ES2373200T3 - Composiciones de pol�?meros reticulados y métodos para su uso. - Google Patents
Composiciones de pol�?meros reticulados y métodos para su uso. Download PDFInfo
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- ES2373200T3 ES2373200T3 ES09010135T ES09010135T ES2373200T3 ES 2373200 T3 ES2373200 T3 ES 2373200T3 ES 09010135 T ES09010135 T ES 09010135T ES 09010135 T ES09010135 T ES 09010135T ES 2373200 T3 ES2373200 T3 ES 2373200T3
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Abstract
Una composición que comprende un primer polímero sintético que tiene m grupos nucleófilos, y un segundo polímero sintético que tiene n grupos electrófilos, en la que dichos grupos nucleófilos y dichos grupos electrófilos son capaces de reaccionar para formar enlaces covalentes entre el primer polímero sintético y el segundo polímero sintético que da como resultado la formación de una matriz tridimensional, en la que m y n son cada uno mayor o igual a tres, en la que los grupos nucleófilos son grupos tiol, en la que los grupos electrófilos son grupos succinimidilo, y en la que el esqueleto de cada polímero sintético es un polietilenglicol.
Description
Composiciones de polfmeros reticulados y metodos para su uso�
Esta invenci6n se refiere, en general, a composiciones de polfmeros reticulados que comprenden un primer polfmero sintetico que contiene multiples grupos nucle6filos reticulados utilizando un segundo polfmero sintetico que contiene
5 multiples grupos electr6filos, y a metodos para utilizar dichas composiciones como bioadhesivos, para el aumento de tejidos, en la prevenci6n de adhesiones quirurgicas, y para revestir superficies de implantes sinteticos, como matrices de administraci6n de farmacos, y para aplicaciones oftalmol6gicas.
La patente de EEUU nO 5.162.430, otorgada el 10 de noviembre de 1992, de Rhee et al., y de propiedad de los cesionarios de la presente invenci6n, describe conjugados de colageno-polfmero sintetico preparados uniendo
10 covalentemente el colageno a polfmeros hidr6filos sinteticos, tales como diversos derivados de polietilenglicol.
La patente de EEUU de propiedad de los solicitantes nO 5.324.775, otorgada el 28 de junio de 1994, de Rhee et al., describe diversos polfmeros de inserto naturales y biocompatibles (tales como polisacaridos) unidos covalentemente a polfmeros de polietilenglicol hidr6filos sinteticos no inmunogenicos.
La patente de EEUU de propiedad de los solicitantes nO 5.328.955, otorgada el 12 de julio de 1994, de Rhee et al.,
15 describe diversas formas activadas de polietilenglicol y diversos enlaces que pueden utilizarse para producir conjugados de colageno-polfmero sintetico que tienen una gama de propiedades ffsicas y qufmicas.
La solicitud de EEUU, en tramitaci6n junto con la presente, de propiedad de los solicitantes nO de serie 08/403.358, presentada el 14 de marzo de 1995, describe una composici6n de biomaterial reticulado que se prepara utilizando un agente reticulante hidr6fobo, o una mezcla de agentes reticulantes hidr6filos e hidr6fobos. Los agentes
20 reticulantes hidr6fobos preferidos incluyen cualquier polfmero hidr6fobo que contenga, o que puede derivatizarse qufmicamente para que contenga, dos o mas grupos succinimidilo.
La solicitud de EEUU, en tramitaci6n junto con la presente, de propiedad de los solicitantes nO de serie 08/403.360, presentada el 14 de marzo de 1995, describe una composici6n util para la prevenci6n de adhesiones quirurgicas que comprende un material de sustrato y un agente de uni6n antiadhesi6n, en la que el material de sustrato comprende
25 preferiblemente colageno, y el agente de uni6n comprende preferiblemente al menos un grupo funcional reactivo con el tejido y al menos un grupo funcional reactivo con el sustrato.
La solicitud de EEUU de propiedad de los solicitantes nO de serie 08/476.825, presentada el 7 de junio de 1995, de Rhee et al., describe composiciones bioadhesivas que comprende colageno reticulado utilizando un polfmero hidr6filo sintetico multifuncionalmente activado, asf como metodos para utilizar dichas composiciones para realizar
30 una adhesi6n entre una primera superficie y una segunda superficie, en las que al menos una de la primera y la segunda superficie es preferiblemente la superficie de un tejido nativo.
La publicaci6n de patente japonesa nO 07090241 describe una composici6n utilizada para la adhesi6n temporal de un material de lente a un soporte, para montar el material sobre un dispositivo mecanizado, que comprende una mezcla de polietilenglicol, que tiene un peso molecular medio en el intervalo de 1000-5000, y poli-N-vinilpirrolidona,
35 que tiene un peso molecular medio en el intervalo de 30.000-200.000.
West y Hubbell, Biomaterials (1995), 16:1153-1156, describen la prevenci6n de adhesiones postoperatorias utilizando un hidrogel de polietilenglicol-co-diacrilato del acido lactico fotopolimerizado y un hidrogel de polietilenglicol-co-polipropilenglicol ffsicamente reticulado, Poloxamer 407®. El documento EP-A-0747066 describe composiciones con base de colageno utiles para la uni6n de tejidos, o para la uni6n de tejidos a materiales de
40 implante sinteticos.
El documento US 4.175.073 describe derivados reactivos de polfmeros que contienen grupos HS- y su uso como agentes tiolantes, o como vehfculos para enzimas u otras protefnas.
Los inventores ofrecen en la presente una descripci6n detallada de realizaciones preferidas de la presente invenci6n, que incluyen composiciones de polfmeros reticulados que comprenden polfmeros sinteticos que contienen
45 multiples grupos nucle6filos reticulados utilizando polfmeros sinteticos que contienen multiples grupos electr6filos, y metodos para utilizar estas composiciones para realizar la adhesi6n entre una primera superficie y una segunda superficie (en los que al menos una de la primera y la segunda superficie es preferiblemente la superficie de un tejido nativo), o para realizar el aumento de un tejido, o para evitar la adhesi6n quirurgica, o para revestir superficies de implantes sinteticos, o para administrar farmacos u otros agentes activos, o para aplicaciones oftalmicas.
50 La presente invenci6n describe una composici6n que comprende un primer polfmero sintetico que tiene m grupos nucle6filos, y un segundo polfmero sintetico que tiene n grupos electr6filos, en la que dichos grupos nucle6filos y dichos grupos electr6filos son capaces de reaccionar para formar enlaces covalentes entre el primer polfmero sintetico y el segundo polfmero sintetico que da como resultado la formaci6n de una matriz tridimensional, en la que m y n son cada uno mayor o igual a tres, en la que los grupos nucle6filos son grupos tiol, en la que los grupos
55 electr6filos son grupos succinimidilo, y en la que el esqueleto de cada polfmero sintetico es un polietilenglicol.
La presente invenci6n proporciona tambien dicha composici6n para su uso para prevenir la formaci6n de adhesiones tras una cirugfa o lesi6n.
La presente invenci6n tambien proporciona dicha composici6n para su uso como un biosellante.
En un uso medico general para prevenir la formaci6n de adhesiones tras una cirugfa, un primer polfmero sintetico que contiene dos o mas grupos nucle6filos se mezcla con un segundo polfmero sintetico que contiene dos o mas grupos electr6filos para proporcionar una mezcla de reacci6n; la mezcla de reacci6n se aplica al tejido que comprende, rodea o es adyacente a un sitio quirurgico antes de que se produzca una reticulaci6n sustancial entre los grupos nucle6filos y los grupos electr6filos; se deja que la mezcla de reacci6n siga reticulandose in situ hasta que se logra el equilibrio de reticulaci6n; y el sitio quirurgico se cierra mediante metodologfas convencionales.
Una caracterfstica de la invenci6n es que las composiciones de polfmeros reticulados son 6pticamente transparentes.
Ademas, las composiciones de la invenci6n estan formadas por componentes biocompatibles y no inmunogenicos que no dejan productos de reacci6n t6xicos, potencialmente inflamatorios o inmunogenicos en el tejido del sitio de administraci6n.
Otra caracterfstica de la invenci6n es que las composiciones de polfmeros reticulados tiene una alta resistencia a la compresi6n y una alta capacidad de hinchamiento, es decir, una composici6n que se ha secado se hinchara hasta tres veces (o mas) de su tamafo seco tras una rehidrataci6n, y es mas "elastica". Puesto que estos polfmeros son, en general, muy hidr6filos, pueden inyectarse con mas facilidad, es decir, la composici6n reticulada se mantiene como una "masa cohesiva" cuando se inyecta a traves de una aguja de calibre fino (calibre 27-30).
Otra caracterfstica de la invenci6n es que los grupos nucle6filos sobre el primer polfmero sintetico pueden unirse covalentemente a grupos amino primarios sobre los restos lisina de las moleculas de colageno en el tejido del sitio de administraci6n, de hecho "anclan biol6gicamente" la composici6n al tejido receptor.
Una caracterfstica de la invenci6n es que los componentes de las composiciones no son inmunogenicos y no requieren un "ensayo dermico" antes de comenzar el tratamiento, como sf necesitan las composiciones de colageno xenogeneicas disponibles en la actualidad, tales como las fabricadas a partir de pieles bovinas.
Otra caracterfstica de la invenci6n es que, a diferencia del colageno, las composiciones de la invenci6n no estan sometidas a una ruptura enzimatica por metaloproteinasas de matriz, tales como colagenasa, y por tanto no se degradan con facilidad in vivo y, por tanto, se espera que tengan mayor persistencia a largo plazo in vivo que las composiciones de colageno de la tecnica anterior.
Otra caracterfstica es que, cuando los grupos sobre cada uno de los polfmeros utilizados reaccionan para formar un enlace amida, la fabricaci6n de las composiciones de la presente invenci6n puede controlarse en gran medida, dando como resultado unos productos con una calidad mas constante.
La figura 1 (referencia) muestra la fuerza de compresi6n frente al desplazamiento para discos (dimensiones aproximadas: 5 mm de espesor x 5 mm de diametro) de composiciones de polfmeros reticulados que comprenden tetra-amino-PEG (10.000 PM) reticulado utilizando SE-PEG tetrafuncionalmente activado (10.000 PM), medido utilizando el equipo de ensayo universal Instron, modelo 4202, a una velocidad de compresi6n de 2 mm por minuto.
La figura 2 (referencia) muestra la fuerza de compresi6n frente al desplazamiento para discos (dimensiones aproximadas: 5 mm de espesor x 5 mm de diametro) de composiciones de polfmeros reticulados que comprenden tetra-amino-PEG (10.000 PM) reticulado utilizando SC-PEG trifuncionalmente activado (5.000 PM), medido utilizando el equipo de ensayo universal Instron, modelo 4202, a una velocidad de compresi6n de 2 mm por minuto.
La figura 3 (referencia) muestra la estructura qufmica de dos polietilenglicoles disponibles en el mercado que contienen multiples grupos amino primarios.
Las figuras 4 a 13 (referencia) muestran la formaci6n de diversas composiciones de polfmeros sinteticos reticulados a partir de polfmeros hidr6filos.
Las figuras 14 a 18 (referencia) muestran la formaci6n de diversas composiciones de polfmeros sinteticos reticulados a partir de polfmeros hidr6fobos.
Segun la presente invenci6n, las composiciones de polfmeros reticulados se preparan haciendo reaccionar un primer polfmero sintetico que contiene dos o mas grupo nucle6filos con un segundo polfmero sintetico que contiene dos o mas grupos electr6filos capaces de unirse covalentemente con los grupos nucle6filos sobre el primer polfmero sintetico.
Los componentes de la presente invenci6n no son inmunogenicos y, por tanto, no requieren un "ensayo dermico" antes de comenzar el tratamiento, como sf requiere el colageno xenogeneico. Ademas, a diferencia del colageno, las composiciones de la invenci6n no estan sometidas a una ruptura enzimatica por las metaloproteinasas de matriz
(por ejemplo, colagenasa) y, por tanto, se espera que tengan mayor persistencia a largo plazo in vivo que las
composiciones de colageno disponibles en la actualidad. El concepto detras de la presente invenci6n es que un polfmero sintetico que contenga multiples grupos nucle6filos (representado a continuaci6n como "X") reaccionara con un polfmero sintetico que contenga multiples grupos electr6filos (representado a continuaci6n como "Y"), dando como resultado una red de polfmeros covalentemente unidos, como sigue:
polfmero-Xm + polfmero-Yn → polfmero-Z-polfmero X = -SH, Y = -CO2N(COCH2)2, -N(COCH)2, y Z = un grupo funcional que surge de la uni6n de un grupo nucle6filo (X) y un grupo electr6filo (Y). El esqueleto de cada polfmero es 6xido de etileno. Los ejemplos de 6xidos de alquileno difuncionales pueden
representarse como:
X-polfmero-X Y-polfmero-y en los que X e Y son como se defini6 anteriormente, y el termino "polfmero" representa -(CH2CH2O)n-. El grupo funcional X o Y requerido habitualmente se acopla al esqueleto del polfmero mediante un grupo conector
(representado a continuaci6n como "Q"), siendo muchos conocidos o posibles. Existen muchas formas de preparar los diversos polfmeros funcionalizados, algunas de las cuales se listan a continuaci6n: polfmero-Q1-X + polfmero-Q2-Y → polfmero-Q1-Z-Q2-polfmero
- en�los�que�Q�=
- Estructura�completa�=
- -O-(CH2)n
- polfmero-O-(CH2)n-X (o Y)
- -S-(CH2)n
- polfmero-S-(CH2)n-X (o Y)
- -NH-(CH2)n
- polfmero-NH-(CH2)n-X (o Y)
- -O2C-NH-(CH2)n
- polfmero-O2C-NH-(CH2)n-X (o Y)
- -O2C-(CH2)n
- polfmero-O2C-(CH2)n-X (o Y)
- -O2C-CR1H
- polfmero-O2C-CRH-X (o Y)
- -O-R2-CO-NH
- polfmero-O-R-CO-NH-X (o Y)
- en los que n = 1-10 en cada caso;
- R1 = H, CH3, C2H5, etc.;
- R2 = CH2, CO-NH-CH2 CH2;
- Q1 y Q2 pueden ser iguales o diferentes.
Porejemplo, cuando Q2 = OCH2CH2(no existe Q1en este caso), Y = -CO2N(COCH2)2;yX= -SH, las reacciones y los grupos Z resultantes serfan los siguientes:
polfmero-SH + polfmero-OCH2CH2-CO2-N(COCH2)2 → polfmero-S-OCH2CH2CO-polfmero (tioester)
Un grupo adicional, representado a continuaci6n como "D", puede insertarse entre el polfmero y el grupo conector para aumentar la degradaci6n de la composici6n de polfmeros reticulados in vivo, por ejemplo, para su uso en aplicaciones de administraci6n de farmacos.
polfmero-D-Q-X + polfmero-D-Q-Y → polfmero-D-Q-Z-Q-D-polfmero
Algunos grupos "D" biodegradables utiles incluyen lactida, glic6lido, ε-caprolactona, poli(α-hidroxiacido), poliaminoacidos, polianhfdridos, y diversos di-o tripeptidos.
Polfmeros sinteticos
Para preparar las composiciones de la presente invenci6n primero es necesario proporcionar un primer polfmero sintetico que contenga un grupo tiol, y un segundo polfmero sintetico que contenga grupos electr6filos capaces de unirse covalentemente con los grupos nucle6filos sobre el segundo polfmero sintetico.
Tal como se emplea en la presente, la expresi6n "polfmero sintetico" se refiere a polfmeros que no son naturales y que se producen mediante sfntesis qufmica. Los tipos de polfmeros sinteticos multifuncionalmente activados incluyen polfmeros tetrafuncionalmente activados, y polfmeros ramificados en forma de estrella.
Los polfmeros sinteticos multifuncionalmente activados para su uso en la presente invenci6n deben contener al menos tres grupos funcionales para formar una red reticulada tridimensional con polfmeros sinteticos que contengan multiples grupos nucle6filos (es decir, "polfmeros multinucle6filos"). En otras palabras, deben estar al menos trifuncional o tetrafuncionalmente activados.
Tanto el primer como el segundo polfmero sintetico contienen al menos tres grupos funcionales.
Polfmeros sinteticos que contienen multiples grupos nucle6filos
Los polfmeros sinteticos que contienen multiples grupos nucle6filos tambien se denominan genericamente en la presente "polfmeros multinucle6filos". Para su uso en la presente invenci6n, los polfmeros multinucle6filos deben contener al menos tres grupos nucle6filos.
El polietilenglicol puede modificarse qufmicamente para que contenga multiples grupos tiol segun los metodos indicados, por ejemplo, en el capftulo 22 de Poly(ethylene Glycol) Chemistry: Biotechnical and Biomedical Applications, J. Milton Harris, ed., Plenum Press, NY (1992).
Los polietilenglicoles que han sido modificados para que contengan grupos tiol se denominan en la presente "multitiol-PEG". Tal como se emplea en la presente, "polietilenglicol(es)" incluye polietilenglicol(es) modificado(s) y/o derivatizado(s).
Polfmeros sinteticos que contienen multiples grupos electr6filos
Los polfmeros sinteticos que contienen multiples grupos electr6filos tambien se denominan en la presente "polfmeros multielectr6filos". Para su uso en la presente invenci6n, los polfmeros sinteticos multifuncionalmente activados deben contener al menos tres grupos electr6filos para formar una red reticulada tridimensional con polfmeros multinucle6filos.
Los polfmeros multielectr6filos para su uso en las composiciones de la invenci6n son polfmeros que contienen grupos succinimidilo capaces de formar enlaces covalentes con grupos electr6filos sobre otras moleculas.
Tal como se emplea en la presente, la expresi6n "que contiene dos o mas grupos succinimidilo" pretende incluir los polfmeros que estan disponibles en el mercado que contienen dos o mas grupos succinimidilo, asf como los que puedan derivatizarse qufmicamente para que contengan dos o mas grupos succinimidilo. Tal como se emplea en la presente, la expresi6n "grupo succinimidilo" pretende incluir grupos sulfosuccinimidilo y otras variaciones del grupo succinimidilo "generico". La presencia del resto sulfito de sodio sobre el grupo sulfosuccinimidilo sirve para aumentar la solubilidad del polfmero.
Polfmeros hidr6filos
Se emplean diversos polietilenglicoles en las composiciones de la presente invenci6n. Tal como se emplea en la presente, el termino "PEG" se refiere a polfmeros que tienen la estructura repetida (OCH2CH2)n.
En las figuras 4 a 13 se muestran estructuras de algunas formas especfficas tetrafuncionalmente activadas de PEG, asf como los productos de reacci6n generalizados obtenidos haciendo reaccionar los PEG tetrafuncionalmente activados con multiamino-PEG. Tal como se muestra en las figuras, el grupo succinimidilo es una estructura de anillo de 5 miembros representada como -N(COCH2)2. En las figuras 4 a 13, el sfmbolo AAA indica un enlace abierto.
La figura 4 muestra la reacci6n de glutarato de succinimidilo-PEG tetrafuncionalmente activado, denominado en la presente SG-PEG, con multiamino-PEG, y el producto de la reacci6n obtenido.
Otra forma activada de PEG se denomina propionato de succinimidilo-PEG (SE-PEG). La f6rmula estructural del SE-PEG tetrafuncionalmente activado y el producto de la reacci6n obtenido haciendolo reaccionar con multiamino-PEG se muestran en la figura 5. En una f6rmula estructural general para el compuesto, el subfndice 3 se reemplaza por "m". En la realizaci6n mostrada en la figura 4, m = 3 porque existen tres grupos CH2 repetidos a cada lado del PEG.
La estructura de la figura 5 da como resultado un conjugado que incluye un enlace "eter" que es menos propenso a la hidr6lisis. Esto lo diferencia del conjugado que se muestra en la figura 4, en el que se proporciona un enlace ester. El enlace ester se somete a hidr6lisis bajo condiciones fisiol6gicas.
Otra forma funcionalmente activada del polietilenglicol, en la que m = 2, se muestra en la figura 6, asf como el conjugado formado haciendo reaccionar el PEG tetrafuncionalmente activado con un multiamino-PEG.
Se proporciona otro PEG funcionalmente activado similar a los compuestos de las figuras 5 y 6, en el que m = 1. La f6rmula estructural del PEG tetrafuncionalmente activado y el conjugado resultante formado haciendo reaccionar el PEG activado con multiamino-PEG se muestran en la figura 7. Se hace notar que este conjugado incluye un enlace eter y un enlace peptfdico. Estos enlaces son estables bajo condiciones fisiol6gicas.
Otra forma funcionalmente activada de PEG se denomina succinimidilsuccinamida-PEG (SSA-PEG). La f6rmula estructural para la forma tetrafuncionalmente activada de este compuesto y el producto de la reacci6n obtenido haciendolo reaccionar multiamino-PEG se muestran en la figura 8. En la estructura que aparece en la figura 8, m = 2; sin embargo, los compuestos relacionados, en los que m = 1 o m = 3-10, tambien pueden utilizarse en las composiciones de la invenci6n.
La estructura en la figura 8 da como resultado un conjugado que incluye un enlace "amida" que, al igual que el enlace eter previamente descrito, es menos propenso a la hidr6lisis y, por tanto, es mas estable que un enlace ester.
Se proporciona otra forma activada de PEG, en la que m = 0. Este compuesto se denomina carbonato de succinimidilo-PEG (SC-PEG). La f6rmula estructural del SC-PEG tetrafuncionalmente activado y el conjugado formado haciendolo reaccionar con multiamino-PEG se muestran en la figura 9.
Tal como se analiz6 anteriormente, los derivados de polietilenglicol activados preferidos para su uso en la invenci6n contienen grupos succinimidilo como grupo reactivo. Sin embargo, pueden unirse diferentes grupos activantes a los sitios a lo largo de la longitud de la molecula de PEG. Por ejemplo, el PEG puede derivatizarse para formar propionaldehfdo-PEG (A-PEG) funcionalmente activado, cuya forma tetrafuncionalmente activada se muestra en la figura 10, asf como el conjugado formado por la reacci6n de A-PEG con multiamino-PEG. El enlace mostrado en la figura 10 se denomina enlace -(CH2)m-NH-, en el que m = 1-10.
Otra forma de polietilenglicol activado es el glicidil eter-PEG (E-PEG) funcionalmente activado, cuyo compuesto tetrafuncionalmente activado se muestra en la figura 11, asf como el conjugado formado haciendolo reaccionar con multiamino-PEG.
Otro derivado activado del polietilenglicol es isocianato-PEG (I-PEG) funcionalmente activado, que se muestra en la figura 12, junto con el conjugado formado haciendolo reaccionar con multiamino-PEG.
Otro derivado activado del polietilenglicol es vinilsulfona-PEG (V-PEG) funcionalmente activado, que se muestra en la figura 13, abajo, junto con el conjugado formado haciendolo reaccionar con multiamino-PEG.
Los polietilenglicoles multifuncionalmente activados preferidos para su uso en las composiciones de la presente invenci6n son los polietilenglicoles que contienen grupos succinimidilo, tales como SO-PEG y SE-PEO (mostrados en las figuras 4-7), preferiblemente en la forma trifuncional o tetrafuncionalmente activada.
Muchas de las formas activadas de polietilenglicol descritas anteriormente estan disponibles en el mercado en Shearrater Polymers, Huntsville, Alabama, y Union Carbide, South Charleston, West Virginia.
Derivatizaci6n de polfmeros para que contengan grupos funcionales
Ciertos polfmeros, tales como poliacidos, pueden derivatizarse para que contengan grupos succinimidilo. Los poliacidos para su uso en la presente invenci6n incluyen, sin limitaci6n, acido tricarboxflico con base de trimetilolpropano, acido tetracarboxflico con base de di(trimetilolpropano), acido heptandioico, acido octandioico (acido suberico), y acido hexadecandioico (acido tapsico). Muchos de estos poliacidos estan disponibles en el mercado en DuPont Chemical Company.
Segun un metodo general, los poliacidos puede derivatizarse qufmicamente para que contengan dos o mas grupos succinimidilo mediante una reacci6n con una cantidad molar apropiada de N-hidroxisuccinimida (NHS) en presencia de N,N'-diciclohexilcarbodiimida (DCC).
Los polialcoholes, tales como trimetilolpropano y di(trimetilolpropano), pueden convertirse en la forma de acido carboxflico utilizando diversos metodos, y despues pueden derivatizarse aun mas mediante una reacci6n con NHS en presencia de DCC para producir polfmeros trifuncional y tetrafuncionalmente activados, respectivamente, segun se describe en la solicitud de EEUU en tramitaci6n junto con la presente, de propiedad de los solicitantes nO de serie 08/403.358.
Preparaci6n de composiciones de polfmeros reticulados
En un metodo general para preparar las composiciones de polfmeros reticulados de la invenci6n, un primer polfmero sintetico que contiene multiples grupos nucle6filos se mezcla con un segundo polfmero sintetico que contiene multiples grupos electr6filos. La formaci6n de una red reticulada tridimensional se produce como resultado de la
reacci6n entre los grupos nucle6filos sobre el primer polfmero sintetico y los grupos electr6filos sobre el segundo polfmero sintetico.
En lo sucesivo, la expresi6n "primer polfmero sintetico" se empleara para hacer referencia a un polfmero sintetico que contiene grupos nucle6filos, y la expresi6n "segundo polfmero sintetico" se empleara para hacer referencia a un polfmero sintetico que contiene grupos electr6filos. Las concentraciones del primer polfmero sintetico y del segundo polfmero sintetico utilizados para preparar las composiciones de la presente invenci6n variaran dependiendo de una serie de factores, incluyendo los tipos y los pesos moleculares de los polfmeros sinteticos concretos utilizados y de la aplicaci6n de uso final deseada.
En general, los inventores han descubierto que, cuando se utiliza multiamino-PEG (referencia) como primer polfmero sintetico, se emplea preferiblemente a una concentraci6n en el intervalo de aproximadamente 0,5% a aproximadamente 20% en peso de la composici6n final, mientras que el segundo polfmero sintetico se utiliza a una concentraci6n en el intervalo de aproximadamente 0,5% a aproximadamente 20% en peso de la composici6n final. Por ejemplo, una composici6n final que tenga un peso total de 1 gramo (1000 miligramos) contendra entre aproximadamente 5 y aproximadamente 200 miligramos de multiamino-PEG, y entre aproximadamente 5 y aproximadamente 200 miligramos del segundo polfmero sintetico.
El uso de concentraciones mayores del primer y segundo polfmero sintetico dara como resultado la formaci6n de una red reticulada mas tupida, produciendo un gel mas robusto y rfgido. Asf, las composiciones previstas para su uso en el aumento de tejidos emplearan, en general, concentraciones del primer y segundo polfmero sintetico que se encuentran mas cerca del extremo mas alto del intervalo de concentraci6n preferido. Las composiciones previstas para su uso como bioadhesivos o para la prevenci6n de la adhesi6n no necesitan ser tan firmes y, por tanto, pueden contener concentraciones menores de polfmero.
Debido a que los polfmeros que contienen multiples grupos electr6filos tambien reaccionan con el agua, el segundo polfmero sintetico en general se conserva y se utiliza en una forma seca y esteril, para evitar la perdida de la capacidad reticulante debido a la hidr6lisis que se produce generalmente tras la exposici6n de dichos grupos electr6filos a un medio acuoso. Los procesos para preparar polfmeros hidr6filos sinteticos que contengan multiples grupos electr6filos en forma seca y esteril se indican en la solicitud de EEUU en tramitaci6n junto con la presente, de propiedad de los solicitantes nO de serie 08/497.573, presentada el 30 de junio de 1995. Por ejemplo, el polfmero sintetico seco puede moldearse por compresi6n para formar una membrana o lamina fina, que entonces puede esterilizarse utilizando irradiaci6n con rayos gamma, o preferiblemente con rayos ε. La membrana o lamina seca resultante puede cortarse en el tamafo adecuado o triturarse para formar partfculas de tamafo mas pequefo.
Los polfmeros que contienen multiples grupos nucle6filos en general no son reactivos frente al agua y, por tanto, pueden conservarse en una disoluci6n acuosa.
Las composiciones de polfmeros reticulados tambien pueden prepararse para que contengan diversos agentes formadores de imagenes, tales como sulfato de yodo o bario, o fluor, para ayudar a la visualizaci6n de las composiciones despues de la administraci6n, mediante rayos X, o 19F-MRI, respectivamente.
Administraci6n de las composiciones de polfmeros sinteticos reticulados
Las composiciones de la presente invenci6n pueden administrarse antes, durante o despues de la reticulaci6n del primer y segundo polfmero sintetico. Ciertos usos, que se analizan con mas detalle a continuaci6n, tales como el aumento de tejido, pueden requerir que las composiciones se reticulen antes de la administraci6n, mientras que otras aplicaciones, tales como la adhesi6n de tejidos, requieren que las composiciones se administren antes de que la reticulaci6n haya alcanzado el "equilibrio". El punto en el que la reticulaci6n ha alcanzado el equilibrio se define en la presente como el punto en el que la composici6n ya no resulte pegajosa al tacto.
Para administrar la composici6n antes de la reticulaci6n, el primer polfmero sintetico y el segundo polfmero sintetico pueden estar contenidos en diferentes tambores de una jeringa de dos compartimentos. En este caso, los dos polfmeros sinteticos no se mezclan realmente hasta el momento en que los dos polfmeros se extrusionan desde la punta de la aguja de la jeringa hacia el tejido del paciente. Esto permite que la mayor parte de la reacci6n de reticulaci6n se realice in situ, evitando el problema del bloqueo de la aguja que se produce habitualmente si los dos polfmeros sinteticos se mezclan demasiado pronto y la reticulaci6n entre los dos componentes ya esta demasiado avanzada antes de su distribuci6n desde la aguja de la jeringa. El uso de una jeringa de dos compartimentos, tal como se describi6 anteriormente, permite el uso de agujas de un diametro mas pequefo, lo cual resulta ventajoso cuando se realiza el aumento de tejido blando en tejido facial delicado, tal como el que rodea los ojos.
Como alternativa, el primer polfmero sintetico y el segundo polfmero sintetico pueden mezclarse segun los metodos descritos anteriormente antes de su administraci6n al sitio del tejido, y despues inyectarse inmediatamente en el sitio del tejido deseado (preferiblemente, en aproximadamente 60 segundos) tras el mezclado.
En otra realizaci6n de la invenci6n, el primer polfmero sintetico y el segundo polfmero sintetico se mezclan, despues se extrusionan y se dejan reticular para formar una lamina u otra forma s6lida. El s6lido reticulado entonces se deshidrata para eliminar sustancialmente toda el agua no unida. El s6lido secado resultante puede pulverizarse o
triturarse para formar partfculas, despues se suspende en un vehfculo fluido no acuoso que incluye, sin limitaci6n, acido hialur6nico, sulfato de dextrano, dextrano, colageno no reticulado succinilado, colageno no reticulado metilado, gluc6geno, glicerol, dextrosa, maltosa, trigliceridos de acidos grasos (tales como aceite de mafz, aceite de soja, y aceite de sesamo), y fosfolfpido de yema de huevo. La suspensi6n de las partfculas puede inyectarse a traves de una aguja de calibre pequefo hacia un sitio de tejido. Cuando estan en el interior del tejido, las partfculas de polfmeros reticulados se rehidratan y se hinchan hasta cinco veces su tamafo.
Uso de polfmeros sinteticos reticulados como bioadhesivos
Los inventores han descubierto que las composiciones preferidas de la invenci6n tienden a tener una pegajosidad muy alta, lo cual hace que sean particularmente adecuados para su uso como bioadhesivos, por ejemplo, para su uso en cirugfa. Tal como se emplean en la presente, el termino y las expresiones "bioadhesivo", "adhesivo biol6gico" y "adhesivo quirurgico" se usan de modo intercambiable para hacer referencia a composiciones biocompatibles capaces de realizar una uni6n temporal o permanente entre las superficies de dos tejidos nativos, o entre la superficie de un tejido nativo y la superficie de un tejido no nativo o la superficie de un implante sintetico.
En un metodo general para realizar la uni6n de una primera superficie a una segunda superficie, el primer polfmero sintetico y el segundo polfmero sintetico se aplican a una primera superficie, despues la primera superficie se pone en contacto con una segunda superficie para realizar la adhesi6n entre la primera superficie y la segunda superficie. Preferiblemente, el primer polfmero sintetico y el segundo polfmero sintetico en primer lugar se mezclan para iniciar la reticulaci6n, y despues se administran a una primera superficie antes de que se haya producido una reticulaci6n sustancial entre los grupos nucle6filos sobre el primer polfmero sintetico y los grupos electr6filos sobre el segundo polfmero sintetico. La primera superficie entonces se pone en contacto con la segunda superficie, preferiblemente de modo inmediato, para realizar la adhesi6n entre las dos superficies. Al menos una de la primera y la segunda superficie es preferiblemente la superficie de un tejido nativo.
Por ejemplo, el primer polfmero sintetico y el segundo polfmero sintetico se proporcionan, en general, en jeringas separadas, cuyos contenidos se mezclan utilizando tecnicas de mezclado de jeringa a jeringa, justo antes de la administraci6n a la primera superficie. El primer polfmero sintetico y el segundo polfmero sintetico preferiblemente se mezclan durante un mfnimo de 20 pases (preferiblemente de 20 a 100, mas preferiblemente de 30 a 60) para asegurar un mezclado adecuado. Puesto que la reticulaci6n entre los correspondientes grupos reactivos sobre los dos polfmeros sinteticos en general se inicia durante el proceso de mezclado, es importante administrar la mezcla de reacci6n a la primera superficie cuanto antes despues del mezclado.
La mezcla de reacci6n puede extrusionarse sobre la primera superficie desde el orificio de una jeringa u otro dispositivo de extrusi6n apropiado. Tras la aplicaci6n, la mezcla de reacci6n extrusionada puede extenderse sobre la primera superficie utilizando una espatula, si es necesario. Como alternativa, el primer polfmero sintetico y el segundo polfmero sintetico pueden mezclarse en un recipiente o placa de mezclado apropiados, y despues aplicarse sobre la primera superficie utilizando una espatula.
En otro metodo para preparar la mezcla de reacci6n, el primer polfmero sintetico y el segundo polfmero sintetico estan contenidos en camaras separadas de una botella o lata de pulverizaci6n con una boquilla, u otro dispositivo de pulverizaci6n adecuado. En este escenario, el primer y el segundo polfmero no se mezclan realmente hasta que son expulsados juntos desde la boquilla del dispositivo de pulverizaci6n. Tras la aplicaci6n de la mezcla de reacci6n a una superficie que contiene colageno, la primera superficie se pone en contacto con una segunda superficie. Si las dos superficies se ponen en contacto antes de que se haya producido una reticulaci6n sustancial entre el polfmero sintetico y el agente reticulante, los grupos reactivos sobre el agente reticulante tambien se uniran covalentemente con los grupos amino primarios sobre los restos lisina de las moleculas de colageno presentes en cualquiera o en ambas superficies, proporcionando una mayor adhesi6n.
Las dos superficies pueden mantenerse juntas de forma manual, o utilizando otro medio apropiado, a medida que la reacci6n de reticulaci6n se desarrolla hasta su conclusi6n. Generalmente, la reticulaci6n concluye en 5 a 60 minutos despues del mezclado del primer y segundo polfmero sintetico. Sin embargo, el tiempo requerido para que se produzca la reticulaci6n completa depende de una serie de factores, incluyendo el tipo y los pesos moleculares de los dos polfmeros sinteticos y, mas en concreto, de las concentraciones de los dos polfmeros sinteticos (es decir, unas concentraciones mayores producen unos tiempos de reticulaci6n mas rapidos).
Al menos una de la primera y la segunda superficie es preferiblemente la superficie de un tejido nativo. Tal como se emplea en la presente, la expresi6n "tejido nativo" se refiere a tejidos biol6gicos que son nativos del cuerpo del paciente concreto que se esta tratando. Tal como se emplea en la presente, la expresi6n "tejido nativo" pretende incluir tejidos biol6gicos que se han elevado o retirado de una parte del cuerpo de un paciente para implantarse en otra parte del cuerpo del mismo paciente (tales como autoinjertos de hueso, autoinjertos de fragmentos de piel, etc.). Por ejemplo, las composiciones de la invenci6n pueden utilizarse para adherir un trozo de piel de una parte del cuerpo del paciente a otra parte del cuerpo, como en el caso de una vfctima de quemaduras.
La otra superficie puede ser la superficie de un tejido nativo, la superficie de un tejido no nativo, o la superficie de un implante sintetico. Tal como se emplea en la presente, la expresi6n "tejido no nativo" se refiere a tejidos biol6gicos
que se han retirado del cuerpo de un paciente donante (que puede ser de la misma especie o de una especie diferente del paciente receptor) para su implantaci6n en el cuerpo de un paciente receptor (por ejemplo, transplantes de tejidos y 6rganos). Por ejemplo, las composiciones de polfmeros reticulados de la presente invenci6n pueden utilizarse para adherir la c6rnea de un donante al ojo de un paciente receptor.
Tal como se emplea en la presente, la expresi6n "implante sintetico" se refiere a cualquier material biocompatible destinado a implantarse en el cuerpo de un paciente que no este incluido en las anteriores definiciones de tejido nativo y tejido no nativo. Los implantes sinteticos incluyen, por ejemplo, vasos sangufneos artificiales, valvulas cardfacas, 6rganos artificiales, pr6tesis 6seas, lentfculas implantables, injertos vasculares, implantes de estenosis, y combinaciones de implante de estenosis/injerto, etc.
Uso de las composiciones de polfmeros sinteticos reticulados para el aumento de tejido
Las composiciones de polfmeros reticulados de la invenci6n tambien pueden utilizarse para el aumento de tejido blando o duro dentro del cuerpo de un sujeto mamffero. Asf, pueden ser mejores que los productos de materiales con base de colageno comercializados en la actualidad para el aumento de tejido blando, porque son menos inmunogenicos y mas persistentes. Los ejemplos de aplicaciones de aumento de tejido blando incluyen aumento de esffnteres (por ejemplo, urinario, anal, esofagico) y el tratamiento de la rinitis y de cicatrices. Los ejemplos de aplicaciones de aumento de tejido duro incluyen la reparaci6n y/o la sustituci6n de hueso y/o tejido cartilaginoso.
Las composiciones de la invenci6n son particularmente adecuadas para su uso como material de sustituci6n para el fluido sinovial en articulaciones osteoartrfticas, en el que las composiciones de polfmeros reticulados actuan para reducir el dolor de las articulaciones y para mejorar la funci6n de la articulaci6n restableciendo una red de hidrogel blando en la articulaci6n. Las composiciones de polfmeros reticulados tambien pueden utilizarse como material de sustituci6n para el nucleo pulposo de un disco intervertebral dafado. Asf, en primer lugar se retira el nucleo pulposo del disco dafado, y despues se inyecta la composici6n de polfmeros reticulados o se introduce de otra manera en el centro del disco. La composici6n puede reticularse antes de su introducci6n en el disco, o dejar que se reticule in situ.
En un metodo general para realizar el aumento de tejido dentro del cuerpo de un sujeto mamffero, el primer y segundo polfmero sintetico se inyectan de modo simultaneo en un sitio de tejido que necesite un aumento a traves de una aguja de calibre pequefo (por ejemplo, calibre 25-32). Una vez que se encuentra en el interior del cuerpo del paciente, los grupos nucle6filos sobre el primer polfmero sintetico y los grupos electr6filos sobre el segundo polfmero sintetico reaccionan entre sf para formar una red de polfmeros reticulados in situ. Los grupos electr6filos sobre el segundo polfmero sintetico tambien pueden reaccionar con grupos amino primarios sobre los restos lisina de las moleculas de colageno dentro del propio tejido del paciente, proporcionando un "anclaje biol6gico" de las composiciones al tejido del receptor.
Uso de las composiciones de polfmeros sinteticos reticulados para evitar adhesiones
Otro uso de las composiciones de polfmeros reticulados de la invenci6n es para revestir tejidos para evitar la formaci6n de adhesiones tras una cirugfa o una lesi6n en tejidos u 6rganos internos. En un metodo general para revestir tejidos para evitar la formaci6n de adhesiones tras una cirugfa, el primer y el segundo polfmero sintetico se mezclan, despues se aplica una capa fina de la mezcla de reacci6n a los tejidos que comprenden, rodean y/o son adyacentes al sitio quirurgico antes de que se haya producido una reticulaci6n sustancial entre los grupos nucle6filos sobre el primer polfmero sintetico y los grupos electr6filos sobre el segundo polfmero sintetico. La aplicaci6n de la mezcla de reacci6n al sitio del tejido puede ser mediante extrusi6n, aplicaci6n con pincel, pulverizaci6n (tal como se describi6 anteriormente), o mediante cualquier otro medio conveniente.
Tras la aplicaci6n de la mezcla de reacci6n al sitio quirurgico se deja que continue la reticulaci6n in situ antes de cerrar la incisi6n quirurgica. Cuando la reticulaci6n ha alcanzado el equilibrio, los tejidos que se ponen en contacto con los tejidos revestidos no se pegaran a los tejidos revestidos. En este momento, el sitio quirurgico puede cerrarse utilizando medios convencionales (suturas, etc.).
En general, las composiciones que logren una reticulaci6n completa en un periodo de tiempo relativamente corto (es decir, 5-15 minutos tras el mezclado del primer polfmero sintetico y el segundo polfmero sintetico) se prefieren para su uso en la prevenci6n de las adhesiones quirurgicas, de forma que el sitio quirurgico pueda cerrarse relativamente pronto despues de finalizar el procedimiento quirurgico.
Uso de polfmeros sintetidos reticulados para revestir implantes
Otro uso de las composiciones de polfmeros reticulados de la invenci6n es como material de revestimiento para implantes sinteticos. En un metodo general para revestir una superficie de un implante sintetico, el primer y el segundo polfmero sintetico se mezclan, y despues se aplica una capa fina de la mezcla de reacci6n sobre la superficie del implante antes de que se haya producido una reticulaci6n sustancial entre los grupos nucle6filos sobre el primer polfmero sintetico y los grupos electr6filos sobre el segundo polfmero sintetico. Para minimizar la reacci6n celular y fibrosa con el implante revestido, la mezcla de reacci6n se prepara preferiblemente para que tenga una carga neta neutra. La aplicaci6n de la mezcla de reacci6n a la superficie del implante puede ser mediante extrusi6n,
aplicaci6n con pincel, pulverizaci6n (tal como se describi6 anteriormente), o mediante cualquier otro medio conveniente. Tras la aplicaci6n de la mezcla de reacci6n a la superficie del implante se deja que la reticulaci6n continue hasta que se logra la reticulaci6n completa.
Aunque este metodo puede utilizarse para revestir la superficie de cualquier tipo de implante sintetico, resulta particularmente util en implantes en los que una trombogenicidad reducida es una consideraci6n importante, tales como vasos sangufneos artificiales y valvulas cardfacas, injertos vasculares, implantes de estenosis vasculares, y combinaciones de implante de estenosis/injerto. El metodo tambien puede utilizarse para revestir membranas quirurgicas implantables (por ejemplo, monofilamentos de polipropileno) o mallas (por ejemplo, para su uso en la reparaci6n de hernias). Los implantes de mama tambien pueden revestirse utilizando el anterior metodo para minimizar la contractura capsular.
Las composiciones de la presente invenci6n tambien pueden utilizarse para revestir lentfculas, que estan fabricadas con polfmeros naturales o sinteticos.
Otros usos para los polfmeros sinteticos reticulados
Tal como se analiza en la solicitud en tramitaci6n junto con la presente, de propiedad de los solicitantes nO de serie 08/574.050, presentada el 18 de diciembre de 1995, las composiciones de polfmeros reticulados de la invenci6n pueden utilizarse para bloquerar o rellenar diversos lumenes y huecos en el cuerpo de un sujeto mamffero. Las composiciones tambien pueden utilizarse como biosellantes para sellar fisuras o grietas dentro de un tejido o una estructura (tal como un vaso), o las uniones entre tejidos o estructuras adyacentes, para evitar el escape de la sangre o de otros fluidos biol6gicos.
Las composiciones de polfmeros reticulados tambien pueden utilizarse como un dispositivo de rellenado de grandes espacios para el desplazamiento de 6rganos en la cavidad del cuerpo durante procedimientos quirurgicos o de radiaci6n, por ejemplo, para proteger los intestinos durante un tratamiento programado de radiaci6n a la pelvis.
Las composiciones de polfmeros reticulados de la invenci6n tambien puede revestirse sobre la superficie interior de un lumen fisiol6gico, tal como un vaso sangufneo o una trompa de Falopio, actuando con ello como sellante para evitar la reestenosis del lumen tras un tratamiento medico tal como, por ejemplo, una cateterizaci6n de bal6n para retirar dep6sitos de placas arteriales de la superficie interior de un vaso sangufneo, o la eliminaci6n de tejido cicatrizal o de tejido endrometrial del interior de una trompa de Falopio. Una capa fina de la mezcla de reacci6n se aplica preferiblemente a la superficie interior del vaso (por ejemplo, mediante un cateter) inmediatamente despues de mezclar el primer y el segundo polfmero sintetico. Debido a que las composiciones de la invenci6n no se degradan con facilidad in vivo, se minimiza el potencial para la reestenosis debido a la degradaci6n del revestimiento. El uso de composiciones de polfmeros reticulados que tienen una carga neta neutra minimiza el potencial para la reestenosis.
Ejemplos
Se ha intentado asegurar la precisi6n con respecto a los numeros utilizados (por ejemplo, cantidades, temperaturas, pesos moleculares, etc.) pero deben tomarse en cuenta algunos errores experimentales y desviaciones. A menos que se indique lo contrario, las partes son partes en peso, el peso molecular es el peso molecular medio ponderado, la temperatura es en grados centfgrados, y la presi6n es la atmosferica o una presi6n cercana a esta.
Ejemplo�(�erererenc)a�
Preparaci6n de composiciones de multiamino-PEG reticuladas
Se mezclaron 0,15 gramos de diamino-PEG (3400 PM, obtenido en Shearrater Polymers, Huntsville, AL) en 250 ul de agua con 0,1 g de SC-PEG trifuncionalmente activado (5000 PM, tambien obtenido en Shearrater Polymers) utilizando un mezclado de jeringa a jeringa. La mezcla de reacci6n se extrusiona sobre una placa Petri y se forma un gel blando a temperatura ambiente.
Se mezclaron 0,15 gramos de diamino-PEG en 250 μl de agua con 0,1 g de SE-PEG tetrafuncionalmente activado (tambien obtenido en Shearrater Polymers) utilizando un mezclado de jeringa a jeringa. La mezcla de reacci6n se extrusiona sobre una placa Petri y se forma un gel blando a temperatura ambiente.
Ejemplo�(�erererenc)a�
Preparaci6n de composiciones de multiamino-PEG reticuladas
Se prepararon las siguientes disoluciones madre de diversos diamino-PEG:
- -
- Se disolvieron 10 gramos de Jeffamine ED-2001 (obtenido en Texaco Chemical Company, Houston, TX) en 9 ml de agua.
- -
- Se disolvieron 10 gramos de Jeffamine ED-4000 (tambien obtenido en Texaco Chemical Company) en 9 ml de agua.
- -
- Se disolvieron 0,1 gramos de diamino-PEG (3400 PM, obtenido en Shearrater Polymers, Huntsville, AL) en 300 μl de agua.
Cada una de las tres disoluciones de diamino-PEG preparadas anteriormente se mezclaron con disoluciones acuosas de SC-PEG trifuncionalmente activado (TSC-PEG, 5000 PM, tambien obtenido en Shearrater Polymers) como se indica en la tabla 1 a continuaci6n.
Tabla 1. Preparaci6n de composiciones de polfmeros reticulados
- Diamino-PEG
- TSC-PEG + disolvente acuoso
- 50 ul
- 0 mg + 50 μl de agua
- 50 ul
- 10 mg + 50 μl de PBS
- 50 ul
- 10 mg + 100 μl de PBS
- 250 ul
- 50 mg + 500 μl de PBS
Las disoluciones de diamino-PEG y TSC-PEG se mezclaron utilizando un mezclado de jeringa a jeringa. Cada uno de los materiales se extrusion6 desde la jeringa y se dej6 endurecer durante 1 hora a 37 OC. Cada uno de los materiales form6 un gel. En general, los geles fueron mas blandos cuanto mayor era el contenido en agua; los geles que contenfan la cantidad mas pequefa de disolvente acuoso (agua o PBS) fueron mas firmes.
Ejemplo�(�erererenc)a�
Caracterizaci6n de las composiciones de multiamino-PEG reticuladas
Se mezclaron 50 miligramos de tetra-amino-PEG (10.000 PM, obtenido en Shearrater Polymers, Huntsville, AL) en 0,5 ml de PBS, utilizando un mezclado de jeringa a jeringa, con 50 mg de SE-PEG tetrafuncionalmente activado ("tetra SE-PEG", 10.000 PM, tambien obtenido en Shearrater Polymers, Huntsville, AL) en 0,5 ml de PBS o SC-PEG trifuncionalmente activado ("tri SC-PEG", 5000 PM, tambien obtenido en Shearrater Polymers, Huntsville, AL) en 0,5 ml de PBS.
Las jeringas que contenfan cada una de las dos mezclas se incubaron a 37 OC durante aproximadamente 16 horas. Ambas composiciones formaron geles elasticos. Los geles se empujaron hacia el exterior de las jeringas y se cortaron en discos de 5-6 mm de espesor con un diametro de 5 mm, para su uso en los ensayos de compresi6n y capacidad de hinchamiento, segun se describe a continuaci6n.
Se midi6 la fuerza de compresi6n frente al desplazamiento para los dos geles con el equipo de ensayo universal Instron, modelo 4202, a una velocidad de compresi6n de 2 mm por minuto, utilizando los discos de los dos geles preparados como se describi6 anteriormente. La fuerza de compresi6n (en Nertons) frente al desplazamiento del gel (en milfmetros) se muestra en las figuras 1 y 2 para los geles preparados utilizando tetra SE-PEG y tri SC-PEG, respectivamente.
Bajo una fuerza de compresi6n tan alta como 30-35 Nertons, los geles no se rompieron sino que permanecieron elasticos.
Los discos de cada uno de los dos geles, preparados como se describi6 anteriormente, se pesaron y se midieron sus dimensiones (diametro y longitud). Los discos entonces se sumergieron en PBS y se incubaron a 37 OC. Despues de 3 dfas de incubaci6n, los discos se retiraron del PBS, se pesaron y se midieron. Los resultados del ensayo de capacidad de hinchamiento se muestran en la tabla 2 siguiente.
Tabla 2. Ensayo de capacidad de hinchamiento de composiciones de multiamino-PEG reticuladas
- Agente reticulante
- Peso del gel (en gramos) Dimensiones (en mm) (diametro/espesor)
- Antes del hinchamiento
- Despues del hinchamiento Antes del hinchamiento Despues del hinchamiento
- Tetra SE-PEG
- 0,116 0,310 5,0/5,0 7,1/8,1
- Tri SC-PEG
- 0,131 0,287 5,0/6,0 6,4/8,5
Tal como se muestra arriba, los geles se hincharon en dos a tres veces su peso, asf como se hincharon una media de aproximadamente 50% en diametro y espesor.
Ejemplo�(�erererenc)a�
Preparaci6n de composiciones de polilisina reticuladas
Se mezclaron 10 miligramos de bromhidrato de poli-L-lisina (8.000 PM, obtenido en Peninsula Laboratories, Belmont, CA) en 0,1 ml de tamp6n fosfato (0,2 M, pH = 6,6) con 10 mg de SE-PEG tetrafuncionalmente activado
(10.000 PM, obtenido en Shearrater Polymers, Huntsville, AL) en 0,1 ml de PBS. La composici6n forma un gel blando casi inmediatamente.
Ejemplo�(�erererenc)a�
Preparaci6n y ensayo mecanico de las composiciones de multiamino-PEG reticuladas
Se prepararon geles que comprenden tetra-amino-PEG (10.000 PM, obtenido en Shearrater Polymers, Huntsville, AL) y 1,4% (en peso) de SE-PEG tetrafuncionalmente activado ("tetra SE-PEG", 10.000 PM, tambien obtenido en Shearrater Polymers) mezclando el tetra-amino-PEG (a una concentraci6n de 25 mg/ml en agua) con el tetra SE-PEG (en PBS) en una placa Petri. Las mezclas de tetra-amino-PEG/SE-PEG resultantes se incubaron durante 16 horas a 37 OC.
La mezcla que contenfa SE-PEG al 1% no form6 un gel debido a la baja concentraci6n de SE-PEG. La mezcla que contenfa SE-PEG al 2% form6 un gel en algun momento del periodo de incubaci6n de 16 horas. Las mezclas que contenfan SE-PEG al 3% y al 4% formaron geles en aproximadamente 4-6 minutos del mezclado. El gel que contenfa SE-PEG al 2% pudo extrusionarse con facilidad a traves de una aguja de calibre 30; el gel que contenfa SE-PEG al 3% pudo extrusionarse a traves de una aguja de calibre 27.
Se evalu6 el efecto de una elevada temperatura sobre la formaci6n del gel. Se preparon geles que comprendfan tetra-amino-PEG y tetra SE-PEG al 2,5% (en peso) y se incubaron a una temperatura de 37 OC y 40-50 OC. Se descubri6 que una elevada temperatura tenfa un marcado efecto sobre el tiempo de gelificaci6n: la mezcla de tetra-amino-PEG/SE-PEG incubada a 37 OC form6 un gel en aproximadamente 20-25 minutos, mientras que las mezclas incubadas a 40-50 OC formaron geles en aproximadamente 5 minutos. Ambos geles pudieron extrusionarse a traves de una aguja de calibre 27.
Se evalu6 el efecto del pH sobre la formaci6n del gel. Se preparon geles que comprendfan tetra-amino-PEG y tetra SE-PEG al 2,5% (en peso) segun se indica en la siguiente tabla 3.
Tabla 3. Efecto del pH sobre la formaci6n del gel de permutaciones de tetra-amino-PEG/tetra SE-PEG
- pH de tetra-amino-PEG
- pH de tetra SE-PEG pH de la mezcla resultante Tiempo de gelificaci6n Temperatura de gelificaci6n
- 10
- 4,1 6,9 10-15 minutos 45 OC
- 10
- 7,0 7,2 <5 minutos 45 OC
Se evalu6 la extrudibilidad a traves de una aguja de calibre 27 para geles que comprendfan tetra-amino-PEG y tetra SE-PEG al 1-3% (en peso). Los geles estaban contenidos en jeringas de 1 cc. Se midi6 la fuerza requerida para empujar el embolo de la jeringa a una velocidad de 5 centfmetros por minuto utilizando un equipo de ensayo universal Instron, modelo 4202. Los resultados del ensayo de extrusi6n se presentan en la siguiente tabla 4.
Tabla 4. Extrusi6n de geles de tetra-amino-PEG/tetra SE-PEG a traves de una aguja de calibre 27
- Concentraci6n de SE-PEG (en peso)
- Fuerza de extrusi6n (N)
- 1,5-2%
- 10-11
- 2-2,5%
- 52
- 2,5-3%
- 88
Unas fuerzas de extrusi6n de 100 N o menores se consideran aceptables para la inyecci6n manual sin la ayuda de un dispositivo de asistencia para la jeringa.
Se midi6 la resistencia a la tracci6n (es decir, elasticidad) de geles de 3 mm de espesor que comprendfan tetraamino-PEG y tetra SE-PEG al 2,5%, 5% y 10% (en peso) utilizando un equipo de ensayo universal Instron, modelo 4202. Geles de longitudes iniciales variadas se estiraron a una velocidad de 10 milfmetros por minuto. La longitud de cada gel, la tensi6n en la rotura (cambio en la longitud como porcentaje de la longitud inicial), y la fuerza en la rotura se indican en la siguiente tabla 5.
Tabla 5. Resistencia a la tracci6n de geles de tetra-amino-PEG/tetra SE-PEG
- Concentraci6n de SE-PEG (% en peso)
- Longitud inicial (cm) Tensi6n en la rotura Fuerza en la rotura (N)
- 10
- 1,4 139% 0,4
- 10
- 1,9 99% 0,5
- 10
- 2,5 78% 0,5
- 5
- 1,3 111% 0,2
- 5
- 1,3 99% 0,2
- 5
- 1,6 94% 0,2
- 2,5
- 1,0 237% <0,1
- 2,5
- 1,5 187% <0,1
- 2,5
- 1,7 129% <0,1
Los geles que contenfan tetra SE-PEG al 5% y 10% aproximadamente doblaban su longitud antes de romperse. Los geles que contenfan SE-PEG al 2,5% aproximadamente triplicaban su longitud antes de romperse, pero eran considerablemente mas debiles (es decir, menor fuerza en la rotura) que los geles mas reticulados.
5 Ejemplo 6 erererenc)a�
Efecto del pH sobre la formaci6n del gel de formulaciones de tetra-amino-PEG/tetra SE-PEG
Se prepararon geles que comprendfan diversas concentraciones de tetra-amino-PEG y tetra SE-PEG a pH 6, 7 y 8 en placas Petri. Tras el mezclado del tetra-amino-PEG y tetra SE-PEG, las placas se inclinaron repetidas veces; se consider6 que el tiempo de gelificaci6n era el punto en el que la formulaci6n ces6 de fluir. El efecto del pH sobre el
10 tiempo de gelificaci6n de las diversas formulaciones de tetra-amino-PEG/tetra SE-PEG a temperatura ambiente se muestra en la siguiente tabla 6.
Tabla 6. Efecto del pH sobre la formaci6n del gel de formulaciones de PEG/tetra SE-PEG
- Conc. de tetra-amino-PEG (mg/ml)
- Conc. de tetra SE-PEG (mg/ml) pH Tiempo de gelificaci6n
- 20
- 20
- 6 >90,0 min
- 20
- 20
- 7 20,0 min
- 20
- 20
- 8 1,4 min
- 50
- 50
- 6 24,0 min
- 50
- 50
- 7 3,5 min
- 50
- 50
- 8 10,0 seg
- 100
- 100
- 6 9,0 min
- 100
- 100
- 7 47,0 seg
- 100
- 100
- 8 10,0 seg
- 200
- 200
- 6 2,0 min
- 200
- 200
- 7 9,0 seg
- 200
- 200
- 8 5,0 seg
El tiempo requerido para la formaci6n del gel disminuy6 a medida que aumentaba el pH y que aumentaban las concentraciones de tetra-amino-PEG y tetra SE-PEO.
15 Ejemplo�(�erererenc)a�
Cultivo de celulas en una matriz de multiamino-PEG reticulada
Se disolvieron 30 miligramos de tetra-amino-PEG (10.000 PM, obtenido en Shearrater Polymers, Huntsville, AL) en 0,6 ml de PBS, y despues se esteriliz6 mediante filtraci6n. Se disolvieron 30 miligramos de SE-PEG
tetrafuncionalmente activado ("tetra SE-PEG", 10.000 PM, tambien obtenido en Shearrater Polymers) en 0,6 ml de PBS, y despues se esteriliz6 mediante filtraci6n.
Las disoluciones de tetra-amino-PEG y tetra SE-PEG se mezclaron con un sedimento que contenfa celulas de fibroblastos de piel humana ("HSF") (CRL nO 1885, transferencia 4, obtenidas de American Tissue Type Culture Collection, Rockville, MD). Se dispensaron 250 microlitros de la disoluci6n resultante de tetra-amino-PEG/tetra SE-PEG (PEG-PEG) que contenfa celulas a cada uno de dos pocillos de una placa de cultivo de 48 pocillos y se dejaron gelificar durante aproximadamente 5 minutos a temperatura ambiente. Se afadi6 1 mililitro de medio de Eagle modificado de Dulbecco (suplementado con suero bovino fetal al 10%, L-glutamina, penicilina-estreptomicina, y aminoacidos no esenciales) a cada uno de los dos pocillos. La concentraci6n de celulas era de aproximadamente 3 x 105 celulas por mililitro de disoluci6n de tetra-amino-PEG/tetra SE-PEG, o 7,5 x 105 celulas por pocillo.
Para preparar un control, un sedimento de celulas HSF se suspendi6 en 1,2 ml de medio completo. Se dispensaron 250 microlitros de la mezcla control en cada uno de tres pocillos sobre la misma placa de 48 pocillos que se utiliz6 anteriormente. Se estim6 que cada pocillo contenfa aproximadamente 7,5 x 105 celulas. Cada pocillo recibi6 medio fresco cada dfa alterno.
Al principio, los geles de tetra-amino-PEG/tetra SE-PEG que contenfan celulas eran transparentes, y se observ6 que habfa una gran densidad de poblaci6n de celulas y que estas tenfan una morfologfa esferoidea, lo cual indica que habfa poca adhesi6n entre las celulas y el gel de PEG/PEG (las celulas normalmente adoptarfan una morfologfa aplanada con forma de huso cuando se adhieren a un sustrato, tal como el plastico tratado de las placas de cultivo de tejidos). Despues de 3 dfas de incubaci6n a 37 OC, se observ6 que el medio en los pocillos que contenfan los geles de PEG/PEG tenfa un color mas claro (el medio de Eagle modificado de Dulbecco normalmente tiene color rojo), lo cual indica un cambio en el pH del medio. Esto indica que las celulas estaban vivas y se estaban alimentando. A los 7 dfas de incubaci6n a 37 OC, las celulas aun se mantenfan con una morfologfa esferoidea (lo cual indica que no estaban adheridas al gel) y el medio tenfan un color aun mas claro, lo cual indica que las celulas todavfa eran viables y continuaban alimentandose.
En el dfa 7, los contenidos de cada pocillo se colocaron en una disoluci6n de formaldehfdo al 10% para la evaluaci6n histol6gica. Segun la evaluaci6n histol6gica, se estim6 que 75% de las celulas en los pocillos que contenfan los geles de PEG/PEG parecfan vivas, pero no parecfa que se estuviesen reproduciendo.
Los resultados del experimento indican que las celulas HSF son viables en los geles de tetra-amino-PEG/tetra SE-PEG reticulados, pero no parece que se adhieran al gel y no parecen que se reproduzcan mientras estan atrapadas en la matriz del gel. Tal como se describi6 anteriormente, la adherencia o no adherencia de las celulas a un material de sustrato puede influir en la morfologfa de las celulas. En ciertos tipos de celulas, la morfologfa celular, a su vez, puede influir en ciertas funciones celulares. Por tanto, la no adherencia de las celulas a la matriz del gel de PEG-PEG puede ser una ventaja para suministrar tipos celulares concretos cuya funci6n se ve influida por la morfologfa celular. Por ejemplo, la capacidad de las celulas de cartflago para producir materiales de la matriz extracelular se ve influida por la morfologfa celular: cuando las celulas estan en una configuraci6n aplanada, con forma de huso, las celulas estan en modo reproductor; cuando las celulas estan en la configuraci6n esferoidea se detiene la reproducci6n, y las celulas comienzan a producir componentes de la matriz extracelular.
Debido a que los geles de PEG-PEG no se degradan con facilidad in vivo, los geles pueden ser particularmente utiles para aplicaciones de suministro de celulas en las que resulta deseable que las celulas permanezcan atrapadas dentro de la matriz durante periodos largos de tiempo.
Claims (2)
- REIVINDICACIONES1.-Una composici6n que comprende un primer polfmero sintetico que tiene m grupos nucle6filos, y un segundo polfmero sintetico que tiene n grupos electr6filos, en la que dichos grupos nucle6filos y dichos grupos electr6filos son capaces de reaccionar para formar enlaces covalentes entre el primer polfmero sintetico y el segundo polfmero5 sintetico que da como resultado la formaci6n de una matriz tridimensional, en la que m y n son cada uno mayor o igual a tres, en la que los grupos nucle6filos son grupos tiol, en la que los grupos electr6filos son grupos succinimidilo, y en la que el esqueleto de cada polfmero sintetico es un polietilenglicol.
- 2.-Una composici6n segun la reivindicaci6n 1 para su uso en la prevenci6n de la formaci6n de adhesiones tras una cirugfa o lesi6n.10 3.-Una composici6n segun la reivindicaci6n 1 para su uso como un biosellante.
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| US57379995A | 1995-12-18 | 1995-12-18 | |
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| ES06006313T Expired - Lifetime ES2420106T3 (es) | 1995-12-18 | 1996-12-18 | Composiciones de polímeros reticulados y métodos para su uso |
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| KR100361933B1 (ko) * | 1993-09-08 | 2003-02-14 | 라 졸라 파마슈티칼 컴파니 | 화학적으로정의된비중합성결합가플랫폼분자및그것의콘주게이트 |
| WO1998020939A2 (en) | 1996-11-15 | 1998-05-22 | Advanced Bio Surfaces, Inc. | Biomaterial system for in situ tissue repair |
| US6551574B2 (en) * | 1995-06-07 | 2003-04-22 | Rhomed Incorporated | Tuftsin metallopeptide analogs and uses thereof |
| US6833408B2 (en) * | 1995-12-18 | 2004-12-21 | Cohesion Technologies, Inc. | Methods for tissue repair using adhesive materials |
| US6458889B1 (en) * | 1995-12-18 | 2002-10-01 | Cohesion Technologies, Inc. | Compositions and systems for forming crosslinked biomaterials and associated methods of preparation and use |
| US7883693B2 (en) * | 1995-12-18 | 2011-02-08 | Angiodevice International Gmbh | Compositions and systems for forming crosslinked biomaterials and methods of preparation of use |
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1996
- 1996-12-18 WO PCT/US1996/019975 patent/WO1997022371A1/en not_active Ceased
- 1996-12-18 AT AT96944824T patent/ATE330644T1/de active
- 1996-12-18 CA CA002239775A patent/CA2239775C/en not_active Expired - Lifetime
- 1996-12-18 EP EP09010135A patent/EP2111876B1/en not_active Expired - Lifetime
- 1996-12-18 DE DE69636289T patent/DE69636289T2/de not_active Expired - Lifetime
- 1996-12-18 PT PT96944824T patent/PT876165E/pt unknown
- 1996-12-18 DK DK09010135.3T patent/DK2111876T3/da active
- 1996-12-18 ES ES09010135T patent/ES2373200T3/es not_active Expired - Lifetime
- 1996-12-18 AT AT09010135T patent/ATE523211T1/de active
- 1996-12-18 PT PT09010135T patent/PT2111876E/pt unknown
- 1996-12-18 EP EP96944824A patent/EP0876165B1/en not_active Revoked
- 1996-12-18 JP JP52293897A patent/JP4193917B2/ja not_active Expired - Lifetime
- 1996-12-18 AU AU13344/97A patent/AU717660B2/en not_active Expired
- 1996-12-18 US US08/769,806 patent/US5874500A/en not_active Expired - Lifetime
- 1996-12-18 DK DK06006313.8T patent/DK1704878T3/da active
- 1996-12-18 ES ES96944824T patent/ES2268714T3/es not_active Expired - Lifetime
- 1996-12-18 ES ES06006313T patent/ES2420106T3/es not_active Expired - Lifetime
- 1996-12-18 PT PT60063138T patent/PT1704878E/pt unknown
- 1996-12-18 EP EP06006313.8A patent/EP1704878B1/en not_active Expired - Lifetime
- 1996-12-18 DK DK96944824T patent/DK0876165T3/da active
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1999
- 1999-01-13 US US09/229,851 patent/US6051648A/en not_active Expired - Lifetime
- 1999-04-30 US US09/302,852 patent/US6166130A/en not_active Expired - Lifetime
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2000
- 2000-12-08 US US09/733,739 patent/US6323278B2/en not_active Expired - Lifetime
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2001
- 2001-08-17 US US09/932,536 patent/US6534591B2/en not_active Expired - Lifetime
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2003
- 2003-02-10 US US10/364,762 patent/US20030149173A1/en not_active Abandoned
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2004
- 2004-01-27 US US10/766,146 patent/US6969400B2/en not_active Expired - Fee Related
- 2004-01-27 US US10/766,726 patent/US6911496B2/en not_active Expired - Lifetime
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- 2004-01-27 US US10/766,095 patent/US20040186231A1/en not_active Abandoned
- 2004-03-26 JP JP2004093835A patent/JP4283719B2/ja not_active Expired - Lifetime
- 2004-06-21 US US10/873,833 patent/US7176256B2/en not_active Expired - Fee Related
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2005
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2006
- 2006-12-13 JP JP2006336436A patent/JP2007231249A/ja not_active Withdrawn
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2008
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2010
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