WO2012014012A1 - Method for producing tablets that dissolve rapidly in the mouth and that include form i of olanzapine, resulting tablets and use thereof in the treatment of schizophrenia - Google Patents

Method for producing tablets that dissolve rapidly in the mouth and that include form i of olanzapine, resulting tablets and use thereof in the treatment of schizophrenia Download PDF

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Publication number
WO2012014012A1
WO2012014012A1 PCT/IB2010/053405 IB2010053405W WO2012014012A1 WO 2012014012 A1 WO2012014012 A1 WO 2012014012A1 IB 2010053405 W IB2010053405 W IB 2010053405W WO 2012014012 A1 WO2012014012 A1 WO 2012014012A1
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weight
olanzapine
ingredients
tablets
procedure
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PCT/IB2010/053405
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Spanish (es)
French (fr)
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Andrés RUDOLPHY FONTAINE
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Laboratorios Andrómaco S.A.
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Application filed by Laboratorios Andrómaco S.A. filed Critical Laboratorios Andrómaco S.A.
Priority to PCT/IB2010/053405 priority Critical patent/WO2012014012A1/en
Priority to PE2010000482A priority patent/PE20120216A1/en
Publication of WO2012014012A1 publication Critical patent/WO2012014012A1/en

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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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • 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

Definitions

  • the present invention is related to a process for preparing a pharmaceutical fast-dissolving oral composition in the form of tablets comprising olanzapine form I.
  • Olanzapine is an antipsychotic agent, used for the treatment of schizophrenia. It was described in US Patent 5,229,382, subsequently several crystalline modifications of olanzapine were revealed, which includes some hydrated or solvated forms that are stable in ambient condition.
  • compositions containing olanzapine such as those described in US patents US 5,229,382, US 5,919,485 and EP0733367, which lead to the obtaining of various pharmaceutical forms, such as tablets, capsules, lyophilized powder for reconstitution in aqueous solvent, controlled release injection for intramuscular application.
  • Patent EP0733367B1 describes a solid oral composition comprising olanzapine as an active ingredient, preferably olanzapine form II, intimately mixed with a filler, a binder, a disintegrant, a dry binder to provide adequate friability, and a lubricant, wherein said formulation is coated with a polymer.
  • the coating with certain polymers aims to provide uniformity and physical stability, in addition to effectively preventing the phenomenon of undesirable color change from the formulation. It is mentioned that olanzapine tends to be metastable, to undergo pharmaceutically unwanted color change and requires treatments to ensure the homogeneity of the final solid formulation. The color change may occur when it comes into contact with certain excipients that include powder mixtures.
  • olanzapine used by these inventors corresponds to the anhydrous form which, as indicated by them, is the most stable form of olanzapine. Even so it is noted that this olanzapine may form an undesirable crystalline form in the presence of certain solvents or excipients.
  • the inventors of the EP0733367 patent believe that a direct compression process of the dry mix or dry granulated processes to prepare the solid oral formulations, are procedures that will create a greater risk of poor dose uniformity. Due to the potent nature of olanzapine, a constant dose uniformity is necessary.
  • patent EP0733367 comprises the stages of wet granulation, drying, mixing with additional excipients and compression.
  • the inventors have discovered and so describe it in the European patent, that an aqueous wet granulation with high shear with fluid bed drying, is the most effective method for preparing pharmaceutically stable oral olanzapine formulations.
  • EP1558219 describes a process for preparing tablets by direct compression of a mixture of the components without the addition of a solvent. It is mentioned that with this procedure it was possible to obtain stable tablets and that have dose uniformity, unlike expected by the background described regarding the instability of olanzapine. For this it was necessary to select certain excipients and exclude others. Thus they describe a formulation with two elementary ingredients that are a monosaccharide and / or oligosaccharide and a polysaccharide in a total concentration of 70 to 90%. It is indicated that the oligosaccharide should not be microcrystalline cellulose because of its hygroscopic characteristics, which decreases the stability of olanzapine.
  • Rapid oral dissolution tablets are an excellent pharmaceutical form to administer to patients with psychosis or other mental disorders that require olanzapine in their treatment, since water intake is avoided, an additional problem in the administration of medications to these patients .
  • Quick dissolving tablets dissolve in saliva immediately after being administered, so the medication can be ingested without the need for water supply.
  • crospovidone is used as a superdisintegrant, in concentrations equal to or less than 3%.
  • oral rapid dissolution tablets refers to tablets that are dispersed in water within 30 seconds, preferably within 10 seconds and more preferably within 5 seconds or less, as specified in the Pharmacopoeia of United States for a rapid dissolution dosage form.
  • Form I of olanzapine has an X-ray powder diffraction pattern as indicated below, where d represents the interplanar space.
  • a Siemens 5000 X-ray diffractometer was used.
  • Table 1 - X-ray powder diffraction pattern of olanzapine form I used in the present invention.
  • the process of the present invention consists of the following steps, where each of the percentages of the indicated ingredients is expressed with respect to the total weight of the pharmaceutical composition or final product: a) Sift by granulator in C-0.7 mesh the following Ingredients in the order indicated:
  • Olanzapine form I (2.0% to 8.0%)
  • Crospovidone (2.5% to 3.0%)
  • Lactose spried dried monohydrate (8.0% to 10.0%)
  • Microcrystalline cellulose 24.0% to 26.0%
  • Manually sift in mesh No. 60 the following ingredients, adding a portion of the previous mixture:
  • Dye 10 D&C yellow 10 u Red iron oxide (0.5% to 0.8%)
  • oral fast dissolving tablets comprising the ingredients listed in Table 2 at the indicated concentrations, which are expressed in% by weight with respect to the total weight of the compressed. Table 2.- Ingredients of the oral fast dissolving tablets obtained with the procedure of Example 1.
  • the oral fast-dissolving tablets obtained according to the composition described in Example 2 were stored since their elaboration in their final containers, in the condition of 40 ⁇ ⁇ 2 ⁇ C and 75% ⁇ 5% relative humidity (CONDITION 1) and in ambient condition of 30 ° C ⁇ 2 ⁇ C and 65% ⁇ 5% relative humidity (CONDITION 2). Samples were taken at time zero (T0), at 30 days (T30), at 60 days (T60), at 90 days (T90) and at 180 days (T180), and the corresponding analyzes were performed.
  • CONDITION 1 • Samples: 10.0 mg / tablet with a range of 93.5% to 102.0%, CV: 1, 86%.

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Abstract

The present invention relates to a method for producing a tablet that dissolves rapidly in the mouth and the only active ingredient of which is form I of olanzapine, said method consisting of the following consecutive stages: a) mill sifting the active ingredient along with three excipients including diluents and a superdisintegrant; b) separate manual sifting of 2 other excipients including coloring and a lubricant, and mixing with the ingredients of the preceding stage; c) granulator sifting of 3 other excipients comprising a sweetener, essence and a diluent, incorporating the ingredients from the preceding stage and mixing; d) manually sifting 2 other excipients including a lubricant and a glidant, mixing them with all the ingredients from the preceding stages; and e) using direct compression to form tablets that dissolve rapidly in the mouth and that contain 2.0% to 8,0% of form I of olanzapine, 44.0% to 48.0% of mannitol powder, 24.0% to 26.0% of microcrystalline cellulose, 8.0% to 10.0% of spray-dried lactose monohydrate, 2.5% to 3.0% of crospovidone, 0.5% to 0.8% of coloring, 4.0% to 6.0% of essence, 0.8% to 1.2% of sucrose powder, 3.2% to 4.8% of talc, 0.8% to 1.0% of colloidal silicon dioxide and 0.8% to 1.0% of magnesium stearate, where all the percentages are expressed in weight with respect to the total weight of the tablet. The invention further relates to the pharmaceutical composition, in the form of tablets that dissolve rapidly in the mouth and that are obtained by means of said method and to the use thereof in the treatment of schizophrenia.

Description

PROCEDIMIENTO PARA PREPARAR COMPRIMIDOS DE DISOLUCION RAPIDA ORAL QUE COMPRENDEN LA FORMA I DE OLANZAPINA, LOS COMPRIMIDOS OBTENIDOS Y SU USO PARA EL TRATAMIENTO DE LA PROCEDURE TO PREPARE ORAL QUICK DISSOLUTION TABLETS THAT INCLUDE OLANZAPINE FORM I, THE TABLES OBTAINED AND ITS USE FOR THE TREATMENT OF THE
ESQUIZOFRENIA. SCHIZOPHRENIA.
La presente invención está relacionada con un procedimiento para preparar una composición farmacéutica de disolución rápida oral en la forma de comprimidos que comprende la forma I de olanzapina. La olanzapina es un agente antipsicótico, utilizado para el tratamiento de la esquizofrenia. Fue descrita en la patente US 5.229.382, posteriormente se revelaron diversas modificaciones cristalinas de la olanzapina, lo que incluye algunas formas hidratadas o solvatadas que son estables en condición ambiente. The present invention is related to a process for preparing a pharmaceutical fast-dissolving oral composition in the form of tablets comprising olanzapine form I. Olanzapine is an antipsychotic agent, used for the treatment of schizophrenia. It was described in US Patent 5,229,382, subsequently several crystalline modifications of olanzapine were revealed, which includes some hydrated or solvated forms that are stable in ambient condition.
Se conocen ciertos procedimientos para preparar composiciones que contienen olanzapina, como los descritos en las patentes norteamericanas US 5.229.382, US 5.919.485 y EP0733367, que llevan a la obtención de diversas formas farmacéuticas, tales como comprimidos, cápsulas, polvo liofilizado para reconstitución en solvente acuoso, inyectable de liberación controlada para aplicación intramuscular. Certain methods are known for preparing compositions containing olanzapine, such as those described in US patents US 5,229,382, US 5,919,485 and EP0733367, which lead to the obtaining of various pharmaceutical forms, such as tablets, capsules, lyophilized powder for reconstitution in aqueous solvent, controlled release injection for intramuscular application.
En la patente EP0733367B1 se describe una composición oral sólida que comprende olanzapina como ingrediente activo, preferentemente la forma II de olanzapina, mezclada íntimamente con un agente de carga, un aglutinante, un disgregante, un aglutinante seco para proporcionar friabilidad adecuada, y un lubricante, donde dicha formulación está recubierta con un polímero. La cubierta con ciertos polímeros tiene como objetivo proporcionar uniformidad y estabilidad física, además de prevenir eficazmente el fenómeno de cambio de color no deseable de la formulación. Se menciona que la olanzapina tiende a ser metaestable, a sufrir cambio de color farmacéuticamente no deseado y requiere tratamientos para asegurar la homogeneidad de la formulación sólida final. El cambio de color puede ocurrir cuando se pone en contacto con ciertos excipientes que incluyen las mezclas en polvo. Se señala que las condiciones del aire ambiental, temperaturas i elevadas y ambientes húmedos agravan el problema de decoloración. La forma II de olanzapina utilizada por esos inventores corresponde a la forma anhidra que según lo señalado por ellos es la forma más estable de la olanzapina. Aun así se señala que esta olanzapina puede formar una forma cristalina no deseada en presencia de ciertos disolventes o excipientes. Los inventores de la patente EP0733367 creen que un procedimiento de compresión directa de la mezcla seca o procedimientos granulados secos para preparar las formulaciones orales sólidas, son procedimientos que crearán un mayor riesgo de que se produzca una mala uniformidad de la dosis. Debido a la naturaleza potente de la olanzapina, es necesaria una uniformidad de dosis constante. El procedimiento descrito en la patente EP0733367 comprende las etapas de granulación húmeda, secado, mezclado con excipientes adicionales y compresión. Los inventores han descubierto y así lo describen en la patente europea, que una granulación húmeda acuosa con alta cizalla con secado en lecho fluido, es el procedimiento más eficaz para preparar formulaciones de olanzapina orales estables farmacéuticamente apropiadas. Patent EP0733367B1 describes a solid oral composition comprising olanzapine as an active ingredient, preferably olanzapine form II, intimately mixed with a filler, a binder, a disintegrant, a dry binder to provide adequate friability, and a lubricant, wherein said formulation is coated with a polymer. The coating with certain polymers aims to provide uniformity and physical stability, in addition to effectively preventing the phenomenon of undesirable color change from the formulation. It is mentioned that olanzapine tends to be metastable, to undergo pharmaceutically unwanted color change and requires treatments to ensure the homogeneity of the final solid formulation. The color change may occur when it comes into contact with certain excipients that include powder mixtures. It is noted that ambient air conditions, temperatures i High and humid environments aggravate the problem of discoloration. The form II of olanzapine used by these inventors corresponds to the anhydrous form which, as indicated by them, is the most stable form of olanzapine. Even so it is noted that this olanzapine may form an undesirable crystalline form in the presence of certain solvents or excipients. The inventors of the EP0733367 patent believe that a direct compression process of the dry mix or dry granulated processes to prepare the solid oral formulations, are procedures that will create a greater risk of poor dose uniformity. Due to the potent nature of olanzapine, a constant dose uniformity is necessary. The process described in patent EP0733367 comprises the stages of wet granulation, drying, mixing with additional excipients and compression. The inventors have discovered and so describe it in the European patent, that an aqueous wet granulation with high shear with fluid bed drying, is the most effective method for preparing pharmaceutically stable oral olanzapine formulations.
En la patente EP1558219 se describe un procedimiento para preparar comprimidos por compresión directa de una mezcla de los componentes sin la adición de un solvente. Se menciona que con dicho procedimiento fue posible obtener comprimidos estables y que tienen uniformidad de dosis, a diferencia de lo esperado por los antecedentes descritos respecto a la inestabilidad de la olanzapina. Para esto fue necesario seleccionar determinados excipientes y excluir otros. Así describen una formulación con dos ingredientes elementales que son un monosacárido y/o oligosacárido y un polisacárido en una concentración total de 70 a 90%. Se indica que el oligosacárido no debe ser celulosa microcristalina por sus características higroscópicas, lo que disminuye la estabilidad de la olanzapina. Muestran un ejemplo de referencia de una composición farmacéutica que comprende celulosa microcristalina y en condiciones de ensayo a 40°C y 75% de humedad relativa en un mes, expuesto al ambiente se formaron un 3,4% de sustancias relacionadas, lo que es inaceptable para una formulación farmacéutica. En cambio los resultados obtenidos según la formulación descrita en la patente EP 1558219 arrojó valores de hasta un 1 ,63% y 0,35% de sustancias relacionadas, en los dos ejemplos mostrados, respectivamente. EP1558219 describes a process for preparing tablets by direct compression of a mixture of the components without the addition of a solvent. It is mentioned that with this procedure it was possible to obtain stable tablets and that have dose uniformity, unlike expected by the background described regarding the instability of olanzapine. For this it was necessary to select certain excipients and exclude others. Thus they describe a formulation with two elementary ingredients that are a monosaccharide and / or oligosaccharide and a polysaccharide in a total concentration of 70 to 90%. It is indicated that the oligosaccharide should not be microcrystalline cellulose because of its hygroscopic characteristics, which decreases the stability of olanzapine. They show a reference example of a pharmaceutical composition comprising microcrystalline cellulose and under test conditions at 40 ° C and 75% relative humidity in one month, exposed to the environment 3.4% of related substances were formed, which is unacceptable For a pharmaceutical formulation. On the other hand, the results obtained according to the formulation described in patent EP 1558219 showed values of up to 1, 63% and 0.35% of related substances, in the two examples shown, respectively.
En la publicación WO 2003/086361 se describen comprimidos de dispersión rápida oral que contienen olanzapina y que se preparan por granulación húmeda. Se señala que también es posible obtenerlos por compresión directa sin la adición de solventes, pero no se demuestra su estabilidad ni uniformidad de dosis. In WO 2003/086361, oral fast dispersion tablets containing olanzapine and which are prepared by wet granulation are described. It is noted that it is also possible to obtain them by direct compression without the addition of solvents, but their stability or dose uniformity is not demonstrated.
No se ha descrito una formulación farmacéutica que comprenda específicamente la forma I de olanzapina y en la que se haya demostrado la estabilidad de la presentación en el tiempo y su uniformidad de dosis.  No pharmaceutical formulation has been described that specifically comprises the form I of olanzapine and in which the stability of the presentation over time and its dose uniformity has been demonstrated.
Los comprimidos de disolución oral rápida son una excelente forma farmacéutica para administrar a los pacientes con psicosis u otros desórdenes mentales que requieren olanzapina en su tratamiento, puesto que se evita la ingesta de agua, un problema adicional en la administración de los medicamentos a estos pacientes. Los comprimidos de disolución rápida se disuelven en la saliva inmediatamente luego de ser administrados, por lo que el medicamento puede ser ingerido sin la necesidad del suministro de agua. Rapid oral dissolution tablets are an excellent pharmaceutical form to administer to patients with psychosis or other mental disorders that require olanzapine in their treatment, since water intake is avoided, an additional problem in the administration of medications to these patients . Quick dissolving tablets dissolve in saliva immediately after being administered, so the medication can be ingested without the need for water supply.
Existe la necesidad de proveer un procedimiento de preparación de comprimidos de disolución bucal rápida que contengan como principio activo la forma I de olanzapina, donde dicho procedimiento sea de fácil manufactura y que a su vez proporcione comprimidos de calidad, estables y que entreguen una apropiada uniformidad de dosis, y donde dicho procedimiento no tenga la necesidad de utilizar etapas de recubrimiento para asegurar la calidad del producto final. There is a need to provide a method of preparing fast-dissolving tablets containing as active ingredient form I of olanzapine, where said procedure is easy to manufacture and in turn provides quality, stable tablets that deliver an appropriate uniformity of dose, and where said procedure does not have the need to use coating steps to ensure the quality of the final product.
Sorprendentemente se ha encontrado que con el procedimiento descrito en la presente invención que emplea cinco etapas simples, que incluyen procesos de tamizado, mezcla y compresión final, y se utiliza como ingredientes esenciales un superdesintegrante y lactosa monohidrato, se obtienen comprimidos de disolución rápida que son estables y con una demostrada uniformidad de dosis. De una manera sorprendente, los inventores de la presente invención han encontrado que es posible preparar comprimidos de disolución rápida oral que contienen celulosa microcristalina, manitol y lactosa como ingredientes de carga y contienen crospovidona como superdesintegrante en una concentración menor o igual al 3%, mediante un procedimiento de granulación en seco y compresión directa de todos los ingredientes. Surprisingly it has been found that with the process described in the present invention which employs five simple steps, which include screening, mixing and final compression processes, and a superdisintegrant and lactose monohydrate are used as essential ingredients, fast dissolving tablets are obtained which are stable and with a proven dose uniformity. Surprisingly, the inventors of the present invention have found that it is possible to prepare oral fast-dissolving tablets containing microcrystalline cellulose, mannitol and lactose as fillers and containing crospovidone as a superdisintegrant in a concentration less than or equal to 3%, by a dry granulation process and direct compression of all ingredients.
Con el procedimiento aquí descrito se obtienen comprimidos de disolución rápida oral que son estables y tienen uniformidad de dosis, contrario a lo descrito en el arte previo donde se señala que no se debe utilizar celulosa microcristalina debido a sus características higroscópicas, puesto que al absorber agua aumenta la inestabilidad de la olanzapina. En este caso se utiliza la forma I de olanzapina y junto con el procedimiento y excipientes utilizados, se obtiene un producto final estable que garantiza las dosis requeridas a los pacientes. With the procedure described here, fast-dissolving oral tablets are obtained which are stable and have a dose uniformity, contrary to that described in the prior art where it is indicated that microcrystalline cellulose should not be used due to its hygroscopic characteristics, since when absorbing water increases the instability of olanzapine. In this case, form I of olanzapine is used and together with the procedure and excipients used, a stable final product is obtained that guarantees the required doses to the patients.
En la presente invención se utiliza crospovidona como un superdesintegrante, en concentraciones iguales o menores al 3%. In the present invention crospovidone is used as a superdisintegrant, in concentrations equal to or less than 3%.
En la presente invención "comprimidos de disolución rápida oral" se refiere a comprimidos que se dispersan en agua dentro de 30 segundos, preferiblemente dentro de 10 segundos y más preferiblemente dentro de 5 segundos o menos, de acuerdo a lo especificado en la Farmacopea de los Estados Unidos para una forma de dosificación de disolución rápida. In the present invention "oral rapid dissolution tablets" refers to tablets that are dispersed in water within 30 seconds, preferably within 10 seconds and more preferably within 5 seconds or less, as specified in the Pharmacopoeia of United States for a rapid dissolution dosage form.
La forma I de olanzapina presenta un patrón de difracción en polvo de rayos X como se indica a continuación, donde d representa el espacio interplanar. Se utilizó un difractómetro de rayos-X Siemens 5000. Form I of olanzapine has an X-ray powder diffraction pattern as indicated below, where d represents the interplanar space. A Siemens 5000 X-ray diffractometer was used.
Tabla 1 .- Patrón de difracción en polvo de rayos X de la forma I de olanzapina utilizada en la presente invención. Angulo Distancia Intensidad Intensidad interplanar (d) Table 1 .- X-ray powder diffraction pattern of olanzapine form I used in the present invention. Angle Distance Intensity Intensity interplanar (d)
2-theta Amstrong (A) Cps %  2-theta Amstrong (A) Cps%
9.6542 580.00 74.456 8.3345 128.00 16.436 8.0252 169.00 21 .696 6.7546 130.00 16.696 6.2556 70.00 8.997 5.8330 33.00 4.243 5.4994 44.00 5.657 4.91 13 96.00 12.323 4.7682 779.00 100.000 4.6768 370.00 47.501 4.5669 262.00 33.639 4.4804 270.00 34.662 4.1909 187.00 24.019 4.0461 276.00 35.430 3.7889 82.00 10.532 3.7213 158.00 20.285 3.6635 282.00 36.202 3.5488 76.00 9.768 3.4704 107.00 13.747 3.3120 66.00 8.477 3.2159 73.00 9.377 3.0830 87.00 1 1 .177 2.9306 48.00 6.167 2.8016 58.00 7.458 2.7365 63.00 8.090 2.5816 53.00 6.806 2.4483 61 .00 7.830 2.3150 61 .00 7.83 EJEMPLOS 9.6542 580.00 74.456 8.3345 128.00 16.436 8.0252 169.00 21 .696 6.7546 130.00 16.696 6.2556 70.00 8.997 5.8330 33.00 4.243 5.4994 44.00 5.657 4.91 13 96.00 12.323 4.7682 779.00 100,000 4.6768 370.00 47.501 4.5669 262.00 33.639 4.480419.00.00.00.00.00.00.00.00 20.285 3.6635 282.00 36.202 3.5488 76.00 9.768 3.4704 107.00 13.747 3.3120 66.00 8.477 3.2159 73.00 9.377 3.0830 87.00 1 1 .177 2.9306 48.00 6.167 2.8016 58.00 7.458 2.7365 63.00 8.090 2.5816 53.00 6.806 2.4483 61 .00 7.830 2.3150 61 .00 7.83 EXAMPLES
Ejemplo 1 Example 1
El procedimiento de la presente invención consiste en las siguientes etapas, donde cada uno de los porcentajes de los ingredientes indicados está expresado respecto al peso total de la composición farmacéutica o producto final: a) Tamizar por granuladora en malla C-0,7 los siguientes ingredientes en el orden indicado:  The process of the present invention consists of the following steps, where each of the percentages of the indicated ingredients is expressed with respect to the total weight of the pharmaceutical composition or final product: a) Sift by granulator in C-0.7 mesh the following Ingredients in the order indicated:
Olanzapina forma I (2,0% a 8,0%)  Olanzapine form I (2.0% to 8.0%)
Crospovidona (2,5% a 3,0%) Crospovidone (2.5% to 3.0%)
Lactosa spried dried monohidrato (8,0% a 10,0%) Lactose spried dried monohydrate (8.0% to 10.0%)
Celulosa microcristalina (24,0% a 26,0%) b) Tamizar manualmente en malla N ° 60 los siguientes ingredientes, adicionando una porción de la mezcla anterior: Microcrystalline cellulose (24.0% to 26.0%) b) Manually sift in mesh No. 60 the following ingredients, adding a portion of the previous mixture:
Colorante 10 D&C amarillo 10 u Oxido rojo de hierro (0,5% a 0,8%)  Dye 10 D&C yellow 10 u Red iron oxide (0.5% to 0.8%)
Dióxido de silicio coloidal (0,8% a 1 ,0%) Colloidal Silicon Dioxide (0.8% to 1.0%)
Posteriormente incorporar a un mezclador en "V" junto con el resto de la mezcla del paso a) y mezclar por 20 minutos. c) Tamizar por granuladora los siguientes ingredientes e incorporarlos al paso anterior b) y mezclar por 20 minutos: Subsequently incorporate a "V" mixer together with the rest of the mixture from step a) and mix for 20 minutes. c) Sift by granulator the following ingredients and incorporate them to the previous step b) and mix for 20 minutes:
Sucralosa polvo (0,8% a 1 ,2%)  Sucralose powder (0.8% to 1.2%)
Esencia de plátano polvo (4,0% a 6,0%) Essence of banana powder (4.0% to 6.0%)
Manitol polvo (44,0% a 48,0%) d) Tamizar manualmente por malla N ° 60 los siguientes ingredientes: Mannitol powder (44.0% to 48.0%) d) Manually sift through mesh No. 60 the following ingredients:
Talco (3,2% a 4,8%) Talc (3.2% to 4.8%)
Estearato de magnesio (0,8% a 1 ,0%) Luego agregar al mezclador en "V" que contiene los ingredientes del paso anterior y mezclar por 5 minutos. e) Con la mezcla completa iniciar proceso de compresión, ajustando peso y dureza de los comprimidos de acuerdo a las siguientes especificaciones: Magnesium Stearate (0.8% to 1.0%) Then add to the "V" mixer that contains the ingredients from the previous step and mix for 5 minutes. e) With the complete mixture start compression process, adjusting weight and hardness of the tablets according to the following specifications:
• Para los comprimidos que contienen 2,0% a 3,5% en peso del principio activo, respecto al peso total de la composición:  • For tablets containing 2.0% to 3.5% by weight of the active substance, based on the total weight of the composition:
Peso: 250,0 mg ± 10,0%  Weight: 250.0 mg ± 10.0%
Dureza: 2 a 10 Kp  Hardness: 2 to 10 Kp
· Para los comprimidos que contienen más de 3% a 8% en peso del principio activo, respecto al peso total de la composición:  For tablets containing more than 3% to 8% by weight of the active substance, based on the total weight of the composition:
Peso: 250 mg ± 5,0%  Weight: 250 mg ± 5.0%
Dureza: 4 a 8 Kp De acuerdo al procedimiento descrito en el Ejemplo 1 , se obtienen comprimidos de disolución rápida oral que comprenden los ingredientes listados en la Tabla 2 en las concentraciones indicadas, las que están expresadas en % en peso respecto al peso total del comprimido. Tabla 2.- Ingredientes de los comprimidos de disolución rápida oral que se obtienen con el procedimiento del Ejemplo 1.  Hardness: 4 to 8 Kp According to the procedure described in Example 1, oral fast dissolving tablets are obtained comprising the ingredients listed in Table 2 at the indicated concentrations, which are expressed in% by weight with respect to the total weight of the compressed. Table 2.- Ingredients of the oral fast dissolving tablets obtained with the procedure of Example 1.
Figure imgf000009_0001
Dióxido de silicio coloidal 0,8 - 1 ,0
Figure imgf000009_0001
Colloidal Silicon Dioxide 0.8-1.0
Estearato de magnesio 0,8 - 1 ,0  Magnesium Stearate 0.8-1.0
Peso total comprimido en mg 250  Total compressed weight in 250 mg
Ejemplo 2 Example 2
De acuerdo al procedimiento descrito en el ejemplo 1 se preparó la siguiente composición farmacéutica en la forma de comprimidos de disolución rápida oral, donde todos los porcentajes están expresados en peso respecto al peso total de la composición:  According to the procedure described in Example 1, the following pharmaceutical composition was prepared in the form of oral fast dissolving tablets, where all percentages are expressed by weight with respect to the total weight of the composition:
Olanzapina forma I 4,0% Olanzapine form I 4.0%
Manitol polvo 44,8% Mannitol powder 44.8%
Celulosa microcristalina 24,8%  24.8% microcrystalline cellulose
Lactosa spray dried monohidrato 10,0%  Lactose spray dried monohydrate 10.0%
Crospovidona 3,0%  Crospovidone 3.0%
Oxido de hierro, rojo 0,7%  Iron Oxide, red 0.7%
Esencia de plátano 6,0% Essence of banana 6.0%
Sucralosa 1 ,0%  Sucralose 1.0%
Talco 4,0%  Talc 4.0%
Dióxido de silicio coloidal 1 ,0%  1.0% colloidal silicon dioxide
Estearato de magnesio 0,5%  0.5% magnesium stearate
Los comprimidos de disolución rápida oral obtenidos según la composición descrita en el Ejemplo 2 fueron almacenados desde su elaboración en sus envases definitivos, en la condición de 40 ^ ± 2 <C y 75% ± 5% de humedad relativa (CONDICION 1 ) y en condición ambiente de 30°C ± 2 <C y 65% ± 5% de humedad relativa (CONDICION 2). Se tomaron muestras al tiempo cero (T0), a los 30 días (T30), a los 60 días (T60), a los 90 días (T90) y a los 180 días (T180), y se realizaron los análisis correspondientes. The oral fast-dissolving tablets obtained according to the composition described in Example 2 were stored since their elaboration in their final containers, in the condition of 40 ^ ± 2 < C and 75% ± 5% relative humidity (CONDITION 1) and in ambient condition of 30 ° C ± 2 < C and 65% ± 5% relative humidity (CONDITION 2). Samples were taken at time zero (T0), at 30 days (T30), at 60 days (T60), at 90 days (T90) and at 180 days (T180), and the corresponding analyzes were performed.
Resultados obtenidos Results obtained
Uniformidad de contenido: Uniformity of content:
CONDICION 1 : • Muestras: 10,0 mg/comprimido con un intervalo de 93,5% a 102,0%, CV: 1 ,86%. CONDITION 1: • Samples: 10.0 mg / tablet with a range of 93.5% to 102.0%, CV: 1, 86%.
• Especificaciones: 8,5 - 1 1 ,5 mg/comprimido (85% - 1 15%), n=10, CV < 6,0%.  • Specifications: 8.5 - 1 1.5 mg / tablet (85% - 1 15%), n = 10, CV <6.0%.
En consecuencia, los comprimidos obtenidos cumplen con la especificación en la Uniformidad de contenido. Consequently, the tablets obtained comply with the specification in the Uniformity of content.
CONDICION 2: CONDITION 2:
• Muestras: 9,5mg/comprimido con un intervalo de 90,4% a 99,3%, CV: 2,5%. · Especificaciones: 8,5 - 1 1 ,5 mg/comprimido (85% - 1 15%), n=10, CV < • Samples: 9.5mg / tablet with a range of 90.4% to 99.3%, CV: 2.5%. Specifications: 8.5 - 1 1.5 mg / tablet (85% - 1 15%), n = 10, CV <
6,0% 6.0%
En consecuencia, los comprimidos obtenidos cumplen con la especificación en la Uniformidad de contenido. Sustancias relacionadas:  Consequently, the tablets obtained comply with the specification in the Uniformity of content. Related Substances:
CONDICION 1 : CONDITION 1:
• Muestras a T60. Individuales: 0,02% a 0,03%; Totales: 0,07% a 0,1 % • Samples at T60. Individuals: 0.02% to 0.03%; Totals: 0.07% to 0.1%
• Especificaciones. Individuales: no mayor a 0,5%; Totales: no mayor a 2% En consecuencia, los comprimidos obtenidos cumplen con la especificación en el contenido de sustancias relacionadas. • Specs. Individuals: no more than 0.5%; Totals: not more than 2% Consequently, the tablets obtained meet the specification in the content of related substances.
CONDICION 2: CONDITION 2:
• Muestras a T60. Individuales: 0,0%; Totales: 0,0  • Samples at T60. Individuals: 0.0%; Totals: 0.0
• Especificaciones. Individuales: no mayor a 0,5%; Totales: no mayor a 2% En consecuencia, los comprimidos obtenidos cumplen con la especificación en el contenido de sustancias relacionadas.  • Specs. Individuals: no more than 0.5%; Totals: not more than 2% Consequently, the tablets obtained meet the specification in the content of related substances.

Claims

REIVINDICACIONES
1 . - Procedimiento para preparar comprimidos de disolución rápida oral que comprenden como único ingrediente activo la forma I de olanzapina CARACTERIZADO porque consiste en las siguientes etapas consecutivas: a) tamizar por molino el ingrediente activo junto a tres excipientes que comprenden diluyentes y superdesintegrante, one . - Procedure for preparing oral fast-dissolving tablets comprising the only active ingredient form I of CHARACTERIZED olanzapine because it consists of the following consecutive stages: a) milling the active ingredient together with three excipients comprising diluents and superdisintegrant,
b) tamizar manualmente por separado otros 2 excipientes que comprenden colorante y lubricante, y mezclar con ingredientes de la etapa anterior, c) tamizar por granuladora otros 3 excipientes que comprenden edulcorante, esencia y diluyente, incorporar los ingredientes de la etapa anterior y mezclar, d) tamizar manualmente otros 2 excipientes que comprenden lubricante y glidante, mezclar con todos los ingredientes de las etapas anteriores, y e) realizar el proceso de compresión directa para formar comprimidos de disolución rápida oral. b) manually sift separately another 2 excipients comprising dye and lubricant, and mix with ingredients of the previous stage, c) sift by granulator another 3 excipients comprising sweetener, essence and diluent, incorporate the ingredients of the previous stage and mix, d) Manually sift another 2 excipients that comprise lubricant and glidant, mix with all the ingredients of the previous stages, and e) carry out the direct compression process to form oral fast dissolving tablets.
2. - Procedimiento para preparar comprimidos de disolución rápida oral de acuerdo a la reivindicación 1 CARACTERIZADO porque la etapa a) consiste en tamizar por molino el ingrediente activo, junto con el superdesintegrante crospovidona, la lactosa spray dried monohidrato y la celulosa microcristalina. 2. - Procedure for preparing oral fast-dissolving tablets according to claim 1 CHARACTERIZED because step a) consists of sieving the active ingredient by mill, together with the super-disintegrant crospovidone, lactose spray dried monohydrate and microcrystalline cellulose.
3. - Procedimiento para preparar comprimidos de disolución rápida oral de acuerdo a la reivindicación 1 CARACTERIZADO porque la etapa b) consiste en tamizar manualmente en malla N ° 60 el colorante y dióxido de silicio coloidal con una porción de la mezcla de la etapa anterior, y luego incorporar en mezclador en "V" junto con la mezcla restante de la etapa a). 3. - Procedure for preparing oral fast dissolving tablets according to claim 1 CHARACTERIZED because step b) consists of manually sieving in mesh No. 60 the colourant and colloidal silicon dioxide with a portion of the mixture of the previous stage, and then incorporate into a "V" mixer together with the remaining mixture from stage a).
4. - Procedimiento para preparar comprimidos de disolución rápida oral de acuerdo a la reivindicación 1 CARACTERIZADO porque la etapa c) consiste en tamizar por granuladora el edulcorante, la esencia y el manitol polvo, luego incorporar la mezcla de la etapa b) y mezclar por 20 minutos. 4. - Procedure for preparing oral fast dissolving tablets according to claim 1 CHARACTERIZED because step c) consists in sieving the sweetener, the essence and the mannitol powder, then incorporating the mixture of stage b) and mixing by 20 minutes.
5. - Procedimiento para preparar comprimidos de disolución rápida oral de acuerdo a la reivindicación 1 CARACTERIZADO porque la etapa d) consiste en tamizar manualmente en malla N ° 60 el talco, y el estearato de magnesio, luego agregar en mezclador en "V" junto con todos los ingredientes de las etapas anteriores y mezclar por 5 minutos. 5. - Procedure for preparing oral fast dissolving tablets according to claim 1 CHARACTERIZED because step d) consists of Manually sift the talc and the magnesium stearate in mesh No. 60, then add in a "V" mixer together with all the ingredients from the previous stages and mix for 5 minutes.
6. - Procedimiento para preparar comprimidos de disolución rápida oral de acuerdo a la reivindicación 1 CARACTERIZADO porque la etapa e) consiste en comprimir la mezcla de la etapa d) para obtener comprimidos redondos, planos, de un peso de 250 mg ± 10%, dureza de 2 a 10 kp y una friabilidad máxima de 0,8%. 6. - Procedure for preparing oral fast dissolving tablets according to claim 1 CHARACTERIZED because step e) consists of compressing the mixture of step d) to obtain round, flat tablets weighing 250 mg ± 10%, hardness of 2 to 10 kp and a maximum friability of 0.8%.
7. - Procedimiento para preparar comprimidos de disolución rápida oral de acuerdo a la reivindicación 1 CARACTERIZADO porque la etapa e) consiste en comprimir la mezcla de la etapa d) para obtener comprimidos que contienen desde un 2,0% a 8,0% en peso de la forma I de olanzapina, desde un 44,0% a 48,0% en peso de manitol polvo, desde un 24,0% a 26,0% en peso de celulosa microcristalina, desde un 8,0% a 10,0% en peso de lactosa spray dried monohidrato, desde un 2,5% a 3,0% en peso de crospovidona, desde un 0,5% a 0,8% en peso de colorante, desde un 4,0% a 6,0% en peso de esencia, desde 0,8% a 1 ,2% en peso de sucralosa polvo, desde un 3,2% a 4,8% en peso de talco, desde un 0,8% a 1 ,0% en peso de dióxido de silicio coloidal y desde un 0,8% a 1 ,0% en peso de estearato de magnesio, donde todos los porcentajes están expresados en peso respecto al peso total del comprimido. 7. - Procedure for preparing oral fast dissolving tablets according to claim 1 CHARACTERIZED because step e) consists of compressing the mixture of step d) to obtain tablets containing from 2.0% to 8.0% in Weight of form I of olanzapine, from 44.0% to 48.0% by weight of mannitol powder, from 24.0% to 26.0% by weight of microcrystalline cellulose, from 8.0% to 10 , 0% by weight of lactose spray dried monohydrate, from 2.5% to 3.0% by weight of crospovidone, from 0.5% to 0.8% by weight of dye, from 4.0% to 6.0% by weight of essence, from 0.8% to 1.2% by weight of sucralose powder, from 3.2% to 4.8% by weight of talc, from 0.8% to 1, 0% by weight of colloidal silicon dioxide and from 0.8% to 1.0% by weight of magnesium stearate, where all percentages are expressed by weight with respect to the total weight of the tablet.
8. - Comprimido de disolución rápida oral que comprende como único ingrediente activo la forma I de olanzapina CARACTERIZADO porque contiene los siguientes ingredientes desde un 2,0% a 8,0% en peso de la forma I de olanzapina, desde un 44,0% a 48,0% en peso de manitol polvo, desde un 24,0% a 26,0% en peso de celulosa microcristalina, desde un 8,0% a 10,0% en peso de lactosa spray dried monohidrato, desde un 2,5% a 3,0% en peso de crospovidona, desde un 0,5% a 0,8% en peso de colorante, desde un 4,0% a 6,0% en peso de esencia, desde 0,8% a 1 ,2% en peso de sucralosa polvo, desde un 3,2% a 4,8% en peso de talco, desde un 0,8% a 1 ,0% en peso de dióxido de silicio coloidal y desde un 0,8% a 1 ,0% en peso de estearato de magnesio, donde todos los porcentajes están expresados en peso respecto al peso total del comprimido. 8. - Oral rapid dissolving tablet comprising the only active ingredient form I of CHARACTERIZED olanzapine because it contains the following ingredients from 2.0% to 8.0% by weight of form I of olanzapine, from 44.0 % to 48.0% by weight of mannitol powder, from 24.0% to 26.0% by weight of microcrystalline cellulose, from 8.0% to 10.0% by weight of lactose spray dried monohydrate, from a 2.5% to 3.0% by weight of crospovidone, from 0.5% to 0.8% by weight of dye, from 4.0% to 6.0% by weight of essence, from 0.8 % to 1.2% by weight of sucralose powder, from 3.2% to 4.8% by weight of talc, from 0.8% to 1.0% by weight of colloidal silicon dioxide and from 0 , 8% to 1.0% by weight of stearate magnesium, where all percentages are expressed by weight with respect to the total weight of the tablet.
9.- Uso de un comprimido de disolución rápida oral de acuerdo a la reivindicación 8 CARACTERIZADO porque sirve para preparar un medicamento destinado para el tratamiento de la esquizofrenia. 9. Use of an oral fast dissolving tablet according to claim 8 CHARACTERIZED because it serves to prepare a medicament intended for the treatment of schizophrenia.
PCT/IB2010/053405 2010-07-27 2010-07-27 Method for producing tablets that dissolve rapidly in the mouth and that include form i of olanzapine, resulting tablets and use thereof in the treatment of schizophrenia WO2012014012A1 (en)

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PE2010000482A PE20120216A1 (en) 2010-07-27 2010-08-02 PROCEDURE FOR PREPARING ORAL RAPID DISSOLUTION TABLETS THAT INCLUDE FORM I OLANZAPINE AND THE OBTAINED TABLETS

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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004035027A1 (en) * 2002-10-18 2004-04-29 Krka, Tovarna Zdravil, D.D., Novo Mesto Pharmaceutical formulation of olanzapine
EP1681048A1 (en) * 2005-01-14 2006-07-19 Krka Tovarna Zdravil, D.D., Novo Mesto Orally disintegrating composition of olanzapine or donepezil
WO2006081779A2 (en) * 2005-02-02 2006-08-10 Zentiva, A.S. A pharmaceutical composition containing olanzapine as the active agent and a process for the preparation thereof
ES2279715A1 (en) * 2005-12-26 2007-08-16 Laboratorios Lesvi, S.L. Oral formulation of anhydrous olanzapine form i
WO2008037502A2 (en) * 2006-09-29 2008-04-03 Synthon B.V. Olanzapine pharmaceutical composition with anhydrous lactose
WO2009043844A2 (en) * 2007-10-01 2009-04-09 Laboratorios Lesvi, S.L. Orodispersible tablets

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004035027A1 (en) * 2002-10-18 2004-04-29 Krka, Tovarna Zdravil, D.D., Novo Mesto Pharmaceutical formulation of olanzapine
EP1681048A1 (en) * 2005-01-14 2006-07-19 Krka Tovarna Zdravil, D.D., Novo Mesto Orally disintegrating composition of olanzapine or donepezil
WO2006081779A2 (en) * 2005-02-02 2006-08-10 Zentiva, A.S. A pharmaceutical composition containing olanzapine as the active agent and a process for the preparation thereof
ES2279715A1 (en) * 2005-12-26 2007-08-16 Laboratorios Lesvi, S.L. Oral formulation of anhydrous olanzapine form i
WO2008037502A2 (en) * 2006-09-29 2008-04-03 Synthon B.V. Olanzapine pharmaceutical composition with anhydrous lactose
WO2009043844A2 (en) * 2007-10-01 2009-04-09 Laboratorios Lesvi, S.L. Orodispersible tablets

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