EP2043606A2 - Formulations d'inhibiteurs de kinase nanoparticulaires - Google Patents

Formulations d'inhibiteurs de kinase nanoparticulaires

Info

Publication number
EP2043606A2
EP2043606A2 EP07798449A EP07798449A EP2043606A2 EP 2043606 A2 EP2043606 A2 EP 2043606A2 EP 07798449 A EP07798449 A EP 07798449A EP 07798449 A EP07798449 A EP 07798449A EP 2043606 A2 EP2043606 A2 EP 2043606A2
Authority
EP
European Patent Office
Prior art keywords
less
composition
nanoparticulate
ammonium chloride
chloride
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.)
Withdrawn
Application number
EP07798449A
Other languages
German (de)
English (en)
Inventor
Elaine Liversidge
Greta Cary
William H. Bosch
Janine Keller
Niels Ryde
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.)
Elan Pharma International Ltd
Original Assignee
Elan Pharma International Ltd
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
Application filed by Elan Pharma International Ltd filed Critical Elan Pharma International Ltd
Publication of EP2043606A2 publication Critical patent/EP2043606A2/fr
Withdrawn legal-status Critical Current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
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • 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
    • 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
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • 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
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/145—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic compounds
    • 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
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
    • 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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2009—Inorganic compounds
    • 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
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • 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
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery

Definitions

  • the present invention relates to kinase inhibitor compounds and compositions useful in the treatment or prevention of disease or disorders such as myeloproliferative diseases, leukemias, and related diseases or conditions. More specifically, the invention relates to nanoparticulate kinase inhibitor compositions, such as nanoparticulate LS 104 compositions having an effective average particle size of less than about 2000 nm. The invention also relates to methods of making and using such nanoparticulate compositions.
  • Leukemias are cancers of the bone marrow and blood. They are characterized by the uncontrolled accumulation of abnormal blood cells. Examples include acute lymphoblastic leukemia (ALL), Chronic Myelogenous Leukemia (CML) and Acute Myelogenous Leukemia (AML). The most common type of leukemia is acute myeloid leukemia (AML) with an estimated 12,000 new cases annually in the United States. AML occurs mostly in adults over the age of 40 and with an average age of occurrence of 65. Cancers such as AML represent an area of high, unmet medical need; current treatments for AML are characterized by poor long-term response rates with fewer than 20 percent of adult patients surviving after diagnosis.
  • ALL acute lymphoblastic leukemia
  • CML Chronic Myelogenous Leukemia
  • AML Acute Myelogenous Leukemia
  • AML acute myeloid leukemia
  • FLT3 Several kinds of mutation have been found in AML; no single one is at fault, and it appears that at least two are required to trigger disease. However, a mutation in the receptor tyrosine kinase FLT3 occurs in about one third of AML patients and carries a particularly poor prognosis. FLT3 conveys a proliferation signal and is normally expressed early in the development of bone marrow stem cells, but in its mutated form, it remains active and helps leukemic cells flourish. Several groups have been working to identify compounds that could inhibit FLT3.
  • CML and some ALLs are chromosomal translocation that occurs between chromosome 22 and chromosome 9, resulting in an altered chromosome 22 which is known as the "Philadelphia chromosome.”
  • Philadelphia chromosome is the result of a portion of chromosome 9 that includes a portion of the Abelson proto-oncogene (AbI), being translocated to chromosome 22.
  • AbI Abelson proto-oncogene
  • the breakpoints on chromosome 9 may vary, the breakpoints on chromosome 22 are relatively clustered.
  • Bcr breakpoint cluster region
  • Bcr- AbI fused gene that results from the translocation.
  • All forms of the fusion protein include a portion of the Abelson protein having tyrosine kinase activity.
  • the tyrosine kinase activity is constitutive in the Bcr-Abl fusion protein; the negative regulators of this activity no longer function in the fusion protein.
  • This constitutive kinase activity has been shown to activate various signal transduction pathways leading to uncontrolled cell growth and division (e.g., by promoting cell proliferation and inhibiting apoptosis).
  • Bcr-Abl may cause undifferentiated blood cells to proliferate massively and fail to mature.
  • Non-CML myeloproliferative diseases such as polycythemia vera (PV), essential thrombocythemia (ET), and chronic idiopathic myelofibrosis (IMF) and as of yet unclassified myeloproliferative diseases (MPD-NC) are characterized by an aberrant increase in blood cells. See e.g., Vainchenker and Constantinescu, Hematology (American Society of Hematology) 195-200 (2005). This increase is generally initiated by a spontaneous mutation in a multipotent hematopoetic stem cell located in the bone marrow. Id.
  • the stem cell Due to the mutation, the stem cell produces far more blood cells of a particular lineage than normal, resulting in the overproduction of cells such as erythroid cells, megakaryocytes, granulocytes and monocytes.
  • Some symptoms common to patients with MPD include enlarged spleen, enlarged liver, elevated white, red and/or platelet cell count, blood clots (thrombosis), weakness, dizziness and headache.
  • Diseases such as PV, ET and IMF may presage leukemia, however the rate of transformation (e.g., to blast crisis) differs with each disease. Id. [0006]
  • the specific gene and concomitant mutation or mutations responsible for many MPDs is not known.
  • J. Biol. 1 a dominant gain of function mutation in the Janus kinase 2 (JAK2) gene, a cytoplasmic, nonreceptor tyrosine kinase, has been identified in a number of MPDs. For example, this mutation has been reported in up to 97% of patients with PV, and in greater than 40% of patients with either ET or IMF. See e.g., Baxter, et al., Lancet 365:1054-1060 (2005); James, et al., Nature 438: 1144-1148 (2005); Zhao, et al., J. Biol.
  • the Janus kinases are a family of tyrosine kinases that play a role in cytokine signaling.
  • JAK2 kinase acts as an intermediary between membrane-bound cytokine receptors such as the erythropoietin receptor (EpoR), and down-stream members of the signal transduction pathway such as STAT5 (Signal Transducers and Activators of Transcription protein 5).
  • EpoR erythropoietin receptor
  • STAT5 Signal Transduction pathway
  • JAK2 is activated when cytokine receptor/ligand complexes phosphorylate the associated JAK2 kinase. Id. JAK2 can then phosphorylate and activate its substrate molecule, for example STAT5, which enters the nucleus and interacts with other regulatory proteins to affect transcription. Id.
  • Treatment of leukemias and myeloproliferative disorders may involve drug therapy (e.g., chemotherapy), bone marrow transplants, radiation therapy, or combinations thereof.
  • drug therapy e.g., chemotherapy
  • bone marrow transplants e.g., bone marrow transplants
  • radiation therapy e.g., radiation therapy
  • kinase inhibitors e.g., one kinase inhibitor called "imatinib mesylate” (i.e., STI571 or 2- phenylaminopyrimidine) has proven effective for treating CML and ALL.
  • Imatinib is marketed as a drug under the tradename "Gleevec" or "Glivec.”
  • LS 104 a styrylacrylonitirle compound, which is chemically known as (E,E)-2-(Benzylaminocarbonyl)-3-(3,4- dihydroxystyryl)acrylonitrile.
  • LS 104 has an empiric formula Of C 1P H 16 O 3 N 2 , with a molecular weight of 320.34.
  • the chemical structure of LS 104 is:
  • LS 104 has been shown to inhibit both Janus Kinase 2 ("JAK2”) activity, a dominant gain of function mutation identified in numerous myeloproliferative disorders, and Bcr-Abl tyrosine kinase activity, a product of the translocation event known as the "Philadelphia Chromosome,” which is present in various
  • Nanoparticulate active agent compositions are particles consisting of a poorly soluble therapeutic or diagnostic agent having adsorbed onto the surface thereof a non-crosslinked surface stabilizer.
  • the '684 patent does not describe nanoparticulate compositions of kinase inhibitors such as LS 104.
  • WASH 1899464 1 beclomethasone dipropionate compositions;" U.S. Patent Publication No. 20040033267 for "Nanoparticulate compositions of angiogenesis inhibitors;” U.S. Patent Publication No. 20040033202 for “Nanoparticulate sterol formulations and novel sterol combinations;” U.S. Patent Publication No. 20040018242 for "Nanoparticulate nystatin formulations;” U.S. Patent Publication No. 20040015134 for "Drug delivery systems and methods;” U.S. Patent Publication No. 20030232796 for "Nanoparticulate polycosanol formulations & novel polycosanol combinations;” U.S. Patent Publication No.
  • WASH 1899464 1 improved efficacy and/or are suitable for administration such as parenteral administration.
  • the present invention fills that need.
  • the LS 104 compositions may not produce significantly different absorption levels when administered under fed as compared to fasting conditions.
  • the nanoparticulate LS 104 compositions exhibit improved bioavailability as compared to conventional LS 104 compositions.
  • the nanoparticulate LS 104 compositions may redisperse such that the particles have an effective average particle size of less than about 2 microns.
  • the invention also relates to methods of making nanoparticulate compositions including an kinase inhibitor, such as LS 104 or salt or derivative thereof.
  • the methods may include contacting particles of an LS 104 with at least one surface stabilizer for a time and under conditions sufficient to provide a nanoparticulate LS 104 composition having an effective average particle size of less than about 2000 nm.
  • the present invention is directed to compositions comprising at least one nanoparticulate kinase inhibitor, such as LS 104 or a salt or derivative thereof, and at least one surface stabilizer.
  • the surface stabilizer may be adsorbed or associated with the surface of the drug.
  • the LS 104 particles, or a salt or derivative thereof have an effective average particle size of less than about 2000 nm.
  • a preferred dosage form of the invention is an injectable dosage form, although any pharmaceutically acceptable dosage form can be utilized.
  • the injectable formulation may provide a high LS 140 concentration in a small volume to be injected.
  • administration comprises a bolus injection of a kinase inhibitor, such as LS 140, with one continuous fast injection, rather than a slow infusion of the drug.
  • Exemplary solid dosage forms include, but are not limited to, tablets, capsules, sachets, lozenges, powders, pills, or granules, and the solid dosage form can be, for example,
  • WASH 1899464 1 a fast melt dosage form, controlled release dosage form, lyophilized dosage form, delayed release dosage form, extended release dosage form, pulsatile release dosage form, mixed immediate release and controlled release dosage form, or a combination thereof.
  • the term "effective average particle size,” as used herein, means that at least about 50% of the nanop articulate kinase inhibitor particles, such as LS104, have a size of less than about 2000 nm (by weight or by other suitable measurement, such as by volume, number, etc.), when measured by, for example, sedimentation flow fractionation, photon correlation spectroscopy, light scattering, disk centrifugation, and other techniques known to those of skill in the art.
  • non-nanoparticulate active agent shall mean an active agent which is solubilized or which has an effective average particle size of greater than about 2000 nm. Nanoparticulate active agents as defined herein have an effective average particle size of less than about 2000 nm.
  • the phrase "therapeutically effective amount” shall mean that drug dosage that provides the specific pharmacological response for which the drug is administered in a significant number of subjects in need of such treatment. It is emphasized that a therapeutically effective amount of a drug that is administered to a particular subject in
  • WASH 1899464 1 a particular instance will not always be effective in treating the conditions/diseases described herein, even though such dosage is deemed to be a therapeutically effective amount by those of skill in the art.
  • hypereosinophilic syndrome HES
  • chronic neutrophilic leukemia CNL
  • myelofibrosis with myeloid metaplasia MMM
  • chronic myelomonocytic leukemia CMML
  • Myeloproliferative disease is also meant to encompass any unclassified myeloproliferative diseases (UMPD or MPD-NC).
  • compositions of the invention comprising at least one kinase inhibitor, such as LS 104, of the invention are contemplated to exhibit increased bioavailability as compared to the same non-nanop articulate kinase inhibitor. Moreover, the compositions of the invention are expected to require smaller doses, and smaller tablet or other solid dosage form size as compared to prior conventional non-nanoparticulate formulations of the same kinase inhibitor to achieve the same pharmacological effect.
  • the increased bioavailability is significant because it means that the nanoparticulate kinase inhibitor dosage form will likely exhibit significantly greater drug absorption.
  • compositions comprising at least one nanoparticulate kinase inhibitor, such as LS 104, having a desirable pharmacokinetic profile when administered to mammalian subjects.
  • the desirable pharmacokinetic profile of the compositions comprising at least one nanoparticulate kinase inhibitor such as LS 104 includes, but is not limited to: (1) a C max for a kinase inhibitor, such as LS 104, when assayed in the plasma of a mammalian subject following administration, that is preferably greater than
  • the desirable pharmacokinetic profile is the pharmacokinetic profile measured after the initial dose of a kinase inhibitor, such as LS 104.
  • a composition comprising a nanoparticulate kinase inhibitor, such as LS 104 exhibits in comparative pharmacokinetic testing with a non-nanoparticulate formulation of the same kinase inhibitor, administered at the same dosage, a T max not greater than about 90%, not greater than about 80%, not greater than about 70%, not greater than about 60%, not greater than about 50%, not greater than about 30%, not greater than about 25%, not greater than about 20%, not greater than about 15%, not greater than about 10%, or not greater than about 5% of the T max exhibited by the non-nanoparticulate kinase inhibitor formulation.
  • the composition comprising a nanoparticulate kinase inhibitor exhibits in comparative pharmacokinetic testing with a non- nanoparticulate formulation of the same kinase inhibitor, administered at the same dosage, a C max which is at least about 50%, at least about 100%, at least about 200%, at least about 300%, at least about 400%, at least about 500%, at least about 600%, at least about 700%, at least about 800%, at least about 900%, at least about 1000%, at least about 1100%, at least about 1200%, at least about 1300%, at least about 1400%, at least about 1500%, at least about 1600%, at least about 1700%, at least about 1800%, or at least about 1900% greater than the C max exhibited by the non-nanoparticulate kinase inhibitor formulation.
  • a C max which is at least about 50%, at least about 100%, at least about 200%, at least about 300%, at least about 400%, at least about 500%, at least about 600%, at least about 700
  • the invention encompasses compositions comprising at least one nanoparticulate kinase inhibitor, such as LS 104, wherein the pharmacokinetic profile of the kinase inhibitor is not substantially affected by the fed or fasted state of a subject ingesting the composition. This means that there is no substantial difference in the quantity of drug absorbed (AUC), the rate of drug absorption (C max ), or the length of time to C max (T max ), when the nanoparticulate kinase inhibitor compositions are administered in the fed versus the fasted state.
  • AUC the quantity of drug absorbed
  • C max rate of drug absorption
  • T max the length of time to C max
  • the difference in absorption (AUC) or C max of the nanoparticulate kinase inhibitor compositions of the invention when administered in the fed versus the fasted state, preferably is less than about 100%, less than about 90%, less than about 80%, less than about 70%, less than about 60%, less than about 55%, less than about 50%, less than about 45%, less than about 40%, less than about 35%, less than about 30%, less than about 25%, less than about 20%, less than about 15%, less than about 10%, less than about 5%, or less than about 3%.
  • compositions comprising at least one nanoparticulate kinase inhibitor, such as LS 104, or a salt or derivative thereof, are proposed to have unexpectedly dramatic dissolution profiles. Rapid dissolution of an administered active agent is preferable, as faster dissolution generally leads to greater bioavailability and faster onset of action. To improve the dissolution profile and bioavailability of the kinase inhibitors it would be useful to increase the drug's dissolution so that it could attain a level close to 100%.
  • the invention provides compositions comprising particles of at least one kinase inhibitor, such as LS 104 or a salt or derivative thereof, and at least one surface stabilizer.
  • the surface stabilizers preferably are adsorbed on, or associated with, the surface of the LS 104 particles.
  • Surface stabilizers especially may physically adhere on, or associate with, the surface of the nanoparticulate kinase inhibitor particles, but ideally do not chemically react with the particles of a kinase inhibitor (such as LS 104) or itself.
  • Individually adsorbed molecules of the surface stabilizer are essentially free of intermolecular cross-linkages.
  • compositions of the invention comprise particles of at least one kinase inhibitor, such as LS 104 or a salt or derivative thereof.
  • the particles can be in a crystalline phase, semi-crystalline phase, amorphous phase, semi-amorphous phase, or a combination thereof.
  • filling agents include lactose monohydrate, lactose anhydrous, and various starches;
  • binding agents include various celluloses and cross-linked polyvinylpyrrolidone, microcrystalline cellulose, such as Avicel ® PHlOl and Avicel ® PH 102, micro crystalline cellulose, and silicified microcrystalline cellulose (ProSolv SMCCTM).
  • Suitable lubricants including agents that act on the flowability of the powder to be compressed, may include colloidal silicon dioxide, such as Aerosil ® 200, talc, stearic acid, magnesium stearate, calcium stearate, and silica gel.
  • the kinase inhibitor particles can be reduced in size in the presence of at least one surface stabilizer.
  • kinase inhibitor particles can be contacted with one or more surface stabilizers after attrition.
  • Other compounds, such as a diluent, can be added to the kinase inhibitor /surface stabilizer composition during the size reduction process.
  • Dispersions can be manufactured continuously or in a batch mode.
  • Terminal sterilization was achieved using gamma irradiation.
  • the final product was packed into a vial, which is also terminally irradiated.
  • Stability studies e.g., 3 months, 6 months and 12 months under various temperature and humidity conditions may be performed on several batches.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Biophysics (AREA)
  • Molecular Biology (AREA)
  • Inorganic Chemistry (AREA)
  • Hematology (AREA)
  • Oncology (AREA)
  • Dermatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

La présente invention concerne des compositions contenant au moins un inhibiteur de kinase nanoparticulaire, tel que le LS 104 ou son sel ou son dérivé, présentant une vitesse de dissolution améliorée qui conduit à une mise à disponibilité du médicament plus rapide. Les particules de l'inhibiteur de kinase nanoparticulaire, tel que le LS 104, ont une dimension moyenne efficace inférieure à environ 2000 nm et elles se révèlent utiles pour le traitement de cancers, tels qu'une leucémie, des troubles myéloproliférants et des maladies associées.
EP07798449A 2006-06-13 2007-06-12 Formulations d'inhibiteurs de kinase nanoparticulaires Withdrawn EP2043606A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US81296006P 2006-06-13 2006-06-13
PCT/US2007/071011 WO2007146943A2 (fr) 2006-06-13 2007-06-12 Formulations d'inhibiteurs de kinase nanoparticulaires

Publications (1)

Publication Number Publication Date
EP2043606A2 true EP2043606A2 (fr) 2009-04-08

Family

ID=38832788

Family Applications (1)

Application Number Title Priority Date Filing Date
EP07798449A Withdrawn EP2043606A2 (fr) 2006-06-13 2007-06-12 Formulations d'inhibiteurs de kinase nanoparticulaires

Country Status (8)

Country Link
EP (1) EP2043606A2 (fr)
JP (1) JP2009540010A (fr)
KR (1) KR20090018864A (fr)
CN (1) CN101500540A (fr)
AU (1) AU2007257667A1 (fr)
CA (1) CA2654909A1 (fr)
TW (1) TW200816987A (fr)
WO (1) WO2007146943A2 (fr)

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8685458B2 (en) 2009-03-05 2014-04-01 Bend Research, Inc. Pharmaceutical compositions of dextran polymer derivatives
US9060938B2 (en) 2011-05-10 2015-06-23 Bend Research, Inc. Pharmaceutical compositions of active agents and cationic dextran polymer derivatives
WO2013105895A1 (fr) 2012-01-13 2013-07-18 Xspray Microparticles Ab Composition pharmaceutique contenant des nanoparticules hybrides amorphes stables d'au moins un inhibiteur de la protéine kinase et d'au moins un constituant polymère stabilisant et matriciel
MX371349B (es) * 2012-01-13 2020-01-27 Xspray Microparticles Ab Una composicion farmaceutica que comprende nanoparticulas hibridas amorfas estables, de al menos un inhibidor de proteina quinasa y al menos un componente estabilizador polimerico y formador de matriz.
TWI535784B (zh) 2014-08-26 2016-06-01 財團法人工業技術研究院 剪切增稠配方、及包含其之複合材料

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
BR0110087A (pt) * 2000-04-13 2004-02-17 Hsc Res Dev Lp Compostos para modular proliferação celular
AU2003230692A1 (en) * 2002-03-20 2003-10-08 Elan Pharma International Ltd. Nanoparticulate compositions of map kinase inhibitors

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2007146943A2 *

Also Published As

Publication number Publication date
WO2007146943A3 (fr) 2008-05-29
CA2654909A1 (fr) 2007-12-21
CN101500540A (zh) 2009-08-05
TW200816987A (en) 2008-04-16
KR20090018864A (ko) 2009-02-23
AU2007257667A1 (en) 2007-12-21
WO2007146943A2 (fr) 2007-12-21
JP2009540010A (ja) 2009-11-19

Similar Documents

Publication Publication Date Title
US11253478B2 (en) Reduction of flake-like aggregation in nanoparticulate active agent compositions
US20080213374A1 (en) Nanoparticulate sorafenib formulations
EP1895984B1 (fr) Formulations d'imatinib mesylate nanoparticulaires
AU2006309295B2 (en) Nanoparticulate acetaminophen formulations
US20070148100A1 (en) Nanoparticulate aripiprazole formulations
US20060159767A1 (en) Nanoparticulate bicalutamide formulations
EP1898882B1 (fr) Formulations d'ebastine nanoparticulaire
US20070042049A1 (en) Nanoparticulate benidipine compositions
US20100221327A1 (en) Nanoparticulate azelnidipine formulations
EP2043606A2 (fr) Formulations d'inhibiteurs de kinase nanoparticulaires

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20090112

AK Designated contracting states

Kind code of ref document: A2

Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IS IT LI LT LU LV MC MT NL PL PT RO SE SI SK TR

AX Request for extension of the european patent

Extension state: AL BA HR MK RS

RIN1 Information on inventor provided before grant (corrected)

Inventor name: RYDE, NIELS

Inventor name: KELLER, JANINE

Inventor name: BOSCH, WILLIAM H.

Inventor name: CARY, GRETA

Inventor name: LIVERSIDGE, ELAINE

17Q First examination report despatched

Effective date: 20100510

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 20130103