MXPA05013580A - Asenapine for the treatment of schizophrenia in a patient with overweight or predisposition for overweight - Google Patents

Abstract

The invention provides means for the treatment of schizophrenia with an antipsychotic agent administered to a patient with overweight, or to a patient that was having weight gain due to an antipsychotic agent, or to a patient that needs to be protected against weight increase due to the presence of risk factors for a disease for which overweight is also a risk factor or due to the presence of other weight increasing factors by using asenapine for the manufacture of a medicine for such treatment.

Description

ASENAPINE FOR THE TREATMENT OF SCHIZOPHRENIA IN AN OVERWEIGHT PATIENT OR PREDISPOSITION TO OVERWEIGHT Field of the Invention The present invention relates to a method for the treatment of schizophrenia with an antipsychotic agent administered to the overweight patient. Background of the Invention The average human population is afflicted with a lifetime occurrence of schizophrenia at an index of about 0.5% to 1% (Goldber et al., Canadian J. of Psychiatry Vol 47; pages 833 to 843; 2002 ). Illness, if not treated, is completely weakening the economic and social functioning of the afflicted person. Fortunately, considerable progress has been made during the last 45 years in the treatment of the disease, resulting in benefits in some social behavior for many patients. It is the use of effective anti-psychotic drugs that has produced this dramatic improvement in the outcome of the treatment. With classic antipsychotic agents, such as chlorpromazine, haloperidol, spiperone, etc., the importance of dopamine receptor blockade as the mechanism of action of antipsychotic effects has been demonstrated. However, these drugs have disadvantages, where the challenge to be overcome has been by new agents. These side effects, which we collectively refer to as extrapyramidal side effects (EPS), are a behavior similar to that of Parkinson's disease, akathisia, dystonia and serious and sometimes irreversible disturbances of the control of muscles known as dyskinesia. late (TD). Clozapine is the oldest drug that showed that antipsychotic effects could be obtained, without the frequent induction of side effects mentioned above. This led to the class of atypical antipsychotic agents, which are those that are effective as the first generation of antipsychotic drugs, but less likely to induce extrapyramidal side effects and that have a broader therapeutic efficacy. The latter refers to efficacy against the negative symptoms of schizophrenia. The atypical antipsychotic drugs can be further subdivided into three categories based on the receptor binding profiles and the following side effects. These categories are (a) relatively pure dopamine antagonists (D2 antagonists, including sulpiride and aminosulpiride), (b) dopamine (D2) antagonists-serotonin (5-HT2) -norepinephrine (alpha 1) (risperidone, ziprazidone and sertindole) and (c) multiple receptor antagonists (clozapine, olanzapine, and seroquel) (See publications by Gerlach and Peacock, in International Clinical Psychopharmacology 10 Suppl 3: pages 39-48, 1995; Tamminga and Lahti, in International Clinical Psychopharmacology 11 Suppl 2: pages 73 to 76, 1996). However, these atypical antipsychotics cause a substantial gain in weight that is somewhat greater than that of conventional antipsychotics and of a clinically important magnitude. This leads, in individual cases, to poor compliance and other adverse health effects. The largest weight gains are associated with clozapine and olanzapine, and the smaller ones with quetiapine and ziprasidone. Risperidone is associated with modest changes in weight that are not dose related. Due to the equivalent efficacy of atypical antipsychotics, the weight gain profile is a legitimate factor to consider, when a treatment is selected (Nasrallah, and Psychoneuroendocrinology, Vol 28, Suppl 1 pages 83 to 96, 2003, Homel, Casey and Allison Schizophrenia Research Vol 55 (3) pages 277 to 284, 2002). This is the most important because obesity is usually seen in patients with schizophrenia. According to some research, the average body mass index (BMI) for individuals with schizophrenia is significantly higher than for individuals who are not schizophrenic (Homel, Casey and Allison, Schizophrenia Research, Vol 55 (3) pages 277 a 284, 2002; Ananth et al Expert Review of Neurotherapeutics Vol 3 (1) pages 59 to 68, 2003). Because overweight and obesity are risk factors for other diseases, such as diabetes and cardiovascular diseases, the need for improved drug treatment for individuals who have both schizophrenia and overweight is clear. Summary of the Invention It has now been found that treatment of such patients with asenapine is safer than treatment with only any of the other antipsychotic agents. The term "treatment" is used in the present description to refer to a measure or set of measures taken and / or prescribed by a doctor, in order to combat the symptoms or consequences of the disease. Treatment with a drug is by administration to the patient by any means known in the art, directly to the patient or indirectly by prescription. The benefit of the improved treatment can be observed in individual patients, for example, when they switch to the new treatment of a treatment with any other antipsychotic agent with side effects of weight gain in that particular patient. The benefit can also be observed as a group effect, where it can not be excluded that certain individuals still gain weight, but the general group has a result that definitely shows an effect of less average weight gain compared to a known treatment. In view of the favorable property of asenapine in the weight, it is an aspect of the present invention to treat a patient of schizophrenia with asenapine, wherein the patient has been having the effect of weight gain due to another antipsychotic agent. In this aspect of the present invention, the patient is not necessarily an overweight patient. In another aspect, the need to avoid weight gain caused by treatment with the drug is related to the special risk that overweight affects in that particular patient, for example, due to the presence of other risk factors, such as diabetes and cardiovascular disease. These risk factors can originate from genetic disposition or behavioral habits, such as smoking or sudden abstinence from smoking. Therefore, another aspect of the present invention is to treat a patient with schizophrenia with asenapine, wherein the patient needs to be protected against weight gain, due to the presence of disease risk factors for which also the overweight is a risk factor Again said patient who needs to avoid the weight gain effect is not necessarily already overweight. Still in an additional aspect, the patient needs to avoid the effect of weight gain due to the presence of other factors of weight gain by themselves, such as nicotine withdrawal in relation to a decision to quit smoking. Schizophrenia is defined in the field of psychiatry as a disease that is within a category of specific diagnosis, with characteristics of cognitive disturbances. The diagnosis can be made according to the criteria provided in the psychiatric manuals, for example, in a (Diagnostic and Statistical Manual of Mental Illness) "Diagnostic and Statistical Manual of Mental Disorders" 4a. edition (DSM-IV) published by the American Psychiatric Association, Washington, D.C. (1994). The antipsychotic agent is a drug with therapeutic activity, but it can be curative or preventive, in patients with schizophrenia and other psychoses. In this description of the present invention no difference is made in the meaning between an antipsychotic drug, and a neuroleptic drug and an anti-schizophrenia drug. In the art terms are used interchangeably, although the term neuroleptic is generally avoided in modern times, because it is associated with classic drugs that have the strongest side effects such as Parkinson's disease, as a result of the uncompensated inhibition of dopaminergic neurotransmission in the brain. The administration to a patient can be by any means that have the objective of making the drug available near the receptors of the body, which are carriers of therapeutic effects. Tablets and capsules for oral administration are the most commonly known. For asenapine, a sublingual formulation was developed, so that the drug can be administered to the oral cavity and made available for general circulation. See, for example, WO9523600. Obesity and overweight are used in the context of the present invention as obesity and overweight according to the judgment of a doctor, so that this term is used in the present description as a medical meaning, rather than a meaning that it refers to the undesirable physical appearance of people. Quantitative measures are defined in the technique in order to have more objective criteria for overweight and obesity. A parameter generally used is the body mass index (BMI) defined with the formula G / L2; where G is the body weight in kg and L is the body height in meters. An acceptable BMI from the medical point of view is 25 kg / m2. The highest values are considered as overweight. Overweight as a risk factor for other health problems, is proportionally operational as such, that is, a higher overweight a higher chance of other diseases, such as diabetes and cardiovascular disease. The World Health Organization and the NIH have defined the term obesity as a physical condition that is characterized by a BMI of = 30 kg / m2. Note that for purposes of clarity of terms, the term overweight includes the term obese, the latter being a more serious form of overweight. Because the effect of overweight is relative to the degree of overweight, cut points other than the aforementioned 25 kg / m2 are used to define overweight that is not healthy. It can be found in the values of the expert literature of 26 kg / m2 and 27.3 kg / m2 as the criteria for the onset of obesity in women, and 28 and 27.8 as the criteria for the onset of obesity in men. The present invention has as additional specific embodiments, the use of asenapine for methods of treating schizophrenia in overweight individuals objectively defined as those men selected with a BMI of > 26, > 26.5, > 27, > 27.3, > 27.5, > 28, > 29, > 30, > 35 or > 40 and / or those women selected with a BMI of = 26, = 26.5, > 27, > 27.5, > 27.8, = 28, > 29, > 30, > 35 or > 40 Asenapine refers to the compound registered by the WHO under that name, whose chemical name is trans-5-chloro-2-methyl-2,3,3a, 12b-tetrahydro-1H-dibenz [2,3: 6,7] oxapino [4,5-cjpirrol. It is generally made available in the form of a 1: 1 salt of maleate, so that asenapine can be referred to the maleate salt specifically or to the base, or to any salt or hydrate of the base. In the present description, the last and broadest meaning was used. The term also encompasses the separate enantiomeric forms of trans-5-chloro-2-methyl-2,3,3a, 12b-tetrahydro-1 H-dibenz- [2,3: 6,7] oxepino [4,5-c ] pyrrole, which can be used in its pure form for the same purpose. When amounts of asenapine are administered, reference is made to the basic content of the substance, unless explicitly stated otherwise. Asenapine is administered in an amount to the patient, which is therapeutically effective. By therapeutically effective amount we mean that this amount is able to prevent, reverse, reduce, alleviate at least partially or otherwise suppress the psychotic disease that is being treated. The final dose to provide for patients depends on the a. or. in individual characteristics, such as the condition and age. A therapeutically effective amount can be determined by one skilled in the art using no more than routine experimentation. The daily dose is the amount of the drug administered for 24 hours in any pharmaceutical formulation. For prolonged-release formulations the intended duration for the effective administration of the dose is divided by the number of days, in order to arrive at an indication of the daily dose of treatment. Asenapine can be used effectively in the category of overweight patients in a daily dose range of 0.5 to 50 mg per person, where the exact amount is selected depending on the route of administration, the intensity of the desired effect and the needs and tolerances of the individual patient. In particular, body weight can influence the daily dose, because portions of the drug can be stored in the fatty tissue, where they are temporarily unavailable to the receptors involved in the anti-schizophrenic effect. The preferred range of daily dosage is from 5 to 20 mg. It is preferred to administer the daily dose with a sublingual or buccal formulation in one or more dosage units (see WO 9523600) containing an amount of asenapine selected from the range of 1 to 15 mg, and preferably 5 or 10 mg. In this aspect of the present invention provides the use of asenapine in a method for the manufacture of a medicine, whose medicine comprises asenapine and is made to be suitable for the treatment of an overweight patient, a patient who has been taking effect of weight gain due to another antipsychotic agent or a patient who needs to be protected against weight gain, due to the presence of risk factors for a disease for which being overweight is also a risk factor, or due to the presence of other factors that increase the weight. In another aspect, the present invention provides a pharmaceutical formulation comprising asenapine suitable for the treatment of an overweight patient, or a patient who was having a weight gain effect due to another antipsychotic agent or a patient who needs to be protected against weight gain, due to the presence of disease risk factors, for which overweight is also a risk factor or due to the presence of other weight gain factors. Pharmaceutical formulations are generally prescribed to the patient in "patient packs" that contain a number of unit doses or other means for the administration of measured dose units to be used during a different treatment period in a single package, usually a blister pack. Patient packages have the advantage over traditional prescriptions, that the pharmacy manager divides a patient's supply of a pharmaceutical from a bulk supply, which can be provided so that the patient has access to an insert in the package contained in the package for the patient. The inclusion of a package insert has been shown to improve patient compliance with the physician's instructions. Therefore, the present invention includes a pharmaceutical formulation, as described above, in combination with a suitable packaging material for said treatment. In such a package for the patient, the intended use of the formulation for treatment according to the present invention can be inferred by instructions, facilities, provisions, adaptations and / or other means to help use the formulation in the most appropriate manner for the treatment. Said measures make the package for the patient specifically adapted and adapted to be used for the treatment according to the present invention. Therefore, the present invention provides a package for the patient for the treatment with asenapine of a schizophrenic patient with overweight or who is at risk of overweight. Which comprise means for the administration of dosage units measured in combination with the packaging material suitable for said dosage units, and the package for the patient comprising means to assist a patient to use the dosage units in the most suitable manner. . Detailed Description of the Example Invention Evaluation of the efficacy and safety of asenapine (5 mg twice daily) in subjects with acute exacerbation of their schizophrenic disease, compared to risperidone (3 mg twice daily) and placebo in a double blind randomized trial and a 6-week fixed-dose trial. The treatment period of 42 days consisted of a phase with the inpatient 21 days, and a phase with the patient was 21 days. The study was done in a multi-center trial. The patients in the study were recruited in 27 centers, and randomly assigned to one of the three test groups. The selection of candidate subjects for recruitment in the trials was done immediately after the informed consent was signed. The investigator or sub-researcher determined whether the subject met the DSM-IV criteria for schizophrenia. On day 0, the first dose of the test drug was administered the day before. Before the test drug was administered, the health status of each subject was re-evaluated to ensure eligibility for randomization of the subject in the trial. A total of 182 subjects were included in the trial and of these 180, they received the treatment: 59 asenapine, 59 risperidone, 62 placebo. To be considered for inclusion in the trial, non-pregnant male or female subjects 18 years of age or older who experience acute exacerbation of their schizophrenic disease diagnosed according to the DSM IV criteria with paranoid-type schizophrenia [295.30] , disorganized type [295.10], catatonic type [295.20], or undifferentiated type [295.90] were selected. The subjects were to have a PANSS score of at least 60 at the baseline. Asenapine and placebo were prepared as sublingual tablets which could not be distinguished according to WO9523600, Example 1, with the adaptation of the amount of asenapine in order to obtain appropriate quantities in the dosage units. After a cleaning period of 3 to 7 days, the trial subjects were placed randomly in the three treatment groups (asenapine, risperidone, placebo). Subjects randomly placed in the asenapine group received the test drug according to the following schedule: 1 mg twice a day on day 1, 2 mg twice a day on day 2, 3 mg twice a day on day 3, 4 mg twice a day on day 4, and 5 mg twice a day on day 5 to 42. Subjects placed Randomly in the risperidone group received the test drug according to the following schedule: 1 mg twice a day on day 1, 2 mg twice a day on day 2, and 3 mg twice daily of the Day 3 to 42. Subjects randomly placed in the placebo group received the placebo twice daily throughout the treatment period. The evaluations during the treatment period were made weekly, except for the vital signs evaluations during the inpatients phase, which were carried out daily. Among other tests, efficacy on the symptoms of the disease was evaluated with the negative or positive syndrome scale (PANSS). Body weight was measured in the selection and on day 42, or the final day of treatment of the subjects. Characterizations of other subjects, and demographic and descriptive statistics were made to obtain age, weight and height by treatment group, and were combined in the treatment groups.

Baseline characteristics for the treatment group: age, weight, and height * BMI was calculated with the average values of weight and height. Results Asenapine and risperidone both were significantly more effective than placebo in reducing the symptoms of schizophrenia. The clinically important weight gain (for example, an increase from the baseline of = 7%) was reported in 4% (N = 2) of the subjects of asenapine, 17% (N = 8) of the treated subjects with risperidone, and 2% (N = 1) of the subjects treated with placebo.

Table: Number of subjects with a clinically important change from the baseline in body weight by the treatment group (All Subjects - Treaties in the Group) N is the total number of subjects with data and n is the number of subjects in the category. Of the 147 subjects in the Group of All Subjects Tested who had weight data recorded in the baseline and at the end of the trial, 11 had a clinically important increase from the baseline in body weight, and 5 had a decrease clinically important from the baseline on body weight. The percentage of subjects with a clinically important weight gain from the baseline was higher, in the risperidone group (17.0%), lower in the asenapine group (4.3%), and the lowest was in the group of placebo (1.9%). Four subjects experienced a gain greater than 10% by weight from the baseline: One subject of the treatment with asenapine, 2 subjects of the risperidone treatment, and 1 subject of the placebo treatment. At the end point, the risperidone group showed a 1.9% increase in body weight from the baseline, compared to a 0.5% increase in the asenapine group and a 0.3% increase in the placebo group. Overall Conclusion The low incidence of clinically important weight gain and the other minimal side effects demonstrated that asenapine has a favorable risk-benefit profile.

Claims (12)

1. CLAIMS 1. A method for the treatment of schizophrenia with an antipsychotic agent administered to an overweight patient characterized in that the antipsychotic agent is asenapine.
2. 2. A method for the treatment of schizophrenia with asenapine in a patient who was gaining weight due to another antipsychotic agent.
3. 3. A method for the treatment of schizophrenia with asenapine in a patient who needs to be protected against weight gain, due to the presence of disease risk factors for which overweight is also a risk factor, or due to the presence of other factors of weight gain.
4. 4. The method as described in claim 1, characterized in that the overweight is defined as being a BMI of = 25.
5. 5. The method as described in claim 4, characterized in that the overweight is defined as which is a BMI of > 27.8 for men and = 27.3 for women.
6. The method as described in any of claims 1 to 5, characterized in that asenapine is administered to the patient by the sublingual route.
7. 7. The use of an antipsychotic agent in the manufacture of a medicament for the treatment of schizophrenia in an overweight patient characterized in that the antipsychotic agent is asenapine.
8. 8. The use of asenapine in the manufacture of a medicament for the treatment of schizophrenia administered to a patient where the patient was having weight gain, due to another antipsychotic agent.
9. 9. The use of asenapine in the manufacture of a medicament for the treatment of schizophrenia administered to a patient in which the patient needs to be protected against weight gain due to the presence of risk factors for a disease for which the overweight It is also a risk factor, or due to the presence of other factors of weight gain.
10. The use as described in claim 7, wherein the overweight is defined as being a BMI of > 25.
11. 11. Use as described in the claim 9, where the overweight is defined as being a BMI of = 27.8 for men and of > 27.3 for women.
12. 12. The use as described in claims 7 to 11, wherein the medicament is to be administered to the patient by the sublingual route.