WO2009071034A1 - Pharmaceutical cyclosporine composition and method for altering the solubility and stability thereof - Google Patents
Pharmaceutical cyclosporine composition and method for altering the solubility and stability thereof Download PDFInfo
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- WO2009071034A1 WO2009071034A1 PCT/CU2008/000011 CU2008000011W WO2009071034A1 WO 2009071034 A1 WO2009071034 A1 WO 2009071034A1 CU 2008000011 W CU2008000011 W CU 2008000011W WO 2009071034 A1 WO2009071034 A1 WO 2009071034A1
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- cyclosporin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
- A61K38/13—Cyclosporins
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1641—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
Definitions
- composition of cyclosporine A and procedure to modify its solubility and stability.
- the present invention relates to the pharmaceutical branch, and in particular the process with the modification of the physical properties of substances with therapeutic activity to improve its effect.
- US 5,051, 402 refers to the use of different types of cyclodextrins ( ⁇ , ⁇ , ⁇ ) and of these, the ⁇ -cyclodextrin is the best as solubilizer, being the proportion of the highest recovery of one part of cyclosporine and 107 parts of ⁇ -cyclodexthna with which it is possible to solubilize only 38% of the cyclosporine.
- US Patent 6,551, 619 refers to the preparation of solid lipid particles by lyophilization or spray drying, loaded with cyclosporin A prepared by high pressure homogenization, using as monoglyceride, diglyceride and / or triglyceride matrix components, fatty alcohol esters, wax and mixtures of these. Mention is made of glycerol trilaurate, glycerol myristate, glycerol palmitate, glycerol stearate and / or glycerol behenate, or mixtures thereof with monoglycerides, diglycerides and triglycerides, also mixtures with glycerides, fatty alcohols and / or waxes.
- poloxamers As additives for dispersion and stabilization are mentioned poloxamers, poloxamines, ethoxylated and diglyceride monoglycerides, ethoxylated lipids, ethoxylated fatty alcohols, alkyl phenols, ethoxylated fatty acid esters, polyglycerin ethers and esters, lecithin, esters and azether ethers and sphingolipids, sterols or their esters and esters.
- Egg lecithin, soy lecithin or hydrated lecithin, and mixtures thereof, plus phospholipid components such as cholesterol, cholesterol palmitate, stigmasterine or other sterols are mentioned.
- sugars they may contain glucose, mannose, trehalose, mannitol and / or sorbitol.
- US 6,572,893 refers to a method of preparing a powder from an organic solution or suspension of a hydrophilic and other hydrophobic component in an organic solvent only, by spray drying using water-soluble carbohydrates and polyvinylpyrrolidone.
- hydrophobic components only steroids such as budesonide, testosterone, progesterone, estrogen, flunisolide, triamcinolone, beclomethasone, betamethasone, dexamethasone, fluticasone, methylprednisolone, prednisone, hydrocortisone are mentioned; other drugs such as cyclosporine, amphotericin B and tetrahydrocanabinol.
- US 6,569,463 refers to the composition of a carrier in solid form of a pharmaceutically active hydrophobic ingredient, solubilized with a hydrophilic surfactant. They are cited among other immunosuppressants and specifically cyclosporine. It is obtained by spray drying; Dextran is used as a cryoprotectant.
- SLS sodium lauryl sulfate
- the objective of the present invention is the use of drying aids such as Maltodextrin DE 10 Dextran, Polyethylene Glycol 4000 (PEG-4000) and mixtures thereof to stabilize the dispersion in water and gastrointestinal fluid of the cyclosporine.
- drying aids such as Maltodextrin DE 10 Dextran, Polyethylene Glycol 4000 (PEG-4000) and mixtures thereof to stabilize the dispersion in water and gastrointestinal fluid of the cyclosporine.
- the water-soluble cyclosporin A microparticles are obtained by dispersing the cyclosporine in a solution of SLS in a ratio (1: 1), a mixture of dextran and polyethylene glycol 4000 in relation (1: 1 to 1: 0.15) is added as stabilizers. Subsequently, spray drying is performed at an inlet temperature between 100 0 C and 150 0 C and an outlet temperature between 50 0 C and 90 0 C.
- the oral solution for microemulsion has a water transmittance of 85.02 ⁇ 0.62%, which demonstrates that the solubility achieved in the present invention, expressed by the transmittance, is superior as shown in the examples.
- the concentration of SLS used as a solubilizer is 350 times lower than its oral lethal dose in humans.
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- Pharmacology & Pharmacy (AREA)
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- Animal Behavior & Ethology (AREA)
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- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Gastroenterology & Hepatology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
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Abstract
Description
Composición farmacéutica de ciclosporina A y procedimiento para modificar su solubilidad y estabilidad. Pharmaceutical composition of cyclosporine A and procedure to modify its solubility and stability.
Rama de Ia TécnicaTechnical Branch
La presente invención se relaciona con Ia rama farmacéutica, y en particular el procedimiento con Ia modificación de las propiedades físicas de sustancias con actividad terapéutica para mejorar su efecto.The present invention relates to the pharmaceutical branch, and in particular the process with the modification of the physical properties of substances with therapeutic activity to improve its effect.
Estado del ArteState of the Art
La patente US 5,051 ,402 refiere el uso de distintos tipos de ciclodextrinas (α, β, δ) y de éstas, Ia α-ciclodextrina es Ia mejor como solubilizante, siendo Ia proporción de mayor recobrado de una parte de ciclosporina y 107 partes de α-ciclodexthna con Ia cual se logra solubilizar solamente un 38 % de Ia ciclosporina.US 5,051, 402 refers to the use of different types of cyclodextrins (α, β, δ) and of these, the α-cyclodextrin is the best as solubilizer, being the proportion of the highest recovery of one part of cyclosporine and 107 parts of α-cyclodexthna with which it is possible to solubilize only 38% of the cyclosporine.
En Ia patente US 6,077,543 se hace referencia al empleo del secado por aspersión en Ia obtención de mezclas de fármacos hidrofóbicos con excipientes hidrofílicos. Se señalan sólo esteroides como Ia budesonida, testosterona, progesterona, estrógeno, flunisolida, triamcinolona, beclometasona, betametasona, dexametasona, fluticasona, metilprednisolona, prednisona, hidrocortisona. Como excipientes se mencionan solamente Ia lactosa, sodio citrato, manitol, povidona, pectina, ácido cítrico, sodio cloruro y mezclas de ellos. Se dispersan los solutos en solventes orgánicos para el secado.In US Patent 6,077,543 reference is made to the use of spray drying in obtaining mixtures of hydrophobic drugs with hydrophilic excipients. Only steroids such as budesonide, testosterone, progesterone, estrogen, flunisolide, triamcinolone, beclomethasone, betamethasone, dexamethasone, fluticasone, methylprednisolone, prednisone, hydrocortisone are indicated. As excipients, only lactose, sodium citrate, mannitol, povidone, pectin, citric acid, sodium chloride and mixtures thereof are mentioned. The solutes are dispersed in organic solvents for drying.
La patente US 6,551 ,619 refiere Ia preparación de partículas lipídicas sólidas mediante liofilización o secado por aspersión, cargadas con ciclosporina A preparadas mediante homogeneización de alta presión, empleando como componentes de Ia matriz monoglicéridos, diglicéridos y/o triglicéridos, esteres de alcoholes grasos, cera y mezclas de éstos. Se mencionan glicerol trilaurato, glicerol miristato, glicerol palmitato, glicerol estearato y/o glicerol behenato, o mezclas de ellos con monoglicéridos, diglicéridos y triglicéridos, también mezclas con glicéridos, alcoholes grasos y/o ceras. Como aditivos para Ia dispersión y estabilización se mencionan los poloxameros, poloxaminas, monoglicéridos etoxilados y diglicéridos, lípidos etoxilados, alcoholes grasos etoxilados, alkil fenoles, esteres de ácidos grasos etoxilados, éteres de poliglicerina y esteres, lecitina, esteres y éteres de azúcares, fosfolípidos y esfingolípidos, esteróles o sus esteres y esteres. Se mencionan lecitina de huevo, lecitina de soya o lecitina hidratada, y sus mezclas, más componentes fosfolipídicos como colesterol, colesterol palmitato, estigmasterina u otros esteróles. Como azúcares pudieran contener glucosa, mañosa, trehalosa, manitol y/o sorbitol.US Patent 6,551, 619 refers to the preparation of solid lipid particles by lyophilization or spray drying, loaded with cyclosporin A prepared by high pressure homogenization, using as monoglyceride, diglyceride and / or triglyceride matrix components, fatty alcohol esters, wax and mixtures of these. Mention is made of glycerol trilaurate, glycerol myristate, glycerol palmitate, glycerol stearate and / or glycerol behenate, or mixtures thereof with monoglycerides, diglycerides and triglycerides, also mixtures with glycerides, fatty alcohols and / or waxes. As additives for dispersion and stabilization are mentioned poloxamers, poloxamines, ethoxylated and diglyceride monoglycerides, ethoxylated lipids, ethoxylated fatty alcohols, alkyl phenols, ethoxylated fatty acid esters, polyglycerin ethers and esters, lecithin, esters and azether ethers and sphingolipids, sterols or their esters and esters. Egg lecithin, soy lecithin or hydrated lecithin, and mixtures thereof, plus phospholipid components such as cholesterol, cholesterol palmitate, stigmasterine or other sterols are mentioned. As sugars they may contain glucose, mannose, trehalose, mannitol and / or sorbitol.
US 6,572,893 refiere un método de preparación de un polvo a partir de una solución o suspensión orgánica de un componente hidrofílico y otro hidrofóbico en un solvente orgánico solamente, mediante secado por aspersión empleando carbohidratos hidrosolubles y polivinilpirrolidona. Como componentes hidrofóbicos se mencionan sólo esteroides como Ia budesonida, testosterona, progesterona, estrógeno, flunisolida, triamcinolona, beclometasona, betametasona, dexametasona, fluticasona, metilprednisolona, prednisona, hidrocortisona; otros fármacos como ciclosporina, anfotericina B y tetrahidrocanabinol. Como excipientes se mencionan solamente Ia lactosa, sodio citrato, manitol, pectina, ácido cítrico, sodio cloruro y mezclas de ellos. En US 6,569,463 se refiere Ia composición de un transportador en forma sólida de un ingrediente farmacéuticamente activo hidrofóbico, solubilizado con un tensoactivo hidrofílico. Se citan entre otros immunodepresores y específicamente ciclosporina. Se obtiene mediante secado por aspersión; como crioprotector se emplea dextrana.US 6,572,893 refers to a method of preparing a powder from an organic solution or suspension of a hydrophilic and other hydrophobic component in an organic solvent only, by spray drying using water-soluble carbohydrates and polyvinylpyrrolidone. As hydrophobic components, only steroids such as budesonide, testosterone, progesterone, estrogen, flunisolide, triamcinolone, beclomethasone, betamethasone, dexamethasone, fluticasone, methylprednisolone, prednisone, hydrocortisone are mentioned; other drugs such as cyclosporine, amphotericin B and tetrahydrocanabinol. As excipients, only lactose, sodium citrate, mannitol, pectin, citric acid, sodium chloride and mixtures thereof are mentioned. US 6,569,463 refers to the composition of a carrier in solid form of a pharmaceutically active hydrophobic ingredient, solubilized with a hydrophilic surfactant. They are cited among other immunosuppressants and specifically cyclosporine. It is obtained by spray drying; Dextran is used as a cryoprotectant.
En US 6,197,335 B1 se refiere que Ia cantidad de sodio laurilsulfato (SLS) recomendada para solubilizar Ia ciclosporina, es de 80 % a 300 % del peso de Ia misma, utilizándose solamente como excipientes para facilitar el secado por aspersión, lactosa y manitol.In US 6,197,335 B1 it is said that the amount of sodium lauryl sulfate (SLS) recommended to solubilize the cyclosporine is 80% to 300% of the weight thereof, being used only as excipients to facilitate spray drying, lactose and mannitol.
El uso de los excipientes citados en los diferentes documentos que conforman el estado del arte aun no garantizan Ia estabilidad de Ia solubilidad de Ia ciclosporina A, Io cual influye directamente sobre su biodisponibilidad, para Ia cual es necesario, en primer lugar, Ia solubilidad de forma estable que garantice Ia absorción de Ia ciclosporina A y su transportación a Ia sangre. El uso de Ia combinación de los excipientes propuestos en este documento, conjuntamente con el procedimiento de preparación, garantizan una solubilidad estable por más de 24 horas, asegurando así su absorción con ausencia de signos tóxicos en comparación con el producto líder del mercado Sandinmune Neoral®.The use of the excipients mentioned in the different documents that make up the state of the art does not yet guarantee the stability of the solubility of cyclosporin A, which directly influences its bioavailability, for which the solubility of stable form that guarantees the absorption of cyclosporin A and its transport to the blood. The use of the combination of the excipients proposed in this document, together with the preparation procedure, guarantee a stable solubility for more than 24 hours, thus ensuring its absorption with the absence of toxic signs compared to the market leading product Sandinmune Neoral ® .
Descripción de Ia invenciónDescription of the invention
El objetivo de Ia presente invención es Ia utilización de coadyuvantes del secado como Maltodextrina DE 10 Dextrana, Polietilenglicol 4000 (PEG - 4000) y mezclas de éstos para estabilizar Ia dispersión en agua y en fluido gastrointestinal de Ia ciclosporina.The objective of the present invention is the use of drying aids such as Maltodextrin DE 10 Dextran, Polyethylene Glycol 4000 (PEG-4000) and mixtures thereof to stabilize the dispersion in water and gastrointestinal fluid of the cyclosporine.
Las micropartículas de ciclosporina A hidrosoluble, se obtienen dispersando Ia ciclosporina en una solución de SLS en relación (1 :1 ), se agrega una mezcla de dextrana y polietilenglicol 4000 en relación (1 :1 hasta 1 :0,15) como estabilizantes. Posteriormente se realiza el secado por atomización a una temperatura de entrada entre 100 0C y 150 0C y una temperatura de salida entre 50 0C y 90 0C.The water-soluble cyclosporin A microparticles are obtained by dispersing the cyclosporine in a solution of SLS in a ratio (1: 1), a mixture of dextran and polyethylene glycol 4000 in relation (1: 1 to 1: 0.15) is added as stabilizers. Subsequently, spray drying is performed at an inlet temperature between 100 0 C and 150 0 C and an outlet temperature between 50 0 C and 90 0 C.
La solución oral para microemulsión presenta una transmitancia en agua de 85,02 ± 0,62 %, Io que demuestra que Ia solubilidad alcanzada en Ia presente invención, expresada por Ia transmitancia, es superior como se muestra en los ejemplos. Por otra parte Ia concentración de SLS empleada como solubilizante es 350 veces inferior a su dosis letal oral en humanos.The oral solution for microemulsion has a water transmittance of 85.02 ± 0.62%, which demonstrates that the solubility achieved in the present invention, expressed by the transmittance, is superior as shown in the examples. On the other hand, the concentration of SLS used as a solubilizer is 350 times lower than its oral lethal dose in humans.
Ejemplo 1 :Example 1 :
1g de ciclosporina A, 1 ,1 g de SLS, 10 mL de etanol al 95 %, 10 mL de propilenglicol y 20 mL de agua destilada. Se obtiene una solución totalmente transparente, con transmitancia de 92 %.1g of cyclosporine A, 1.1 g of SLS, 10 mL of 95% ethanol, 10 mL of propylene glycol and 20 mL of distilled water. A completely transparent solution is obtained, with transmittance of 92%.
Ejemplo 2:Example 2:
1 g de ciclosporina A, 1 g de SLS, 1 g de Maltodextrina DE 10, 100 mL de agua destilada. Se obtiene una solución totalmente transparente. Después de secada por aspersión se obtiene un polvo blanco, con un rendimiento de 80 %, con una transmitancia en agua de 96 % y una transmitancia en jugo gástrico simulado de 68 %. Se recupera un 98 % de ciclosporina en Ia solución. Ejemplo 3:1 g of cyclosporine A, 1 g of SLS, 1 g of Maltodextrin DE 10, 100 mL of distilled water. A completely transparent solution is obtained. After spray drying, a white powder is obtained, with a yield of 80%, with a transmittance in water of 96% and a transmittance in simulated gastric juice of 68%. 98% of cyclosporine is recovered in the solution. Example 3:
10 g de ciclosporina A, 10 g de SLS, 10 g de Dextrana, 100 ml_ de agua destilada. Se obtiene una solución totalmente transparente. Después de secada por aspersión se obtiene un polvo blanco, con un rendimiento de 81 %, con una transmitancia en agua de 97 % y una transmitancia en jugo gástrico simulado de 76 %. Se recupera un 101 % de ciclosporina en Ia solución.10 g of cyclosporine A, 10 g of SLS, 10 g of Dextrana, 100 ml_ of distilled water. A completely transparent solution is obtained. After spray drying, a white powder is obtained, with a yield of 81%, with a transmittance in water of 97% and a transmittance in simulated gastric juice of 76%. 101% cyclosporine is recovered in the solution.
Ejemplo 4:Example 4:
10 g de ciclosporina A, 10 g de SLS, 10 g de PEG 4000, 100 mL de agua destilada. Se obtiene una solución totalmente transparente. Después de secada por aspersión se obtiene un polvo blanco, con un rendimiento de 75 %, con una transmitancia en agua de 94 % y una transmitancia en jugo gástrico simulado de 78 %. Se recupera un 100,4 % de ciclosporina en Ia solución.10 g of cyclosporine A, 10 g of SLS, 10 g of PEG 4000, 100 mL of distilled water. A completely transparent solution is obtained. After spray drying, a white powder is obtained, with a yield of 75%, with a transmittance in water of 94% and a transmittance in simulated gastric juice of 78%. 100.4% of cyclosporine is recovered in the solution.
Ejemplo 5:Example 5:
10 g de ciclosporina A, 10 g de SLS, 10 g de mezcla Dextrana/PEG 4000, 100 mL de agua destilada. Se obtiene una solución totalmente transparente. Después de secada por aspersión se obtiene un polvo blanco, con un rendimiento de 85 %, con una transmitancia en agua de 98% y una transmitancia en jugo gástrico simulado de 77 %. Se recupera un 101 ,2 % de ciclosporina en Ia solución.10 g of cyclosporine A, 10 g of SLS, 10 g of Dextrana / PEG 4000 mixture, 100 mL of distilled water. A completely transparent solution is obtained. After spray drying, a white powder is obtained, with a yield of 85%, with a transmittance in water of 98% and a transmittance in simulated gastric juice of 77%. 101.2% of cyclosporine is recovered in the solution.
Ejemplo 6:Example 6:
10 g de ciclosporina A, 10 g de SLS, 10 g de mezcla Dextrana/PEG 4000, 100 mL de agua destilada. Se obtiene una solución totalmente transparente. Se seca por aspersión con una temperatura de salida de 90 0C y a una concentración de 8 %. Se obtiene un polvo blanco, con un rendimiento de 77 %, con una transmitancia en agua de 97 % y una transmitancia en jugo gástrico simulado de 78 %. Una concentración de solvente residual de 0,8 ± 0,10 %. Se recupera un 102,2 % de ciclosporina en Ia solución.10 g of cyclosporine A, 10 g of SLS, 10 g of Dextrana / PEG 4000 mixture, 100 mL of distilled water. A completely transparent solution is obtained. It is spray dried with an outlet temperature of 90 0 C and at a concentration of 8%. A white powder is obtained, with a yield of 77%, with a transmittance in water of 97% and a transmittance in simulated gastric juice of 78%. A residual solvent concentration of 0.8 ± 0.10%. 102.2% of cyclosporine is recovered in the solution.
Ejemplo 7:Example 7:
10 g de ciclosporina A, 10 g de SLS, 10 g de mezcla Dextrana/PEG 4000, 100 mL de agua destilada. Se obtiene una solución totalmente transparente. Se seca por aspersión con una temperatura de salida de 70 0C y a una concentración de 8 %. Se obtiene un polvo blanco, con un rendimiento de 75 %, con una transmitancia en agua de 95 % y una transmitancia en jugo gástrico simulado de 76 %. Una concentración de solvente residual de 1 ,0 ± 0,08 %. Se recupera un 99,2 % de ciclosporina en Ia solución.10 g of cyclosporine A, 10 g of SLS, 10 g of Dextrana / PEG 4000 mixture, 100 mL of distilled water. A completely transparent solution is obtained. It is spray dried with an outlet temperature of 70 0 C and at a concentration of 8%. A white powder is obtained, with a yield of 75%, with a transmittance in water of 95% and a transmittance in simulated gastric juice of 76%. A residual solvent concentration of 1.0 ± 0.08%. 99.2% of cyclosporine is recovered in the solution.
Ejemplo 8:Example 8:
10 g de ciclosporina A, 10 g de SLS, 10 g de mezcla Dextrana/PEG 4000, 100 mL de agua destilada. Se obtiene una solución totalmente transparente. Se seca por aspersión con una temperatura de salida de 90 °C y a una concentración de 16 %. Se obtiene un polvo blanco, con un rendimiento de 81 ,6 %, con una transmitancia en agua de 98,6 % y una transmitancia en jugo gástrico simulado de 79 %. Una concentración de solvente residual de 1 ,1 ± 0,06 %. Se recupera un 100,2 % de ciclosporina en Ia solución. Ejemplo 9:10 g of cyclosporine A, 10 g of SLS, 10 g of Dextrana / PEG 4000 mixture, 100 mL of distilled water. A completely transparent solution is obtained. It is spray dried with an outlet temperature of 90 ° C and a concentration of 16%. A white powder is obtained, with a yield of 81.6%, with a transmittance in water of 98.6% and a transmittance in simulated gastric juice of 79%. A residual solvent concentration of 1.1 ± 0.06%. 100.2% of cyclosporine is recovered in the solution. Example 9:
10 g de ciclosporina A, 10 g de SLS, 10 g de mezcla Dextrana/PEG 4000, 100 ml_ de agua destilada. Se obtiene una solución totalmente transparente. Se seca por aspersión con una temperatura de salida de 70 0C y a una concentración de 16 %. Se obtiene un polvo blanco, con un rendimiento de 82,4 %, con una transmitancia en agua de 98,9 % y una transmitancia en jugo gástrico simulado de 81 %. Una concentración de solvente residual de 0,8 ± 0,12 %. Se recupera un 101 ,2 % de ciclosporina en Ia solución. 10 g of cyclosporine A, 10 g of SLS, 10 g of Dextrana / PEG 4000 mixture, 100 ml of distilled water. A completely transparent solution is obtained. It is spray dried with an outlet temperature of 70 0 C and at a concentration of 16%. A white powder is obtained, with a yield of 82.4%, with a transmittance in water of 98.9% and a transmittance in simulated gastric juice of 81%. A residual solvent concentration of 0.8 ± 0.12%. 101.2% of cyclosporine is recovered in the solution.
Claims
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CUCU2007/0274 | 2007-12-07 | ||
| CUP2007000274A CU23892B1 (en) | 2007-12-07 | 2007-12-07 | CYCLOSPORINE MICROENCAPSULATED PHARMACEUTICAL COMPOSITION A |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2009071034A1 true WO2009071034A1 (en) | 2009-06-11 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/CU2008/000011 Ceased WO2009071034A1 (en) | 2007-12-07 | 2008-12-05 | Pharmaceutical cyclosporine composition and method for altering the solubility and stability thereof |
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| Country | Link |
|---|---|
| AR (1) | AR069578A1 (en) |
| CU (1) | CU23892B1 (en) |
| WO (1) | WO2009071034A1 (en) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20030133984A1 (en) * | 2000-04-10 | 2003-07-17 | Ambuehl Michael | Pharmaceutical compositions |
| WO2004012714A1 (en) * | 2002-08-05 | 2004-02-12 | Dsm Ip Assets B.V. | Oral dosage forms of water insoluble drugs and methods of making the same |
| WO2005079752A2 (en) * | 2004-02-11 | 2005-09-01 | Rubicon Research Private Limited | Controlled release pharmaceutical compositions with improved bioavailability |
-
2007
- 2007-12-07 CU CUP2007000274A patent/CU23892B1/en active IP Right Grant
-
2008
- 2008-12-04 AR ARP080105294A patent/AR069578A1/en unknown
- 2008-12-05 WO PCT/CU2008/000011 patent/WO2009071034A1/en not_active Ceased
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20030133984A1 (en) * | 2000-04-10 | 2003-07-17 | Ambuehl Michael | Pharmaceutical compositions |
| WO2004012714A1 (en) * | 2002-08-05 | 2004-02-12 | Dsm Ip Assets B.V. | Oral dosage forms of water insoluble drugs and methods of making the same |
| WO2005079752A2 (en) * | 2004-02-11 | 2005-09-01 | Rubicon Research Private Limited | Controlled release pharmaceutical compositions with improved bioavailability |
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| Publication number | Publication date |
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| CU20070274A6 (en) | 2011-10-31 |
| AR069578A1 (en) | 2010-02-03 |
| CU23892B1 (en) | 2013-04-19 |
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