WO2007146943A2 - Nanoparticulate kinase inhibitor formulations - Google Patents

Nanoparticulate kinase inhibitor formulations Download PDF

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Publication number
WO2007146943A2
WO2007146943A2 PCT/US2007/071011 US2007071011W WO2007146943A2 WO 2007146943 A2 WO2007146943 A2 WO 2007146943A2 US 2007071011 W US2007071011 W US 2007071011W WO 2007146943 A2 WO2007146943 A2 WO 2007146943A2
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composition
nanoparticulate
ammonium chloride
chloride
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PCT/US2007/071011
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French (fr)
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WO2007146943A3 (en
Inventor
Elaine Liversidge
Greta Cary
William H. Bosch
Janine Keller
Niels Ryde
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Elan Pharma International Ltd.
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Priority to JP2009515607A priority Critical patent/JP2009540010A/en
Priority to AU2007257667A priority patent/AU2007257667A1/en
Priority to EP07798449A priority patent/EP2043606A2/en
Priority to CA002654909A priority patent/CA2654909A1/en
Publication of WO2007146943A2 publication Critical patent/WO2007146943A2/en
Publication of WO2007146943A3 publication Critical patent/WO2007146943A3/en

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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
    • 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:
  • Styrylacrylonitrile compounds such as LS104 are useful in treating a variety of cell proliferative disorders such as cancer. Styrylacrylonitrile compounds are disclosed, for
  • Strylacrylonitrile compounds such as LS 104 act, generally, by inhibiting abnormal cellular signaling that may be specific to the growth of cancer cells.
  • LS 104 functions as a small molecule kinase inhibitor, specifically, as a tyrosine kinase inhibitor. By blocking the action of specific kinases, LS 104 targets cancer cell pathways in contrast to many chemotherapy compounds, which attack cancerous and non-cancerous cells alike causing serious side effects.
  • LS 104 is a member of a new class of synthetic, small molecule, non-ATP competitive kinase inhibitors. Most kinase inhibitors currently in development for use as a therapeutic compete with adenosine triphosphate (ATP), the cell's energy source. Thus, LS 104 has the potential of being effective in restricting cancer development with a significantly lower toxicity than chemotherapy currently used in cancer treatment.
  • ATP adenosine triphosphate
  • AML Acute Myelogenous Leukemia
  • ALL Acute Lymphocytic Leukemia
  • CML Chronic Myelogenous Leukemia
  • PV polycythemia vera
  • ET essential thrombocythemia
  • MMM myeloid metaplasia with myelofibrosis
  • IM idiopathic myelofibrosis
  • 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
  • LS 104 may not become readily bioavailable when administered.
  • Such a formulation would be faster acting, thereby providing relief to a subject suffering from diseases or disorders involving unregulated, overactive kinase activity, such as tyrosine kinase activity.
  • diseases or disorders involving unregulated, overactive kinase activity such as tyrosine kinase activity.
  • Leukemias, myeloproliferative disorders, or other blood related cancers, or diseases are examples of such disorders.
  • Such a formulation may also overcome other problems associated with conventional drug formulations. The present invention satisfies these needs.
  • the present invention then, relates to nanoparticulate kinase inhibitor compositions, such as nanoparticulate LS 104, or a salt or derivative thereof, compositions for the treatment of blood cancers and related diseases, disorders, conditions and symptoms.
  • nanoparticulate kinase inhibitor compositions such as nanoparticulate LS 104, or a salt or derivative thereof, compositions for the treatment of blood cancers and related diseases, disorders, conditions and symptoms.
  • 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.
  • Nanoparticulate active agent compositions are also described, for example, in U.S. Patent Nos. 5,298,262 for "Use of Ionic Cloud Point Modifiers to Prevent Particle Aggregation During Sterilization;" 5,302,401 for “Method to Reduce Particle Size Growth During Lyophilization;” 5,318,767 for “X-Ray Contrast Compositions Useful in Medical Imaging;” 5,326,552 for “Novel Formulation For Nanoparticulate X-Ray Blood Pool Contrast Agents Using High Molecular Weight Non-ionic Surfactants;” 5,328,404 for “Method of X-Ray Imaging Using Iodinated Aromatic Propanedioates;” 5,336,507 for "Use of Charged Phospholipids to Reduce Nanoparticle Aggregation;” 5,340,564 for
  • WASH 1899464 1 "Formulations Comprising Olin 10-G to Prevent Particle Aggregation and Increase Stability;" 5,346,702 for "Use of Non-Ionic Cloud Point Modifiers to Minimize Nanoparticulate Aggregation During Sterilization;" 5,349,957 for “Preparation and Magnetic Properties of Very Small Magnetic-Dextran Particles;” 5,352,459 for “Use of Purified Surface Modifiers to Prevent Particle Aggregation During Sterilization;” 5,399,363 and 5,494,683, both for "Surface Modified Anticancer Nanoparticles;” 5,401,492 for "Water Insoluble Non-Magnetic Manganese Particles as Magnetic Resonance Enhancement Agents;” 5,429,824 for “Use of Tyloxapol as a Nanoparticulate Stabilizer;” 5,447,710 for "Method for Making Nanoparticulate X-Ray Blood Pool Contrast Agents Using High Molecular
  • 20070065374 for "Nanoparticulate leukotriene receptor antagonist/corticosteroid formulations;" U.S. Patent Publication No. 20070059371 for “Nanoparticulate ebastine formulations;” U.S. Patent Publication No. 20070048378 for "Nanoparticulate anticonvulsant and immunosuppressive compositions;” U.S. Patent Publication No. 20070042049 for "Nanoparticulate benidipine compositions;” U.S. Patent Publication No. 20070015719 for "Nanoparticulate clarithromycin formulations;” U.S. Patent Publication No. 20070003628 for "Nanoparticulate clopidogrel formulations;” U.S.
  • Patent Publication No. 20070003615 for "Nanoparticulate clopidogrel and aspirin combination formulations;” U.S. Patent Publication No. 20060292214 for “Nanoparticulate acetaminophen formulations;” U.S. Patent Publication No. 20060275372 for "Nanoparticulate imatinib mesylate formulations;” U.S. Patent Publication No. 20060246142 for "Nanoparticulate quinazoline derivative formulations," U.S. Patent Publication No. 20060246141 for "Nanoparticulate lipase inhibitor formulations," U.S. Patent Publication No.
  • 20060216353 for "Nanoparticulate corticosteroid and antihistamine formulations," U.S. Patent Publication No. 20060210639 for” Nanoparticulate bisphosphonate compositions," U.S. Patent Publication No. 20060210638 for "Injectable compositions of nanoparticulate immunosuppressive compounds," U.S. Patent Publication No. 20060204588 for "Formulations of a nanoparticulate finasteride, dutasteride or tamsulosin hydrochloride, and mixtures thereof," U.S. Patent Publication No. 20060198896 for "Aerosol and injectable formulations of nanoparticulate benzodiazepine," U.S. Patent Publication No.
  • 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.
  • Amorphous small particle compositions are described, for example, in U.S. Patent Nos. 4,783,484 for "Particulate Composition and Use Thereof as Antimicrobial Agent;” 4,826,689 for “Method for Making Uniformly Sized Particles from Water-Insoluble Organic Compounds;” 4,997,454 for “Method for Making Uniformly-Sized Particles From Insoluble Compounds;” 5,741,522 for "Ultrasmall, Non-aggregated Porous Particles of Uniform Size for Entrapping Gas Bubbles Within and Methods;” and 5,776,496, for "Ultrasmall Porous Particles for Enhancing Ultrasound Back Scatter.” These are also specifically incorporated herein by reference.
  • WASH 1899464 1 improved efficacy and/or are suitable for administration such as parenteral administration.
  • the present invention fills that need.
  • the present invention then, relates to nanoparticulate compositions comprising a kinase inhibitors such as LS 104, which may be useful in the treatment and prevention of diseases and disorders, such as CML, AML, ALL, myeloproliferative diseases, and other blood-related cancers and diseases.
  • a kinase inhibitors such as LS 104
  • diseases and disorders such as CML, AML, ALL, myeloproliferative diseases, and other blood-related cancers and diseases.
  • the present invention relates to stable nanoparticulate compositions comprising a kinase inhibitor, such as LS 104, or a salt or derivative thereof, and at least one surface stabilizer.
  • a kinase inhibitor such as LS 104
  • the surface stabilizer may be associated with the surface of the particles, for example, the surface stabilizer may be adsorbed onto the surface of the LS 104 particle.
  • the drug nanoparticles have an effective average particle size of less than about 2000 nm.
  • compositions may include LS 104 particles which are in a crystalline phase, an amorphous phase, a semi-crystalline phase, a semi-amorphous phase and mixtures thereof.
  • the compositions may include one or more surface stabilizers.
  • some compositions may include at least one primary and at least one secondary surface stabilizer.
  • Exemplary surface stabilizers include, but are not limited to non-ionic surface stabilizers, ionic surface stabilizers, anionic surface stabilizers, cationic surface stabilizers, zwitterionic surface stabilizers and combinations thereof.
  • the invention also relates to compositions comprising nanoparticulate kinase inhibitors such as LS 104 or a salt or derivative thereof, at least one surface stabilizer, and optionally one or more pharmaceutically acceptable excipients, carriers, and optionally one or more active agents useful for the treatment of cancers such as leukemias, myeloproliferative diseases and related disorders, or a combination thereof.
  • nanoparticulate kinase inhibitors such as LS 104 or a salt or derivative thereof
  • at least one surface stabilizer and optionally one or more pharmaceutically acceptable excipients, carriers, and optionally one or more active agents useful for the treatment of cancers such as leukemias, myeloproliferative diseases and related disorders, or a combination thereof.
  • compositions of the invention comprising a nanoparticulate kinase inhibitor, such as LS 104 or a salt or derivative thereof, are proposed to exhibit improved pharmacokinetic profiles as compared to conventional kinase inhibitor (e.g., LS104) compositions.
  • a nanoparticulate kinase inhibitor such as LS 104 or a salt or derivative thereof
  • the C max and/or AUC of the nanoparticulate compositions may be greater than the C max and/or AUC for conventional compositions administered at the same dosage while the T max may be lower; any combination of an improved C max , AUC and T max profile may be exhibited by the nanoparticulate LSO 14 compositions as compared to
  • 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 invention also relates to methods of treatment using the nanoparticulate LS 104 compositions.
  • a composition comprising a nanoparticulate LS 104 or salt or derivative thereof, having an effective average particle size of less than about 2000 nm, and at least one surface stabilizer, may be administered to a subject.
  • the composition may be formulated for parental injection (e.g., intravenous, intramuscular, or subcutaneous), in a therapeutically effective amount.
  • 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.
  • a kinase inhibitor such as LS 140
  • the composition may be administered to treat myeloproliferative disorders, diseases, symptoms or conditions associated with myeloproliferative disorders, and cancers such as leukemias like CML, AML and ALL.
  • the subject may be suffering from such a disease, disorder, symptom or condition.
  • Other methods of treatment using the nanoparticulate compositions of the invention are known to those of skill in the art.
  • 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.
  • compositions comprising at least one nanoparticulate kinase inhibitor, such as LS 104, as compared to conventional non-nanoparticulate (microcrystalline or solubilized) formulations of the same kinase inhibitor include, but are not limited to: (1) smaller tablet or other solid dosage form size; (2) smaller doses of drug required to obtain the same pharmacological effect; (3) increased bioavailability; (4) improved pharmacokinetic profiles; (5) substantially similar pharmacokinetic profiles when administered in the fed versus the fasted state; (6) bioequivalency when administered in the fed versus the fasted state; (7) increased rate of absorption of nanoparticulate compositions; (8) an increased rate of dissolution; and (9) the kinase inhibitor compositions can be used in conjunction with other active agents useful in the treatment of myeloproliferative disorders, cancers such as leukemias and related disorders, diseases, symptoms, or conditions.
  • the present invention also includes compositions comprising at least one nanoparticulate kinase inhibitors, such as LS 104 or a salt or derivative thereof, together with one or more non-toxic physiologically acceptable carriers, adjuvants, or vehicles, collectively referred to as carriers.
  • the compositions can be formulated for parental injection (e.g., intravenous, intramuscular, or subcutaneous), oral administration in solid, liquid, or aerosol form, bioadhesive, vaginal, nasal, rectal, ocular, local (powders, ointments, or drops), buccal, intracisternal, intraperitoneal, or topical administrations, and the like.
  • 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.
  • stable connotes, but is not limited to one or more of the following parameters: (1) the particles do not appreciably flocculate or agglomerate due to interparticle attractive forces or otherwise significantly increase in particle size over time; (2) the physical structure of the particles is not altered over time, such as by conversion from an amorphous phase to a crystalline phase; (3) the particles are chemically stable; and/or (4) where the kinase inhibitor has not been subject to a heating step at or above the melting point of the kinase inhibitor particles in the preparation of the nanoparticles of the present invention.
  • 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.
  • pooledly water soluble drugs refers to those drugs that have a solubility in water of less than about 30 mg/ml, less than about 20 mg/ml, less than about 10 mg/ml, or less than about 1 mg/ml.
  • 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.
  • myeloproliferative disease or “myeloproliferative disorder” is meant to include non-lymphoid dysplastic or neoplastic conditions arising from a haematopoietic stem cell or its progeny.
  • MPD patient includes a patient who has been diagnosed with an MPD.
  • Myeloproliferative disease is meant to encompass the specific, classified types of myeloproliferative diseases including polycythemia vera (PV), essential thrombocythemia (ET) and idiopathic myelofibrosis (IMF).
  • PV polycythemia vera
  • ET essential thrombocythemia
  • IMF idiopathic myelofibrosis
  • 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
  • WASH 1899464 1 the C max for a non-nanoparticulate formulation of the same kinase inhibitor, administered at the same dosage; and/or (2) an AUC for an kinase inhibitor, such as LS 104, when assayed in the plasma of a mammalian subject following administration, that is preferably greater than the AUC for a non-nanoparticulate formulation of the same kinase inhibitor, administered at the same dosage; and/or (3) a T max for a kinase inhibitor, such as LS 104, when assayed in the plasma of a mammalian subject following administration, that is preferably less than the T max for a non-nanoparticulate formulation of the same kinase inhibitor, administered at the same dosage.
  • 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 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, an AUC which is at least about 25%, at least about 50%, at least about 75%, at least about 100%, at least about 125%, at least about 150%, at least about 175%, at least about 200%, at least about 225%, at least about 250%, at least about 275%, at least about 300%, at least about 350%, at least about 400%, at least about 450%, at least about 500%, at least about
  • an AUC which is at least about 25%, at least about 50%, at least about 75%, at least about 100%, at least about 125%, at least about 150%, at least about 175%, at least about 200%, at least about 225%, at least about 250%, at least about 275%, at least about 300%, at least about 350%, at least about 400%, at least about 450%, at least about 500%, at
  • WASH 1899464 1 least about 800%, at least about 850%, at least about 900%, at least about 950%, at least about 1000%, at least about 1050%, at least about 1100%, at least about 1150%, or at least about 1200% greater than the AUC exhibited by the non-nanop articulate kinase inhibitor formulation.
  • the T max of the kinase inhibitor, such as LS 104 when assayed in the plasma of the mammalian subject, is less than about 6 to about 8 hours. In other embodiments of the invention, the T max of the LS 104 is less than about 6 hours, less than about 5 hours, less than about 4 hours, less than about 3 hours, less than about 2 hours, less than about 1 hour, or less than about 30 minutes after administration.
  • the desirable pharmacokinetic profile is the pharmacokinetic profile measured after the initial dose of an kinase inhibitor, such as LS 104.
  • the compositions can be formulated in any way as described herein and as known to those of skill in the art.
  • 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%.
  • the invention also encompasses a composition comprising a nanoparticulate kinase inhibitor, such as LS 104, in which administration of the composition to a subject in a fasted state is bioequivalent to administration of the composition to a subject in a fed state.
  • the invention encompasses compositions comprising a nanoparticulate kinase inhibitors, such as LS 104, wherein administration of the composition to a subject in a fasted state is bioequivalent to administration of the composition to a subject in a fed state, in particular as defined by C max and AUC guidelines given by the U.S. Food and Drug Administration and the corresponding European regulatory agency (EMEA). Under U.S.
  • 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 kinase inhibitors such as LS 104, compositions of the invention preferably have a dissolution profile in which within about 5 minutes at least about 20% of the composition is dissolved. In other embodiments of the invention, at least about 30% or at least about 40% of the kinase inhibitor composition is dissolved within about 5 minutes. In yet other embodiments of the invention, preferably at least about 40%, at least about 50%, at least about 60%, at least about 70%, or at least about 80% of the kinase inhibitor composition is dissolved within about 10 minutes. Finally, in another embodiment of the invention, preferably at least about 70%, at least about 80%, at least about 90%, or at least about 100% of the kinase inhibitor composition is dissolved within 20 minutes.
  • Dissolution is preferably measured in a medium which is discriminating.
  • a discriminating dissolution medium is one that will produce two very different dissolution curves for two products having very different dissolution profiles in gastric juices; i.e., the dissolution medium is predictive of the in vivo dissolution of a composition.
  • An exemplary dissolution medium is an aqueous medium containing the surfactant sodium lauryl sulfate at 0.025 M. Determination of the amount dissolved can be carried out by spectrophotometry. The rotating blade method (European Pharmacopoeia) can be used to measure dissolution.
  • compositions comprising at least one nanoparticulate kinase inhibitor, such as LS 104 or a salt or derivative thereof, is that the compositions redisperse such that the effective average particle size of the redispersed kinase inhibitor particles is less than about 2 microns. This is significant, as upon administration, if the kinase inhibitor particles of the compositions of the present invention agglomerated or did not redisperse to a substantially nanoparticulate size, then the dosage form may lose the benefits afforded by formulating the kinase inhibitors into a nanoparticulate size. [0062] This is because nanoparticulate active agent compositions benefit from the small particle size of the active agent.
  • the active agent does not disperse into the small particle sizes upon administration, then "clumps" or agglomerated active agent particles are formed, owing to the extremely high surface free energy of the nanoparticulate system and the thermodynamic driving force to achieve an overall reduction in free energy. With the formulation of such agglomerated particles, the bioavailability of the dosage form may fall well below that observed with the liquid dispersion form of the nanoparticulate active agent.
  • compositions comprising at least one nanoparticulate kinase inhibitor, such as LS 104, of the invention exhibit dramatic redispersion of the nanoparticulate kinase inhibitor particles upon administration to a mammal, such as a human or animal, as demonstrated by reconstitution/ redispersion in a biorelevant aqueous media such that the effective average particle size of the redispersed kinase inhibitor particles is less than about 2 microns.
  • biorelevant aqueous media can be any aqueous media that exhibit the desired ionic strength and pH, which form the basis for the biorelevance of the media.
  • the desired pH and ionic strength are those that are representative of physiological conditions found in the human body.
  • Such biorelevant aqueous media can be, for example, aqueous electrolyte solutions or aqueous solutions of any salt, acid, or base, or a combination thereof, which exhibit the desired pH and ionic strength.
  • Biorelevant pH is well known in the art.
  • the pH ranges from slightly less than 2 (but typically greater than 1) up to 4 or 5.
  • the pH can range from 4 to 6, and in the colon it can range from 6 to 8.
  • Biorelevant ionic strength is also well known in the art. Fasted state gastric fluid has an ionic strength of about 0. IM while fasted state intestinal fluid has an ionic strength of about 0.14. See e.g. , Lindahl et al., "Characterization of Fluids from the Stomach and Proximal Jejunum in Men and Women," Pharm. Res., 14 (4): 497-502 (1997).
  • pH and ionic strength of the test solution is more critical than the specific chemical content. Accordingly, appropriate pH and ionic strength values can be obtained through numerous combinations of strong acids, strong bases, salts, single or multiple conjugate acid-base pairs ⁇ i.e., weak acids and corresponding salts of that acid), monoprotic and polyprotic electrolytes, etc.
  • Representative electrolyte solutions can be, but are not limited to, HCl solutions, ranging in concentration from about 0.001 to about 0.1 M, and NaCl solutions, ranging in concentration from about 0.001 to about 0.1 M, and mixtures thereof.
  • electrolyte solutions can be, but are not limited to, about 0.1 M HCl or less, about 0.01 M HCl or less, about 0.001 M HCl or less, about 0.1 M NaCl or less, about 0.01 M NaCl or less, about 0.001 M NaCl or less, and mixtures thereof.
  • Electrolyte concentrations of 0.001 M HCl, 0.01 M HCl, and 0.1 M HCl correspond to pH 3, pH 2, and pH 1, respectively.
  • a 0.01 M HCl solution simulates typical acidic conditions found in the stomach.
  • a solution of 0.1 M NaCl provides a reasonable approximation of the ionic strength conditions found throughout the body, including the gastrointestinal fluids, although concentrations higher than 0.1 M may be employed to simulate fed conditions within the human GI tract.
  • Exemplary solutions of salts, acids, bases or combinations thereof, which exhibit the desired pH and ionic strength include but are not limited to phosphoric acid/phosphate salts + sodium, potassium and calcium salts of chloride, acetic acid/acetate salts + sodium, potassium and calcium salts of chloride, carbonic acid/bicarbonate salts + sodium, potassium and calcium salts of chloride, and citric acid/citrate salts + sodium, potassium and calcium salts of chloride.
  • the redispersed particles of a kinase inhibitor such as LS 104 or a salt or derivative thereof (redispersed in water, a biorelevant
  • WASH 1899464 1 media or any suitable redispersion media
  • WASH 1899464 1 media have an effective average particle size of less than about 1900 nm, less than about 1800 nm, less than about 1700 nm, less than about 1600 nm, less than about 1500 nm, less than about 1400 nm, less than about 1300 nm, less than about 1200 nm, less than about 1100 nm, less than about 1000 nm, less than about 990 nm, less than about 980 nm, less than about 970 nm, less than about 960 nm, less than about 950 nm, less than about 940 nm, less than about 930 nm, less than about 920 nm, less than about 910 nm, less than about 900 nm, less than about 890 nm, less than about 880 nm, less than about 870 nm, less than about 860 nm, less than about 850 nm, less
  • compositions comprising at least one nanoparticulate kinase inhibitor can additionally comprise one or more compounds useful in the treatment of cancers such as leukemias or other related diseases, disorders, conditions or symptoms, or the kinase inhibitor compositions can be administered in conjunction with such a compound.
  • Nanoparticulate kinase inhibitor compositions, such as LS 104 may provide broad opportunities for use in combination with other kinase inhibitors, such as Gleevec®, as well as current standard chemotheraphy treatments, bone marrow transplants, etc.
  • 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.
  • the present invention also includes kinase inhibitors such as LS 104, (or a salt or derivative thereof), compositions together with one or more non-toxic physiologically acceptable carriers, adjuvants, or vehicles, collectively referred to as carriers.
  • the compositions can be formulated for parenteral injection (e.g., intravenous, intramuscular, or subcutaneous), oral administration in solid, liquid, or aerosol form, vaginal, nasal, rectal, ocular, local (powders, ointments or drops), buccal, intracisternal, intraperitoneal, or topical administration, and the like.
  • 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.
  • a surface stabilizer for a kinase inhibitor such as LS 104 is non-trivial. Accordingly, the present invention is directed to the surprising discovery that nanoparticulate kinase inhibitor compositions can be made.
  • Combinations of more than one surface stabilizers can be used in the invention.
  • Useful surface stabilizers which can be employed in the invention include, but are not limited to, known organic and inorganic pharmaceutical excipients. Such excipients include various polymers, low molecular weight oligomers, natural products, and surfactants.
  • Exemplary surface stabilizers include nonionic and ionic (e.g. , anionic, cationic, and zwitterionic) surfactants or compounds.
  • surface stabilizers include albumin, including but not limited to human serum albumin and bovine albumin, hydroxypropyl methylcellulose (now known as hypromellose), hydroxypropylcellulose, polyvinylpyrrolidone, sodium lauryl sulfate, dioctylsulfosuccinate, gelatin, casein, lecithin (phosphatides), dextran, gum acacia, cholesterol, tragacanth, stearic acid, benzalkonium chloride, calcium stearate, glycerol monostearate, cetostearyl alcohol, cetomacrogol emulsifying wax, sorbitan esters, polyoxyethylene alkyl ethers (e.g., macrogol ethers such as cetomacrogol 1000), polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters (e.g., the commercially available Tween ® products such as e.g., Tween ® products such as
  • compositions of the invention can be formulated to be phospholipid-free.
  • Examples of useful cationic surface stabilizers include, but are not limited to, polymers, biopolymers, polysaccharides, cellulosics, alginates, phospholipids, and nonpolymeric compounds, such as zwitterionic stabilizers, poly-n-methylpyridinium, anthryul pyridinium chloride, cationic phospholipids, chitosan, polylysine, polyvinylimidazole, polybrene, polymethylmethacrylate trimethylammoniumbromide bromide (PMMTMABr), hexyldesyltrimethylammonium bromide (HDMAB), and polyvinylpyrrolidone-2-dimethylaminoethyl methacrylate dimethyl sulfate.
  • cationic stabilizers include, but are not limited to, cationic lipids, sulfonium, phosphonium, and quarternary ammonium compounds, such as stearyltrimethylammonium chloride, benzyl-di(2-chloroethyl)ethylammonium bromide, coconut trimethyl ammonium chloride or bromide, coconut methyl dihydroxyethyl ammonium chloride or bromide, decyl triethyl ammonium chloride, decyl dimethyl hydroxyethyl ammonium chloride or bromide, hydroxyethyl ammonium chloride or bromide, coconut dimethyl hydroxyethyl ammonium chloride or bromide, myristyl trimethyl ammonium methyl sulphate, lauryl dimethyl benzyl ammonium chloride or bromide, lauryl dimethyl (ethenoxy) 4 ammonium chloride or bromide, N-al
  • WASH 1899464 1 didecyldimethyl ammonium chloride, N-tetradecyldimethylbenzyl ammonium, chloride monohydrate, N-alkyl(Ci 2 -i 4 ) dimethyl 1-naphthylmethyl ammonium chloride and dodecyldimethylbenzyl ammonium chloride, dialkyl benzenealkyl ammonium chloride, lauryl trimethyl ammonium chloride, alkylbenzyl methyl ammonium chloride, alkyl benzyl dimethyl ammonium bromide, C 12 , C 1S , C 17 trimethyl ammonium bromides, dodecylbenzyl triethyl ammonium chloride, poly-diallyldimethylammonium chloride (DADMAC), dimethyl ammonium chlorides, alkyldimethylammonium halogenides, tricetyl methyl ammonium chloride, decyltrimethylammonium bromid
  • Such exemplary cationic surface stabilizers and other useful cationic surface stabilizers are described in J. Cross and E. Singer, Cationic Surfactants: Analytical and Biological Evaluation (Marcel Dekker, 1994); P. and D. Rubingh (Editor), Cationic Surfactants: Physical Chemistry (Marcel Dekker, 1991); and J. Richmond, Cationic Surfactants: Organic Chemistry, (Marcel Dekker, 1990).
  • Nonpolymeric surface stabilizers are any nonpolymeric compound, such benzalkonium chloride, a carbonium compound, a phosphonium compound, an oxonium compound, a halonium compound, a cationic organometallic compound, a quarternary phosphorous compound, a pyridinium compound, an anilinium compound, an ammonium compound, a hydroxylammonium compound, a primary ammonium compound, a secondary ammonium compound, a tertiary ammonium compound, and quarternary ammonium compounds of the formula NR 1 R 2 R 3 R 4 ⁇ .
  • benzalkonium chloride a carbonium compound, a phosphonium compound, an oxonium compound, a halonium compound, a cationic organometallic compound, a quarternary phosphorous compound, a pyridinium compound, an anilinium compound, an ammonium compound, a hydroxylammonium compound, a primary ammoni
  • two OfR 1 -R 4 are CH 3 , one OfR 1 -R 4 is C 6 H 5 CH 2 , and one Of R 1 -R 4 is an alkyl chain of nineteen carbon atoms or more;
  • two OfR 1 -R 4 are CH 3 , one of R 1 -R 4 is C 6 H 5 CH 2 , and one of R 1 -R 4 comprises at least one heteroatom;
  • R 1 -R 4 two Of R 1 -R 4 are CH 3 , one of R 1 -R 4 is C 6 H 5 CH 2 , and one of R 1 -R 4 comprises at least one halogen;
  • R 1 -R 4 two Of R 1 -R 4 are CH 3 , one of R 1 -R 4 is C 6 H 5 CH 2 , and one of R 1 -R 4 comprises at least one cyclic fragment;
  • Such compounds include, but are not limited to, behenalkonium chloride, benzethonium chloride, cetylpyridinium chloride, behentrimonium chloride, lauralkonium chloride, cetalkonium chloride, cetrimonium bromide, cetrimonium chloride, cethylamine hydro fluoride, chlorallylmethenamine chloride (Quaternium-15), distearyldimonium chloride
  • the surface stabilizers may be a copovidone (e.g., Plasdone
  • S630 which is a random copolymer of vinyl acetate and vinyl pyrrolidone) and/or docusate sodium.
  • the surface stabilizers are commercially available and/or can be prepared by techniques known in the art. Most of these surface stabilizers are known pharmaceutical excipients and are described in detail in the Handbook of Pharmaceutical Excipients, published jointly by the American Pharmaceutical Association and The Pharmaceutical Society of Great Britain (The Pharmaceutical Press, 2000), specifically incorporated by reference.
  • compositions according to the invention may also comprise one or more binding agents, filling agents, lubricating agents, suspending agents, sweeteners, flavoring agents, preservatives, buffers, wetting agents, disintegrants, effervescent agents, and other excipients.
  • excipients are known in the art.
  • 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.
  • sweeteners may include any natural or artificial sweetener, such as sucrose, xylitol, sodium saccharin, cyclamate, aspartame, and acsulfame.
  • sweeteners may include any natural or artificial sweetener, such as sucrose, xylitol, sodium saccharin, cyclamate, aspartame, and acsulfame.
  • flavoring agents are Magnasweet ® (trademark of MAFCO), bubble gum flavor, and fruit flavors, and the like.
  • preservatives include potassium sorbate, methylparaben, propylparaben, benzoic acid and its salts, other esters of parahydroxybenzoic acid such as butylparaben, alcohols such as ethyl or benzyl alcohol, phenolic compounds such as phenol, or quarternary compounds such as benzalkonium chloride.
  • Suitable diluents include pharmaceutically acceptable inert fillers, such as microcrystalline cellulose, lactose, dibasic calcium phosphate, saccharides, and/or mixtures of any of the foregoing.
  • examples of diluents include microcrystalline cellulose, such as Avicel ® PHlOl and Avicel ® PH 102; lactose such as lactose monohydrate, lactose anhydrous, and Pharmatose ® DCL21; dibasic calcium phosphate such as Emcompress ® ; mannitol; starch; sorbitol; sucrose; and glucose.
  • Suitable disintegrants include lightly crosslinked polyvinyl pyrrolidone, corn starch, potato starch, maize starch, and modified starches, croscarmellose sodium, cross-povidone, sodium starch glycolate, and mixtures thereof.
  • effervescent agents include effervescent couples such as an organic acid and a carbonate or bicarbonate.
  • Suitable organic acids include, for example, citric, tartaric, malic, fumaric, adipic, succinic, and alginic acids and anhydrides and acid salts.
  • Suitable carbonates and bicarbonates include, for example, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, magnesium carbonate, sodium glycine carbonate, L-lysine carbonate, and arginine carbonate.
  • only the sodium bicarbonate component of the effervescent couple may be present.
  • compositions of the invention comprise particles of at least one nanoparticulate kinase inhibitor, such as LS 104 (or a salt or derivative thereof), which have an effective average particle size of less than about 2000 nm (i.e., 2 microns), less than about 1900 nm, less than about 1800 nm, less than about 1700 nm, less than about 1600 nm, less than about 1500 nm, less than about 1400 nm, less than about 1300 nm, less than about 1200 nm, less than about 1100 nm, less than about 1000 nm, less than about 990 nm, less than about 980 nm, less than about 970 nm, less than about 960 nm, less than about 950 nm, less than about 940 nm, less than about 930 nm, less than about 920 nm, less than about 910 nm, less than about 900 nm, less than about 890 nm, less than about 2000 nm
  • an effective average particle size of less than about 2000 nm it is meant that at least 50% of the kinase inhibitor, such as LS104, particles have a particle size less than the effective average, by weight (or by other suitable measurement techniques, such as by volume, number, etc.), i.e., less than about 2000 nm, 1900 nm, 1800 nm, etc., when measured by the above-noted techniques.
  • At least about 60%, at least about 70%, at least about 80% at least about 90%, at least about 95%, or at least about 99% of the kinase inhibitor, such as LS 104, particles have a particle size of less than the effective average, i.e., less than about 2000 nm, 1900 nm, 1800 nm, 1700 nm, etc.
  • the value for D50 of a nanoparticulate kinase inhibitor, such as LS 104 composition is the particle size below which 50% of the kinase inhibitor particles fall, by weight.
  • D90 is the particle size below which 90% of the kinase inhibitor particles fall, by weight.
  • kinase inhibitor such as LS 104 or a salt or derivative thereof
  • one or more surface stabilizers may vary.
  • the optimal amount of the individual components can depend, for example, upon the particular kinase inhibitor selected, the hydrophilic lipophilic balance (HLB), melting point, and the surface tension of water solutions of the stabilizer, etc.
  • the concentration of the kinase inhibitor may be present from about 99.5% to about 0.001%, from about 95% to about 0.1%, or from about 90% to about 0.5%, by weight, based on the total combined dry weight of the kinase inhibitor and at least one surface stabilizer, not including other excipients.
  • the concentration of the at least one surface stabilizer may be present from about 0.5% to about 99.999%, from about 5.0% to about 99.9%, or from about 10% to about 99.5%, by weight, based on the total combined dry weight of the kinase inhibitor and at least one surface stabilizer, not including other excipients.
  • LS 104 tablet formulations are given below. These examples are not intended to limit the claims in any respect, but rather to provide exemplary tablet formulations of LS 104 which can be utilized in the methods of the invention. Such exemplary tablets may also include a coating agent.
  • the invention provides injectable compositions comprising at least one nanoparticulate small molecule kinase inhibitor, such as LS 104, that may include high drug concentrations in low injection volumes, with rapid drug dissolution upon administration.
  • the injectable nanoparticulate kinase inhibitors, such as LS 104 formulations of the invention may eliminate the need to use solubilizers such as polyoxyl 60 hydrogenated castor oil (HCO-60).
  • Exemplary injectable compositions comprises, base on % w/w: Small molecule, synthetic kinase inhibitor such as LS 104: 5 - 50% Povidone polymer: 0.1 - 50%
  • Preservatives 0.05 - 0.25% pH adjusting agent: pH about 6 to about 7
  • Exemplary preservatives include methylparaben (about 0.18% based on % w/w), propylparaben (about 0.02% based on % w/w), phenol (about 0.5% based on % w/w), and benzyl alcohol (up to 2% v/v).
  • An exemplary pH adjusting agent is sodium hydroxide
  • an exemplary liquid carrier is sterile water for injection.
  • Other useful preservatives, pH adjusting agents, and liquid carriers are well-known in the art.
  • compositions comprising at least one nanoparticulate kinase inhibitor can be made using, for example, milling or attrition (including but not limited to wet milling), homogenization, precipitation, freezing, template emulsion techniques, supercritical fluid techniques, nano-electrospray techniques, or any combination thereof.
  • milling or attrition including but not limited to wet milling
  • homogenization precipitation
  • freezing template emulsion techniques
  • supercritical fluid techniques nano-electrospray techniques, or any combination thereof.
  • Exemplary methods of making nanoparticulate compositions are described in the '684 patent. Methods of making nanoparticulate compositions are also described in U.S. Patent No. 5,518,187 for "Method of Grinding Pharmaceutical Substances;" U.S. Patent No. 5,718,388 for "Continuous Method of Grinding Pharmaceutical Substances;” U.S. Patent No.
  • the resultant nanoparticulate kinase inhibitor compositions or dispersions can be utilized in solid or liquid dosage formulations, such as injectable form, liquid dispersions, gels, aerosols, ointments, creams, controlled release formulations, fast melt formulations, lyophilized formulations, tablets, capsules, delayed release formulations, extended release formulations, pulsatile release formulations, mixed immediate release and controlled release formulations, etc.
  • Milling an kinase inhibitor, such as LS 104 or a salt or derivative thereof, to obtain a nanoparticulate kinase inhibitor dispersion comprises dispersing the kinase inhibitor particles in a liquid dispersion medium in which the kinase inhibitor is poorly soluble, followed by applying mechanical means in the presence of grinding media to reduce the particle size of the kinase inhibitor to the desired effective average particle size.
  • the dispersion medium can be, for example, water, safflower oil, ethanol, t-butanol, glycerin, polyethylene glycol (PEG), hexane, or glycol.
  • a preferred dispersion medium is water.
  • 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.
  • the grinding media can comprise particles that are preferably substantially spherical in shape, e.g., beads, consisting essentially of polymeric or copolymeric resin.
  • the grinding media can comprise a core having a coating of a polymeric or copolymeric resin adhered thereon.
  • suitable polymeric or copolymeric resins are chemically and physically inert, substantially free of metals, solvent, and monomers, and of sufficient hardness and friability to enable them to avoid being chipped or crushed during grinding.
  • Suitable polymeric or copolymeric resins include crosslinked polystyrenes, such as polystyrene crosslinked with divinylbenzene; styrene copolymers; polycarbonates; polyacetals, such as DelrinTM (E.I. du Pont de Nemours and Co.); vinyl chloride polymers and copolymers; polyurethanes; polyamides; poly(tetrafluoroethylenes), e.g., Teflon® (E.I.
  • du Pont de Nemours and Co. and other fluoropolymers
  • high density polyethylenes polypropylenes
  • cellulose ethers and esters such as cellulose acetate
  • polyhydroxymethacrylate polyhydroxyethyl acrylate
  • silicone-containing polymers such as polysiloxanes and the like.
  • the polymer can be biodegradable.
  • biodegradable polymers or copolymers include poly(lactides), poly(glycolide) copolymers of lactides and glycolide, polyanhydrides, poly(hydroxyethyl methacylate), poly(imino carbonates), poly(N-acylhydroxyproline)esters, poly(N-palmitoyl hydroxyproline) esters, ethylene -vinyl acetate copolymers, poly(orthoesters), poly(caprolactones), and poly(phosphazenes).
  • contamination from the media itself advantageously can metabolize in vivo into biologically acceptable products that can be eliminated from the body.
  • the grinding media preferably ranges in size from about 0.01 to about 3 mm.
  • the grinding media is preferably from about 0.02 to about 2 mm, and more preferably from about 0.03 to about 1 mm in size.
  • the polymeric or copolymeric resin can have a density from about 0.8 to about 3.0 g/cm 3 .
  • the particles are made continuously.
  • Such a method comprises continuously introducing a composition according to the invention into a milling chamber, contacting the composition according to the invention with grinding media while in the chamber to reduce the particle size of the composition according to the invention, and continuously removing the nanoparticulate composition according to the invention nanoparticles from the milling chamber.
  • the grinding media is separated from the milled nanoparticulate composition according to the invention nanoparticles using conventional separation techniques, in a secondary process such as by simple filtration, sieving through a mesh filter or screen, and the like. Other separation techniques such as centrifugation may also be employed.
  • Another method of forming the desired composition comprising at least one nanoparticulate kinase inhibitor, such as LS 104 or a salt or derivative thereof, is by microprecipitation.
  • This is a method of preparing stable dispersions of poorly soluble active agents in the presence of one or more surface stabilizers and one or more colloid stability enhancing surface active agents free of any trace toxic solvents or solubilized heavy metal impurities.
  • Such a method comprises, for example: (1) dissolving the kinase inhibitor in a suitable solvent; (2) adding the formulation from step (1) to a solution comprising at least one surface stabilizer; and (3) precipitating the formulation from step (2) using an appropriate non-solvent.
  • the method can be followed by removal of any formed salt, if present, by dialysis or diafiltration and concentration of the dispersion by conventional means.
  • Exemplary homogenization methods of preparing active agent nanoparticulate compositions are described in U.S. Patent No. 5,510,118, for "Process of Preparing Therapeutic Compositions Containing Nanoparticles.” Such a method comprises dispersing particles of an LS 104, (or a salt or derivative thereof), in a liquid dispersion medium, followed by subjecting the dispersion to homogenization to reduce the particle size of an LS 104, (or a salt or derivative thereof), in a liquid dispersion medium, followed by subjecting the dispersion to homogenization to reduce the particle size of an LS 104, (or a salt or derivative thereof), in a liquid dispersion medium, followed by subjecting the dispersion to homogenization to reduce the particle size of an LS 104, (or a salt or derivative thereof), in a liquid dispersion medium, followed by subjecting the dispersion to homogenization to reduce the particle size of an LS 104, (or a salt or derivative thereof), in a liquid dispersion
  • WASH 1899464 1 kinase inhibitor to the desired effective average particle size.
  • the particles can be reduced in size in the presence of at least one surface stabilizer.
  • the kinase inhibitor particles can be contacted with one or more surface stabilizers either before or after attrition.
  • Other compounds, such as a diluent, can be added to the kinase inhibitor /surface stabilizer composition either before, during, or after the size reduction process.
  • Dispersions can be manufactured continuously or in a batch mode.
  • nanoparticulate kinase inhibitor such as LS 104 (or a salt or derivative thereof), composition
  • SFL liquid
  • This technology comprises an organic or organoaqueous solution of kinase inhibitor with stabilizers, which is injected into a cryogenic liquid, such as liquid nitrogen.
  • the droplets of the LS 104 solution freeze at a rate sufficient to minimize crystallization and particle growth, thus formulating nanostructured LS 104 particles.
  • the nanoparticulate kinase inhibitor particles can have varying particle morphology.
  • the nitrogen and solvent are removed under conditions that avoid agglomeration or ripening of the kinase inhibitor particles.
  • URF ultra rapid freezing
  • Template emulsion creates nanostructured kinase inhibitor or derivative particles with controlled particle size distribution and rapid dissolution performance.
  • the method comprises an oil-in-water emulsion that is prepared, then swelled with a non-aqueous solution comprising the kinase inhibitor and stabilizers.
  • the particle size distribution of kinase inhibitor is a direct result of the size of the emulsion droplets prior to loading with the kinase inhibitor, a property which can be controlled and optimized in this process.
  • solvents and stabilizers emulsion stability is achieved with no or suppressed Ostwald ripening. Subsequently, the solvent and water are removed, and the stabilized nanostructured kinase inhibitor particles are
  • WASH 1899464 1 recovered.
  • Various kinase inhibitor particles morphologies can be achieved by appropriate control of processing conditions.
  • Nanop articulate compositions can also be made in methods utilizing supercritical fluids.
  • a inase inhibitor such as LS 104
  • a solution or vehicle which can also contain at least one surface stabilizer.
  • the solution and a supercritical fluid are then co-introduced into a particle formation vessel. If a surface stabilizer was not previously added to the vehicle, it can be added to the particle formation vessel
  • the temperature and pressure are controlled, such that dispersion and extraction of the vehicle occur substantially simultaneously by the action of the supercritical fluid.
  • Chemicals described as being useful as supercritical fluids include carbon dioxide, nitrous oxide, sulphur hexafluoride, xenon, ethylene, chlorotrifluoromethane, ethane, and trifluoromethane.
  • Examples of known supercritical methods of making nanoparticles include International Patent Application No. WO 97/144407 to Pace et al, published on April 24, 1997, which refers to particles of water insoluble biologically active compounds with an average size of 100 nm to 300 nm prepared by dissolving the compound in a solution and then spraying the solution into compressed gas, liquid, or supercritical fluid in the presence of appropriate surface stabilizers.
  • U.S. Patent No. 6,406,718 to Cooper et al. describes a method for forming a particulate fluticasone propionate product comprising the co-introduction of a supercritical fluid and a vehicle containing at least fluticasone propionate in solution or suspension into a particle formation vessel, the temperature and pressure in which are controlled, such that dispersion and extraction of the vehicle occur substantially simultaneously by the action of the supercritical fluid.
  • Chemicals described as being useful as supercritical fluids include carbon dioxide, nitrous oxide, sulphur hexafluoride, xenon, ethylene, chlorotrifluoromethane, ethane, and trifluoromethane.
  • the supercritical fluid may optionally contain one or more modifiers, such as methanol, ethanol, ethyl acetate, acetone, acetonitrile or any mixture thereof.
  • a supercritical fluid modifier is a chemical which, when added to a supercritical fluid, changes the intrinsic properties of the supercritical fluid in or around the critical point. According to Cooper et al., the fluticasone propionate particles produced using supercritical fluids have a particle size range of 1 to 10 microns, preferably 1 to 5 microns.
  • a liquid is pushed through a very small charged, usually metal, capillary.
  • This liquid contains the desired substance, e.g., a kinase inhibitor (or "analyte"), dissolved in a large amount of solvent, which is usually much more volatile than the analyte. Volatile acids, bases or buffers are often added to this solution as well.
  • the analyte exists as an ion in solution either in a protonated form or as an anion. As like charges repel, the liquid pushes itself out of the capillary and forms a mist or an aerosol of small droplets about 10 ⁇ m across.
  • This jet of aerosol droplets is at least partially produced by a process involving the formation of a Taylor cone and a jet from the tip of this cone.
  • a neutral carrier gas such as nitrogen gas, is sometimes used to help nebulize the liquid and to help evaporate the neutral solvent in the small droplets.
  • the small droplets evaporate, suspended in the air, the charged analyte molecules are forced closer together.
  • the drops become unstable as the similarly charged molecules come closer together and the droplets once again break up. This is referred to as Coulombic fission because it is the repulsive Coulombic forces between charged analyte molecules that drive it. This process repeats itself until the analyte is free of solvent and is a lone ion.
  • the electrospray method may be employed to deposit single particles on surfaces, e.g., particles of a kinase inhibitor. This is accomplished by spraying colloids and making sure that on average there is not more than one particle per droplet. Consequent drying of the surrounding solvent results in an aerosol stream of single particles of the desired type.
  • the ionizing property of the process is not crucial for the application but may be put to use in electrostatic precipitation of the particles.
  • the invention provides a method of increasing bioavailability (e.g. , increasing the plasma levels) of an kinase inhibitor such as LS 104 (or a salt or derivative thereof), in a subject.
  • a method comprises orally administering to a subject an effective amount of a composition comprising a nanoparticulate kinase inhibitor.
  • the nanoparticulate kinase inhibitor such as LS 104
  • composition in accordance with standard pharmacokinetic practice, is expected to exhibit a bioavailability that is about 50% greater, about 40% greater, about 30% greater, about 20% greater, or about 10% greater than a conventional dosage form.
  • compositions when tested in fasting subjects in accordance with standard pharmacokinetic practice are proposed to produces a maximum blood plasma concentration profile in less than about 6 hours, less than about 5 hours, less than about 4 hours, less than about 3 hours, less than about 2 hours, less than about 1 hour or less than about 30 minutes after the initial dose of the composition.
  • the compositions of the invention may be useful in the treatment of cell proliferative diseases such as cancer, for example leukemias such as CML and ALL, and myeloproliferative diseases, such as PV, ET and IMF.
  • compositions of the invention comprising at least one nanoparticulate kinase inhibitor, such as LS 104 (or a salt or derivative thereof), can be administered to a subject via any conventional means including, but not limited to, orally, rectally, ocularly, parenterally (e.g., intravenous, intramuscular, or subcutaneous), intracisternally, pulmonary, intravaginally, intraperitoneally, locally (e.g., powders, ointments or drops), or as a buccal or nasal spray. In some embodiments, parenteral administration is preferred.
  • parenteral administration is preferred.
  • the term "subject” is used to mean an animal, preferably a mammal, including a human or non-human.
  • compositions suitable for parenteral injection may comprise physiologically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions.
  • suitable aqueous and nonaqueous carriers, diluents, solvents, or vehicles including water, ethanol, polyols (propyleneglycol, polyethylene-glycol, glycerol, and the like), suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate.
  • Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
  • compositions comprising at least one nanoparticulate kinase inhibitor may also contain adjuvants such as preserving, wetting, emulsifying, and dispensing agents.
  • adjuvants such as preserving, wetting, emulsifying, and dispensing agents.
  • Prevention of the growth of microorganisms can be ensured by various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like.
  • Prolonged absorption of the injectable pharmaceutical form can be brought about by the use of agents delaying absorption, such as aluminum monostearate and gelatin.
  • Solid dosage forms for oral administration include, but are not limited to, capsules, tablets, pills, powders, and granules.
  • the active agent is admixed with at least one of the following: (a) one or more inert excipients (or carriers), such as sodium citrate or dicalcium phosphate; (b) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and silicic acid; (c) binders, such as carboxymethylcellulose, alignates, gelatin, polyvinylpyrrolidone, sucrose, and acacia; (d) humectants, such as glycerol; (e) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (f) solution retarders, such as paraffin; (g) absorption accelerators, such as paraffin; (g) absorption accelerators, such as
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs.
  • the liquid dosage forms may comprise inert diluents commonly used in the art, such as water or other solvents, solubilizing agents, and emulsifiers.
  • Exemplary emulsifiers are ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3 -butyl eneglycol, dimethylformamide, oils, such as cottonseed oil, groundnut oil, corn germ oil, olive oil, castor oil, and sesame oil, glycerol, tetrahydrofurfuryl alcohol, polyethyleneglycols, fatty acid esters of sorbitan, or mixtures of these substances, and the like.
  • oils such as cottonseed oil, groundnut oil, corn germ oil, olive oil, castor oil, and sesame oil
  • glycerol tetrahydrofurfuryl alcohol
  • polyethyleneglycols fatty acid esters of sorbitan, or mixtures of these substances, and the like.
  • the composition can also include adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • “Therapeutically effective amount” as used herein with respect to, for example a kinase inhibitor such as LS 104 dosage shall mean that dosage that provides the specific pharmacological response for which an LS 104 is administered in a significant number of subjects in need of such treatment. It is emphasized that "therapeutically effective amount,” administered to a particular subject in a particular instance will not always be effective in treating the diseases described herein, even though such dosage is deemed a "therapeutically effective amount” by those skilled in the art. It is to be further understood that LS 104 dosages are, in particular instances, measured as oral dosages, or with reference to drug levels as measured in blood.
  • a kinase inhibitor such as LS 104 can be determined empirically and can be employed in pure form or, where such forms exist, in pharmaceutically acceptable salt, ester, or prodrug form. Actual dosage levels of kinase inhibitor such as LS 104 in the nanoparticulate compositions of the invention may be varied to obtain an amount of a kinase inhibitor such as LS 104 that is effective to obtain a desired therapeutic response for a particular composition and method of administration. The selected dosage level therefore depends upon the desired therapeutic effect, the route of administration, the potency of the administered kinase inhibitor such as LS104, the desired duration of treatment, and other factors.
  • Dosage unit compositions may contain such amounts of such submultiples thereof as may be used to make up the daily dose. It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors: the type and degree of the cellular or physiological response to be achieved; activity of the specific agent or composition employed; the specific agents or composition employed; the age, body weight, general health, sex, and diet of the patient; the time of administration, route of administration, and rate of excretion of the agent; the duration of the treatment; drugs used in combination or coincidental with the specific agent; and like factors well known in the medical arts.
  • NBD nanoparticulate dispersion formulation
  • the initial formulation screening was done using a low energy roller mill (Stoneware) approach.
  • the grinding media utilized was 0.8 mm yittrium treated zirconia
  • WASH 1899464 1 Light microscopy was performed using a Leica Light microscope with 10Ox objective. All particle sizes were measured using the Horiba LA 910 with deionized (DI) water as the diluent and 30 seconds sonication.
  • DI deionized
  • the first comprised Poloxamer 338 (Pluronic F108) as the stabilizer. Large crystals were observed at the end of the process. This may be a result of crystal growth (Ostwald ripening), suggesting that this stabilizer may not be optimal under certain milling parameters (i.e., the particular drug concentration and surface stabilizer concentration utilized).
  • the second formulation comprised Polysorbate 80 (Tween 80). A dispersion comprising small, well-dispersed particles was observed at the end of the process.
  • the third formulation comprised hydroxy propyl cellulose (HPC-SL). This formulation also comprised small, well- dispersed particles.
  • the fourth formulation comprised a mixture of povidone K- 12 (Plasdone K- 12, a low molecular weight grade polyvinylpyrrolidone) and sodium deoxycholate. This formulation also comprised small, well-dispersed particles and the end of the process. The results are summarized in Table 1 below.
  • 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.
  • Table 3 details additional exemplary nanoparticulate LS104 formulations. All of these formulations were prepared using the NanoMill-01 (NanoMill Systems, King of Prussia, PA; see e.g., U.S. Patent No. 6,431,478), along with 500 micron PolyMill® attrition media (Dow Chemical). Again, light microscopy was performed using a Leica Light microscope with IOOX oil objective. All particle sizes were determined using the Horiba LA 910 with distilled, deionized water as the diluent and 30 second sonication. Table 3, Column 1 shows the formulation; Column 2 shows both the mean and D90 particle size (PS); Column
  • WASH 1899464 1 3 includes microscopy observations; Column 4 shows milling time; Column 5 indicates mill size; Column 6, indicates mill load; Column 7 shows mill speed; and Column 8 contains comments regarding the formulation.

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Abstract

The invention is directed to compositions comprising at least one nanop articulate kinase inhibitor, such as LS 104 or a salt or derivative thereof, having improved dissolution rate providing a faster onset of drug availability. The nanoparticulate kinase inhibitor particles, such as LS 104, have an effective average particle size of less than about 2000 nm and are useful in the treatment of cancers, such as leukemia, myeloproliferative disorders and related diseases.

Description

NANOPARTICULATE KINASE INHIBITOR FORMULATIONS
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application claims priority from U.S. Provisional Patent Application No. 60/812,960, filed on June 13, 2006, the contents of which are hereby incorporated by reference in its entirety.
FIELD OF THE INVENTION
[0002] 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.
BACKGROUND OF THE INVENTION
A. Background Regarding LS104
[0003] Aberrant kinase activity has been implicated in numerous diseases. 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. 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. [0004] The hallmark of CML and some ALLs is a chromosomal translocation that occurs between chromosome 22 and chromosome 9, resulting in an altered chromosome 22 which is known as the "Philadelphia chromosome." The 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. Although the breakpoints on chromosome 9 may vary, the breakpoints on chromosome 22 are relatively clustered. This region on chromosome 22 is termed the "breakpoint cluster region" ("Bcr"), and the fused gene that results from the translocation is called "Bcr- AbI." 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). For example, Bcr-Abl may cause undifferentiated blood cells to proliferate massively and fail to mature.
[0005] Non-CML myeloproliferative diseases (MPDs) 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. 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. However, 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.
WASH 1899464 1 Chem. 280(24):22788-22792 (2005); Levine et al, Cancer Cell 7:387-397 (2005); Kralovics, et al., New Eng. J. Med. 352(17): 1779-1790 (2005); Jones, et al., Blood 106:2162-2168 (2005); Steensma, et al., Blood 106:1207-2109 (2005).
[0007] The Janus kinases are a family of tyrosine kinases that play a role in cytokine signaling. For example, 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). See, e.g, Schindler, C.W., J. Clin Invest. 109:1133-1137 (2002); Tefferi and Gilliland, Mayo Clin. Proc. 80:947-958 (2005); Giordanetto and Kroemer, Protein Engineering 15(9):727-737 (2002). 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.
[0008] Treatment of leukemias and myeloproliferative disorders may involve drug therapy (e.g., chemotherapy), bone marrow transplants, radiation therapy, or combinations thereof. One class of drugs that may be used for treating such diseases includes kinase inhibitors. For example, 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."
[0009] Another class of kinase inhibitors includes 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 C1PH16O3N2, with a molecular weight of 320.34. [0010] The chemical structure of LS 104 is:
Figure imgf000004_0001
[0011] Styrylacrylonitrile compounds such as LS104 are useful in treating a variety of cell proliferative disorders such as cancer. Styrylacrylonitrile compounds are disclosed, for
3
WASH 1899464.1 example, in United States Patent Nos. 6,800,659 for "Compounds for Modulating Cell Proliferation," 7,012,095 for "Compounds for Modulating Cell Proliferation," Published Application No.: 2006/0058554, entitled "Novel Compounds Useful For Modulating Abnormal Cell Proliferation;" Published U.S. Application No.: 2006/0058297, entitled "Novel Compounds Useful For Modulating Abnormal Cell Proliferation;" Published Application No. 2005/0085538, entitled "Compounds For Modulating Cell Proliferation;" Published Application No: 2005/0014690, entitled "Styryl Acrylonitrile Compounds And Their Use To Promote Myelopoiesis;" Published Application No.: 2004/0247592, entitled "Ephrin And EPH Receptor Mediated Immune Modulation;" Published Application No. 2004/0209845, entitled "Novel Compounds For Modulating Cell Proliferation;" Published Application No. 2004/0006777, entitled "Human Lymphoid Protein Tyrosine Phosphatases;" Published Application No. 2003/0113328, entitled "Methods Of Modulation Of The Immune System;" all of which are incorporated herein by reference in their entirety. [0012] Strylacrylonitrile compounds such as LS 104 act, generally, by inhibiting abnormal cellular signaling that may be specific to the growth of cancer cells. LS 104 functions as a small molecule kinase inhibitor, specifically, as a tyrosine kinase inhibitor. By blocking the action of specific kinases, LS 104 targets cancer cell pathways in contrast to many chemotherapy compounds, which attack cancerous and non-cancerous cells alike causing serious side effects.
[0013] LS 104 is a member of a new class of synthetic, small molecule, non-ATP competitive kinase inhibitors. Most kinase inhibitors currently in development for use as a therapeutic compete with adenosine triphosphate (ATP), the cell's energy source. Thus, LS 104 has the potential of being effective in restricting cancer development with a significantly lower toxicity than chemotherapy currently used in cancer treatment. [0014] These compounds have shown great promise as potential treatment of acute leukemias such as Acute Myelogenous Leukemia (AML), Acute Lymphocytic Leukemia (ALL), Chronic Myelogenous Leukemia (CML) and may also prove beneficial for other myeloproliferative diseases or disorders such as polycythemia vera (PV), essential thrombocythemia (ET), myeloid metaplasia with myelofibrosis (MMM), and idiopathic myelofibrosis (IM). For example, 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
WASH 1899464 1 leukemia patients. Further, LS 104 has demonstrated very low or no toxicity toward normal cells.
[0015] However, LS 104 may not become readily bioavailable when administered. Thus, it would be desirable to formulate a more bioavailable form of kinase inhibitors such as LS104. Such a formulation would be faster acting, thereby providing relief to a subject suffering from diseases or disorders involving unregulated, overactive kinase activity, such as tyrosine kinase activity. Leukemias, myeloproliferative disorders, or other blood related cancers, or diseases are examples of such disorders. Such a formulation may also overcome other problems associated with conventional drug formulations. The present invention satisfies these needs.
[0016] The present invention then, relates to nanoparticulate kinase inhibitor compositions, such as nanoparticulate LS 104, or a salt or derivative thereof, compositions for the treatment of blood cancers and related diseases, disorders, conditions and symptoms.
B. Background Regarding Nanoparticulate Active Agent Compositions
[0017] Nanoparticulate active agent compositions, first described in U.S. Patent No. 5,145,684 ("the '684 patent"), 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.
[0018] Methods of making nanoparticulate active agent compositions are described in, for example, U.S. Patent Nos. 5,518,187 and 5,862,999, both for "Method of Grinding Pharmaceutical Substances;" U.S. Patent No. 5,718,388, for "Continuous Method of Grinding Pharmaceutical Substances;" and U.S. Patent No. 5,510,118 for "Process of Preparing Therapeutic Compositions Containing Nanoparticles."
[0019] Nanoparticulate active agent compositions are also described, for example, in U.S. Patent Nos. 5,298,262 for "Use of Ionic Cloud Point Modifiers to Prevent Particle Aggregation During Sterilization;" 5,302,401 for "Method to Reduce Particle Size Growth During Lyophilization;" 5,318,767 for "X-Ray Contrast Compositions Useful in Medical Imaging;" 5,326,552 for "Novel Formulation For Nanoparticulate X-Ray Blood Pool Contrast Agents Using High Molecular Weight Non-ionic Surfactants;" 5,328,404 for "Method of X-Ray Imaging Using Iodinated Aromatic Propanedioates;" 5,336,507 for "Use of Charged Phospholipids to Reduce Nanoparticle Aggregation;" 5,340,564 for
WASH 1899464 1 "Formulations Comprising Olin 10-G to Prevent Particle Aggregation and Increase Stability;" 5,346,702 for "Use of Non-Ionic Cloud Point Modifiers to Minimize Nanoparticulate Aggregation During Sterilization;" 5,349,957 for "Preparation and Magnetic Properties of Very Small Magnetic-Dextran Particles;" 5,352,459 for "Use of Purified Surface Modifiers to Prevent Particle Aggregation During Sterilization;" 5,399,363 and 5,494,683, both for "Surface Modified Anticancer Nanoparticles;" 5,401,492 for "Water Insoluble Non-Magnetic Manganese Particles as Magnetic Resonance Enhancement Agents;" 5,429,824 for "Use of Tyloxapol as a Nanoparticulate Stabilizer;" 5,447,710 for "Method for Making Nanoparticulate X-Ray Blood Pool Contrast Agents Using High Molecular Weight Non-ionic Surfactants;" 5,451,393 for "X-Ray Contrast Compositions Useful in Medical Imaging;" 5,466,440 for "Formulations of Oral Gastrointestinal Diagnostic X-Ray Contrast Agents in Combination with Pharmaceutically Acceptable Clays;" 5,470,583 for "Method of Preparing Nanoparticle Compositions Containing Charged Phospholipids to Reduce Aggregation;" 5,472,683 for "Nanoparticulate Diagnostic Mixed Carbamic Anhydrides as X-Ray Contrast Agents for Blood Pool and Lymphatic System Imaging;" 5,500,204 for "Nanoparticulate Diagnostic Dimers as X-Ray Contrast Agents for Blood Pool and Lymphatic System Imaging;" 5,518,738 for "Nanoparticulate NSAID Formulations;" 5,521,218 for "Nanoparticulate Iododipamide Derivatives for Use as X-Ray Contrast Agents;" 5,525,328 for "Nanoparticulate Diagnostic Diatrizoxy Ester X-Ray Contrast Agents for Blood Pool and Lymphatic System Imaging;" 5,543,133 for "Process of Preparing X-Ray Contrast Compositions Containing Nanoparticles;" 5,552,160 for "Surface Modified NSAID Nanoparticles;" 5,560,931 for "Formulations of Compounds as Nanoparticulate Dispersions in Digestible Oils or Fatty Acids;" 5,565,188 for "Polyalkylene Block Copolymers as Surface Modifiers for Nanoparticles;" 5,569,448 for "Sulfated Non-ionic Block Copolymer Surfactant as Stabilizer Coatings for Nanoparticle Compositions;" 5,571,536 for "Formulations of Compounds as Nanoparticulate Dispersions in Digestible Oils or Fatty Acids;" 5,573,749 for "Nanoparticulate Diagnostic Mixed Carboxylic Anydrides as X-Ray Contrast Agents for Blood Pool and Lymphatic System Imaging;" 5,573,750 for "Diagnostic Imaging X-Ray Contrast Agents;" 5,573,783 for "Redispersible Nanoparticulate Film Matrices With Protective Overcoats;" 5,580,579 for "Site-specific Adhesion Within the GI Tract Using Nanoparticles Stabilized by High Molecular Weight, Linear Poly(ethylene Oxide) Polymers;" 5,585,108 for "Formulations of Oral Gastrointestinal Therapeutic Agents in Combination with Pharmaceutically Acceptable Clays;" 5,587,143 for "Butylene Oxide- Ethylene Oxide Block Copolymers Surfactants as Stabilizer Coatings for Nanoparticulate
WASH 1899464 1 Compositions;" 5,591,456 for "Milled Naproxen with Hydroxypropyl Cellulose as Dispersion Stabilizer;" 5,593,657 for "Novel Barium Salt Formulations Stabilized by Non- ionic and Anionic Stabilizers;" 5,622,938 for "Sugar Based Surfactant for Nanocrystals;" 5,628,981 for "Improved Formulations of Oral Gastrointestinal Diagnostic X-Ray Contrast Agents and Oral Gastrointestinal Therapeutic Agents;" 5,643,552 for "Nanoparticulate Diagnostic Mixed Carbonic Anhydrides as X-Ray Contrast Agents for Blood Pool and Lymphatic System Imaging;" 5,718,388 for "Continuous Method of Grinding Pharmaceutical Substances;" 5,718,919 for "Nanoparticles Containing the R(-)Enantiomer of Ibuprofen;" 5,747,001 for "Aerosols Containing Beclomethasone Nanoparticle Dispersions;" 5,834,025 for "Reduction of Intravenously Administered Nanoparticulate Formulation Induced Adverse Physiological Reactions;" 6,045,829 "Nanocrystalline Formulations of Human Immunodeficiency Virus (HIV) Protease Inhibitors Using Cellulosic Surface Stabilizers;" 6,068,858 for "Methods of Making Nanocrystalline Formulations of Human Immunodeficiency Virus (HIV) Protease Inhibitors Using Cellulosic Surface Stabilizers;" 6,153,225 for "Injectable Formulations of Nanoparticulate Naproxen;" 6,165,506 for "New Solid Dose Form of Nanoparticulate Naproxen;" 6,221,400 for "Methods of Treating Mammals Using Nanocrystalline Formulations of Human Immunodeficiency Virus (HIV) Protease Inhibitors;" 6,264,922 for "Nebulized Aerosols Containing Nanoparticle Dispersions;" 6,267,989 for "Methods for Preventing Crystal Growth and Particle Aggregation in Nanoparticle Compositions;" 6,270,806 for "Use of PEG-Derivatized Lipids as Surface Stabilizers for Nanoparticulate Compositions;" 6,316,029 for "Rapidly Disintegrating Solid Oral Dosage Form," 6,375,986 for "Solid Dose Nanoparticulate Compositions Comprising a Synergistic Combination of a Polymeric Surface Stabilizer and Dioctyl Sodium Sulfosuccinate;" 6,428,814 for "Bioadhesive Nanoparticulate Compositions Having Cationic Surface Stabilizers;" 6,431,478 for "Small Scale Mill;" and 6,432,381 for "Methods for Targeting Drug Delivery to the Upper and/or Lower Gastrointestinal Tract," 6,592,903 for "Nanoparticulate Dispersions Comprising a Synergistic Combination of a Polymeric Surface Stabilizer and Dioctyl Sodium Sulfosuccinate," 6,582,285 for "Apparatus for sanitary wet milling;" 6,656,504 for "Nanoparticulate Compositions Comprising Amorphous Cyclosporine;" 6,742,734 for "System and Method for Milling Materials;" 6,745,962 for "Small Scale Mill and Method Thereof;" 6,811,767 for "Liquid droplet aerosols of nanoparticulate drugs;" 6,908,626 for "Compositions having a combination of immediate release and controlled release characteristics;" 6,969,529 for "Nanoparticulate compositions comprising copolymers of vinyl pyrrolidone and vinyl acetate as surface
7
WASH 1899464 1 stabilizers;" 6,976,647 for "System and Method for Milling Materials," 6,991,191 for "Method of Using a Small Scale Mill;" 7,101,576 for "Nanoparticulate Megestrol Formulation," 7,198,795 for "In vitro methods for evaluating the in vivo effectiveness of dosage forms of microparticulate of nanoparticulate active agent compositions;" all of which are specifically incorporated by reference.
[0020] In addition, U.S. Patent Publication No. 20070122486 for "Nanoparticulate insulin;" U.S. Patent Publication No. 20070110776 for "In vitro methods for evaluating the in vivo effectivness of dosage forms of microparticulate or nanoparticulate active agent compositions;" U.S. Patent Publication No. 20070104792 for "Nanoparticulate tadalafϊl formulations;" U.S. Patent Publication No. 20070098805 for "Methods of making and using novel griseofulvin compositions;" U.S. Patent Publication No. 20070065374 for "Nanoparticulate leukotriene receptor antagonist/corticosteroid formulations;" U.S. Patent Publication No. 20070059371 for "Nanoparticulate ebastine formulations;" U.S. Patent Publication No. 20070048378 for "Nanoparticulate anticonvulsant and immunosuppressive compositions;" U.S. Patent Publication No. 20070042049 for "Nanoparticulate benidipine compositions;" U.S. Patent Publication No. 20070015719 for "Nanoparticulate clarithromycin formulations;" U.S. Patent Publication No. 20070003628 for "Nanoparticulate clopidogrel formulations;" U.S. Patent Publication No. 20070003615 for "Nanoparticulate clopidogrel and aspirin combination formulations;" U.S. Patent Publication No. 20060292214 for "Nanoparticulate acetaminophen formulations;" U.S. Patent Publication No. 20060275372 for "Nanoparticulate imatinib mesylate formulations;" U.S. Patent Publication No. 20060246142 for "Nanoparticulate quinazoline derivative formulations," U.S. Patent Publication No. 20060246141 for "Nanoparticulate lipase inhibitor formulations," U.S. Patent Publication No. 20060216353 for "Nanoparticulate corticosteroid and antihistamine formulations," U.S. Patent Publication No. 20060210639 for" Nanoparticulate bisphosphonate compositions," U.S. Patent Publication No. 20060210638 for "Injectable compositions of nanoparticulate immunosuppressive compounds," U.S. Patent Publication No. 20060204588 for "Formulations of a nanoparticulate finasteride, dutasteride or tamsulosin hydrochloride, and mixtures thereof," U.S. Patent Publication No. 20060198896 for "Aerosol and injectable formulations of nanoparticulate benzodiazepine," U.S. Patent Publication No. 20060193920 for "Nanoparticulate Compositions of Mitogen-Activated (MAP) Kinase Inhibitors," U.S. Patent Publication No. 20060188566 for "Nanoparticulate formulations of docetaxel and analogues thereof," U.S. Patent Publication No. 20060165806 for "Nanoparticulate candesartan formulations," "U.S. Patent Publication No. 20060159767
8
WASH 1899464 1 for "Nanoparticulate bicalutamide formulations," U.S. Patent Publication No. 20060159766 for "Nanoparticulate tacrolimus formulations," U.S. Patent Publication No. 20060159628 for "Nanoparticulate benzothiophene formulations," U.S. Patent Publication No. 20060154918 for "Injectable nanoparticulate olanzapine formulations," U.S. Patent Publication No. 20060121112 for "Topiramate pharmaceutical composition," U.S. Patent Publication No. 20020012675 Al, for "Controlled Release Nanoparticulate Compositions," U.S. Patent Publication No. 20040195413 Al, for "Compositions and method for milling materials," U.S. Patent Publication No. 20040173696 Al for "Milling microgram quantities of nanoparticulate candidate compounds," U.S. Patent Application No. 20020012675 Al, published on January 31, 2002, for "Controlled Release Nanoparticulate Compositions;" U.S. Patent Publication No. 20050276974 for "Nanoparticulate Fibrate Formulations;" U.S. Patent Publication No. 20050238725 for "Nanoparticulate compositions having a peptide as a surface stabilizer;" U.S. Patent Publication No. 20050233001 for "Nanoparticulate megestrol formulations;" U.S. Patent Publication No. 20050147664 for "Compositions comprising antibodies and methods of using the same for targeting nanoparticulate active agent delivery;" U.S. Patent Publication No. 20050063913 for "Novel metaxalone compositions;" U.S. Patent Publication No. 20050042177 for "Novel compositions of sildenafil free base;" U.S. Patent Publication No. 20050031691 for "Gel stabilized nanoparticulate active agent compositions;" U.S. Patent Publication No. 20050019412 for " Novel glipizide compositions;" U.S. Patent Publication No. 20050004049 for "Novel griseofulvin compositions;" U.S. Patent Publication No. 20040258758 for "Nanoparticulate topiramate formulations;" U.S. Patent Publication No. 20040258757 for " Liquid dosage compositions of stable nanoparticulate active agents;" U.S. Patent Publication No. 20040229038 for "Nanoparticulate meloxicam formulations;" U.S. Patent Publication No. 20040208833 for "Novel fluticasone formulations;" U.S. Patent Publication No. 20040195413 for " Compositions and method for milling materials;" U.S. Patent Publication No. 20040156895 for "Solid dosage forms comprising pullulan;" U.S. Patent Publication No. U.S. Patent Publication No. U.S. Patent Publication No. 20040156872 for "Novel nimesulide compositions;" U.S. Patent Publication No. 20040141925 for "Novel triamcinolone compositions;" U.S. Patent Publication No. 20040115134 for "Novel nifedipine compositions;" U.S. Patent Publication No. 20040105889 for "Low viscosity liquid dosage forms;" U.S. Patent Publication No. 20040105778 for "Gamma irradiation of solid nanoparticulate active agents;" U.S. Patent Publication No. 20040101566 for "Novel benzoyl peroxide compositions;" U.S. Patent Publication No. 20040057905 for "Nanoparticulate
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. 20030215502 for "Fast dissolving dosage forms having reduced friability;" U.S. Patent Publication No. 20030185869 for "Nanoparticulate compositions having lysozyme as a surface stabilizer;" U.S. Patent Publication No. 20030181411 for "Nanoparticulate compositions of mitogen-activated protein (MAP) kinase inhibitors;" U.S. Patent Publication No. 20030137067 for "Compositions having a combination of immediate release and controlled release characteristics;" U.S. Patent Publication No. 20030108616 for "Nanoparticulate compositions comprising copolymers of vinyl pyrrolidone and vinyl acetate as surface stabilizers;" U.S. Patent Publication No. 20030095928 for "Nanoparticulate insulin;" U.S. Patent Publication No. 20030087308 for "Method for high through put screening using a small scale mill or microfiuidics;" U.S. Patent Publication No. 20030023203 for "Drug delivery systems & methods;" U.S. Patent Publication No. 20020179758 for "System and method for milling materials; and U.S. Patent Publication No. 20010053664 for "Apparatus for sanitary wet milling," describe nanoparticulate active agent compositions and are specifically incorporated by reference.
[0021] Amorphous small particle compositions are described, for example, in U.S. Patent Nos. 4,783,484 for "Particulate Composition and Use Thereof as Antimicrobial Agent;" 4,826,689 for "Method for Making Uniformly Sized Particles from Water-Insoluble Organic Compounds;" 4,997,454 for "Method for Making Uniformly-Sized Particles From Insoluble Compounds;" 5,741,522 for "Ultrasmall, Non-aggregated Porous Particles of Uniform Size for Entrapping Gas Bubbles Within and Methods;" and 5,776,496, for "Ultrasmall Porous Particles for Enhancing Ultrasound Back Scatter." These are also specifically incorporated herein by reference.
[0022] While the high therapeutic value of the kinase inhibitors such as LS 104 are recognized in the art, poorly water soluble inhibitors are limited in their bioavailability upon oral administration or injection and can be difficult or impossible to formulate as safe and effective products for other types of administration. Thus, there is a need in the art for formulations comprising kinase inhibitors which have improved bioavailability, and thus
10
WASH 1899464 1 improved efficacy and/or are suitable for administration such as parenteral administration. The present invention fills that need.
[0023] The present invention then, relates to nanoparticulate compositions comprising a kinase inhibitors such as LS 104, which may be useful in the treatment and prevention of diseases and disorders, such as CML, AML, ALL, myeloproliferative diseases, and other blood-related cancers and diseases.
SUMMARY OF THE INVENTION
[0024] The present invention relates to stable nanoparticulate compositions comprising a kinase inhibitor, such as LS 104, or a salt or derivative thereof, and at least one surface stabilizer. In some embodiments, the surface stabilizer may be associated with the surface of the particles, for example, the surface stabilizer may be adsorbed onto the surface of the LS 104 particle. In general, the drug nanoparticles have an effective average particle size of less than about 2000 nm.
[0025] The compositions may include LS 104 particles which are in a crystalline phase, an amorphous phase, a semi-crystalline phase, a semi-amorphous phase and mixtures thereof. [0026] The compositions may include one or more surface stabilizers. For example, some compositions may include at least one primary and at least one secondary surface stabilizer. Exemplary surface stabilizers include, but are not limited to non-ionic surface stabilizers, ionic surface stabilizers, anionic surface stabilizers, cationic surface stabilizers, zwitterionic surface stabilizers and combinations thereof.
[0027] The invention also relates to compositions comprising nanoparticulate kinase inhibitors such as LS 104 or a salt or derivative thereof, at least one surface stabilizer, and optionally one or more pharmaceutically acceptable excipients, carriers, and optionally one or more active agents useful for the treatment of cancers such as leukemias, myeloproliferative diseases and related disorders, or a combination thereof.
[0028] The compositions of the invention comprising a nanoparticulate kinase inhibitor, such as LS 104 or a salt or derivative thereof, are proposed to exhibit improved pharmacokinetic profiles as compared to conventional kinase inhibitor (e.g., LS104) compositions. For example, the Cmax and/or AUC of the nanoparticulate compositions may be greater than the Cmax and/or AUC for conventional compositions administered at the same dosage while the Tmax may be lower; any combination of an improved Cmax, AUC and Tmax profile may be exhibited by the nanoparticulate LSO 14 compositions as compared to
11
WASH 1899464 1 conventional LS 104 compositions. In further embodiments, the LS 104 compositions may not produce significantly different absorption levels when administered under fed as compared to fasting conditions.
[0029] In some embodiments, the nanoparticulate LS 104 compositions exhibit improved bioavailability as compared to conventional LS 104 compositions. For example, upon administration to a mammal, the nanoparticulate LS 104 compositions may redisperse such that the particles have an effective average particle size of less than about 2 microns. [0030] The invention also relates to methods of making nanoparticulate compositions including an kinase inhibitor, such as LS 104 or salt or derivative thereof. In some embodiments, 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. [0031] The invention also relates to methods of treatment using the nanoparticulate LS 104 compositions. In some methods, a composition comprising a nanoparticulate LS 104 or salt or derivative thereof, having an effective average particle size of less than about 2000 nm, and at least one surface stabilizer, may be administered to a subject. In some methods, the composition may be formulated for parental injection (e.g., intravenous, intramuscular, or subcutaneous), in a therapeutically effective amount. In some embodiments, the injectable formulation may provide a high LS 140 concentration in a small volume to be injected. In other embodiments, 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. By way of example, but not by way of limitation, the composition may be administered to treat myeloproliferative disorders, diseases, symptoms or conditions associated with myeloproliferative disorders, and cancers such as leukemias like CML, AML and ALL. In some methods, the subject may be suffering from such a disease, disorder, symptom or condition. Other methods of treatment using the nanoparticulate compositions of the invention are known to those of skill in the art.
[0032] Both the foregoing summary of the invention and the following detailed description of the invention are exemplary and explanatory and are intended to provide further details of the invention as claimed. Other objects, advantages, and novel features will be readily apparent to those skilled in the art from the following detailed description of the invention.
12
WASH 1899464 1 DETAILED DESCRIPTION OF THE INVENTION
[0033] 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. Generally, the LS 104 particles, or a salt or derivative thereof, have an effective average particle size of less than about 2000 nm.
[0034] Advantages of the compositions comprising at least one nanoparticulate kinase inhibitor, such as LS 104, as compared to conventional non-nanoparticulate (microcrystalline or solubilized) formulations of the same kinase inhibitor (e.g., LS 104) include, but are not limited to: (1) smaller tablet or other solid dosage form size; (2) smaller doses of drug required to obtain the same pharmacological effect; (3) increased bioavailability; (4) improved pharmacokinetic profiles; (5) substantially similar pharmacokinetic profiles when administered in the fed versus the fasted state; (6) bioequivalency when administered in the fed versus the fasted state; (7) increased rate of absorption of nanoparticulate compositions; (8) an increased rate of dissolution; and (9) the kinase inhibitor compositions can be used in conjunction with other active agents useful in the treatment of myeloproliferative disorders, cancers such as leukemias and related disorders, diseases, symptoms, or conditions.
[0035] The present invention also includes compositions comprising at least one nanoparticulate kinase inhibitors, such as LS 104 or a salt or derivative thereof, together with one or more non-toxic physiologically acceptable carriers, adjuvants, or vehicles, collectively referred to as carriers. The compositions can be formulated for parental injection (e.g., intravenous, intramuscular, or subcutaneous), oral administration in solid, liquid, or aerosol form, bioadhesive, vaginal, nasal, rectal, ocular, local (powders, ointments, or drops), buccal, intracisternal, intraperitoneal, or topical administrations, and the like. [0036] In some embodiments, a preferred dosage form of the invention is an injectable dosage form, although any pharmaceutically acceptable dosage form can be utilized. In some embodiments, the injectable formulation may provide a high LS 140 concentration in a small volume to be injected. In other embodiments, 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.
[0037] 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,
13
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. [0038] The present invention is described herein using several definitions, as set forth below and throughout the application.
[0039] 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.
[0040] As used herein, "about" will be understood by persons of ordinary skill in the art and will vary to some extent on the context in which it is used. If there are uses of the term which are not clear to persons of ordinary skill in the art given the context in which it is used, "about" will mean up to plus or minus 10% of the particular term. [0041] As used herein with reference to stable particles of a nanoparticulate kinase inhibitor, such as LS 104, "stable" connotes, but is not limited to one or more of the following parameters: (1) the particles do not appreciably flocculate or agglomerate due to interparticle attractive forces or otherwise significantly increase in particle size over time; (2) the physical structure of the particles is not altered over time, such as by conversion from an amorphous phase to a crystalline phase; (3) the particles are chemically stable; and/or (4) where the kinase inhibitor has not been subject to a heating step at or above the melting point of the kinase inhibitor particles in the preparation of the nanoparticles of the present invention. [0042] The term "conventional" or "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.
[0043] The phrase "poorly water soluble drugs" as used herein refers to those drugs that have a solubility in water of less than about 30 mg/ml, less than about 20 mg/ml, less than about 10 mg/ml, or less than about 1 mg/ml.
[0044] As used herein, 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
14
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.
[0045] The term "myeloproliferative disease" or "myeloproliferative disorder" is meant to include non-lymphoid dysplastic or neoplastic conditions arising from a haematopoietic stem cell or its progeny. "MPD patient" includes a patient who has been diagnosed with an MPD. "Myeloproliferative disease" is meant to encompass the specific, classified types of myeloproliferative diseases including polycythemia vera (PV), essential thrombocythemia (ET) and idiopathic myelofibrosis (IMF). Also included in the definition are hypereosinophilic syndrome (HES), chronic neutrophilic leukemia (CNL), myelofibrosis with myeloid metaplasia (MMM), chronic myelomonocytic leukemia (CMML), juvenile myelomonocytic leukemia, chronic basophilic leukemia, chronic eosinophilic leukemia, and systemic mastocytosis (SM). "Myeloproliferative disease" is also meant to encompass any unclassified myeloproliferative diseases (UMPD or MPD-NC).
A. Characteristics of the Nanoparticulate Kinase Inhibitor Compositions of the Invention
1. Increased Bioavailability
[0046] The 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.
[0047] The increased bioavailability is significant because it means that the nanoparticulate kinase inhibitor dosage form will likely exhibit significantly greater drug absorption.
2. Improved Pharmacokinetic Profiles
[0048] The invention also contemplates 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 Cmax for a kinase inhibitor, such as LS 104, when assayed in the plasma of a mammalian subject following administration, that is preferably greater than
15
WASH 1899464 1 the Cmax for a non-nanoparticulate formulation of the same kinase inhibitor, administered at the same dosage; and/or (2) an AUC for an kinase inhibitor, such as LS 104, when assayed in the plasma of a mammalian subject following administration, that is preferably greater than the AUC for a non-nanoparticulate formulation of the same kinase inhibitor, administered at the same dosage; and/or (3) a Tmax for a kinase inhibitor, such as LS 104, when assayed in the plasma of a mammalian subject following administration, that is preferably less than the Tmax for a non-nanoparticulate formulation of the same kinase inhibitor, administered at the same dosage. The desirable pharmacokinetic profile, as used herein, is the pharmacokinetic profile measured after the initial dose of a kinase inhibitor, such as LS 104. [0049] In one embodiment, 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 Tmax 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 Tmax exhibited by the non-nanoparticulate kinase inhibitor formulation.
[0050] In another embodiment, the 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 Cmax 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 Cmax exhibited by the non-nanoparticulate kinase inhibitor formulation. [0051] In yet another embodiment, the 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, an AUC which is at least about 25%, at least about 50%, at least about 75%, at least about 100%, at least about 125%, at least about 150%, at least about 175%, at least about 200%, at least about 225%, at least about 250%, at least about 275%, at least about 300%, at least about 350%, at least about 400%, at least about 450%, at least about 500%, at least about
550%, at least about 600%, at least about 750%, at least about 700%, at least about 750%, at
16
WASH 1899464 1 least about 800%, at least about 850%, at least about 900%, at least about 950%, at least about 1000%, at least about 1050%, at least about 1100%, at least about 1150%, or at least about 1200% greater than the AUC exhibited by the non-nanop articulate kinase inhibitor formulation.
[0052] In one embodiment of the invention, the Tmax of the kinase inhibitor, such as LS 104, when assayed in the plasma of the mammalian subject, is less than about 6 to about 8 hours. In other embodiments of the invention, the Tmax of the LS 104 is less than about 6 hours, less than about 5 hours, less than about 4 hours, less than about 3 hours, less than about 2 hours, less than about 1 hour, or less than about 30 minutes after administration. [0053] The desirable pharmacokinetic profile, as used herein, is the pharmacokinetic profile measured after the initial dose of an kinase inhibitor, such as LS 104. The compositions can be formulated in any way as described herein and as known to those of skill in the art.
3. The Pharmacokinetic Profiles of the Kinase Inhibitor Compositions of the Invention are not Affected by the Fed or Fasted State of the Subject Ingesting the Compositions
[0054] 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 (Cmax), or the length of time to Cmax (Tmax), when the nanoparticulate kinase inhibitor compositions are administered in the fed versus the fasted state. [0055] The difference in absorption (AUC) or Cmax of the nanoparticulate kinase inhibitor compositions of the invention (such as LS 104 compositions), 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%.
17
WASH 1899464 1 4. Bioequivalency of Kinase Inhibitor Compositions of the Invention When Administered in the Fed Versus the Fasted State
[0056] The invention also encompasses a composition comprising a nanoparticulate kinase inhibitor, such as LS 104, in which administration of the composition to a subject in a fasted state is bioequivalent to administration of the composition to a subject in a fed state. [0057] In one embodiment of the invention, the invention encompasses compositions comprising a nanoparticulate kinase inhibitors, such as LS 104, wherein administration of the composition to a subject in a fasted state is bioequivalent to administration of the composition to a subject in a fed state, in particular as defined by Cmax and AUC guidelines given by the U.S. Food and Drug Administration and the corresponding European regulatory agency (EMEA). Under U.S. FDA guidelines, two products or methods are bioequivalent if the 90% Confidence Intervals (CI) for AUC and Cmax are between 0.80 to 1.25 (Tmax measurements are not relevant to bioequivalence for regulatory purposes). To show bioequivalency between two compounds or administration conditions pursuant to Europe's EMEA guidelines, the 90% CI for AUC must be between 0.80 to 1.25 and the 90% CI for Cmax must between 0.70 to 1.43.
5. Dissolution Profiles of the Kinase Inhibitor Compositions of the Invention
[0058] The 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%.
[0059] The kinase inhibitors, such as LS 104, compositions of the invention preferably have a dissolution profile in which within about 5 minutes at least about 20% of the composition is dissolved. In other embodiments of the invention, at least about 30% or at least about 40% of the kinase inhibitor composition is dissolved within about 5 minutes. In yet other embodiments of the invention, preferably at least about 40%, at least about 50%, at least about 60%, at least about 70%, or at least about 80% of the kinase inhibitor composition is dissolved within about 10 minutes. Finally, in another embodiment of the invention, preferably at least about 70%, at least about 80%, at least about 90%, or at least about 100% of the kinase inhibitor composition is dissolved within 20 minutes.
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WASH 1899464 1 [0060] Dissolution is preferably measured in a medium which is discriminating. A discriminating dissolution medium is one that will produce two very different dissolution curves for two products having very different dissolution profiles in gastric juices; i.e., the dissolution medium is predictive of the in vivo dissolution of a composition. An exemplary dissolution medium is an aqueous medium containing the surfactant sodium lauryl sulfate at 0.025 M. Determination of the amount dissolved can be carried out by spectrophotometry. The rotating blade method (European Pharmacopoeia) can be used to measure dissolution.
6. Redispersibility of the Kinase Inhibitor Compositions of the Invention
[0061] An additional feature of the compositions comprising at least one nanoparticulate kinase inhibitor, such as LS 104 or a salt or derivative thereof, is that the compositions redisperse such that the effective average particle size of the redispersed kinase inhibitor particles is less than about 2 microns. This is significant, as upon administration, if the kinase inhibitor particles of the compositions of the present invention agglomerated or did not redisperse to a substantially nanoparticulate size, then the dosage form may lose the benefits afforded by formulating the kinase inhibitors into a nanoparticulate size. [0062] This is because nanoparticulate active agent compositions benefit from the small particle size of the active agent. If the active agent does not disperse into the small particle sizes upon administration, then "clumps" or agglomerated active agent particles are formed, owing to the extremely high surface free energy of the nanoparticulate system and the thermodynamic driving force to achieve an overall reduction in free energy. With the formulation of such agglomerated particles, the bioavailability of the dosage form may fall well below that observed with the liquid dispersion form of the nanoparticulate active agent. [0063] Moreover, the compositions comprising at least one nanoparticulate kinase inhibitor, such as LS 104, of the invention exhibit dramatic redispersion of the nanoparticulate kinase inhibitor particles upon administration to a mammal, such as a human or animal, as demonstrated by reconstitution/ redispersion in a biorelevant aqueous media such that the effective average particle size of the redispersed kinase inhibitor particles is less than about 2 microns. Such biorelevant aqueous media can be any aqueous media that exhibit the desired ionic strength and pH, which form the basis for the biorelevance of the media. The desired pH and ionic strength are those that are representative of physiological conditions found in the human body. Such biorelevant aqueous media can be, for example, aqueous electrolyte solutions or aqueous solutions of any salt, acid, or base, or a combination thereof, which exhibit the desired pH and ionic strength.
19
WASH 1899464 1 [0064] Biorelevant pH is well known in the art. For example, in the stomach, the pH ranges from slightly less than 2 (but typically greater than 1) up to 4 or 5. In the small intestine the pH can range from 4 to 6, and in the colon it can range from 6 to 8. Biorelevant ionic strength is also well known in the art. Fasted state gastric fluid has an ionic strength of about 0. IM while fasted state intestinal fluid has an ionic strength of about 0.14. See e.g. , Lindahl et al., "Characterization of Fluids from the Stomach and Proximal Jejunum in Men and Women," Pharm. Res., 14 (4): 497-502 (1997).
[0065] It is believed that the pH and ionic strength of the test solution is more critical than the specific chemical content. Accordingly, appropriate pH and ionic strength values can be obtained through numerous combinations of strong acids, strong bases, salts, single or multiple conjugate acid-base pairs {i.e., weak acids and corresponding salts of that acid), monoprotic and polyprotic electrolytes, etc.
[0066] Representative electrolyte solutions can be, but are not limited to, HCl solutions, ranging in concentration from about 0.001 to about 0.1 M, and NaCl solutions, ranging in concentration from about 0.001 to about 0.1 M, and mixtures thereof. For example, electrolyte solutions can be, but are not limited to, about 0.1 M HCl or less, about 0.01 M HCl or less, about 0.001 M HCl or less, about 0.1 M NaCl or less, about 0.01 M NaCl or less, about 0.001 M NaCl or less, and mixtures thereof. Of these electrolyte solutions, 0.01 M HCl and/or 0.1 M NaCl, are most representative of fasted human physiological conditions, owing to the pH and ionic strength conditions of the proximal gastrointestinal tract. [0067] Electrolyte concentrations of 0.001 M HCl, 0.01 M HCl, and 0.1 M HCl correspond to pH 3, pH 2, and pH 1, respectively. Thus, a 0.01 M HCl solution simulates typical acidic conditions found in the stomach. A solution of 0.1 M NaCl provides a reasonable approximation of the ionic strength conditions found throughout the body, including the gastrointestinal fluids, although concentrations higher than 0.1 M may be employed to simulate fed conditions within the human GI tract.
[0068] Exemplary solutions of salts, acids, bases or combinations thereof, which exhibit the desired pH and ionic strength, include but are not limited to phosphoric acid/phosphate salts + sodium, potassium and calcium salts of chloride, acetic acid/acetate salts + sodium, potassium and calcium salts of chloride, carbonic acid/bicarbonate salts + sodium, potassium and calcium salts of chloride, and citric acid/citrate salts + sodium, potassium and calcium salts of chloride. [0069] In other embodiments of the invention, the redispersed particles of a kinase inhibitor, such as LS 104 or a salt or derivative thereof (redispersed in water, a biorelevant
20
WASH 1899464 1 media, or any suitable redispersion media), have an effective average particle size of less than about 1900 nm, less than about 1800 nm, less than about 1700 nm, less than about 1600 nm, less than about 1500 nm, less than about 1400 nm, less than about 1300 nm, less than about 1200 nm, less than about 1100 nm, less than about 1000 nm, less than about 990 nm, less than about 980 nm, less than about 970 nm, less than about 960 nm, less than about 950 nm, less than about 940 nm, less than about 930 nm, less than about 920 nm, less than about 910 nm, less than about 900 nm, less than about 890 nm, less than about 880 nm, less than about 870 nm, less than about 860 nm, less than about 850 nm, less than about 840 nm, less than about 830 nm, less than about 820 nm, less than about 810 nm, less than about 800 nm, less than about 790 nm, less than about 780 nm, less than about 770 nm, less than about 760 nm, less than about 750 nm, less than about 740 nm, less than about 730 nm, less than about 720 nm, less than about 710 nm, less than about 700 nm, less than about 690 nm, less than about 680 nm, less than about 670 nm, less than about 660 nm, less than about 650 nm, less than about 640 nm, less than about 630 nm, less than about 620 nm, less than about 610 nm, less than about 600 nm, less than about 590 nm, less than about 580 nm, less than about 570 nm, less than about 560 nm, less than about 550 nm, less than about 540 nm, less than about 530 nm, less than about 520 nm, less than about 510 nm, less than about 500 nm, less than about 490 nm, less than about 480 nm, less than about 470 nm, less than about 460 nm, less than about 450 nm, less than about 440 nm, less than about 430 nm, less than about 420 nm, less than about 410 nm, less than about 400 nm, less than about 390 nm, less than about 380 nm, less than about 370 nm, less than about 360 nm, less than about 350 nm, less than about 340 nm, less than about 330 nm, less than about 320 nm, less than about 310 nm, less than about 300 nm, less than about 290 nm, less than about 280 nm, less than about 270 nm, less than about 260 nm, less than about 250 nm, less than about 240 nm, less than about 230 nm, less than about 220 nm, less than about 210 nm, less than about 200 nm, less than about 190 nm, less than about 180 nm, less than about 170 nm, less than about 160 nm, less than about 150 nm, less than about 140 nm, less than about 130 nm, less than about 120 nm, less than about 110 nm, less than about 100, less than about 75 nm, or less than about 50 nm, as measured by light-scattering methods, microscopy, or other appropriate methods. Such methods suitable for measuring effective average particle size are known to a person of ordinary skill in the art. [0070] Redispersibility can be tested using any suitable means known in the art. See e.g., the example sections of U.S. Patent No. 6,375,986 for "Solid Dose Nanop articulate Compositions Comprising a Synergistic Combination of a Polymeric Surface Stabilizer and
Dioctyl Sodium Sulfosuccinate."
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WASH 1899464 1 7. Nanoparticulate Kinase Inhibitor Compositions Used in Conjunction with Other Active Agents
[0071] The compositions comprising at least one nanoparticulate kinase inhibitor, such as LS 104 or a salt or derivative thereof, can additionally comprise one or more compounds useful in the treatment of cancers such as leukemias or other related diseases, disorders, conditions or symptoms, or the kinase inhibitor compositions can be administered in conjunction with such a compound. Nanoparticulate kinase inhibitor compositions, such as LS 104 may provide broad opportunities for use in combination with other kinase inhibitors, such as Gleevec®, as well as current standard chemotheraphy treatments, bone marrow transplants, etc.
B. Nanoparticulate Kinase Inhibitor Compositions
[0072] 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. [0073] The present invention also includes kinase inhibitors such as LS 104, (or a salt or derivative thereof), compositions together with one or more non-toxic physiologically acceptable carriers, adjuvants, or vehicles, collectively referred to as carriers. The compositions can be formulated for parenteral injection (e.g., intravenous, intramuscular, or subcutaneous), oral administration in solid, liquid, or aerosol form, vaginal, nasal, rectal, ocular, local (powders, ointments or drops), buccal, intracisternal, intraperitoneal, or topical administration, and the like.
1. Kinase Inhibitor Particles
[0074] The 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.
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WASH 1899464 1 2. Surface Stabilizers
[0075] The choice of a surface stabilizer for a kinase inhibitor such as LS 104 is non-trivial. Accordingly, the present invention is directed to the surprising discovery that nanoparticulate kinase inhibitor compositions can be made.
[0076] Combinations of more than one surface stabilizers can be used in the invention. Useful surface stabilizers which can be employed in the invention include, but are not limited to, known organic and inorganic pharmaceutical excipients. Such excipients include various polymers, low molecular weight oligomers, natural products, and surfactants. Exemplary surface stabilizers include nonionic and ionic (e.g. , anionic, cationic, and zwitterionic) surfactants or compounds.
[0077] Representative examples of surface stabilizers include albumin, including but not limited to human serum albumin and bovine albumin, hydroxypropyl methylcellulose (now known as hypromellose), hydroxypropylcellulose, polyvinylpyrrolidone, sodium lauryl sulfate, dioctylsulfosuccinate, gelatin, casein, lecithin (phosphatides), dextran, gum acacia, cholesterol, tragacanth, stearic acid, benzalkonium chloride, calcium stearate, glycerol monostearate, cetostearyl alcohol, cetomacrogol emulsifying wax, sorbitan esters, polyoxyethylene alkyl ethers (e.g., macrogol ethers such as cetomacrogol 1000), polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters (e.g., the commercially available Tween® products such as e.g., Tween 20® and Tween 80® (ICI Speciality Chemicals)); polyethylene glycols (e.g., Carbowaxs 3550® and 934® (Union Carbide)), polyoxyethylene stearates, colloidal silicon dioxide, phosphates, carboxymethylcellulose calcium, carboxymethylcellulose sodium, methylcellulose, hydroxyethylcellulose, hypromellose phthalate, noncrystalline cellulose, magnesium aluminium silicate, triethanolamine, polyvinyl alcohol (PVA), 4-(l,l,3,3-tetramethylbutyl)- phenol polymer with ethylene oxide and formaldehyde (also known as tyloxapol, superione, and triton), poloxamers (e.g., Pluronics F68® and F 108®, which are block copolymers of ethylene oxide and propylene oxide); poloxamines (e.g., Tetronic 908®, also known as Poloxamine 908®, which is a tetrafunctional block copolymer derived from sequential addition of propylene oxide and ethylene oxide to ethylenediamine (BASF Wyandotte Corporation, Parsippany, N.J.)); Tetronic 1508® (T- 1508) (BASF Wyandotte Corporation), Tritons X-200®, which is an alkyl aryl polyether sulfonate (Rohm and Haas); Crodestas F- 110®, which is a mixture of sucrose stearate and sucrose distearate (Croda Inc.); p- isononylphenoxypoly-(glycidol), also known as Olin-IOG® or Surfactant 10-G® (Olin
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WASH 1899464 1 Chemicals, Stamford, CT); Crodestas SL-40® (Croda, Inc.); and SA9OHCO, which is Ci8H37CH2(CON(CH3)-CH2(CHOH)4(CH2OH)2 (Eastman Kodak Co.); decanoyl-N- methylglucamide; n-decyl β-D-glucopyranoside; n-decyl β-D-maltopyranoside; n-dodecyl β- D-glucopyranoside; n-dodecyl β-D-maltoside; heptanoyl-N-methylglucamide; n-heptyl-β-D- glucopyranoside; n-heptyl β-D-thioglucoside; n-hexyl β-D-glucopyranoside; nonanoyl-N- methylglucamide; n-noyl β-D-glucopyranoside; octanoyl-N-methylglucamide; n-octyl-β-D- glucopyranoside; octyl β-D-thioglucopyranoside; PEG-phospholipid, PEG-cholesterol, PEG- cholesterol derivative, PEG-vitamin A, PEG-vitamin E, lysozyme, random copolymers of vinyl pyrrolidone and vinyl acetate, and the like.
[0078] If desirable, the nanoparticulate kinase inhibitors, such as LS 104, compositions of the invention can be formulated to be phospholipid-free.
[0079] Examples of useful cationic surface stabilizers include, but are not limited to, polymers, biopolymers, polysaccharides, cellulosics, alginates, phospholipids, and nonpolymeric compounds, such as zwitterionic stabilizers, poly-n-methylpyridinium, anthryul pyridinium chloride, cationic phospholipids, chitosan, polylysine, polyvinylimidazole, polybrene, polymethylmethacrylate trimethylammoniumbromide bromide (PMMTMABr), hexyldesyltrimethylammonium bromide (HDMAB), and polyvinylpyrrolidone-2-dimethylaminoethyl methacrylate dimethyl sulfate. [0080] Other useful cationic stabilizers include, but are not limited to, cationic lipids, sulfonium, phosphonium, and quarternary ammonium compounds, such as stearyltrimethylammonium chloride, benzyl-di(2-chloroethyl)ethylammonium bromide, coconut trimethyl ammonium chloride or bromide, coconut methyl dihydroxyethyl ammonium chloride or bromide, decyl triethyl ammonium chloride, decyl dimethyl hydroxyethyl ammonium chloride or bromide,
Figure imgf000025_0001
hydroxyethyl ammonium chloride or bromide, coconut dimethyl hydroxyethyl ammonium chloride or bromide, myristyl trimethyl ammonium methyl sulphate, lauryl dimethyl benzyl ammonium chloride or bromide, lauryl dimethyl (ethenoxy)4 ammonium chloride or bromide, N-alkyl (C12- 18)dimethylbenzyl ammonium chloride, N-alkyl (C14_1g)dimethyl-benzyl ammonium chloride, N-tetradecylidmethylbenzyl ammonium chloride monohydrate, dimethyl didecyl ammonium chloride, N-alkyl and (C12-I4) dimethyl 1-napthylmethyl ammonium chloride, trimethylammonium halide, alkyl-trimethylammonium salts and dialkyl-dimethylammonium salts, lauryl trimethyl ammonium chloride, ethoxylated alkyamidoalkyldialkylammonium salt and/or an ethoxylated trialkyl ammonium salt, dialkylbenzene dialkylammonium chloride, N-
24
WASH 1899464 1 didecyldimethyl ammonium chloride, N-tetradecyldimethylbenzyl ammonium, chloride monohydrate, N-alkyl(Ci2-i4) dimethyl 1-naphthylmethyl ammonium chloride and dodecyldimethylbenzyl ammonium chloride, dialkyl benzenealkyl ammonium chloride, lauryl trimethyl ammonium chloride, alkylbenzyl methyl ammonium chloride, alkyl benzyl dimethyl ammonium bromide, C12, C1S, C17 trimethyl ammonium bromides, dodecylbenzyl triethyl ammonium chloride, poly-diallyldimethylammonium chloride (DADMAC), dimethyl ammonium chlorides, alkyldimethylammonium halogenides, tricetyl methyl ammonium chloride, decyltrimethylammonium bromide, dodecyltriethylammonium bromide, tetradecyltrimethylammonium bromide, methyl trioctylammonium chloride (ALIQUAT 336™), POLYQUAT 10™, tetrabutylammonium bromide, benzyl trimethylammonium bromide, choline esters (such as choline esters of fatty acids), benzalkonium chloride, stearalkonium chloride compounds (such as stearyltrimonium chloride and Di- stearyldimonium chloride), cetyl pyridinium bromide or chloride, halide salts of quaternized polyoxyethylalkylamines, MIRAPOL™ and ALKAQUAT™ (Alkaril Chemical Company), alkyl pyridinium salts; amines, such as alkylamines, dialkylamines, alkanolamines, polyethylenepolyamines, N,N-dialkylaminoalkyl acrylates, and vinyl pyridine, amine salts, such as lauryl amine acetate, stearyl amine acetate, alkylpyridinium salt, and alkylimidazolium salt, and amine oxides; imide azolinium salts; protonated quaternary acrylamides; methylated quaternary polymers, such as poly[diallyl dimethylammonium chloride] and poly-[N-methyl vinyl pyridinium chloride]; and cationic guar. [0081] Such exemplary cationic surface stabilizers and other useful cationic surface stabilizers are described in J. Cross and E. Singer, Cationic Surfactants: Analytical and Biological Evaluation (Marcel Dekker, 1994); P. and D. Rubingh (Editor), Cationic Surfactants: Physical Chemistry (Marcel Dekker, 1991); and J. Richmond, Cationic Surfactants: Organic Chemistry, (Marcel Dekker, 1990).
[0082] Nonpolymeric surface stabilizers are any nonpolymeric compound, such benzalkonium chloride, a carbonium compound, a phosphonium compound, an oxonium compound, a halonium compound, a cationic organometallic compound, a quarternary phosphorous compound, a pyridinium compound, an anilinium compound, an ammonium compound, a hydroxylammonium compound, a primary ammonium compound, a secondary ammonium compound, a tertiary ammonium compound, and quarternary ammonium compounds of the formula NR1R2R3R4^. For compounds of the formula NR1R2R3R4^: [0083] (i) none Of R1-R4 are CH3;
[0084] (ii) one Of R1-R4 is CH3;
25
WASH 1899464 1 [0085] (iii) three OfR1-R4 are CH3;
[0086] (iv) all OfR1-R4 are CH3;
[0087] (v) two Of R1-R4 are CH3, OnC OfR1-R4 Is C6H5CH2, and one of R1-R4 is an alkyl chain of seven carbon atoms or less;
[0088] (vi) two OfR1-R4 are CH3, one OfR1-R4 is C6H5CH2, and one Of R1-R4 is an alkyl chain of nineteen carbon atoms or more;
[0089] (vii) two of R1-R4 are CH3 and one of R1-R4 is the group C6H5(CH2)n, where n>l;
[0090] (viii) two OfR1-R4 are CH3, one of R1-R4 is C6H5CH2, and one of R1 -R4 comprises at least one heteroatom;
[0091] (ix) two Of R1-R4 are CH3, one of R1-R4 is C6H5CH2, and one of R1 -R4 comprises at least one halogen;
[0092] (x) two Of R1-R4 are CH3, one of R1-R4 is C6H5CH2, and one of R1 -R4 comprises at least one cyclic fragment;
[0093] (xi) two of R1-R4 are CH3 and one of R1-R4 is a phenyl ring; or
[0094] (xii) two OfR1-R4 are CH3 and two OfR1-R4 are purely aliphatic fragments.
[0095] Such compounds include, but are not limited to, behenalkonium chloride, benzethonium chloride, cetylpyridinium chloride, behentrimonium chloride, lauralkonium chloride, cetalkonium chloride, cetrimonium bromide, cetrimonium chloride, cethylamine hydro fluoride, chlorallylmethenamine chloride (Quaternium-15), distearyldimonium chloride
(Quaternium-5), dodecyl dimethyl ethylbenzyl ammonium chloride(Quaternium-14),
Quaternium-22, Quaternium-26, Quaternium-18 hectorite, dimethylaminoethylchloride hydrochloride, cysteine hydrochloride, diethanolammonium POE (10) oletyl ether phosphate, diethanolammonium POE (3)oleyl ether phosphate, tallow alkonium chloride, dimethyl dioctadecylammoniumbentonite, stearalkonium chloride, domiphen bromide, denatonium benzoate, myristalkonium chloride, laurtrimonium chloride, ethylenediamine dihydrochloride, guanidine hydrochloride, pyridoxine HCl, iofetamine hydrochloride, meglumine hydrochloride, methylbenzethonium chloride, myrtrimonium bromide, oleyltrimonium chloride, polyquaternium-1, procainehydrochloride, cocobetaine, stearalkonium bentonite, stearalkoniumhectonite, stearyl trihydroxyethyl propylenediamine dihydrofluoride, tallowtrimonium chloride, and hexadecyltrimethyl ammonium bromide.
[0096] In some embodiments, the surface stabilizers may be a copovidone (e.g., Plasdone
S630, which is a random copolymer of vinyl acetate and vinyl pyrrolidone) and/or docusate sodium.
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WASH 1899464 1 [0097] The surface stabilizers are commercially available and/or can be prepared by techniques known in the art. Most of these surface stabilizers are known pharmaceutical excipients and are described in detail in the Handbook of Pharmaceutical Excipients, published jointly by the American Pharmaceutical Association and The Pharmaceutical Society of Great Britain (The Pharmaceutical Press, 2000), specifically incorporated by reference.
3. Other Pharmaceutical Excipients
[0098] Pharmaceutical compositions according to the invention may also comprise one or more binding agents, filling agents, lubricating agents, suspending agents, sweeteners, flavoring agents, preservatives, buffers, wetting agents, disintegrants, effervescent agents, and other excipients. Such excipients are known in the art.
[0099] Examples of filling agents include lactose monohydrate, lactose anhydrous, and various starches; examples of 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 SMCC™). [0100] 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.
[0101] Examples of sweeteners may include any natural or artificial sweetener, such as sucrose, xylitol, sodium saccharin, cyclamate, aspartame, and acsulfame. Examples of flavoring agents are Magnasweet® (trademark of MAFCO), bubble gum flavor, and fruit flavors, and the like.
[0102] Examples of preservatives include potassium sorbate, methylparaben, propylparaben, benzoic acid and its salts, other esters of parahydroxybenzoic acid such as butylparaben, alcohols such as ethyl or benzyl alcohol, phenolic compounds such as phenol, or quarternary compounds such as benzalkonium chloride.
[0103] Suitable diluents include pharmaceutically acceptable inert fillers, such as microcrystalline cellulose, lactose, dibasic calcium phosphate, saccharides, and/or mixtures of any of the foregoing. Examples of diluents include microcrystalline cellulose, such as Avicel® PHlOl and Avicel® PH 102; lactose such as lactose monohydrate, lactose anhydrous, and Pharmatose® DCL21; dibasic calcium phosphate such as Emcompress®; mannitol; starch; sorbitol; sucrose; and glucose.
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WASH 1899464 1 [0104] Suitable disintegrants include lightly crosslinked polyvinyl pyrrolidone, corn starch, potato starch, maize starch, and modified starches, croscarmellose sodium, cross-povidone, sodium starch glycolate, and mixtures thereof.
[0105] Examples of effervescent agents include effervescent couples such as an organic acid and a carbonate or bicarbonate. Suitable organic acids include, for example, citric, tartaric, malic, fumaric, adipic, succinic, and alginic acids and anhydrides and acid salts. Suitable carbonates and bicarbonates include, for example, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, magnesium carbonate, sodium glycine carbonate, L-lysine carbonate, and arginine carbonate. Alternatively, only the sodium bicarbonate component of the effervescent couple may be present.
4. Nanoparticulate Kinase Inhibitor Particle Size
[0106] The compositions of the invention comprise particles of at least one nanoparticulate kinase inhibitor, such as LS 104 (or a salt or derivative thereof), which have an effective average particle size of less than about 2000 nm (i.e., 2 microns), less than about 1900 nm, less than about 1800 nm, less than about 1700 nm, less than about 1600 nm, less than about 1500 nm, less than about 1400 nm, less than about 1300 nm, less than about 1200 nm, less than about 1100 nm, less than about 1000 nm, less than about 990 nm, less than about 980 nm, less than about 970 nm, less than about 960 nm, less than about 950 nm, less than about 940 nm, less than about 930 nm, less than about 920 nm, less than about 910 nm, less than about 900 nm, less than about 890 nm, less than about 880 nm, less than about 870 nm, less than about 860 nm, less than about 850 nm, less than about 840 nm, less than about 830 nm, less than about 820 nm, less than about 810 nm, less than about 800 nm, less than about 790 nm, less than about 780 nm, less than about 770 nm, less than about 760 nm, less than about 750 nm, less than about 740 nm, less than about 730 nm, less than about 720 nm, less than about 710 nm, less than about 700 nm, less than about 690 nm, less than about 680 nm, less than about 670 nm, less than about 660 nm, less than about 650 nm, less than about 640 nm, less than about 630 nm, less than about 620 nm, less than about 610 nm, less than about 600 nm, less than about 590 nm, less than about 580 nm, less than about 570 nm, less than about 560 nm, less than about 550 nm, less than about 540 nm, less than about 530 nm, less than about 520 nm, less than about 510 nm, less than about 500 nm, less than about 490 nm, less than about 480 nm, less than about 470 nm, less than about 460 nm, less than about 450 nm, less than about 440 nm, less than about 430 nm, less than about 420 nm, less than about 410 nm, less than about 400 nm, less than about 390 nm, less than about 380 nm, less than about
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WASH 1899464 1 370 nm, less than about 360 nm, less than about 350 nm, less than about 340 nm, less than about 330 nm, less than about 320 nm, less than about 310 nm, less than about 300 nm, less than about 290 nm, less than about 280 nm, less than about 270 nm, less than about 260 nm, less than about 250 nm, less than about 240 nm, less than about 230 nm, less than about 220 nm, less than about 210 nm, less than about 200 nm, less than about 190 nm, less than about 180 nm, less than about 170 nm, less than about 160 nm, less than about 150 nm, less than about 140 nm, less than about 130 nm, less than about 120 nm, less than about 110 nm, less than about 100, less than about 75 nm, or less than about 50 nm, as measured by light- scattering methods, microscopy, or other appropriate methods.
[0107] By "an effective average particle size of less than about 2000 nm" it is meant that at least 50% of the kinase inhibitor, such as LS104, particles have a particle size less than the effective average, by weight (or by other suitable measurement techniques, such as by volume, number, etc.), i.e., less than about 2000 nm, 1900 nm, 1800 nm, etc., when measured by the above-noted techniques. In other embodiments of the invention, at least about 60%, at least about 70%, at least about 80% at least about 90%, at least about 95%, or at least about 99% of the kinase inhibitor, such as LS 104, particles have a particle size of less than the effective average, i.e., less than about 2000 nm, 1900 nm, 1800 nm, 1700 nm, etc. [0108] In the present invention, the value for D50 of a nanoparticulate kinase inhibitor, such as LS 104 composition is the particle size below which 50% of the kinase inhibitor particles fall, by weight. Similarly, D90 is the particle size below which 90% of the kinase inhibitor particles fall, by weight.
5. Concentration of Kinase Inhibitor Receptor Antagonist and Surface Stabilizers
[0109] The relative amounts of kinase inhibitor, such as LS 104 or a salt or derivative thereof, and one or more surface stabilizers may vary. The optimal amount of the individual components can depend, for example, upon the particular kinase inhibitor selected, the hydrophilic lipophilic balance (HLB), melting point, and the surface tension of water solutions of the stabilizer, etc.
[0110] The concentration of the kinase inhibitor (such as LS104) may be present from about 99.5% to about 0.001%, from about 95% to about 0.1%, or from about 90% to about 0.5%, by weight, based on the total combined dry weight of the kinase inhibitor and at least one surface stabilizer, not including other excipients.
29
WASH 1899464 1 [0111] The concentration of the at least one surface stabilizer may be present from about 0.5% to about 99.999%, from about 5.0% to about 99.9%, or from about 10% to about 99.5%, by weight, based on the total combined dry weight of the kinase inhibitor and at least one surface stabilizer, not including other excipients.
6. Exemplary Nanoparticulate LS 104 Tablet Formulations
[0112] Several exemplary LS 104 tablet formulations are given below. These examples are not intended to limit the claims in any respect, but rather to provide exemplary tablet formulations of LS 104 which can be utilized in the methods of the invention. Such exemplary tablets may also include a coating agent.
Figure imgf000031_0001
30
WASH 1899464 1
Figure imgf000032_0001
7. Exemplary Injectable Nanoparticulate LS 104 Formulations
The invention provides injectable compositions comprising at least one nanoparticulate small molecule kinase inhibitor, such as LS 104, that may include high drug concentrations in low injection volumes, with rapid drug dissolution upon administration. In addition, the injectable nanoparticulate kinase inhibitors, such as LS 104 formulations of the invention may eliminate the need to use solubilizers such as polyoxyl 60 hydrogenated castor oil (HCO-60). Exemplary injectable compositions comprises, base on % w/w: Small molecule, synthetic kinase inhibitor such as LS 104: 5 - 50% Povidone polymer: 0.1 - 50%
Preservatives : 0.05 - 0.25% pH adjusting agent: pH about 6 to about 7
Water for injection: q.s.
31
WASH 1899464 1 [0113] Exemplary preservatives include methylparaben (about 0.18% based on % w/w), propylparaben (about 0.02% based on % w/w), phenol (about 0.5% based on % w/w), and benzyl alcohol (up to 2% v/v). An exemplary pH adjusting agent is sodium hydroxide, and an exemplary liquid carrier is sterile water for injection. Other useful preservatives, pH adjusting agents, and liquid carriers are well-known in the art.
C. Methods of Making Nanoparticulate Kinase Inhibitor Compositions
[0114] The compositions comprising at least one nanoparticulate kinase inhibitor, such as LS 104 (or a salt or derivative thereof), can be made using, for example, milling or attrition (including but not limited to wet milling), homogenization, precipitation, freezing, template emulsion techniques, supercritical fluid techniques, nano-electrospray techniques, or any combination thereof. Exemplary methods of making nanoparticulate compositions are described in the '684 patent. Methods of making nanoparticulate compositions are also described in U.S. Patent No. 5,518,187 for "Method of Grinding Pharmaceutical Substances;" U.S. Patent No. 5,718,388 for "Continuous Method of Grinding Pharmaceutical Substances;" U.S. Patent No. 5,862,999 for "Method of Grinding Pharmaceutical Substances;" U.S. Patent No. 5,665,331 for "Co-Microprecipitation of Nanoparticulate Pharmaceutical Agents with Crystal Growth Modifiers;" U.S. Patent No. 5,662,883 for "Co-Microprecipitation of Nanoparticulate Pharmaceutical Agents with Crystal Growth Modifiers;" U.S. Patent No. 5,560,932 for "Microprecipitation of Nanoparticulate Pharmaceutical Agents;" U.S. Patent No. 5,543,133 for "Process of Preparing X-Ray Contrast Compositions Containing Nanoparticles;" U.S. Patent No. 5,534,270 for "Method of Preparing Stable Drug Nanoparticles;" U.S. Patent No. 5,510,118 for "Process of Preparing Therapeutic Compositions Containing Nanoparticles;" and U.S. Patent No. 5,470,583 for "Method of Preparing Nanoparticle Compositions Containing Charged Phospholipids to Reduce Aggregation," all of which are specifically incorporated by reference. [0115] The resultant nanoparticulate kinase inhibitor compositions or dispersions can be utilized in solid or liquid dosage formulations, such as injectable form, liquid dispersions, gels, aerosols, ointments, creams, controlled release formulations, fast melt formulations, lyophilized formulations, tablets, capsules, delayed release formulations, extended release formulations, pulsatile release formulations, mixed immediate release and controlled release formulations, etc.
32
WASH 1899464 1 1. Milling to Obtain Nanoparticulate Kinase Inhibitor Dispersions
[0116] Milling an kinase inhibitor, such as LS 104 or a salt or derivative thereof, to obtain a nanoparticulate kinase inhibitor dispersion comprises dispersing the kinase inhibitor particles in a liquid dispersion medium in which the kinase inhibitor is poorly soluble, followed by applying mechanical means in the presence of grinding media to reduce the particle size of the kinase inhibitor to the desired effective average particle size. The dispersion medium can be, for example, water, safflower oil, ethanol, t-butanol, glycerin, polyethylene glycol (PEG), hexane, or glycol. In some embodiments, a preferred dispersion medium is water. [0117] The kinase inhibitor particles can be reduced in size in the presence of at least one surface stabilizer. Alternatively, 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.
[0118] The grinding media can comprise particles that are preferably substantially spherical in shape, e.g., beads, consisting essentially of polymeric or copolymeric resin. Alternatively, the grinding media can comprise a core having a coating of a polymeric or copolymeric resin adhered thereon.
[0119] In general, suitable polymeric or copolymeric resins are chemically and physically inert, substantially free of metals, solvent, and monomers, and of sufficient hardness and friability to enable them to avoid being chipped or crushed during grinding. Suitable polymeric or copolymeric resins include crosslinked polystyrenes, such as polystyrene crosslinked with divinylbenzene; styrene copolymers; polycarbonates; polyacetals, such as Delrin™ (E.I. du Pont de Nemours and Co.); vinyl chloride polymers and copolymers; polyurethanes; polyamides; poly(tetrafluoroethylenes), e.g., Teflon® (E.I. du Pont de Nemours and Co.), and other fluoropolymers; high density polyethylenes; polypropylenes; cellulose ethers and esters such as cellulose acetate; polyhydroxymethacrylate; polyhydroxyethyl acrylate; and silicone-containing polymers such as polysiloxanes and the like. The polymer can be biodegradable. Exemplary biodegradable polymers or copolymers include poly(lactides), poly(glycolide) copolymers of lactides and glycolide, polyanhydrides, poly(hydroxyethyl methacylate), poly(imino carbonates), poly(N-acylhydroxyproline)esters, poly(N-palmitoyl hydroxyproline) esters, ethylene -vinyl acetate copolymers, poly(orthoesters), poly(caprolactones), and poly(phosphazenes). For biodegradable polymers or copolymers, contamination from the media itself advantageously can metabolize in vivo into biologically acceptable products that can be eliminated from the body.
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WASH 1899464 1 [0120] The grinding media preferably ranges in size from about 0.01 to about 3 mm. For fine grinding, the grinding media is preferably from about 0.02 to about 2 mm, and more preferably from about 0.03 to about 1 mm in size.
[0121] The polymeric or copolymeric resin can have a density from about 0.8 to about 3.0 g/cm3.
[0122] In a preferred grinding process the particles are made continuously. Such a method comprises continuously introducing a composition according to the invention into a milling chamber, contacting the composition according to the invention with grinding media while in the chamber to reduce the particle size of the composition according to the invention, and continuously removing the nanoparticulate composition according to the invention nanoparticles from the milling chamber.
[0123] The grinding media is separated from the milled nanoparticulate composition according to the invention nanoparticles using conventional separation techniques, in a secondary process such as by simple filtration, sieving through a mesh filter or screen, and the like. Other separation techniques such as centrifugation may also be employed.
2. Precipitation to Obtain Nanoparticulate Kinase Inhibitor Compositions
[0124] Another method of forming the desired composition comprising at least one nanoparticulate kinase inhibitor, such as LS 104 or a salt or derivative thereof, is by microprecipitation. This is a method of preparing stable dispersions of poorly soluble active agents in the presence of one or more surface stabilizers and one or more colloid stability enhancing surface active agents free of any trace toxic solvents or solubilized heavy metal impurities. Such a method comprises, for example: (1) dissolving the kinase inhibitor in a suitable solvent; (2) adding the formulation from step (1) to a solution comprising at least one surface stabilizer; and (3) precipitating the formulation from step (2) using an appropriate non-solvent. The method can be followed by removal of any formed salt, if present, by dialysis or diafiltration and concentration of the dispersion by conventional means.
3. Homogenization to Obtain Nanoparticulate Kinase Inhibitor Compositions
[0125] Exemplary homogenization methods of preparing active agent nanoparticulate compositions are described in U.S. Patent No. 5,510,118, for "Process of Preparing Therapeutic Compositions Containing Nanoparticles." Such a method comprises dispersing particles of an LS 104, (or a salt or derivative thereof), in a liquid dispersion medium, followed by subjecting the dispersion to homogenization to reduce the particle size of an
34
WASH 1899464 1 kinase inhibitor to the desired effective average particle size. The particles can be reduced in size in the presence of at least one surface stabilizer. Alternatively, the kinase inhibitor particles can be contacted with one or more surface stabilizers either before or after attrition. Other compounds, such as a diluent, can be added to the kinase inhibitor /surface stabilizer composition either before, during, or after the size reduction process. Dispersions can be manufactured continuously or in a batch mode.
4. Cryogenic Methodologies to Obtain Nanoparticulate Kinase Inhibitor Compositions
[0126] Another method of forming the desired nanoparticulate kinase inhibitor such as LS 104 (or a salt or derivative thereof), composition is by spray freezing into liquid (SFL). This technology comprises an organic or organoaqueous solution of kinase inhibitor with stabilizers, which is injected into a cryogenic liquid, such as liquid nitrogen. The droplets of the LS 104 solution freeze at a rate sufficient to minimize crystallization and particle growth, thus formulating nanostructured LS 104 particles. Depending on the choice of solvent system and processing conditions, the nanoparticulate kinase inhibitor particles can have varying particle morphology. In the isolation step, the nitrogen and solvent are removed under conditions that avoid agglomeration or ripening of the kinase inhibitor particles. [0127] As a complementary technology to SFL, ultra rapid freezing (URF) may also be used to created equivalent nanostructured kinase inhibitor particles with greatly enhanced surface area. URF comprises an organic or organoaqueous solution of kinase inhibitor with stabilizers onto a cryogenic substrate.
5. Emulsion Methodologies to Obtain Nanoparticulate Kinase Inhibitor Compositions
[0128] Another method of forming the desired nanoparticulate kinase inhibitor, such as LS 104, composition is by template emulsion. Template emulsion creates nanostructured kinase inhibitor or derivative particles with controlled particle size distribution and rapid dissolution performance. The method comprises an oil-in-water emulsion that is prepared, then swelled with a non-aqueous solution comprising the kinase inhibitor and stabilizers. The particle size distribution of kinase inhibitor is a direct result of the size of the emulsion droplets prior to loading with the kinase inhibitor, a property which can be controlled and optimized in this process. Furthermore, through selected use of solvents and stabilizers, emulsion stability is achieved with no or suppressed Ostwald ripening. Subsequently, the solvent and water are removed, and the stabilized nanostructured kinase inhibitor particles are
35
WASH 1899464 1 recovered. Various kinase inhibitor particles morphologies can be achieved by appropriate control of processing conditions.
6. Supercritical Fluid Methods of Making Nanoparticles
[0129] Nanop articulate compositions can also be made in methods utilizing supercritical fluids. In such a method, a inase inhibitor, such as LS 104, is dissolved in a solution or vehicle which can also contain at least one surface stabilizer. The solution and a supercritical fluid are then co-introduced into a particle formation vessel. If a surface stabilizer was not previously added to the vehicle, it can be added to the particle formation vessel The temperature and pressure are controlled, such that dispersion and extraction of the vehicle occur substantially simultaneously by the action of the supercritical fluid. Chemicals described as being useful as supercritical fluids include carbon dioxide, nitrous oxide, sulphur hexafluoride, xenon, ethylene, chlorotrifluoromethane, ethane, and trifluoromethane. [0130] Examples of known supercritical methods of making nanoparticles include International Patent Application No. WO 97/144407 to Pace et al, published on April 24, 1997, which refers to particles of water insoluble biologically active compounds with an average size of 100 nm to 300 nm prepared by dissolving the compound in a solution and then spraying the solution into compressed gas, liquid, or supercritical fluid in the presence of appropriate surface stabilizers.
[0131] Similarly, U.S. Patent No. 6,406,718 to Cooper et al. describes a method for forming a particulate fluticasone propionate product comprising the co-introduction of a supercritical fluid and a vehicle containing at least fluticasone propionate in solution or suspension into a particle formation vessel, the temperature and pressure in which are controlled, such that dispersion and extraction of the vehicle occur substantially simultaneously by the action of the supercritical fluid. Chemicals described as being useful as supercritical fluids include carbon dioxide, nitrous oxide, sulphur hexafluoride, xenon, ethylene, chlorotrifluoromethane, ethane, and trifluoromethane. The supercritical fluid may optionally contain one or more modifiers, such as methanol, ethanol, ethyl acetate, acetone, acetonitrile or any mixture thereof. A supercritical fluid modifier (or co-solvent) is a chemical which, when added to a supercritical fluid, changes the intrinsic properties of the supercritical fluid in or around the critical point. According to Cooper et al., the fluticasone propionate particles produced using supercritical fluids have a particle size range of 1 to 10 microns, preferably 1 to 5 microns.
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WASH 1899464 1 7. Nano-Electrospray Techniques Used to Obtain Nanoparticulate Compositions
[0132] In electrospray ionization a liquid is pushed through a very small charged, usually metal, capillary. This liquid contains the desired substance, e.g., a kinase inhibitor (or "analyte"), dissolved in a large amount of solvent, which is usually much more volatile than the analyte. Volatile acids, bases or buffers are often added to this solution as well. The analyte exists as an ion in solution either in a protonated form or as an anion. As like charges repel, the liquid pushes itself out of the capillary and forms a mist or an aerosol of small droplets about 10 μm across. This jet of aerosol droplets is at least partially produced by a process involving the formation of a Taylor cone and a jet from the tip of this cone. A neutral carrier gas, such as nitrogen gas, is sometimes used to help nebulize the liquid and to help evaporate the neutral solvent in the small droplets. As the small droplets evaporate, suspended in the air, the charged analyte molecules are forced closer together. The drops become unstable as the similarly charged molecules come closer together and the droplets once again break up. This is referred to as Coulombic fission because it is the repulsive Coulombic forces between charged analyte molecules that drive it. This process repeats itself until the analyte is free of solvent and is a lone ion.
[0133] In nanotechnology the electrospray method may be employed to deposit single particles on surfaces, e.g., particles of a kinase inhibitor. This is accomplished by spraying colloids and making sure that on average there is not more than one particle per droplet. Consequent drying of the surrounding solvent results in an aerosol stream of single particles of the desired type. Here the ionizing property of the process is not crucial for the application but may be put to use in electrostatic precipitation of the particles.
D. Methods of Using the Nanoparticulate Kinase Inhibitor Compositions of the Invention
[0134] The invention provides a method of increasing bioavailability (e.g. , increasing the plasma levels) of an kinase inhibitor such as LS 104 (or a salt or derivative thereof), in a subject. Such a method comprises orally administering to a subject an effective amount of a composition comprising a nanoparticulate kinase inhibitor.
[0135] In one embodiment of the invention, the nanoparticulate kinase inhibitor, such as LS 104, composition, in accordance with standard pharmacokinetic practice, is expected to exhibit a bioavailability that is about 50% greater, about 40% greater, about 30% greater, about 20% greater, or about 10% greater than a conventional dosage form.
37
WASH 1899464 1 [0136] In another embodiment of the invention, the compositions when tested in fasting subjects in accordance with standard pharmacokinetic practice, are proposed to produces a maximum blood plasma concentration profile in less than about 6 hours, less than about 5 hours, less than about 4 hours, less than about 3 hours, less than about 2 hours, less than about 1 hour or less than about 30 minutes after the initial dose of the composition. [0137] The compositions of the invention may be useful in the treatment of cell proliferative diseases such as cancer, for example leukemias such as CML and ALL, and myeloproliferative diseases, such as PV, ET and IMF.
[0138] The compositions of the invention comprising at least one nanoparticulate kinase inhibitor, such as LS 104 (or a salt or derivative thereof), can be administered to a subject via any conventional means including, but not limited to, orally, rectally, ocularly, parenterally (e.g., intravenous, intramuscular, or subcutaneous), intracisternally, pulmonary, intravaginally, intraperitoneally, locally (e.g., powders, ointments or drops), or as a buccal or nasal spray. In some embodiments, parenteral administration is preferred. As used herein, the term "subject" is used to mean an animal, preferably a mammal, including a human or non-human. The terms patient and subject may be used interchangeably. [0139] Compositions suitable for parenteral injection may comprise physiologically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents, or vehicles including water, ethanol, polyols (propyleneglycol, polyethylene-glycol, glycerol, and the like), suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
[0140] The compositions comprising at least one nanoparticulate kinase inhibitor, such as LS 104 (or a salt or derivative thereof) may also contain adjuvants such as preserving, wetting, emulsifying, and dispensing agents. Prevention of the growth of microorganisms can be ensured by various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like. Prolonged absorption of the injectable pharmaceutical form can be brought about by the use of agents delaying absorption, such as aluminum monostearate and gelatin.
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WASH 1899464 1 [0141] Solid dosage forms for oral administration include, but are not limited to, capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active agent is admixed with at least one of the following: (a) one or more inert excipients (or carriers), such as sodium citrate or dicalcium phosphate; (b) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and silicic acid; (c) binders, such as carboxymethylcellulose, alignates, gelatin, polyvinylpyrrolidone, sucrose, and acacia; (d) humectants, such as glycerol; (e) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (f) solution retarders, such as paraffin; (g) absorption accelerators, such as quaternary ammonium compounds; (h) wetting agents, such as cetyl alcohol and glycerol monostearate; (i) adsorbents, such as kaolin and bentonite; and (j) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. For capsules, tablets, and pills, the dosage forms may also comprise buffering agents.
[0142] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs. In addition to kinase inhibitor such as LS 104, the liquid dosage forms may comprise inert diluents commonly used in the art, such as water or other solvents, solubilizing agents, and emulsifiers. Exemplary emulsifiers are ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3 -butyl eneglycol, dimethylformamide, oils, such as cottonseed oil, groundnut oil, corn germ oil, olive oil, castor oil, and sesame oil, glycerol, tetrahydrofurfuryl alcohol, polyethyleneglycols, fatty acid esters of sorbitan, or mixtures of these substances, and the like.
[0143] Besides such inert diluents, the composition can also include adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
[0144] "Therapeutically effective amount" as used herein with respect to, for example a kinase inhibitor such as LS 104 dosage shall mean that dosage that provides the specific pharmacological response for which an LS 104 is administered in a significant number of subjects in need of such treatment. It is emphasized that "therapeutically effective amount," administered to a particular subject in a particular instance will not always be effective in treating the diseases described herein, even though such dosage is deemed a "therapeutically effective amount" by those skilled in the art. It is to be further understood that LS 104 dosages are, in particular instances, measured as oral dosages, or with reference to drug levels as measured in blood.
39
WASH 1899464 1 [0145] One of ordinary skill will appreciate that effective amounts of a kinase inhibitor such as LS 104 can be determined empirically and can be employed in pure form or, where such forms exist, in pharmaceutically acceptable salt, ester, or prodrug form. Actual dosage levels of kinase inhibitor such as LS 104 in the nanoparticulate compositions of the invention may be varied to obtain an amount of a kinase inhibitor such as LS 104 that is effective to obtain a desired therapeutic response for a particular composition and method of administration. The selected dosage level therefore depends upon the desired therapeutic effect, the route of administration, the potency of the administered kinase inhibitor such as LS104, the desired duration of treatment, and other factors.
[0146] Dosage unit compositions may contain such amounts of such submultiples thereof as may be used to make up the daily dose. It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors: the type and degree of the cellular or physiological response to be achieved; activity of the specific agent or composition employed; the specific agents or composition employed; the age, body weight, general health, sex, and diet of the patient; the time of administration, route of administration, and rate of excretion of the agent; the duration of the treatment; drugs used in combination or coincidental with the specific agent; and like factors well known in the medical arts.
E. Examples
[0147] The following examples are provided to illustrate the present invention. It should be understood, however, that the invention is not to be limited to the specific conditions or details described in these examples. Throughout the specification, any and all references to a publicly available document, including a U.S. patent, are specifically incorporated by reference.
Example 1
[0148] The purpose of this example was to prepare a nanoparticulate formulation of LS 104 which would be suitable for intravenous administration. As described below, an exemplary successful nanoparticulate dispersion formulation ("NCD") comprised 10% LS 104, 2.5% Povidone K- 12 PF and 0.1% sodium deoxycholate.
[0149] The initial formulation screening was done using a low energy roller mill (Stoneware) approach. The grinding media utilized was 0.8 mm yittrium treated zirconia
(Tosoh). All formulations were milled at 170 rpm. Milling time is noted below in Table 1.
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WASH 1899464 1 Light microscopy was performed using a Leica Light microscope with 10Ox objective. All particle sizes were measured using the Horiba LA 910 with deionized (DI) water as the diluent and 30 seconds sonication.
[0150] Four different formulations were screened, identified below in Table 1. The first comprised Poloxamer 338 (Pluronic F108) as the stabilizer. Large crystals were observed at the end of the process. This may be a result of crystal growth (Ostwald ripening), suggesting that this stabilizer may not be optimal under certain milling parameters (i.e., the particular drug concentration and surface stabilizer concentration utilized). The second formulation comprised Polysorbate 80 (Tween 80). A dispersion comprising small, well-dispersed particles was observed at the end of the process. The third formulation comprised hydroxy propyl cellulose (HPC-SL). This formulation also comprised small, well- dispersed particles. The fourth formulation comprised a mixture of povidone K- 12 (Plasdone K- 12, a low molecular weight grade polyvinylpyrrolidone) and sodium deoxycholate. This formulation also comprised small, well-dispersed particles and the end of the process. The results are summarized in Table 1 below.
Table 1
Figure imgf000042_0001
[0151] 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.
41
WASH 1899464 1 Example 2
[0152] The second and the fourth formulation were further evaluated. Past experiences with PVP K- 12 and NaDOC together with the slightly smaller particle size makes the fourth formulation slightly more favored. Therefore, the PVP K12/NaDeoxycholate combination was chosen as one desired stabilizer combination for LS 104.
[0153] All processing following the initial rollermilling screening was performed using high energy media mills in which highly crosslinked polystyrene beads were used as the grinding media. It was demonstrated that the lead formulation can be manufactured using this process as the high shear environment sometimes may induce aggregation. A formulation comprising the same stabilizer components was adapted for the high-energy process. The formulation comprised 5% LS104/ 1.25% PVP K- 12/ 0.05% NaDOC, and was successfully evaluated in the high energy mill.
[0154] The product particle size was measured on a Horiba LA910 particle size analyzer using a standard R&D procedure in which a sample concentration was targeted at 80% transmission and using a relative complex refractive index of m = 1.2 - 0.1/. The results are shown in table 2 below.
Table 2. High energy milling of lead formulation.
Figure imgf000043_0001
[0155] This suggests that the formulation comprising 5% LS 104/ 1.25% PVP K- 12/ 0.05% Na Deoxycholate is feasible for high energy processing. The concentration of active pharmaceutical ingredient (API) may be increased in later experiments for process efficiency in which case the ratio of API/Stabilizers remains the same.
[0156] Table 3, below details additional exemplary nanoparticulate LS104 formulations. All of these formulations were prepared using the NanoMill-01 (NanoMill Systems, King of Prussia, PA; see e.g., U.S. Patent No. 6,431,478), along with 500 micron PolyMill® attrition media (Dow Chemical). Again, light microscopy was performed using a Leica Light microscope with IOOX oil objective. All particle sizes were determined using the Horiba LA 910 with distilled, deionized water as the diluent and 30 second sonication. Table 3, Column 1 shows the formulation; Column 2 shows both the mean and D90 particle size (PS); Column
42
WASH 1899464 1 3 includes microscopy observations; Column 4 shows milling time; Column 5 indicates mill size; Column 6, indicates mill load; Column 7 shows mill speed; and Column 8 contains comments regarding the formulation.
Table 3.
Figure imgf000044_0001
43
WASH 1899464 1 [0157] It will be apparent to those skilled in the art that various modifications and variations can be made in the methods and compositions of the present inventions without departing from the spirit or scope of the invention. Thus, it is intended that the present invention cover the modification and variations of the invention provided they come within the scope of the appended claims and their equivalents.
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WASH 1899464 1

Claims

WHAT IS CLAIMED IS:
1. A stable nanoparticulate nanoparticulate kinase inhibitor composition comprising:
(a) particles of LS 104 or a salt or derivative thereof having an effective average particle size of less than about 2000 nm; and
(b) at least one surface stabilizer.
2. The composition of claim 1, wherein the LS 104 is in a crystalline phase, an amorphous phase, a semi-crystalline phase, a semi amorphous phase, or mixtures thereof.
3. The composition of claim 1 or claim 2, wherein the effective average particle size of the particles of LS 104 or a salt or derivative thereof is selected from the group consisting of less than about 1900 nm, less than about 1800 nm, less than about 1700 nm, less than about 1600 nm, less than about 1500 nm, less than about 1400 nm, less than about 1300 nm, less than about 1200 nm, less than about 1100 nm, less than about 1000 nm, less than about 990 nm, less than about 980 nm, less than about 970 nm, less than about 960 nm, less than about 950 nm, less than about 940 nm, less than about 930 nm, less than about 920 nm, less than about 910 nm, less than about 900 nm, less than about 890 nm, less than about 880 nm, less than about 870 nm, less than about 860 nm, less than about 850 nm, less than about 840 nm, less than about 830 nm, less than about 820 nm, less than about 810 nm, less than about 800 nm, less than about 790 nm, less than about 780 nm, less than about 770 nm, less than about 760 nm, less than about 750 nm, less than about 740 nm, less than about 730 nm, less than about 720 nm, less than about 710 nm, less than about 700 nm, less than about 690 nm, less than about 680 nm, less than about 670 nm, less than about 660 nm, less than about 650 nm, less than about 640 nm, less than about 630 nm, less than about 620 nm, less than about 610 nm, less than about 600 nm, less than about 590 nm, less than about 580 nm, less than about 570 nm, less than about 560 nm, less than about 550 nm, less than about 540 nm, less than about 530 nm, less than about 520 nm, less than about 510 nm, less than about 500 nm, less than about 490 nm, less than about 480 nm, less than about 470 nm, less than about 460 nm, less than about 450 nm, less than about 440 nm, less than about 430 nm, less than about 420 nm, less than about 410 nm, less than about 400 nm, less than about 390 nm, less than about 380 nm, less than about 370 nm, less than about 360 nm, less than about 350 nm, less than about 340 nm, less than about 330 nm, less than about 320 nm, less than about 310 nm, less than about 300 nm, less than about 290 nm, less than about 280 nm, less than about 270 nm,
45
WASH 1899464 1 less than about 260 nm, less than about 250 nm, less than about 240 nm, less than about 230 nm, less than about 220 nm, less than about 210 nm, less than about 200 nm, less than about 190 nm, less than about 180 nm, less than about 170 nm, less than about 160 nm, less than about 150 nm, less than about 140 nm, less than about 130 nm, less than about 120 nm, less than about 110 nm, less than about 100, less than about 75 nm, and less than about 50 nm.
4. The composition of any one of claims 1 to 3, wherein the nanoparticulate LS 104 composition has improved bioavailability as compared to conventional LS 104 compositions.
5. The composition of any one of claims 1 to 4, wherein the composition is formulated:
(a) for administration selected from the group consisting of oral, pulmonary, intravenous, rectal, opthalmic, colonic, parenteral, intracisternal, intravaginal, intraperitoneal, local, buccal, nasal, and topical administration;
(b) into a dosage form selected from the group consisting of liquid dispersions, gels, aerosols, ointments, creams, tablets, sachets and capsules;
(c) into a dosage form selected from the group consisting of lyophilized formulations, fast melt formulations, controlled release formulations, delayed release formulations, extended release formulations, pulsatile release formulations, and mixed immediate release and controlled release formulations; or
(d) any combination of (a), (b), and (c).
6. The composition of any one of claims 1 to 5, wherein the composition further comprises one or more pharmaceutically acceptable excipients, carriers, or a combination thereof.
7. The composition of any one of claims 1 to 6, wherein:
(a) the amount of LS 104 is selected from the group consisting of from about 99.5% to about 0.001%, from about 95% to about 0.1%, and from about 90% to about 0.5%, by weight, based on the total combined dry weight of LS 104 and at least one surface stabilizer, not including other excipients;
(b) at least one surface stabilizer is present in an amount selected from the group consisting 0.01% to about 99.5% by weight, form about 0.1% to about 95% by weight, from about 0.5% to about 90% by weight, from about 5.0% to about 99.9% by weight, and from about 10% to about 99.5% by weight, based on the total combined dry weight of LS 104 and at least one surface stabilizer, not including other excipients; or
46
WASH 1899464 1 (c) a combination of (a) and (b).
8. The composition of any one of claims 1 to 7, comprising at least one primary surface stabilizer and at least one secondary surface stabilizer.
9. The composition of any one of claims 1 to 8, wherein at least one surface stabilizer is selected from the group consisting of a non-ionic surface stabilizer, an ionic surface stabilizer, an anionic surface stabilizer, a cationic surface stabilizer, and a zwitterionic surface stabilizer.
10. The composition of any one of claims 1 to 9, wherein at least one surface stabilizer is selected from the group consisting of cetyl pyridinium chloride, gelatin, casein, phosphatides, dextran, glycerol, gum acacia, cholesterol, tragacanth, stearic acid, benzalkonium chloride, calcium stearate, glycerol monostearate, cetostearyl alcohol, cetomacrogol emulsifying wax, sorbitan esters, polyoxyethylene alkyl ethers, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, polyethylene glycols, dodecyl trimethyl ammonium bromide, polyoxyethylene stearates, colloidal silicon dioxide, phosphates, sodium dodecylsulfate, carboxymethylcellulose calcium, hydroxypropyl celluloses, hypromellose, carboxymethylcellulose sodium, methylcellulose, hydroxyethylcellulose, hypromellose phthalate, noncrystalline cellulose, magnesium aluminum silicate, triethanolamine, polyvinyl alcohol, polyvinylpyrrolidone, 4-(l,l,3,3-tetramethylbutyl)-phenol polymer with ethylene oxide and formaldehyde, poloxamers; poloxamines, a charged phospholipid, dioctylsulfosuccinate, dialkylesters of sodium sulfosuccinic acid, sodium lauryl sulfate, alkyl aryl polyether sulfonates, mixtures of sucrose stearate and sucrose distearate, CI8H37CH2C(O)N(CHS)-CH2(CHOH)4(CH2OH)2, p-isononylphenoxypoly-(glycidol), decanoyl-N-methylglucamide; n-decyl β-D-glucopyranoside; n-decyl β-D-maltopyranoside; n-dodecyl β-D-glucopyranoside; n-dodecyl β-D-maltoside; heptanoyl-N-methylglucamide; n- heptyl-β-D-glucopyranoside; n-heptyl β-D-thioglucoside; n-hexyl β-D-glucopyranoside; nonanoyl-N-methylglucamide; n-noyl β-D-glucopyranoside; octanoyl-N-methylglucamide; n-octyl-β-D-glucopyranoside; octyl β-D-thioglucopyranoside; lysozyme, PEG-phospholipid, PEG-cholesterol, PEG-cholesterol derivative, lysozyme, PEG-vitamin A, PEG-vitamin E, random copolymers of vinyl acetate and vinyl pyrrolidone, a cationic polymer, a cationic biopolymer, a cationic polysaccharide, a cationic cellulosic, a cationic alginate, a cationic nonpolymeric compound, a cationic phospholipid, cationic lipids, polymethylmethacrylate
47
WASH 1899464 1 trimethylammonium bromide, sulfonium compounds, polyvinylpyrrolidone-2- dimethylamino ethyl methacrylate dimethyl sulfate, hexadecyltrimethyl ammonium bromide, phosphonium compounds, quarternary ammonium compounds, benzyl-di(2- chloroethyl)ethylammonium bromide, coconut trimethyl ammonium chloride, coconut trimethyl ammonium bromide, coconut methyl dihydroxyethyl ammonium chloride, coconut methyl dihydroxyethyl ammonium bromide, decyl triethyl ammonium chloride, decyl dimethyl hydroxyethyl ammonium chloride, decyl dimethyl hydroxyethyl ammonium chloride bromide, C12- 15 dimethyl hydroxyethyl ammonium chloride,
Figure imgf000049_0001
hydroxyethyl ammonium chloride bromide, coconut dimethyl hydroxyethyl ammonium chloride, coconut dimethyl hydroxyethyl ammonium bromide, myristyl trimethyl ammonium methyl sulphate, lauryl dimethyl benzyl ammonium chloride, lauryl dimethyl benzyl ammonium bromide, lauryl dimethyl (ethenoxy)4 ammonium chloride, lauryl dimethyl (ethenoxy)4 ammonium bromide, N-alkyl (C12-18)dimethylbenzyl ammonium chloride, N- alkyl (C14_1g)dimethyl-benzyl ammonium chloride, N-tetradecylidmethylbenzyl ammonium chloride monohydrate, dimethyl didecyl ammonium chloride, N-alkyl and (C12-I4) dimethyl 1-napthylmethyl ammonium chloride, trimethylammonium halide, alkyl-trimethylammonium salts, dialkyl-dimethylammonium salts, lauryl trimethyl ammonium chloride, ethoxylated alkyamidoalkyldialkylammonium salt, an ethoxylated trialkyl ammonium salt, dialkylbenzene dialkylammonium chloride, N-didecyldimethyl ammonium chloride, N- tetradecyldimethylbenzyl ammonium, chloride monohydrate, N-alkyl(C12-14) dimethyl 1- naphthylmethyl ammonium chloride, dodecyldimethylbenzyl ammonium chloride, dialkyl benzenealkyl ammonium chloride, lauryl trimethyl ammonium chloride, alkylbenzyl methyl ammonium chloride, alkyl benzyl dimethyl ammonium bromide, C12 trimethyl ammonium bromides, C15 trimethyl ammonium bromides, C17 trimethyl ammonium bromides, dodecylbenzyl triethyl ammonium chloride, poly-diallyldimethylammonium chloride (DADMAC), dimethyl ammonium chlorides, alkyldimethylammonium halogenides, tricetyl methyl ammonium chloride, decyltrimethylammonium bromide, dodecyltriethylammonium bromide, tetradecyltrimethylammonium bromide, methyl trioctylammonium chloride, POLYQUAT 10™, tetrabutylammonium bromide, benzyl trimethylammonium bromide, choline esters, benzalkonium chloride, stearalkonium chloride compounds, cetyl pyridinium bromide, cetyl pyridinium chloride, halide salts of quaternized polyoxyethylalkylamines, MIRAPOL™, ALKAQUAT™, alkyl pyridinium salts; amines, amine salts, amine oxides, imide azolinium salts, protonated quaternary acrylamides, methylated quaternary polymers, and cationic guar.
48
WASH 1899464 1
11. The composition of any one of claims 1 to 10, additionally comprising one or more active agents useful for the treatment of cell proliferative diseases or disorders.
12. The composition of any one of claims 1 to 11, wherein:
(a) upon administration to a mammal the particles of LS 104 or a salt or derivative thereof redisperse such that the particles have an effective average particle size selected from the group consisting of less than about 2 microns, less than about 1900 nm, less than about 1800 nm, less than about 1700 nm, less than about 1600 nm, less than about 1500 nm, less than about 1400 nm, less than about 1300 nm, less than about 1200 nm, less than about 1100 nm, less than about 1000 nm, less than about 990 nm, less than about 980 nm, less than about 970 nm, less than about 960 nm, less than about 950 nm, less than about 940 nm, less than about 930 nm, less than about 920 nm, less than about 910 nm, less than about 900 nm, less than about 890 nm, less than about 880 nm, less than about 870 nm, less than about 860 nm, less than about 850 nm, less than about 840 nm, less than about 830 nm, less than about 820 nm, less than about 810 nm, less than about 800 nm, less than about 790 nm, less than about 780 nm, less than about 770 nm, less than about 760 nm, less than about 750 nm, less than about 740 nm, less than about 730 nm, less than about 720 nm, less than about 710 nm, less than about 700 nm, less than about 690 nm, less than about 680 nm, less than about 670 nm, less than about 660 nm, less than about 650 nm, less than about 640 nm, less than about 630 nm, less than about 620 nm, less than about 610 nm, less than about 600 nm, less than about 590 nm, less than about 580 nm, less than about 570 nm, less than about 560 nm, less than about 550 nm, less than about 540 nm, less than about 530 nm, less than about 520 nm, less than about 510 nm, less than about 500 nm, less than about 490 nm, less than about 480 nm, less than about 470 nm, less than about 460 nm, less than about 450 nm, less than about 440 nm, less than about 430 nm, less than about 420 nm, less than about 410 nm, less than about 400 nm, less than about 390 nm, less than about 380 nm, less than about 370 nm, less than about 360 nm, less than about 350 nm, less than about 340 nm, less than about 330 nm, less than about 320 nm, less than about 310 nm, less than about 300 nm, less than about 290 nm, less than about 280 nm, less than about 270 nm, less than about 260 nm, less than about 250 nm, less than about 240 nm, less than about 230 nm, less than about 220 nm, less than about 210 nm, less than about 200 nm, less than about 190 nm, less than about 180 nm, less than about 170 nm, less than about 160 nm, less than about 150 nm, less than about 140 nm, less than about 130 nm, less than about 120 nm, less than about 110 nm, less than about 100, less than about 75 nm, and less than about 50 nm;
49
WASH 1899464 1 (b) the composition redisperses in a biorelevant medium such that the LS 104 particles have an effective average particle size selected from the group consisting of less than about 2 microns, less than about 1900 nm, less than about 1800 nm, less than about 1700 nm, less than about 1600 nm, less than about 1500 nm, less than about 1400 nm, less than about 1300 nm, less than about 1200 nm, less than about 1100 nm, less than about 1000 nm, less than about 990 nm, less than about 980 nm, less than about 970 nm, less than about 960 nm, less than about 950 nm, less than about 940 nm, less than about 930 nm, less than about 920 nm, less than about 910 nm, less than about 900 nm, less than about 890 nm, less than about 880 nm, less than about 870 nm, less than about 860 nm, less than about 850 nm, less than about 840 nm, less than about 830 nm, less than about 820 nm, less than about 810 nm, less than about 800 nm, less than about 790 nm, less than about 780 nm, less than about 770 nm, less than about 760 nm, less than about 750 nm, less than about 740 nm, less than about 730 nm, less than about 720 nm, less than about 710 nm, less than about 700 nm, less than about 690 nm, less than about 680 nm, less than about 670 nm, less than about 660 nm, less than about 650 nm, less than about 640 nm, less than about 630 nm, less than about 620 nm, less than about 610 nm, less than about 600 nm, less than about 590 nm, less than about 580 nm, less than about 570 nm, less than about 560 nm, less than about 550 nm, less than about 540 nm, less than about 530 nm, less than about 520 nm, less than about 510 nm, less than about 500 nm, less than about 490 nm, less than about 480 nm, less than about 470 nm, less than about 460 nm, less than about 450 nm, less than about 440 nm, less than about 430 nm, less than about 420 nm, less than about 410 nm, less than about 400 nm, less than about 390 nm, less than about 380 nm, less than about 370 nm, less than about 360 nm, less than about 350 nm, less than about 340 nm, less than about 330 nm, less than about 320 nm, less than about 310 nm, less than about 300 nm, less than about 290 nm, less than about 280 nm, less than about 270 nm, less than about 260 nm, less than about 250 nm, less than about 240 nm, less than about 230 nm, less than about 220 nm, less than about 210 nm, less than about 200 nm, less than about 190 nm, less than about 180 nm, less than about 170 nm, less than about 160 nm, less than about 150 nm, less than about 140 nm, less than about 130 nm, less than about 120 nm, less than about 110 nm, less than about 100, less than about 75 nm, and less than about 50 nm; or
(c) a combination of (a) and (b).
50
WASH 1899464 1
13. The composition of claim 12, wherein the biorelevant medium is selected from the group consisting of water, aqueous electrolyte solutions, aqueous solutions of a salt, aqueous solutions of an acid, aqueous solutions of a base, and combinations thereof.
14. The composition of any one of claims 1 to 13, wherein:
(a) the Tmax of the nanoparticulate LS 104 composition, when assayed in the plasma of a mammalian subject following administration, is less than the Tmax for a non- nanoparticulate composition of the same LS 104, administered at the same dosage;
(b) the Cmax of the nanoparticulate LS 104 composition, when assayed in the plasma of a mammalian subject following administration, is greater than the Cmax for a non- nanoparticulate composition of the same LS 104, administered at the same dosage;
(c) the AUC of the nanoparticulate LS 104 composition, when assayed in the plasma of a mammalian subject following administration, is greater than the AUC for a non- nanoparticulate composition of the same LS 104, administered at the same dosage; or
(d) any combination of (a), (b) and (c).
15. The composition of claim 14, wherein:
(a) the Tmax is selected from the group consisting of 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%, and not greater than about 5% of the Tmax exhibited by a non-nanoparticulate composition of the same LS104, administered at the same dosage;
(b) the Cmax is selected from the group consisting of 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 Cmax exhibited by a non- nanoparticulate composition of the same LS 104, administered at the same dosage;
(c) the AUC is selected from the group consisting of at least about 25%, at least about 50%, at least about 75%, at least about 100%, at least about 125%, at least about 150%, at least about 175%, at least about 200%, at least about 225%, at least about 250%, at least about 275%, at least about 300%, at least about 350%, at least about 400%, at least about
51
WASH 1899464 1 450%, at least about 500%, at least about 550%, at least about 600%, at least about 750%, at least about 700%, at least about 750%, at least about 800%, at least about 850%, at least about 900%, at least about 950%, at least about 1000%, at least about 1050%, at least about 1100%, at least about 1150%, or at least about 1200% greater than the AUC exhibited by the non-nanoparticulate formulation of the same LS 104, administered at the same dosage; or (d) any combination of (a), (b), and (c).
16. The composition of any one of claims 1 to 15 which does not produce significantly different absorption levels when administered under fed as compared to fasting conditions.
17. The composition of claim 16, wherein the difference in absorption of the active agent composition of the invention, when administered in the fed versus the fasted state, is selected from the group consisting of less than about 100%, less than about 90%, less than about 80%, less than about 70%, less than about 60%, less than about 50%, less than about 40%, less than about 30%, less than about 25%, less than about 20%, less than about 15%, less than about 10%, less than about 5%, and less than about 3%.
18. The composition of any one of claims 1 to 17, wherein administration of the composition to a human in a fasted state is bioequivalent to administration of the composition to a subject in a fed state.
19. The composition of claim 18, wherein "bioequivalency" is established by:
(a) a 90% Confidence Interval of between 0.80 and 1.25 for both Cmax and AUC; or
(b) a 90% Confidence Interval of between 0.80 and 1.25 for AUC and a 90% Confidence Interval of between 0.70 to 1.43 for Cmax.
20. Use of a composition according to any one of claims 1 to 19 for the manufacture of a medicament.
21. The use of claim 20, wherein the medicament is useful in treating leukemia, myeloproliferative diseases and related diseases or disorders.
22. A method of making a nanoparticulate LS104, or a salt or derivative thereof, composition comprising contacting particles of an LS 104 with at least one surface stabilizer
52
WASH 1899464 1 for a time and under conditions sufficient to provide a nanop articulate LS 104 composition having an effective average particle size of less than about 2000 nm.
23. The method of claim 22, wherein the contacting comprises milling, wet milling, homogenizing, precipitation, freezing, supercritical fluid particle generation techniques, emulsion techniques, nano-electrospray techniques, or any combination thereof.
53
WASH 1899464 1
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US9757464B2 (en) 2009-03-05 2017-09-12 Bend Research, Inc. Pharmaceutical compositions of dextran polymer derivatives
US9084727B2 (en) 2011-05-10 2015-07-21 Bend Research, Inc. Methods and compositions for maintaining active agents in intra-articular spaces
US10314830B2 (en) 2012-01-13 2019-06-11 Xspray Microparticles Ab Pharmaceutical compositions
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AU2013208323B2 (en) * 2012-01-13 2017-07-06 Xspray Microparticles Ab A method for producing stable, amorphous hybrid nanoparticles comprising at least one protein kinase inhibitor and at least one polymeric stabilizing and matrix- forming component.
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