.0 mg., per dose unit.

The benzodiazepine agent used in the pharmaceutical composition object of the present invention is the active ingredient: Clonazepam, which is present in the formulation in a concentration range of 0.5 mg. to 6.0 mg., a concentration of approximately 0.5 mg being preferably used. at 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 ingredients is contained: Risperidone and Clonazepam, as well as excipients. 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: lower concentrations of the active principles contained in the formulation , lower doses administered, greater rapidity of action, greater efficacy of the therapeutic effect, satisfactory control of 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 reason for the present In addition to the invention, as well as the synergistic effect of the active ingredients Risperidone and Clonazepam combined in a single dosage unit, a comparative clinical study was conducted in which the aforementioned active ingredients were administered separately, as well as the combination thereof.

COMPARATIVE CLINICAL STUDY OF THE RISPERIDONA / CLONAZEPAM COMBINATION.

This study compared the efficacy and safety of an oral treatment consisting of a combination of an atypical benzisoxazole derived antipsychotic agent, such as the active substance: Risperidone and a benzodiazepine agent, such as the active substance: Clonazepam, against the administration of Risperidone and Clonazepam independently and with 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 diagnosed with psychotic disorder (schizoaffective disorder, mania with psychotic findings, paranoid reaction, delusional disorder).

- Men or women. - Ages between 18 and 65 years.

- A score of> 14 on the PANSS scale (Positive and Negative Syndrome Scale).

A score of> 3 on the CGI-S scale (Global Clinical Printing 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 carried out with a physical and mental medical history, the PANSS scale was applied, which evaluates: excitability, hostility, non-cooperation, hallucinations and poor impulse control; each of them scored 7 points (1 = absent to 7 = extreme); PANSS also included the evaluation of: symptoms positive, negative symptoms, disorganized thoughts, uncontrollable excitability / hostility and anxiety / depression.

The improvement was evaluated with the CGI-S scale (range from 1 = No symptoms to 7 = 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 itself (rated 3 to 6) and physical aggression against others (rated 3 to 6). The aggression rating is the sum of all ratings 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 medications was evaluated.

Physical and neurological examinations 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 (Barnes Acatisia Scale) and the SAS scale (Simpson Scale - Angus) for patients with Parkinson's symptoms. Sedation was assessed 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.

Antiparkinsonian medications could be administered at effective doses if movement disorders or extrapyramidal effects were present during the study.

RESULTS

Eighty patients were included who met the inclusion criteria and were assigned to one of the two groups at random: 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 differences significant between groups in their baseline characteristics. The 80 patients completed the study (Table D.

Study patients experienced behavioral emergencies upon entering the study, which is reflected in the Agitation rating.

Acute (PANSS) of> 20; 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 patients on enrollment day.

Table 1. Basic characteristics of the 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)

Acute agitation rating PANSS 20 20

OAS rating

Aggression Rating 19 20

CGI-S Disease severity (n = 80)

Soft 1 1

Moderate 10 12

Dial 23 20

Severe 7 6

Functional liver tests S. A. S. A.

SA (without alteration). Twenty-three patients (57.5%) in Group 1 received medication to control extrapyramidal symptoms.

Sixty-eight patients completed the study, twelve of them (15%) discontinued treatment, 11 of the

Group I and I of Group 2, the reasons were the extrapyramidal effects in 10 patients of Group 1; as well as

1 patient for non-compliance with treatment; 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 disposition (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 P. F. H. 13 (32.5%)

Liver function tests performed on the last day of the study showed transaminases alteration in 13 patients in Group 1.

For Group 1 there was significant improvement in the Acute Agitation Scale 30 minutes after the administration of the first dose and this continued for 120 minutes.

For Group 2 there was significant improvement in the Acute 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 of the baseline at the end P = O.001.

The results of the PANSS scale showed that both treatments were equivalently effective in reducing agitation ratings in groups with and with less severe aggression.

Both groups were shown to reduce physical and verbal aggression (OAS), without differences between the groups. The evaluation of the severity of the baseline CGI-S disease up to 24 hours after the administration of the first dose was similarly distributed between both groups. The proportions of patients with severity of the disease was 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 symptoms in the two groups of patients, except for the adverse events shown; It is vitally important to note to the doctors that the increase in concentrations and dosages will eventually result in adverse events such as: extrapyramidal effects and when administered concomitantly, medications can cause adverse effects such as: liver abnormalities where appropriate, or elevation of transaminases.

Therefore, the importance of conducting research that leads us to develop medications combined with the use of lower concentrations and lower doses administered to avoid or reduce the risk of adverse events.

Claims

 NEW OF THE INVENTION Having described the present invention, it is considered as novelty and, therefore, what is contained in the following is claimed as property CLAIMS 1. Pharmaceutical composition composed of the synergistic combination of a benzisoxazole derived agent and a benzodiazepine agent, characterized in that the benzisoxazole derived agent is the active substance: Risperidone and the benzodiazepine agent is the active substance: Clonazepam, in addition to pharmaceutically acceptable excipients; wherein said active ingredients are present in the formulation in a concentration range of 1.0 mg. at 10.0 mg for Risperidone and 0.5 mg. at 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. at 10.0 mg , a concentration of 1.0 mg being preferably used in the formulation. at 2.0 mg., per dose unit. 3. Pharmaceutical composition according to claims 1 and 2, characterized in that the benzodiazepine agent, as is the active ingredient: Clonazepam, is present in the formulation in a concentration range of 0.5 mg. at 6.0 mg., a concentration of 0.5 mg is preferably used in the formulation. at 2.0 mg., per dose unit. 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. 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.