ES2536235T3 - Dispositivo polimérico de liberación prolongada - Google Patents

Dispositivo polimérico de liberación prolongada Download PDF

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Publication number
ES2536235T3
ES2536235T3 ES11180259.1T ES11180259T ES2536235T3 ES 2536235 T3 ES2536235 T3 ES 2536235T3 ES 11180259 T ES11180259 T ES 11180259T ES 2536235 T3 ES2536235 T3 ES 2536235T3
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sucrose
composition
oil
mecl2
formulations
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Inventor
Steven G. Wright
Troy Christenson
Thean Y. Yeoh
Michael E. Rickey
Joyce M. Hotz
Rajesh Kumar
Henry R. Costantino
Christine Smith
David Lokensgord
John Ong
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Alkermes Pharma Ireland Ltd
Amylin Pharmaceuticals LLC
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Alkermes Pharma Ireland Ltd
Amylin Pharmaceuticals LLC
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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
    • A61K9/20—Pills, tablets, discs, rods
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/2278—Vasoactive intestinal peptide [VIP]; Related peptides (e.g. Exendin)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/26—Glucagons
    • 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
    • A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
    • 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
    • A61K9/1647—Polyesters, e.g. poly(lactide-co-glycolide)
    • 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
    • A61K9/1682—Processes
    • A61K9/1694—Processes resulting in granules or microspheres of the matrix type containing more than 5% of excipient
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5089—Processes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Epidemiology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Endocrinology (AREA)
  • Immunology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Zoology (AREA)
  • Diabetes (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Vascular Medicine (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Inorganic Chemistry (AREA)
  • Child & Adolescent Psychology (AREA)
  • Emergency Medicine (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Cardiology (AREA)
  • Medicinal Preparation (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Agricultural Chemicals And Associated Chemicals (AREA)
  • Fats And Perfumes (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Silicon Polymers (AREA)
  • Addition Polymer Or Copolymer, Post-Treatments, Or Chemical Modifications (AREA)
  • Lubricants (AREA)
  • Ceramic Products (AREA)

Abstract

Una composición para la liberación prolongada de un polipéptido biológicamente activo, que comprende un polímero biocompatible que tiene el polipéptido biológicamente activo dispersado en él de modo que esté presente de un 3% (p/p) a un 10% (p/p) del peso de la composición y sacarosa dispersada en él de modo que esté presente en un 2% (p/p) del peso de la composición, donde el polipéptido biológicamente activo es exendina-4, donde el volumen de poro total de la composición es de 0.1 mL/g o menos según se determina utilizando porosimetría por intrusión de mercurio y donde la composición está exenta de tampones y de sales de desestabilización salina.

Description

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E11180259
04-05-2015
donde:
D = diámetro del poro γ = tensión superficial (constante) θ = ángulo de contacto (constante)
5 P = presión
Por lo tanto, el tamaño del poro en el cual se introducirá el mercurio es inversamente proporcional a la presión aplicada. Asumiendo que todos los poros son cilindros rígidos, el diámetro del poro promedio (D=4V/A) se puede calcular dividiendo el volumen del poro (V=πD2h/4) por el área del poro (A=πDh).
DISOLVENTES RESIDUALES
10 Se utilizó un único método para la cuantificación de heptano, etanol y diclorometano. El equipo estuvo constituido por un cromatógrafo de gases HP 5890 Serie 2 con una columna Rtx 1301, 30 cm x 0.53 mm. Se disolvieron aproximadamente 130 mg de micropartículas en 10 mL de N,N-dimetilformamida. Se utilizó acetato de propilo como patrón interno. Se ajustó la preparación de la muestra de modo que se pudieran cuantificar concentraciones de diclorometano de tan solo un 0.03%.
15 PREPARACIÓN DE MICROPARTÍCULAS
Se prepararon los lotes de micropartículas expuestos en la Tabla 1 según se ha descrito anteriormente a una escala de 100 gramos utilizando el polímero 4A y una relación de aceite de silicona respecto al diclorometano de 1.5:1 o de
1:1 y el aceite de silicona tuvo una viscosidad de 350 cs. La cantidad de exendina-4 y los excipientes utilizados en la formulación también se exponen en la Tabla 1.
20 TABLA 1
Lote n.º
Formulación Liberación brusca in vitro (%) Observaciones
02-019-147(n.º 1)
0% de sacarosa, 0% de SA 0.40 1.5:1 Aceite de Si: MeCl2
02-019-167(n.º 2)
2% de sacarosa (F16) 0.40 1.5:1 Aceite de Si: MeCl2
02-019-160(n.º 2.1)
2% de sacarosa (F16) 0.44 1.5:1 Aceite de Si l: MeCl2
02-019-164(n.º 2-2)
2% de sacarosa (F16) 0.45 1.5:1 Aceite de Si: MeCl2
02-030-08(n.º 2-3)
2% de sacarosa (F16) 0.80 1:1 Aceite de Si: MeCl2
02-030-01(n.º 2-4)
2% de sacarosa (F16) 1.0 1:1 Aceite de Si: MeCl2
02-030-04(n.º 2-5)
2% de sacarosa (F16) 1.1 1:1 Aceite de Si: MeCl2
02-019-136(n.º 3-1)
2% de sacarosa, 0.5% de SA (F14) 1.3 50:50 Desactivación
02-019-115(n.º 3-2)
2% de sacarosa, 0.5% de SA (F14) 2.2 1.5:1 Aceite de Si: MeCl2
02-019-170(n.º 4)
0% de sacarosa, 0.5% de SA 3.8 1.5:1 Aceite de Si: MeCl2
02-019-133A(n.º 3-3)
2% de sacarosa, 0.5% de SA (F14) 12.7 100% Desactivación con heptano
02-019-185(n.º 5) (5% de adición del fármaco)
2% de sacarosa (F17) 0.5 5% de adición del fármaco, 1.5:1 Aceite de Si: MeCl2
02-019-64 (n.º 3-4)
2% de sacarosa, 0.5% de SA (F14) 0.5 1.5:1 Aceite de Si: MeCl2
02-019-10(n.º 3-5)
2% de sacarosa, 0.5% de SA (F14) 1.30 1:1 Aceite de Si: MeCl2
02-001-196(n.º 3-6)
2% de sacarosa, 0.5% de SA (F14) 2.70 1:1 Aceite de Si: MeCl2
02-019-24(n.º 3-7)
2% de sacarosa, 0.5% de SA (F14) 6.70 1:1 Aceite de Si: MeCl2
*TODAS LAS FORMULACIONES TUVIERON UNA ADICIÓN DEL FÁRMACO DE UN 3% CON LA EXCEPCIÓN
12
E11180259
04-05-2015
Lote n.º
Formulación Liberación brusca in vitro (%) Observaciones
DE LA POROSIDAD N.º 5
El volumen de intrusión total obtenido de la porosimetría por intrusión de mercurio y los diámetros de poro promedio calculados se proporcionan en la TABLA 2. La relación entre el diámetro de poro promedio y la liberación in vitro se muestra en la FIG. 1.
TABLA 2
Lot n.º
Volumen del Poro Total (mL/g) Liberación brusca in vitro (%) Diámetro del poro promedio (µm)
02-019-147(n.º 1)
0.033 0.40 0.0068
02-019-167(n.º 2)
0.035 0.40 0.0069
02-019-160(n.º 2-1)
0.037 0.44 0.0070
02-019-164(n.º 2-2)
0.035 0.45 0.0070
02-030-08(n.º 2-3)
0.036 0.80 0.0070
02-030-01 (n.º 2-4)
0.038 1.0 0.0073
02-030-04(n.º 2-5)
0.039 1.1 0.0074
02-019-136(n.º 3-1)
0.041 1.3 0.0073
02-019-115(n.º 3-2)
0.039 2.2 0.0078
02-019-170(n.º 4)
0.067 3.8 0.0125
02-019-133A(n.º 33)
0.513 12.7 0.0277
02-019-64 (n.º 3-4)
0.030 0.5 0.0060
02-019-10(n.º 3-5)
0.060 1.30 0.0090
02-001-196(n.º 3-6)
0.060 2.70 0.0100
02-019-24(n.º 3-7)
0.180 6.70 0.0170
La FIG. 1 muestra el efecto del sulfato de amonio en la liberación inicial in vitro. Los datos indican que la liberación inicial in vitro se correlaciona con el diámetro del poro de las micropartículas. Las formulaciones hechas con sulfato de amonio mostraron niveles variables de liberación in vitro y una porosidad variable a diferencia de las 10 formulaciones sin sulfato de amonio que exhibieron una porosidad y liberación constantes. Durante la fabricación de micropartículas, la presencia de sulfato de amonio en la fase acuosa puede provocar la desestabilización salina de la sustancia farmacológica durante la preparación de la emulsión interna. Las diferencias en el microentorno de los precipitados pueden contribuir a las diferencias en la porosidad y, por lo tanto, la variación en la liberación inicial. El efecto no se observó en formulaciones preparadas sin sulfato de amonio. Las formulaciones con sacarosa y
15 exendina-4 muestran un nivel de liberación inicial más deseable y constante en comparación con formulaciones que tienen exendina-4, sacarosa y sulfato de amonio.
La FIG. 2 demuestra además el efecto de la porosidad en la liberación in vitro y el impacto que las condiciones del procesamiento, concretamente la relación del aceite de silicona respecto al diclorometano, tiene en la porosidad de las micropartículas formadas. Resumiendo, las formulaciones de micropartículas preparadas utilizando una relación
20 del aceite de silicona respecto al diclorometano de 1:1 (Formulaciones 2-4 y 2-5 de la Tabla 1) tienen una liberación inicial más elevada que las mismas formulaciones preparadas utilizando una relación del aceite de silicona respecto al diclorometano de 1.5:1 (Formulaciones 2, 2-1 y 2-2 de la Tabla 1). La FIG. 2 sugiere que una relación más elevada del aceite de silicona respecto al diclorometano conlleva una porosidad menor lo que conlleva una liberación inicial menor.
25 SEM CRIOGÉNICA
Se llevaron a cabo análisis por SEM criogénica tal y como se ha descrito anteriormente con las Formulaciones de los tipos 2, 3 y 5 de la Tabla 1. Las FIGS. 3A-3B son barridos de micrografías para formulaciones seleccionadas de tipo 2 (Formulación 2-2, FIG. 3A) y de tipo 5 (5% de exendina-4, 2% de sacarosa, FIG. 3B). Las FIGS. 4A-D son barridos
13
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Claims (1)

  1. imagen1
ES11180259.1T 2004-04-15 2004-04-15 Dispositivo polimérico de liberación prolongada Expired - Lifetime ES2536235T3 (es)

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Application Number Priority Date Filing Date Title
EP20110180259 EP2409707B8 (en) 2004-04-15 2004-04-15 Polymer-based sustained release device
PCT/US2004/011547 WO2005110425A1 (en) 2004-04-15 2004-04-15 Polymer-based sustained release device

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ES2536235T3 true ES2536235T3 (es) 2015-05-21

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ES11180259.1T Expired - Lifetime ES2536235T3 (es) 2004-04-15 2004-04-15 Dispositivo polimérico de liberación prolongada
ES04750134T Expired - Lifetime ES2375802T3 (es) 2004-04-15 2004-04-15 Dispositivo de liberación sostenida a base de pol�?mero.

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US (7) US8617613B2 (es)
EP (2) EP2409707B8 (es)
JP (1) JP5030292B2 (es)
KR (2) KR20100129799A (es)
CN (1) CN1968700A (es)
AT (1) ATE531374T1 (es)
AU (1) AU2004319756C1 (es)
BR (1) BRPI0418702A (es)
CA (1) CA2560981C (es)
CY (2) CY2012010I1 (es)
DE (1) DE122012000028I1 (es)
DK (1) DK1734971T3 (es)
EA (1) EA200601904A1 (es)
ES (2) ES2536235T3 (es)
FR (1) FR12C0029I1 (es)
HR (2) HRP20110831T1 (es)
IL (1) IL178589A0 (es)
LU (1) LU91989I2 (es)
MX (1) MXPA06011924A (es)
NO (1) NO20065217L (es)
PL (2) PL1734971T3 (es)
PT (2) PT1734971E (es)
SI (1) SI2409707T1 (es)
WO (1) WO2005110425A1 (es)

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