PT2023902E - Formulações de inibidor de dpp iv - Google Patents

Formulações de inibidor de dpp iv Download PDF

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PT2023902E
PT2023902E PT07728658T PT07728658T PT2023902E PT 2023902 E PT2023902 E PT 2023902E PT 07728658 T PT07728658 T PT 07728658T PT 07728658 T PT07728658 T PT 07728658T PT 2023902 E PT2023902 E PT 2023902E
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methyl
amino
xanthine
piperidin
butyn
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PT07728658T
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Anja Kohlrausch
Patrick Romer
Gerd Seiffert
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Boehringer Ingelheim Int
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Description

DESCRIÇÃO "FORMULAÇÕES DE INIBIDOR DE DPP IV" A presente invenção refere-se a composições farmacêuticas de inibidores de DPP IV seleccionados, sua preparação e sua utilização para tratar estados médicos seleccionados. A enzima DPP-IV (dipeptidil peptidase IV), também conhecida como CD2 6, é uma serina protease conhecida por conduzir à clivagem de um dipéptido a partir da extremidade N-terminal de várias proteínas tendo nas suas extremidades N-terminal um resíduo de prolina ou alanina. Devido a esta propriedade, os inibidores de DPP-IV interferem com o nível de plasma de péptidos bioactivos incluindo o péptido GLP-1 e são considerados como fármacos promissores para o tratamento de diabetes mellitus.
Em tentativas para preparar composições farmacêuticas de inibidores de DPP-IV seleccionados, tem sido observado que os inibidores de DPP-IV, com um grupo amino primário ou secundário, apresentam incompatibilidades, problemas de degradação ou problemas de extracção com vários dos excipientes comuns, tais como celulose microcristalina, amidoglicolato de sódio, croscarmelose de sódio, ácido tartárico, ácido cítrico, glucose, frutose, sacarose, lactose, maltodextrinas. Apesar dos compostos sozinhos serem muito estáveis, reagem com muitos excipientes utilizados em formas de dosagem sólidas e com impurezas de excipientes, especialmente, em contacto próximo proporcionado em comprimidos e em razões elevadas de excipiente/fármaco. 0 grupo 1 amino parece reagir com açúcares redutores e com outros grupos carbonilo reactivos e com grupos funcionais de ácidos carboxilicos formados, por exemplo, na superfície de celulose microcristalina por oxidação. Estas dificuldades imprevistas são principalmente observadas em gamas de dosagem baixas, as quais são necessárias devido à potência surpreendente dos inibidores seleccionados. Assim, são necessárias composições farmacêuticas para resolver estes problemas técnicos associados com a potência inesperada de compostos inibidores de DPP-IV seleccionados.
Uma composição farmacêutica de acordo com a presente invenção é pretendida para o tratamento para conseguir o controlo glicémico num doente de diabetes mellitus de tipo 1 ou tipo 2 e compreende um inibidor de DPP-IV com um grupo amino, especialmente, um grupo amino livre ou primário, como um ingrediente activo, um primeiro e segundo diluente, um ligante, um desintegrante e um lubrificante. Um desintegrante opcional e um agente de deslizamento opcional são ainda uma opção. Além disso, as composições podem ser utilizadas para tratar artrite reumatóide, obesidade e osteoporose, bem como para suportar transplante de enxertos.
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 di-hidratado, eritritol, hidroxipropilcelulose pouco substituída, manitol, amido pré-gelatinizado ou xilitol. Entre esses diluentes, são preferidos o manitol e o amido pré-gelatinizado.
Os diluentes preferidos como o segundo diluente são os diluentes acima mencionados amido pré-gelatinizado e 2 hidroxipropilcelulose pouco substituída (L-HPC), os quais demonstram propriedades ligantes adicionais.
Os lubrificantes adequados para uma composição farmacêutica de acordo com a invenção são talco, polietilenoglicol, beenato de cálcio, estearato de cálcio, óleo de rícino hidrogenado ou estearato de magnésio. 0 lubrificante preferido é estearato de magnésio.
Os ligantes adequados para uma composição farmacêutica de acordo com a invenção são copivodona (copolimerizados de vinilpirrolidona com outros derivados de vinilo), hidroxipropilmetilcelulose (HPMC), hidroxipropilcelulose (HPC), polivinilpirrolidona (povidona), amido pré-gelatinizado, hidroxipropilcelulose pouco substituída (L-HPC), copovidona e sendo preferido o amido pré-gelatinizado.
Os ligantes acima mencionados, amido pré-gelatinizado e L-HPC, apresentam propriedades diluentes e desintegrantes adicionais e também podem ser utilizados como o segundo diluente ou o desintegrante.
Os desintegrantes adequados para uma composição farmacêutica de acordo com a presente invenção são amido de milho, crospovidona, hidroxipropilcelulose pouco substituída (L-HPC) ou amido pré-gelatinizado, sendo preferido amido de milho.
Como um agente de deslizamento opcional, pode ser utilizado dióxido de silício coloidal. 3
Uma composição exemplificativa, de acordo com a presente invenção, compreende o diluente manitol, amido pré-gelatinizado como um diluente com propriedades ligantes adicionais, o ligante copovidona, o desintegrante amido de milho, e estearato de magnésio como o lubrificante.
As formas de dosagem preparadas com uma composição farmacêutica de acordo com a presente invenção contêm ingredientes activos em gamas de dosagem de 0,1-100 mg. Dosagens preferidas são 0,5 mg, 1 mg, 2,5 mg, 5 mg e 10 mg.
Composições farmacêuticas típicas compreendem (% em peso) 0,5-20% 40-88% 3-40% 1-5% 5-15% 0,1-4% ingrediente activo diluente 1, diluente 2, ligante, desintegrante, e lubrificante.
Composiçoes peso) farmacêuticas preferidas compreendem (% em 0,5-7% 50-75% 5-15% 2-4% 8-12% 0,5-2% ingrediente activo diluente 1, diluente 2, ligante, desintegrante, e lubrificante
As composições farmacêuticas de acordo com a invenção são projectadas para utilização oral e podem ser utilizadas na forma 4 de dosagem de uma cápsula, um comprimido ou um comprimido revestido com película. Tipicamente, o revestimento de película representa 2-4%, de um modo preferido, 3% da composição e compreende um agente filmogénico, um plasticizante, um agente de deslizamento e, opcionalmente, um ou mais pigmentos. Uma composição de revestimento exemplificativa pode compreender hidroxipropilmetilcelulose (HPMC), polietilenoglicol (PEG) , talco, dióxido de titânio e, opcionalmente, óxido de ferro.
Os ingredientes activos preferidos no contexto da presente invenção são inibidores de DPP-IV com um grupo amino primário e seus sais, tal como qualquer inibidor de DPP-IV e seu sal definido pela fórmula (I)
ou fórmula (II)
(N) em que RI é ([1,5]naftiridin-2-il)metilo, (quinazolin-2-il)metilo], (quinoxalin-6-il)metilo, (4-Metil-quinazolin-2-il)metilo, 2-Ciano-benzilo, (3-ciano-quinolin-2-il)metilo, (3-Ciano-piridin-2-il)metilo, (4-Metil-pirimidin-2-il)metilo ou (4,6-Dimetil-pirimidin-2-il)metilo, e R2 é 3-(R)-amino- 5 piperidin-l-ilo, (2-amino-2-metil-propil)-metilamino ou (2-(S)-amino-propil)-metilamino.
Os compostos inibidores de DPP IV preferidos são os seguintes compostos e seus sais: 1-[(4-metil-quinazolin-2-il)metil]-3-meti1-7-(2-butin-1-il)-8-(3-(R)-amino-piperidin-l-il)-xantina (comparar documento W02004/018468, exemplo 2(142):
1— [ ([ 1,5]naftiridin-2-il)metil]-3-meti1-7-(2-butin-l-il)-8-((R)-3-amino-piperidin-l-il)-xantina (comparar documento W02004/018468, exemplo 2(252)):
1—[(Quinazolin-2-il)metil]-3-meti1-7-(2-butin-l-il)-8-((R)-3-amino-piperidin-l-il)-xantina (comparar documento W02004/018468, exemplo 2(80)): 6
2-((R)-3-Amino-piperidin-l-il)-3-(but-2-inil)-5-(4-metil-quinazolin-2-ilmetil)-3,5-di-hidro-imidazo[4,5-d]piridazin-4-ona (comparar documento W02004/050658, exemplo 136):
• 1-[(4-Metil-quinazolin-2-il)metil]-3-meti1-7-(2-butin-1- il)-8-[(2-amino-2-metil-propil)-metilamino]-xantina (comparar documento WO 2006/029769, exemplo 2(1)):
l-[(3-Ciano-quinolin-2-il)metil]-3-meti1-7-(2-butin-l-il)-8-((R)-3-amino-piperidin-l-il)-xantina (comparar documento W02005/085246, exemplo 1(30)): 7
• 1-(2-Ciano-benzil)-3-metil-7-(2-butin-l-il)-8-((R)-3-amino- piperidin-l-il)-xantina (comparar documento W02005/085246, exemplo 1(39)):
• 1-[(4-Metil-quinazolin-2-il)metil]-3-meti1-7-(2-butin-l- il )-8-[(S)-(2-amino-propil)-metilamino]-xantina (comparar documento W02006/029769, exemplo 2(4)):
• 1 —[(3-Ciano-piridin-2-il)metil]-3-meti1-7-(2-butin-l-il)-8- ((R)-3-amino-piperidin-l-il)-xantina (comparar documento W02005/085246, exemplo 1(52)):
• 1-[(4-Metil-pirimidin-2-il)metil]-3-meti1-7-(2-butin-l-il)- 8-((R)-3-amino-piperidin-l-il)-xantina (comparar documento W02005/085246, exemplo 1(81)):
1-[(4,6-Dimetil-pirimidin-2-il)metil]-3-meti1-7-(2-butin-l-il) -8-((R)-3-amino-piperidin-l-il)-xantina (comparar documento W02005/085246, exemplo 1(82)):
O
N 9 1-[(Quinoxalin-6-il)metil]-3-metil-7-(2-butin-l-il)-8-((R)-3-amino-piperidin-l-il)-xantina (comparar documento WO2005/085246, exemplo 1(83)):
Para preparar composições de acordo com a invenção pode ser preparado um granulado por um processo de granulação húmida. Métodos alternativos para granulação de ingrediente activo e excipientes com um liquido de granulação são granulação em leito fluidizado ou granulação de um só passo.
No processo de granulação húmida, o liquido de granulação é um solvente, tais como água, etanol, metanol, isopropanol, acetona, de um modo preferido, água purificada, e contém um ligante, tal como copovidona. 0 solvente é um componente volátil, o qual não permanece no produto final. 0 ingrediente activo e os outros excipientes, com a excepção do lubrificante, são pré-misturados e granulados com o liquido de granulação aquoso utilizando um granulador de alto cisalhamento. 0 passo de granulação húmida é seguido de um passo de peneiração húmida opcional, secagem e peneiração seca dos grânulos. Por exemplo, um secador de leito fluidizado pode então ser utilizado para secagem.
Os grânulos secos são peneirados através de um peneiro adequado. Após adição dos outros excipientes, com excepção do lubrificante, a mistura é misturada num misturador convencional 10 adequado, tal como um misturador de queda livre seguido de adição do lubrificante, tal como estearato de magnésio e mistura final no misturador.
Assim, um processo de granulação húmida exemplificativo para a preparação de uma composição farmacêutica de acordo com a invenção compreende a. dissolver um ligante, tal como copovidona, num solvente, tal como água purificada, à temperatura ambiente, para produzir um liquido de granulação; b. misturar um inibidor de DPP-IV, um diluente e um desintegrante num misturador adequado, para produzir uma pré-mistura; c. humedecer a pré-mistura com o líquido de granulação e, subsequentemente, granular a pré-mistura húmida, por exemplo, num misturador de alto cisalhamento; d. opcionalmente, peneirar a pré-mistura granulada através de um peneiro com um tamanho de malha de pelo menos 1,0 mm e, de um modo preferido, 3 mm; e. secar o granulado a 40-75 °C e, de um modo preferido, com temperatura de ar de entrada de 55-65 °C, por exemplo, num secador de leito fluidizado até ser obtido a perda desejada no valor de secagem na gama de 1-5%; f. desaglomeração o granulado seco, por exemplo, por peneiração através de um peneiro com um tamanho de malha de 0,6 mm-1,6 mm, de um modo preferido, 1,0 mm; e 11 g. adicionar, de um modo preferido, lubrificante peneirado ao granulado para mistura final, por exemplo, num misturador cúbico.
Num processo alternativo, parte dos excipientes, tal como parte de um desintegrante (e.g., amido de milho) ou um diluente (e.g., amido pré-gelatinizado) ou um desintegrante adicional (crospovidona) pode ser adicionado de forma extragranular antes da mistura final do passo g.
Noutra versão alternativa do processo, o granulado produzido nos passos a a e é produzido num processo de granulação de um só passo de alto cisalhamento e subsequente secagem num granulador de um só passo.
Para a preparação de cápsulas, a mistura final é ainda enchida em cápsulas.
Para a preparação de comprimidos ou núcleos de comprimidos, a mistura final é ainda comprimida em comprimidos do peso do núcleo de comprimido alvo com tamanho e força de esmagamento adequados, utilizando uma prensa de comprimidos adequada.
Para a preparação de comprimidos revestidos por película, uma suspensão de revestimento é preparada e os núcleos de comprimido comprimidos são revestidos com a suspensão de revestimento até um ganho em peso de cerca de 2-4%, de um modo preferido, cerca de 3%, utilizando um revestidor de película padrão. 0 solvente de revestimento de película é um componente volátil, o qual não permanece no produto final. Para reduzir a 12 quantidade de lubrificante necessária nos comprimidos, é uma opção utilizar um sistema de lubrificação externo.
Exemplos
Exemplo 1 - Formulação para compressão directa
Um ingrediente inibidor de DPP IV activo com um grupo amino primário e todos os outros excipientes, com excepção de estearato de magnésio, são misturados num misturador de alto cisalhamento. Esta pré-mistura é peneirada através de um peneiro de 1 mm. Após adição de estearato de magnésio, a pré-mistura é misturada num misturador de queda livre para produzir a mistura final. A mistura final é comprimida em comprimidos utilizando uma prensa para comprimidos adequada. As seguintes composições podem ser obtidas:
Componente mg/comprimido %/comprimido mg/comprimido %/comprimido Ingrediente activo 1,000 2, 000 2,500 2, 000 Manitol 43,250 86,500 108,125 86,500 Amido pré-gelatinizado 5,000 10,000 12,500 10,000 Estearato de magnésio 0, 750 1, 500 1, 875 1,500 Total 50,000 100,000 125,000 100,000 13
Componente mg/comprimldo %/comprimido mg/comprimido %/comprimido Ingrediente activo 5, 000 2, 000 10,000 2, 000 Manitol 216,250 86,500 432,500 86,500 Amido pré-gelatinizado 25,000 10,000 50,000 10,000 Estearato de magnésio 3,750 1,500 7,500 1,500 Total 250,000 100,000 500,000 100,000
Exemplo 2 - Formulação alternativa para compressão directa
Um ingrediente inibidor de DPP IV activo com um grupo amino primário e todos os outros excipientes, com excepção de estearato de magnésio, são misturados num misturador de alto cisalhamento. Esta pré-mistura é peneirada através de um peneiro de 1 mm. Após adição de estearato de magnésio, a pré-mistura é misturada num misturador de queda livre para produzir a mistura final. A mistura final é comprimida em comprimidos utilizando uma prensa para comprimidos adequada. As seguintes composições podem ser obtidas: 14
Componente mg/comprimido %/comprimido mg/comprimido %/comprimido Ingrediente activo 1,000 1,667 0, 500 0, 833 Fosfato de cálcio dibásico, anidro 46,400 77,333 46,900 78,177 Hidroxipropil-celulose pouco substituída 12,000 20,000 12,000 20,000 Estearato de magnésio 0,600 1,000 0,600 1, 000 Total 60,000 100,000 60,000 100,000
Componente mg/comprimido %/comprimido mg/comprimido %/comprimido Ingrediente activo 10,000 1,667 10,000 2,222 Fosfato de cálcio dibásico, anidro 464,000 77,333 344,000 76,788 Hidroxipropil-celulose pouco substituída 120,000 20,000 90,000 20,000 Estearato de magnésio 6, 000 1,000 6, 000 1, 000 Total 600,000 100,000 450,000 100,000
Exemplo 3 - Formulação em comprimido A copovidona é dissolvida em água purificada, à temperatura ambiente, para produzir um líquido de granulação. Um ingrediente 15 inibidor de DPP IV activo com um grupo amino primário, manitol e parte do amido pré-gelatinizado são misturados num misturador adequado para produzir uma pré-mistura. A pré-mistura é humedecida com o liquido de granulação e subsequentemente granulada. 0 granulado húmido é opcionalmente peneirado através de um peneiro com um tamanho de malha de 1,6-3,0 mm. O granulado é seco a 55 °C num secador adequado até um teor de humidade residual correspondendo a 2-5% de perda na secagem. O granulado seco é peneirado através de um peneiro com um tamanho de malha de 1,0 mm. O granulado é misturado com parte do amido pré-gelatinizado num misturador adequado. O estearato de magnésio é adicionado a esta mistura após passagem através de um peneiro de 1,0 mm para desaglomeração. Subsequentemente, a mistura final é produzida por mistura final num misturador adequado e comprimida em comprimidos. A seguinte composição de comprimido pode ser obtida:
Componente mg/comprimido %/comprimido Ingrediente activo 10,000 1,667 Amido pré-gelatinizado 210,000 35,000 Manitol 236,000 39,333 Copovidona 18,000 3,000 Total (granulado) 474,000 79,000 Amido pré-gelatinizado 120,000 20,000 Estearato de magnésio 6,000 1,000 Total 600,000 100,000 16
Exemplo 4 - Formulação em comprimido revestido A copovidona é dissolvida em água purificada, à temperatura ambiente, para produzir um liquido de granulação. Um ingrediente inibidor de DPP IV activo com um grupo amino primário, manitol, amido pré-gelatinizado e amido de milho são misturados num misturador adequado para produzir uma pré-mistura. A pré-mistura é humedecida com o liquido de granulação e subsequentemente granulada utilizando um misturador de alto cisalhamento. 0 granulado húmido é opcionalmente peneirado através de um peneiro com um tamanho de malha de 1,6-3,0 mm. O granulado é seco a cerca de 60 °C num secador de leito fluidizado até ser obtido um valor de perda na secagem de 2-4%. A Mistura Final é comprimida em núcleos de comprimido.
Hidroxipropilmetilcelulose, polietilenoglicol, talco, dióxido de titânio e óxido de ferro são suspensos em água purificada num misturador adequado, 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 cerca de 3% para produzir comprimidos revestidos com pelicula. As seguintes composições de comprimido podem ser obtidas: 17
Componente mg mg mg mg mg Ingrediente activo 0,500 1, 000 2, 500 5, 000 10,000 Manitol 67,450 66,950 65,450 130,900 125,900 Amido pré-gelatinizado 9,000 9, 000 9, 000 18,000 18,000 Amido de milho 9,000 9, 000 9, 000 18,000 18,000 Copovidona 2,700 2, 700 2, 700 5, 400 5, 400 Estearato de magnésio 1,350 1,350 1,350 2, 700 2, 700 Massa Total (núcleo do comprimido) 90,000 90,000 90,000 180,000 180,000 HPMC 1,500 1,500 1, 500 2, 500 2, 500 PEG 0,150 0,150 0, 150 0, 250 0, 250 Dióxido de titânio 0,750 0,750 0, 750 1, 250 1, 250 Talco 0,525 0,525 0, 525 0, 875 0, 875 Óxido de ferro, amarelo 0,075 0,075 0, 075 0,125 0, 125 Massa Total (comprimido revestido) 93,000 93,000 93,000 185,000 185,000
Exemplo 5 - Formulação em comprimido A copovidona é dissolvida em água purificada à temperatura ambiente para produzir um liquido de granulação. Um ingrediente inibidor de DPP IV activo com um grupo amino primário, manitol e amido pré-gelatinizado são misturados num misturador adequado 18 para produzir uma pré-mistura. A pré-mistura é humedecida com o liquido de granulação e subsequentemente granulada. 0 granulado húmido é opcionalmente peneirado através de um peneiro adequado. 0 granulado é seco a cerca de 50 °C num secador adequado até ser obtido um valor de perda na secagem de 3-5%. O granulado seco é peneirado através de um peneiro com um tamanho de malha de 1.0 mm. O estearato de magnésio é passado através de um peneiro de 1.0 mm e adicionado ao granulado. Subsequentemente, a mistura final é produzida por mistura final num misturador adequado e a mistura final é comprimida em comprimidos. As seguintes composições de comprimido podem ser obtidas:
Componente mg mg mg mg mg Ingrediente activo 0,500 1,000 2, 500 5, 000 10,000 Manitol 27,500 27,000 67,500 135,000 130,000 Amido pré-gelatinizado 20,000 20,000 50,000 100,000 100,000 Copovidona 1,500 1,500 3, 750 7,500 7, 500 Estearato de magnésio 0,500 0,500 1,250 2,500 2, 500 Massa do comprimido total 50,000 50,000 125,000 250,000 250,000
Exemplo 6 - Variantes de formulação em comprimido A copovidona é dissolvida em água purificada, à temperatura ambiente, para produzir um liquido de granulação. Um ingrediente inibidor de DPP IV activo com um grupo amino primário e uma parte de manitol, amido pré-gelatinizado e amido de milho são misturados num misturador adequado para produzir uma 19 pré-mistura. A pré-mistura é humedecida com o líquido de granulação e subsequentemente granulada. 0 granulado húmido é peneirado através de um peneiro adequado. 0 granulado é seco com uma temperatura de ar de entrada de cerca de 60 °C num secador de leito fluidizado até ser obtido um valor de perda na secagem de 1-4%. O granulado seco é peneirado através de um peneiro com um tamanho de malha de 1,0 mm. O estearato de magnésio é passado através de um peneiro para desaglomeração e adicionado ao granulado. Adicionalmente, a parte remanescente dos excipientes é adicionada de forma extragranular neste passo do processo. Subsequentemente, a mistura final é produzida por mistura final num misturador adequado e comprimida em núcleos de comprimido.
Hidroxipropilmetilcelulose, polietilenoglicol, talco, dióxido de titânio e óxido de ferro são suspensos em água purificada num misturador adequado, 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 cerca de 3% para produzir comprimidos revestidos com película. As seguintes variantes de formulação podem ser obtidas: 20
Exemplo 6.1 - Variantes de formulação com excipientes extragranulares
Componente Formulação E Formulação F mg/Comprimido %/Comprimido mg/Comprimido %/Comprimido Ingrediente activo 1,000 1,111 1,000 1,111 Manitol 23,300 25,889 66,950 74,389 Amido pré-gelatinizado 4, 500 5, 000 4,500 5, 000 Amido de milho 4,500 5, 000 4,500 5, 000 Copovidona 1,350 1,500 2,700 3, 000 Total (granulado) 34,650 38,500 79,650 88,500 Amido de milho 4,500 5, 000 4,500 5, 000 Amido pré-gelatinizado 4, 500 5, 000 4,500 5, 000 Manitol 45,000 50,000 Estearato de magnésio 1,350 1,500 1,350 1,500 Total (núcleo do comprimido) 90,000 100,000 90,000 100,000 21
Exemplo 6.2 - Variantes de formulação com desintegrante extragranular adicional
Componente mg mg mg mg mg Ingrediente activo 0,500 1, 000 2,500 5, 000 10,000 Manitol 67,450 66,950 65,450 130,900 125,900 Amido pré-gelatinizado 9,000 9, 000 9,000 18,000 18,000 Amido de milho 9,000 9, 000 9,000 18,000 18,000 Copovidona 2,700 2, 700 2,700 5, 400 5, 400 Massa Total (granulado) 88,650 88,650 88,650 177,300 177,300 Estearato de magnésio 1,350 1,350 1,350 2, 700 2,700 Crospovidona 2,000 2, 000 2,000 4, 000 4, 000 Massa Total (núcleo do comprimido) 92,000 92,000 92,000 184,000 184,000 HPMC 1,500 1,500 1,500 2,500 2,500 PEG 0, 150 0, 150 0, 150 0,250 0,250 Dióxido de titânio 0, 750 0, 750 0, 750 1,250 1,250 Talco 0,525 0,525 0,525 0, 875 0, 875 Óxido de ferro, amarelo 0, 075 0, 075 0, 075 0, 125 0, 125 Massa Total (comprimido revestido) 95,000 95,000 95,000 189,000 189,000 22
Exemplo 6.3 - Formulações de dose elevada D
Componente mg/comprimido %/comprimido mg/comprimido %/comprimido Ingrediente activo 25,000 27,778 50,000 27,778 Manitol 40,700 45,222 81,400 45,222 Amido pré-gelatinizado 9, 000 10,000 18,000 10,000 Amido de milho 9, 000 10,000 18,000 10,000 Copovidona 2, 700 3, 000 5, 400 3,000 Total (granulado) 86,400 96,000 172,800 96,000 Crospovidona 2, 700 3,000 5, 400 3, 000 Estearato de magnésio 0,900 1,000 1, 800 1,000 Total (núcleo de comprimido) 90,000 100,000 180,000 100,000 Hidroxipropil- metilcelulose 1,500 1,667 2, 500 1,389 Polietilenoglicol 0,150 0,167 0, 250 0,139 Dióxido de titânio 0,750 0,833 1, 250 0,694 Talco 0,525 0,583 0, 875 0,486 Óxido de ferro amarelo 0,075 0,083 0, 125 0, 069 Total (comprimido revestido com película) 93,000 103,333 185,000 102,778
Lisboa, 30 de Setembro de 2010 23

Claims (14)

  1. REIVINDICAÇÕES 1. Composição farmacêutica compreendendo, como um ingrediente activo, um composto inibidor de DPP IV activo com um grupo amino seleccionado de • 1-[(4-metil-quinazolin-2-il)metil]-3-meti1-7-(2-butin-1-il)-8-(3-(R)-amino-piperidin-l-il)-xantina, • 1— [ ( [l,5]naftiridin-2-il)metil]-3-meti1-7-(2-butin-l-il)-8-((R)-3-amino-piperidin-l-il)-xantina, • 1-[(Quinazolin-2-il)metil]-3-meti1-7-(2-butin-l-il)-8-((R)-3-amino-piperidin-l-il)-xantina, • 2-((R)-3-Amino-piperidin-l-il)-3-(but-2-inil)-5-(4-metil-quinazolin-2-ilmetil)-3,5-di-hidro-imidazo[4,5-d]piridazin-4-ona, • 1-[(4-Metil-quinazolin-2-il)metil]-3-meti1-7-(2-butin-l-il) -8-[(2-amino-2-metil-propil)-metilamino]-xantina, • 1-[(3-Ciano-quinolin-2-il)metil]-3-meti1-7-(2-butin-l-il) -8-((R)-3-amino-piperidin-l-il)-xantina, • 1-(2-Ciano-benzil)-3-meti1-7-(2-butin-l-il)-8-((R)-3-amino-piperidin-l-il)-xantina, • 1-[(4-Metil-quinazolin-2-il)metil]-3-meti1-7-(2-butin-l-il) -8-[(5)-(2-amino-propil)-metilamino]-xantina, 1 • 1—[(3-Ciano-piridin-2-il)metil]-3-meti1-7-(2-butin-l-il)-8-((R)-3-amino-piperidin-l-il)-xantina, • 1-[(4-Metil-pirimidin-2-il)metil]-3-meti1-7-(2-butin-l-il)-8-((R)-3-amino-piperidin-l-il)-xantina, • 1-[(4,6-Dimetil-pirimidin-2-il)metil]-3-metil-7-(2-butin-l-il)-8-((R)-3-amino-piperidin-l-il)-xantina, • l-[(Quinoxalin-6-il)metil]-3-meti1-7-(2-butin-l-il)-8-((R)-3-amino-piperidin-l-il)-xantina, ou um seu sal, um primeiro diluente o qual é manitol, um segundo diluente o qual é amido pré-gelatinizado, um ligante o qual é copovidona, um desintegrante o qual é amido de milho e um lubrificante o qual é estearato de magnésio.
  2. 2. Composição farmacêutica da reivindicação 1 compreendendo 0,5-20% ingrediente activo 40-88% diluente 1, 3-40% diluente 2, 1-5% ligante, 5-15% desintegrante, e 0,1-4% lubrificante 2
  3. 3. Composição farmacêutica da reivindicação 1 compreendendo 0,5-7% 50-75% 5-15% 2-4% 8-12% 0,5-2% ingrediente activo, diluente 1, diluente 2, ligante, desintegrante, e lubrificante
  4. 4. Composição farmacêutica de acordo com a reivindicação 1 na forma de dosagem de uma cápsula, um comprimido ou um comprimido revestido com película.
  5. 5. Composição farmacêutica da reivindicação 4 compreendendo 2-4% de revestimento de película.
  6. 6. Composição farmacêutica da reivindicação 4, em que o revestimento de película compreende um agente filmogénico, um plasticizante, um agente de deslizamento e, opcionalmente, um ou mais pigmentos.
  7. 7. Composição farmacêutica da reivindicação 6, em que o revestimento de película compreende hidroxipropilmetilcelulose (HPMC), polietilenoglicol (PEG), talco, dióxido de titânio e óxido de ferro. 3
  8. 8. Processo para a preparaçao de uma composição farmacêutica de acordo com a reivindicação 1 compreendendo a. dissolver o ligante num solvente para produzir um líquido de granulação; b. misturar o inibidor de DPP-IV, os diluentes e o desintegrante para produzir uma pré-mistura; c. humedecer a pré-mistura com o líquido de granulação e, subsequentemente, granular a pré-mistura húmida; d. opcionalmente, peneirar a pré-mistura granulada através de um peneiro com um tamanho de malha de, pelo menos, 1,0 mm; e. secar o granulado a cerca de 40-75 °C até ser obtido a perda desejada no valor de secagem na gama de 1-5%; f. peneirar o granulado seco através de um peneiro com um tamanho de malha de pelo menos 0,6 mm; g. adicionar o lubrificante ao granulado para mistura final.
  9. 9. Processo de acordo com a reivindicação 8 compreendendo ainda h. comprimir a mistura final em núcleos de comprimido; i. preparar a suspensão de revestimento; 4 j. revestir os núcleos de comprimido com a suspensão de revestimento até um ganho de peso de cerca de 2-4% para produzir comprimidos revestidos com pelicula.
  10. 10. Processo de acordo com a reivindicação 8, em que parte dos excipientes são adicionados de forma extragranular antes da mistura final do passo g.
  11. 11. Processo de acordo com a reivindicação 8, em que o granulado produzido nos passos a-e é produzido num processo de granulação de um só passo de alto cisalhamento e, subsequentemente, seco num granulador de um só passo.
  12. 12. Forma de dosagem preparada com a composição farmacêutica, de acordo com a reivindicação 1, contendo o ingrediente activo numa dosagem de 0,5 mg, 1 mg, 2,5 mg, 5 mg ou 10 mg.
  13. 13. Composição farmacêutica de acordo com a reivindicação 1, em que o inibidor de DPP IV é 1-[(4-metil-quinazolin-2-il)metil]-3-meti1-7-(2-butin-l-il)-8-(3-(R)-amino-piperidin-l-il)-xantina.
  14. 14. Processo de acordo com a reivindicação 8 ou 9, em que o inibidor de DPP IV é 1-[(4-metil-quinazolin-2-il)metil]-3-metil-7-(2-butin-l-il)-8-(3-(R)-amino-piperidin-l-il)-xantina. Lisboa, 30 de Setembro de 2010 5
PT07728658T 2006-05-04 2007-04-30 Formulações de inibidor de dpp iv PT2023902E (pt)

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