KR20090018864A - Nanoparticulate kinase inhibitor formulations - Google Patents

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 of Related Application

This application claims the priority of US Provisional Application No. 60 / 812,960, filed June 13, 2006, the contents of which are incorporated herein by reference in their entirety.

The present invention relates to kinase inhibitor compounds and compositions useful for the treatment or prevention of diseases or disorders such as myeloproliferative disease, leukemia, and related diseases or conditions. More specifically, the present invention relates to nanoparticulate kinase inhibitor compositions, such as nanoparticulate LS104 compositions, having an effective average particle size of less than about 2000 nm. The present invention also relates to methods of making and using such nanoparticulate compositions.

A. LS104 Prior art on

Abnormal kinase activity is associated with a number of diseases. Leukemia is bone marrow and blood cancer. 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 form of leukemia is acute myeloid leukemia (AML) with an estimated 12,000 new cases annually in the United States. AML occurs mostly in adults older than 40 years and occurs at an average age of 65 years. Cancers such as AML represent areas with high unfilled medical needs; Current treatments for AML are characterized by poor long-term response rates with fewer than 20% of adult patients surviving after diagnosis. Several types of mutations are found in AML; One mutation is not wrong, and two or more mutations seem to be necessary to cause the disease. However, mutations in receptor tyrosine kinase FLT3 occur in about one third of AML patients, leading to particularly poor prognosis.

FLT3 carries a proliferative signal and is usually expressed early in the growth of bone marrow stem cells, but in the mutated form of FLT3, FLT3 remains active, helping leukemia cells to multiply. Several groups are working to identify compounds that can inhibit FLT3.

A feature of CML and some ALL is the chromosomal translocation that occurs between chromosome 22 and chromosome 9, resulting in the generation of a modified chromosome 22 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 (Abl) that is translocated to chromosome 22. The cleavage points on chromosome 9 may vary, but the cleavage points on chromosome 22 are relatively crowded. This region on chromosome 22 is called a "breakpoint cluster region" ("Bcr") and the fused gene resulting from the translocation is called "Bcr-Abl". All forms of fusion proteins include a portion of Abelson protein with tyrosine kinase activity. Tyrosine kinase activity constitutes a Bcr-Abl fusion protein; The negative regulator of this activity no longer acts on the fusion protein. This constitutive kinase activity has been shown to activate various signal transduction pathways leading to uncontrolled cell growth and division (eg, by promoting cell proliferation and inhibiting apoptosis). For example, Bcr-Abl can prevent undifferentiated blood cells from proliferating and maturing in large quantities.

Non-CML myeloproliferative disease (MPD) and yet such as polycythemia vera (PV), essential thrombocythemia (ET), and chronic idiopathic myelofibrosis (IMF) Unclassified myeloproliferative disease (MPD-NC) is characterized by abnormal increases in blood cells. See, eg, Vainchenker and Constantinescu, Hematology (American Society of Hematology) 195-200 (2005). This increase is usually initiated by spontaneous mutations in multipotent hematopoetic stem cells located in the bone marrow. Id. Due to the mutation, hematopoietic stem cells produce much more of a certain family of blood cells than normal, which causes an overproduction of cells such as red blood cells, megakaryocytes, granulocytes and monocytes. Some symptoms common to patients with MPD include enlarged spleen, enlarged liver, elevated white blood cells, red blood cells, and / or platelet cell counts, blood clots (thrombosis), weakness, dizziness, and headache. Diseases such as PV, ET and IMF can be precursors of leukemia, but the rate of conversion (eg, conversion to blast crisis) is different for each disease. Id.

The specific genes that cause many MPDs and the mutations or mutations that occur simultaneously are not known. However, the gain of function mutations in the Janus kinase 2 (JAK2) gene, a cytoplasmic non-receptor tyrosine kinase, have been identified in many MPDs. For example, such mutations are reported in up to 97% of patients with PV and in more than 40% of patients with ET or IMF. See, for example, 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); See Steensma, et al., Blood 106: 1207-2109 (2005).

Janus kinase is a family of tyrosine kinases that play a role in cytokine signaling. JAK2 kinases, for example, are downstream of cytokine receptors bound to membranes such as the erythropoietin receptor (EpoR) and signal transduction pathways such as Signal Transducers and Activators of Transcription protein 5 (STAT5). -stream) acts as an intermediary between members. See, eg, Schindler, C.W., J. Clin Invest. 109: 1133-1137 (2002); Tefferi and Gilliland, Mayo Clin. Proc. 80: 947-958 (2005); See Giordanetto and Kroemer, Protein Engineering 15 (9): 727-737 (2002). JAK2 is activated when phosphorylating JAK2 kinase to which the cytokine receptor / ligand complex is bound. Id. JAK2 can then phosphorylate and activate its substrate molecule, such as STAT5, which enters the nucleus and interacts with other regulatory proteins that act on transcription. Id.

Treatment of leukemia and myeloid proliferative disorders may include drug treatment (eg, chemotherapy), bone marrow transplantation, radiation therapy, or a combination thereof. One class of drugs that can be used to treat such diseases includes kinase inhibitors. For example, one kinase inhibitor called “imatinib mesylate” (ie STI571 or 2-phenylaminopyrimidine) has proven effective for treating CML and ALL. Imatinib is marketed as a drug under the trade names "Gleevec" or "Glivec".

Another class of kinase inhibitors is the styrylacrylonitrile compound, chemically known as (E, E) -2- (benzylaminocarbonyl) -3- (3,4-dihydroxystyryl) acrylonitrile LS104 which is LS104 has the empirical formula C ₁₉ H ₁₆ O ₃ N ₂ of molecular weight 320.34.

The chemical structure of the LS104 is as follows:

Styrylacrylonitrile compounds such as LS104 are useful for treating various cell proliferative diseases such as cancer. Styrylacrylonitrile compounds are described, for example, in US Pat. No. 6,800,659 for "Compounds for Regulating Cell Proliferation," US Pat. No. 7,012,095 for "Compounds for Regulating Cell Proliferation," "Abnormal Published US Application 2006/0058554, entitled Novel Compounds Useful to Regulate Cell Proliferation, Published US Application 2006/0058297, entitled “Regulating New Cells Useful to Regulate Abnormal Cell Proliferation,” Published application 2005/0085538, entitled "Styryl Acrylonitrile Compounds and Their Uses to Promote Myeloid Cell Formation," published application 2005/0014690, "Ephrin," and Published application 2004/0247592, entitled EPH Receptor Mediated Immune Regulation, published application 2004/0209845 entitled “New Compounds for Regulating Cell Proliferation,” Human Lymphoprotein Tyrosine Shin phosphatase "published application 2004/0006777, published application 2003/0113328 entitled" Methods for Regulating Immune Systems ", all of which are incorporated herein by reference in their entirety.

Styrylacrylonitrile compounds such as LS104 generally work by inhibiting abnormal cell signals that may be specific for the growth of cancer cells. LS104 functions as a small molecule kinase inhibitor, in particular as a tyrosine kinase inhibitor. LS104 targets the cancer cell pathway by blocking the action of certain kinases, in contrast to many chemotherapeutic compounds that attack cancer cells and non-cancerous cells and cause serious side effects.

LS104 is a small molecule synthesized and is one of a new class of non-ATP competitive kinase inhibitors. Most kinase inhibitors currently under development for use as therapeutic agents compete with adenosine triphosphate (ATP), a cell's energy source. Thus, LS104 has the potential to be effective in limiting cancer progression with significantly lower toxicity than the chemotherapy currently used in cancer therapy.

This compound has shown great potential as a potential treatment for acute leukemias such as acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), and chronic myelogenous leukemia (CML), as well as true myelogenous hyperplasia (PV), essential It may prove beneficial for other myeloproliferative diseases or disorders such as thrombocytopenia (ET), myeloid metaplasia with myelofibrosis (MMM), and idiopathic myelofibrosis (IM). For example, LS104 is active in Janus kinase 2 ("JAK2") activity, a major functioning mutation identified in numerous myeloproliferative disorders, and Bcr-Abl, the product of a translocation event present in various leukemia patients and known as the "Philadelphia chromosome". It has been shown to inhibit both tyrosine kinase activity. In addition, LS104 has demonstrated very low toxicity or no toxicity to normal cells.

However, LS104 may not be readily bioavailable when administered. Therefore, it would be desirable to formulate more bioavailable formulations of kinase inhibitors such as LS104. Such agents will act faster and thus provide relief for individuals suffering from diseases or disorders that include unregulated and overactive kinase activity such as tyrosine kinase activity. Leukemia, myeloproliferative disease, or other blood related cancers, or diseases are examples of such diseases. Such formulations can overcome other problems associated with conventional drug formulations. The present invention satisfies this need.

The present invention relates to nanoparticulate kinase inhibitor compositions, such as nanoparticulate LS104, or salts or derivatives thereof, for the treatment of blood cancers and related diseases, disorders, conditions and symptoms.

B. Prior Art Regarding Nanoparticulate Active Agent Compositions

The nanoparticulate active agent compositions disclosed for the first time in U.S. Patent No. 5,145,684 ("'684 patent") are poorly soluble in which non-crosslinked surface stabilizers are adsorbed on the surface. soluble) particles consisting of therapeutic or diagnostic agents. The '684 patent does not describe nanoparticulate compositions of kinase inhibitors such as LS104.

Methods for preparing nanoparticulate active agent compositions are described, for example, in US Pat. Nos. 5,518,187 and 5,862,999 for "Methods for Grinding Pharmaceutical Substances"; US Patent No. 5,718,388 for "Method of Continuously Grinding Pharmaceutical Substances"; and US Patent No. 5,510,118 for "Methods for Preparing Therapeutic Compositions Comprising Nanoparticles."

Nanoparticulate active agent compositions also include, for example, US Pat. No. 5,298,262 for "Use of an Ionic Cloud Point Modifier to Block Particle Accumulation During Sterilization"; US Patent No. 5,302,401 for "Method of Reducing Particle Size Growth During Freeze Drying"; US Patent No. 5,318,767 for "X-Ray Contrast Compositions Useful for Medical Imaging"; US Patent No. 5,326,552 for "Novel Formulations for Nanoparticulate X-Ray Blood Pool Contrast Drugs Using High Molecular Weight Non-ionic Surfactants;" US Patent No. 5,328,404 for "X-Ray Imaging Method Using Iodide Aromatic Propanedioate"; US Patent No. 5,336,507 for "Use to Reduce Nanoparticulate Integration of Charged Phospholipids"; US Patent No. 5,340,564 for "Formulations Containing Olin 10-G for Blocking Particle Aggregation and Enhancing Stability"; US Patent No. 5,346,702 for "Use of Non-Ionic Cloud Point Modifiers to Minimize Nanoparticulate Integration During Sterilization"; US Patent No. 5,349,957 for "Preparation and Magnetic Properties of Very Small Magnetic-Dextran Particles"; US Patent No. 5,352,459 for "Use of Purified Surface Modifiers to Block Particle Accumulation During Sterilization"; US Pat. Nos. 5,399,363 and 5,494,683 for "Surface Modified Anticancer Nanoparticles"; US Patent No. 5,401,492 for "Water Insoluble and Non-Magnetic Manganese Particles as a Magnetic Resonance Enhancement Agent"; US Patent No. 5,429,824 for "Use of Tyloxapol as Nanoparticulate Stabilizer"; US Patent No. 5,447,710 for "Method for Preparing Nanoparticulate X-Ray Blood Pool Contrast Agents Using High Molecular Weight Non-ionic Surfactants; US Patent No. 5,451,393 for "X-Ray Contrast Compositions Useful for Medical Imaging"; US Patent No. 5,466,440 for "Formulations of Oral Gastrointestinal Diagnostic X-Ray Contrast Agents in Combination with Pharmaceutically Acceptable Clays; US Patent No. 5,470,583 for "Method of Making Nanoparticulate Compositions Containing Charged Phospholipids with Reduced Density"; US Patent No. 5,472,683 for "Nanoparticulate Diagnostic Mixed Carbamic Anhydrides as X-Ray Contrast Drugs for Blood Pool and Lymphatic System Imaging;" US Patent No. 5,500,204 for "Nanoparticulate Diagnostic Dimers as X-Ray Contrast Agents for Blood Pool and Lymphatic System Imaging;" US Patent No. 5,518,738 for "Nanoparticulate NSAID Formulations"; US Patent No. 5,521,218 for "Nanoparticulate Iododipamide Derivatives for Use as X-Ray Contrast Drugs; US Patent No. 5,525,328 for "Nanoparticulate Diagnostic Diatrizoxy Ester as X-Ray Contrast Agent for Blood Pool and Lymphatic System Imaging;" US Patent No. 5,543,133 for "Method for Preparing X-Ray Contrast Compositions Comprising Nanoparticles"; US Patent No. 5,552,160 for "Surface Modified NSAID Nanoparticles"; US Patent No. 5,560,931 for "Formulation of Compounds in the Form of Nanoparticulate Dispersions in Digestible Oils or Fatty Acids; US Patent No. 5,565,188 for "Polyalkylene Block Copolymers That Are Surface Modifiers for Nanoparticles"; US Patent No. 5,569,448 for "Sulfated Non-Ionic Block Copolymers That Are Stabilizer Coatings of Nanoparticle Compositions;" US Patent No. 5,571,536 for "Formulation of Compounds in Nanoparticulate Dispersions in Digestible Oils or Fatty Acids"; US Patent No. 5,573,749 for "Nanoparticulate Diagnostic Mixed Carboxy Anhydrides as X-Ray Contrast Agents for Blood Pool and Lymphatic System Imaging;" US Patent No. 5,573,750 for "Diagnostic Imaging X-Ray Contrast Agents;" US Patent No. 5,573,783 for "Redispersible Nanoparticulate Film Matrix with Protective Overcoat"; US Pat. No. 5,580,579 for "Site-specific Attachment in the GI tract, Using Nanoparticles Stabilized by High Molecular Weight Linear Poly (ethyleneoxide) Polymer"; US Patent No. 5,585,108 for "Formulations of Oral Gastrointestinal Therapeutic Agents in Combination with Pharmaceutically Acceptable Clays"; US Pat. No. 5,587,143 for "Butylene Oxide-Ethylene Oxide Block Copolymer Surfactant as Stabilizer Coatings for Nanoparticulate Compositions;" US Patent No. 5,591,456 for "Naproxen milled with hydroxypropyl cellulose as a dispersion stabilizer"; US Patent No. 5,593,657 for "New Barium Salt Formulations Stabilized with Non-ionic and Anionic Stabilizers"; US Patent No. 5,622,938 for "Sugar Based Surfactants for Nanocrystals"; No. 5,628,981 for "Improved Formulation of Oral Gastrointestinal Diagnostic X-Ray Contrast Agents and Oral Gastrointestinal Therapeutics"; US Pat. No. 5,643,552 for "Carbonic Anhydride Mixed for Nanoparticulate Diagnostics as X-Ray Contrast Agents for Blood Pool and Lymphatic System Imaging; US Patent No. 5,718,388 for "Method of Continuously Grinding Pharmaceutical Substances"; US Patent No. 5,718,919 for "Nanoparticles Containing R (-) Enantiomers of Ibuprofen"; US Patent No. 5,747,001 for "Aerosol comprising Baclomethasone Nanoparticle Dispersion"; US Patent No. 5,834,025 for "Reduction of Negative Physiological Responses Induced by Nanoparticulate Formulations Administered Intravenously"; US Patent No. 6,045,829 for "Nanocrystalline Forms of Human Immunodeficiency Virus (HIV) Protease Inhibitors Using Surface Stabilizers, Cellulose Compounds; US Patent No. 6,068,858 for "Methods for Preparing Nanocrystalline Formulations of Human Immunodeficiency Virus (HIV) Protease Inhibitors Using Surface Stabilizers, Cellulose Compounds; US Patent No. 6,153,225 for "Injectable Formulations of Nanoparticulate Naproxen"; US Patent No. 6,165,506 for "Novel Solid Dosage Forms of Nanoparticulate Naproxen"; US Patent No. 6,221,400 for "Methods for Treating Mammals Using Nanocrystalline Forms of Human Immunodeficiency Virus (HIV) Protease Inhibitors; US Patent No. 6,264,922 for "Nebulized aerosols comprising nanoparticulate dispersions; US Patent No. 6,267,989 for "Method of Blocking Crystal Growth and Particle Accumulation in Nanoparticulate Compositions; US Patent No. 6,270,806 for "Use of PEG-derivatized lipids as surface stabilizers for nanoparticulate compositions"; US Patent No. 6,316,029 for "Oral Solid Dosage Forms That Are Degraded Rapidly"; No. 6,375,986 for "Nanoparticulate Compositions for Solid Administration Including Synergistic Combination of Polymeric Surface Stabilizers with Dioctyl Sodium Sulfosuccinate; US Patent No. 6,428,814 for "bioadhesive nanoparticulate compositions comprising cationic surface stabilizers"; US Patent No. 6,431,478 for "Small Milling"; And US Pat. No. 6,432,381 for "Methods for Targeting Drug Delivery to the Upper and / or Lower Gastrointestinal Tract"; US Pat. No. 6,592,903 for "Nanoparticulate Dispersions Containing Synergistic Blending of Polymeric Surface Stabilizers with Dioctyl Sodium Sulfosuccinate; US Pat. No. 6,582,285 for "sanitary wet milling apparatus"; US Patent No. 6,656,504 for "Nanoparticulate compositions comprising amorphous cyclosporin"; US Patent No. 6,742,734 for "System and Method for Milling Materials"; US Patent No. 6,745,962 for "Small Milling and Methods thereof"; US Patent No. 6,811,767 for "Liquid Droplet Aerosols of Nanoparticulate Drugs"; US Patent No. 6,908,626 for "compositions comprising a combination of immediate release and controlled release"; US Pat. No. 6,969,529 for "Nanoparticulate compositions comprising a copolymer of vinyl pyrrolidone and vinyl acetate as surface stabilizer"; And US Pat. No. 6,976,647 for "System and Method for Milling Materials"; And US Pat. No. 6,991,191 for "Method of Using Small Milling"; US Patent No. 7,101,576 for "nanoparticulate megestrol formulations"; And US Pat. No. 7,198,795 for "In Vitro Evaluation Methods for Evaluating In vivo Efficiency of Dosage Formulations of Microparticles of Nanoparticulate Active Agent Compositions, all of which are specifically incorporated by reference.

See also US Patent Publication No. 20070104792 for "Nanoparticulate Tadalafil Formulations;" US Patent Publication No. 20070098805 for "Method of Making and Using the New Griseofulvin Composition; US Patent Publication No. 20070065374 for "Nanoparticulate Leukotriene Receptor Antagonist / Corticosteroid Formulations"; US Patent Publication No. 20070059371 for "Nanoparticulate Evastin Formulations" US Patent Publication No. 20070048378 for "Nanoparticulate Anticonvulsant and Immunosuppressive Compositions"; US Patent Publication No. 20070042049 for "Nanoparticulate Benidipine Compositions"; US Patent Publication No. 20070015719 for "nanoparticulate clarithromycin formulations"; US Patent Publication No. 20070003628 for "Nanoparticulate Clopidogrel Formulations"; US Patent Publication No. 20070003615 for "Nanoparticulate Clopidogrel with Aspirin Formulations;" US Patent Publication No. 20060292214 for "Nanopartic Acetaminophen Formulations"; US Patent Publication No. 20060275372 for "Nanoparticulate Imatinib Mesylate Formulations"; US Patent Publication No. 20060246142 for "nanoparticulate quinazoline derivative formulations"; US Patent Publication No. 20060246141 for "Nanoparticulate Lipase Inhibitor Formulations;" US Patent Publication No. 20060216353 for "Nanoparticulate Corticosteroids and Antihistamine Agents"; US Patent Publication No. 20060210639 for "Nanoparticulate Bisphosphonate Compositions"; US Publication No. 20060210638 for "Injectable Compositions of Nanoparticulate Immunosuppressive Compounds"; US Patent Publication No. 20060204588 for "Nanoparticulate finasterides, dutasterides or Namsulrosine hydrochloride, and mixtures thereof"; US Patent Publication No. 20060198896 for "Aerosol and Injectable Formulations of Nanoparticulate Benzodiazepines"; US Patent Publication No. 20060193920 for "Nanoparticulate Compositions of Mitogen-Activated Protein (MAP) Kinase Inhibitors"; US Patent Publication No. 20060188566 for "Nanoparticulate Formulations of Docetaxel and Its Analogues"; US Patent Publication No. 20060165806 for "Nanoparticulate Candesartan Formulations;" US Patent Publication No. 20060159767 for "Nanoparticulate Bicalutamide Formulations;" US Patent Publication No. 20060159766 for "Nanoparticulate Tacrolimus Formulations"; US Patent Publication No. 20060159628 for "Nanoparticulate Benzothiophene Formulations"; US Patent Publication No. 20060154918 for "Injectable Nanoparticulate Olanzapine Formulations; US Patent Publication No. 20060121112 for "Topiramate Pharmaceutical Compositions"; US Patent Publication No. 20020012675 A1 for "Controlled Release Nanoparticulate Compositions"; US Patent Publication No. 20040195413 for "Method for Milling Compositions and Materials"; US Patent Publication No. 20040173696 A1 for "Milling Microgram Content of Nanoparticulate Candidate Compounds"; Published on January 31, 2002, published in US Patent Publication No. 20020012675 A1 for "Controlled Release Nanoparticulate Compositions"; US Patent Publication No. 20050276974 for "Nanoparticulate Fibrate Formulations"; US Patent Publication No. 20050238725 for "Nanoparticulate Compositions Having Peptides as Surface Stabilizers;" US Patent Publication No. 20050233001 for "Nanoparticulate Megestrol Formulations"; US Patent Publication No. 20050147664 for "Compositions Containing Antibodies and Methods of Using the Same to Target Nanoparticulate Active Agent Delivery; 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US Patent Publication No. 20040141925 for "Novel Triamcinolone Compositions"; US Patent Publication No. 20040115134 for "New Nifedipine Compositions"; US Publication No. 20040105889 for "Low Viscosity Liquid Dosage Formulations"; US Patent Publication No. 20040105778 for "Gamma Irradiation of Solid Nanoparticulate Active Agents"; US Patent Publication No. 20040101566 for "Novel Benzyl Peroxide Compositions"; US Patent Publication No. 20040057905 for "Nanoparticulate Beclomethasone Dipropionate Compositions"; US Patent Publication No. 20040033267 for "Nanoparticulate Compositions of Angiogenesis Inhibitors;" US Patent Publication No. 20040033202 for "Nanoparticulate Sterol Formulations and Novel Sterol Formulations"; US Patent Publication No. 20040018242 for "Nanoparticulate Nistatin Formulations"; US Patent Publication No. 20040015134 for "Drug Delivery Systems and Methods"; US Patent Publication No. 20030232796 for "Nanoparticulate Policosanol Formulations and Novel Policosanol Formulations"; US Publication No. 20030215502 for "Quickly Dissolving Dosage Forms with Reduced Fragment"; US Patent Publication No. 20030185869 for "Nanoparticulate Compositions Having Lysozyme as Surface Stabilizer"; US Patent Publication No. 20030181411 for "Nanoparticulate Compositions of Mitogen-activated Protein (MAP) Kinase Inhibitors"; US Patent Publication No. 20030137067 for "Compositions Having a Combination of Immediate Release and Controlled Release Features"; US Patent Publication No. 20030108616 for "Nanoparticulate compositions comprising a copolymer of vinyl pyrrolidone and vinyl acetate as a surface stabilizer; US Patent Publication No. 20030095928 for "nanoparticulate insulin"; US Patent Publication No. 20030087308 for "High Power Screening Methods Using Small Milling or Microfluidics"; US Patent Publication No. 20030023203 for "Drug Delivery System &Method"; US Patent Publication No. 20020179758 for "System and Method of Milling Materials"; And US Patent Publication No. 20010053664 for "Hygienic Wet Milling Apparatus" describe nanoparticulate active agent compositions, which are specifically incorporated by reference.

Amorphous small particle compositions are described, for example, in US Pat. No. 4,783,484 for "particulate compositions and use as antimicrobials"; US Patent No. 4,826,689 for "Method for Producing Uniformly Sized Particles from Water-Insoluble Organic Compounds"; US Patent No. 4,997,454 for "Method for Producing Uniformly Sized Particles from Insoluble Compounds"; US Patent No. 5,741,522 for "Uniform, Non-Integrated Porous Particles of Uniform Size and Process for Capturing Gas Bubbles"; US Pat. No. 5,776,496 for "Microporous Particles to Enhance Ultrasonic Back Scatter." They are also incorporated herein by reference.

While the high therapeutic value of kinase inhibitors such as LS104 is recognized in the art, poorly water soluble inhibitors are limited in their bioavailability after oral administration or infusion, and are safe and effective products for other forms of administration. Formulation may be difficult or impossible. Accordingly, there is a need in the art for formulations having improved bioavailability with improved efficiency and / or comprising kinase inhibitors suitable for administration such as parenteral administration. The present invention fulfills this need.

The present invention relates to nanoparticulate compositions comprising kinase inhibitors such as LS104, which may be useful for the treatment and prevention of diseases and disorders such as CML, AML, ALL, myeloproliferative diseases, and other blood-related cancers and diseases. It is about.

Summary of the Invention

The present invention relates to a stable nanoparticulate composition comprising a kinase inhibitor such as LS104 or a salt or derivative thereof and at least one surface stabilizer. In some embodiments, the surface stabilizer may be bound to the surface of the particles, for example the surface stabilizer may be adsorbed to the surface of the LS104 particles. In general, drug nanoparticles have an effective average particle size of less than about 2000 nm.

The composition may comprise LS104 particles in crystalline phase, amorphous phase, semi-crystalline phase, semi-amorphous phase, and mixtures thereof.

The composition may comprise one or more surface stabilizers. For example, some compositions may include one or more primary surface stabilizers and one or more secondary surface stabilizers. Representative 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 no.

The present invention relates to nanoparticulate kinase inhibitors such as LS104 or salts or derivatives thereof, one or more surface stabilizers, and optionally one or more pharmaceutically acceptable excipients, carriers, and optionally cancers such as leukemia, myeloproliferative diseases And one or more active agents, or combinations thereof, useful for the treatment of related diseases.

Compositions of the invention comprising nanoparticulate kinase inhibitors such as LS104 or salts or derivatives thereof are proposed to exhibit improved pharmacokinetic profiles compared to conventional kinase inhibitor (eg LS104) compositions. For example, the C _max and / or AUC of the nanoparticulate compositions of the invention are greater than the C _max and / or AUC of conventional compositions administered at the same dosage, while the T _max may be lower; Any combination of improved C _max , AUC and T _max profiles can be exhibited by the nanoparticulate LS104 composition as compared to conventional LS104 compositions. In additional embodiments, the LS104 composition may not produce significantly different levels of absorption when administered in fed conditions compared to fasting conditions.

In some embodiments, nanoparticulate LS104 compositions exhibit improved bioavailability over conventional LS104 compositions. For example, after administration to a mammal, the nanoparticulate LS104 composition can be redispersed so that the particles have an effective average particle size of less than about 2 microns.

The present invention relates to a process for preparing nanoparticulate compositions comprising kinase inhibitors, such as LS104 or salts or derivatives thereof. In some embodiments, the method can include contacting the LS104 particles with one or more surface stabilizers for a time and under conditions sufficient to provide a nanoparticulate LS104 composition having an effective average particle size of less than about 2000 nm. .

The invention also relates to a method of treatment using the nanoparticulate LS104 composition. In some methods, a composition comprising nanoparticulate LS104 or a salt or derivative thereof and an at least one surface stabilizer having an effective average particle size of less than about 2000 nm can be administered to the subject. In some methods, the compositions may be formulated for parenteral infusion (eg, intravenously, intramuscularly, or subcutaneously) in a therapeutically effective amount. In some methods, the injectable formulation can provide a high concentration of LS140 in a small volume injected. In another method, administration includes a large pill infusion of a kinase inhibitor, such as LS140, with one continuous rapid infusion, rather than a slow infusion of the drug. For example, the composition can be administered to treat myeloproliferative diseases, diseases associated with myeloproliferative diseases, diseases, symptoms or conditions, and cancers such as leukemias such as CML, AML and ALL. In some methods, an individual may be suffering from such a disease, disorder, symptom or condition. Other therapeutic methods using the nanoparticulate compositions of the invention are known to those skilled in the art.

Both the foregoing summary of the invention and the following detailed description of the invention are representative and illustrative, 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.

Detailed description of the invention

The present invention relates to a composition comprising at least one nanoparticulate kinase inhibitor, such as LS104 or a salt or derivative thereof, and at least one surface stabilizer. Surface stabilizers can be adsorbed or bound to the surface of the drug. Generally, LS104 particles or salts or derivatives thereof have an effective average particle size of less than about 2000 nm.

Advantages of compositions comprising one or more nanoparticulate kinase inhibitors such as LS104 include the following when compared to conventional non-nanoparticulate (microcrystalline or solubilized) formulations of the same kinase inhibitor (eg, LS104). However, they are not limited to: (1) smaller size tablets or other solid dosage forms of smaller size; (2) smaller doses of the drug needed to achieve the same pharmacological effect; (3) increased bioavailability; (4) improved pharmacokinetic profile; (5) a substantially similar pharmacokinetic profile when administered in the fasted versus the fed state; (6) bioequivalency when administered in a fasted state versus an fed state; (7) increased absorption rate of nanoparticulate compositions; (8) increased dissolution rate; And (9) kinase inhibitor compositions may be combined with other active agents useful in the treatment of myeloproliferative diseases, cancers such as leukemia and related disorders, diseases, symptoms, or conditions.

The present invention encompasses compositions comprising one or more nanoparticulate kinase inhibitors, such as LS104 or salts or derivatives thereof, together with one or more nontoxic physiologically acceptable carriers, adjuvants, or carriers, collectively referred to as carriers. do. The compositions may be used for parenteral infusion (eg, intravenous, intramuscular, or subcutaneous), oral administration of solid, liquid, or aerosol formulations, biosorbent, vaginal, nasal, rectal, eye, topical (powder, ointment or drip) Drug), oral, intracranial, intraperitoneal, or topical administration, and equivalents thereof.

In some embodiments, any pharmaceutically acceptable dosage form can be used, but preferred dosage forms of the invention are injectable dosage forms. In some embodiments, the injectable formulation can provide a high concentration of LS 140 in a small volume injected. In another embodiment, the administration comprises a pill infusion of a kinase inhibitor, such as LS 140, with one continuous rapid infusion, rather than a slow infusion of the drug.

Representative solid dosage forms include, but are not limited to, tablets, capsules, sachets, lozenges, powders, pills, or granules, which solid dosage forms can be, for example, rapid dissolution dosage forms, controlled release dosage forms. , Lyophilized dosage forms, delayed release dosage forms, extended release dosage forms, pulsatile release dosage forms, mixed dosage forms of immediate release and controlled release, or combinations thereof.

The invention has been described herein using several definitions, described below and throughout the application.

As used herein, the term "effective average particle size" refers to, for example, sedimentation field flow fractionation, photon correlation spectroscopy, light scattering, disk centrifugation, and About 50% of nanoparticulate kinase inhibitor particles, such as LS104, when measured using other methods known to those skilled in the art (by other suitable measurement methods such as weight, volume, number, etc.). This means that it has a size of less than about 2000 nm.

As used herein, "about" will be understood by those skilled in the art, and changes may be made to some extent in the context when "about" is used. Unless the context in which "about" is used is apparent to those skilled in the art, "about" will mean up to 10% or minus 10% of a particular value.

When "stable" is used herein in connection with stable nanoparticulate kinase inhibitor particles such as LS104, this means, but is not limited to, one or more of the following parameters: (1) The particles are due to attraction between particles Does not aggregate or clump considerably or do not significantly increase particle size over time; (2) does not change over time, as the physical structure of the particles is converted from an amorphous state to a crystalline state; (3) the particles are chemically stable; And / or (4) the kinase inhibitor does not undergo a heating step above the melting point of the kinase inhibitor particles in the preparation of the nanoparticles of the invention.

The term "conventional" or "non-nanoparticulate active agent" shall mean an active agent that is solubilized or has an effective average particle size of greater than about 2000 nm. Nanoparticulate active agents as defined herein have an effective average particle size of less than about 2000 nm.

The phrase “poorly water soluble drug” as used herein refers to 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 in water. It refers to a drug having solubility.

When the phrase “therapeutically effective amount” is used herein, it is meant a drug dose that provides a specific pharmacological response when the drug is administered to a significant number of individuals in need of treatment. Although the dosage is a therapeutically effective amount for those skilled in the art, it should be emphasized that in certain cases the therapeutically effective amount of the drug administered to a particular individual will not always be effective when treating the conditions / diseases described herein. do.

The term "myeloproliferative disease" or "myeloproliferative disorder" includes non-lymphocytic abnormalities or tumor conditions arising from hematopoietic stem cells or progeny thereof. "MPD patient" includes patients diagnosed with MPD. "Myeloproliferative disorders" includes special and classified forms of myeloproliferative disorders, including true thrombocytopenia (PV), essential thrombocytopenia (ET) and idiopathic osteofibrosis (IMF). The definition also includes hypereosinophilic syndrome (HES), chronic neutrophilic leukemia (CNL), myeloid myeloid fibrosis (MMM), chronic myeloid mononuclear leukemia (CMML), pediatric mononuclear leukemia, Chronic basophilic leukemia, chronic eosinophilic leukemia, and systemic mastocytosis (SM). In addition, “myeloproliferative disease” includes any unclassified myeloproliferative disease (UMPD or MPD-NC).

A. Nanoparticle Type of the Invention Kinase  Characteristics of Inhibitor Composition

One. Increased  Biological Utilization rate

Compositions of the present invention comprising one or more kinase inhibitors such as LS104 of the present invention are expected to exhibit increased bioavailability compared to the same non-nanoparticulate kinase inhibitors. In addition, the compositions of the present invention provide smaller dosages and smaller size tablets or other solid dosage formulation sizes compared to non-nanoparticulate formulations of previous conventional identical kinase inhibitors to achieve the same pharmacological effect. It is expected to need.

Increased bioavailability is important because this means that nanoparticulate kinase inhibitor dosage formulations will exhibit significantly greater drug uptake.

2. Improved Pharmacokinetics  profile

The present invention also contemplates a composition comprising one or more nanoparticulate kinase inhibitors, such as LS104, having a desirable pharmacokinetic profile when administered to a mammalian subject. Preferred pharmacokinetic profiles of compositions comprising one or more nanoparticulate kinase inhibitors, such as LS104, include, but are not limited to: (1) the same administration, as analyzed in the plasma of a mammalian subject after administration; the ratio of the same kinase inhibitor administered in an amount - than the C _max of the nanoparticles formulation preferably larger, C _max of kinase inhibitors, such as LS104; And / or (2) a kinase inhibitor, such as LS104, which is preferably larger than the AUC of a non-nanoparticulate formulation of the same kinase inhibitor administered at the same dose, as analyzed in the plasma of the mammalian subject after administration. AUC; And / or (3) a kinase inhibitor, such as LS104, preferably less than the T _max of the non-nanoparticulate formulation of the same kinase inhibitor administered at the same dose, as analyzed in the plasma of the mammalian subject after administration. T _max . A preferred pharmacokinetic profile as used herein is a pharmacokinetic profile measured after initial administration of a kinase inhibitor such as LS104.

In one embodiment, a composition comprising a nanoparticulate kinase inhibitor such as LS104 is a non-nanoparticulate kinase inhibitor formulation in a comparative pharmacokinetic test with a non-nanoparticulate formulation of the same kinase inhibitor administered at the same dose. About 90% or less, about 80% or less, about 70% or less, about 60% or less, about 50% or less, about 30% or less, about 25% or less, about 20% or less, about 15% or less of the T _max represented by T _max , about 10% or less, or about 5% or less.

In another embodiment, a composition comprising a nanoparticulate kinase inhibitor, such as LS104, is a non-nanoparticulate kinase inhibitor in a comparative pharmacokinetic test with a non-nanoparticulate formulation of the same kinase inhibitor administered at the same dose. 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%, about 800% above the C _max exhibited by the formulation. 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%, about 1800% Above, or at least about 1900% greater C _max .

In another embodiment, a composition comprising a nanoparticulate kinase inhibitor, such as LS104, is a non-nanoparticulate kinase inhibitor in a comparative pharmacokinetic test with a non-nanoparticulate formulation of the same kinase inhibitor administered at the same dose. 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% above the AUC represented by the formulation. , 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 650% , 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 AUC.

In one embodiment of the invention, the T _max of a kinase inhibitor such as LS104 is less than about 6 hours or about 8 hours when analyzed in the plasma of a mammalian subject. In another embodiment of the invention, the T _max of LS104 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 to be.

When a preferred pharmacokinetic profile is used herein, it is the pharmacokinetic profile measured after the initial administration of a kinase inhibitor such as LS104. The composition may be formulated in any manner as described herein and as known to those skilled in the art.

3. of the present invention Kinase  Of inhibitor composition Pharmacokinetics  The profile is not affected by the fed or fasted state of the individual who has consumed the composition.

The present invention includes a composition comprising one or more nanoparticulate kinase inhibitors, such as LS104, wherein the pharmacokinetic profile of the kinase inhibitor is substantially unaffected by the fed or fasted state of the individual ingesting the composition. This is a substantial difference in the amount of drug absorbed (AUC), drug absorption rate (C _max ), or length of time up to C _max (T _max ) when the nanoparticulate kinase inhibitor composition is administered in a fasted state versus the fed state. Means none.

When the nanoparticulate kinase inhibitor composition (such as the LS104 composition) of the present invention is administered in a fasted state versus a fed state, the difference in absorption (AUC) or C _max is preferably 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%.

4. feeding  Of the present invention when administered in a state of fasting versus state Kinase  Biological Equivalence of Inhibitor Compositions

The invention also includes compositions comprising nanoparticulate kinase inhibitors, such as LS104, wherein the administration of the composition to a fasting subject is biologically equivalent to the administration of the composition to a fed subject.

In one embodiment of the invention, the invention relates to a fasting subject, in particular as determined by the C _max and AUC guidelines set forth by the US Food and Drug Administration and the corresponding European Regulatory Authority (EMEA). A composition comprising a nanoparticulate kinase inhibitor, such as LS104, wherein the administration of the composition to the subject is biologically equivalent to administration of the composition to an individual in a fed state. According to the US FDA guidelines, two products or methods are biologically equivalent if the 90% Confidence Interval (CI) of AUC and C _max is between 0.80 and 1.25 (T _max measurements are not equivalent to biological equivalents for regulatory purposes). Not relevant). To show the biological equivalence between two compounds or administration conditions according to the European EMEA Directive, 90% CI of AUC must be 0.80 to 1.25 and 90% CI of C _max must be 0.70 to 1.43.

5. of the present invention Kinase  Dissolution Profile of Inhibitor Composition

Compositions comprising one or more nanoparticulate kinase inhibitors, such as LS104 or salts or derivatives thereof, are unexpectedly proposed to have significant dissolution profiles. Fast dissolution of the administered active agent is preferred because generally faster dissolution leads to greater bioavailability and faster onset of action. In order to improve the dissolution profile and bioavailability of the kinase inhibitor, it will be useful to increase the dissolution of the molar so that the dissolution of the drug can reach levels close to 100%.

Kinase inhibitor compositions, such as the LS104 of the present invention, preferably have a dissolution profile in which at least about 20% of the composition dissolves within about 5 minutes. In another embodiment of the present invention, at least about 30% or at least about 40% of the kinase inhibitor composition dissolves within about 5 minutes. In another embodiment of the present 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 dissolves within about 10 minutes. Finally, in another embodiment of the present invention, preferably at least about 70%, at least about 80%, at least about 90%, or at least about 100% of the kinase inhibitor composition dissolves within 20 minutes.

Dissolution is preferably measured in discernable media. This dissolution medium will produce two very different dissolution curves for the two products with very different dissolution profiles in gastric fluid; In other words, the dissolution medium leads to the expected in vivo dissolution of the composition. An exemplary dissolution medium is an aqueous medium comprising 0.025 M of surfactant sodium lauryl sulfate. Determination of the dissolved content can be performed by spectrometer. A rotating blade method (European Pharmacopoeia) can be used to measure dissolution.

6. Redispersibility of Kinase Inhibitor Compositions of the Invention

A further feature of the composition comprising one or more nanoparticulate kinase inhibitors such as LS104 or salts or derivatives thereof is that the composition redisperses so that the effective average particle size of the redispersed kinase inhibitor particles is less than about 2 microns. This is important if, after administration, the kinase inhibitor particles of the composition of the present invention do not aggregate or redisperse substantially to nanoparticulate size, the dosage form may lose the gains obtained by formulating the kinase inhibitor to nanoparticulate size. Because there is.

This is because nanoparticulate active agent compositions benefit from the small particle size of the active agent. If the active agent does not disperse to small particle sizes after administration, due to the thermodynamic motive force to achieve the extremely high surface free energy and overall reduction of free energy of the nanoparticulate system, "aggregated" or agglomerated active agent particles are produced. . In the preparation of such agglomerated particles, the bioavailability of the dosage form may drop below the bioavailability observed in the liquid dispersion of the nanoparticulate active agent.

Furthermore, one or more nanoparticulate kinase inhibitors, such as the LS104 of the present invention, as evidenced by reconstitution / redispersion in a biorelated aqueous medium such that the effective average particle size of the redispersed kinase inhibitor particles is less than about 2 microns. Compositions comprising exhibits significant redispersion of nanoparticulate kinase inhibitor particles after administration to a mammal, such as a human or animal. Such biorelevant aqueous media can be any aqueous media exhibiting the desired ionic strength and pH to form the basis of the biorelevance of the media. Target pH and ionic strength are representative of the physiological conditions found in the human body. Such biorelevant aqueous media can be, for example, aqueous solutions of electrolytes, aqueous solutions of any salts, acids or bases, or combinations thereof, which exhibit the desired pH and ionic strength.

Biorelevant pH is well known in the art. For example, in the stomach pH is lower than 2 (but usually greater than 1) and up to 4 or 5. In the small intestine the pH may range from 4 to 6, and in the colon the pH may range from 6 to 8. Biorelated ionic strength is also well known in the art. Fasting gastric juice has an ionic strength of about 0.1M, while fasting intestinal fluid has an ionic strength of about 0.14. For example, Lindahl et al., "Characterization of Fluids from the Stomach and Proximal Jejunum in Men and Women," Pharm. Res., 14 (4): 497-502 (1997).

It is believed that the pH and ionic strength of the test solution is more important than the specific compound content. Accordingly, appropriate pH and ionic strength values include strong acids, strong bases, salts, one or more conjugate acid-base pairs (ie, weak acids and their corresponding salts), single protic and multiple protic electrolytes, and the like. It can be obtained through several combinations of

Representative electrolyte solutions can be, but are not limited to, HCl solutions in the range of about 0.001 to about 0.1 M concentration, and NaCl solutions in the range of about 0.001 to about 0.1 M concentration, and mixtures thereof. For example, the electrolyte solution may contain about 0.1 M or less HCl, about 0.01 M or less HCl, about 0.001 M or less HCl, about 0.1 M or less NaCl, about 0.01 M or less NaCl, about 0.001 M or less NaCl, and mixtures thereof, but is not limited to these. Of these electrolyte solutions, 0.01 M HCl and / or 0.1 M NaCl are most representative of fasting human physiological conditions because of the pH and ionic strength conditions of the adjacent gastrointestinal tract.

The electrolyte concentrations of 0.001 M HCl, 0.01 M HCl, and 0.1 M HCl are consistent with pH 3, pH 2, and pH 1, respectively. Thus, 0.01 M HCl solution simulates the usual acidic conditions found in the stomach. Although concentrations higher than 0.1 M can be used to simulate feeding conditions in the human GI tract, 0.1 M NaCl solution provides an approximation to the ionic strength conditions found throughout the body, including gastrointestinal fluid. do.

Representative salts, acids, base solutions or combinations thereof that exhibit the desired pH and ionic strength include sodium, potassium and calcium salts of phosphoric acid / phosphate + chlorides, sodium, potassium and calcium salts of carbonic acid / acetate salts, chlorides, carbonic acid / Sodium, potassium and calcium salts of bicarbonate salt + chloride, and sodium, potassium and calcium salts of citric acid / citrate salt + chloride.

In another embodiment of the invention, the redispersed particles of a kinase inhibitor, such as LS104 or salts thereof or derivatives thereof (redispersed in water, in a bio-relevant medium, or in any suitable redispersing medium), are prepared by light-scattering methods, microscopy. Or 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, as measured by other suitable methods, 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, 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, about 120 nm Have an effective average particle size of less than, less than about 110 nm, less than about 100 nm, less than about 75 nm, or less than about 50 nm. Such methods suitable for determining the effective average particle size are known to those skilled in the art.

Redispersibility can be tested using any suitable means known in the art. See, for example, the Examples section of US Pat. No. 6,375,986 for "Solid Dosing Nanoparticulate Compositions Comprising Synergistic Combinations of Polymeric Surface Stabilizers with Dioctyl Sodium Sulfosuccinate."

7. with other active agents Combined  Nanoparticulate Used Kinase  Inhibitor composition

Compositions comprising one or more nanoparticulate kinase inhibitors, such as LS104 or salts or derivatives thereof, may further comprise one or more compounds useful for the treatment of cancer or other related diseases, disorders, conditions or symptoms such as leukemia, Alternatively, the kinase inhibitor composition can be administered in combination with such a compound. Nanoparticulate kinase inhibitor compositions such as LS104 can offer a wide range of opportunities for use in combination with current chemotherapeutic agents, bone marrow transplants, etc., as well as other kinase inhibitors such as Gleevec®.

B. Nanoparticle Type Kinase  Inhibitor composition

The present invention provides compositions comprising one or more kinase inhibitor particles such as LS104 or salts or derivatives thereof and one or more surface stabilizers. The surface stabilizer is preferably adsorbed or bound to the surface of the LS104 particles. In particular, the surface stabilizer may adsorb or bind to the surface of the nanoparticulate kinase inhibitor particles, but ideally does not chemically react with the kinase inhibitor (such as LS104) particles or by themselves. Single adsorbed surface stabilizer molecules are essentially free of intermolecular cross-linking.

The invention also encompasses a kinase inhibitor (or salt thereof or derivative thereof) composition, such as LS104, with one or more nontoxic physiologically acceptable carriers, adjuvants or carriers, collectively referred to as carriers. The composition may be used for parenteral infusion (eg, intravenous, intramuscular, or subcutaneous), oral administration of a solid, liquid or aerosol formulation, vagina, nose, rectum, eye, topical (powder, ointment or drop), oral cavity, It may be formulated for intraretinal, intraperitoneal, or topical administration and equivalents thereof.

One. Kinase  Inhibitor particles

The composition of the present invention comprises one or more kinase inhibitor particles such as LS104 or salts or derivatives thereof. The particles can be in crystalline phase, semi-crystalline phase, amorphous phase, semi-amorphous phase, or a combination thereof.

2. Surface Stabilizer

The choice of surface stabilizers for kinase inhibitors such as LS104 is not obvious. Accordingly, the present invention relates to the surprising findings in which nanoparticulate kinase inhibitor compositions can be prepared.

Combinations of more than one surface stabilizer may be used in the present invention. Useful surface stabilizers that can be used in the present 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. Representative surface stabilizers include nonionic and ionic (eg, anionic, cationic and zwitterionic) surfactants or compounds.

Representative examples of surface stabilizers include albumin, including human serum albumin and bovine albumin, hydroxypropyl methylcellulose (now known as hypromellose), hydroxypropylcellulose, polyvinylpyrrolidone, sodium la Uryl sulfate, dioctylsulfosuccinate, gelatin, casein, lecithin (phosphatide), dextran, gum acacia, cholesterol, tragacanth, stearic acid, benzalkonium chloride, calcium stearate, glycerol monostearate, Cetostearyl alcohol, cetomacrogol emulsifying wax, sorbitan esters, polyoxyethylene alkyl ethers (eg macrogol ethers such as cetomacrogol 1000), polyoxyethylene caster oil derivatives, Polyoxyethylene sorbitan fatty acid esters (e.g., Tween 20 ^® and Tween 80 ^® (ICI Specialty Chemical commercially available Tweens ^® products such as s); Polyethylene glycols (eg Carbowax 3550 ^® and 934 ^® (Union Carbide)), polyoxyethylene stearate, colloidal silicon dioxide, phosphate, carboxymethylcellulose calcium, carboxymethylcellulose sodium, methylcellulose , 4- (1,1,3) comprising hydroxyethyl cellulose, hypromellose phthalate, noncrystalline cellulose, magnesium aluminum silicate, triethanolamine, polyvinyl alcohol (PVA), ethylene oxide and formaldehyde , 3-tetramethylbutyl) -phenolic polymer (also known as tyloxapol, superione, and triton), poloxamer (e.g. Pluronic, a block copolymer of ethylene oxide and propylene oxide) F68 ^® and F108 ^® ); Pollock samin (e. G., Also, known as Poloxamine ^® 908, ethylenediaminetetraacetate on propylene oxide and ethylene tetrafunctional shelf (tetrafunctional) block copolymer is Tetronic 908 ^® is derived from a continuous addition of the oxide (BASF Wyandotte Corporation , Parsippany, NJ)); Tetronic 1508 ^® (T-1508) from BASF Wyandotte Corporation, Triton X-200 ^® (Rohm and Haas), an alkyl aryl polyether sulfonate; Crodestas F-110 ^® (Croda Inc.), a mixture of sucrose stearate and sucrose distearate; P-isononylphenoxypoly- (glycidol), also known as Olin-1OG ^® or Surfactant 10-G ^® (Olin Chemicals, Stamford, CT); And Crodestas SL-40 ^® (Croda, Inc.); And SA9OHCO (Eastman Kodak Co.) with C ₁₈ H ₃₇ CH ₂ (CON (CH ₃ ) —CH ₂ (CHOH) ₄ (CH ₂ 0H) ₂ ; 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-methylglycol Lucamide, 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-phosphori Feed, PEG-cholesterol, PEG-cholesterol derivatives, PEG-vitamin A, PEG-vitamin E, lysozyme, random copolymers of vinyl pyrrolidone and vinyl acetate, and equivalents thereof.

If desired, nanoparticulate kinase inhibitor compositions such as LS104 of the present invention may be formulated without phospholipids.

Examples of useful cationic surface stabilizers include polymers, biopolymers, polysaccharides, cellulosic, alginates, phospholipids, and zwitterionic stabilizers, poly-n-methylpyridinium, anthriol ( anthryul) pyridinium chloride, cationic phospholipid, chitosan, polylysine, polyvinylimidazole, polybrene, polymethylmethacrylate trimethylammonium bromide bromide (PMMTMABr), hexyldecyltrimethylammonium bromide (HDMAB) And nonpolymeric compounds such as, but not limited to, polyvinylpyrrolidone-2-dimethylaminoethyl methacrylate dimethyl sulfate.

Other useful cationic stabilizers include cationic lipids, sulfonium, phosphonium, and 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, C _{12 - 15} dimethyl hydroxyethyl ammonium chloride or bromide, coconut dimethyl hydroxyethyl ammonium chloride or bromide, myristyl trimethyl ammonium methyl alcohol sulphate, lauryl dimethyl benzyl ammonium chloride or bromide, La (not tenok a) lauryl dimethyl _quaternary ammonium chloride or bromide, N- alkyl (C _{12 -18)} dimethyl benzyl ammonium chloride, N- alkyl (C _14-18) dimethyl - Be chloride, N- tetradecyl dimethyl benzyl ammonium chloride monohydrate, dimethyl didecyl ammonium chloride, N- alkyl and (C _{12 -14)} dimethyl 1-naphthylmethyl ammonium chloride, trimethylammonium halide, alkyl-trimethyl ammonium salt And dialkyl-dimethylammonium salts, lauryl trimethyl ammonium chloride, ethoxylated alkylamidoalkyldialkylammonium salts and / or ethoxylated trialkyl ammonium salts, dialkylbenzene dialkylammonium chlorides, N - didecyl dimethyl ammonium chloride, N- tetradecyl dimethyl benzyl ammonium chloride monohydrate, N- alkyl (C _{12 -14)} dimethyl 1-naphthylmethyl ammonium chloride and dodecyl dimethyl benzyl ammonium chloride, dialkyl benzene alkyl ammonium chloride, Lauryl trimethyl ammonium chloride, alkylbenzyl methyl ammonium chloride, al Kyl benzyl dimethyl ammonium bromide, C ₁₂ , C ₁₅ , C ₁₇ trimethyl ammonium bromide, dodecylbenzyl triethyl ammonium chloride, poly-diallyldimethylammonium chloride (DADMAC), dimethyl ammonium chloride, alkyldimethylammonium halogenide, tricetyl Methyl ammonium chloride, decyltrimethylammonium bromide, dodecyltriethylammonium bromide, tetradecyltrimethylammonium bromide, methyl trioctylammonium chloride (ALIQUAT 336 ^TM ), polyquat 10 (POLYQUAT 10 ^TM ), tetrabutylammonium bromide, benzyl trimethylammonium Bromide, choline esters (choline esters such as choline esters of fatty acids), benzalkonium chloride, stearalkonium chloride compounds (compounds such as stearyltrimonium chloride and di-stearyldimonium chloride), Cetyl Quaternary ammonium compounds such as 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 and amine oxides such as lauryl amine acetate, stearyl amine acetate, alkylpyridinium salts, and alkylimidazolysone salts; 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, but is not limited to these.

Such representative 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 include benzalkonium chloride, carbonium compounds, phosphonium compounds, oxonium compounds, halonium compounds, cationic organometallic compounds, quaternary phosphorus compounds, pyridinium compounds, anilinium compounds, ammonium compounds Certain nonpolymeric compounds such as hydroxyammonium compounds, primary ammonium compounds, secondary ammonium compounds, tertiary ammonium compounds, and quaternary ammonium compounds such as the formula NR ₁ R ₂ R ₃ R ₄ ⁽⁺⁾ . For compounds of formula NR ₁ R ₂ R ₃ R ₄ ⁽⁺⁾ ,

(i) none of R ₁ -R ₄ are CH ₃ ;

(ii) one of R ₁ -R ₄ is CH ₃ ;

(iii) three of R ₁ -R ₄ are CH ₃ ;

(iv) all of R ₁ -R ₄ are CH ₃ ;

(v) 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 has 7 or less carbon atoms Alkyl chains;

(vi) alkyl of two of R ₁ -R ₄ is CH ₃ , one of R ₁ -R ₄ is C ₆ H ₅ CH ₂ , and one of R ₁ -R ₄ has 19 or more carbon atoms A chain;

(vii) two of R ₁ -R ₄ are CH ₃ and _one of R ₁ -R ₄ is a C ₆ H ₅ (CH ₂ ) _n group where n>1;

(viii) 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 one or more heteroatoms;

(ix) 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;

(x) 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 is one or more cyclic fragments It includes;

(xi) two of R ₁ -R ₄ are CH ₃ and one of R ₁ -R ₄ is a phenyl ring; or

(xii) two of R ₁ -R ₄ are CH ₃ and two of R ₁ -R ₄ are purely aliphatic fragments.

Such compounds include behenalkonium chloride, benzethonium chloride, cetylpyridinium chloride, behentrimonium chloride, lauralkonium chloride, cetalkonium chloride, cetrimonium (cetrimonium) bromide, cetrimonium chloride, cetylamine hydrofluoride, chlorallylmethenamine chloride (Quaternium-15), distearyldimonium chloride (Quaternium-5), dodecyl Dimethyl ethylbenzyl ammonium chloride (Quaternium-14), quaternium-22, quaternium-26, quaternium-18 hectorite, dimethyl Aminoethylchloride hydrochloride, cysteine hydrochloride, diethanolammonium POE (10) oletyl ether phosphate, diethanolammonium POE (3) Rail ether phosphate, tallow alcoholic chloride, dimethyl dioctadecylammonium bentonite, 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, procaine hydrochloride, cocobetaine, stearalkonium bentonite, stearalkonium hectorite, stearyl trihydroxyethyl propylenediamine Dihydrofluoride, resinous Including trimonium chloride, and hexadecyl trimethyl ammonium bromide, but not limited to these.

In some embodiments, the surface stabilizer may be copovidone (eg, Plasdone S630, a random copolymer of vinyl acetate and vinyl pyrrolidone) and / or docusate sodium.

Surface stabilizers are commercially available and / or can be prepared by methods known in the art. Most of these surface stabilizers are known pharmaceutical excipients, Handbook of Pharmaceutical Excipients (The Pharmaceutical Press), published jointly by the American Pharmaceutical Association and The Pharmaceutical Society of Great Britain. , 2000), which is specifically incorporated herein by reference.

3. Other Pharmaceutical Excipients

Pharmaceutical compositions of the invention may include one or more binders, fillers, lubricants, suspending agents, sweetening agents, flavoring agents, preservatives, buffers, humectants, disintegrants, effervescent agents, and other excipients. Such excipients are known in the art.

Examples of fillers include lactose monohydrate, lactose anhydrous and various starches; And a combination of polyvinyl pyrrolidone, microcrystalline cellulose, microcrystalline cellulose, and silicified microcrystalline cellulose such as Avicel ^® the PH1O1 and ^{Avicel ® PH102 (ProSolv SMCC TM)} - Examples of the binders include various cellulose and cross-linked.

Including agents that act on the fluidity (flowability) of the powder to be pressed, an appropriate lubricant will comprise a colloidal silicon dioxide, talc, stearic acid, magnesium stearate, calcium stearate, and silica gels such as Aerosil ^® 200 Can be.

Examples of sweeteners may include certain natural or artificial sweeteners such as sucrose, xylitol, sodium saccharin, cyclamate, aspartame and assulfame. Examples of flavoring agents are Magnasweet ^® (trade name of MAFCO), bubble gum flavorings, and fruit flavoring flavorings, and equivalents thereof.

Examples of preservatives include potassium sorbate, methylparaben, propylparaben, benzoic acid and salts thereof, other esters of parahydroxybenzoic acid such as butylparaben, alcohols such as ethyl alcohol or benzyl alcohol, phenolic compounds such as phenol, and benzal Quaternary compounds such as cornium chloride.

Suitable diluents include pharmaceutically acceptable inert fillers, such as microcrystalline cellulose, lactose, dibasic calcium phosphate, saccharides, and / or mixtures of those described above. Examples of diluents include microcrystalline celluloses such as Avicel ^® PH101 and Avicel ^® PH102; Lactose monohydrate, lactose such as anhydrous lactose, and Pharmatose ^® DCL21; 2, such as Emcompress ^® basic calcium phosphate; Mannitol; Starch; Sorbitol; Sucrose; And glucose.

Suitable disintegrants include polyvinyl pyrrolidone, corn starch, potato starch, maize starch, and modified starch, croscarmellose sodium, cross-povidone, sodium starch glycolate which are slightly crosslinked , And mixtures thereof.

Examples of blowing agents include organic acids and a foamable pair, such as carbonate or bicarbonate. Suitable organic acids include, for example, citric acid, tartaric acid, malic acid, fumaric acid, adipic acid, succinic acid, and alginic acid, and their anhydrides and acid salts thereof. 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 one sodium bicarbonate component may be present in the effervescent pair.

4. Nano particle type Kinase  Inhibitor particle size

The compositions of the present invention, when measured by light-scattering methods, microscopes or other suitable methods, are less than about 2000 nm (ie, 2 microns), less than about 1900 nm, less than about 1800 nm, less than about 1700 nm, 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, 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, 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, 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, about 660 nm under 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, about 130 nm One or more nanoparticles, such as LS104 (or a salt or derivative thereof), having an effective average particle size of less than about 120 nm, less than about 110 nm, less than about 100 nm, less than about 75 nm, or less than about 50 nm. Type kinase inhibitor particles.

The term “effective average particle size of less than about 2000 nm” is one of kinase inhibitor particles such as LS104 when measured by the above-initiated method, by weight (or other suitable measurement method such as number, volume, etc.). At least 50% having a particle size below the effective average, ie, less than about 2000 nm, less than about 1900 nm, less than about 1800 nm. In another embodiment 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 kinase inhibitor particles, such as LS104, are below the effective average That is, less than about 2000 nm, less than about 1900 nm, less than about 1800 nm, less than about 1700 nm, and the like.

In the present invention, the D50 value of a nanoparticulate kinase inhibitor composition such as LS104 is the particle size corresponding to 50% by weight of the kinase inhibitor particles. Likewise, D90 is the particle size corresponding to 90% by weight of the kinase inhibitor particles.

5. Kinase  Inhibitor receptor With the antagonist  Use of Surface Stabilizers

The relative content of kinase inhibitors and one or more surface stabilizers such as LS104 or salts or derivatives thereof may vary. The optimum content of each component may depend, for example, on the particular kinase inhibitor selected, hydrophilic lipophilic balance (HLB), melting point, and surface tension of the surface stabilizer aqueous solution.

The concentration of the kinase inhibitor (such as LS104) may range from about 99.5 weight percent to about 0.001 weight percent, from about 95 weight percent to about 0.1 weight based on the total dry weight of the kinase inhibitor and one or more surface stabilizers that do not include other excipients. %, Or from about 90% to about 0.5% by weight.

The concentration of the at least one surface stabilizer is from about 0.5% to about 99.999% by weight, from about 5.0% to about 99.9% by weight relative to the total mixed dry weight of the kinase inhibitor and at least one surface stabilizer that does not include other excipients, Or from about 10% to about 99.5% by weight.

6. Representative Nanoparticulate LS104 Tablet Formulations

Several representative LS104 tablet formulations are provided below. These examples are not intended to limit the claims in any respect, but to provide a representative tablet formulation of LS104 that can be used in the methods of the present invention. Such representative tablets may also include a coating.

7. Representative Injectable Nanoparticulate LS104 Formulations

The present invention provides an injectable composition comprising one or more nanoparticulate small molecule kinase inhibitors, such as LS104, which may include high concentrations of drug in low injection volumes, with rapid drug dissolution after administration. Injectable nanoparticulate kinase inhibitors, such as the LS104 formulations of the present invention, may also obviate the need to use solubilizers such as polyoxyl 60 hydrogenated castor oil (HCO-60). Representative injectable compositions include the following in% W / W:

Small molecule, synthetic kinase inhibitors such as LS104: 5-50%

Povidone Polymer: 0.1-50%

Preservative: 0.05-0.25%

pH adjusters: pH about 6 to about 7

Water for injection: fill

Representative preservatives are 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) Representative pH adjusters are sodium hydroxide, and representative liquid carriers are sterile water for injection Other useful preservatives, pH adjusters, and liquid carriers are known in the art. It is well known.

C. Nanoparticle Type Kinase  How to Prepare an Inhibitor Composition

Compositions comprising one or more nanoparticulate kinase inhibitors, such as LS104 (or salts or derivatives thereof), may, for example, be milled or attrition (including but not limited to wet milling), homogenization, precipitation , Freezing, template emulsion methods, supercritical fluid methods, nano-electron spray methods, or any combination thereof. Representative methods for preparing nanoparticulate compositions are described in the '684 patent. In addition, methods for preparing nanoparticulate compositions include US Pat. No. 5,518,187 for "Method of Grinding Pharmaceutical Substances;" US Patent No. 5,718,388 for "Continuous Method of Grinding Pharmaceutical Substances"; US Patent No. 5,862,999 for "Method of Grinding Pharmaceutical Substances"; US Patent No. 5,665,331 for "co-microprecipitation of nanoparticulate pharmaceutical drugs by crystal growth modifiers;" US Patent No. 5,662,883 for "Co-Microprecipitation of Nanoparticulate Pharmaceutical Drugs by Crystal Growth Modifiers; US Patent No. 5,560,932 for "Microprecipitation of Nanoparticulate Pharmaceutical Drugs"; US Patent No. 5,543,133 for "Method for Preparing X-Ray Contrast Compositions Comprising Nanoparticles"; US Patent No. 5,534,270 for "Method for Preparing Stable Drug Nanoparticles"; US Patent No. 5,510,118 for "Method for Preparing a Therapeutic Composition Including Nanoparticles"; And US Pat. No. 5,470,583 for "Methods for Producing Nanoparticulate Compositions Containing Charged Phospholipids for Reduced Density," all of which are specifically incorporated by reference. .

The resulting nanoparticulate kinase inhibitor composition or dispersion may be injectable formulations, liquid dispersions, gels, aerosols, ointments, creams, controlled release formulations, rapid dissolving formulations, lyophilized formulations, tablets, capsules, delayed release formulations, elongations. It can be used in solid or liquid dosage forms such as release formulations, pulsatile release formulations, mixed formulations of immediate release and controlled release.

1. Nanoparticle type Kinase  To obtain inhibitor dispersion milling

To obtain nanoparticulate kinase inhibitor dispersions, milling kinase inhibitors such as LS104 or salts or derivatives thereof may be achieved by dispersing the kinase inhibitor particles in a liquid dispersion medium in which the kinase inhibitor is poorly soluble, followed by grinding media. Applying mechanical means in the presence of to reduce the particle size of the kinase inhibitor to the targeted effective mean particle size. The dispersion medium can be, for example, water, safflower seed oil, ethanol, t-butanol, glycerin, polyethylene glycol (PEG), hexane or glycol. In some embodiments, the preferred dispersion medium is water.

Kinase inhibitor particles may be reduced in size in the presence of one or more surface stabilizers. Alternatively, the kinase inhibitor particles may be contacted with one or more surface stabilizers after wear. Other compounds, such as diluents, can be added to the kinase inhibitor / surface stabilizer composition during the size reduction process. Dispersions can be prepared continuously or in batch mode.

The grinding media may comprise particles which are essentially composed of polymeric resins or copolymer resins, preferably substantially spherical, for example beads. Alternatively, the grinding media may comprise a core having a coating of polymeric resin or copolymer resin adsorbed to the core.

In general, suitable polymeric resins or copolymer resins are chemically and materially inert, substantially free of metals, solvents, and monomers, sufficiently rigid and friability to avoid chipping or breaking during grinding. You should be able to. Suitable polymer resins or copolymer resins include crosslinked polystyrenes such as polystyrene crosslinked with divinylbenzene; Styrene copolymers; Polycarbonate; Polyacetals such as Delrin ^™ (EI du Pont de Nemours and Co.); Vinyl chloride polymers and copolymers; Polyurethane; Polyamides; For example ^{Teflon ® (EI du Pont de Nemours} and Co.) poly (tetrafluoroethylene), such as and polymers with other fluoro; High density polyethylene; Polypropylene; Cellulose esters such as cellulose ether and cellulose acetate; Polyhydroxy methacrylate; Polyhydroxyethyl acrylate; And silicone-comprising polymers such as polysiloxanes and their equivalents. The polymer may be biodegradable. Representative biodegradable polymers or copolymers include poly (lactide), poly (glycolide) copolymers of lactide and glycolide, polyanhydrides, poly (hydroxyethyl methacrylate), poly (imino) Carbonates), poly (N-acylhydroxyproline) esters, poly (N-palmitoyl hydroxyproline) esters, ethylene-vinyl acetate copolymers, poly (orthoesters), poly (caprolactones), and poly (phosphazenes) (phosphazene)). In the case of biodegradable polymers or copolymers, contamination of the medium itself can advantageously be metabolized in vivo into a biologically acceptable product that can be removed from the body.

The grinding media is preferably in the range of about 0.01 mm to about 3 mm in size. For fine grinding, the grinding media is preferably in the range of about 0.02 mm to about 2 mm, more preferably about 0.03 mm to about 1 mm in size.

The polymeric resin or copolymer resin may have a density of about 0.8 to about 3.0 g / cm ³ .

In a preferred grinding process, the particles are made continuously. This method comprises the steps of continuously injecting a composition according to the invention into a milling chamber, reducing the particle size of the composition according to the invention in the chamber while contacting the composition according to the invention with a grinding media, and from the milling chamber. Continuously removing the nanoparticles of the nanoparticulate composition according to the invention.

The grinding media can be separated from the milled nanoparticulate composition according to the invention using conventional separation methods in secondary processes such as simple filtration, sieving through a mesh filtration or screen, and equivalents thereof. Other separation methods such as centrifugation can also be used.

2. Nano particle type Kinase  Precipitation to Obtain Inhibitor Composition

Another method of producing a targeted composition comprising one or more nanoparticulate kinase inhibitors such as LS104 or salts or derivatives thereof is by microprecipitation. This is a method of producing a stable dispersion of sparingly soluble active agents in the presence of one or more surface stabilizers and one or more colloidal stability that increases the stability of one or more colloids free of any trace toxic solvents or solubilized heavy metal impurities. Such methods include, for example: (1) dissolving a 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 may then proceed to remove any resulting salt, if present, by dialysis or diafiltration, and concentrate the dispersion in a conventional manner.

3. Nano particle type Kinase  To obtain an inhibitor composition Homogenization

Representative homogenization methods for preparing active agent nanoparticulate compositions are described in US Pat. No. 5,510,118 for "Methods for Preparing Therapeutic Compositions Including Nanoparticles." This method comprises dispersing LS104 (or a salt thereof or derivative thereof) particles in a liquid dispersion medium and then homogenizing the dispersion obtained to reduce the particle size of the kinase inhibitor to the target effective mean particle size. The particles can be reduced in size in the presence of one or more surface stabilizers. Alternatively, the kinase inhibitor particles may be contacted with one or more surface stabilizers before or after attrition. Other compounds, such as diluents, may be added to the kinase inhibitor / surface stabilizer composition before, during or after the size reduction process. Dispersions can be prepared continuously or batchwise.

4. Nano particle type Kinase  Cryogenic method for obtaining inhibitor composition ( cryogenic methodology )

Another method of producing targeted nanoparticulate kinase inhibitors such as LS104 (or salts or derivatives thereof) is by spray freezing into liquid (SFL). The method comprises the step of injecting an organic solution or an organic aqueous solution of a kinase inhibitor with stabilizer into a cryogenic liquid, such as liquid nitrogen. Droplets of the LS104 solution are frozen at a rate sufficient to minimize crystallization and particle growth, thus formulating nanostructured LS104 particles. Depending on the choice of solvent system and the process conditions, the nanoparticulate kinase inhibitor particles can have various particle forms. In the separation step, the nitrogen and the solvent are removed under conditions that avoid aggregation or ripening of the kinase inhibitor particles.

As a complementary method of SFL, ultra rapid freezing (URF) can also be used to make equivalent nanostructured kinase inhibitors with very increased surface area. URF includes organic solutions or organic solutions of kinase inhibitors with stabilizers on cryogenic substrates.

5. Nano particle type Kinase  To obtain an inhibitor composition emulsion  Way

Another method for producing targeted nanoparticulate kinase inhibitor compositions such as LS104 is by template emulsions. Template emulsions produce nanostructured kinase inhibitor or derivative particles with controlled particle size distribution and fast dissolution performance. The method comprises an oil-in-water emulsion prepared and then expanded with a non-aqueous solution comprising a kinase inhibitor and a stabilizer. The particle size distribution of the kinase inhibitor is a direct result of the size of the emulsion droplets before being deposited with the kinase inhibitor, a feature that can be controlled and optimized in this process. In addition, through the selected use of solvents and stabilizers, emulsion stability is achieved without Ostwald ripening, or while Ostwald maturation is inhibited. Subsequently, the solvent and water are removed and the stabilized nanostructured kinase inhibitor particles are recovered. Various kinase inhibitor particle morphologies can be achieved through appropriate control of process conditions.

6. Manufacturing Nanoparticles Supercritical  Fluid method

Nanoparticulate compositions can also be prepared by methods using supercritical fluids. In this method, a kinase inhibitor such as LS104 is dissolved in a solution or carrier that may also include one or more surface stabilizers. The solution and supercritical fluid are then injected simultaneously into the particle production vessel. If no surface stabilizer has been previously added to the carrier, the surface stabilizer may be added to the particle production vessel. The temperature and pressure are adjusted so that dispersion and extraction of the carrier occur substantially simultaneously by the action of the supercritical fluid. Chemicals described as useful as supercritical fluids include carbon dioxide, nitric oxide, sulfur hexafluoride, xenon, ethylene, chlorotrifluoromethane, ethane, and trifluoromethane.

Examples of known supercritical methods for preparing nanoparticles include international patent application WO 97/144407 by Pace et al., Published April 24, 1997, in which a water-insoluble biologically active compound is dissolved in a solution and such Reference is then made to particles of the compound having an average size of 100 nm to 300 nm, which are prepared by spraying the solution with pressurized gas, liquid, or supercritical fluid in the presence of a suitable surface stabilizer.

Similarly, US Pat. No. 6,406,718 to Cooper et al. Comprises co-injecting a carrier or supercritical fluid comprising at least fluticasone propionate into a particle production vessel in a solution or suspension, wherein A method of producing a fluticasone propionate product in the form of particles is described that includes controlling temperature and pressure such that extraction of the carrier occurs substantially simultaneously by the action of a supercritical fluid. Chemicals described as useful as supercritical fluids include carbon dioxide, nitrogen oxides, sulfur hexafluoride, xenon, ethylene, chlorotrifluoromethane, ethane and trifluoromethane. The supercritical fluid may optionally include one or more modifiers such as methanol, ethanol, ethyl acetate, acetone, acetonitrile or mixtures thereof. Supercritical fluid modifying materials (or co-solvents) are chemicals that, when added into a supercritical fluid, change the intrinsic properties of the supercritical fluid at or near the critical point. According to Cooper et al, fluticasone propionate particles produced using supercritical fluids have a particle size range of 1 to 10 microns, preferably 1 to 5 microns.

7. Nano-electron spray method used to obtain nanoparticulate compositions

In electrospray ionization, the liquid is forced through a small, charged, generally metal, capillary tube. This liquid contains a target substance, such as a kinase inhibitor (or “analyte”), dissolved in a large amount of solvent, which solvent is generally much more volatile than the analyte. Volatile acids, bases or buffers are likewise often added to this solution. The analyte is present in the solution as ions in quantized form or as anions. As the same charge repels, the liquid is pushed out of the capillary itself, forming a mist or aerosol of small droplets of about 10 μm diameter. The ejection of this aerosol droplet is produced at least in part by a process involving the production of a Taylor cone and the ejection from the end of the cone. Neutral carrier gases, such as nitrogen gas, are sometimes used to help spray liquids and to help the neutral solvent evaporate in small droplets. As the solvent evaporates in small droplets suspended in air, the charged analyte molecules are drawn closer together. As the similarly charged molecules get closer, the droplet becomes unstable and the droplet breaks once again. This is called Coulombic fission because it is the Coulomb force that pushes between charged analytical molecules that move it. This process is repeated until the solvent disappears from the analyte and becomes a single ion.

In nanotechnology, electrospray methods can be used to deposit single particles, such as kinase inhibitor particles, on a surface. This is done by spraying the colloid and confirming that on average there are no more than one particle per droplet. Drying of the surrounding solvent results in aerosol flow of a single particle of the desired form. Here, the ionization properties of the process are not critical for the application but can be used for the electrostatic precipitation of the particles.

D. Nanoparticle Form of the Invention Kinase  How to Use Inhibitor Composition

The present invention provides a method of increasing the bioavailability (eg, increasing plasma levels) of a kinase inhibitor, such as LS104 (or a salt or derivative thereof), in a subject. Such methods include orally administering to a subject an effective amount of a composition comprising a nanoparticulate kinase inhibitor.

In one embodiment of the invention, according to standard pharmacokinetic practice, nanoparticulate kinase inhibitor compositions, such as LS104, are about 50%, about 40%, about 30%, about 20% or about 10% more than conventional dosage formulations. It is expected to show great bioavailability.

In another embodiment of the invention, when tested in fasted subjects according to standard pharmacokinetic practices, the composition is less than about 6 hours, less than about 5 hours, less than about 4 hours, less than about 3 hours, about 2 after the initial administration of the composition It is proposed to produce a maximum blood plasma concentration after less than one hour, less than about 1 hour or less than about 30 minutes.

The compositions of the present invention may be useful for the treatment of cancer, for example, cell proliferative diseases such as leukemias such as CML and ALL, and myeloproliferative diseases such as PV, ET and IMF.

Compositions of the invention comprising one or more nanoparticulate kinase inhibitors, such as LS104 (or salts or derivatives thereof), include, but are not limited to oral, rectal, ocular, parenteral (e.g., intravenous, Intramuscularly, or subcutaneously), intramurally, lung, intravaginally, intraperitoneally, topically (eg, powders, ointments or drops), or via any conventional means, including oral or nasal sprays. It can be administered to. In some embodiments, parenteral administration is preferred. When the term "individual" is used herein, it is used to mean an animal, preferably a mammal, such as a human or non-human. Patients and individuals may be used interchangeably.

Suitable compositions for parenteral injection include sterile powders for reconstitution into physiologically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, and sterile injectable solutions or dispersions. It may include. Examples of suitable aqueous and non-aqueous carriers, diluents, solvents, or carriers include water, ethanol, polyols (propylene glycol, polyethylene-glycol, glycerol, and their equivalents), suitable mixtures thereof, vegetable oils (such as olive oils) 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 one or more nanoparticulate kinase inhibitors such as LS104 (or salts or derivatives thereof) may also include adjuvants such as preservatives, wetting agents, emulsifiers and dispersants. Prevention of microbial growth can be ensured by various antibacterial and antifungal agents such as parabens, chlorobutanol, phenol, sorbic acid, and equivalents thereof. It may be desirable to include isotonic agents such as sugars, sodium chloride, and equivalents thereof. Prolonged absorption of injectable pharmaceutical formulations can be brought about by the use of agents that delay 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. In such solid dosage forms, the active agent is mixed with one or more of the following components: (a) one or more inert excipients (or carriers), such as sodium citrate or dicalcium phosphate; (b) one or more fillers or extenders such as starch, lactose, sucrose, glucose, mannitol, and silicic acid; (c) binders such as carboxymethylcellulose, alginates, 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 composite silicates, and sodium carbonate; (f) solution retarders such as paraffin; (g) absorption accelerators, such as quaternary ammonium compounds; (h) humectants, 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 form may also include a buffer.

Liquid dosage forms for oral administration may include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs. Liquid dosage forms can include kinase inhibitors such as LS104 as well as inert diluents, solubilizers, and emulsifiers commonly used in the art, such as water or other solvents. Representative emulsifiers are ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, cottonseed oil, peanut oil, corn germinated oil, olive oil, Castor oil, and oils such as sesame oil, glycerol, tetrahydrofurfuryl alcohol, polyethyleneglycol, fatty acid esters of sorbitan, or mixtures of these materials, and equivalents thereof.

In addition to these inert diluents, the compositions may also include adjuvants such as moisturizers, emulsifiers and suspending agents, sweetening agents, flavoring agents, and perfuming agents.

As used herein, for example, a kinase inhibitor such as administration of LS104, a "therapeutically effective amount" will mean a drug dosage that provides a specific pharmacological response when LS104 is administered to a significant number of individuals in need of treatment. Although such a dosage is a “therapeutically effective amount” to those skilled in the art, it should be emphasized that in certain cases, a “therapeutically effective amount” administered to a particular individual will not always be effective when treating a disease described herein. do. In certain instances, it should be further understood that the LS104 dosage is measured by oral dosage or by reference to drug levels measured in blood.

One skilled in the art can determine the effective amount of a kinase inhibitor such as LS104 by experiment and, when present in its pure form, or in the form of such a pharmaceutically acceptable salt, ester, or pro-drug You will see that. Substantial dosages of kinase inhibitors, such as LS104, in the nanoparticulate compositions of the invention can be varied to obtain an amount of kinase inhibitor, such as LS104, that is effective for obtaining a targeted therapeutic response for a particular composition and method of administration. . Thus, the dosage level chosen depends on the desired therapeutic effect, the route of administration, the potency of the kinase inhibitor such as LS104 administered, the targeted duration of treatment, and other factors.

Dosage unit compositions can include a submultiple of that content so that it can be used to supplement a daily dose. However, the specific degree of administration for a particular patient may include the type and degree of cellular or physiological response to be achieved; The activity of the specific agent or composition employed; The specific agent or composition employed; The age, body weight, general health, sex and food intake of the patient; Time of administration, route of administration, and rate of excretion of the agent; Duration of treatment; Drugs used in combination or coincidental with certain agents; And equivalent factors well known in the medical arts.

E. Example

The following examples are provided to illustrate the present invention. However, it should be understood that the present invention is not limited to the specific conditions or details described in this embodiment. Throughout the specification, any and all references to publicly available documents, including US patents, are specifically incorporated by reference.

Example 1

The purpose of this example was to prepare nanoparticulate formulations of LS104 suitable for intravenous administration. As described below, representative and successful nanoparticulate dispersion formulations (“NCDs”) included 10% LS104, 2.5% Povidone K-12 PF and 0.1% sodium deoxycholate.

Initial formulation screening was performed using a low energy roller milling (Stoneware) approach. The grinding media used was 0.8 mm yttrium treated zirconium (Tosoh). All formulations were milled at 170 rpm. Milling times are reported in Table 1 below.

Optical microscopy was performed using a Leica optical microscope with a 100x objective. All particle sizes were measured using Horiba LA 910 with deionized (DI) water as a diluent and 30 sec sonication.

Four different formulations were screened, identified in Table 1 below. The first formulation included Poloxamer 338 (Pluronic F108) as a stabilizer. At the end of the process large crystals were observed. This may be the result of crystal growth (Ostwald maturation), which suggests that this stabilizer may not be optimal under any milling parameters (ie the specific drug concentration and surface stabilizer concentration used). The second formulation included Polysorbate 80 (Tween 80). At the end of the process, a dispersion comprising small, well dispersed particles was observed. The third formulation included hydroxy propyl cellulose (HPC-SL). This formulation also contained small, well dispersed particles. The fourth formulation included a mixture of povidone K-12 (Plasdone K-12, low molecular weight grade polyvinylpyrrolidone) and sodium deoxycholate. This formulation also contained small, well dispersed particles at the end of the process. The results are summarized in Table 1 below.

Table 1

Using gamma irradiation, final sterilization was performed. Finally, also into the irradiated vial, the final product was charged. In several batches, stability studies (eg, 3 months, 6 months and 12 months under various temperature and humidity conditions) were performed.

Example  2

The second and fourth formulations were further evaluated. Past experience of having slightly smaller particle size when having PVP K-12 and NaDOC together makes the fourth formulation slightly better. Therefore, as one target stabilizer for LS104, the PVP K12 / Nadeoxycholate combination was chosen.

Initial Roller Milling Screening All of the following processes were performed using high energy medium milling where highly crosslinked polystyrene beads were used as grinding media. Since high shear force environments can sometimes lead to aggregation, it has been demonstrated that lead formulations can be prepared using this process. Formulations containing the same stabilizer components have been adapted for high energy processing. The formulation included 5% LS104 / 1.25% PVP K-12 / 0.05% NaDOC, which was successfully evaluated in high energy milling.

Product particle size was measured on a Horiba LA910 particle size analyzer using a standard R & D procedure with a sample concentration targeted at 80% transmission and using a relative complex refractive index m = 1.2-0.1 i . The results are shown in Table 2 below.

Table 2. High Energy Milling of Lead Formulations

This suggests that formulations comprising 5% LS104 / 1.25% PVP K-12 / 0.05% Na deoxycholate are suitable for high energy processes. The concentration of active pharmaceutical ingredient (API) can be increased in subsequent experiments for process efficiency while maintaining the same API / stabilizer ratio.

Table 3 below details additional exemplary nanoparticulate LS104 formulations. All such formulations are 500 micron PolyMill ^® attrition media (Dow Chemical) and with, NanoMill-01; was prepared using (NanoMill Systems, King of Prussia, PA, for example, reference is made to U.S. Patent No. 6431478 No.). Optical microscopy was performed using a Leica optical microscope with a 100x oil objective. All particle sizes were determined using Horiba LA 910 with distilled, deionized water as diluent and 30 sec sonication. In Table 3, the first column represents the formulation; The second column shows both mean and D90 particle size (PS); The third column contains microscopic observations; The fourth column represents the milling time; The fifth column represents the milling size; The sixth column represents the mill load; The seventh column represents the milling speed; The eighth column gives a description of the formulation.

Table 3.

It will be apparent to those skilled in the art that various modifications and variations can be made in the compositions, methods, and uses of the invention without departing from the spirit and scope of the invention. Accordingly, the invention includes the modifications and variations of the invention provided they come within the scope of the appended claims and their equivalents.

Claims (23)

(a) LS104 or a salt or derivative thereof thereof having an effective average particle size of less than about 2000 nm; And (b) Stable nanoparticulate kinase inhibitor composition comprising at least one surface stabilizer. The composition of claim 1, wherein the LS104 is a crystalline phase, an amorphous phase, a semi-crystalline phase, a semi amorphous phase, or a mixture thereof. The method according to claim 1 or 2, wherein the effective average particle size of the particles of LS104 or salts or derivatives thereof is 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 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, about Less than 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, About Less than 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, About 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, about Less than 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, about Less than 140 nm, less than about 130 nm, about 120 nm But, less than about 110 nm, less than about 100 nm, less than about 75 nm, and which is selected from the group consisting of less than about 50 nm compositions. The composition of claim 1, wherein the nanoparticulate LS104 composition has improved bioavailability compared to conventional LS104 compositions. The composition of claim 1, wherein the composition is (a) Formulated for administration selected from the group consisting of oral, pulmonary, intravenous, rectal, eye, colon, parenteral, intracranial, intravaginal, intraperitoneal, topical, oral, nasal, and topical administration. Or; (b) is formulated in a dosage form selected from the group consisting of liquid dispersions, gels, aerosols, ointments, creams, tablets, sachets and capsules; (c) a dosage form selected from the group consisting of freeze dried formulations, rapid dissolution formulations, controlled release formulations, delayed release formulations, extended release formulations, pulsatile release formulations, and mixed formulations of immediate release and controlled release; or and (d) a combination of (a), (b), and (c). 6. The composition of claim 1, wherein the composition further comprises one or more pharmaceutically acceptable excipients, carriers, or combinations thereof. 7. The method according to any one of claims 1 to 6, (a) the content of LS104 is from about 99.5% to about 0.001% by weight, from about 95% to about 0.1% by weight, relative to the total dry weight of the LS104 and at least one surface stabilizer that does not include other excipients, and From about 90% to about 0.5% by weight; (b) the at least one stabilizer is from 0.01 wt% to about 99.5 wt%, from about 0.1 wt% to about 95 wt%, based on the total dry weight of the LS104 and at least one surface stabilizer that does not include other excipients, Is present in an amount selected from the group consisting of about 0.5% to about 90%, about 5.0% to about 99.9%, and about 10% to about 99.5% by weight; or (c) is a combination of (a) and (b). 8. The composition of claim 1, comprising at least one primary surface stabilizer and at least one secondary surface stabilizer. 9. The method of claim 1, wherein the one or more surface stabilizers are non-ionic surface stabilizers, ionic surface stabilizers, anionic surface stabilizers, cationic surface stabilizers, and zwitterions. The composition is selected from the group consisting of surface surface stabilizers. The method of claim 1, wherein the one or more surface stabilizers are cetyl pyridinium chloride, gelatin, casein, phosphatide, dextran, glycerol, gum acacia, cholesterol, tragacanth, stearic acid , Benzalkonium chloride, calcium stearate, glycerol monostearate, cetostearyl alcohol, cetomacrogol emulsifying wax, sorbitan ester, polyoxyethylene alkyl ether, polyoxyethylene caster oil oil derivatives, polyoxyethylene sorbitan fatty acid esters, polyethylene glycol, dodecyl trimethyl ammonium bromide, polyoxyethylene stearate, colloidal silicon dioxide, phosphate, sodium dodecyl sulfate, carboxymethyl cellulose calcium, Hydroxypropyl Cellulose, Hypromelo , Carboxymethylcellulose sodium, methylcellulose, hydroxyethylcellulose, hypromellose phthalate, noncrystalline cellulose, magnesium aluminum silicate, triethanolamine, polyvinyl alcohol, polyvinylpyrrolidone, ethylene oxide and formaldehyde 4- (1,1,3,3-tetramethylbutyl) -phenol polymer having poloxamer; Poloxamine, charged phospholipid, dioctylsulfosuccinate, dialkyl ester of sodium sulfosuccinic acid, sodium lauryl sulfate, alkyl aryl polyether sulfonate, a mixture of sucrose stearate and sucrose distearate, C ₁₈ H ₃₇ CH ₂ C (O) N (CH ₃ ) -CH ₂ (CHOH) ₄ (CH ₂ OH) ₂ , p-isononylphenoxypoly- (glycidol), decanoyl-N-methylgluka mid; 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, lysozyme, random copolymer of vinyl acetate and vinyl pyrrolidone, cationic poly Mercury, cationic biopolymers, cationic polysaccharides, cationic cellulose compounds (cellulosic), cationic alginates, cationic nonpolymeric compounds, cationic phospholipids, cationic lipids, polymethylmethacryl Laterate trimethylammonium bromide, sulfonium compound, polyvinylpyrrolidone-2-dimethylaminoethyl methacrylate dimethyl sulfate, hexadecyltrimethyl ammonium bromide, phosphonium compound, quaternary ammonium compound, 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, C _{12 - 15} dimethyl hydroxyethyl ammonium chloride, C _{12 - 15} dimethyl 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, la (not tenok a) lauryl dimethyl _quaternary ammonium chloride, lauryl dimethyl (when the tenok) ₄ ammonium bromide, N- alkyl (C _{12 -18)} dimethyl benzyl ammonium chloride, N- alkyl (C _14-18) dimethyl benzyl Ammonium chloride, N- tetradecyl dimethyl benzyl ammonium chloride monohydrate, dimethyl didecyl ammonium chloride, N- alkyl and (C _{12 -14)} dimethyl 1-naphthylmethyl ammonium chloride, trimethylammonium fluoride to ammonium, alkyl-trimethylammonium salts, dialkyl Dimethylammonium salts, lauryl trimethyl ammonium chloride, ethoxylated alkylamidoalkyldialkylammonium salts, ethoxylated trialkyl ammonium salts, dialkylbenzene dialkylammonium chlorides, N-decedyldimethyl ammonium Chloride, N-tetradecyldimethylbenzyl ammonium chloride monohydrate, N-alkyl (C _12-14 ) 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, C ₁₂ trimethyl ammonium bromide, C ₁₅ trimethyl ammonium bromide, C ₁₇ trimethyl ammonium bromide, dodecylbenzyl triethyl ammonium chloride, poly-diallyldimethylammonium chloride (DADMAC), dimethyl ammonium chloride, alkyldimethylammonium halogenide, tricetyl Methyl ammonium chloride, decyltrimethylammonium bromide, dodecyltriethylammonium bromide, tetradecyltrimethylammonium bromide, methyl trioctylammonium chloride, POLYQUAT 10TM, tetrabutylammonium bromide, benzyl trimethylammonium bromide, choline esters, benzal benzalkonium chloride, stearic benzalkonium chloride compounds, cetyl pyridinium bromide, cetyl pyridinium chloride, halide salts of quaternized poly-oxyethyl-alkyl amine, Mira pole (MIRAPOL) ^TM, alkaryl quart (ALKAQUAT) ^TM, alkyl pyridinium Salt; Selected from the group consisting of amines, amine salts, amine oxides, imide azolinium salts, quantized quaternary acrylamides, methylated quaternary polymers, and cationic guar Composition. The composition of claim 1, further comprising one or more active agents useful for the treatment of cell proliferative diseases or disorders. The method according to any one of claims 1 to 11, (a) After administration to a mammal, the LS104 or a salt or derivative thereof thereof may have particles 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, 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, 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, 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, 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, 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, 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, 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, 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, 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, about 150 nm Less than about 140 nm, less than about 130 nm, Less than 120 nm, less than about 110 nm, less than about 100 nm, less than about 75 nm, and the dispersed material have an effective average particle size selected from the group consisting of less than about 50 nm, or; (b) the composition has an LS104 particle 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, about 61 Less than 0 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, about Less than 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, About 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, about Less than 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, about Less than 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, about Less than 110 nm, less than about 100 nm, less than about 75 nm, And redispersed in a biorelevant medium to have an effective average particle size selected from the group consisting of less than about 50 nm; or (c) is a combination of (a) and (b). The composition of claim 12, wherein the biorelated medium is selected from the group consisting of water, aqueous electrolyte solution, aqueous solution of salt, aqueous solution of acid, aqueous solution of base, and combinations thereof. The method according to any one of claims 1 to 13, (a) when analyzed in plasma of a mammalian subject following administration, the T _max of the nanoparticulate LS104 composition is less than the T _max of the non-nanoparticulate composition of the same LS104 administered at the same dose; (b) C _max of the nanoparticulate LS104 composition when administered in plasma of the following mammalian subject is greater than C _max of the non-nanoparticulate composition of the same LS104 administered at the same dose; (c) the AUC of the nanoparticulate LS104 composition when administered in plasma of the following mammalian subject is greater than the AUC of a non-nanoparticulate composition of the same LS104 administered at the same dose; or (d) a composition which is a combination of (a), (b) and (c). The method of claim 14, (a) The T _max is about 90% or less, about 80% or less, about 70% or less, about 60% or less, about 50 or less of T _max represented by the same non-nanoparticulate composition of the same LS104 administered at the same dose Up to about 30%, up to about 25%, up to about 20%, up to about 15%, up to about 10%, and up to about 5%; (b) the C _max is at least about 50%, at least about 100%, at least about 200%, at least about 300%, at least about C _max represented by the non-nanoparticulate composition of the same LS104 administered at the same dose 400% or more, about 500% or more, about 600% or more, about 700% or more, about 800% or more, about 900% or more, about 1000% or more, about 1100% or more, about 1200% or more, about 1300% or more, about At least 1400%, at least about 1500%, at least about 1600%, at least about 1700%, at least about 1800%, or at least about 1900%; (c) the AUC is at least about 25%, at least about 50%, at least about 75%, at least about 100%, at least about 125% of the AUC exhibited by a non-nanoparticulate formulation of the same LS104 administered at the same dose , 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 650%, 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%; or (d) a composition which is a combination of (a), (b) and (c). The composition of claim 1, wherein the composition does not produce significantly different levels of absorption when administered under fasting conditions when administered under fasting conditions. The method of claim 16, wherein the difference in absorption of the active agent composition of the present invention when administered in a fasted state versus a fed state is less than about 100%, less than about 90%, less than about 80%, less than about 70%, 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% The composition is selected from the group. The composition of claim 1, wherein the administration of the composition to a human in a fasted state is biologically equivalent to the administration of the composition to an individual in a fed state. 19. The method of claim 18, wherein the "bioequivalency" (a) a 90% confidence interval of 0.80 to 1.25 for both C _max and AUC; or (b) a composition established by a 90% confidence interval of 0.80 to 1.25 for AUC and a 90% confidence interval of 0.70 to 1.43 for C _max . Use of the composition of any one of claims 1 to 19 for the manufacture of a medicament. The composition of claim 20, wherein the medicament is useful for treating leukemia, myeloproliferative diseases and related diseases or disorders. Contacting the LS104 particles with one or more surface stabilizers for a time and under conditions sufficient to provide a nanoparticulate LS104 composition having an effective average particle size of less than about 2000 nm, or a nanoparticulate LS104 or salt thereof A method of making a derivative composition. The method of claim 22, wherein the contacting comprises milling, wet milling, homogenizing, precipitation, freezing, supercritical fluid particle production methods, emulsion methods, nano-electrospray methods, or combinations thereof.