ES2536235T3 - Dispositivo polimérico de liberación prolongada - Google Patents

Dispositivo polimérico de liberación prolongada Download PDF

Info

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
Authority
ES
Spain
Prior art keywords
sucrose
composition
oil
mecl2
formulations
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
Application number
ES11180259.1T
Other languages
English (en)
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
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Alkermes Pharma Ireland Ltd
Amylin Pharmaceuticals LLC
Original Assignee
Alkermes Pharma Ireland Ltd
Amylin Pharmaceuticals LLC
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=35393985&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=ES2536235(T3) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Application filed by Alkermes Pharma Ireland Ltd, Amylin Pharmaceuticals LLC filed Critical Alkermes Pharma Ireland Ltd
Application granted granted Critical
Publication of ES2536235T3 publication Critical patent/ES2536235T3/es
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

Links

Classifications

    • 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

Landscapes

  • 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)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Epidemiology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Endocrinology (AREA)
  • Immunology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Zoology (AREA)
  • Diabetes (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (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)
  • Fats And Perfumes (AREA)
  • Agricultural Chemicals And Associated Chemicals (AREA)
  • Silicon Polymers (AREA)
  • Addition Polymer Or Copolymer, Post-Treatments, Or Chemical Modifications (AREA)
  • Ceramic Products (AREA)
  • Vending Machines For Individual Products (AREA)
  • Lubricants (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (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

imagen1
imagen2
imagen3
imagen4
imagen5
imagen6
imagen7
imagen8
imagen9
imagen10
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
imagen11
imagen12
imagen13

Claims (1)

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

Applications Claiming Priority (2)

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

Publications (1)

Publication Number Publication Date
ES2536235T3 true ES2536235T3 (es) 2015-05-21

Family

ID=35393985

Family Applications (2)

Application Number Title Priority Date Filing Date
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.

Family Applications After (1)

Application Number Title Priority Date Filing Date
ES04750134T Expired - Lifetime ES2375802T3 (es) 2004-04-15 2004-04-15 Dispositivo de liberación sostenida a base de pol�?mero.

Country Status (24)

Country Link
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) CY2012010I2 (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) PL2409707T3 (es)
PT (2) PT1734971E (es)
SI (1) SI2409707T1 (es)
WO (1) WO2005110425A1 (es)

Families Citing this family (52)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7731947B2 (en) 2003-11-17 2010-06-08 Intarcia Therapeutics, Inc. Composition and dosage form comprising an interferon particle formulation and suspending vehicle
PL2409707T3 (pl) 2004-04-15 2015-08-31 Amylin Pharmaceuticals Llc Urządzenie o przedłużonym uwalnianiu na bazie polimeru
US7456254B2 (en) * 2004-04-15 2008-11-25 Alkermes, Inc. Polymer-based sustained release device
US20090069226A1 (en) * 2004-05-28 2009-03-12 Amylin Pharmaceuticals, Inc. Transmucosal delivery of peptides and proteins
EP1679065A1 (en) * 2005-01-07 2006-07-12 OctoPlus Sciences B.V. Controlled release compositions for interferon based on PEGT/PBT block copolymers
US11246913B2 (en) 2005-02-03 2022-02-15 Intarcia Therapeutics, Inc. Suspension formulation comprising an insulinotropic peptide
WO2006083761A2 (en) 2005-02-03 2006-08-10 Alza Corporation Solvent/polymer solutions as suspension vehicles
NZ565535A (en) * 2005-06-30 2011-03-31 Ipsen Pharma Sas GLP-1 pharmaceutical compositions
LT2347762T (lt) 2005-08-19 2019-08-26 Amylin Pharmaceuticals, Llc Eksendinas, skirtas diabeto gydymui ir kūno svorio mažinimui
KR101106510B1 (ko) 2006-05-30 2012-01-20 인타르시아 세라퓨틱스 인코포레이티드 투피스, 내부채널 삼투압 전달 시스템 유동 조절기
CA2670821C (en) 2006-08-09 2012-05-15 Intarcia Therapeutics, Inc. Osmotic delivery systems and piston assemblies
US20080233199A1 (en) * 2007-03-22 2008-09-25 Alkermes, Inc. Coacervation Process
KR100805208B1 (ko) * 2007-03-27 2008-02-21 주식회사 펩트론 엑센딘 함유 서방성 제제 조성물, 엑센딘 함유 서방성미립구 및 이의 제조 방법
EP2139458A4 (en) 2007-04-19 2013-01-23 Dong A Pharm Co Ltd BIODEGRADABLE MICRO BEADS COMPOSITION FOR CONTROLLED RELEASE OF GLUCOSE-CONTROLLED PEPTIDE AND FORMULATION THEREOF
CA2683610C (en) * 2007-04-23 2013-01-08 Intarcia Therapeutics, Inc. Suspension formulations of insulinotropic peptides and uses thereof
US20080317865A1 (en) * 2007-06-20 2008-12-25 Alkermes, Inc. Quench liquids and washing systems for production of microparticles
US20090004243A1 (en) 2007-06-29 2009-01-01 Pacetti Stephen D Biodegradable triblock copolymers for implantable devices
US8642062B2 (en) 2007-10-31 2014-02-04 Abbott Cardiovascular Systems Inc. Implantable device having a slow dissolving polymer
WO2009102467A2 (en) 2008-02-13 2009-08-20 Intarcia Therapeutics, Inc. Devices, formulations, and methods for delivery of multiple beneficial agents
US8916188B2 (en) * 2008-04-18 2014-12-23 Abbott Cardiovascular Systems Inc. Block copolymer comprising at least one polyester block and a poly (ethylene glycol) block
WO2009143285A2 (en) 2008-05-21 2009-11-26 Amylin Pharmaceuticals, Inc. Exendins to lower cholestrol and triglycerides
SMT202000405T1 (it) 2008-09-04 2020-09-10 Amylin Pharmaceuticals Llc Formulazioni a rilascio prolungato usando veicolanti non acquosi
MX378797B (es) 2009-09-28 2025-03-10 Intarcia Therapeutics Inc Establecimiento y/o terminacion rapidos de suministro de estado estable sustancial de farmaco.
US20120208755A1 (en) 2011-02-16 2012-08-16 Intarcia Therapeutics, Inc. Compositions, Devices and Methods of Use Thereof for the Treatment of Cancers
UA116217C2 (uk) 2012-10-09 2018-02-26 Санофі Пептидна сполука як подвійний агоніст рецепторів glp1-1 та глюкагону
JP2016506401A (ja) 2012-12-21 2016-03-03 サノフイ 二重ｇｌｐ１／ｇｉｐまたは三方ｇｌｐ１／ｇｉｐ／グルカゴンアゴニストとしてのエキセンジン−４誘導体
EP3080150B1 (en) 2013-12-13 2018-08-01 Sanofi Exendin-4 peptide analogues as dual glp-1/gip receptor agonists
WO2015086733A1 (en) 2013-12-13 2015-06-18 Sanofi Dual glp-1/glucagon receptor agonists
TW201609799A (zh) 2013-12-13 2016-03-16 賽諾菲公司 雙重ｇｌｐ－１／ｇｉｐ受體促效劑
TW201609796A (zh) 2013-12-13 2016-03-16 賽諾菲公司 非醯化之艾塞那肽－４（ｅｘｅｎｄｉｎ－４）胜肽類似物
CN103720663B (zh) * 2014-01-08 2016-04-06 昆药集团股份有限公司 一种促卵泡激素缓释微球及其制备方法
TW201625670A (zh) 2014-04-07 2016-07-16 賽諾菲公司 衍生自ｅｘｅｎｄｉｎ－４之雙重ｇｌｐ－１／升糖素受體促效劑
TW201625668A (zh) 2014-04-07 2016-07-16 賽諾菲公司 作為胜肽性雙重ｇｌｐ－１／昇糖素受體激動劑之艾塞那肽－４衍生物
TW201625669A (zh) 2014-04-07 2016-07-16 賽諾菲公司 衍生自艾塞那肽－４（Ｅｘｅｎｄｉｎ－４）之肽類雙重ＧＬＰ－１／升糖素受體促效劑
US9932381B2 (en) 2014-06-18 2018-04-03 Sanofi Exendin-4 derivatives as selective glucagon receptor agonists
US9889085B1 (en) 2014-09-30 2018-02-13 Intarcia Therapeutics, Inc. Therapeutic methods for the treatment of diabetes and related conditions for patients with high baseline HbA1c
CN105769771B (zh) * 2014-12-25 2019-02-01 四川科伦药物研究院有限公司 一种艾塞那肽缓释微球组合物及其制备方法
SMT202100668T1 (it) 2015-05-22 2022-01-10 Univ Leland Stanford Junior Trattamento dell'ipoglicemia post-bariatrica con antagonisti del glp-1
CN113598842A (zh) 2015-06-03 2021-11-05 因塔西亚制药公司 植入物放置和移除系统
AR105319A1 (es) 2015-06-05 2017-09-27 Sanofi Sa Profármacos que comprenden un conjugado agonista dual de glp-1 / glucagón conector ácido hialurónico
TW201706291A (zh) 2015-07-10 2017-02-16 賽諾菲公司 作為選擇性肽雙重ｇｌｐ－１／升糖素受體促效劑之新毒蜥外泌肽（ｅｘｅｎｄｉｎ－４）衍生物
US10653753B2 (en) 2016-03-04 2020-05-19 Eiger Biopharmaceuticals, Inc. Treatment of hyperinsulinemic hypoglycemia with exendin-4 derivatives
KR102574993B1 (ko) 2016-05-16 2023-09-06 인타르시아 세라퓨틱스 인코포레이티드 글루카곤-수용체 선택적 폴리펩티드 및 이들의 이용 방법
USD860451S1 (en) 2016-06-02 2019-09-17 Intarcia Therapeutics, Inc. Implant removal tool
USD840030S1 (en) 2016-06-02 2019-02-05 Intarcia Therapeutics, Inc. Implant placement guide
US20190224122A1 (en) 2016-09-23 2019-07-25 Delpor, Inc. Stable compositions for incretin mimetic compounds
JP7584894B2 (ja) 2016-11-21 2024-11-18 アイガー・バイオファーマシューティカルズ・インコーポレイテッド エキセンディン（９－３９）の緩衝製剤
WO2018129058A1 (en) 2017-01-03 2018-07-12 Intarcia Therapeutics, Inc. Methods comprising continuous administration of a glp-1 receptor agonist and co-adminstration of a drug
EP3372224A1 (en) 2017-03-07 2018-09-12 Alrise Biosystems GmbH New controlled drug delivery system using water miscible solvents for production of drug loaded micro- and nanoparticles
CA3135500A1 (en) * 2019-04-02 2020-10-08 Cytomatrix Limited A composition for the delivery of biologically active agents and uses thereof
WO2021214023A1 (en) 2020-04-22 2021-10-28 Bayer Aktiengesellschaft Combination of finerenone and a sglt2 inhibitor for the treatment and/or prevention of cardiovascular and/or renal diseases
US11930804B2 (en) 2020-05-21 2024-03-19 Florida Power & Light Company Avian streamer deterrent for electric power line support structures

Family Cites Families (95)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
NL280825A (es) 1962-07-11
BE744162A (fr) 1969-01-16 1970-06-15 Fuji Photo Film Co Ltd Procede d'encapsulage
US3773919A (en) 1969-10-23 1973-11-20 Du Pont Polylactide-drug mixtures
DE2010115A1 (de) 1970-03-04 1971-09-16 Farbenfabriken Bayer Ag, 5090 Leverkusen Verfahren zur Herstellung von Mikrogranulaten
JPS523342B2 (es) 1972-01-26 1977-01-27
GB1413186A (en) 1973-06-27 1975-11-12 Toyo Jozo Kk Process for encapsulation of medicaments
JPS523653A (en) 1975-06-27 1977-01-12 Fuji Photo Film Co Ltd Process for producing fine polymer particles
US4384975A (en) 1980-06-13 1983-05-24 Sandoz, Inc. Process for preparation of microspheres
US4389330A (en) 1980-10-06 1983-06-21 Stolle Research And Development Corporation Microencapsulation process
PH19942A (en) 1980-11-18 1986-08-14 Sintex Inc Microencapsulation of water soluble polypeptides
JPS57119318A (en) * 1981-01-16 1982-07-24 Minolta Camera Co Ltd Filter having special effect
US4530840A (en) 1982-07-29 1985-07-23 The Stolle Research And Development Corporation Injectable, long-acting microparticle formulation for the delivery of anti-inflammatory agents
US5385738A (en) 1983-10-14 1995-01-31 Sumitomo Pharmaceuticals Company, Ltd. Sustained-release injection
US4840896A (en) 1983-11-02 1989-06-20 Integrated Genetics, Inc. Heteropolymeric protein
US5639639A (en) 1983-11-02 1997-06-17 Genzyme Corporation Recombinant heterodimeric human fertility hormones, and methods, cells, vectors and DNA for the production thereof
US4923805A (en) 1983-11-02 1990-05-08 Integrated Genetics, Inc. Fsh
IE58110B1 (en) 1984-10-30 1993-07-14 Elan Corp Plc Controlled release powder and process for its preparation
IE59361B1 (en) 1986-01-24 1994-02-09 Akzo Nv Pharmaceutical preparation for obtaining a highly viscous hydrogel or suspension
US4737437A (en) 1986-03-27 1988-04-12 East Shore Chemical Co. Light sensitive diazo compound, composition and method of making the composition
US4897268A (en) 1987-08-03 1990-01-30 Southern Research Institute Drug delivery system and method of making the same
GB8723846D0 (en) 1987-10-10 1987-11-11 Danbiosyst Ltd Bioadhesive microsphere drug delivery system
WO1989003678A1 (en) 1987-10-30 1989-05-05 Stolle Research & Development Corporation Low residual solvent microspheres and microencapsulation process
JP2827287B2 (ja) 1988-07-05 1998-11-25 武田薬品工業株式会社 水溶性薬物含有徐放型マイクロカプセル
US5271945A (en) 1988-07-05 1993-12-21 Takeda Chemical Industries, Ltd. Sustained release microcapsule for water soluble drug
IL92344A0 (en) 1989-01-04 1990-07-26 Gist Brocades Nv Microencapsulation of bioactive substances in biocompatible polymers,microcapsules obtained and pharmaceutical preparation comprising said microcapsules
DK0432232T3 (da) 1989-05-01 1994-01-31 Alkermes Inc Fremgangsmåde til fremstilling af små partikler af biologisk aktive molekyler
US5019400A (en) 1989-05-01 1991-05-28 Enzytech, Inc. Very low temperature casting of controlled release microspheres
ES2084698T5 (es) 1989-05-04 2005-03-01 Southern Research Institute Procedimiento de encapsulacion.
US5225205A (en) 1989-07-28 1993-07-06 Debiopharm S.A. Pharmaceutical composition in the form of microparticles
JPH05502465A (ja) 1989-08-28 1993-04-28 ファーマスーティカル　デリバリー　システムズ 治療薬剤の制御放出のために有用な生体内で分解し得るポリマー
US5707644A (en) 1989-11-04 1998-01-13 Danbiosyst Uk Limited Small particle compositions for intranasal drug delivery
US5312335A (en) 1989-11-09 1994-05-17 Bioject Inc. Needleless hypodermic injection device
US5126147A (en) 1990-02-08 1992-06-30 Biosearch, Inc. Sustained release dosage form
US5478564A (en) 1990-02-22 1995-12-26 Teva Pharmaceutical Industries, Ltd. Preparation of microparticles for controlled release of water-soluble substances
IT1243390B (it) 1990-11-22 1994-06-10 Vectorpharma Int Composizioni farmaceutiche in forma di particelle atte al rilascio controllato di sostanze farmacologicamente attive e procedimento per la loro preparazione.
EP0720478A1 (en) 1991-05-07 1996-07-10 Dynagen, Inc. A controlled, sustained release delivery system for smoking cessation
HU222501B1 (hu) 1991-06-28 2003-07-28 Endorecherche Inc. MPA-t vagy MGA-t tartalmazó nyújtott hatóanyag-felszabadulású gyógyászati készítmény és eljárás előállítására
US5658593A (en) 1992-01-16 1997-08-19 Coletica Injectable compositions containing collagen microcapsules
DK0632820T3 (da) 1992-02-28 2000-10-02 Collagen Corp Højkoncentrerede, homogeniserede collagensammensætninger
US5656297A (en) 1992-03-12 1997-08-12 Alkermes Controlled Therapeutics, Incorporated Modulated release from biocompatible polymers
US5912015A (en) 1992-03-12 1999-06-15 Alkermes Controlled Therapeutics, Inc. Modulated release from biocompatible polymers
US6514533B1 (en) 1992-06-11 2003-02-04 Alkermas Controlled Therapeutics, Inc. Device for the sustained release of aggregation-stabilized, biologically active agent
ATE188375T1 (de) 1992-11-17 2000-01-15 Yoshitomi Pharmaceutical Ein antipsychotikum enthaltende mikrokugel zur verzögerten freisetzung und verfahren für ihre herstellung
DK0674506T3 (da) 1992-12-02 2001-01-08 Alkermes Inc Væksthormonholdige mikrosfærer med styret frigivelse
JP3698721B2 (ja) * 1993-02-23 2005-09-21 ジェネンテク・インコーポレイテッド 有機溶媒を用いて処理したポリペプチドの賦形剤安定化
US5981719A (en) 1993-03-09 1999-11-09 Epic Therapeutics, Inc. Macromolecular microparticles and methods of production and use
TW360548B (en) 1993-04-08 1999-06-11 Powderject Res Ltd Products for therapeutic use
US5424286A (en) * 1993-05-24 1995-06-13 Eng; John Exendin-3 and exendin-4 polypeptides, and pharmaceutical compositions comprising same
US5385887A (en) 1993-09-10 1995-01-31 Genetics Institute, Inc. Formulations for delivery of osteogenic proteins
ATE288270T1 (de) 1993-11-19 2005-02-15 Janssen Pharmaceutica Nv Mikroverkapselte 1,2-benzazole
US5650173A (en) 1993-11-19 1997-07-22 Alkermes Controlled Therapeutics Inc. Ii Preparation of biodegradable microparticles containing a biologically active agent
EP2283821A1 (en) 1993-11-19 2011-02-16 Alkermes, Inc. Preparation of biodegradable microparticles containing a biologically active agent
JPH07196479A (ja) 1994-01-04 1995-08-01 Unitika Ltd マイクロカプセルの製造法
US5922253A (en) 1995-05-18 1999-07-13 Alkermes Controlled Therapeutics, Inc. Production scale method of forming microparticles
US6369116B1 (en) 1995-06-02 2002-04-09 Oculex Pharmaceuticals, Inc. Composition and method for treating glaucoma
US5904935A (en) 1995-06-07 1999-05-18 Alza Corporation Peptide/protein suspending formulations
US5747058A (en) 1995-06-07 1998-05-05 Southern Biosystems, Inc. High viscosity liquid controlled delivery system
US5942253A (en) 1995-10-12 1999-08-24 Immunex Corporation Prolonged release of GM-CSF
SE505146C2 (sv) 1995-10-19 1997-06-30 Biogram Ab Partiklar för fördröjd frisättning
EP0787569B1 (en) 1996-01-31 2002-10-02 Sumitomo Bakelite Company Limited Method of producing epoxy resin-encapsulated semiconductor device
DK1975177T3 (da) * 1996-03-01 2011-07-25 Novo Nordisk As Appetitundertrykkende peptid, formuleringer dermed og anvendelse deraf
EP0889722B1 (en) * 1996-03-28 2002-11-20 Takeda Chemical Industries, Ltd. Sustained-release preparation and its production
US5792477A (en) 1996-05-07 1998-08-11 Alkermes Controlled Therapeutics, Inc. Ii Preparation of extended shelf-life biodegradable, biocompatible microparticles containing a biologically active agent
DK0942740T3 (da) 1996-12-06 2003-12-15 Amgen Inc Kombinationsterapi under anvendelse af et TFN-bindende protein til behandling af TFN-medierede sygdomme
US5945126A (en) 1997-02-13 1999-08-31 Oakwood Laboratories L.L.C. Continuous microsphere process
AR012448A1 (es) 1997-04-18 2000-10-18 Ipsen Pharma Biotech Composicion en forma de microcapsulas o de implantes que comprende un excipiente biodegradable, polimero o co-polimero, o una mezcla de talesexcipientes, y una sustancia activa o una mezcla de sustancias activas, procedimiento para la preparacion de una sustancia soluble en agua de elevada
US6113947A (en) 1997-06-13 2000-09-05 Genentech, Inc. Controlled release microencapsulated NGF formulation
GB9718986D0 (en) 1997-09-09 1997-11-12 Danbiosyst Uk Controlled release microsphere delivery system
US5989463A (en) 1997-09-24 1999-11-23 Alkermes Controlled Therapeutics, Inc. Methods for fabricating polymer-based controlled release devices
EP1096957A1 (en) 1998-06-18 2001-05-09 Johns Hopkins University School of Medicine Methods and reagents for intramuscular delivery of nucleic acids
US6194006B1 (en) 1998-12-30 2001-02-27 Alkermes Controlled Therapeutics Inc. Ii Preparation of microparticles having a selected release profile
US20030087820A1 (en) 1999-01-14 2003-05-08 Young Andrew A. Novel exendin agonist formulations and methods of administration thereof
US6268630B1 (en) * 1999-03-16 2001-07-31 Sandia Corporation Silicon-on-insulator field effect transistor with improved body ties for rad-hard applications
CA2367131C (en) 1999-04-05 2007-07-03 Solomon S. Steiner Methods for fine powder formation
US6291013B1 (en) 1999-05-03 2001-09-18 Southern Biosystems, Inc. Emulsion-based processes for making microparticles
US6506724B1 (en) 1999-06-01 2003-01-14 Amylin Pharmaceuticals, Inc. Use of exendins and agonists thereof for the treatment of gestational diabetes mellitus
SE9903236D0 (sv) 1999-09-10 1999-09-10 Astra Ab Method to obtain microparticles
US6284283B1 (en) 1999-10-21 2001-09-04 Alkermes Controlled Therapeutics, Inc. Method of producing sub-micron particles of biologically active agents and uses thereof
US6465425B1 (en) 2000-02-10 2002-10-15 Alkermes Controlled Therapeutics, Inc. Microencapsulation and sustained release of biologically active acid-stable or free sulfhydryl-containing proteins
US6495164B1 (en) 2000-05-25 2002-12-17 Alkermes Controlled Therapeutics, Inc. I Preparation of injectable suspensions having improved injectability
US6479065B2 (en) 2000-08-10 2002-11-12 Alkermes Controlled Therapeutics, Inc. Process for the preparation of polymer-based sustained release compositions
US6824822B2 (en) * 2001-08-31 2004-11-30 Alkermes Controlled Therapeutics Inc. Ii Residual solvent extraction method and microparticles produced thereby
US6558702B2 (en) 2001-04-13 2003-05-06 Alkermes Controlled Therapeutics, Inc. Method of modifying the release profile of sustained release compositions
US20030003074A1 (en) 2001-06-14 2003-01-02 Macromed, Inc. Formulations of lymphokines and method of use thereof for local or both local and systemic control of proliferative cell disorders
JP4665141B2 (ja) * 2001-06-29 2011-04-06 富士通セミコンダクター株式会社 半導体装置とその製造方法
NZ535008A (en) 2002-02-08 2005-09-30 Alkermes Inc Polymer-based compositions for sustained release
AU2003284028B2 (en) 2002-10-17 2007-05-10 Alkermes, Inc. Sustained release profile modification
WO2004036186A2 (en) 2002-10-17 2004-04-29 Alkermes Controlled Therapeutics, Inc. Ii Microencapsulation and sustained release of biologically active polypeptides
US6887613B2 (en) 2002-12-04 2005-05-03 General Motors Corporation Corrosion resistant PEM fuel cell
US20040247672A1 (en) 2003-05-16 2004-12-09 Alkermes Controlled Therapeutics, Inc. Injectable sustained release compositions
US6968927B2 (en) * 2003-10-10 2005-11-29 Brian Scura Bicycle force balancing mechanism with a brake arm actuation assembly and a pivot member for dual main brake cable segments
PL2409707T3 (pl) 2004-04-15 2015-08-31 Amylin Pharmaceuticals Llc Urządzenie o przedłużonym uwalnianiu na bazie polimeru
US7456254B2 (en) 2004-04-15 2008-11-25 Alkermes, Inc. Polymer-based sustained release device
US20060110423A1 (en) 2004-04-15 2006-05-25 Wright Steven G Polymer-based sustained release device
US20080233199A1 (en) 2007-03-22 2008-09-25 Alkermes, Inc. Coacervation Process

Also Published As

Publication number Publication date
KR20070011506A (ko) 2007-01-24
PL2409707T3 (pl) 2015-08-31
US20130130977A1 (en) 2013-05-23
EP1734971B1 (en) 2011-11-02
JP5030292B2 (ja) 2012-09-19
CA2560981C (en) 2013-02-19
NO20065217L (no) 2006-11-14
HRP20150272T1 (hr) 2015-07-03
HK1166606A1 (en) 2012-11-02
KR20100129799A (ko) 2010-12-09
ATE531374T1 (de) 2011-11-15
AU2004319756A1 (en) 2005-11-24
JP2007532640A (ja) 2007-11-15
US8877252B2 (en) 2014-11-04
CY2012010I1 (el) 2015-08-05
EP1734971A4 (en) 2009-12-23
US20140088003A1 (en) 2014-03-27
LU91989I2 (fr) 2012-07-02
CN1968700A (zh) 2007-05-23
DK1734971T3 (da) 2012-02-13
BRPI0418702A (pt) 2007-09-11
EP2409707B1 (en) 2015-02-25
US20090247463A1 (en) 2009-10-01
EP2409707B8 (en) 2015-05-06
US20080260847A1 (en) 2008-10-23
EP2409707A1 (en) 2012-01-25
DE122012000028I1 (de) 2012-07-12
WO2005110425A1 (en) 2005-11-24
IL178589A0 (en) 2007-02-11
AU2004319756B2 (en) 2010-08-05
MXPA06011924A (es) 2007-06-11
US9238076B2 (en) 2016-01-19
US20080119569A1 (en) 2008-05-22
CY1116337T1 (el) 2017-02-08
PT1734971E (pt) 2012-02-02
AU2004319756C1 (en) 2014-02-20
US8617613B2 (en) 2013-12-31
PL1734971T3 (pl) 2012-08-31
HRP20110831T1 (hr) 2012-01-31
EP1734971B8 (en) 2012-02-29
US7563871B2 (en) 2009-07-21
US20080125351A1 (en) 2008-05-29
EA200601904A1 (ru) 2007-02-27
FR12C0029I1 (fr) 2012-06-15
KR101040415B1 (ko) 2011-06-09
PT2409707E (pt) 2015-04-08
CY2012010I2 (el) 2015-08-05
ES2375802T3 (es) 2012-03-06
EP1734971A1 (en) 2006-12-27
US20070166352A1 (en) 2007-07-19
HK1099693A1 (en) 2007-08-24
CA2560981A1 (en) 2005-11-24
SI2409707T1 (sl) 2015-07-31
LU91989I9 (es) 2019-01-03

Similar Documents

Publication Publication Date Title
Peira et al. Transdermal permeation of apomorphine through hairless mouse skin from microemulsions
Liu et al. Preparation of insulin-loaded PLA/PLGA microcapsules by a novel membrane emulsification method and its release in vitro
CA2012791C (en) Spray gel base and spray gel preparation
Abdul-Fattah et al. Preparation and in vitro evaluation of solid dispersions of halofantrine
US20260060929A1 (en) Peptide particles and methods of formation
RU2004137118A (ru) Фармацевтическая композиция для контролируемого высвобождения активных веществ и способ ее изготовления
RU2009116933A (ru) Новые депо-композиции для инъекций и способ изготовления указанных композиций
Hämäläinen et al. Estimation of pore size and pore density of biomembranes from permeability measurements of polyethylene glycols using an effusion-like approach
EP2127642A3 (en) Microemulsions as solid dosage forms for oral administration
RU2333745C2 (ru) Композиции с контролируемым высвобождением
EA200500084A1 (ru) Фармацевтическая композиция для чрескожной доставки активного агента
Malakar et al. Candesartan cilexetil microemulsions for transdermal delivery: formulation, in-vitro skin permeation and stability assessment
ES2895764T3 (es) Dispositivo de microagujas
Zhang et al. Bupivacaine-loaded biodegradable poly (lactic-co-glycolic) acid microspheres: I. Optimization of the drug incorporation into the polymer matrix and modelling of drug release
Aburub et al. A critical evaluation of fasted state simulating gastric fluid (FaSSGF) that contains sodium lauryl sulfate and proposal of a modified recipe
RU96120199A (ru) Иммуносупрессорная композиция, содержащая циклоспорин, и способ ее получения
AR045094A1 (es) Formulaciones liofilizadas de cci-779
US11660344B2 (en) Transdermal colloidal solution agent
Pupe et al. Development of a doxazosin and finasteride transdermal system for combination therapy of benign prostatic hyperplasia
CA2737463C (en) Freeze-dried powder preparation of tetrodotoxin and the producing method thereof
CR7936A (es) Formulaciones parenterales de un peptido para el tratamiento de lupus sitemico eritematoso
Dixit et al. Lyophilization monophase solution technique for improvement of the solubility and dissolution of piroxicam
Shin et al. Application of TPX polymer membranes for the controlled release of triprolidine
US20090054531A1 (en) Eye drop preparation comprising xanthan gum and terpenoid
Orienti et al. Crosslinked polyvinylalcohol hydrogels as vehicles for hydrophilic drugs