ES2556947T3 - Composición sólida oral que comprende un agonista del receptor S1P y un alcohol de azúcar - Google Patents
Composición sólida oral que comprende un agonista del receptor S1P y un alcohol de azúcar Download PDFInfo
- Publication number
- ES2556947T3 ES2556947T3 ES10184951.1T ES10184951T ES2556947T3 ES 2556947 T3 ES2556947 T3 ES 2556947T3 ES 10184951 T ES10184951 T ES 10184951T ES 2556947 T3 ES2556947 T3 ES 2556947T3
- Authority
- ES
- Spain
- Prior art keywords
- sugar alcohol
- receptor agonist
- mannitol
- oral composition
- solid oral
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
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- 239000000018 receptor agonist Substances 0.000 title abstract description 11
- 229940044601 receptor agonist Drugs 0.000 title abstract description 11
- 239000007787 solid Substances 0.000 title abstract 2
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- 235000010355 mannitol Nutrition 0.000 abstract description 14
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Classifications
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K31/13—Amines
- A61K31/145—Amines having sulfur, e.g. thiurams (>N—C(S)—S—C(S)—N< and >N—C(S)—S—S—C(S)—N<), Sulfinylamines (—N=SO), Sulfonylamines (—N=SO2)
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- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
- A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
- A61K31/138—Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
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- A—HUMAN NECESSITIES
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Abstract
Un procedimiento para producir una composición farmacéutica en forma de una formulación sólida adecuada para la administración oral en forma de una cápsula, que comprende: (a) mezclar un agonista del receptor de S1P con un alcohol de azúcar; (b) moler y/o granular la mezcla obtenida en (a); y (c) mezclar la mezcla molida y/o granulada obtenida en (b) con un lubricante, en donde el agonista del receptor de S1P es 2-amino-2-[2-(4-octilfenil)etil]propano-1,3-diol (FTY720) en su forma libre o sal farmacéuticamente aceptable; el alcohol de azúcar es manitol.
Description
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Un compuesto preferido de fórmula VIII es el (2R)-2-amino-4-[3-(4-ciclohexiloxibutil)-benzo[b]tien-6-il]-2-metilbutan-1ol.
Cuando los compuestos de fórmulas I a XIII tienen uno o más centros asimétricos en la molécula los diversos isómeros ópticos, así como los racematos, diastereoisómeros y sus mezclas están incluidas.
Ejemplos de sales farmacéuticamente aceptables de los compuestos de fórmulas I a XIII incluyen sales con ácidos inorgánicos, tales como hidrocloruro, hidrobromuro y sulfato, sales con ácidos orgánicos, tales como sales de acetato, fumarato, maleato, benzoato, citrato, malato, metanosulfonato y bencenosulfonato, o, cuando sea apropiado, sales con metales, tales como de sodio, potasio, calcio y aluminio, sales con aminas, tales como trietilamina y sales con ácidos de amino dibásicos, tales como lisina. Los compuestos y sales de la presente descripción abarcan formas de hidrato y solvato.
La unión a los receptores de S1P puede ser determinada de acuerdo con los siguientes ensayos.
A. Afinidad de unión de agonistas del receptor de S1P a receptores de S1P humanos individuales
Transfección transitoria de receptores de S1P humanos en células HEK293
Se clonan receptores de S1P y proteínas Gi, y se mezclan cantidades iguales de 4 cADN para el receptor de EDG, Gi-α, Gi-β y Gi-γ y se usan para transfectar monocapas de células HEK293 usando el método del precipitado de fosfato de calcio (M. Wigler et al., Cell. 1977; 11; 223 y DS. Im et al., Mol. Pharmacol. 2000; 57; 753). Brevemente, una mezcla de ADN que contiene 25 µg de ADN y CaCl2 0,25 M se añade a Na2HPO4 2 mM tamponado con HEPES. Las monocapas subconfluentes de células HEK293 se envenenan con cloroquina 25 mM, y el precipitado de ADN se aplica entonces a las células. Después de 4 h, las monocapas se lavan con solución salina tamponada con fosfato y medio realimentado (1:1 medio modificado esencial de Dulbecco (DMEM):F-12 al 90% + suero bovino fetal al 10%). Las células se recogen 48-72 h después de la adición del ADN raspándolas en tampón HME (en mM: HEPES 20, MgCl2 5, EDTA 1, pH 7,4) conteniendo sacarosa al 10% en hielo, y se rompen usando un homogenizador Dounce. Después de una centrifugación a 800×g, el sobrenadante se diluye con HME sin sacarosa y se centrifuga a 100.000×g durante 1 h. El pelete resultante se homogeniza de nuevo y se centrifuga una segunda hora a 100.000×g. Este pelete de membranas crudo se suspende de nuevo en HME con sacarosa, se separa en alícuotas y se congelan instantáneamente por inmersión en nitrógeno líquido. Las membranas se almacenan a 70°C. La concentración de proteínas se determina espectroscópicamente mediante el ensayo de proteínas de Bradford.
Ensayo de unión de GTPγS usando preparaciones de receptor de S1P/membrana de HEK293
Se realizan experimentos de unión de GTPγS como se describe en DS. Im et al., Mol. Pharmacol. 2000; 57:753. La unión de GTPγS mediada por ligando a proteínas G se mide en tampón de unión de GTP (en mM: HEPES 50, NaCl 100, MgCl2 10, pH 7,5) usando 25 µg de una preparación de membranas a partir de células HEK293 transfectadas transitoriamente. El ligando se añade a las membranas en presencia de GDP 10 µM y [35S]GTPγS 0,1 nM (1200 Ci/mmol) y se incuba a 30°C durante 30 min. El GTPγS unido se separa del no unido usando un cultivador Brandel (Gaithersburg, MD) y se cuentan con un contador centelleante de líquidos.
La composición, especialmente la obtenida en el procedimiento de la invención, contiene preferiblemente de 0,01 a 20% en peso de agonistas del receptor de S1P, más preferiblemente de 0,1 a 10%, por ejemplo de 0,5 a 5% en peso, basado en el peso total de la composición.
El alcohol de azúcar puede actuar como un diluyente, vehículo, carga o agente de relleno y es, por ejemplo, manitol (D-manitol).
En una realización particularmente preferida del procedimiento de la presente invención, el alcohol de azúcar se prepara a partir de una composición secada por pulverización; por ejemplo, una composición de manitol, que tenga un área superficial altamente específica. El uso de este tipo de composición de manitol puede ayudar a promocionar una distribución uniforme del agonista del receptor de S1P de todo el manitol en la composición. Puede lograrse un área superficial mayor proporcionando una preparación de manitol que consista en partículas con un tamaño promedio más pequeño y/o una superficie más grande en cada partícula. El uso de un manitol secado por pulverización, por ejemplo con un tamaño de partículas promedio de 300 µm o menos, también se ha encontrado que mejora la compresibilidad y dureza de los comprimidos formados a partir de la composición.
Preferiblemente el área superficial de un solo punto de la preparación del alcohol de azúcar, por ejemplo, el manitol, tiene de 1 a 7 m2/g, por ejemplo de 2 a 6 m2/g o de 3 a 5 m2/g. La preparación de manitol puede tener adecuadamente un tamaño de partículas promedio de 100 a 300 µm, por ejemplo de 150 a 250 µm y una densidad aparente de 0,4 a 0,6 g/mL, por ejemplo de 0,45 a 0,55 g/mL. Un manitol de alta área superficial adecuada es Parteck M200, disponible comercialmente de E. Merck.
La composición farmacéutica obtenible de acuerdo con la invención preferiblemente contiene de 75 a 99,99% en peso del alcohol de azúcar, más preferiblemente de 85 a 99,9%, por ejemplo, de 90 a 99,5% en peso, basada en el peso total de la composición.
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El agonista del receptor de S1P, por ejemplo el hidrocloruro de 2-amino-2-[2-(4-octilfenil)etil]propano-1,3-diol puede ser micronizado opcionalmente, y/o pre-cribado, por ejemplo, con una pantalla de malla de 400 a 500 µm, antes de la etapa (a) para eliminar grumos. La etapa de mezcla (a) puede comprender adecuadamente mezclar el agonista del receptor de S1P y el alcohol de azúcar, por ejemplo, el manitol en cualquier mezclador o combinador adecuado durante, por ejemplo, de 100 a 400 revoluciones.
El procedimiento se puede llevar a cabo mezclando en seco los componentes. En esta realización, la etapa de molido (b) puede comprender adecuadamente hacer pasar la mezcla obtenida en (a) a través de una malla, que preferiblemente tiene un tamaño de malla de 400 a 500 µm. La etapa del procedimiento (a) puede comprender la etapa de mezclar la cantidad total de agonista del receptor de S1P al principio con una baja cantidad de alcohol de azúcar, por ejemplo de 5 a 25% en peso del peso total de alcohol de azúcar, para formar una pre-mezcla. Posteriormente, la cantidad restante de alcohol de azúcar se añade a la pre-mezcla. La etapa (a) también puede comprender la etapa de añadir una solución de aglomerante, por ejemplo, una solución acuosa de metilcelulosa y/o xilitol, por ejemplo, a la mezcla. De forma alternativa, el aglomerante se añade a la mezcla seca y se añade agua en la etapa de granulación.
La mezcla molida obtenida en (b) puede mezclarse opcionalmente una vez más antes de mezclar con el lubricante. El lubricante, por ejemplo, el estearato de magnesio, preferiblemente se pre-criba, por ejemplo, con una malla de 800 a 900 µm, antes de mezclar.
De forma alternativa, se emplea un procedimiento de granulación en húmedo. En esta realización, el agonista del receptor de S1P preferiblemente primero se mezcla en seco con el alcohol de azúcar deseado, por ejemplo, manitol, y la mezcla de alcohol de azúcar/agonista del receptor de S1P obtenida se mezcla entonces en seco con un aglomerante tal como hidroxipropilcelulosa o hidroxipropilmetilcelulosa. Después se añade agua y la mezcla granulada, por ejemplo, usando un granulador automatizado. La granulación se seca después y se muele.
Si fuera deseable, puede añadirse una cantidad de aglomerante adicional en la etapa (c) a la mezcla obtenida en (b).
El procedimiento puede comprender una etapa más de preparación de comprimidos o encapsulación de la mezcla obtenida en (c), por ejemplo, en una cápsula de gelatina dura usando un dispositivo de encapsulación automatizado. Las cápsulas pueden colorearse o marcarse para impartirles una apariencia individual y para hacerlas instantáneamente reconocibles. El uso de tintes puede servir para potenciar la apariencia así como para identificar las cápsulas. Los tintes adecuados para uso en farmacia incluyen típicamente carotinoides, óxidos de hierro y clorofila. Preferiblemente, las cápsulas de la invención se marcan usando un código.
Las composiciones farmacéuticas obtenibles de acuerdo con la presente invención son útiles, tanto solas como en combinación con otros agentes activos, para el tratamiento y la prevención de condiciones, por ejemplo, como se describen en los documentos US 5.604.229 , WO 97/24112 , WO 01/01978 , US 6.004.565 , US 6.274.629 y JP14316985 .
En particular, las composiciones farmacéuticas son útiles para:
a) el tratamiento y la prevención del rechazo de transplantes de órganos o tejidos, por ejemplo, para el tratamiento de los receptores de transplantes de corazón, pulmón, combinado de corazón-pulmón, hígado, riñón, páncreas, piel
o de córnea, y la prevención de la enfermedad de injerto contra huésped, tales como algunas veces ocurre después de un trasplante de médula ósea; particularmente en el tratamiento del rechazo agudo o crónico de aloinjerto o xenoinjerto o en el trasplante de células productoras de insulina, por ejemplo, células de islotes pancreáticos;
b) el tratamiento y la prevención de enfermedades autoinmunes o inflamatorias, por ejemplo la esclerosis múltiple, artritis (por ejemplo, artritis reumatoide), enfermedad inflamatoria del intestino, hepatitis, etc.;
c) el tratamiento y la prevención de miocarditis viral y enfermedades virales causadas por miocarditis viral, incluyendo hepatitis y SIDA.
De acuerdo con esto, en otros aspectos la presente descripción proporciona:
- 1.
- Una composición farmacéutica como se define anteriormente, para el uso en el tratamiento o la prevención de una enfermedad o condición como se define anteriormente.
- 2.
- Un método para tratar a un sujeto con necesidad de inmunomodulación, que comprende administrar al sujeto una cantidad eficaz de una composición farmacéutica como se define anteriormente.
- 3.
- Un método para tratar o prevenir una enfermedad o condición como se define anteriormente, que comprende administrar al sujeto una composición farmacéutica como se define anteriormente.
- 4.
- El uso de una composición farmacéutica como se define anteriormente para la preparación de un medicamento para la prevención o el tratamiento de una enfermedad o condición como se define anteriormente.
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Caudal de la solución de pulverización 15 mL/min Presión del aire de pulverización 15 N/cm2 Volumen del aire de pulverización 30 L/min Volumen de la solución de aglomerante 351 mL Ejemplos de 32 a 39 Se producen los comprimidos que contienen los siguientes ingredientes (en mg):
- Ex. 32
- Ex. 33 Ex. 34 Ex. 35 Ex. 36 Ex. 37 Ex. 38 Ex. 39
- FTY720
- 1 1 1 1 1 1 1 1
- D-manitol
- 116,6 114,2 104,6 114,2 104,6 116,6 115,4 113
- Estearato de magnesio
- 2,4 2,4 2,4 2,4 2,4 - - -
- Glicina HCl
- - 2,4 12 - - - - -
- Bicarbonato de sodio
- - - - 2,4 12 - - -
- Estearato de cinc
- - - - - - 2,4 - -
- Silicona fluida
- - - - - - - 3,6 -
- Aceite mineral
- - - - - - - 6
- Total
- 120,0 120,0 120,0 120,0 120,0 120,0 120,0 120,0
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Claims (1)
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US461215P | 2003-04-08 |
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ES10184951.1T Expired - Lifetime ES2556947T3 (es) | 2003-04-08 | 2004-04-06 | Composición sólida oral que comprende un agonista del receptor S1P y un alcohol de azúcar |
ES04725895T Expired - Lifetime ES2320767T3 (es) | 2003-04-08 | 2004-04-06 | Composiciones farmaceuticas solidas que comprenden un agonista del receptor s1p y un alcohol de azuzar. |
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US20080096972A1 (en) * | 2004-07-30 | 2008-04-24 | Thitiwan Buranachokpaisan | Compound formulations of 2-amino-1, 3-propanediol compounds |
CN1891212B (zh) * | 2005-07-07 | 2010-10-13 | 马启明 | 一种口服制剂及其制备方法 |
ES2357426T3 (es) * | 2005-09-09 | 2011-04-26 | Novartis Ag | Tratamiento de enfermedades autoinmunes. |
NZ595196A (en) | 2005-11-09 | 2013-03-28 | Proteolix Inc | Peptide-based compounds for enzyme inhibition |
TWI389683B (zh) * | 2006-02-06 | 2013-03-21 | Kyorin Seiyaku Kk | A therapeutic agent for an inflammatory bowel disease or an inflammatory bowel disease treatment using a 2-amino-1,3-propanediol derivative as an active ingredient |
PL2041158T3 (pl) | 2006-06-19 | 2013-08-30 | Onyx Therapeutics Inc | Peptydowe epoksyketony do hamowania proteasomu |
GB0612721D0 (en) | 2006-06-27 | 2006-08-09 | Novartis Ag | Organic compounds |
KR102044064B1 (ko) * | 2006-09-26 | 2019-11-12 | 노파르티스 아게 | S1p 조정제를 포함하는 제약 조성물 |
AU2011235934A1 (en) * | 2006-09-26 | 2011-11-03 | Novartis Ag | Pharmaceutical compositions comprising an S1P modulator |
EP1923055A1 (en) * | 2006-09-26 | 2008-05-21 | Novartis AG | Freeze-dried pharmaceutical composition comprising an S1P agonist or modulator |
EP1905434A1 (en) * | 2006-09-26 | 2008-04-02 | Novartis AG | Organic compounds comprising an S1P receptor agonist and their therapeutic use |
EP1923054A1 (en) * | 2006-09-26 | 2008-05-21 | Novartis AG | Fast disintegrating pharmaceutical composition comprising an S1P agonist or modulator |
EP1923058A1 (en) * | 2006-09-26 | 2008-05-21 | Novartis AG | Coated pharmaceutical composition comprising an S1P agonist or modulator |
WO2008124210A1 (en) * | 2007-02-14 | 2008-10-16 | Emory University | Methods and compositions for treating or preventing infection using leukocyte sequestration agents |
HUE035990T2 (en) | 2007-03-29 | 2018-05-28 | Daiichi Sankyo Co Ltd | Pharmaceutical preparation |
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