ES2661487T3 - Preconcentrado lipídico de liberación sostenida de sustancia farmacológicamente activa y composición farmacéutica que comprende el mismo - Google Patents

Preconcentrado lipídico de liberación sostenida de sustancia farmacológicamente activa y composición farmacéutica que comprende el mismo Download PDF

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ES2661487T3
ES2661487T3 ES12826818.2T ES12826818T ES2661487T3 ES 2661487 T3 ES2661487 T3 ES 2661487T3 ES 12826818 T ES12826818 T ES 12826818T ES 2661487 T3 ES2661487 T3 ES 2661487T3
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sustained release
pharmaceutical composition
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same
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Jin Young Ko
Ji Yeon Kim
So Hyun Park
Sung Won An
Min Hyo Ki
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Chong Kun Dang Corp
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    • A—HUMAN NECESSITIES
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    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
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    • 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
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • A—HUMAN NECESSITIES
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    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
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    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
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    • A61K48/0016—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy characterised by an aspect of the 'non-active' part of the composition delivered, e.g. wherein such 'non-active' part is not delivered simultaneously with the 'active' part of the composition wherein the nucleic acid is delivered as a 'naked' nucleic acid, i.e. not combined with an entity such as a cationic lipid

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Abstract

Un preconcentrado lipídico de liberación sostenida, que comprende: a) un éster de ácido graso insaturado de sorbitano con al menos dos o más grupos -OH (hidroxilo) en una cabeza polar; b) un fosfolípido; y c) un endurecedor de cristal líquido, libre de un grupo ionizable, que tiene un resto hidrófobo de 15 a 40 átomos de carbono con un grupo triacilo o una estructura de anillo de carbono, donde el preconcentrado lipídico existe como un estado líquido en ausencia de un fluido acuoso y se transforma del estado líquido a un cristal líquido de tipo gel en presencia de un fluido acuoso.

Description

imagen1
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El éster de ácido graso de sorbitano, que explica la formación de un cristal líquido en la presente invención, es diferente de homólogos convencionales tales como glicerato de oleílo (OG), glicerato de fitanilo (PG) y monooleato de glicerina (GMO), dioleato de glicerina (GDO, un tipo de diacilglicerol) de la siguiente Fórmula Química 2. Es decir, las moléculas convencionales responsables de las fases cristalinas líquidas comparten la estructura común que consiste en una cabeza polar derivada de glicerina o ácido glicérico y una cola no polar derivada de un alcohol lipídico o ácido graso.
[Fórmula química 2]
imagen3
Sin embargo, las moléculas convencionales responsables de las fases cristalinas líquidas son un tanto difíciles de aplicar al desarrollo de medicaciones debido a las siguientes desventajas. El glicerato de oleílo (OG) y el glicerato de fitanilo (PG), a pesar de ser capaces de adoptar fácilmente la forma de cristales líquidos, rara vez se usan como excipientes farmacéuticos para la medicina humana debido a su toxicidad relativamente alta. Por otro lado, el monooleato de glicerina es útil como un excipiente farmacéuticamente aceptable, pero presenta una cristalinidad débil para formar cristales líquidos necesarios para medicaciones de liberación sostenida.
El dioleato de glicerol, que se usa en la publicación de patente internacional con n.º WO 2005/117830 tal como se ha descrito anteriormente, es un diacil lípido con glicerina que funciona como una cabeza polar. Esta molécula no se usa generalmente como un excipiente farmacéutico debido a que su seguridad no se ha probado aún. Además, esta presenta una biodegradabilidad significativamente pobre.
Como resultado de una investigación intensiva y minuciosa, los inventores de la presente invención hallaron que los ésteres de ácidos grasos insaturados de sorbitano tienen ventajas frente a las moléculas cristalinas líquidas usadas convencionalmente, derivados de glicerina o de ácido glicérico ya que estas forman cristales líquidos muy eficaces para la liberación sostenida de principios activos, con superioridad en cuanto a la seguridad y biodegradabilidad y son aplicables al desarrollo de productos médicos superando los problemas encontrados en la técnica anterior. Para su uso en composiciones para medicamentos, se ha de garantizar que los materiales sean seguros y biodegradables. Además, la biodegradabilidad es un factor muy importante para el material que es responsable de la liberación sostenida en el cuerpo. si la inyección de liberación sostenida usando PLGA se diseña para liberar un principio activo durante una semana, es ideal que el PLGA se degrade in vivo una semana después de la inyección. De hecho, sin embargo, el PLGA permanece intacto durante de uno a varios meses incluso después de que haya acabado la función de liberación sostenida. Por lo tanto, el éster de ácido graso insaturado de sorbitano de la presente invención, que presenta una propiedad de liberación sostenida, una seguridad y una biodegradabilidad excelentes, es aplicable para un material inductor de cristal líquido novedoso con gran valor en la industria farmacéutica.
El ácido graso de éster de ácido graso insaturado de sorbitano de la presente invención se puede derivar de aceite vegetal (por ejemplo, aceite de palma, aceite de ricino, aceite de oliva, aceite de cacahuete, aceite dulce, aceite de maíz, aceite de sésamo, aceite de semilla de algodón, aceite de soja, aceite de girasol, aceite de cártamo, aceite de linaza), grasa y aceite animal (por ejemplo, grasa de leche, tocino, sebo, etc.), aceite de ballena y aceite de pescado. El éster de ácido graso insaturado de sorbitano de la presente invención se puede seleccionar de entre monoésteres
4
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Ingrediente
Ejemplo n.º (unidad: mg)
18
19 20 21
Dutasterida
0,5 0,5
Tamsulosina
0,2 0,2
Monooleato de sorbitano
49 45
Sesquioleato de sorbitano
59 35
Fosfatidilcolina
46 40
Fosfatidiletanolamina
36 50
Acetato de tocoferilo
5 15
Palmitato de retinilo
5 15
EJEMPLOS COMPARATIVOS 1 A 4
En los ejemplos comparativos 1 a 3, dioleil glicérido, una clase de diacil glicéridos, se usó en las cantidades 5 mostradas en la Tabla 3, junto con fosfatidilcolina, tocoferol y/o etanol, seguido de homogeneización durante aproximadamente 10 min a 3.000 rpm en un homogeneizador (PowerGen modelo 125. Fisher).
En el ejemplo comparativo 4, monooleato de polioxietilen sorbitano, fosfatidilcolina y acetato de tocoferilo se usaron en las cantidades mostradas en la Tabla 3, seguido de homogeneización durante aproximadamente 30 min para
10 3.000 rpm en un homogeneizador. En el presente caso, el monooleato de polioxietilen sorbitano tiene un grupo -OH sustituido por un grupo polioxietileno en la cabeza polar de sorbitano y es diferente del monooleato de sorbitano, usado en la presente invención. El monooleato de polioxietilen sorbitano se usa generalmente como un tensioactivo hidrófilo o emulsionante debido al resto de polioxietileno voluminoso.
15 [TABLA 3]
Ejemplo comparativo n.º (unidad: mg)
Ingrediente
1 2
3
4
Dioleato de glicerilo
65 55
52,5
-
Monooleato de polioxietilen sorbitano
-
60
Tocoferol
7,5
-
Acetato de tocoferilo
-
10
Fosfatidilcolina
35 35
30
30
Etanol
-10
10
-
EJEMPLO COMPARATIVO 5
A 1 ml de solución salina fisiológica se añadieron 20 µg de exenatida, seguido de homogeneización a temperatura 20 ambiente. EJEMPLO EXPERIMENTAL 1: Comparación de la seguridad in vitro
La seguridad de las composiciones de la presente invención se examinó in vitro mediante la ejecución de una
prueba de citotoxicidad de ensayo en colonia con extracción tal como sigue. En 18 ml de medio esencial mínimo de
Eagle (EMEM) complementado con un 10 % de suero fetal bovino, se extrajeron 2 g de cada una de las 25 composiciones de los ejemplos 1, 4 y los ejemplos comparativos 1 y 2. Células L929 (fibroblasto de ratón, Colección
Americana de Cultivos Tipo) se sembraron con una densidad de 1x102 células/pocillo en placas de 6 pocillos y se
incubaron durante 24 horas a 37 ºC en una incubadora humidificada con CO2 al 5 %. Los extractos se diluyeron en
EMEM (0, 5, 25, 50 %) y entonces se colocaron en una cantidad de 2 ml/pocillo en contacto con las células L929
estabilizadas. Después de la incubación durante 7 días a 37 ºC en una incubadora humidificada con CO2 al 5 %, las 30 células se fijaron con una solución de formalina al 10 % y se tiñeron con una solución de Giemsa para contar las
colonias. Los resultados se resumen en la Tabla 4, a continuación.
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Claims (1)

  1. imagen1
    imagen2
ES12826818.2T 2011-08-30 2012-08-28 Preconcentrado lipídico de liberación sostenida de sustancia farmacológicamente activa y composición farmacéutica que comprende el mismo Active ES2661487T3 (es)

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KR20110087160 2011-08-30
KR20110087160 2011-08-30
PCT/KR2012/006855 WO2013032207A1 (en) 2011-08-30 2012-08-28 Sustained-release lipid pre-concentrate of pharmacologically active substance and pharmaceutical composition comprising the same

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EP (1) EP2750667B1 (es)
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KR (1) KR101494594B1 (es)
CN (1) CN103764127B (es)
AU (1) AU2012302422B2 (es)
BR (1) BR112014004967B1 (es)
CA (1) CA2845784C (es)
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ES (1) ES2661487T3 (es)
HU (1) HUE036150T2 (es)
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MX (1) MX351430B (es)
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PT (1) PT2750667T (es)
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