BRPI0722388B1 - Forma de dosagem oral farmacêutica sólida de composto inibidor de dpp iv - Google Patents

Forma de dosagem oral farmacêutica sólida de composto inibidor de dpp iv Download PDF

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BRPI0722388B1
BRPI0722388B1 BRPI0722388-9A BRPI0722388A BRPI0722388B1 BR PI0722388 B1 BRPI0722388 B1 BR PI0722388B1 BR PI0722388 A BRPI0722388 A BR PI0722388A BR PI0722388 B1 BRPI0722388 B1 BR PI0722388B1
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methyl
amino
xanthine
piperidin
butyn
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BRPI0722388-9A
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Anja Kohlrausch
Patrick Romer
Gerd Seifert
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Boehringer Ingelheim International Gmbh
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Abstract

FORMA DE DOSAGEM ORAL FARMACÊUTICA PREPARADA COM UMA COMPOSIÇÃO FARMACÊUTICA COMPREENDENDO COMPOSTO INIBIDOR DE DPP IV. A presente invenção refere-se uma forma de dosagem oral farmacêutica preparada com composições farmacêuticas compreendendo de inibidores de DPP IV com um grupo amino.

Description

[0001] Pedido dividido do PI0711179-7, depositado em 30.04.2007.
[0002] A presente invenção refere-se a composições farmacêuticas de inibidores de DPP IV selecionados, à preparação dos mesmos e ao uso dos mesmos para tratar estados de saúde médicos selecionados.
[0003] A enzima DPP-IV (dipeptidil peptidase IV) também conhecida como CD26 é uma serina protease conhecida por levar à clivagem de um dipeptídeo partindo da extremidade N-terminal de um número de proteínas que possuem em sua extremidade N-terminal um resíduo de prolina ou de alanina. Devido a esta propriedade, os inibidores de DPP-IV interferem no nível plasmático de peptídeos bioativos incluindo o peptídeo GLP-1 e são considerados como sendo fármacos promissores para o tratamento de diabetes mellitus.
[0004] Em tentativas de preparar composições farmacêuticas de inibidores de DPP-IV selecionados foi observado, que os inibidores de DPP-IV com um grupo amino primário ou secundário exibem incompatibilidades, problemas de degradação ou problemas de extração com um número de excipientes costumeiros tais como celulose microcristalina, amido glicolato de sódio, croscarmelose de sódio, ácido tartárico, ácido cítrico, glicose, frutose, sacarose, lactose, maltodextrinas. Embora os próprios compostos sejam muito estáveis, reagem com muitos excipientes utilizados em formas de dosagem sólidas e com impurezas dos excipientes, especialmente em contato íntimo fornecidos em comprimidos e em altas proporções de excipiente/fármaco. O grupo amino parece reagir com açúcares redutores e com outros grupos carbonila reativos e com grupos funcionais de ácido carboxílico formados, por exemplo, na superfície de celulose microcristalina através da oxidação. Estas dificuldades inesperadas são primariamente observadas em faixas de dosagem baixas que são requeridas devido à potência surpreendente dos inibidores selecionados. Assim, são necessárias composições farmacêuticas para solucionar estes problemas técnicos associados com a potência inesperada de compostos inibidores de DPP-IV selecionados.
[0005] Uma composição farmacêutica de acordo com a presente invenção é pretendida para o tratamento para atingir o controle glicêmico em um paciente com diabetes mellitus do tipo 1 ou do tipo 2 e compreende um inibidor de DPP-IV com um grupo amino, especialmente um grupo amino livre ou primário, como um ingrediente ativo, um primeiro e um segundo diluentes, um agente aglutinante, um agente de desintegração e um agente lubrificante. Um agente de desintegração adicional e um agente de deslizamento adicional constituem uma opção adicional. Adicionalmente, as composições podem ser utilizadas para tratar artrite reumatóide, obesidade e osteoporose assim como para sustentar o transplante de aloenxerto.
[0006] Os diluentes adequados para uma composição farmacêutica de acordo com a invenção são pó de celulose, fosfato de cálcio dibásico anidro, fosfato de cálcio dibásico diidratado, eritritol, hidroxipropil celulose substituída inferior, manitol, amido pré-gelatinizado ou xilitol. Entre estes diluentes o manitol e o amido pré-gelatinizado são preferidos.
[0007] Os diluentes preferidos como o segundo diluente são os diluentes mencionados anteriormente amido pré-gelatinizado e hidroxipropilcelulose substituída inferior (L-HPC) que exibem propriedades aglutinantes adicionais.
[0008] Os agentes lubrificantes adequados para uma composição farmacêutica de acordo com a invenção são talco, polietilenoglicol, behenato de cálcio, estearato de cálcio, óleo de mamona hidrogenado ou estearato de magnésio. O agente lubrificante preferido é o estearato de magnésio.
[0009] Os agentes aglutinantes adequados para uma composição farmacêutica de acordo com a invenção são copovidona (co- polimerizados de vinilpirrolidona com outros derivados de vinila), hidroxipropil metilcelulose (HPMC), hidroxipropilcelulose (HPC), polivinilpirrolidona (povidona), amido pré-gelatinizado,hidroxipropilcelulose substituída inferior (L-HPC), a copovidona e o amido pré-gelatinizado sendo os preferidos.
[00010] Os agentes aglutinantes mencionados anteriormente amido pré-gelatinizado e L-HPC exibem propriedades diluentes e de desintegração adicionais e podem também ser utilizados como o segundo diluente ou o agente de desintegração.
[00011] Os agentes de desintegração adequados para uma composição farmacêutica de acordo com a presente invenção são amido de milho, crospovidona, hidroxipropilcelulose substituída inferior (L-HPC) ou amido pré-gelatinizado, o amido de milho sendo o preferido.
[00012] Como um agente de deslizamento opcional pode ser utilizado o dióxido de silício coloidal.
[00013] Um exemplo de composição de acordo com a presente invenção compreende o diluente manitol, amido pré-gelatinizado como um diluente com propriedades de agente aglutinante adicionais, o agente aglutinante copovidona, o agente de desintegração amido de milho e o estearato de magnésio como o agente lubrificante.
[00014] As formas de dosagem preparadas com as composições farmacêuticas de acordo com a presente invenção contêm ingredientes ativos nas faixas de dosagem de 0,1-100 mg. As dosagens preferidas são 0,5 mg, 1 mg, 2,5 mg, 5 mg e 10 mg.
[00015] As composições farmacêuticas típicas compreendem (% em peso) 0,5-20 % de ingrediente ativo 40-88 % de diluente 1, 3-40 % de diluente 2, 1-5 % de agente aglutinante, 5-15 % de agente de desintegração e 0,1-4 % de agente lubrificante. As composições farmacêuticas preferidas compreende (% em peso) 0,5-7 % de ingrediente ativo 50-75 % de diluente 1, 5-15 % de diluente 2, 2-4 % de agente aglutinante, 8-12 % de agente de desintegração e 0,5-2 % de agente lubrificante
[00016] As composições farmacêuticas de acordo com a invenção são pretendidas para uso oral e podem ser utilizadas na forma de dosagem de uma cápsula, um comprimido ou de um comprimido revestido com filme. Tipicamente o revestimento de filme representa 24%, preferencialmente 3% da composição e compreende um agente formador de filme, um agente de plastificação, um agente de deslizamento e opcionalmente um ou mais pigmentos. Um exemplo de composição de revestimento pode compreender hidroxipropilmetil- celulose (HPMC), polietileno glicol (PEG), talco, dióxido de titânio e opcionalmente óxido de ferro.
[00017] Os ingredientes ativos preferidos no contexto da presente invenção são inibidores de DPP-IV com um grupo amino primário e sais dos mesmos tal como qualquer inibidor de DPP-IV e sal do mesmo definido pela fórmula (I)
Figure img0001
ou fórmula (II)
Figure img0002
em que R1 é ([1,5]naftiridin-2-il)metila, (quinazolin-2- il)metila, (quinoxalin-6-il) metila, (4-Metil-quinazolin-2-il)metila, 2-Ciano- benzila, (3-Ciano-quinolin-2-il) metila, (3-Ciano-piridin-2-il)metila, (4- Metil-pirimidin-2-il)metila ou (4,6-Dimetil -pirimidin-2-il)metila e R2 é 3- (R)-amino-piperidin-1-ila, (2-amino-2-metil-propil)-metilamino ou (2-(S)- amino-propil)-metilamino.
[00018] Os compostos inibidores de DPP IV preferidos são os compostos a seguir e os sais dos mesmos: • 1-[(4-metil-quinazolin-2-il)metil]-3-metil-7-(2-butin-1-il)-8-(3- (R)-amino-piperidin-1-il)-xantina (comparar com WO 2004/018468, exemplo 2(142)):
Figure img0003
• 1-[([1,5]naftiridin-2-il)metil]-3-metil-7-(2-butin-1-il)-8-((R)-3- amino-piperidin-1-il)-xantina (comparar com WO 2004/018468, exemplo 2(252)):
Figure img0004
• 1-[(Quinazolin-2-il)metil]-3-metil-7-(2-butin-1-il)-8-((R)-3- amino-piperidin-1-il)-xantina (comparar com WO 2004/018468, exemplo 2(80)):
Figure img0005
• 2-((R)-3-Amino-piperidin-1-il)-3-(but-2-iinil)-5-(4-metil- quinazolin-2-ilmetil)-3,5-dihidro-imidazo[4,5-d]piridazin-4-ona (comparar com WO 2004/050658, exemplo 136):
Figure img0006
• 1-[(4-Metil-quinazolin-2-il)metil]-3-metil-7-(2-butiin-1-il)-8- [(2-amino-2-metil-propil)-metilamino]-xantina (comparar com WO2006/029769, exemplo 2(1)):
Figure img0007
• 1-[(3-Ciano-quinolin-2-il)metil]-3-metil-7-(2-butin-1-il)-8-((R)-3-amino-piperidin-1-il)-xantina (comparar com WO 2005/085246, exemplo 1(30)):
Figure img0008
• 1-(2-Ciano-benzil)-3-metil-7-(2-butin-1-il)-8-((R)-3-amino-piperidin-1-il)-xantina (comparar com WO 2005/085246, exemplo 1(39)):
Figure img0009
• 1-[(4-Metil-quinazolin-2-il)metil]-3-metil-7-(2-butin-1-il)-8- [(S)-(2-amino-propil)-metilamino]-xantina (comparar com WO 2006/029769, exemplo 2(4)):
Figure img0010
• 1-[(3-Ciano-piridin-2-il)metil]-3-metil-7-(2-butin-1-il)-8-((R)- 3-amino-piperidin-1-il)-xantina (comparar com WO 2005/085246, exemplo 1(52)):
Figure img0011
• 1-[(4-Metil-pirimidin-2-il)metil]-3-metil-7-(2-butin-1-il)-8- ((R)-3-amino-piperidin-1-il)-xantina (comparar com WO 2005/085246, exemplo 1(81)):
Figure img0012
• 1-[(4,6-Dimetil-pirimidin-2-il)metil]-3-metil-7-(2-butin-1-il)-8- ((R)-3-amino -piperidin-1-il)-xantina (comparar com WO 2005/085246, exemplo 1(82)):
Figure img0013
• 1-[(Quinoxalin-6-il)metil]-3-metil-7-(2-butin-1-il)-8-((R)-3- amino-piperidin-1-il)-xantina (comparar com WO 2005/085246, exemplo 1(83)):
Figure img0014
[00019] Para preparar as composições de acordo com a invenção, um granulado pode ser preparado através de um processo de granulação úmida. Os métodos alternativos para a granulação de ingrediente ativo e excipientes com um líquido de granulação são a granulação em leito fluidizado ou a granulação em um recipiente.
[00020] No processo de granulação úmida o líquido de granulação é um solvente tal como água, etanol, metanol, isopropanol, acetona, preferencialmente água purificada e contém um agente aglutinante tal como copovidona. O solvente é um componente volátil, que não permanece no produto final. O ingrediente ativo e os outros excipientes com a exceção do agente lubrificante são pré-misturados e granulados com o líquido aquoso de granulação utilizando um granulador de alto cisalhamento. A etapa de granulação úmida é seguida por uma etapa de peneiração úmida opcional, secagem e peneiração seca dos grânulos. Por exemplo, uma secadora em leito fluidizado pode ser então utilizada para a secagem.
[00021] Os grânulos secos são peneirados através de uma peneira apropriada. Após a adição dos outros excipientes com a exceção do agente lubrificante a mistura é misturada em uma misturadora convencional adequada tal como uma misturadora de queda livre seguida pela adição do agente lubrificante tal como estearato de magnésio e pela mistura final na misturadora.
[00022] Assim, um exemplo de processo de granulação úmida para a preparação de uma composição farmacêutica de acordo com a presente invenção compreende a. dissolver um agente aglutinante tal como copovidona em um solvente tal como água purificada à temperatura ambiente para produzir um líquido de granulação; b. misturar um inibidor de DPP-IV, um diluente e um agente de desintegração em uma misturadora adequada para produzir uma pré-mistura; c. umedecer a pré-mistura com o líquido de granulação e a granulação subseqüente da pré-mistura umedecida, por exemplo, em uma misturadora de alto cisalhamento; d. peneirar opcionalmente a pré-mistura granulada através de uma peneira com um tamanho de trama de pelo menos 1,0 mm e preferencialmente 3 mm; e. secar o granulado à temperatura de ar de entrada de aproximadamente 40-75°C e preferencialmente 55-65°C, por exemplo, em uma secadora em leito fluidizado até que a perda desejada no valor de secagem de 1-5 % seja obtida; f. desagregar o granulado seco, por exemplo, peneirando através de uma peneira com um tamanho de trama de 0,6 mm-1,6 mm, preferencialmente 1,0 mm; e g. adicionar preferencialmente o agente lubrificante peneirado no granulado para a mistura final, por exemplo, em uma misturadora de cuba.
[00023] Em um processo alternativo, parte dos excipientes tal como parte de um agente de desintegração (por exemplo, amido de milho) ou um diluente (por exemplo, amido pré-gelatinizado) ou um agente de desintegração adicional (crospovidona) pode ser adicionada de forma extragranular antes do final da mistura da etapa g.
[00024] Em uma outra versão alternativa do processo o granulado produzido nas etapas a até e é produzido em um processo de granulação de alto cisalhamento em um recipiente e a secagem subseqüente é em um granulador de um recipiente.
[00025] Para a preparação de cápsulas, a mistura final é preenchida dentro de cápsulas.
[00026] Para a preparação de comprimidos ou núcleos de comprimidos, a mistura final é adicionalmente comprimida em comprimidos do peso do núcleo de comprimido-alvo com tamanho e força de compressão apropriados, utilizando uma prensa de comprimidos apropriada.
[00027] Para a preparação de comprimidos revestidos com filme é preparada uma suspensão de revestimento e os núcleos de comprimidos comprimidos são revestidos com a suspensão de revestimento até um ganho de peso de aproximadamente 2-4 %, preferencialmente aproximadamente 3%, utilizando um aparato de revestimento com filme padronizado. O solvente de revestimento com filme é um componente volátil, que não fica no produto final. Para reduzir a quantidade requerida de agente lubrificante nos comprimidos é uma opção utilizar um sistema de lubrificação externa.
Exemplos Exemplo 1 - Formulação para compressão direta
[00028] Um ingrediente inibidor de DPP IV ativo com um grupo amino primário e todos os outros excipientes com a exceção de estearato de magnésio são misturados em uma misturadora de alto cisalhamento. A pré-mistura é peneirada através de uma peneira de 1 mm. Após a adição de estearato de magnésio, a pré-mistura é misturada em uma misturadora de queda livre para produzir a mistura final. A mistura final é comprimida em comprimidos utilizando uma prensa de comprimidos adequada. Podem ser obtidas as composições a seguir:
Figure img0015
Exemplo 2 - Formulação alternativa para compressão direta
[00029] Um ingrediente inibidor de DPP IV ativo com um grupo amino primário e todos os outros excipientes com a exceção de estearato de magnésio são misturados em uma misturadora de alto cisalhamento. Esta pré-mistura é peneirada através de uma peneira de 1 mm. Após a adição de estearato de magnésio, a pré-mistura é misturada em uma misturadora de queda livre para produzir a mistura final. A mistura final é comprimida em comprimidos utilizando uma prensa de comprimidos adequada. Podem ser obtidas as composições a seguir:
Figure img0016
Figure img0017
Exemplo 3 - Formulação de comprimido
[00030] A copovidona é dissolvida em água purificada à temperatura ambiente para produzir um líquido de granulação. Um ingrediente inibidor de DPP IV ativo com um grupo amino primário, manitol e parte do amido pré-gelatinizado são misturados em uma misturadora adequada, para produzir uma pré-mistura. A pré-mistura é umedecida com o líquido de granulação e granulada subseqüentemente. O granulado umedecido é opcionalmente peneirado através de uma peneira com um tamanho de trama de 1,6-3,0 mm. O granulado é seco a 55 °C em uma secadora adequada até um teor de umidade residual correspondendo a 2-5 % de perda na secagem. O granulado seco é peneirado através de uma peneira com um tamanho de trama de 1,0 mm. O granulado é misturado com parte do amido pré-gelatinizado em uma misturadora adequada. O estearato de magnésio é adicionado a esta mistura após passar através de uma peneira de 1,0 mm para desagregação.
[00031] Subseqüentemente, a mistura final é produzida através da mistura final em uma misturadora adequada e comprimida em comprimidos. Pode ser obtida a composição de comprimido a seguir:
Figure img0018
Figure img0019
Exemplo 4 - Formulação de comprimido revestido
[00032] A copovidona é dissolvida em água purificada à temperatura ambiente para produzir um líquido de granulação. Um ingrediente inibidor de DPP IV ativo com um grupo amino primário, manitol, amido pré- gelatinizado e amido de milho são misturados em uma misturadora adequada para produzir a pré-mistura. A pré-mistura é umedecida com o líquido de granulação e granulada subseqüentemente utilizando uma misturadora de alto cisalhamento. O granulado umedecido é opcionalmente peneirado através de uma peneira com tamanho de trama de 1,6-3,0 mm. O granulado é seco a aproximadamente 60 °C em uma secadora em leito fluidizado até que uma perda no valor de secagem de 2-4 % seja obtida. A mistura final é comprimida em núcleos de comprimido.
[00033] A hidroxipropil metilcelulose, o polietileno glicol, o talco, o dióxido de titânio e o óxido de ferro são suspensos em água purificada em uma misturadora adequada à temperatura ambiente para produzir uma suspensão de revestimento. Os núcleos de comprimidos são revestidos com uma suspensão de revestimento até um ganho de peso de aproximadamente 3 % para produzir comprimidos revestidos com filme. Podem ser obtidas as composições de comprimido a seguir:
Figure img0020
Figure img0021
Exemplo 5 - Formulação de comprimido
[00034] A copovidona é dissolvida em água purificada à temperatura ambiente para produzir um líquido de granulação. Um ingrediente inibidor de DPP IV ativo com um grupo amino primário, manitol e amido pré- gelatinizado são misturados em uma misturadora adequada para produzir uma pré-mistura. A pré-mistura é umedecida com o líquido de granulação e subseqüentemente granulada. O granulado umedecido é opcionalmente peneirado através de uma peneira adequada. O granulado é seco a aproximadamente 50 °C em uma secadora adequada até que uma perda no valor de secagem de 3-5% seja obtida. O granulado seco é peneirado através de uma peneira com tamanho de trama de 1,0 mm.
[00035] O estearato de magnésio é passado através de uma peneira de 1,0 mm e adicionado no granulado. Subseqüentemente, a mistura final é produzida através da mistura final e uma misturadora adequada e a misturação final é comprimida em comprimidos. Podem ser obtidas as composições de comprimido a seguir:
Figure img0022
Exemplo 6 - Variações de formulações de comprimido
[00036] A copovidona é dissolvida em água purificada à temperature ambiente para produzir um líquido de granulação. Um ingrediente inibidor de DPP IV ativo com um grupo amino primário e uma parte do manitol, amido pré-gelatinizado e amido de milho são misturados em uma misturadora adequada, para produzir uma pré-mistura. A pré- mistura é umedecida com o líquido de granulação e subseqüentemente granulada. O granulado umedecido é peneirado através de uma peneira adequada. O granulado é seco à temperatura do ar de entrada a aproximadamente 60 °C em uma secadora em leito fluidizado até que uma perda no valor de secagem de 1-4 % seja obtida. O granulado seco é peneirado através de uma peneira com tamanho de trama de 1,0 mm.
[00037] O estearato de magnésio é passado através de uma peneira para a desagregação e é adicionado no granulado. Adicionalmente, a parte restante dos excipientes é adicionada de forma extragranular nesta etapa do processo. Subseqüentemente, a mistura final é produzida através da misturação final em uma misturadora adequada e comprimida em núcleos de comprimido.
[00038] A hidroxipropil metilcelulose, o polietileno glicol, o talco, o dióxido de titânio e o óxido de ferro são suspensos em água purificada em uma misturadora adequada à temperatura ambiente para produzir uma suspensão de revestimento. Os núcleos de comprimido são revestidos com a suspensão de revestimento até um ganho de peso de aproximadamente 3 % para produzir comprimidos revestidos com filme. Podem ser obtidas as variações de formulações a seguir: Exemplo 6.1 - Variações de formulação com excipients extragranulares
Figure img0023
Figure img0024
Exemplo 6.2 - Variações de formulação com agente de desintegração extragranular adicional
Figure img0025
Exemplo 6.3 - Formulações D de dose alta
Figure img0026

Claims (7)

1. Forma de dosagem oral farmacêutica sólida, caracterizada pelo fato de que compreende: (i) 0,5% a 7% (em peso) de um composto inibidor de DPP IV com um grupo amino ou um sal do mesmo, como insumo farmacêutico ativo; (ii) 50% a 75% (em peso) de manitol como primeiro diluente; (iii) 5% a 15% (em peso) de amido pré-gelatinizado como segundo diluente; (iv) 2% a 4% (em peso) copovidona como agente aglutinante; (v) 8% a 12% (em peso) de amido de milho como agente de desintegração; e (vi) 0,5% a 2% (em peso) de estearato de magnésio, como agente lubrificante, em que o composto inibidor de DPP IV com um grupo amino é selecionado a partir de: 1-[([1,5]naftiridin-2-il)metil]-3-metil-7-(2-butin-1-il)-8-((R)-3- amino-piperidin-1-il)-xantina, 1-[(Quinazolin-2-il)metil]-3-metil-7-(2-butin-1-il)-8-((R)-3- amino-piperidin-1-il)-xantina, 2-((R)-3-Amino-piperidin-1-il)-3-(but-2-iinil)-5-(4-metil- quinazolin-2-ilmetil)-3,5-dihidro-imidazo[4,5-d]piridazin-4-ona, 1-[(4-Metil-quinazolin-2-il)metil]-3-metil-7-(2-butiin-1-il)-8-[(2- amino-2-metil-propil)-metilamino]-xantina, 1-[(3-Ciano-quinolin-2-il)metil]-3-metil-7-(2-butin-1-il)-8-((R)- 3-amino-piperidin-1-il)-xantina, 1-(2-Ciano-benzil)-3-metil-7-(2-butin-1-il)-8-((R)-3-amino- piperidin-1-il)-xantina, 1-[(4-Metil-quinazolin-2-il)metil]-3-metil-7-(2-butin-1-il)-8- [(S)-(2-amino-propil)-metilamino]-xantina, 1-[(3-Ciano-piridin-2-il)metil]-3-metil-7-(2-butin-1-il)-8-((R)-3- amino-piperidin-1-il)-xantina, 1-[(4-Metil-pirimidin-2-il)metil]-3-metil-7-(2-butin-1-il)-8-((R)- 3-amino-piperidin-1-il)-xantina, 1-[(4,6-Dimetil-pirimidin-2-il)metil]-3-metil-7-(2-butin-1-il)-8- ((R)-3-amino -piperidin-1-il)-xantina, 1-[(Quinoxalin-6-il)metil]-3-metil-7-(2-butin-1-il)-8-((R)-3- amino-piperidin-1-il)-xantina.
2. Forma de dosagem oral farmacêutica sólida de acordo com a reivindicação 1, caracterizada pelo fato de que a quantidade do insumo farmacêutico ativo é igual a 0,5 mg, 1,0 mg, 2,5 mg, 5,0 mg, ou 10,0 mg.
3. Forma de dosagem oral farmacêutica sólida de acordo com a reivindicação 2, caracterizada pelo fato de que a quantidade do insumo farmacêutico ativo é 5mg.
4. Forma de dosagem oral farmacêutica sólida de acordo com qualquer uma das reivindicações 1 a 3, caracterizada pelo fato de que é um comprimido.
5. Forma de dosagem oral farmacêutica sólida de acordo com a reivindicação 4, caracterizada pelo fato de que é um comprimido revestido com filme.
6. Forma de dosagem oral farmacêutica sólida de acordo com a reivindicação 5, caracterizada pelo fato de que o comprimido revestido com filme compreende de 2 a 4 % de revestimento de filme, em que o revestimento de filme compreende um agente formador de filme, um agente de plastificação, um agente de deslizamento e opcionalmente um ou mais pigmentos.
7. Forma de dosagem oral farmacêutica sólida, de acordo com a reivindicação 6, caracterizada pelo fato de que o revestimento de filme compreende hidroxipropilmetilcelulose (HPMC), polietileno glicol (PEG), talco, dióxido de titânio e óxido de ferro.
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