MX2007008642A - Pharmaceutical composition comprising the combination of a benzisoxazolic derived agent and a reversible inhibiting agent of the cholinesterase enzyme prescribed for the control and treatment of psychotic disorders and dementias. - Google Patents

Abstract

The invention relates to a pharmaceutical composition comprising a synergic combination of a benzisoxazolic agent such as the active principle: Risperidone and a cholinesterase reversible inhibiting agent, such as the active principle: Donepezil, 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, such as schizophrenia, vascular dementia, Alzheimer type dementia and related pathologies.

Description

PHARMACEUTICAL COMPOSITION COMPRISING THE COMBINATION OF A BENZISOXAZOLIC DERIVATIVE AGENT AND A REVERSIBLE INHIBITOR AGENT OF THE COLINESTERASE ENZYME, INDICATED FOR THE CONTROL AND TREATMENT OF PSYCHOTIC DISORDERS AND DEMENTIA.

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 principle: Risperidone and a reversible inhibitor of the cholinesterase enzyme, as is the active principle : Donepezil, which are formulated in a single dosage unit, which is indicated for the control and treatment of psychotic states and dementias, such as schizophrenia and Alzheimer's. The combination of the aforementioned active principles 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 active principles administered, higher speed of action and fewer side effects.

BACKGROUND OF THE INVENTION Schizophrenia is a particular type of psychosis that is characterized by profound alterations in thinking, perception, language, behavior and affectivity. It is diagnosed as such when two or more of the positive or negative symptoms characteristic of schizophrenia occur during a certain period of time. Positive symptoms are caused by an exaggeration or distortion of the functions normally present. Negative symptoms represent a decrease or loss of functions: Positive symptom Distorted function - Hallucinations Perception. - Delusions Thought. - Speech disorganized Language. - Extravagant behavior Behavior control.

Negative symptom Lost function. - Affective dullness Flow of emotional expression. - Alogia Fluency of speech. - Avición Volición.

Anhedonia Capacity hedon In some cases the patient shows signs of agitation and aggression. Schizophrenia begins affecting teenagers frequently and is chronic and disabling. This disease has a high genetic component and probably reflects a complex biochemical abnormality in which other neurochemical systems (5-HT, glutamate, noradrenaline and various neuropeptides) may be involved in addition to a dopaminergic hyperactivity.

Schizophrenia is a neurodegenerative disorder, since it has 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 the decrease of markers to various neurotransmitters.

Alzheimer's disease is characterized by a progressive loss of memory and cognitive functions, which affects 15 million people around the world. The incidence increases by 0.5% per year, after 65 years and up to 8% per year, after 85 years. At the beginning, this disease was no more than a scientific curiosity. Over the years it has become a pathology not only very frequent, but also a tremendous impact on health, due to the inconveniences and suffering that it causes the family and the economic cost that it entails. In the United States, the cost of this pathology is estimated at 75 billion dollars per year, with a very stressful burden for family members and caregivers. For this reason, the cost of the disease and that of drugs that are usually expensive should be evaluated. Memory, learning and behavior so altered in Alzheimer's disease, make up a succession of differentiated mechanisms, where each one can depend on different psychobiological and neurochemical processes. For this reason, the treatment should be focused on the neurobiochemical components of the brain. Seventy years after the description of Alzheimer's, in London, Davis and Maloney discovered the lack of a neurotransmitter: acetylcholine, in the brains of these patients. They found a marked decrease in acetylcholine and gave a name to what we now know as the "hypocholinergic hypothesis" of Alzheimer's disease. It has been seen especially in specific areas: the hippocampus, frontal cortex, parietal, temporal and even earlier in the entorhinal cortex, the cingulate girus and other areas. This deficit has also been found in patients with Parkinson's, dementia due to Lewy bodies, vascular dementia and other dementias. The symptoms of any type of dementia regardless of the cause, are due to this cholinergic deficit. This produces a failure in acetylcholinergic neurotransmission and degeneration of neuronal circuits. Alzheimer's disease (AD) is a brain degenerative process that causes the deposit of intracellular and extracellular insoluble protein substances. It is considered that the deposition of amyloid peptide aP42 is the fundamental factor, although not unique, for the development of the disease. This deposit is due to an increase in the production of this substance in hereditary cases, while in sporadic cases, the increase is probably related to a decrease in its clearance. Acetylcholine remains active until it is rapidly hydrolyzed (80 to 150 microseconds) by the enzyme acetylcholinesterase (ACE) through a successive process of acetylation, separating it into choline and acetate. By inhibiting ACE and, thereby, the hydrolysis of acetylcholine, ACEIs (Acetylcholinesterase Inhibitors) effectively increase the amount of acetylcholine available in the synaptic cleft, thus facilitating neurotransmission in nicotinic and / or muscarinic receptors, which it leads to an improvement in cognition.

Choline is synthesized first in the liver and is transported to other organs by blood. Free choline is specifically captured in the cholinergic nerve terminals, by means of a high-affinity, sodium-dependent pump. Choline is present in the extracellular space, as a result of the external hydrolysis of previously released acetylcholine. Acetate is derived from glucose via the pyruvate route and the mitochondrial pyruvate dehydrogenase complex, which generates acetyl-CoA. Acetylcholine transferase is a globular protein found in the brain. The regulation of its synthesis is due to the fact that the high affinity choline pump is inhibited by an excess of acetylcholine. This reaction takes place, for the most part, in the nerve terminals, rather than in other neuronal regions. The enzyme acetylcholine transferase is synthesized in the body of the neuron and is transported by axoplasmic flow to the terminals, where it is activated. The first psychic symptoms of the disease Alzheimer's can go unnoticed. Initially, small and imperceptible memory losses arise, but with the passage of time, this deficiency becomes increasingly noticeable and incapacitating for the affected, which will have problems to perform daily activities and simple, as well as other intellectual, such as: speaking, understanding, reading or writing. Basically, there are 3 stages that manifest themselves in individuals ering from Alzheimer's disease: 1.-Mild Stage: the damage of the disease still goes unnoticed, both for the patient and for the family members. The patient forgets small things or details. At this stage you can still perform activities such as working or driving a car, although you may begin to experience lack of spontaneity, initiative and certain depressive features; 2.- Moderate Stage: the disease is already evident for family and friends. The patient has difficulties in carrying out certain activities such as buying, following a program or planning, it is no longer just a memory loss, but also a capacity for reasoning and understanding. At this stage, the deterioration progresses fairly quickly and those affected may get lost in familiar places, in addition they are visibly apathetic and depressed; and 3.- Grave Stage: in the final stage of Alzheimer's disease all areas related to the cognitive function of the patient are affected, lose the ability to speak correctly or repeat incoherent sentences over and over again, can not recognize their family and friends, they do not even recognize themselves in a mirror. The disorientation is constant. Serious patients forget to walk and sit and, in general, they lose control over their organic functions. They stop being autonomous individuals and they need to be fed and cared for. The cholinergic hypothesis proposes that the cognitive deficits of Alzheimer's disease are related to the decrease in central acetylcholine activity and that the increase in intrasynaptic acetylcholine will improve cognitive function, decreasing behavioral disorders, as well as the burden of the caregiver. Approaches to cholinergic therapy have included administration of the acetylcholine precursor and indirect cholinergic stimulation. Unfortunately, most of these cholinergic strategies have been ineffective, sometimes effective but too toxic or not fully developed. By definition, acetylcholinesterase inhibitors intervene in this process, by interacting with the enzyme and inactivating it. The intensity and duration of the cholinesterase action depend on the intensity with which they are fixed to the enzyme and the rapidity with which this fixation spontaneously reverts. The pharmacological actions derive from the inactivation of acetylcholine, in the places where it is released physiologically, both in the central nervous system and in the peripheral, somatic or vegetative nerve endings. So that it can produce adverse effects, due to different mechanisms: a) stimulation of the muscarinic receptors of the vegetative effector organs; b) stimulation followed by depression or paralysis of all the vegetative ganglia and the skeletal muscles by nicotinic action; c) stimulation with occasional posterior depression of central cholinergic receptors. Some of the effects on the central nervous system are: desynchronization of the electroencephalogram, generalized activation and increased wakefulness. This effect is used for the treatment of Alzheimer's disease, where cholinergic activity is diminished by the loss of neurons of this type. The most frequent adverse effects with the use of acetylcholinesterase inhibitors consist in an extension of the cholinergic effects in the different organs; they appear more frequently as the doses of the medicines increase rapidly. Muscle fasciculations, pallor, sweating, miosis, salivation, bronchial constriction, vomiting, diarrhea and muscle weakness could be observed, to the point that it could be confused with a myasthenic crisis.

Affectation of the frontal and temporal lobes, typical in this pathology, explains the behavior disorders and the emotional changes. The underlying cause of these alterations is a cholinergic deficit in the limbic or paralimbic area, which is why they respond to substances that improve this neurotransmitter. This is the reason why drugs that will positively modify these behavior disorders will be highly appreciated. Of course, antipsychotics, known as dopamine inhibitors, reduce aggression, agitation and psychosis; However, they will not cure the disease, but they will positively influence the clinic of the pathology: in the cognitive field, the behavior and activities of daily life.

SUMMARY OF THE INVENTION In order to offer a pharmacological alternative that achieves a better quality of life in patients suffering from diseases such as: psychotic disorders of the type of schizophrenia and dementias such as Alzheimer's and vascular, the development of the pharmaceutical composition was carried out as follows It is described.

BRIEF DESCRIPTION OF THE FIGURES Figure 1 shows the results of the clinical study of the invention carried out with schizophrenic patients.

DETAILED DESCRIPTION OF THE INVENTION Patients with psychoses such as schizophrenics and those with vascular or Alzheimer's dementias poorly perform a cognitive domain. The introduction of atypical antipsychotic drugs represented an advance in the treatment of psychotic states and especially of schizophrenia producing effects on cognitive functioning compared with typical antipsychotics. While dopamine has been linked as the main neurotransmitter involved in the pathogenesis of the symptoms of schizophrenia, there is a significant number of studies implicating cholinergic neurons in schizophrenic activity. Although the obvious pathology of the cholinergic system is seen in Alzheimer's disease (decreased cell density in Maynert's basal nuclei), it is absent in the patients' brains. schizophrenics. A post-mortem correlation has been found between the decrease in choline acetyltransferase levels in the brain and the severity of cognitive failure before death. Hence, changes in cholinergic function may contribute to the cognitive failure associated with schizophrenia. Patients with schizophrenia have a deficit in episodic memory, a cognitive ability dependent on normal hippocampal function. Nevertheless, a reduction in the volume and hippocampal function of these patients has been identified, both structurally and as an image. At the receptor level, muscarinic receptors, important for hippocampal functions such as learning and memory, are reduced in the brains of schizophrenic patients. These changes may contribute to the memory failure associated with schizophrenia. Currently, most of the drugs found on the market for the control and treatment of psychotic disorders such as schizophrenia and Alzheimer's and vascular dementias are composed of by active ingredients that are formulated independently, which comply with a specific therapeutic activity; however, these medications when administered in combination produce an effect significant synergy, reducing the symptomatology of patients, reducing the concentrations of the active principles present in the formulation, reducing the number of doses administered per day, reducing the manifestation of adverse events and reducing the risk of interactions that cause harm to liver level. For this reason and in order to eliminate all the disadvantages that arise when the active ingredients are administered independently, it 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 reversible inhibitor of the cholinesterase enzyme, which produce a satisfactory therapeutic effect when administered together in a single oral dosage unit, unlike when they are administered independently, generating benefits as they are: lower concentrations of the active principles formulated, lower doses administered, greater speed of action, greater efficacy of the therapeutic effect, reduction of the symptomatology suffered by the patients and lesser manifestations of adverse effects. The benzisoxazolicos derivative agents also receive the denomination of new antipsychotics or antipsychotics atypical 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 antipsychotics clearly differentiated: - ATYPICS: They have antipsychotic action without producing extrapyramidal reactions (motor disorders), in addition They simultaneously block the D2 dopaminergic receptors and the 5HT2 serotonergic receptors, and of these we can expect: a) minimal or no extrapyramidal effects, b) action on the negative symptoms of schizophrenia (in addition to positive ones), c) a significant degree of efficacy in refractory pictures to typical antipsychotics. TYPICAL: They have mainly two effects, extrapyramidal reactions and sedation. The main challenges in research on antipsychotics have been to define their mechanism of action, increase efficacy in patients with resistant schizophrenia (about a third of patients do not respond to classical antipsychotics) and in the so-called negative symptoms of antipsychotics. 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 1 disorganization of thought. As you can appreciate, positive symptoms respond better to pharmacological therapy than negative symptoms. 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 eye movements 7 exaggerated 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 cause constipation, dry mouth, nasal congestion, blurred vision, pupillary dilation, photophobia (fear of light), tachycardia, urinary retention, increased body weight and blood disorders. Risperidone is an atypical antipsychotic benzisoxazole derivative, selective monoaminergic antagonist. It has a high affinity for serotonergic receptors 5-HT2 and dopaminergic D2; binds also to alpha-adrenergic receptors and with lower affinity to the histamine Hx and alpha2 adrenergic receptors, has no affinity for cholinergic receptors. Although Risperidone is a potent D2 antagonist, which improves 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. It 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 about 3 hours The elimination half-life of the metabolite 9-hydroxy-risperidone and of the active antipsychotic fraction is 24 hours. It is distributed quickly. In plasma, it binds to albumin and alphai acid glycoprotein. Its binding 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 represent between 35 and 45% of the total dose administered, the rest are inactive metabolites. Plasma concentrations of Risperidone were normal in patients with hepatic impairment. Risperidone can alter hepatic transaminase values. Cholinesterase inhibiting agents have the potential to interfere with the activity of anticholinergic drugs. It has been shown that cholinergic neurons decrease in critical areas of the brain of patients with Alzheimer's disease (AD). Although acetylcholine deficiency plays a role in AD, it is increasingly recognized that this occurs within a complex medium of changes in the neurotransmitters in the brain of patients. By inhibiting the degradation of acetylcholine released by cholinergic neurons When presynaptic, cholinesterase inhibitors increase the amount of acetylcholine available for neurotransmission. Recent evidence indicates that long-term treatment with cholinesterase inhibitors not only improves knowledge and behavior, but may also influence neuronal function and survival.

There are 4 cholinesterase inhibitor drugs approved for the treatment of AD: Tacrine, Donepezil, Rivastigmine and Galantamine. Tacrine was the first cholinesterase inhibitor drug that showed positive results in the improved knowledge of patients with EA treated. The use of tacrine is associated with hepatotoxicity and with clinically significant drug interactions, and due to the availability of other inhibitory drugs with better side effect profiles and fewer drug interactions, tacrine is rarely used today. The measurement of the results demonstrating the benefits of cholinesterase inhibitor therapy comprises: knowledge (measured according to the cognitive subscale of the Alzheimer's Disease Assessment Scale and the Minimum Mental State Examination), impression of changes based in the interview with the specialist doctor, activities of daily life, disability, quality of life and placement in specialized homes for their care and attention. The magnitude of the response to treatment with cholinesterase inhibitors is the stabilization or retardation of the progression of the disease that is equivalent to 6 months of cognitive decline. Although most studies are short-term, there are several studies that show the durability of the response for 1 or 2 years. It has been revealed that Donepezil is effective in moderate to severe AD, improving neuropsychiatric symptoms. Donepezil, Rivastigmine and Galantamine have the same mechanism of action that inhibits cholinesterase to allow more acetylcholine in the synaptic cleft. Likewise, these three drugs share common cholinergic side effects, among which are: nausea, vomiting, diarrhea, anorexia and abdominal pain; however, patients tend to develop tolerance to these gastrointestinal symptoms. Because cholinesterase inhibitors increase acetylcholine and may increase parasympathetic tone, these medications should be used with caution in patients with bronchospasm, active peptic ulcer, bradycardia, or cardiac conduction disorders. In addition, care must be taken if the patients who consume them are going to be Surgical interventions under general anesthesia, since these medications can prolong the effects of neuromuscular blocking agents. Donepezil is a selective cholinergic drug piperidinic derivative, reversible and non-competitive central inhibitor of acetylcholinesterase (enzyme responsible for the hydrolysis of acetylcholine), which acts to prevent the degradation of acetylcholine, which results in an increase in the levels of acetylcholine in various brain regions, thereby improving cholinergic neurotransmission, these levels being decreased in patients with Alzheimer's disease. Donepezil is indicated for the treatment of patients who manifest mild to moderate symptoms of Alzheimer's disease, producing a significant improvement in cognitive function and performance, as well as memory in 80% of patients suffering from this disease. Donepezil selectively inhibits acetylcholinesterase, the enzyme responsible for the destruction of acetylcholine, increasing the bioavailability of this substance. Donepezil binds to the enzyme by means of an easily hydrolysable hydrogen bond, so that the duration of enzymatic inhibition is short. Due to the long half-life plasma levels of Donepezil, its inhibitory effects are longer than those shown by other inhibitors. In addition, Donepezil shows a much higher selectivity to acetylcholinesterase (ACE) of the central nervous system (> 1000 times more potent) than to butyrylcholinesterase (BCE), an enzyme found mainly in the periphery or outside the CNS; unlike organophosphates, acridines, carbamates, physostigmine and anticholinergics derived from quaternary ammonium, which show the same affinity for both enzymes. Maximum plasma concentrations are reached approximately 3 to 4 hours after oral administration. The elimination half-life is approximately 70 hrs., Therefore, the administration of multiple daily single doses results in a gradual approach to the stable state. The approach to steady state is reached within 3 weeks after the start of treatment. The bioavailability of Donepezil is practically 100%, and is not modified by the intake of food. After its absorption, approximately 95% of Donepezil binds to human plasma proteins. The binding of the active metabolite 6-0-demethyldonepezil to plasma proteins is not known. He Donepezil may persist in the body for more than 10 days. Donepezil is metabolized in the liver through the cytochrome P450 system 2D6 and 3A4 (CYP2D6 and CYP3A4), resulting in active and inactive metabolites. Subsequently, both the drug without metabolism and its metabolites are going to be eliminated mainly by urinary route (57%) and in a smaller proportion by faeces (15%). There is no evidence to suggest an enterohepatic recirculation of Donepezil and / or any of its metabolites. It can alter the values of hepatic transaminases. In Alzheimer's disease there is a rapid deterioration of cognitive function and ability to maintain daily activities, along with a significant loss of neurons, mainly manifested at the level of cholinergic structures. This "cholinergic hypothesis" of Alzheimer's disease proposes that an important part of the cognitive loss associated with this disease is related to the deficit of cholinergic neurotransmission, which is why increasing the efficacy of cholinergic neurotransmission could improve the cognitive situation of these patients. Donepezil reversibly inhibits the activity of the enzyme acetylcholinesterase, an enzyme responsible for the rapid degradation of acetylcholine at the synaptic level. When degradation is inhibited of acetylcholine, this neurotransmitter will remain longer at the level of the synaptic cleft and cholinergic neurotransmission may be improved to some extent. The action of Donepezil is selective on the cholinergic system, and no significant effects have been observed on the alpha and beta adrenergic receptors, serotonin, dopamine, histamine, muscarinic receptors or receptors for GABA. The use of Risperidone and Donepezil can often be done concomitantly in these patients; however, there is an interaction problem due to the activity of both at the cytochrome P450 level; however, the formulation described by the present invention includes both active ingredients in a single dosage unit, but with a lower concentration of the active ingredients, thereby producing a satisfactory synergistic effect, an optimal therapeutic effect, a reduction in administered doses, lower risks of drug interaction and lower risks of adverse events. The benzisoxazole derivative used in the pharmaceutical composition object of the present invention is the active principle: Risperidone, which is present in the formulation in a concentration range of 1.0 mg. to 10.0 mg., preferably one being used concentration of approximately 1.0 mg. to 3.0 mg., per unit dose. The reversible cholinesterase inhibitory agent used in the pharmaceutical composition object of the present invention is the active substance: Donepezil, which 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. to 5.0 mg., per unit dose. 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: Risperidone and Donepezil, 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 states and dementias, such as schizophrenia and vascular or Alzheimer type dementia; which offers significant advantages such as: lower concentrations of the active ingredients contained in the formulation, effective control of symptoms suffered by patients with psychotic disorders and dementias such as schizophrenia, vascular dementia or Alzheimer's type, lower doses administered, lower risk of drug interaction at the liver level and lower risk of adverse events. To evaluate the efficacy and tolerance of the pharmaceutical composition of the present invention, as well as the synergistic effect of the active ingredients Risperidone and Donepezil 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 STUDY BETWEEN RISPERIDONA, DONEPEZILO AND THE COMBINATION RISPERIDONA / DONEPEZILO IN PATIENTS WITH SCHIZOPHRENIA. A double-blind, prospective clinical study was carried out in a population of schizophrenic patients. The patients filled the diagnostic criteria according to the DSM-IV. As inclusion criteria, it was requested that the patients were under drug control with Risperidone for at least 4 weeks prior to the study and that they did not present changes in their symptoms in more than 20%, according to the scale of positive and negative symptoms. The minimum level of cognitive failure required for the participation was made with the California Verbal Learning Test (CVLT). This test was chosen because it is consistent with the average level of secondary memory failure observed in schizophrenic patients. Materials and methods. To evaluate the severity of psychiatric symptoms, we used the PA SS scale and the ESRS scale, which is the average scale of extrapyramidal symptoms. The cognitive evaluation included assessments of attention, memory and executive function. Patients also underwent liver function tests to observe any possible interaction during treatment. The patients were divided into 2 treatment groups: - Group 1 received Risperidone 1 mg. / Placebo. - Group 2 received the combination Risperidone 1 mg. / Donepezil 5 mg. A follow-up of 3 months of treatment was carried out. Results Thirty patients diagnosed with schizophrenia were included in the study, which were randomized to any of the treatment groups. The baseline data were not significantly different in both groups.

Table 1. Baseline demographic and cognitive data of the subjects. Group 1 Group 2 (n = 15) (n = 15) Age 49.7 51.2 Duration of illness (years) 27.3 28.1 PANSS positive scale 16.9 16.7 PANSS negative scale 20.3 20.6 CVLT total learning 16.5 18.1 PANSS: Scale of Positive and Negative Symptoms. CVLT: California Verbal Learning Test.

The data showed better learning.

Table 2. Liver functional test data. BASAL 3 MONTHS Group 1 ALT 0 - 37 U / L 0 - 37 U / L AST 0 - 41 U / L 0 - 41 U / L GGT 1 1 - 50 U / L 11 - 50 U / L Group 2 ALT 0 - 37 U / L 0 - 37 U / L AST 0 - 41 U / L 0 - 41 U / L GGT 11 - 50 U / L 1 1 - 50 U / L The liver function tests showed no alteration in both groups. Conclusions The combination of Risperidone / Donepezil improves the alteration of cognitive function manifested in patients with schizophrenia, compared to the administration of Risperidone with Placebo. There were no alterations in the liver that could have suspended the study treatment.

The data make us think that the combination acts synergistically at different levels, improving patient conditions.

Claims (5)

NOVELTY OF THE INVENTION Having described the present invention, it is considered as a novelty and, therefore, the content of the following is claimed as property CLAIMS

1. Pharmaceutical composition composed of the synergistic combination of a benzisoxazolic derivative and a reversible inhibitor of cholinesterase characterized in that the benzisoxazole derivative is the active substance: Risperidone and the reversible inhibitor of cholinesterase is the active substance: Donepezil; as well as 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 1.0 mg. to 10.0 mg. for Donepezil; which are formulated in a single dosage unit to be administered orally, which is indicated for the control and treatment of psychotic disorders and dementias, such as: schizophrenia, dementia vascular or Alzheimer's type and other related diseases.

2. Pharmaceutical composition according to claim 1, characterized in that the benzisoxazole derivative agent, such as the active principle: 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 3.0 mg. per unit dose.

3. Pharmaceutical composition according to claim 1 and 2 characterized in that the reversible inhibitor of cholinesterase, such as the active substance: Donepezil 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 5.0 mg. per unit dose.

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 a capsule or tablet.

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, such as schizophrenia and dementias of vascular or Alzheimer type, in addition to other related diseases.