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WO2009011560A1 - Composition pharmaceutique combinant de la rispéridone et du donepezile, et utilisation de celle-ci dans le traitement de troubles psychotiques tels que la schizophrénie et la démence du type alzheimer - Google Patents

Composition pharmaceutique combinant de la rispéridone et du donepezile, et utilisation de celle-ci dans le traitement de troubles psychotiques tels que la schizophrénie et la démence du type alzheimer Download PDF

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Publication number
WO2009011560A1
WO2009011560A1 PCT/MX2008/000092 MX2008000092W WO2009011560A1 WO 2009011560 A1 WO2009011560 A1 WO 2009011560A1 MX 2008000092 W MX2008000092 W MX 2008000092W WO 2009011560 A1 WO2009011560 A1 WO 2009011560A1
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Prior art keywords
risperidone
donepezil
pharmaceutical composition
schizophrenia
alzheimer
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PCT/MX2008/000092
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English (en)
Spanish (es)
Inventor
Leopoldo de Jesús ESPINOSA ABDALA
María Elena GARCÍA ARMENTA
Josefina Santos Murillo
Victor Guillero ÁLVAREZ OCHOA
Original Assignee
Espinosa Abdala Leopoldo De Je
Garcia Armenta Maria Elena
Josefina Santos Murillo
Alvarez Ochoa Victor Guillero
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Application filed by Espinosa Abdala Leopoldo De Je, Garcia Armenta Maria Elena, Josefina Santos Murillo, Alvarez Ochoa Victor Guillero filed Critical Espinosa Abdala Leopoldo De Je
Priority to ARP080103048A priority Critical patent/AR069538A1/es
Publication of WO2009011560A1 publication Critical patent/WO2009011560A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia

Definitions

  • 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 reversible cholinesterase enzyme inhibitor, such as the active ingredient. : 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 ingredients produces a greater synergistic effect when they are administered together in a single dose unit unlike when they are administered in independently, generating benefits such as: lower concentrations of the active ingredients administered, faster action and lower side effects.
  • 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 for 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:
  • Schizophrenia begins frequently affecting adolescents 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, norepinephrine and various neuropeptides) may be involved, in addition to a dopamine hyperactivity.
  • other neurochemical systems (5-HT, glutamate, norepinephrine and various neuropeptides) may be involved, in addition to a dopamine hyperactivity.
  • Schizophrenia is a neurodegenerative disorder, since it has been found in these patients smaller brain size, greater volume ventricular, anatomical alterations in the frontal and temporal lobes, particularly of the left cerebral hemisphere, as well as decreased 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 0.5% per year, after age 65 and up to 8% per year, after age 85.
  • this disease did not happen to be a scientific curiosity. Over the years it has become a pathology not only very frequent, but of a tremendous impact on health, due to the inconvenience and suffering caused to the family and the economic cost involved. In the United States, the cost of this disease 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 the cost of medications that are usually expensive should be evaluated.
  • acetylcholine in the brains of these patients. They found a marked decrease in acetylcholine and gave name to what we know today 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, cingulate girus and other areas. This deficit has also been found in patients with Parkinson's, Lewy body dementia, vascular dementia and other dementias. The symptoms of any type of dementia, regardless of the cause, are due to this cholinergic deficit.
  • AD Alzheimer's disease
  • a ⁇ 42 amyloid peptide deposition is considered to be the fundamental, although not unique, factor in 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) by a successive process of acetylation, separating it in choline and acetate.
  • ACE acetylcholinesterase
  • IACE Alcoholylcholinesterase Inhibitors
  • Choline is first synthesized in the liver and is transported to other organs via blood Free choline is specifically captured in cholinergic nerve terminals, using a high-affinity pump, dependent on sodium. Choline is present in the extracellular space, as a result of the external hydrolysis of previously released acetylcholine.
  • Acetate is derived from glucose via pyruvate 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.
  • 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 Alzheimer's disease can go unnoticed. Initially, small and imperceptible memory losses arise, but over time, this deficiency becomes increasingly noticeable and disabling for the affected, which will have problems to carry out daily and simple activities, as well as others of an intellectual type, such as: speaking, understanding, reading or writing.
  • the patient has difficulties to carry out certain activities such as buying, following a program or planning, it is not only a loss of memory, but also of reasoning and understanding. In this stage, the deterioration progresses quite quickly and those affected can get lost in familiar places, they are also visibly apathetic and depressed; and 3.- Grave Stage: in the final stage of the disease of Alzheimer's all areas related to the patient's cognitive function are affected, he loses the ability to speak correctly or he repeats incoherent phrases over and over again, he cannot recognize his relatives and friends, they do not even recognize themselves before a mirror. The disorientation is constant. The most serious patients forget about walking and sitting and, in general, lose control over their organic functions. They stop being autonomous individuals and need to be fed and taken care of.
  • the cholinergic hypothesis proposes that the cognitive deficits of Alzheimer's disease are related to the decrease in central acetylcholinergic activity and that the increase in intrasynaptic acetylcholine will improve cognitive function, reducing behavioral disorders, as well as the caregiver's burden.
  • Cholinergic treatment approaches have included administration of the acetylcholine precursor and indirect cholinergic stimulation. Unfortunately, most of these cholinergic strategies have proved ineffective, sometimes effective but too toxic or not fully developed.
  • acetylcholinesterase inhibitors are involved in this process, by interacting with the enzyme and inactivating it.
  • the intensity and duration of the cholinesteratic action depend on the intensity with which they are fixed to the enzyme and on the speed with which this fixation spontaneously reverses.
  • Pharmacological actions derive from the inactivation of acetylcholine, in the places where it is released physiologically, both in the central nervous system and in peripheral, somatic or vegetative nerve endings.
  • Some of the effects on the central nervous system are: electroencephalogram desynchronization, generalized activation and increase of the waking situation. This effect is the one used for the treatment of Alzheimer's disease, where cholinergic activity is diminished by the loss of neurons of this type.
  • acetylcholinesterase inhibitors consist of an extension of the cholinergic effects in the different organs; they appear more frequently when rapidly increasing the doses of medications. Muscular fasciculations, paleness, sweating, myosis, salivation, bronchial constriction, vomiting, diarrhea and muscle weakness could be observed, to the point that it could be confused with a myasthenic crisis.
  • Figure 1 shows the results of the clinical study of the invention conducted with schizophrenic patients.
  • cholinergic system 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 brains of schizophrenic patients. A post-mortem correlation has been found between decreased levels of choline acetyltransferase 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 episodic memory deficits, a cognitive ability dependent on normal hippocampal function. However, a reduction in the volume and hippocampal function of these patients, both structural and imaging, has been identified. At the level of receptors, muscarinic receptors, important for hippocampal functions such as learning and memory, are reduced in the brains of schizophrenic patients. These changes may contribute to memory failure associated with schizophrenia.
  • the pharmaceutical composition object of the present invention is composed of the combination synergistic of a benzisoxazole derivative agent and a reversible cholinesterase enzyme inhibitor agent, which produce a satisfactory therapeutic effect when administered together in a single oral dosing 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, reduction of the symptomatology suffered by the patients and minor manifestations of adverse effects.
  • 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.
  • the new antipsychotics differ in their low affinity for D2 receptors and their greater selectivity over other neuroreceptors for serotonin and norepinephrine, as well as their modulating action of glutamate receptor mediated functions.
  • the relationship between activity on D2 and 5HT2 receptors is typically low in The 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.
  • ATYPICS They have antipsychotic action without producing extrapyramidal reactions (motor disorders), they also simultaneously block D2 dopaminergic receptors and 5HT2 serotonergic receptors and these can be expected: 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 mainly have 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 one third of the patients do not respond to the classic antipsychotics) and in the so-called negative symptoms of the disease (affective dullness, apathy, anhedonia, isolation, attention deficit and alogia), 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 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 drug therapy than negative symptoms.
  • 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 the blood flow, so richly irrigated organs, such as the brain, receive a large amount of the drug.
  • 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 requires several weeks or months to manifest.
  • akatisia is the most frequent; It can be defined as the inability to remain calm; dystonia, are involuntary muscle contractions that can manifest as gestures, grimaces, torticollis or exaggerated eye movements; Parkinsonian 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, of the extremities 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.
  • 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 atypical antipsychotic benzisoxazole derivative, selective monoaminergic antagonist. It has a high affinity for serotonergic 5-HT 2 and dopamine D 2 receptors; It also binds to alpha adrenergic receptors ! and with lower affinity to histamine H 1 receptors and Adrenergic alpha 2 , has no affinity for cholinergic receptors.
  • Risperidone is a potent D 2 antagonist, which improves 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 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 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. It is distributed quickly. In plasma, it binds to albumin and glycoprotein acid alphai. Its binding to plasma proteins is 88%, the metabolite 9-hydroxy-risperidone is 77%.
  • 70% of the dose is excreted in urine and 14% in feces.
  • Risperidone and its 9-hydroxy-risperidone metabolite represent between 35 and 45% of the total dose administered, the rest are inactive metabolites.
  • Risperidone plasma concentrations were normal in patients with hepatic impairment. Risperidone may alter liver transaminase values.
  • Cholinesterase inhibitors have the potential to interfere with the activity of anticholinergic drugs. Cholinergic neurons have been shown to decrease in critical areas of the brain of patients with Alzheimer's disease (EA). Although acetylcholine deficit plays a role in AD, it is increasingly recognized that this occurs within a complex medium of changes in the neurotransmitters of the brain of patients. By inhibiting the degradation of acetylcholine released by presynaptic cholinergic neurons, 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 can influence neuronal function and survival.
  • Tacrine was the first cholinesterase inhibitor drug that showed positive results in improved knowledge of patients with AD treated. Tacrine use is associated with hepatotoxicity and clinically significant drug interactions, and due to the availability of other inhibitory drugs with better side effect profiles and less Drug interactions, Tacrine is little used today.
  • the measurement of the results that demonstrate the benefits of cholinesterase inhibitor-based therapy includes: 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 medical specialist, activities of daily living, disability, quality of life and placement in specialized homes for your care and attention.
  • the magnitude of the response to cholinesterase inhibitor treatment is the stabilization or delay of disease progression that is equivalent to 6 months of cognitive decline.
  • 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 fissure.
  • 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.
  • cholinesterase inhibitors increase acetylcholine and may increase parasympathetic tone
  • these medications should be used with care in patients with bronchospasm, active peptic ulcer, bradycardia, or cardiac conduction disorders.
  • care should be taken if patients who consume them will be surgically operated with general anesthesia, since these medications can prolong the effects of neuromuscular blocking agents.
  • Donepezil is a selective cholinergic drug derived from piperidine, a reversible and non-competitive central inhibitor of acetylcholinesterase (enzyme responsible for the hydrolysis of acetylcholine), which It acts by preventing the degradation of acetylcholine, which translates into an increase in acetylcholine levels in various brain regions, thereby improving cholinergic neurotransmission, these levels being the ones that are diminished in Alzheimer's patients.
  • Donepezil is indicated for the treatment of patients who show 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 said disease.
  • Donepezil selectively inhibits acetylcholinesterase, the enzyme responsible for the destruction of acetylcholine, increasing the bioavailability of this substance.
  • Donepezil is fixed to the enzyme by an easily hydrolysable hydrogen bridge, so the duration of enzyme inhibition is short. Due to the long plasma half-life of Donepezil, its inhibitory effects are longer than those shown by other inhibitors.
  • Donepezil shows a much greater selectivity towards acetylcholinesterase (ACE) of the central nervous system (> 1000 times more potent) than towards butyrylcholinesterase (ECB), an enzyme that is 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 towards both enzymes.
  • ACE acetylcholinesterase
  • ERB butyrylcholinesterase
  • Donepezil The bioavailability of Donepezil is practically 100%, not being modified by food intake. After absorption, approximately 95% of Donepezil binds to human plasma proteins. The binding of the active metabolite 6-0- desmethyldonepezil to the plasma proteins Donepezil can persist in the body for more than 10 days.
  • Donepezil is metabolized at the liver level through the cytochrome P450 2D6 and 3A4 system (CYP2D6 and CYP3A4), resulting in active and inactive metabolites. Subsequently, both the non-metabolized drug and its metabolites will be eliminated mainly by urinary tract (57%) and to a lesser extent by feces (15%). There is no evidence to suggest an enterohepatic recirculation of Donepezil and / or any of its metabolites. May alter liver transaminase values.
  • Alzheimer's disease there is a rapid deterioration of cognitive function and the ability to maintain daily activities, together 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, so 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.
  • Donepezil is selective on the cholinergic system, and no significant effects on alpha and beta adrenergic receptors, serotonin, dopamine, histamine, muscarinic receptors or GABA receptors have been observed.
  • Risperidone and Donepezil can often be done concomitantly in these patients; however, there is the problem of interaction due to the activity of both at the level of cytochrome P450; however, the formulation described through 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 of dose administered, lower risks of drug interaction and lower risks of adverse events.
  • the benzisoxazole derivative 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 , preferably a concentration of approximately 1.0 mg being used. at 3.0 mg., per unit dose.
  • the reversible cholinesterase inhibitor used in the pharmaceutical composition object of the present invention is the active ingredient: Donepezil, which is present in the formulation in a concentration range of 1.0 mg. at 10.0 mg., a concentration of 1.0 mg is preferably used. at 5.0 mg., per unit dose.
  • 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 principles is contained.
  • active Risperidone and Donepezil, as well as pharmaceutically acceptable excipients.
  • 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 dementia or Alzheimer's type; which offers significant advantages such as: lower concentrations of the active ingredients contained in the formulation, effective control of the symptoms suffered by patients with psychotic disorders and dementias such as schizophrenia, vascular or Alzheimer's dementia, lower doses administered, lower risk of drug interaction at the liver level and lower risk of adverse events.
  • a double-blind, prospective clinical study was conducted in a population of schizophrenic patients. Patients filled the diagnostic criteria according to the DSM-IV. As inclusion criteria, it was requested that the patients be under medication control with Risperidone for at least 4 weeks prior to the study and that they do 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 participation was performed 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.
  • CVLT California Verbal Learning Test
  • ESRS 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 some possible interaction during treatment.
  • the data makes us think that the combination acts synergistically at different levels, improving the conditions of the patients.

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Abstract

L'invention concerne une composition pharmaceutique composée par la combinaison synergique d'un agent dérivé de benzisoxazolique, tel que l'est le principe actif: la rispéridone et un agent inhibiteur réversible de cholinestérase, tel que l'est le principe actif: le donepezile, - lesquels se rencontrent formulés en une seule unité de dosage pour être administrés par voie orale sous forme de capsule ou de tablette; de même que pour réguler et traiter des maladies telles que: les troubles psychotiques, notamment la schizophrénie, la démence vasculaire, la démence du type Alzheimer et d'autres maladies associées.
PCT/MX2008/000092 2007-07-16 2008-07-16 Composition pharmaceutique combinant de la rispéridone et du donepezile, et utilisation de celle-ci dans le traitement de troubles psychotiques tels que la schizophrénie et la démence du type alzheimer WO2009011560A1 (fr)

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ARP080103048A AR069538A1 (es) 2007-07-16 2008-07-16 Composicion farmaceutica que comprende la combinacion de un agente derivado benzisoxazolico y un agente inhibidor reversible de la enzima colinesterasa, indicada para el control y tratamiento de trastornos psicoticos y demencias

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MXMX/A/2007/008642 2007-07-16
MX2007008642A MX2007008642A (es) 2007-07-16 2007-07-16 Composicion farmaceutica que comprende la combinacion de un agente derivado benzisoxazolico y un agente inhibidor reversible de la enzima colinesterasa, indicada para el control y tratamiento de trastornos psicoticos y demencias.

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000023057A2 (fr) * 1998-10-16 2000-04-27 Janssen Pharmaceutica N.V. Therapie visant a ameliorer la cognition
WO2005065645A2 (fr) * 2003-12-31 2005-07-21 Actavis Group Hf Formulations de donepezil

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000023057A2 (fr) * 1998-10-16 2000-04-27 Janssen Pharmaceutica N.V. Therapie visant a ameliorer la cognition
WO2005065645A2 (fr) * 2003-12-31 2005-07-21 Actavis Group Hf Formulations de donepezil

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
FORMIGA F. ET AL.: "Risperidona and acontecimientos adversos cerebrovasculares in los pacientes ancianos con demencia", REVISTA CLINICA SPANISH, vol. 206, no. 8, 2006, pages 411 - 412 *
HSING-CHEN L. ET AL.: "Extrapyramidal side-effect due to drug combination of risperidone and donepezil", PSYCHIATRY AND CLINICAL NEUROSCIENCES, vol. 56, 2002, pages 479 *
MAGNUSON T.M. ET AL.: "Extrapyramidal side effects in a patient treated with risperiodone plus donepezil", THE AMERICAN JOURNAL OF PSYCHIATRY, vol. 155, 1998, pages 1458 - 1459 *
REYES J.F. ET AL.: "Concurrent administration of donepezil HCl and risperidone in patients with schizophrenia: assessment of pharmacokinetic changes and safety following multiple oral doses", BRITISH JOURNAL OF CLINICAL PHARMACOLOGY, vol. 58, no. SUPPL. 1, 2004, pages 50 - 57 *

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