MXPA98007430A - Medications for the treatment of the car - Google Patents

Abstract

The invention provides a method for the treatment of autistic disorder and / or mental retardation comprising administering an effective amount of olanzapine to a patient in need of

Description

MEDICATIONS FOR THE TREATMENT OF AUTISM FIELD OF THE INVENTION This invention provides a method for the use of 2-methyl-4- (4-methyl-1-piperazinyl) -10H-thieno [2, 3-b] [1, 5] enzodiazepine, (hereinafter referred to as "olanzapine"), for the treatment of autism and mental retardation.

BACKGROUND DB THE INVENTION Autism and mental retardation are seriously disabling conditions for which there could be a small treatment available. Patients suffering from autism have a heavy and prolonged damage in their reciprocal social interaction. The damage in communication is marked and sustained as good. The autistic patient suffers from stereotype patterns and repetitive restrictions and stereotypes of behavior, interest and activities in which they are not functional and / or abnormal in each focus and intensity. Furthermore, a young patient may look as young as 3 years old and REF: 028168.

Show signs of delay in each of the following areas: social interaction, language used in social communication, symbolic or imaginative play. The patient suffering from mental retardation has an intellectual functioning below average. Both mental retardation and autism are debilitating conditions that may require institutionalization, if they are severe. We know that olanzapine provides antipsychotic activity and is generally used in the investigation of this goal. Olanzapine is a known compound and is described in U.S. Pat. No. 5,229,382 as used in the treatment of schizophrenia, schizophrenic disorder, acute mania, mild states of anxiety and psychosis. The U.S. patent No. 5,229,382 is incorporated herein by reference in this set. Either way, olanzapine was little known to be used in the treatment of autism and mental retardation. The discovered applications of olanzapine can be used for the treatment of autism and / or mental retardation. Olanzapine can be directed to a long exploration necessary for treatments which provide a favorable protective profile * and effectively provide help for the patient suffering from autism and / or mental retardation.

DESCRIPTION OF THE INVENTION The present claimed invention provides a method for the treatment of autistic disorder, including the administration of an effective amount of olanzapine or a pharmaceutically acceptable salt thereof, to a patient in need of such treatment. The present claimed invention further provides a method for the treatment of mental retardation, including the administration of an effective amount of olanzapine or a pharmaceutically acceptable salt thereof, to a patient in need of such treatment. Olanzapine is of the formula: (D) or an acid addition salt thereof It is especially preferred that olanzapine may be of the form II of polymorphic olanzapine having a typical X-ray energy diffraction pattern as represented by the following interplanar spacings: d 10.2689 8.577 7.4721 7.125 '6.1459 6.071 5.4849 5.2181 5.1251 4.9874 4.7665 4.7158 4.4787 4.3307 4.2294 4.141 3.9873 3.7206 3.5645 3.5366 3.3828 3.2516 3.134 3.0848 3.0638 3.0111 2.8739 2.8102 2.7217 2.6432 2.6007 A typical example of a diffraction pattern of an X ray for form II is the following, where d represents the interplanar space and I / Ii, represents the typical relative intensities: d I / Il 10.2689 100.00 8.577 7.96 7.472L 1.41 7.125 6.50 6.1459 3.12 6.071 7.48 4.2294 23.19 4.141 11.28 3.9873 6.86 5.1251 2.346 4.8474 2.27 3.5366 4.85 3.3828 3.47 3.2516 1.25 3.134 0.81 3.0848 0.45 3.0638 1.34 3.0111 3.51 2.8739 0.79 2.8102 1.47 2.7217 0.20 2.6432 1.26 2.6007 0.77 The X-ray diffraction pattern is obtained even using a D5000 sieve X-ray energy diffractometer, which has a copper radiation ka because of the wavelength,? = 1.541A. More preferred is form II of olanzapine polymorph which can be administered as form II of substantially pure polymorph olanzapine. We use the term "substantially pure" when referring to the associated form II less than about 5% of Form I, preferably less than about 2% of Form I, and more preferably less than about 1% of Form I Moreover, the "substantially pure" form II may contain less than about 0.5% of related substances, where related substances refer to undesirable chemical impurities, or residual solvents or water. The particular "pure substance" of form II may contain less than about 0.05% of the acetonitrile content, more preferably, it may be about 0.005% of the acetonitrile content. Additionally the polyform of the invention may contain less than about 0.5% association in water. The polymorph obtained by the process taught in the '382 Patent, can be designated as the I form and has a typical X-ray energy diffraction pattern, substantially as follows, it is obtained using X-ray energy diffractometer in a D5000 screen , where d represents the interplanar spacer: d 9.9463 8.5579 8.2445 6.8862 6.3787 6.2439 5.5895 5 5.3055 4.9815 4.8333 4.2755 4.6286 4,533 4.4624 4.2915 4.2346 4.0855 3.8254 3.7489 3.6983 3.5817 3.5064 3.3392 3.2806 3.2138 3.0507 2.948 2.8172 2.7589 2.6597 2.6336 2.5956 A typical example of a diffraction pattern of an X-ray for form I is as follows, where d represents the interplanar spacer and I / Ii, represents the typical relative intensities: d I / Il '9.9463 100.00 8.5579 15.18 8.2445 1.96 6.8862 14.73 6.3787 4.25 6.2439 5.21 5.5895 1.10 5.3055 0.95 4.9815 6.14 4.8333 68.37 4.7255 21.88 4.6286 3.82 4.533 17.83 4.4624 5.02 4.2915 9.19 4.2346 18.88 4.0855 17.29 3.8254 6.49 3.7489 10.64 3.6983 14.65 3.5817 3.04 3.5064 9.23 3.3392 4.67 3.2806 1.96 3.2138 2.52 3.1118 4.81 3.0507 1.96 2.948 2.40 2.8172 2.89 2.7589 2.27 2.6597 1.86 2.6336 1.10 2.5956 1.73 The X-ray energy diffraction pattern can obtained with a Ka copper of wavelength? = 1.541A. The interplanar spaces marked in column d are in Angstroms. The typical relative intensities are in the "I / Ii" column. We use here, the term "mammal" to refer to the mammalian class of large vertebrates. The term "mammal" includes but is not limited to humans. The term "treatment" is used herein including the prophylaxis of the so-called condition of improvement or elimination of the condition each time it has stabilized. We use here, the term "autistic disorder" when referring to a condition characterized as autistic disorder, in the DSM-IV-R as category 299. **. Thus, it includes but is not limited to 299.00, 299.80 and 299.10. Diagnostic and Statistical Manual of Mental Disorders, Revised, 3rd Ed. (1994). It is preferred, for the treatment of autistic disorder, category 299.00 using olanzapine. According to the term "mental retardation" we can refer to the condition characterized as such in the DSM-IV-R as categories 317. **, 318. **, and 319. Thus, including but not limited to 317, 318.0 , 318.1, 318.2 and 319. It is especially preferred for category 318 treatment. * Using olanzapine. The DSM-IV-R, was prepared with hard work in nomenclature and statistics of the American Psychiatric Association, and provides clear descriptions of diagnostic categories. The expert in art can * recognize that these are alternative nomenclatures, nosological and classification systems of pathological-psychological conditions r and that these systems are related to medical scientific progress. The results of pharmacological studies show that olanzapine has muscarinic chlorinergic receptor activity. The compound is activated with the Dopamine D-1 and D-2 receptors as indicated by an IC 50 of less than 1UM within 3H-SCH233390 (Billard, et al., Life Sciencesa 35: 1885 (1984)) and 3H Spiperone. (Seeman et al. Nature 216: 717 (1976)) linking the trials respectively. Furthermore, olanzapine is activated at the 5-HT-2 receptor and the 5-HT 1C receptor. The profile of the pharmaceutical complex provides a medication which may be useful for the treatment of autism and mental retardation. The utility of the compound activity for the treatment of autistic disorder and mental retardation can be supported in the following studies as described. I.- clinical observations. A double and false experiment in a multi-center clinic was assigned to assess the safety and efficacy of olanzapine. Patients were randomized with olanzapine or placebo. The study results suggest that olanzapine may be useful for the treatment of autism. In addition, the results of the study suggest that olanzapine may be useful for the treatment of mental retardation. Olanzapine is effective in a wide range of doses, the current dose administered depends on the condition to be treated. For example, in the treatment of adult humans, the dose ranges from 0.25 to 50 mg, preferably from 1 to 30 mg, and more preferably from 1 to 20 mg per day that can be used. Sometimes a daily dose is usually sufficient, even if the dose that can be used is divided. For the treatment of autistic disorder, the range of doses ranges from 1 to 30 mg, preferably from 2.5 to 30 mg per day appropriately. For the treatment of mental retardation, a dose range of about 1 to 30 mg per day in an acceptable form. The classified olanzapine can be detected in the saliva and thus the compound can potentially be monitored in patients, to evaluate its docility. A preferred formulation of the invention is the formulation of an oral solid comprising from about 1 to 30 mg or 1 to 10 mg of olanzapine as an effective amount of the active ingredient. More preferably, the oral solid formulation, which contains packaging materials that protect the wet and light formulation. For example, appropriate packaging materials including, amber colored high density polyethylene bottles, amber glass bottles, and other containers made of material that inhibit the passage of light. More preferably, the package may include a desiccant package. The container can be sealed with an aluminum sheet that provides protection and keeps the product stable. Olanzapine can normally be administered orally or by injection and, for this purpose, usually is in the form of a pharmaceutical composition. Accordingly, the pharmaceutical compositions comprise olanzapine, as an active ingredient associated with a pharmaceutically acceptable carrier for its preparation, in the preparation of the compositions of the conventional techniques of the invention for the preparation of the pharmaceutical compositions that can be used. For example, the active ingredient will usually be mixed with a carrier, or diluted with a carrier, or enclosed in a carrier which may be in the form of capsules, sachets, paper or other container. The carrier then serves as a diluent, and can be solid, semi-solid, or liquid material, which acts as a carrier, excipient or medium for the active ingredient. The active ingredient can be absorbed in a solid granulated container, for example in sachets.

Examples of suitable carriers are lactose, dextrose, sucrose, sorbitol, mannitol, starches, acacia gum, calcium phosphate, alginates, tragacanth, gelatin, syrup, methyl cellulose, methyl- and propuhydroxybenzoate, talc, magnesium stearate or mineral oil. The compositions of the invention can be formulated to rapidly provide and sustain or release the active ingredient, after being administered to the patient. Depending on the method of administration, the compositions for the treatment of the conditions of the central nervous system can be formulated as tablets, capsules, injectable solutions, for parenteral use, gel or suspension for cutaneous use, suspensions or syrups for oral use or suppositories. Preferably the compositions are formulated in dosage unit form, each dose contains 0.25 to 30 mg, more usually 1 to 30 mg, of the active ingredient. The materials of the present invention can be made or developed by a variety of methods known to the ordinarily skilled artisan. Olanzapine can be prepared as described by Chkrabarti, in U.S. Pat. Do not. ,229, 382 ('382), incorporated herein by reference in this work. In addition, the following preparations illustrate a method for the preferred preparation especially of Form II polymorphous olanzapine. Composition characterization methods include, for example, x-ray energy pattern analysis, thermogravimetric analysis (TGA), differential scanning calorimeter (DSC), titrametric water analysis and H1-NMR analysis for solvent content.

The following examples are provided for the purpose of illustration and are not explained as limiting the summary of the claimed invention. PREPARATION 1, technical grade olanzapine Intermediary 1 The following is conveniently added to a three-bead flask: Dimethyl sulfoxide (analytical): 6 volumes Intermediator 1: 75 g N-Methylpiperazine (reagent): 6 equivalents Intermediator 1 can be prepared using methods known to the person skilled in the art. For example, the preparation of the -intermediator 1 is indicated in the '382 patent. A line spreads nitrogen from the sub-surface is added to remove the formation formed during the reaction. The reaction is heated to 120 C and maintained at this temperature during the reaction time. The The reactions are left by HPLC until < 5% of the intermediary 1 is allowed to react. After the reaction is complete, the mixture is allowed to cool slowly to 20 ° C (about 2 hours). The reaction mixture is then transferred to a three neck round bottom flask and the water bath. To this solution with stirring, 10 volumes of reagent grade methanol are added and the reaction is stirred at 20 C for 30 minutes. The three volumes of water are slowly added for about 30 minutes. The reaction is slowly cooled from 0 to 5C and stirred for 30 minutes. The product is filtered and the cake moisture is washed with cold methanol. The moisture cake is dried under vacuum at 45C at night. The product is identified as technical olanzapine.

Yield: 76.7%; Power: 98.1% PREPARATION 2 FORM II OLANZAPINE POLIMORFA A 270 g sample of the technical grade olanzapine 2-methyl-4- (4-methyl-1-piperazinyl) -10H-thieno [2,3-b] [1,5] benzodiazepine is suspended in anhydrous ethyl acetate ( 2.7 L). The mixture is heated to 76 ° C and maintained at 76 ° C per minute. The mixture is allowed to cool to 25C. The resulting product is isolated using vacuum filtration. The product is identified as form II using X-ray energy analysis. Yield 197g. The process described above for the preparation of Form II provides a pharmaceutically refined product having a potential of > 97%, with a total of related substances from < 0.5% and an isolated performance of > 73%.

EXAMPLE 1 A portion of hydroxypropyl cellulose is dissolved in purified water to form a solution by granulation. The remaining hydroxypropyl cellulose (the total final weight of the tablet at 4.0% w / w), which is found in extra fine grade, is combined with olanzapine (1.18% w / w), lactose (79.32% w / w) and a portion of the crospovidone (5% w / w) in a high shear granulator. All ingredients are separated before addition and mixed in the granulator. This mixture is then granulated with the hydroxypropyl cellulose solution in the high shear granulator. The granulation can be done using the standard methods. The moisture granulation is then dried in a large, fluidized cleaning chamber. The material is then added to a mixed rotating box. The powder obtained consists of microcrystalline cellulose (granular) (10% w / w), magnesium stearate (0.5% w / w), and the rest of crospovidone is added to the graded granulation. The mixture is removed and compressed with the appropriate instruments in tablet compression equipment.

OVERRIDING: Hydroxypropyl methylcellulose (10% w / w) is added with purified water to form a solution. The coated tablets are divided into approximately equal sections and bathed with the hydroxypropyl methylcellulose solution. The operation is carried out in a coating peforadora pot. COATING OF THE TABLET CENTER The white mixture of (hydroxypropyl methylcellulose, polyethylene glycol, polysorbate 80, and titanium dioxide) is mixed with purified water to form the coated suspension. Under coated tablets are divided into approximately equal sections and sprayed with the coated suspension described above. The operation was carried out in a casing drilling pan. The coated tablets are lightly powdered with carnauba wax and printed with appropriate identification.

Claims (4)

1. - The use of olanzapine or a pharmaceutically acceptable salt or solvent for the drainage of urine for the treatment of autistic desort in a mammal. 2"- A -use in accordance with the claim 1, characterized in that the autistic disorder is classified as category DSM-IV-R selected from the group consisting of 299.0, 299.80, and 299.10. 3. .- A use in accordance with the claim

2, characterized in that the autistic disorder is classified as category 299.0 DSM-IV-R. 4"- A use according to claim 1, characterized in that olanzapine is form II of polymorphic olanzapine having typical X-ray energy diffraction patterns, where d represents the interplanar spacer: d 10.2689 8.577 7.4721 7.125 6.1459 6.071 5.4849 5.2181 5.1251 4.9874 4.7665 '4.7158 4.4787 4.3307 4.2294 4.141 3.9873 3.7206 3.5645 3. 5366 3.3828 3.2516 3.134 3.0848 3.0638 3.0111 2.8739 2.8102 2.7217 2.6432 2.6007 5. - A use according to claim 2, characterized in that olanzapine is form II of polymorphic olanzapine having patterns, typical X-ray energy diffraction, where d represents the interplanar spacer: d 10.2689 8.577 7.4721 6. 1459 6.071 5.4849 5 5.2181 5.1251 4.9874 4.7665 4.7158 10 4.4787 4.3307 4.2294 4.141 3.9873 15 3.7206 3.5645 3.5366 3.3828 3.2516 20 3.134 3.0848 3.0638 3. 0111 2.8739 2.8102 2.7217 2.6432 2.6007 6. Use according to claim 1, characterized in that the effective amount is from about 1 mg to about 25 mg per day. 7. - A use according to claim 4, characterized in that the effective amount is from about 1 mg to about 30 mg per day. 8. - A use for the treatment of mental retardation comprising the administration to a mammal in need of such treatment, an effective amount of olanzapine, or a pharmaceutically acceptable salt or a solvent thereof. 9. - A use according to claim 8, characterized in that the mental retardation is classified as a category DSM-IV-R selected from the group consisting of 317, 318.0, 318.1, 318.2, and 319. 10. - A use according to claim 9, characterized in that the mental retardation is selected from the group consisting of 318.0, 318.1, and 318.2. 11. - A use according to claim 8, characterized in that olanzapine is form II of polymorphic olanzapine having typical X-ray diffraction patterns as follows, where d represents the interplanar spacer: d 10.2689 8.577 7.4721 7. 125 6.1459 6.071 5.4849 5 5.2181 5.1251 4.9874 4.7665 4.7158 10 4.4787 4.3307 4.2294 4.141 3.9873 15 3.7206 3.5645 3.5366 3.3828 3.2516 20 3.134 3.0848 3.0638

3. 0111 2.8739 2.8102 2.7217 2.6432 2.6007 12. - A use according to claim 8, characterized in that the effective amount is from about 1 mg to about 25 mg per day. 13. - A use according to claim 11, characterized in that the effective amount is from about 1 mg to about 30 mg per day. 14. - A use of olanzapine or a pharmaceutically acceptable salt or a solvent thereof for the manufacture of a medicament for therapeutic use in the treatment of autistic disorder. 15. - A use of olanzapine or a pharmaceutically acceptable salt or a solvent thereof for the manufacture of a medicament for therapeutic use in the treatment of mental retardation. 16. - A use as claimed in any of claims 14 or 15, characterized in that the olanzapine is form II of polymorphic olanzapine having a typical X-ray diffraction pattern as follows, wherein d represents the interplanar spacer: d 10.2689 8.577 7.4721 7.125 '6.1459 6.071 5.4849 5.2181 5.1251 4.9874 4.7665 4.7158

4. 4787 4.3307 4.2294 4.141 3.9873 3.7206 3.5645 3.5366 3.3828 10 3.2516 3.134 3.0848 3.0638 3.0111 15 2.8739 2.8102 2.7217 2.6432 2.6007 twenty