WO2007125134A1 - Formulación de vesículas liposomales en soluciones acuosas con características de película lagrimal - Google Patents
Formulación de vesículas liposomales en soluciones acuosas con características de película lagrimal Download PDFInfo
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- WO2007125134A1 WO2007125134A1 PCT/ES2006/000208 ES2006000208W WO2007125134A1 WO 2007125134 A1 WO2007125134 A1 WO 2007125134A1 ES 2006000208 W ES2006000208 W ES 2006000208W WO 2007125134 A1 WO2007125134 A1 WO 2007125134A1
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- ophthalmic composition
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- BOLDJAUMGUJJKM-LSDHHAIUSA-N renifolin D Natural products CC(=C)[C@@H]1Cc2c(O)c(O)ccc2[C@H]1CC(=O)c3ccc(O)cc3O BOLDJAUMGUJJKM-LSDHHAIUSA-N 0.000 description 1
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Definitions
- TITLE Formulation of liposomal vesicles in aqueous solutions with characteristics of tear film.
- the present invention relates to the formulation of liposomal vesicles in aqueous solutions with tear film characteristics.
- the present invention describes a formulation of liposomes in aqueous vehicles containing mucin or mucin-like substances, mucomimetic substances or polymers with mucoadhesive properties that, at the temperature of the corneal surface, have characteristics similar to the precorneal film of the human eye.
- This preparation could be used as a substitute for the natural film and as a medicinal preparation in some pathologies of the eye such as dry eye syndrome.
- This invention falls within the areas of pharmacy and medicine.
- the ocular surface is known to be formed by the conjunctival epithelium, corneal epithelium, accessory lacrimal glands and meibomian glands. Said surface is covered by a continuous film, of a thickness of approximately 10 ⁇ m, called precorneal film or tear film.
- lipid, sero-aqueous and mucinous distributed in three layers: lipid, aqueous and mucinous (Ibrahim H, Buri P, Gurny R. Pharm Acta HeIv 1988, 63: 146-53).
- the precorneal film is a structure formed by the combined aqueous-protein and mucinous components to form a hydrated gel.
- this gel would be protected by a film of a lipidic nature, whose components would be produced mainly by the meibomian glands and whose function would be to prevent the evaporation of the tear and improve the stability of the tear film (Pflugfelder SC, Solomon A, Stern ME. Cornea 2000; 19 (5): 644-649. McCulley JP, Shine W. Tr Am Ophth Soc 1997; 95: 79-93).
- the precorneal film would consist of two phases: - Hydrophilic polar phase, in contact with the aqueous-mucinous layer that is composed of phospholipids, sphingomyelin, ceramides and cerebrosides.
- Non-polar lipids such as wax esters, cholesterol esters, triglycerides, free fatty acids and hydrocarbons.
- the phospholipid fraction represents approximately 1-5% of the total lipid secretion, with the highest concentration being phosphatidylcholine (FC) with a percentage close to 40% of the total phospholipids.
- Other phospholipids such as phosphatidylethane lamina, appear in a percentage of 18%, the remaining ones (a total of 10) being in a range between 3 and 9%.
- This fraction probably produces a decrease in the surface tension of the aqueous phase, facilitating the extensibility of the precorneal film during the flickering movement.
- the usual treatment of dry eye is to relieve symptoms by applying tear substitutes topically.
- the typical composition of these preparations includes polymer solutions such as the one collected in the U. S, patent No. 4,973,580 (Babiole) in which the ophthalmic formulation includes hyaluronic acid using hydrogen peroxide as a preservative.
- Formulations are also described in which tear film-like components are provided as hypotonic solutions of lecithin including cellulose-derived viscosifying agents as it appears in US Patent No. 4,421,748 (Trager).
- the use of phospholipids for the treatment of dry eye appears in various patents. Emulsion-like systems containing positively charged phospholipids are described as described in the following: US Patent No.
- Emulsions containing phospholipids, non-polar oils and emulsifiers such as US Patent No. 6,656,460 (Benite) are also collected. None of these patents shows the use of neutral or negatively charged liposomes that are destabilized at the temperature of the precorneal film or that are associated with mucin or with mucoadhesive or mucin-like or mucomimetic substances, as is the case of the invention that outlined below.
- the method object of the invention described herein refers to the preparation of a pharmaceutical formulation that acts as a substitute for the precorneal film.
- the formulation incorporates phospholipid liposomal vesicles such as hydrophilic polar phase and non-polar lipids, both vehiculized in aqueous solutions containing mucin or substances with properties similar to mucin or mucomimetic substances or mucoadhesive polymers.
- phosphatidylcholine whose transition temperature is lower than the surface temperature of the cornea and also incorporates polymers or mucoadhesive and / or mucomimetic substances (mucin or polymers such as hyaluronic acid, derivatives of cellulose, chondroitin sulfate, chitosan, colominic acid, thiol derivatives or other similar component).
- the components of the formulation and in particular the phospholipids that make up the liposomes will allow the formation, on the corneal surface, after the destabilization of the liposomal vesicles, of a water-insoluble monomolecular film that acts preventing the evaporation of the aqueous phase and In addition, they will reduce the surface tension of the latter, which favors its rapid extensibility.
- Liposomes are prepared with phosphatidylcholine obtained from soy lecithin as a major component, cholesterol and ⁇ -tocopherol.
- Phosphatidylcholine contains acyl residues of unsaturated fatty acids having a transition temperature lower than the surface temperature of the cornea, which guarantees the rapid formation of the film on the aqueous phase, once applied on the surface of the coma.
- Cholesterol stabilizes this film by reducing the fluidity of the matrix formed by the polyunsaturated moieties of phosphatidylcholine.
- ⁇ -tocopherol ensures the chemical stability of the double bonds avoiding possible peroxidation.
- the liposomes are transported in aqueous solution containing an isotonic agent (trehalose, sodium chloride, glucose ...) to achieve adequate osmolarity according to their clinical use.
- the solutions may be isotonic, or hypotonic.
- the liposomes are incorporated into aqueous solutions containing one or more substances or polymers with mucoadhesive or mucomimetic characteristics in order to produce an increase in the residence time of the formulation and the components of the destabilized liposomes on the ocular surface .
- the concentrations of this last component will depend on the final viscosity desired in the formulation, its interaction with the mucin, its surface tension and the rheological behavior expected after administration.
- Proteins are also included in the formulation in order to promote the stability of the film formed and improve its lubricating properties. These proteins are found in natural tears and can be ⁇ -macro globulin, lysozyme, lipocalin and lactoferrin.
- Mucoadhesive polymers such as hyaluronic acid, cellulose derivatives, chondroitin sulfate, chitosan, colominic acid, thiol derivatives (or other similar component).
- Neutral lipids and low polar lipids such as waxes, cholesterol esters, triglycerides, free fatty acids and hydrocarbons.
- Vitamin C • Albumin or pre-albumin.
- EGF Epithelial growth factor
- TGF- ⁇ Beta transforming growth factor
- Acidic fibroblast growth factor (aFGF).
- bFGF Basic fibroblast growth factor
- Antiproteases such as macroglobulin.
- Neural factors such as substance P and insulinlike growth factor.
- Antibacterial agents such as Ig G, lysozyme and complement.
- Long chain fatty acids such as gadoleic, palmitic, palmitoleic, stearic, oleic, linoleic, arachidic, linolenic, eicosenic, lignoceric, lactic and myristic acids.
- Hydrophilic lipids such as phospholipids, sphingomyelin, ceramides and cerebrosides.
- the present invention which relates to the formulation of liposomal vesicles in aqueous solutions with tear film characteristics, is further illustrated by the following examples, which are not limiting of their scope, which is defined by the attached claim.
- the liposomal vesicles object of the present invention were made according to the classic Bangham method. For this, phosphatidylcholine, cholesterol and ⁇ -tocopherol (in different proportions) were dissolved in chloroform to obtain a final phosphatidylcholine concentration of 8 mg / ml. Once this solution saturated with nitrogen was introduced into the flask rotary evaporator at a temperature of 30-35 0 C with moderate vacuum. After evaporation of the solvent, a thin lipid film was formed on the walls, which was then hydrated.
- the hydration step is performed with a saturated aqueous solution of nitrogen containing the isotonizing agent at a temperature of 37 0 C, using glass beads produced by shear forming multilamellar vesicles.
- the final phosphatidylcholine concentration was adjusted based on the volume of isotonic vehicle. After two hours of rest and in the absence of light proceeded to the sonication of the dispersion while maintaining the temperature of the product between 5 and 10 0 C with crushed ice.
- the preparation was completed by performing 5 passes of the dispersion through 0.8 ⁇ m filters.
- the mucin or mucoadhesive and / or mucomimetic substance was added by diluting the liposomes to the desired final concentration.
- the final concentrations of the liposomes in the polymer solution may range from Img / ml to 40 mg / ml.
- the rest of the possible components are added, depending on their physical-chemical characteristics, with the isotonizing agent or with the mucomimetic substances.
- the base liposomes were prepared from phosphatidylcholine from soybeans, and cholesterol (8: 1) and reconstituted with water and hypotonic sodium chloride solutions.
- the influence of the sonication process on the final size of the vesicles was studied by comparing the use of an ultrasound probe for 2.5 min. and an ultrasonic bath for 15 min. ( Figure 1).
- the dispersions of the liposomes in water at an FC concentration of 20 mg / ml had pH values between 6.9 and 7.2.
- the average particle diameters for the different batches prepared with an ultrasonic bath ranged from 392 to 478 nm.
- the percentage of particles greater than 1 ⁇ m was, in all cases, less than 2%.
- Figure 1 Influence of the sonication process on the final size of the vesicles, comparing the use of an ultrasound probe for 2.5 minutes (-4-) and an ultrasonic bath for 15 minutes (- «-). The frequency of each class, expressed as a percentage, is plotted against its average size in ⁇ m.
- Figure 2 Surface tension of the aqueous liposome dispersion (mN / m) as a function of its concentration. The concentration of liposomes in the solution is expressed in phosphatidylcholine concentration (mM).
- Figure 3 Cell Viability (%) with hypotonic aqueous solutions of base liposomes with () and without vitamin E () incubated at 37 0 C for 1 hour. Two concentrations of liposomes (20 and 40 mg / ml) and two controls, one positive (0.005% benzalkonium chloride) and the other negative (culture medium) are studied.
- Figure 4 Cell Viability (%) with hypotonic aqueous solutions of base liposomes with () and without vitamin E () incubated at 37 0 C for 4 hours. Two concentrations of liposomes (20 and 40 mg / ml) and two controls, one positive (0.005% benzalkonium chloride) and the other negative (culture medium) are studied.
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Abstract
Formulación de vesículas liposomales en vehículos acuosos con características de película lagrimal. La presente invención trata sobre la preparación de un sistema farmacéutico liposomal en una solución acuosa que incorpora una sustancia o polímero con propiedades mucomiméticas y/o mucoadhesivas y que debido a sus componentes y características puede sustituir a la película precorneal. Esta invención se encuadra dentro de las áreas de farmacia y medicina.
Description
TITULO: Formulación de vesículas liposomales en soluciones acuosas con características de película lagrimal.
OBJETO DE LA INVENCIÓN: La presente invención se refiere a la formulación de vesículas liposomales en soluciones acuosas con características de película lagrimal. La presente invención describe una formulación de liposomas en vehículos acuosos que contienen mucina o sustancias similares a la mucina, sustancias mucomiméticas o polímeros con propiedades mucoadhesivas que, a la temperatura de la superficie corneal, presentan características similares a la película precorneal del ojo humano. Dicha preparación podría ser utilizada en sustitución de la película natural y como preparado medicinal en algunas patologías del ojo como es el caso del síndrome de ojo seco.
Esta invención se encuadra dentro de las áreas de farmacia y medicina.
ESTADO DE LA TÉCNICA:
La superficie ocular se sabe que esta formada por el epitelio conjuntival, el epitelio corneal, las glándulas lacrimales accesorias y las glándulas de meibomio. Dicha superficie se encuentra recubierta por una película continua, de un espesor de aproximadamente 10 μm, denominada película precorneal o film lagrimal. Hasta hace pocos años la estructuración teórica, generalmente aceptada, incluía tres tipos de componentes (lipídico, seroacuoso y mucinoso) repartidos en tres capas: lipídica, acuosa y mucinosa (Ibrahim H, Buri P, Gurny R. Pharm Acta HeIv 1988, 63:146-53). Estudios recientes consideran que la película precorneal es una estructura formada por los componentes acuoso-proteicos y mucinosos combinados para formar un gel hidratado. A su vez, este gel quedaría protegido por una película de carácter lipídico, cuyos componentes serían producidos principalmente por las glándulas de meibomio y cuya función seria impedir la evaporación de la lágrima y mejorar la estabilidad de la película lacrimal (Pflugfelder SC, Solomon A, Stern ME. Cornea 2000; 19 (5): 644-649. McCulley JP, Shine W. Tr Am Ophth Soc 1997; 95: 79-93).
De acuerdo con el modelo propuesto, la película precorneal constaría de dos fases:
- Fase polar hidrofílica, en contacto con la capa acuo-mucinosa que esta compuesta por fosfolípidos, esfingomielina, ceramidas y cerebrósidos.
- Fase no polar hidrofóbica en contacto con la atmósfera y compuesta por lípidos no polares tales como esteres de cera, esteres de colesterol, triglicéridos, ácidos grasos libres e hidrocarburos.
La fracción de fosfolípidos representa aproximadamente entre el 1 - 5 % del total de la secreción lipídica, siendo el de mayor concentración la fosfatidilcolina (FC) con un porcentaje cercano al 40% del total de fosfolípidos. Otros fosfolípidos, como la fosfatidiletano lamina aparecen en un porcentaje del 18%, encontrándose los restantes (un total de 10) en un rango comprendido entre el 3 y el 9%. Probablemente, esta fracción produce una disminución de la tensión superficial de la fase acuosa facilitando la extensibilidad de la película precorneal durante el movimiento de parpadeo.
El tratamiento usual del ojo seco consiste en aliviar los síntomas mediante la aplicación de sustitutos de las lágrimas por vía tópica. La composición típica de estos preparados incluye soluciones poliméricas como la recogida en la U. S, patent No 4,973,580 (Babiole) en la que la formulación oftálmica incluye ácido hialurónico empleando como conservante peróxido de hidrógeno. También se describen formulaciones en las que se aportan componentes semejantes a la película lagrimal como soluciones hipotónicas de lecitina incluyendo agentes viscosizantes derivados de la celulosa como aparece en la U.S. patent No. 4,421,748 (Trager). La utilización de fosfolípidos para el tratamiento del ojo seco aparece en diversas patentes. Se describen sistemas tipo emulsión conteniendo fosfolípidos cargados positivamente como las descritas en las siguientes: U.S. patent No. 4,914,088 (1990) (Korb:); 5,278,151 (1994) (Korb:); 5,371,108 (1994) (Korb:), 5,294,607 (1994) (Korb:). Asimismo se describen liposomas cargados positivamente U.S. patent No 4,804,539 (Guo) (1989) y U.S. Patent No 4,818,537 (Guo) en las que se emplean liposomas con carga positiva que se suspenden en soluciones acuosas conteniendo polímeros de alta viscosidad como la hidroxietilcelulosa, metilcelulosa, hidroxipropilcelulosa y derivados vinílicos como la polivinilpirrolidona, polivinilalcohol y sus mezclas. También se recogen emulsiones conteniendo fosfolípidos, aceites no polares y emulsificantes como la U.S. Patent No 6,656,460 (Benita).
En ninguna de estas patentes aparece la utilización de liposomas neutros o con carga negativa que se desestabüicen a la temperatura de la película precorneal ni que se asocien con mucina o con sustancias mucoadhesivas o semejantes a la mucina o mucomiméticas como es el caso de la invención que se describe a continuación.
DESCRIPCIÓN DE LA INVENCIÓN.
El método objeto de la invención que aquí se describe se refiere a la preparación de una formulación farmacéutica que actúa como sustituto de la película precorneal. La formulación incorpora vesículas liposomales de fosfolípidos como fase polar hidrofilica y lípidos no polares, ambos vehiculizados en soluciones acuosas que contengan mucina ó sustancias con propiedades semejantes a la mucina o sustancias mucomiméticas o polímeros mucoadhesivos. Las ventajas más relevantes de esta invención consisten en la utilización de fosfatidilcolina cuya temperatura de transición es inferior a la temperatura de la superficie de la córnea y además incorpora polímeros o sustancias mucoadhesivas y/o mucomiméticas ( mucina o polímeros como el ácido hialuronico, derivados de la celulosa, condroitín sulfato, quitosano, ácido colomínico, derivados tiólicos u otro componente similar).
Los componentes de la formulación y en concreto los fosfolipidos que componen los liposomas van a permitir la formación, en la superficie corneal, tras la desestabilización de las vesículas liposomales, de una película monomolecular insoluble en agua que actúa impidiendo la evaporación de la fase acuosa y, además, van a disminuir la tensión superficial de esta última lo que favorece su rápida extensibilidad. Los liposomas se preparan con fosfatidilcolina obtenida a partir de lecitina de soja como componente mayoritario, colesterol y α-tocoferol. La fosfatidilcolina contiene restos acilos de ácidos grasos insaturados presentando una temperatura de transición inferior a la temperatura de la superficie de la córnea, lo que garantiza la rápida formación de la película sobre la fase acuosa, una vez aplicada en la superficie de la comea. El colesterol, por su parte, estabiliza esta película al reducir la fluidez de la matriz formada por los restos poliinsaturados de la fosfatidilcolina. Finalmente el α-tocoferol asegura la estabilidad química de los dobles enlaces evitando la posible peroxidación .
Los liposomas se vehiculizan en solución acuosa que contiene un agente isotonizante (trehalosa, cloruro sódico, glucosa...) para conseguir la osmolaridad adecuada según su uso clínico. Las soluciones podrán ser isotónicas, o hipotónicas. Una vez formados los liposomas se incorporan en soluciones acuosas que contengan una o varias sustancias o polímeros con características mucoadhesivas o mucomiméticas con la finalidad de producir un aumento en el tiempo de permanencia de la formulación y de los componentes de los liposomas desestabilizados sobre la superficie ocular. Así se favorece el mantenimiento de la nueva película una vez formada y se evita la evaporación acuosa de la superficie corneal. Las concentraciones de este último componente dependerán de la viscosidad final deseada en la formulación, de su interacción con la mucina, de su tensión superficial y del comportamiento reológico esperado tras su administración. También se incluyen proteínas en la formulación con el fin de favorecer la estabilidad de la película formada y mejorar sus propiedades lubricantes. Estas proteínas se encuentran en las lágrimas naturales y pueden ser α-macro globulina, lisozima, lipocalina y lactoferrina.
A esta formulación se le pueden añadir diferentes compuestos, en su mayoría componentes de la película lagrimal natural, que mejoran las características de formación y permanencia de la película precorneal y/o que actúan como reepitelizantes, antiinflamatorios y antioxidantes de la superficie ocular, y/o favorecedores de la diferenciación epitelial corneal y conjuntival. Dentro de estas sustancias se encuentran:
• Polímeros mucoadhesivos como el ácido hialurónico, derivados de la celulosa, condroitín sulfato, quitosano, ácido colomínico, derivados tiólicos (u otro componente similar). • Lípidos neutros y lípidos de baja polaridad como ceras, esteres del colesterol, triglicéridos, ácidos grasos libres e hidrocarburos.
• Vitamina A.
• Iones sodio, potasio, calcio, cloro y bicarbonato.
• Vitamina C. • Albúmina o pre-albúmina.
• Inmuno globulina A (IGA).
• Factor de crecimiento epitelial (epithelial growth factor: EGF).
• Beta transforming growth factor (TGF-β).
• Acidic fibroblast growth factor (aFGF).
• Basic fibroblast growth factor (bFGF).
• Antiproteasas como la macroglobulina. • Factores neurales como la sustancia P e insulinlike growth factor.
• Agentes antibacterianos como la Ig G, lisozima y complemento.
• Ácidos grasos de cadena larga como el ácido gadoleico, palmítico, palmitoleico, esteárico, oleico, linoleico, araquídico, linolénico, eicosénico, lignocérico, láctico y mirístico. • Lípidos hidrofílicos como fosfolípidos, esfingomielina, ceramidas y cerebrósidos.
MODO DE REALIZACIÓN DE LA INVENCIÓN.
La presente invención que se refiere a la formulación de vesículas liposomales en soluciones acuosas con características de película lagrimal, se ilustra adicionalmente mediante los siguientes ejemplos, los cuales no son limitativos de su alcance, el cuál viene definido por la nota reivindicatoría adjunta.
Las vesículas liposomales objeto de la presente invención se realizaron según el clásico método de Bangham. Para esto, se disolvieron fosfatidilcolina, colesterol y α-tocoferol (en distintas proporciones) en cloroformo obteniéndose una concentración final de fosfatidilcolina de 8 mg/ml. Una vez saturada esta disolución con nitrógeno se introdujo en el matraz del rotavapor a una temperatura de 30-350C con un vacío moderado. Tras la evaporación del disolvente se formó una fina película lipídica en las paredes que, a continuación, se hidrató. La fase de hidratación se realizó con una solución acuosa saturada de nitrógeno que contenía el agente isotonizante a una temperatura de 370C, utilizando perlas de vidrio que por cizalla producían la formación de vesículas multilamelares. La concentración final de fosfatidilcolina se ajustó en función del volumen de vehículo isotonizante. Después de dos horas de reposo y en ausencia de luz, se procedió a la sonicación de la dispersión manteniendo la temperatura del producto entre 5 y 10 0C con hielo picado. La preparación finalizó realizando 5 pases de la dispersión por filtros de 0,8 μm.
La mucina o sustancia mucoadhesiva y/o mucomimética se añadió al diluir los liposomas a la concentración final deseada. Las concentraciones finales de los liposomas en la solución polímérica pueden oscilar entre Img/ml y 40 mg/ml.
El resto de los posibles componentes se añaden, en función de sus características físico-químicas, con el agente isotonizante o con las sustancias mucomiméticas.
Los liposomas base se prepararon a partir de fosfatidilcolina procedente de soja, y colesterol (8:1) y se reconstituyeron con agua y soluciones hipotónicas de cloruro sódico. Se estudio la influencia del proceso de sonicación en el tamaño final de las vesículas comparando la utilización de una sonda de ultrasonidos durante 2,5 min. y un baño de ultrasonidos durante 15 min. (Figura 1). El rendimiento del proceso de preparación de las vesículas lipídicas, en ambos casos, fue superior a un 90%.
Las dispersiones de los liposomas en agua a una concentración de FC de 20 mg/ml presentaron unos valores de pH comprendidos entre 6,9 y 7,2. Los diámetros medios de partículas para los distintos lotes preparados con baño de ultrasonidos oscilaron entre 392 y 478 nm. El porcentaje de partículas superiores a 1 μm fue, en todos los casos, inferior al 2%.
Se realizaron medidas de tensión superficial con soluciones de distintas concentraciones de liposomas, obteniéndose los datos de la Figura 2. Se realizaron pruebas de viabilidad celular con soluciones acuosas hipotónicas de liposomas base y de liposomas base con vitamina E en cultivos celulares de macrófagos. Para el estudio de citotoxicidad se utilizó la técnica de reducción, a nivel mitocondrial, de la sal bromuro de 3(4,5-dimetiltiazol-2-il)-2,5-difeniltetrazolio (MTT). a un producto coloreado (formazán) (Mossman T. J Immun Methods 1983, 65:55-63). Se emplearon macrófagos peritoneales obtenidos de ratones Swiss machos. Las células fueron expuestas a formulaciones que contenían soluciones acuosas hipotónicas de liposomas base. Como control negativo se utilizó medio de cultivo y como control positivo cloruro de benzalconio al 0,005%. Las soluciones se incubaron a 370C durante 1 y 4 horas. Los resultados obtenidos demostraron una tolerancia óptima para los liposomas base con y sin vitamina E (Figuras 3 y 4).
BREVE DESCRIPCIÓN DE LAS FIGURAS
Figura 1: Influencia del proceso de sonicación en el tamaño final de las vesículas, comparando la utilización de una sonda de ultrasonidos durante 2,5 minutos (-4-) y un baño de ultrasonidos durante 15 minutos (-«-). Se representa la frecuencia de cada clase, expresada en porcentaje, frente al tamaño medio de la misma en μm.
Figura 2: Tensión superficial de la dispersión acuosa de liposomas (mN/m) en función de su concentración. La concentración de los liposomas en la solución se expresa en concentración de fosfatidilcolina (mM).
Figura 3: Viabilidad celular (%) con soluciones acuosas hipotónicas de liposomas base con ( ) y sin vitamina E ( ) incubadas a 370C durante 1 hora. Se estudian dos concentraciones de liposomas (20 y 40 mg/ml) y dos controles, uno positivo (cloruro de benzalconio 0,005%) y otro negativo (medio de cultivo).
Figura 4: Viabilidad celular (%) con soluciones acuosas hipotónicas de liposomas base con ( ) y sin vitamina E ( ) incubadas a 370C durante 4 horas. Se estudian dos concentraciones de liposomas (20 y 40 mg/ml) y dos controles, uno positivo (cloruro de benzalconio 0,005%) y otro negativo (medio de cultivo).
Claims
REIVINDICACIONES
L- Composición oftálmica destinada a actuar como sustituto de la película precorneal, caracterizada por contener vesículas liposomales de fosfolípidos neutros o con carga negativa como fase polar hidrofílica y lípidos no polares, ambos vehiculizados en soluciones acuosas que contengan mucina ó sustancias con propiedades semejantes a la mucina ó polímeros mucoadhesivos.
2.- La composición oftálmica de la reivindicación 1 que contenga polímeros mucoadhesivos como el ácido hialurónico, derivados de la celulosa, condroitín sulfato, quitosano, ácido colomínico, derivados tiólicos (u otro componente similar).
3.- La composición oftálmica de la reivindicación 1 que contenga una sustancia con propiedades mucomiméticas.
4.- La composición oftálmica de la reivindicación 1 que contenga lípidos neutros y lípidos de baja polaridad como ceras, esteres del colesterol, triglicéridos, ácidos grasos libres e hidrocarburos.
5.- La composición oftálmica de la reivindicación 1 que contenga lipocalinas.
6.- La composición oftálmica de la reivindicación 1 que contenga vitamina A.
7.- La composición oftálmica de la reivindicación 1 que contenga iones sodio, potasio, calcio, cloro y bicarbonato.
8.-La composición oftálmica de la reivindicación 1 que contenga vitamina C.
9.- La composición oftálmica de la reivindicación 1 que contenga lactoferrina.
10.- La composición oftálmica de la reivindicación 1 que contenga albúmina o pre- albúmina. 1 L-La composición oftálmica de la reivindicación 1 que contenga inmunoglobulina A
(IGA).
12.- La composición oftálmica de la reivindicación 1 que contenga factor de crecimiento epitelial (epithelial growth factor: EGF).
13.-. La composición oftálmica de la reivindicación 1 que contenga beta transforming growth factor (TGF-β) .
14.- La composición oftálmica de la reivindicación 1 que contenga acidic fibroblast growth factor (aFGF).
15.- La composición oftálmica de la reivindicación 1 que contenga basic fibroblast growth factor (bFGF) -
16.- La composición oftálmica de la reivindicación 1 que contenga antiproteasas como la macroglobulina.
17.- La composición oftálmica de la reivindicación 1 que contenga factores neurales como la sustancia P e insulinlike growth factor.
18.- La composición oftálmica de la reivindicación 1 que contenga agentes antibacterianos como la Ig G, lisozima y complemento.
19.- La composición oftálmica de la reivindicación 1 que contenga ácidos grasos de cadena larga como el ácido gadoleico, palmítico, palmitoleico, esteárico, oleico, linoleico, araquídico, linolénico, eicosénico, lignocérico, láctico y mirístico.
20.- La composición oftálmica de la reivindicación 1 que contenga lípidos hidrofílicos como fosfolípidos, esfingomielina, ceramidas y cerebrósidos.
21- Uso, de acuerdo con las reivindicaciones anteriores, de estos preparados medicinales en determinadas patologías como es el caso del síndrome de ojo seco.
Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
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PL06743460T PL2016937T3 (pl) | 2006-04-27 | 2006-04-28 | Formulacja pęcherzyków liposomalnych w wodnych roztworach o cechach filmu łzowego |
EP06743460.5A EP2016937B1 (en) | 2006-04-27 | 2006-04-28 | Formulation of liposomal vesicles in aqueous solutions with tear film characteristics |
ES06743460.5T ES2535189T3 (es) | 2006-04-27 | 2006-04-28 | Formulación de vesículas liposomales en soluciones acuosas con características de película lagrimal |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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ES200601078A ES2284398B2 (es) | 2006-04-27 | 2006-04-27 | Formulacion de vesiculas liposomales en soluciones acuosas con caracteristicas de pelicula lagrimal. |
ESP200601078 | 2006-04-27 |
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WO2007125134A1 true WO2007125134A1 (es) | 2007-11-08 |
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PCT/ES2006/000208 WO2007125134A1 (es) | 2006-04-27 | 2006-04-28 | Formulación de vesículas liposomales en soluciones acuosas con características de película lagrimal |
Country Status (4)
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EP (1) | EP2016937B1 (es) |
ES (2) | ES2284398B2 (es) |
PL (1) | PL2016937T3 (es) |
WO (1) | WO2007125134A1 (es) |
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WO2020053609A1 (en) | 2018-09-11 | 2020-03-19 | Lead Biotherapeutics Ltd. | Mucoadhesive dispersion nanoparticle system and method for production the same |
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CN104546538B (zh) * | 2013-12-26 | 2018-06-26 | 华东理工大学 | 一种壳聚糖包覆的vc-ve脂质体及其制备方法和应用 |
IT201800007677A1 (it) * | 2018-07-31 | 2020-01-31 | Tdc Tech Dedicated To Care Srl | Liposomi per il trattamento di patologie oculari |
FI20225982A1 (fi) * | 2022-11-02 | 2024-05-03 | Univ Helsinki | Uudet formulaatiot |
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WO2020053609A1 (en) | 2018-09-11 | 2020-03-19 | Lead Biotherapeutics Ltd. | Mucoadhesive dispersion nanoparticle system and method for production the same |
Also Published As
Publication number | Publication date |
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ES2535189T3 (es) | 2015-05-06 |
EP2016937A4 (en) | 2013-02-20 |
PL2016937T3 (pl) | 2015-07-31 |
EP2016937A1 (en) | 2009-01-21 |
ES2284398A1 (es) | 2007-11-01 |
EP2016937B1 (en) | 2015-01-21 |
ES2284398B2 (es) | 2008-12-16 |
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