FR2945950A1 - ANTICANCER NANOPARTICLE COMPOSITIONS AND METHODS FOR PREPARING THE SAME - Google Patents

Abstract

Injectable formulations of particulate 3- (2,4-dichloro-phenyl) -1,6-dimethyl-1,9-dihydro-pyrido [2,3-b] indol-2-one are described which produce a duration of prolonged action during administration, and methods of making and using such formulations. Injectable formulations include particulate 3- (2,4-dichloro-phenyl) -1,6-dimethyl-1,9-dihydro-pyrido [2,3-b] indol-2-one.

Description

FIELD OF THE INVENTION The present invention relates generally to 3- (2,4-dichloro-phenyl) -1,6-dimethyl-1,9-dihydropyrido [2,3-b] indol nanoparticle compositions. -2-one, and in particular a nanoparticle composition useful in the treatment of cancer. BACKGROUND OF THE INVENTION The following discussion of the context of the invention is simply provided to readers to help understand the invention and is not intended to describe or constitute prior art for the present invention.

3- (2,4-Dichloro-phenyl) -1,6-dimethyl-1,9-dihydro-pyrido [2,3-b] indol-2-one has been shown to have the structure of the formula ( I). It is particularly potent as an anticancer agent. The preparation, physical properties and beneficial pharmacological properties of 3- (2,4-dichloro-phenyl) -1,6- • 2945950 2 dimethyl-1,9-dihydro-pyrido [2,3-b] indol- 2-one are described, for example, in WO 2004/041 817 (also US Pat. No. 7,390,818) incorporated herein by reference. The limited solubility of 3- (2,4-dichloro-phenyl) -1,6-dimethyl-1,9-dihydropyrido [2,3-b] indol-2-one in aqueous solutions presents difficulties in administration and formulation of the drug and may lead to poor bioavailability. Bioavailability is the degree to which a drug becomes available to the target tissue after administration. Many factors may affect bioavailability including the dosage form and various properties, for example the rate of dissolution of the drug. Poor bioavailability is a significant problem encountered in the development of pharmaceutical compositions, particularly those containing an active ingredient that is poorly soluble in water, such as 3- (2,4-dichlorophenyl) -1.6 dimethyl-1,9-dihydro-pyrido [2,3-b] indol-2-one. Medications that are poorly soluble in water tend to be dangerous for intravenous administration techniques, which are used primarily with fully soluble drug substances. The nanoparticle compositions disclosed for the first time in US Patent No. 5,145,684 (the `684 patent), incorporated herein by reference, are particles consisting of a poorly soluble therapeutic or diagnostic agent having adsorbed a uncrosslinked surface on its surface. The '684 patent does not disclose 3- (2,4-dichloro-phenyl) -1,6-dimethyl-1,9-dihydropyrido [2,3-b] indol-2-one nanoparticle compositions. Processes for preparing nanoparticle compositions are described, for example, in U.S. Patent No. 5,518,187 for Method of Grinding Pharmaceutical Substances; U.S. Patent No. 5,718,388 to Continuous Method of Grinding Pharmaceutical Substances; U.S. Patent No. 5,862,999 for Method of Grinding Pharmaceutical Substances; U.S. Patent No. 5,665,331 for Co-Microprecipitation of Nanoparticulate Pharmaceutical Agents with Crystal Growth Modifiers; U.S. Patent No. 5,662,883 for Co-Microprecipitation of Nanoparticulate Pharmaceutical Agents with Crystal Growth Modifiers; U.S. Patent No. 5,560,932 for Microprecipitation of Nanoparticulate Pharmaceutical Agents; U.S. Patent No. 5,543,133 for Process of Preparing X-Ray Contrast Compositions Containing Nanoparticles; U.S. Patent No. 5,534,270 to Method of Preparing Stable Drug Nanoparticles; U.S. Patent No. 5,510,118 to Process of Preparing Therapeutic Compositions Containing Nanoparticles; and U.S. Patent No. 5,470,583 to Method of Preparing Nanoparticle Compositions Containing Charged Phospholipids to Reduce Aggregation, all of the above patents are incorporated herein by reference, as are all the aforementioned prior patents. Nanoparticle compositions are also described, for example, in U.S. Patent Nos. 5,298,262 for Use of Ionic Cloud Point Modifiers to Prevent Particle Aggregation During Sterilization; 5,302,401 for Method to Reduce Particle Size Growth During Lyophilization; 5,318,767 for X-Ray Contrast Compositions Useful in Medical Imaging; 5,326,552 for Novel Formulation For Nanoparticulate X-Ray Blood Pool Contrast Agents Using High Molecular Weight Nonionic Surfactants; 5,328,404 for Method of X-Ray Imaging Using Iodinated Aromatic Propanedioates; 5,336,507 for Use of Charged Phospholipids to Reduce Nanoparticle Aggregation; 5,340,564 for Comprising Olin Formulations 10-G to Prevent Particle Aggregation and Increase Stability; 5,346,702 for Use of Non-Ionic Cloud Point Modifiers to Minimize Nanoparticulate Aggregation During Sterilization; 5,349,957 for Preparation and Magnetic Properties of Very Small Magnetic Dextran Particles; 5,352,459 for Use of Purified Surface Modifiers to Prevent Particle Aggregation During Sterilization; 5,399,363 and 5,494,683 both for Surface Modified Anticancer Nanoparticles; 5,401,492 for Water Insoluble Non-Magnetic Manganese Particles as Magnetic Resonance Enhancement Agents; 5,429,824 for Use of Tyloxapol as a Nanoparticulate Stabilizer; 5,447,710 for Method for Making Nanoparticulate X-Ray Blood Pool Contrast Agents Using High Molecular Weight Non-ionic Surfactants; 5,451,393 for X-Ray Contrast Compositions Useful in Medical Imaging; 5,466,440 for Formulations of Oral Gastrointestinal Diagnosis X-Ray Contrast Agents in Combination with Pharmaceutically Acceptable Clays; 5,470,583 for Method of Preparing Nanoparticle Compositions Containing Charged Phospholipids to Reduce Aggregation; 5,472,683 for Nanoparticulate Diagnostic Mixed Carbamic Anhydrides as X-Ray Contrast Agents for Blood Pool and Lymphatic System Imaging; 5,500,204 for Nanoparticulate Diagnostics Dimers as X-Ray Contrast Agents for Blood Pool and Lymphatic Systcm Imaging; 5,518,738 for Nanoparticulate NSAID Formulations; 5,521,218 for Nanoparticulate Iododipamide Derivatives for Use as X-Ray Contrast Agents; 5,525,328 for Nanoparticulate Diagnostic Diatrizoxy Ester X-Ray Contrast Agents for Blood Pool and Lymphatic System Imaging; 5,543,133 for Process of Preparing Contrast X-Ray Compositions Containing Nanoparticles; 5,552,160 for Surface Modified NSAID Nanoparticles; 5,560,931 for Formulations of Compounds as Nanoparticulate Dispersions in Digestible Oils or Fatty Acids; 5,565,188 for Polyalkylene Block Copolymers as Surface Modifiers for Nanoparticles; 5,569,448 for Sulfated Non-ionic Block Copolymer Surfactant as Stabilizer Coatings for Nanoparticle Compositions; 5,571,536 for Formulations of Compounds as Nanoparticulate Dispersions in Digestible Oils or Fatty Acids; 5,573,749 for Nanoparticulate Diagnostic Mixed Carboxylic Anhydrides as X-Ray Contrast Agents for Blood Pool and Lymphatic System Imaging; 5,573,750 for Diagnostic Imaging X-Ray Contrast Agents; 5,573,783 for Redispersible Nanoparticulate Film Matrices With Protective Overcoats; 5,580,579 for Site-specific Adhesion Within the GI Tract Using Nanoparticles Stabilized by High Molecular Weights, Linear Poly (ethylene Oxide) Polymers; 5,585,108 for Formulations of Oral Gastrointestinal Therapeutic Agents in Combination with Pharmaceutically Acceptable Clays; 5,587,143 for Butylene Oxide-Ethylene Oxide Block Copolymers Surfactants as Stabilizer Coatings for Nanoparticulate Compositions; 5,591,456 for Milled Naproxen with Hydroxypropyl Cellulose as Dispersion Stabilizer; 5,593,657 to Novel Barium Salt Formulations Stabilized by Non-ionic and Anionic Stabilizers; 5,622,938 for Sugar Based Surfactant for Nanocrystals; 5,628,981 for Improved Formulations of Oral Gastrointestinal Diagnosis X-Ray Contrast Agents and Oral Gastrointestinal Therapeutic Agents; 5,643,552 for Nanoparticulate Diagnostic Mixed Carbonic Anhydrides as X-Ray Contrast Agents for Blood Pool and Lymphatic System Imaging; 5,718,388 for Continuous Method of Grinding Pharmaceutical Substances; 5,718,919 for Nanoparticles Containing the R (-) Enantiomer of Ibuprofen; 5,747,001 for Formulations of Human Immunodeficiency Virus (HIV) Protease Inhibitors Using Cellulosic Surface Stabilizers; 6,068,858 to Methods of Making Nanocrystalline Formulations of Human Immunodeficiency Virus (HIV) Protease Inhibitors Using Cellulosic Surface Stabilizers; 6,153,225 for Injectable Formulations of Nanoparticulate Naproxen; 6,165,506 for New Solid Dose Form of Nanoparticulate Naproxen; 6,221,400 for Methods of Treating Mammals Using Nanocrystalline Formulations of Human Immunodeficiency Virus (HIV) Protease Inhibitors; 6,264,922 for Nebulized Aerosols Containing Nanoparticle Dispersions; 6,267,989 for Methods for Preventing Crystal Growth and Particle Aggregation in Nanoparticle Compositions; 6,270,806 for Use of PEGDerivatized Lipids as Surface Stabilizers for Nanoparticulate Compositions; 6,316,029 for Rapidly Disintegrating Solid Oral Dosage Form, "6,375,986 for Solid Dose Nanoparticulate Compositions Comprising a Synergistic Combination of a Polymeric Surface Stabilizer and Dioctyl Sodium Sulfosuccinate; 6,428,814 for Bioadhesive Nanoparticulate Compositions Having Cationic Surface Stabilizers; 6,431,478 for Small Scale Mill, and 6,432,381 for Methods for Targeting Drug Delivery to the Upper and / or Lower Gastrointestinal Tract, all of which are incorporated herein by reference, and US Patent Application Serial No. 2002/0121267 January 31, 2002, for Controlled Release Nanoparticulate Compositions, describes nanoparticle compositions, and is specifically incorporated by reference, like all of the foregoing prior patents.Amorphous small particle compositions are described, for example, in US Patents No. 4,783,484 for Particulate Composition and Use Thereof as Antimicrobial Agent; 4,826,689 to Method for Making Uniformly Sized Particles from Water-Insoluble Organic Compounds; 4,997,454 to Method for Making Uniformly-Sized Particles From Insoluble Compounds; 5,741,522 to Ultrasmall, Non-aggregated Porous Particles of Uniform Size for Gas Bubbles Within and Methods; and 5,776,496 to Ultrasmall Porous Particles for Ultrasound Back Scatter Enhancement, which are also incorporated herein by reference.

The present invention relates, in certain aspects, to nanoparticle compositions comprising 3- (2,4-dichloro-phenyl) -1,6-dimethyl-1,9-dihydro-pyrido [2,3-b] indol- 2-one, which may be useful in the treatment of cancer, as well as methods for their preparation and use. SUMMARY OF THE INVENTION The present invention relates to nanoparticle compositions comprising 3- (2,4-dichlorophenyl) -1,6-dimethyl-1,9-dihydro-pyrido [2,3-b] indol-2-one, as well as methods of preparing and using them. In one aspect of the invention, the composition comprises particles comprising 3- (2,4-dichloro-phenyl) -1,6-dimethyl-1,9-dihydropyrido [2,3-b] indol-2- one, where the particles have an average size of less than about 2000 nm. The composition may also comprise at least one surface stabilizer adsorbed on or associated with the surface of the particles. The surface stabilizer is present in an amount sufficient to maintain 3- (2,4-dichloro-phenyl-1,6-dimethyl-1,9-dihydro-pyrido [2,3-b] indol-2-one to an effective average particle size that maintains the drug's effectiveness over a period of time The nanoparticle size of 3- (2,4-dichloro-phenyl) -1,6-dimethyl-1,9-dihydropyrido particles [2,3-b] indol-2-one can be manipulated to provide the desired blood profile and duration of action when administered In another aspect of the invention, the composition may further comprise other excipients such as aggregation reducing agents, pH modifiers and the like.

Another aspect of the present invention is a composition of 3- (2,4-dichloro-phenyl) -1,6-dimethyl-1,9-dihydro-pyrido [2,3-b] indol-2-one nanoparticles. wherein the composition comprises: (a) 3- (2,4-dichloro-phenyl) -1,6-dimethyl-1,9-dihydro-pyrido [2,3-b] indol-2-one particles having an effective average particle size of less than about 400 nm; and (b) at least one surface stabilizer as a medicament for the treatment of cancer. Additional aspects of the present invention relate to dosage forms prepared from the compositions of the present invention. In another embodiment, the nanoparticle composition is an injectable formulation. In another embodiment, the nanoparticle composition is an intraperitoneal or intramuscular formulation. A preferred dosage form of the invention is a formulation suitable for intravenous administration. Additional aspects of the invention relate to methods for preparing compositions according to the invention. According to one aspect of the invention, a process for the preparation of a composition of 3- (2,4-dichlorophenyl) -1,6-dimethyl-1,9-dihydro-pyrido [2,3-b] indol 2 nanoparticles -one comprises the step of bringing into contact 3- (2,4-dichloro-phenyl) -1,6-dimethyl-1,9-dihydro-pyrido [2,3-b] indol-2-one with at least one surface stabilizer and optionally additional excipients for a time and under conditions sufficient to form a nanoparticle composition having an effective average particle size of less than about 2000 nm. According to one aspect of the invention, a process for the preparation of a composition of 3- (2,4-dichloro-phenyl) -1,6-dimethyl-1,9-dihydropyrido [2,3-b] indol nanoparticle -2-one comprises contacting the particles of 3- (2,4-dichloro-phenyl) -1,6-dimethyl-1,9-dihydro-pyrido [2,3-b] indol-2-one with at least one surface stabilizer for a time and under conditions sufficient to form a composition of 3- (2,4-dichloro-phenyl) -1,6-dimethyl-1,9-dihydropyrido [2,3-b] nanoparticles indol-2-one having an effective average particle size of less than about 400 nm. According to another aspect of the invention, a process for the preparation of a sterile composition of 3- (2,4-dichloro-phenyl) -1,6-dimethyl-1,9-dihydro-pyrido [2,3] nanoparticles b) indol-2-one comprises the steps of: (a) contacting the particles of 3- (2,4-dichlorophenyl) -1,6-dimethyl-1,9-dihydropyrido [2, 3-b] indol-2-one with at least one surface stabilizer and at least one excipient for a time and under conditions sufficient to form a dispersion of 3- (2,4-dichloro-phenyl) nanoparticles, 6-dimethyl-1,9-dihydropyrido [2,3-b] indol-2-one having an average particle size effective at about 400 nm; (b) lyophilizing the dispersion to form a lyophilizate; and (c) sterilizing the lyophilizate to produce a sterile composition of 3- (2,4-dichlorophenyl) -1,6-dimethyl-1,9-dihydro-pyrido [2,3-b] indol nanoparticles 2-one. Additional aspects of the present invention relate to methods of treating cancer comprising administering an effective amount of a nanoparticle composition comprising 3- (2,4-dichloro-phenyl) -1,6-dimethyl -1,9-dihydro-pyrido [2,3-b] indol-2-one to a subject who needs it. Another aspect of the present invention is the use of a nanoparticle formulation composition comprising 3- (2,4-dichlorophenyl) -1,6-dimethyl-1,9-dihydro-pyrido [2,3] -b] indol2-one in the treatment of cancers. Both the foregoing general description and the following detailed description are given by way of example and explanation, and are intended to provide a better explanation of the invention as claimed. Other objects, advantages and novel features will be apparent to those skilled in the art upon reading the following detailed description of the invention. DETAILED DESCRIPTION OF THE INVENTION Definitions As used above and throughout the disclosure, the following terms, unless otherwise indicated, will be understood to have the following meanings. As used herein, the term will be understood by those skilled in the art and will vary to some extent depending on the context in which it is used. If uses of the term are unclear to those skilled in the art given the context in which it is used, about will mean up to plus or minus 10% of the particular term. As used herein, the term particle refers to a state of matter that is characterized by the presence of discrete particles, pellets, beads, or granules regardless of size, shape, or morphology. As used herein, the term nanoparticle refers to a composition in which the average effective particle size of the enclosed particles is less than about 2,000 nm (2 microns). As used herein, the terms conventional and non-nanoparticulate qualifying an active agent will mean 3- (2,4-dichloro-phenyl) -1,6-dimethyl-1,9-dihydro-pyrido [2,3-b] indol-2-one, which is solubilized or has an average effective particle size greater than about 2000 nm. As used herein, the term effective mean particle size describes a population of particles in a composition wherein 50% of the particles are smaller than a specified size. Therefore, the average effective particle size expression of less than about 2000 nm means that at least 50% of the enclosed particles are less than about 2000 nm. As used herein, D50 refers to a particle size below which 50% of the particles in a composition are smaller than this particle size. Similarly, D90 refers to the particle size below which 90% of the particles in a composition are smaller than this particle size. As used herein with reference to stable particles, the term stable refers to, but is not limited to, one or more of the following parameters: (1) the particles do not flocculate or agglomerate appreciably because of interparticle attraction forces or their size does not increase significantly over time; (2) the physical structure of the particles is not changed over time, such as by conversion of an amorphous phase to a crystalline phase; (3) the particles are chemically stable; and / or (4) in the case where the active ingredient has not been subjected to the heating step at the melting point of the active agent or beyond it in the preparation of the particles of the present invention. As used herein, the term poorly water-soluble drug refers to a drug that has a solubility in water of less than about 30 mg / mL, less than about 20 mg / mL, less than about 10 mg / mi, or less than about 1 mg / mL.

As used herein, the term therapeutically effective amount means the dosage that provides the specific pharmacological response to which the active agent is administered to a significant number of subjects in need of the treatment of interest. It should be emphasized that a therapeutically effective amount of the active agent that is administered to a particular subject in a particular case will not always be effective in the treatment of the conditions described herein, although such a dosage appears to be a therapeutically effective amount. by the skilled person.

As used herein, the term active agent, unless otherwise indicated, refers to 3- (2,4-dichloro-phenyl) -1,6-dimethyl-1,9-dihydropyrido [2,3-b] indol-2-one.

The terms sterilize and sterilize as used in the present application generally mean the inactivation of biological contaminants present in the product. In typical pharmaceutical applications, autoclaving of the drug product, exposure to at least 25 kGray of irradiation dose, or sterile filtration on a 0.2 micron sieve sterilizes the drug product.

Nanoparticle Compositions In one aspect of the invention, the composition comprises particles comprising 3- (2,4-dichloro-phenyl) -1,6-dimethyl-1,9-dihydropyridone (2,3-b). indol-2-one wherein the particles have an effective average particle size of less than about 2000 nm, and at least one surface stabilizer adsorbed on one surface of the particles optionally with other excipients, such as reducing agents; The nanoparticles described herein may exist in a crystalline phase, an amorphous phase, a semi-crystalline phase, or a mixture thereof. average effective particle size less than about 2000 nm means that about 50% of the active agent particles have a particle size below the effective average, by weight (or by other suitable measuring techniques, such as by volume, number, etc.), i.e. less than about 2000 nm, 1900 nm, 1800 nm, etc., when measured by techniques well known to those skilled in the art. Such techniques include, for example, sedimentation field flux fractionation, photon correlation spectroscopy, light scattering and disk centrifugation. In other embodiments of the invention, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, or at least about 99% of the active agent have a particle size below the effective average, i.e. less than about 2000 nm, 1900 nm, 1800 nm, etc. The compositions of the invention comprise particles of 3- (2,4-dichloro-phenyl) -1,6-dimethyl-1,9-dihydro-pyrido [2,3-b] indol-2-one having a effective particle average less than about 2 microns. In other embodiments of the invention, the particles of 3- (2,4-dichloro-phenyl) -1,6-dimethyl-1,9-dihydro-pyrido [2,3-b] indol-2 -one have an effective average particle size of less than about 1900 nm, less than about 1800 nm, less than about 1700 nm, less than about 1600 nm, less than about 1500 nm, less than about 1400 nm , less than about 1,300 nm, less than about 1,200 nm, less than about 1,100 nm, less than about 1,000 nm, less than about 900 nm, less than about 800 nm, less than about 700 nm, less than about 650 nm, less than about 600 nm, less than about 550 nm, less than about 500 nm, less than about 450 nm, less than about 400 nm, less than about 350 nm, less than about 300 nm, less than about 250 nm nm, less than about 200 nm, less than about 150 nm, less than about 100 nm, lower e at about 75 nm or less than about 50 nm, as measured by light scattering methods, microscopy, or other suitable methods.

In another embodiment of the invention, the compositions of the invention are in injectable dosage form and the particles of 3- (2,4-dichloro-phenyl) -1,6-dimethyl-1,9-dihydropyrido [2,3-b] indol-2-one have an effective average particle size of less than about 1000 nm, less than about 900 nm, less than about 800 nm, less than about 700 nm, less than about 650 nm, less than about 600 nm, less than about 550 nm, less than about 500 nm, less than about 450 nm, less than about 400 nm, less than about 350 nm, less than about 300 nm, less than about 250 nm, less than about 200 nm, less than about 150 nm, less than about 100 nm, less than about 75 nm or less than about 50 nm. Injectable compositions may include 3- (2,4-dichloro-phenyl) -1,6-dimethyl-1,9-dihydropyrido [2,3-b] indol-2-one having an average effective upper particle size at about 1 micron, up to about 2 microns. If the average effective particle size is less than about 600 nm, then at least about 50% of the 3- (2,4-dichloro-phenyl) -1,6-dimethyl-1,9-dihydropyrido [2 , 3-b] indol-2-one are less than about 600 nm in size when measured by the techniques noted above. The same applies to the other particle sizes referred to above.

In some embodiments, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, or at least about 99% of the particles of -dichloro-phenyl) -1,6-dimethyl-1,9-dihydropyrido [2,3-b] indol-2-one have a particle size below the effective average, i.e., below at about 1000 nm, less than about 900 nm, less than about 800 nm, etc. In other embodiments, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, or at least about 99% of the redispersed active agent particles. have a particle size below the effective average, i.e. less than about 2000 nm, less than about 1900 nm, less than about 1800 nm, less than about 1700 nm, etc. In some aspects, the invention provides compositions comprising 3- (2,4-dichloro-phenyl) -1,6-dimethyl-1,9-dihydro-pyrido [2,3-b] indol-2-nanoparticles. and at least one surface stabilizer and optionally additional excipients, such as aggregation reducing agents, pH modifying agents and the like. Surface stabilizers are preferably adsorbed on or associated with the surface of 3- (2,4-dichloro-phenyl) -1,6-dimethyl-1,9-dihydro-pyrido [2,3-b] indol particles -2-one. Surface stabilizers useful herein can physically adhere or associate with the surface of the nanoparticulate active agent but can not chemically react with the active agent particles. In another embodiment, the compositions of the present invention may include two or more surface stabilizers. The present invention also includes compositions of 3- (2,4-dichlorophenyl) -1,6-dimethyl-1,9-dihydro-pyrido [2,3-b] indol-2-one nanoparticles together with one or more carriers, physiologically acceptable and non-toxic adjuvants or vehicles, collectively referred to as carriers. The compositions may be formulated for parenteral (e.g., intravenous, intramuscular or subcutaneous) injection. 3- (2,4-Dichloro-phenyl) -1,6-dimethyl-1,9-dihydro-pyrido [2,3-b] indol-2-one may be in a crystalline phase, an amorphous phase, a semi-crystalline phase or their mixtures. The choice of a surface stabilizer for - (2,4-dichloro-phenyl) -1,6-dimethyl-1,9-dihydropyrido [2,3-b] indol-2-one is non-trivial and requires experimentation to achieve a desirable formulation. Combinations of more than one surface stabilizer may be used in the invention.

Surface Stabilizers The compositions of the invention include one or more surface stabilizers. The surface stabilizers of the invention are preferably adsorbed on or associated with the surface of the active agent particles. Preferably, surface stabilizers especially useful herein do not react chemically with the active agent particles or itself. Preferably, the individual molecules of the auxiliary surface stabilizer are essentially free of intermolecular crosslinks. Two or more surface stabilizers may be employed in the compositions and methods of the invention.

Suitable surface stabilizers may preferably be selected from known pharmaceutically organic and inorganic excipients. Such excipients include various polymers, low molecular weight oligomers, natural products and surfactants. Preferred surface stabilizers include nonionic, anionic, cationic and zwitterionic surfactants or compounds.

Examples of useful nonionic stabilizers include, but are not limited to, dextran, gum arabic, gum tragacanth, glycerol monostearate, cetostearyl alcohol, cetomacrogol emulsifying wax, sorbitan esters, pol (oxyethylene) alkyl ethers (eg, macrogol) ethers such as cetomacrogol 1000), poly (ethylene) alkyl esters, poly (oxyethylene) castor oil derivatives, poly (oxyethylene) sorbitan fatty acid esters (for example commercially available Tween such as, for example Tween 20 and Tween 80 (ICI Specialty Chemicals)); poly (ethylene glycols) (e.g. Carbowaxs 3550 and 934 (Union Carbide)), poly (oxyethylene) stearates, methylcellulose, hydroxyethylcellulose, hydroxypropyl celluloses (e.g., HPC, HPC-SL and HPC-L), hydroxypropyl methylcellulose (HPMC) hydroxypropylmethylcellulose phthalate, noncrystalline cellulose, triethanolamine, polyvinyl alcohol (PVA), polyvinylpyrrolidone (PVP), 4- (1,1,3,3-tetramethylbutyl) phenol polymer with oxide ethylene and formaldehyde (also known as tyloxapol, supione and triton), poloxamers (e.g., Pluronics F68 and F108, which are block copolymers of ethylene oxide and propylene oxide); poloxamines (e.g., Tetronic 908, also known as Poloxamine 908, which is a tetrafunctional block copolymer derived from the sequential addition of propylene oxide and ethylene oxide to ethylenediamine (BASF Wyandotte Corporation, Parsippany, NJ)); Tetronic 1508 (T-1508) (BASF Wyandotte Corporation), ethylene alkyl phenol oxide (Triton X-100, Triton X-405, etc., Dow Chemical), Crodestas F-110, which is a mixture of sucrose stearate and sucrose distearate (Croda Inc.); poly (p-isononylphenoxy) - (glycidol), also known as Olin-IOG or Surfactant 10-G (Olin Chemicals, Stamford, CT) Crodestas SL-40 (Croda, Inc.); and SA90HCO, which is C18H37CH2C (O) N (CH3) -CH2 (CHOH) 4 (CH2OH) 2 (Eastman Kodak Co.); decanoyl-N-methylglucamide; n-decyl (3-D-glucopyranoside, n-decyl (3-D-maltopyranoside, n-dodecyl (3-D-glucopyranoside, n-dodecyl) -R-maltoside, heptanoyl-N-methylglucamide, n-heptyl-3-D -glucopyranoside, n-heptyl (3-D-thioglucoside) n-hexyl (3-D-glucopyranoside, nonanoyl-N-methylglucamide, n-butyl PD-glucopyranoside octanoyl-N-methylglucamide, n-octyl-3-D-glucopyranoside; octyl β-D-thioglucopyranoside lysozyme, PEG derivatized phospholipid, PEG derivatized cholesterol, PEG derivatized cholesterol derivative, PEG derivatized vitamin A, PEG derivatized vitamin E, PEG derivatized castor oil (Cremafor), random copolymers of vinylpyrrolidone and sodium acetate vinyl (an example would be Plasdone S-630, ISP) Preferred nonionic stabilizers include, but are not limited to, hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose grade HPC-SL, poly (vinylpyrrolidones), Kollidone K12 (BASF) or Plasdone C-12 (ISP Technologies, Inc.) Kollidone K17 (BASF) - Plasd one C-17 (ISP Technologies, Inc.), Kollidone K29 / 32 (BASF) - Plasdone C-29/32 (ISP Technologies, Inc. (USA)), block copolymers based on ethylene oxide and propylene oxide - poloxamers sold under the brand name Pluronics by BASF (sold under Lutrol in the EU), specifically Pluronic F68 also known as poloxamer 188, Pluronic F108 also known as poloxamer 338, Pluronic F127 also known as poloxamer 407, copolymer of vinylpyrrolidone and vinyl acetate - Copovidone sold under the brand name Plasdone S-630 (ISP Technologies, Inc.), distearyl palmitate, glyceryl, poly (oxyethylene) sorbitan fatty acid esters such as that poly (oxyethylene) 20 sorbitan monolaurate, polysorbate 20 also known as Tween 20 by ICI Americas, poly (oxyethylene) 20 sorbitan monopalmitate, polysorbate 40 also known as Tween 40 by ICI Americas, poly (oxyethylene) sorbitan monooleate ) 20, polysorbate 80 also known as Tween 80 by ICI Americas, macrogol 15-hydroxystearate - Solutol BASF, Tyloxapol and Cremaphor. Examples of useful anionic stabilizers include, but are not limited to, fatty acids as well as their salt forms, such as oleic acid, stearic acid, palmitic acid, lauric acid, myristic acid, calcium stearate. Other common anionic stabilizers include sodium dodecyl sulfate, Duponol P, which is sodium lauryl sulfate (DuPont), calcium carboxymethylcellulose, sodium carboxymethylcellulose, sodium sulfosuccinic acid dialkyl esters (eg, Aerosol OT, which is a sodium sulfosuccinic acid dioctyl ester (DOSS) (American Cyanamid)), Triton X-200, which is an alkyl aryl polyether sulfonate (Union Carbide). Saline forms of bile acids are also useful as anionic stabilizers, such as sodium deoxycholate, sodium cholate, sodium chenodeoxycholate, sodium dehydrocholate, disuccinylursodeoxycholic acid disodium salt, sodium hyodeoxycholate and sodium ursodeoxycholate. Preferred anionic stabilizers include, but are not limited to, sodium dioctyl succinate (DOSS) sodium lauryl sulfate (SIS) also known as sodium dodecyl sulfate (SDS) and sodium deoxycholate. Examples of useful cationic surface stabilizers include, but are not limited to, polymers, biopolymers, poly (n-methylpyridinium), anthryl pyridinium chloride, cationic phospholipids, chitosan, poly (lysine), poly (vinylimidazole), poly (brene), poly (methyl methacrylate) trimethylammonium bromide (PMMTMABr), hexyldésyltriméthylammonium bromide (HDMAB), and dimethyl sulfate of poly (vinylpyrrolidone-2-dimethylaminoethyl methacrylate). Other useful cationic stabilizers include, but are not limited to, cationic lipids, sulfonium, phosphonium and quaternary ammonium compounds, such as stearyltrimethylammonium chloride, benzyl-di (2-chloroethyl) ethylammonium bromide, chloride or coconut trimethylammonium bromide, coconut methylhydroxyethylammonium chloride or bromide, dodecyltrimethylammonium bromide, decyltrimethylammonium chloride, decyl dimethylhydroxyethylammonium chloride or bromide, hydroxyethylammonium (C12 to C12) dimethylchloride or bromide, chloride or bromide coconut dimethyl hydroxyethylammonium, methylmethyltrimethylammonium sulfate, lauryl dimethylbenzylammonium chloride or bromide, lauryl dimethyl (ethenoxy) 4 ammonium chloride or bromide, N - alkyl (C12-18) dimethylbenzylammonium chloride, N - chloride alkyl (C14 to 1a) dimethylbenzylammonium, N-tetradecylidimethyl chloride nzylammonium monohydrate, dimethyl didecylammonium chloride, N-alkyl chloride and dimethyl (C12-14) 1-naphthylmethylammonium, trimethylammonium halide, alkyltrimethylammonium salts and dialkyl dimethylammonium salts, lauryltrimethylammonium chloride, alkylamidoalkyldialkylammonium salt ethoxylated and / or ethoxylated trialkylammonium salt, dialkylbenzene dialkylammonium chloride, N-didecyldimethylammonium chloride, N-tetradecyl dimethylbenzylammonium chloride monohydrate, N-alkyl (C12-14) dimethyl-naphthylmethylammonium chloride and dodecyldimethylbenzylammonium chloride, dialkyl chloride benzenealkylammonium, lauryl trimethylammonium chloride, alkylbenzylmethylammonium chloride, alkyl benzyldimethylammonium bromide, C12, C15, C17 trimethylammonium bromides, dodecylbenzyltriethylammonium chloride, poly (diallyldimethylammonium) chloride (DADMAC), dimethylammonium chlorides, alkali metal halides yldimethylammonium, tricetylmethylammonium chloride, decyltrimethylammonium bromide, dodecyltriethylammonium bromide, tetradecyltrimethylammonium bromide, methyl trioctylammonium chloride (ALIQUAT 336TM), POLYQUAT 10TM, tetrabutylammonium bromide, benzyltrimethylammonium bromide, choline esters (such as choline esters of fatty acids), benzalconium chloride, stearalkonium chloride compounds (such as stearyltrimonium chloride and di-stearyldimonium chloride), cetyl pyridinium bromide or chloride, quaternized poly (oxyethylalkylamine) halide salts, MIRAPOLTM and ALKAQUATTM (Alkaril Chemical Company), alkyl pyridinium salts; amines, such as alkylamines, dialkylamines, alkanolamines, poly (ethylenepolyamines), N, N-dialkylaminoalkyl acrylates, and vinylpyridine, amine salts, such as laurylamine acetate, stearylamine acetate, alkylpyridinium salt, and salt thereof. alkylimidazolium, and amine oxides; azolidone imide salts; protonated quaternary acrylamides; methylated quaternary polymers, such as poly [diallyldimethylammonium chloride] and poly [N-methylvinylpyridinium chloride]; and cationic guar.

These examples of 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. Ruhingh (Editor), Cationic Surfactants: Physical Chemistry (Marcel Dekker, 1991); and J. Richmond, Cationic Surfactants: Organic Chemistry), (Marcel Dekker, 1990). Particularly preferred non-polymeric primary stabilizers are any non-polymeric compound, such as benzalkonium chloride, carbonium compound, phosphonium compound, oxonium compound, halonium compound, cationic organometallic compound, quaternary phosphorus compound, pyridinium compound, anilinium compound, immonium compound, hydroxylammonium compound, primary ammonium compound, secondary ammonium compound, tertiary ammonium compound, and quaternary ammonium compounds of formula NR1R2R3R4 (+). For compounds of formula NR1R2R3R4w: (i) none of R1 to R4 is CH3; (ii) one of R1 to R4 is CH3; (iii) three of R1 to R4 are CH3; (iv) all R1 to R4 are CH3; (v) two of R1 to R4 are CH3, one of R1 to R4 is C6H5CH2, and one of R1 to R4 is an alkyl chain of seven carbon atoms or less; (vi) two of R1 to R4 are CH3, one of R1 to R4 is C6H5CH2r and one of R1 to R4 is an alkyl chain of nineteen or more carbon atoms; (vii) two of R1 to R4 are CH3, and one of R1 to R4 is C6H5 (CH2) n, where n> 1; (viii) two of R1 to R4 are CH3r one of R1 to R4 is C6H5CH2, and one of R1 to R4 comprises at least one heteroatom; (ix) two of R1 to R4 are CH3r; one of R1 to R4 is C6H5CH2, and one of R1 to R4 comprises at least one halogen atom; (x) two of R1 to R4 are CH3r one of R1 to R4 is C6H5CH2, and one of R1 to R4 comprises at least one ring moiety; (Xi) two of R1 to R4 are CH3r and one of R1 to R4 is a phenyl ring; or (xii) two of R1 to R4 are CH3 and two of R1 to R4 are purely aliphatic moieties. Such compounds include, but are not limited to, behenalkonium chloride, benzethonium chloride, cetylpyridinium chloride, behentrimonium chloride, lauronium chloride, cetalononium chloride, cetrimonium bromide, cetrimonium chloride, cetylamine hydrofluoride, chloride. chlorallylmethenamine (Quaternium-15), distearyldimonium chloride (Quaternium-5), dodecyl dimethylethylbenzylammonium chloride (Quaternium-14), Quaternium-22, Quaternium-26, Quaternium-18 hectorite, Dimethylaminoethyl chloride hydrochloride, Hydrochloride. cysteine, diethanolammonium phosphate POE (10) oletyl ether, diethanolammonium phosphate POE (3) oleyl ether, tallow alconium chloride, dimethyl dioctadecylammonium bentonite, stearalkonium chloride, domiphen bromide, denatonium benzoate, myristalconium chloride, chloride laurtrimonium, ethylenediamine dihydrochloride, guanidine hydrochloride, pyridoxi HC1 ne, iofetamine hydrochloride, meglumine hydrochloride, methylbenzethonium chloride, myrtrimonium bromide, oleyltrimonium chloride, polyquaternium-I, procaine hydrochloride, cocobetaine, stearalkonium bentonite, stearalconium hectonite, stearyl trihydroxyethyl propylenediamine difluoride, sulphtrimonium chloride , and hexadecyltrimethylammonium bromide. Examples of zwitterionic stabilizers include, but are not limited to, proteins, phospholipids, zwitterionic polymers, and zwitterionic surfactant molecules. Examples of albumin proteins include, but are not limited to, human serum albumin and bovine serum albumin, gelatin, casein and lysozyme. Examples of phospholipids include phosphotidylcholine and lecithin. The proteins and peptides are zwitterionic and can become cationic or anionic depending on the pH of the medium to which they are exposed. In this embodiment, it should be understood that in the pH range considered, these molecules are zwitterionic. Most surface stabilizers are known pharmaceutical excipients and are described in detail in the Handbook of Pharmaceutical Excipients, jointly published by the American Pharmaceutical Association and the Pharmaceutical Society of Great Britain (The Pharmaceutical Press, 5th ed., 2005), specifically incorporated in reference. Surface stabilizers are commercially available or can be prepared by techniques known in the art.

Other pharmaceutical excipients The pharmaceutical compositions according to the invention may also comprise one or more aggregation reducing agents, binding agents, bulking agents, lubricating agents, suspending agents, preservatives, pH modifying agents, wetting agents, disintegrants, effervescent agents and other excipients. Such excipients are known in the art. Examples of aggregation reducing agents include sugars, sugar alcohols and buffers. Examples of sugars and sugar alcohols include, but are not limited to, sucrose, fructose, glucose, erythritol, isomalt, mannitol, sorbitol, xylitol, sorbitol and dextrose. Any pH-modifying agent system suitable for I.V. or I.M. administration may be used such as, but not limited to, phosphate buffer, acetate buffer or citrate buffer. In some embodiments, the buffer is a potassium phosphate buffer, a sodium phosphate buffer, or a sodium acetate buffer. Examples of bulking agents include lactose monohydrate, anhydrous lactose and various starches; examples of binding agents include various celluloses and crosslinked poly (vinylpyrrolidone), microcrystalline cellulose, such as Avicel PH101 and Avicel PH102, microcrystalline cellulose and silicified microcrystalline cellulose (ProSolv SMCCTM). Suitable lubricants including agents which affect the fluidity of the tablet powder, may include colloidal silicon dioxide, such as Aerosil 200, talc, stearic acid, magnesium stearate, calcium stearate and silica gel. Examples of preservatives include potassium sorbate, methylparaben, propyleneparaben, benzoic acid and its salts, other parahydroxybenzoic acid esters such as butylparaben, alcohols such as ethyl or benzyl alcohol, phenolic compounds such as phenol, or quartenary compounds such as benzalconium chloride. Suitable diluents include pharmaceutically acceptable inert fillers, such as microcrystalline cellulose, lactose, dibasic calcium phosphate, saccharides and / or mixtures of any of the foregoing. Examples of diluents include microcrystalline cellulose, such as Avicel PH101 and Avicel PH102; lactose such as lactose monohydrate, anhydrous lactose and Pharmatose DCL21; dibasic calcium phosphate such as Emcompress; mannitol; starch; sorbitol; sucrose; and glucose. Suitable disintegrants include lightly cross-linked poly (vinylpyrrolidone), corn starch, potato starch, corn starch and modified starches; croscarmellose sodium, crosspovidone, sodium glycolate starch and mixtures thereof.

Examples of effervescent agents include effervescent couples such as an organic acid and a carbonate or bicarbonate. Suitable organic acids include, for example, citric, tartaric, malic, fumaric, adipic, succinic and alginic acids and anhydrides and acid salts. Suitable carbonates and bicarbonates include, for example, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, magnesium carbonate, sodium glycine carbonate, L-Lysine carbonate and arginine carbonate. Alternatively, only the sodium bicarbonate component of the effervescent couple may be present. pH of the composition The pH of the composition for administration IV or IM is a buffered formulation which is at a sufficiently high pH to reduce aggregation. The compositions of the invention have a pH level of about 7.0, about 7.1, about 7.2, about 7.3, about 7.4, about 7.5, about 7.6, about 7. , 7, about 7.8, about 7.9, about 8.0, about 8.1, about 8.2, about 8.3, about 8.4, about 8.5, about 8.6, about 8 , 7, about 8.8, about 8.9, about 9.0, about 9.1, about 9.2, about 9.3, about 9.4, about 9.5, about 9.6, about 9 , 7, about 9.8, about 9.9, about 10.0, about 10.1, about 10.2, about 10.3, about 10.4, about 10.5, about 10.6, about 10.1 , 7, about 10.8, about 10.9, about 11.0, about 11.1, about 11.2, about 11.3, about 11.4, about 11.5, about 11.6, about 11.1 , 7, about 11.8, about 11.9, about 12.0, about 12.1, about 12.2, about 12.3, about 12.4, about 12.5, about 12.6, about 12 , 7, about 12.8, about 12.9, about 13.0, about 13.1, about 13.2, about 13.3, about 13.4, about 13.5, about 13.6, about 13 , 7, about 13.8, about 13 , 9, or about 14.0, or above about 14.0. In one embodiment, the pH of the formulation of the invention is in a range selected from the group consisting of pH of about 9.0 to about 10.0, about 10.0 to about 11.0, about 0 to about 12.0; about 12.0 to about 14.0. In another embodiment, the pH of the formulation is in the pH range of about 9.5 to about 11.0. In yet another embodiment, the pH of the formulation is in the pH range of about 7.0 to about 9.5. Concentration of the composition The relative amounts of 3- (2,4-dichlorophenyl) -1,6-dimethyl-1,9-dihydro-pyrido [2,3-b] indol-2-one and one or several surface stabilizers can vary greatly. The optimum amount of the individual components depends, for example, on the physical and chemical attributes of the surface stabilizer (s) and 3- (2,4-dichlorophenyl) -1,6-dimethyl-1,9-dihydro-pyrido. [2,3-b] indol-2-one selected, such as hydrophilic-lipophilic label (HLB), melting point and surface tension of aqueous stabilizer solutions, etc. Preferably, the concentration of 3- (2,4-dichloro-phenyl) -1,6-dimethyl-1,9-dihydropyrido [2,3-b] indol-2-one may vary from about 99.5 % to about 0.001%, from about 95% to about 0.1%, or from about 90% to about 0.5%, by weight, based on the total combined weight of 3- (2,4-dichlorobenzene). phenyl) -1,6-dimethyl-1,9-dihydropyrido [2,3-b] indol-2-one and at least one surface stabilizer, not including other excipients. Higher concentrations of the active ingredient are generally preferred in terms of dose and cost-effectiveness. Preferably, the surface stabilizer concentration may range from about 0.5% to about 99.999%, from about 5.0% to about 99.9%, or from about 10% to about 99.5%, by weight, based on the total combined dry weight of 3- (2,4-dichloro-phenyl) -1,6-dimethyl-1,9-dihydro-pyrido (2,3-b) indol-2-one and of at least one surface stabilizer, not including other excipients Certain embodiments of the invention may comprise compositions of 3- (2,4-dichloro-phenyl) -1,6-dimethyl nanoparticles -1,9-dihydro-pyrido [2,3-b] indol-2-one together with one or more physiologically acceptable and non-toxic excipients, carriers, adjuvants or carriers, collectively referred to as carriers. for example, for parenteral (e.g., intravenous, intramuscular, intrathecal, or subcutaneous), intracisternal, or intraperitoneal injection, and the like. Included in the invention are diluents, crystal growth inhibitors, free radical scavengers and redispersing agents. Preferably the excipient may be present in an amount of from about 1 to about 50, from about 1 to about 40, from about 1 to about 30, from about 1 to about 20, from about 1 to about 15, from about 1 to about 10 or from about 1 to about 5, as measured in w / w of the composition. The prevention of growth of microorganisms can be ensured by the addition of various antibacterial and antifungal agents such as, for example, parabens, chlorobutanol, phenol, sorbic acid and the like. For use in injectable formulations, the composition may also comprise isotonic agents, such as sugars, sodium chloride and the like, and agents for use in retarding the absorption of the injectable pharmaceutical form such as, for example , aluminum monostearate and gelatin. Compositions suitable for parenteral injection may include, for example, sterile and physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions and sterile powders for reconstitution into sterile injectable solutions or dispersions. Examples of suitable aqueous, non-aqueous carriers, diluents, solvents or vehicles include water, ethanol, sodium chloride, Ringer's solution, lactated Ringer's solution, stabilizer solutions, tonicity enhancers (sucrose, dextrose, mannitol, etc.). polyols (propylene glycol, poly (ethylene glycol), glycerol, and the like), their appropriate mixtures, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate. A number of fluids that may be suitable are referenced in Remington's Pharmaceutical Sciences, 17th Edition, published by Mack Publishing Co., page 1543. Examples of preservatives useful in certain embodiments of the invention include, but are not limited to, methylparaben ( about 0.18% w / w) propylparaben (about 0.02% w / w), phenol (about 0.5% w / w) and benzyl alcohol (up to 2 v / v). Examples of pH adjusting agents are sodium hydroxide and hydrochloric acid, and an example of a liquid carrier is sterile water for injection. Other preservatives, pH adjusting agents, and useful liquid carriers are well known in the art. In some embodiments, the compositions of the invention may comprise, in addition to 3- (2,4-dichloro-phenyl) -1,6-dimethyl-1,9-dihydro-pyrido [2,3-b] ] indol-2-one, one or more compounds useful in the treatment of cancer. Representative examples include, but are not limited to, alkylating agents, such as alkyl sulfonates (busulfan), dacarbazine, procarbazine, nitrogen mustards (chlormethine, melphalan, chlorambucil), cyclophosphamide or ifosfamide; nitrosoureas, such as carmustine, lomustine, semustine or streptozocin; antineoplastic alkaloids, such as vincristine or vinblastine; taxanes, such as paclitaxel or taxotere; antineoplastic antibiotics, such as actinomycin intercalators, antineoplastic antimetabolites, folate antagonists or methotrexate; inhibitors of purine synthesis; purine analogs, such as mercaptopurine or 6-thioguanine; pyrimidine synthesis inhibitors, aromatase inhibitors, capecitabine or pyrimidine analogues, such as fluorouracil, gemcitabine, cytarabine and cytosine arabinoside; to breed; topoisomerase inhibitors, such as camptothecin or etoposide; anticancer hormone agonists and antagonists, including tamoxifen; kinase inhibitors, imatinib; growth factor inhibitors; anti-inflammatories, such as pentosan polysulfate, corticosteroids, prednisone or dexamethasone; anti-topoisomerases, such as etoposide, anthracyclines, including doxorubicin, bleomycin, mitomycin and mithramycin; anticancer metal complexes, platinum complexes, cisplatin, carboplatin or oxaliplatin; interferon-alpha, triphenyl thiophosphoramide or altretamine; antiangiogenic agents; thalidomide; immunotherapy adjuvants; or vaccines. Characteristics of the Nanoparticle Compositions In certain aspects of the invention, the nanoparticle compositions of the invention having a surprisingly fast dissolution profile are provided. The rapid dissolution of 3- (2,4-dichlorophenyl) -1,6-dimethyl-1,9-dihydro-pyrido [2,3-b] indol-2-one is preferable because a faster dissolution leads to usually a faster onset of action and greater bioavailability. To improve the dissolution profile and bioavailability of 3- (2,4-dichloro-phenyl) -1,6-dimethyl-1,9-dihydropyrido [2,3-b] indol-2-one, it would be useful to to increase the dissolution of the drug so that it reaches a level close to 100 of dissolution. Additional benefits of a nanoparticle formulation include, without limitation, (1) a decrease in the setting frequency and / or prolonged therapeutic drug levels after taking; (2) smaller doses of 3- (2,4-dichloro-phenyl) -1,6-dimethyl-1,9-dihydropyrido [2,3-b] indol-2-one required to obtain the same pharmacological effect; (3) increased bioavailability; (4) improved performance characteristics for intravenous, subcutaneous or intramuscular injection, such as higher dose loading and smaller liquid dose volumes; (5) improved pharmacokinetic profiles, such as improved Cmax and ASC (air-under-the-curve) profiles; (6) bioadhesive 3- (2,4-dichloro-phenyl) -1,6-dimethyl-1,9-dihydro-pyrido [2,3-b] indol-2-one formulations, which may be coated at the site desired application and can be retained for a duration, thereby increasing the effectiveness of the drug while eliminating or decreasing the setting frequency; (7) high redispersibility of the 3- (2,4-dichloro-phenyl) -1,6-dimethyl-1,9-dihydro-pyrido [2,3-b] indol-2-one nanoparticles present in the compositions of the invention after administration; (8) dosage forms of low viscosity liquid 3- (2,4-dichloro-phenyl) -1,6-dimethyl-1,9-dihydro-pyrido [2,3-b] indol-2-one nanoparticles can be prepared; (9) the compositions of 3- (2,4-dichloro-phenyl) -1,6-dimethyl-1,9-dihydropyrido [2,3-b] indol-2-one nanoparticles can be used in conjunction with other active agents; (10) 3- (2,4-dichlorophenyl) -1,6-dimethyl-1,9-dihydro-pyrido [2,3-b] indol-2-one nanoparticle compositions can be sterile filtered; (11) 3- (2,4-dichloro-phenyl) -1,6-dimethyl-1,9-dihydropyrido [2,3-b] indol-2-one nanoparticle compositions can be autoclaved; (12) 3- (2,4-dichloro-phenyl) -1,6-dimethyl-1,9-dihydropyrido [2,3-b] indol-2-one nanoparticle compositions are suitable for parenteral administration; and (13) the compositions of 3- (2,4-dichlorophenyl) -1,6-dimethyl-1,9-dihydro-pyrido [2,3-b] indol-2-one nanoparticles do not require organic solvents or extreme pH. According to some embodiments of the invention, the compositions of the invention preferably have a dissolution profile wherein in less than about 5 minutes, at least about 20% of the 3- (2,4-dichlorophenyl) ) -1,6-dimethyl-1,9-dihydropyrido [2,3-b] indol-2-one are dissolved. In other embodiments of the invention, at least about 30% or at least about 40% of the 3- (2,4-dichloro-phenyl) -1,6-dimethyl-1,9-dihydropyrido [2] , 3-b] indol-2-one are dissolved in less than about 5 minutes. In yet other embodiments of the invention, preferably at least about 40%, at least about 50%, at least about 60%, at least about 70%, or at least about 80% of the 3- ( 2,4-dichloro-phenyl) -1,6-dimethyl-1,9-dihydro-pyrido [2,3-b] indol-2-one are dissolved in less than about 10 minutes. Finally, in another embodiment of the invention, preferably at least about 70%, at least about 80%, at least about 90%, or at least about 100% of the 3- (2,4-dichlorobenzene). phenyl) -1,6-dimethyl-1,9-dihydro-pyrido [2,3-b] indol-2-one are dissolved in less than about 20 minutes. The dissolution is preferably measured in a medium that is discriminating. Such a dissolution medium will produce two very different dissolution curves for two products having very different dissolution profiles in the gastric juices; i.e., the dissolution medium is predictive of the in vivo dissolution of a composition. An example of a dissolution medium is an aqueous medium containing 0.025 M sodium lauryl sulphate surfactant. The determination of the dissolved amount can be carried out spectrophotometrically. The rotary blade method (European Pharmacopoeia) can be used to measure dissolution.

In one embodiment of the invention, the nanoparticles of the composition are redispersed so that the particles have an effective average particle size of less than about 2000 nm.

This is significant because, if the particles do not redisperse so that they have an effective average particle size of less than 2000 nm, the composition could lose its benefits by the formulation of the 3- (2,4 -dichloro-phenyl) -1,6-dimethyl-1,9-dihydropyrido [2,3-b] indol-2-one in the form of nanoparticles. This is because the nanoparticle compositions benefit from the small particle size comprising 3- (2,4-dichloro-phenyl) -1,6-dimethyl-1,9-dihydropyrido [2,3-b] indol -2-one. If the particles do not redisperse in small particle sizes during administration, then agglomerated pieces or particles may form, due to the extremely high free surface energy of the nanoparticle system and the driving force. thermodynamics aimed at achieving an overall reduction in free energy. With the formation of such agglomerated particles, the bioavailability of the dosage form may fall well below that observed with the liquid dispersion form of the nanoparticle composition.

While the applicants do not wish to develop theoretical mechanisms, the stabilizer is believed to interfere with the flocculation and / or agglomeration of 3- (2,4-dichlorophenyl) -1,6-dimethyl-1,9-dihydro -pyrido [2,3-b] indol-2-one function as a mechanical or steric barrier between the particles, minimizing the narrow interparticle approach required for agglomeration and flocculation. 42 It should be recognized that nanoscale particles are inherently unstable in the absence of stabilization. The presence of a surface stabilizer adsorbed on the surface of the particles ensures the maintenance of a small particle size. Thus, the claimed interaction between the surface stabilizer and the particle surface maintains the small particle size because the particles are prevented from getting close enough to aggregate. In other embodiments of the invention, the redispersed particles of the invention (redispersed in water, a biopertinent medium, or any other suitable liquid medium) have an effective average particle size of less than about 2000 nm. , 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 900 nm, less than about 800 nm, less than about 700 nm, less than about 600 nm, less than about 500 nm , less than about 400 nm, less than about 300 nm, less than about 250 nm, less than about 200 nm, less than about 150 nm, less than about 100 nm, less than about 75 nm or less than about 50 nm of diameter, as measured by light scattering methods, microscopy or other suitable methods. Such methods suitable for measuring effective average particle size are known to those skilled in the art. Redispersibility can be evaluated using any suitable means known in the art. See, for example, the example sections of U.S. Patent No. 6,375,986 for Solid Dose Nanoparticulate Compositions Comprising Synergistic Polymeric Surface Stabilizer and Sulfosuccinate incorporated herein by reference. Pharmaceutical Formulations According to certain aspects of the invention, the compositions may be formulated for administration via any pharmaceutically acceptable route of administration including, but not limited to, parenteral, intracisternal, intravaginal, intraperitoneal and local administration. Dosage forms that are preferably sterile include, but are not limited to, injectable dosage forms.

In one embodiment of the invention, formulations of 3- (2,4-dichloro-phenyl) -1,6-dimethyl-1,9-dihydropyrido [2,3-b] indol-2 nanoparticles are proposed. -one injectable which may include high concentrations in low injection volumes, with rapid dissolution upon administration, which can be infused more rapidly than conventional formulations. The composition of the present invention may be formulated as a powder or solid for reconstitution prior to injectable administration, such as by lyophilization.

Examples of preservatives useful with injectable formulations of the invention include, without limitation, methylparaben (about 0.18% w / w) propylparaben (about 0.02% w / w), phenol (about 0.5% w / w). p) and benzyl alcohol (up to 2% v / v).

An example of a pH adjusting agent is sodium hydroxide, and an example of a liquid carrier is sterile water for injection. Other preservatives, pH adjusting agents, and useful liquid carriers are well known in the art.

Compositions suitable for parenteral injection may comprise sterile and physiologically acceptable aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Examples of suitable aqueous, nonaqueous carriers, diluents, solvents, or vehicles include water, ethanol, polyols (propylene glycol, poly (ethylene glycol), glycerol, and the like), their appropriate mixtures, vegetable oils ( such as olive oil) and injectable organic esters such as ethyl oleate. Correct fluidity can be maintained, for example, using a coating such as lecithin, maintaining the required particle size in the case of dispersions, and using surfactants.

In certain embodiments of the invention, the composition of 3- (2,4-dichloro-phenyl) -1,6-dimethyl-1,9-dihydropyrido [2,3-b] indol-2-one nanoparticles , comprising an injectable composition, is devoid of polysorbate, ethanol or combinations thereof. In addition, once formulated into an injectable composition, the compositions of the invention can provide a high concentration in a small volume to be injected.

The injectable 3- (2,4-dichloro-phenyl) -1,6-dimethyl-1,9-dihydro-pyrido [2,3-b] indol-2-one compositions of the invention may be administered by example, in a bolus injection or with a slow infusion over a suitable duration. In certain embodiments of the invention, the compositions of 3- (2,4-dichloro-phenyl) -1,6-dimethyl-1,9-dihydropyrido [2,3-b] indol-2-one nanoparticles are formulated as a subcutaneous or intramuscular deposit. The deposit is preferably formulated to release 3- (2,4-dichlorophenyl) -1,6-dimethyl-1,9-dihydropyrido [2,3-b] indol-2-one over a period from about a week to about four weeks.

In other embodiments of the invention, the composition of 3- (2,4-dichloro-phenyl) -1,6-dimethyl-1,9-dihydro-pyrido [2,3-b] indole nanoparticles 2-one injectable depot provides therapeutic drug levels for up to about a week, up to about two weeks, up to about three weeks or up to about four weeks. Processes for the preparation of 3- (2,4-dichloro-phenyl) -1,6-dimethyl-1,9-dihydro-pyrido [2,3-b] indol-2-one nanoparticle formulations According to certain aspects of the In the present invention, the active agent nanoparticle compositions can be prepared using methods well known in the art such as, for example, grinding, homogenization and precipitation techniques. Examples of methods for preparing active agent nanoparticle compositions are generally described in U.S. Patent No. 5,145,684 (the `684 patent). The `684 patent discloses nanoparticles of poorly soluble therapeutic or diagnostic agents having an uncrosslinked surface stabilizer adsorbed on or associated with their surface. In one embodiment of the invention, the particles comprise 3- (2,4-dichloro-phenyl) -1,6-dimethyl-1,9-dihydro-pyrido [2,3-b] indol-2 -one can be dispersed in a liquid dispersion medium in which 3- (2,4-dichloro-phenyl) -1,6-dimethyl-1,9-dihydro-pyrido [2,3-b] indol-2- one is poorly soluble. Mechanical means are then used in the presence of grinding media to reduce the particle size to the desired average effective particle size. The dispersion medium may be, for example, water, safflower oil, ethanol, t-butanol, glycerin, polyethylene glycol (PEG), hexane or glycol. A preferred dispersion medium is water.

The particles can be reduced in size in the presence of at least one surface stabilizer. Particles comprising 3- (2,4-dichloro-phenyl) -1,6-dimethyl-1,9-dihydro-pyrido [2,3-b] indol-2-one may be contacted with one or several surface stabilizers after attrition. Other compounds, such as diluent, aggregation reducing agents, pH buffers, etc., may be added to the composition during the size reduction process. The dispersions can be manufactured continuously or in a batch mode. Those skilled in the art will understand that it is possible, after grinding, that the particles may not all be reduced to the desired size. In this case, particles of the desired size can be separated and used in the practice of the present invention. The grinding media may comprise particles which are preferably substantially spherical in shape, for example beads, essentially consisting of polymer resin or glass or zirconium silicate or other suitable compositions. Alternatively, the grinding media may comprise a core on which a polymer resin coating adheres. In general, the appropriate polymeric resins are chemically and physically inert, substantially free of metals, solvents and monomers, and of sufficient hardness and friability to avoid being chipped or crushed during milling. Suitable polymeric resins include cross-linked poly (styrenes), such as poly (styrene) cross-linked with divinylbenzene; styrene copolymers; polycarbonates; poly (acetals), such as Delrin (E.I. from Pont de Nemours and Co.); polymers and copolymers of vinyl chloride; poly (urethanes); polyamides; poly (tetrafluoroethylenes), for example, Teflon (E. 1. from Pont de Nemours and Co.), and other fluoropolymers; high density poly (ethylene); poly (propylenes); cellulose ethers and esters such as cellulose acetate; poly (hydroxymethacrylate); poly (hydroxyethyl acrylate); and silicone-containing polymers such as poly (siloxanes) and the like.

The polymer can be biodegradable. Examples of biodegradable polymers include poly (lactides), poly (glycolide) copolymers of lactides and glycolide, poly (anhydrides), 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). For biodegradable polymers, contamination of the media themselves can advantageously metabolize them into biologically acceptable products that can be removed from the body. The grinding media preferably vary in size from about 0.01 to about 3 mm. For fine grinding, the grinding media are preferably from about 0.02 to about 2 mm, and more preferably from about 0.03 to about 1 mm in size. The polymer resin may have a density of from about 0.8 to about 3.0 g / cm 3. According to one embodiment of the invention, solid or powder forms of active agent nanoparticle dispersions can also be prepared by freeze-drying the liquid dispersion of active agent nanoparticles after reduction of the particle size. In the lyophilization step, the water is removed from the active agent nanoparticle formulations after the dispersion is frozen and placed under vacuum, allowing the ice to change directly from the solid state to the vapor state without go through a liquid phase. The freeze-drying process consists of four independent processes: freezing, sublimation, primary drying step and desorption, which is the secondary drying step. Many lyophilizers can be used to accomplish the lyophilization step of the active agent nanoparticle dispersions. Suitable freeze drying conditions include, for example, those described in EP 0 363 365 (McNeil-PPC Inc.), U.S. Patent No. 4,178,695 (A. Erbeia), and U.S. Patent No. 5,384,124. (Farmalyoc). Typically, the dispersion of active agent nanoparticles is placed in a suitable vessel and frozen at a temperature of from about -5 ° C to about -100 ° C. The frozen dispersion is then subjected to reduced pressure for up to about 48 hours. The combination of parameters such as temperature, pressure, dispersion media and batch size will have an impact on the time required for the lyophilization process. Under reduced temperature and pressure conditions, the frozen solvent is removed by sublimation, giving a solid, porous and immediate-release dosage form over all of which the nanoparticulate active agent is dispensed.

After sterilization, the lyophilized solid form can be reconstituted into a liquid dosage form, such as injectable compositions, etc. One embodiment of the invention comprises a method for preparing a composition of 3- (2,4-dichloro-phenyl) -1,6-dimethyl-1,9-dihydro-pyrido [2,3-dihydro-pyrido] nanoparticles. b) sterilized indol-2-one comprising the steps of: mixing 3- (2,4-dichloro-phenyl) -1,6-dimethyl-1,9-dihydro-pyrido [2,3-b] indol -2-one, at least one excipient, and at least one surface stabilizer in an aqueous medium comprising grinding media for a time and under conditions sufficient to form a dispersion of particles of 3- (2,4-dichlorobenzene); phenyl) -1,6-dimethyl-1,9-dihydropyrido [2,3-b] indol-2-one having an effective average particle size of less than about 2000 nm and the at least one surface stabilizer adsorbed on the particle surface; eliminate grinding media from the dispersion; lyophilizing the dispersion to form a lyophilizate; and sterilizing the lyophilizate to produce a sterilized 3- (2,4-dichloro-phenyl) -1,6-dimethyl-1,9-dihydro-pyrido [2,3-b] indol-2-one composition.

According to one embodiment of the invention, the solid nanoparticles of active agent are subjected to gamma radiation at room temperature, which remains relatively constant during the irradiation period. The gamma radiation is applied in an amount sufficient to expose the drug product to at least 25 k irradiation. The total amount of gamma radiation to which the solid nanoparticulate active agent is exposed has been tested which has shown: (1) that it sterilized the active agent composition, and (2) that it maintained the integrity of the active agent nanoparticle composition. Application of gamma radiation does not significantly degrade the active agent or significantly reduce the effectiveness of the active agent. In this way, it is possible to provide products that meet cGMP requirements for sterile products without prejudice to the active agent. In a preferred aspect of the invention, the gamma radiation is applied to a preferred cumulative amount of about 5 kGray to about 50 kGray or less. Generally, the gamma radiation will normally be applied in a range of about 5 kGray to about 25 kGray or less.

An aspect of the invention is that during reconstitution or redispersion after gamma irradiation, the terminally sterilized solid nanoparticulate active agent maintains its overall stability. Specifically, the terminally sterilized solid nanoparticulate active agent maintains its redispersibility as evidenced by particle size retention, pH, osmolality, dosage and stabilizer concentration after redispersion of the solid in liquid media. In other embodiments, a method of manufacture of the present invention is employed which is similar to typical known manufacturing processes for sterile suspensions. A typical sterile suspension manufacturing process flowchart is as follows: Combination Particle Size Reduction 1 Vial Filling 1 Freeze Drying and / or Terminal Sterilization or Autoclaving As indicated by the optional steps in parentheses, part of the treatment is process dependent particle reduction and / or sterilization process. For example, media conditioning is not required for a milling process that does not require a medium. If terminal sterilization is not feasible due to chemical and / or chemical instability, aseptic treatment can be used. Methods of Treatment In some embodiments, the present invention also provides methods comprising administering to a subject in need thereof an effective amount of a nanoparticulate composition comprising 3- (2,4-dichlorophenyl) -1,6-dimethyl-1,9-dihydro-pyrido [2,3-b] indol-2-one. As used herein, the term subject is used to indicate an animal, preferably a mammal, including a human being. The terms patient and subject can be used interchangeably. Thus, certain embodiments of the invention relate to suitable dosage forms useful in the administration of 3- (2,4-dichloro-phenyl) -1,6-dimethyl-1,9-dihydro-pyrido [2, 3-b] indol-2-one to a subject.

Aspects of the invention include methods comprising administering an effective amount of a nanoparticle composition comprising 3- (2,4-dichloro-phenyl) -1,6-dimethyl-1,9-dihydro -pyrido [2,3-b] indol-2-one to a subject who needs it. According to some aspects of the invention, there are provided methods of treating cancer. Other aspects of the invention relate to the use of a nanoparticle composition comprising 3- (2,4-dichloro-phenyl) -1,6-dimethyl-1,9-dihydro-pyrido [2, 3-b] indol-2-one in the treatment of cancer. 3- (2,4-dichloro-phenyl) -1,6-dimethyl-1,9-dihydro-pyrido [2,3-b] indol-2-one has in vitro and in vivo activity indicating that it is a strong inhibitor of tumor cell proliferation and, as such, can be used in the treatment or prevention of diseases caused or exacerbated by the proliferation of tumor cells. In particular, the compositions of 3- (2,4-dichloro-phenyl) -1,6-dimethyl-1,9-dihydro-pyrido [2,3-b] indol-2-one nanoparticles of the invention can be be used in the treatment of solid tumors, both primary and metastatic solid tumors, carcinomas and cancers, in particular: breast cancer; lung cancer ; cancer of the small intestine, cancer of the colon and rectum; cancer of the respiratory tract, oropharynx and hypopharynx; cancer of the esophagus; liver cancer, stomach cancer, major bile duct cancer, gall bladder cancer, pancreatic cancer; cancers of the urinary tract, including kidney, urothelium and bladder; cancers of the female genital tract, including cancer of the uterus, cervix and ovaries, choriocarcinomas and trophoblastic cancer; cancers of the male reproductive system, including prostate cancer, seminal vesicles and testes, germ cell tumors; endocrine gland cancers, including thyroid cancer, pituitary gland and adrenal gland cancer; skin cancers, including hemangiomas, melanomas and sarcomas, including Kaposi's sarcoma; tumors of the brain, nerves, eyes and meninges, including astrocytomas, gliomas, glioblastomas, retinoblastomas, neuromas, neuroblastomas, schwannomas and meningiomas; solid tumors resulting from hematopoietic malignancies, including leukemias, chloromas, plasmacytomas, fungal mycosis, lymphoma or T cell leukemia, non-Hodgkin's lymphoma, hematological malignancy and myeloma.

In some embodiments, the compositions of the invention may also be administered together with one or more additional active agents. These other active agents preferably include those useful for the treatment of cancer as well as agents useful for treating the detrimental events that may be associated with treatment with 3- (2,4-dichloro-phenyl) -1,6-dimethyl- 1,9-Dihydropyrido [2,3-b] indol-2-one. Such active agents are preferably present as determined by those skilled in the art, so as not to interfere with the therapeutic effect (s) of 3- (2,4-dichlorophenyl) -1 , 6-dimethyl-1,9-dihydro-pyrido [2,3-b] indol-2-one.

In human therapy, it is important to provide dosage forms of 3- (2,4-dichlorophenyl) -1,6-dimethyl-1,9-dihydro-pyrido [2,3-b] indol-2-one that deliver the amount of required drug in vivo, and render the drug bioavailable consistently. Bioavailability is the degree to which the drug becomes available to the target tissue after administration. Many factors can affect bioavailability, including the dosage form and various properties of the drug; for example, the dissolution rate. Poor bioavailability is a significant problem encountered in the development of pharmaceutical compositions, particularly those containing an active ingredient that is poorly soluble in water. Medications that are poorly soluble in water tend to be removed from the gastrointestinal tract before being absorbed into the circulation. In addition, poorly water-soluble drugs tend to be unsafe for intravenous administration techniques, which are used primarily in conjunction with fully soluble drug substances. While the high therapeutic value of 3- (2,4-dichloro-phenyl) -1,6-dimethyl-1,9-dihydro-pyrido [2,3-b] indol-2-one is recognized in the In the art, poorly soluble compounds such as 3- (2,4-dichloro-phenyl) -1,6-dimethyl-1,9-dihydropyrido [2,3-h] indol-2-one are limited by their bioavailability during oral administration and may be difficult to formulate as harmless and effective products for other types of administration. Thus, there is a need for formulations comprising 3- (2,4-dichlorophenyl) -1,6-dimethyl-1,9-dihydro-pyrido [2,3-b] indol-2-one which may be appropriate. for injectable administration, such as intravenous administration. An improvement in the dissolution rate would enhance the bioavailability of 3- (2,4-dichloro-phenyl-1,6-dimethyl-1,9-dihydro-pyrido [2,3-b] indol-2-one, allowing a smaller dose to provide effective in vivo blood levels of the active agent, and an increased dissolution rate will absorb a larger dose, which may increase the effectiveness of the 3- (2) , 4-dichlorophenyl) -1,6-dimethyl-1,9-dihydro-pyrido [2,3-b] indol-2-one A injectable nanoparticle formulation of 3- (2,4-dichlorophenyl) -1, 6-dimethyl-1,9-dihydro-pyrido [2,3-b] indol-2-one could eliminate the need for toxic cosolvents and enhance the efficacy of 3- (2,4-dichlorophenyl) treatment The present invention, which relates to nanoparticle compositions comprising 3- (2,4-dichlorophenyl) -1,6-dimethyl-1,9-dihydro-pyrido [2,3-b] indol-2-one. 1,6-dimethyl-1,9-dihydro-pyrido [2,3-b] indol-2-one addresses these issues. size of the solid dosage form, the nanoparticle compositions of the present invention may have increased bioavailability, and may require the administration of smaller doses of 3- (2,4-dichloro-phenyl) -1,6-dimethyl- 1,9-Dihydropyrido [2,3-b] indol-2-one, in comparison to conventional non-nanoparticulate compositions which include 3- (2,4-dichloro-phenyl) -1,6-dimethyl -1,9-dihydro-pyrido [2,3-b] indol-2-one. In one embodiment of the invention, a nanoparticle composition may have a bioavailability that is approximately 50% greater than 3- (2,4-dichloro-phenyl) -1,6-dimethyl-1,9-dihydropyrido [ 2,3-b] indol-2-one when administered in conventional dosage form. In other embodiments, the nanoparticulate compositions of the present invention may have a bioavailability that is about 40% greater, about 30% greater, about 20% greater, or about 10% greater than the 3- (2,4- dichlorophenyl) -1,6-dimethyl-1,9-dihydro-pyrido [2,3-b] indol-2-one when administered in a non-particulate dosage form. In one embodiment of the present invention, a nanoparticle composition of the present invention may have, for example, a Cmax for 3- (2,4-dichloro-phenyl) -1,6-dimethyl-1,9- dihydro-pyrido [2,3-b] indol-2-one contained therein which is at least about 50% Cmax for the same 3- (2,4-dichloro-phenyl) -1,6-dimethyl - 1,9-Dihydro-pyrido [2,3-b] indol-2-one once delivered at the same dosage by a non-nanoparticulate composition. In other embodiments of the present invention, the nanoparticle composition of the present invention may have, for example, a Cmax for 3- (2,4-dichloro-phenyl) -1,6-dimethyl-1, 9-dihydropyrido [2,3-b] indol-2-one contained therein which is at least about 100%, at least about 200%, at least about 300%, at least about 400%, at least about 500% %, at least about 600%, at least about 700%, at least about 800%, at least about 900%, at least about 1000%, at least about 1100%, at least about 1200%, at least about 1,300%, at least about 1,400%, at least about 1,500%, at least about 1,600%, at least about 1,700%, at least about 1,800%, or at least about 1,900% above Cmax for the same 3- (2,4-dichloro-phenyl) -1,6-dimethyl-1,9-dihydro-pyrido [2,3-b] indol-2-one when delivered at the same dosage by a nanoparticulate composition . In one embodiment of the present invention, a nanoparticle composition of the present invention can display, for example, an ASC for 3- (2,4-dichloro-phenyl) -1,6-dimethyl-1,9- dihydro-pyrido [2,3-b] indol-2-one contained within that is at least about 25% greater than the AUC for the same 3- (2,4-dichlorophenyl) -1,6-dimethyl -1,9-dihydro-pyrido [2,3-b] indol-2-one when delivered at the same dosage by a non-nanoparticulate composition. In other embodiments of the present invention, the nanoparticle composition of the present invention can display, for example, an ASC for 3- (2,4-dichloro-phenyl) -1,6-dimethyl-1, 9-dihydropyrido [2,3-b] indol-2-one contained therein which is at least about 50%, at least about 75%, at least about 100%, at least about 125%, at least about 150% %, at least about 175%, at least about 200%, at least about 225%, at least about 250%, at least about 275%, at least about 300%, at least about 350%, at least about 400%, at least about 450%, at least about 500%, at least about 550%, at least about 600%, at least about 750%, at least about 700%, at least about 750%, at least about 800%, at least about 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 1 150% or at least about 1200% greater than about 100%. the po The same 3- (2,4-dichlorophenyl) -1,6-dimethyl-1,9-dihydro-pyrido [2,3-b] indol-2-one when delivered at the same dosage by a composition. nonnanoparticulaire. Examples The examples were given below for purposes of illustration and to describe the best mode of the invention at present. The scope of the invention should in no way be limited by the examples given here. Drug Particle Count (DPC) Test. This microscopic test was conducted to enumerate undissolved particles in specific size ranges that are unintentionally present in the formulation for IV administration. The entire contents of a vial, 5 ml volume for this system, were filtered through a 5.0 μm gym membrane filter and the particles captured on the filter were manually enumerated using a microscope. composite. A circular diameter graticule provides comparisons for particle sizes. The result is reported on the basis of particle counts per container. EXAMPLE 1 Example of a Composition According to the Invention Component Active Agent Poly (vinylpyrrolidone) (PVP) K12 Sodium Deoxycholate (NaDOC) Sucrose TRIS Concentration (mg / mL) 50 mg 12.5 mg 3 mg 100 mg 1 mg 61 Sterile Water for Injection (SWFI) QSP at 1 mL pH 8.0 The manufacturing process was as follows. The stabilizers (poly (vinylpyrrolidone) and sodium deoxycholate) and a portion of the sucrose were dissolved in sterile water for injection and further filtered through a sterilization quality filter. The active ingredient was then added to the stabilizer / sucrose solution to create a slurry of the following composition: 24.0% active agent, 6.0% K12 PVP, 1.4% NaDOC, 8, 0% sucrose and 60.6% SWFI -% w / w. The high energy slurry was then crushed in the presence of PolyMill 500 to reduce the particle size of the drug to a sufficiently small size. After grinding, the NanoCrystal Colloidal Dispersion was harvested from the grinding equipment through a 5 μm capsule filter. Separately from the harvesting step, a separate solution of the remaining sucrose, TRIS and SWFI was made and passed through a sterilization quality filter. This solution was mixed with the harvested dispersion to create the preferred composition mentioned above. The pH of the preferred composition was further adjusted with hydrochloric acid to bring the pH to -8.0. Vials of the resulting composition were filled and autoclaved at 121 ° C for approximately 21 minutes. EXAMPLE 2 Example of a Composition According to the Invention Component Active Agent Poly (vinylpyrrolidone) (PVP) K12 Sodium Deoxycholate Sucrose Sterile Water for Injection, USP This composition was prepared in a manner similar to Example 1 to except that it was not stamped with TRIS. Even though it was not buffered, the formulation was able to withstand autoclaving at 121 ° C for approximately 26 minutes. EXAMPLE 3 Example of a Composition According to the Invention Concentration (mg / mL) 50 mg 12.5 mg 3 mg 100 mg QSP at 1 mL Component Active agent Poly (vinylpyrrolidone) (PVP) K12 Sodium deoxycholate Saccharose TRIS Sterile water for injection, USP pH Concentration (mg / mL) 50 mg 12.5 mg 3 mg 100 mg 1 mg QSP at 1 mL 10.0 This composition was prepared in a manner similar to Example 1 with the exception that buffered with TRIS and the pH was adjusted to approximately pH 10. This formulation was capable of autoclaving at 121 ° C for approximately 26 minutes.

EXAMPLE 4 Example of a Composition According to the Invention Component Active Agent Poly (vinylpyrrolidone) (PVP) K12 Sodium Deoxycholate Sorbitol TRIS Sterile Water for Injection, USP Concentration (mg / mL) 50 mg 12.5 mg 3 mg 100 mg 1 mg QSP at 1 mL This composition was prepared in a manner similar to Example 1 except that the formulation was milled without sucrose or sorbitol and that sorbitol was added during the harvesting step. It was buffered with TRIS and the pH was adjusted to approximately 9.5. This formulation was capable of autoclaving at 121 ° C for approximately 26 minutes. EXAMPLE 5 Example of a Composition According to the Invention

Component Concentration (mg / mL) Active Agent 50 mg Tween 80 12.5 mg Sodium Deoxycholate 1 mg Sterile Water for Injection, USP QSP at 1 mL This composition was prepared in a manner similar to Example 1 with the exception that the formulation was milled without sucrose or sorbitol and Tween 80 was used as a primary stabilizer instead of K12 PVP. It was not buffered with TRIS, nor adjusted to pH. This formulation was unable to autoclave at 121 ° C for approximately 20 minutes. EXAMPLE 6 Example of a Composition According to the Invention Component Active Agent Poly (vinylpyrrolidone) (PVP) K12 Sodium Deoxycholate Sucrose Sterile Water for Injection, USP Concentration (mg / mL) 50 mg 10 mg 2.5 mg 50 mg QSP This composition was prepared in a manner similar to Example 1 except that the formulation was milled without sucrose, but sucrose was added during the harvesting step. The primary and secondary stabilizers, PVP and NaDOC, were lower than the preferred system of 5 mg and 0.5 mg, respectively. It was not buffered with TRIS, nor adjusted to pH. This formulation was unable to autoclave at 121 ° C for approximately 20 minutes. Formulation Condition pH DPC Dmoyen, Dmoyen, (> 25} gym) (nm) Horiba LA- Horiba LB-950 500 Example 1 Pre-244 148 152 Example autoclave Post 7.97 215 164 237 autoclave Formulation Condition pH DPC Dmoyen Dmoyen (nm) (nm) (> 25 μm) Horiba LA-Horiba LB-950 500 Example 2 Pre 8.38 22 143 131 autoclave Post 7.47 83 165 203 autoclave Example 3 Pre 9.41 14 143 135 autoclave Post 8.75 45 166 217 autoclave Example 4 Pre 9.3 - 140 110 autoclave Post 8.8 209 170 281 autoclave Pre-NE - non-NE - non-NE Example 5 147 autoclave evaluated evaluated Not evaluated Post NE - no TNPC NE (Too many 620 autoclaves evaluated to be Unassessed Counts Pre- NE - No NE - No NE Example 6 142 Autoclave Assessed Assessed Not Assessed Post NE - No NE 6,089 159 Autoclave Assessed Not Assessed

Claims (26)

REVENDICATIONS1. A nanoparticle composition comprising: (a) 3- (2,4-dichloro-phenyl) -1,6-dimethyl-1,9-dihydro-pyrido [2,3-b] indol-2-one particles having average particle size effective less than about 400 nm; and (b) at least one surface stabilizer. 2. Composition according to claim 1, wherein the 3- (2,4-dichloro-phenyl) -1,6-dimethyl-1,9-dihydro-pyrido [2,3-b] indol-2-one is in a crystalline phase, an amorphous phase, a phase semi-crystalline or any of their mixtures. 3. A composition according to claim 1 or claim 2, wherein the particles of 3- (2,4-dichloro-phenyl) -1,6-dimethyl-1,9-dihydropyrido [2,3-b] indol- 2-one have an effective average particle size selected from the group consisting of less than about 350 nm, less than about 300 nm, less than about 250 nm, less than about 200 nm, less than about 150 nm, less than about 100 nm, less than about 75 nm, and less than about 50 nm. 4. A composition according to any one of claims 1 to 3, wherein the composition is formulated for parenteral, intracisternal, intravaginal, intraperitoneal or local administration. The composition of claim 4, wherein the parenteral injection is selected from the group consisting of intravenous injection, intramuscular injection and subcutaneous injection. The composition of any one of claims 1 to 5, wherein the composition is sterile. 10 The composition of any one of claims 1 to 6, wherein the composition further comprises one or more pharmaceutically acceptable excipients, carriers, antibacterials, antifungal agents, or any combination thereof. The composition of claim 7, wherein the pharmaceutically acceptable excipient is selected from the group consisting of an aggregation reducing agent, a binding agent, a bulking agent, a blowing agent, a lubricating agent, a suspending agent. a preservative, a pH modifier, a wetting agent, a disintegrant, a crystal growth inhibitor, a free radical scavenger, a redispersion agent and an effervescent agent. The composition of claim 1 to 8, wherein the composition comprises two or more surface stabilizers. A composition according to any one of claims 1 to 9, wherein the surface stabilizer is selected from the group consisting of a nonionic surface stabilizer, an ionic surface stabilizer, an anionic stabilizer, a cationic surface stabilizer, and a zwitterionic surface stabilizer. A composition according to any one of claims 1 to 10, wherein the surface stabilizer is selected from the group consisting of dextran, gum arabic, gum tragacanth, glycerol monostearate, cetostearyl alcohol, cetomacrogol emulsifying wax, sorbitan esters poly (oxyethylene) alkyl ethers, poly (ethylene) alkyl esters, poly (oxyethylene) castor oil derivatives, poly (oxyethylene) sorbitan fatty acid esters, poly (ethylene) glycols, poly (oxyethylene) stearates, methylcellulose, hydroxyethyl cellulose, hydroxypropyl celluloses, hydroxypropyl methylcellulose, hydroxypropylmethylcellulose phthalate, noncrystalline cellulose, triethanolamine, polyvinyl alcohol, poly (vinylpyrrolidone), 4- (1,1,3,3-tetramethylbutyl) polymer phenol with ethylene oxide and formaldehyde, poloxamers, poloxamines, Tetronic 1508, alkyl phenol ethylene oxide, Crodestas F-110, p-isononylphenoxypoly- (glycidol), Crodesta SL-40, SA9OHCO, decanoyl-N-methylglucamide, n-decyl RD-glucopyranoside, n-decyl RD-maltopyranoside, n-dodecyl RD-glucopyranoside, n-dodecyl RD-maltoside, heptanoyl-N-methylglucamide, n-heptyl -RD-glucopyranoside, n-heptyl-RD-thioglucoside, n-hexyl-R-glucopyranoside, nonanoyl-N-methylglucamide, n-nitr-R-D-glucopyranoside, octanoyl-N-methylglucamide, noctyl-R-glucopyranoside, octyl R-thioglucopyranoside, lysozyme, PEG derivatized phospholipid, PEG derivatized cholesterol, PEG derivatized cholesterol derivative, PEG derivatized vitamin A, PEG derivatized vitamin E, PEG derivatized castor oil, random copolymers of vinyl pyrrolidone and vinyl acetate, block copolymers based on ethylene and propylene oxide, copolymer of vinylpyrrolidone and vinyl acetate, distearyl glyceryl palmitate, poly (oxyethylene) sorbitan fatty acid esters, macrogol hydroxystearate, oleic acid, stearic acid ue, palmitic acid, lauric acid, myristic acid, calcium stearate, sodium dodecyl sulphate, sodium lauryl sulfate, calcium carboxymethylcellulose, sodium carboxymethylcellulose, sodium sulfosuccinic acid dialkyl esters, dioctyl sulfosuccinic acid ester of sodium, alkyl aryl polyether sulfonate, sodium deoxycholate, sodium cholate, sodium chenodeoxycholate, sodium dehydrocholate, disuccinylursodeoxycholic acid bisodic salt, sodium hyodeoxycholate, sodium ursodeoxycholate, sodium dodecyl sulfate, polymers, biopolymers, poly ( N-methylpyridinium), anthryl pyridinium chloride, cationic phospholipids, chitosan, poly (lysine), poly (vinylimidazole), poly (brene), poly (methyl trimethylammonium bromide methacrylate) (PMMTMABr), hexyldésyltriméthylammonium bromide (HDMAB) ), and poly (vinylpyrrolidone-dimethylaminoethyl methacrylate 2-dimethylaminoethyl sulfate), cationic lipids, sulfo nium, phosphonium, stearyltrimethylammonium chloride, benzyl-di (2-chloroethyl) ethylammonium bromide, coconut trimethylammonium chloride or bromide, coconut methylmethyl dihydroxyethyl ammonium chloride or bromide, dodecyltrimethylammonium bromide, sodium chloride decyl triethyl ammonium, decyl dimethyl hydroxyethyl ammonium chloride or bromide, dimethyl hydroxyethyl ammonium chloride or dimethyl bromide, coconut dimethyl hydroxyethyl ammonium chloride or bromide, myristyl trimethyl ammonium methyl sulfate, lauryl dimethyl benzyl chloride or bromide ammonium, chloride or lauryl dimethyl (ethenoxy) 4 ammonium bromide, N-alkyl (C12 to 1s) chloride dimethylbenzyl ammonium chloride, N-alkyl (C14 to C15) dimethyl benzyl ammonium chloride, N-tetradecylidmethylbenzyl ammonium chloride monohydrate, dimethyl didecyl ammonium chloride, N-alkyl chloride and (C12-14) dimethyl 1-naptylmethyl ammonium, halo trimethylammonium genius, alkyltrimethylammonium salts and dialkyl dimethylammonium salts, lauryl trimethylammonium chloride, ethoxylated alkylamidoalkyldialkylammonium salt and / or ethoxylated trialkylammonium salt, dialkylbenzene dialkylammonium chloride, N-didecyldimethylammonium chloride, chloride N-tetradecyl dimethyl benzyl ammonium monohydrate, N-alkyl (C 12-14) dimethyl-naphthyl methyl ammonium chloride and dodecyl dimethyl benzyl ammonium chloride, dialkyl benzenalkyl ammonium chloride, lauryl trimethyl ammonium chloride, alkyl benzyl methyl ammonium chloride, bromide alkyl benzyl dimethyl ammonium, C12, C15, C1-trimethyl ammonium bromides, dodecylbenzyl triethyl ammonium chloride, poly (diallyldimethylammonium chloride) (DADMAC), dimethyl ammonium chlorides, alkyl dimethyl ammonium halides, tricetyl methyl ammonium chloride, bromide decyltrimethylammonium, dodecyltriethylammonium bromide nium, tetradecyltrimethylammonium bromide, methyl trioctylammonium chloride, POLYQUAT 10TM, tetrabutylammonium bromide, benzyltrimethylammonium bromide, choline esters (such as fatty acid choline esters), benzalkonium chloride, stearalkonium chloride compounds (such as stearyltrimonium chloride and distearyldimonium chloride), cetyl pyridinium bromide or chloride, quaternized poly (oxyethylalkylamine) halide salts, MIRAPOLTM and ALKAQUATTM, alkyl pyridinium salts, alkylamines, dialkylamines, alkanolamines, polyethylene polyamines, N acrylates, N-dialkylaminoalkyl, vinyl pyridine, lauryl amine acetate, stearyl amine acetate, alkylpyridinium salt, and alkylimidazolium salt, amine oxides, azolinium imide salts, protonated quaternary acrylamides, methylated quaternary polymers, poly [chloride] of dimethylammonium diallyl], poly- [N-methyl vinyl pyridinium chloride], cationic guar, benzalkonium chloride, n carbonium compound, a phosphonium compound, an oxonium compound, a halonium compound, a cationic organometallic compound, a quaternary phosphorus compound, a pyridinium compound, an anilinium compound, an immonium compound, a hydroxylammonium compound, a primary ammonium compound, an ammonium compound secondary, a tertiary ammonium compound, quartenary ammonium compounds of formula NRIR2R3R4 t + W, behenalkonium chloride, benzethonium chloride, cetylpyridinium chloride, behentrimonium chloride, lauralkonium chloride, cetalkonium chloride, 72 cetrimonium bromide, cetrimonium chloride , cetylamine hydrofluoride, chlorallylmethenamine chloride, distearyldimonium chloride, dodecyl dimethyl ethylbenzyl ammonium chloride, Quaternium-22, Quaternium-26, Quaternium-18 hectorite, dimethylaminoethyl chloride hydrochloride, cysteine hydrochloride, diethanolammonium phosphate POE (10) oleyl ether, diethyl phosphate ammonium POE (3) oleyl ether phosphate, tallow alkonium chloride, dimethyl dioctadecylammonium bentonite, stearalkonium chloride, domiphen bromide, denatonium benzoate, myristalkonium chloride, laurtrimonium chloride, ethylene diamine dihydrochloride, guanidine hydrochloride, pyridoxine HC1, iofetamine hydrochloride, meglumine hydrochloride, methylbenzethonium chloride, myrtrimonium bromide, oleyltrimonium chloride, polyquaternium - 1, procaine hydrochloride, cocobetaine, stearalkonium bentonite, stearalkonium hectonite, stearyl trihydroxyethyl propylene diamine difluorhydrate, trimonium tallow chloride, hexadecyltrimethyl ammonium bromide , proteins, phospholipids, zwitterionic polymers and zwitterionic surfactant molecules, human serum albumin, bovine serum albumin, gelatin, casein, lysozyme, phosphotidylcholine, and lecithin. The composition of any one of claims 1 to 11, wherein the composition has a pH level of about 7.0, about 7.1, about 7.2, about 7.3 about 7.4, about 7.5, about 7.6, about 7.7, about 7.8, about 7.9, about 8.0, about 8.1, about 8, 2, about 8.3, about 8.4, about 8.5, about 8, 6, about 8.7, d. about 8, 8, about 8, 9, about 9, about 9.1, about 9.2, about 9, 3, about 9, 4, about 9, 5, about 9, 6, about 9, 7, about 9, 8, about 9, 9, about 10.0, about 10.1, about 10.2, about 10.3, about 10.4, about 10.5, about 10, 6, about 10, 7, about 10.8, about 10 , 9, about 11.0, about 11.1, about 11.2, about 11.3, about 11.4, about 11, 5, about 11, 6, about 11.7, about 11, 8, about 11, 9, about 12.0, about 12.1, about 12.2, about 12.3. about 12.4 12.5, about 12.6, about 12.7, about 12.8, about 12.9, about 13.0, about 13.1, about 13.2, about 13, 3, about 13, 4, about 13.5, about 13, 6, about 13, 7, about 13.8, about 13 , 9, or about 14.0, or beyond about 14.0. The composition of claim 12, wherein the pH of the composition is in a range selected from the group consisting of about 9.0 to about 10.0, about 10.0 to about 11.0, about 11.0 to about 10.0, and about 14.0. about 12.0, and about 12.0 to The composition of claim 12 wherein the pH of the composition is in the range of about 9.5 to about 11.0. The composition of claim 12 wherein the pH of the composition is in the range of about 7.0 to about 9.5. The composition according to any one of claims 1 to 15, wherein: (a) the concentration of 3- (2,4-dichlorophenyl) -1,6-dimethyl-1,9-dihydro-pyrido [2, 3-b] indol-2-one is from about 99.5% to about 0.001 from about 95% to about 0.1 or from about 90% to about 0.5%, by weight; and (b) the concentration of the surface stabilizer is from about 0.5% to about 99.999 from about 5.0% to about 99.9% or from about 10% to about 99.5% by weight, relative to the combined total weight of 3- (2,4-dichloro-phenyl) -1,6-dimethyl-1,9-dihydro-pyrido [2,3-b] indol-2-one and at least one surface stabilizer , not including other excipients. 20 17. A composition according to any one of claims 1 to 16, wherein the composition comprises an additional anticancer active agent. 18. The composition of claim 17, wherein the additional anticancer active agent is selected from the group consisting of alkylating agents, alkylsulphonates, busulfan, dacarbazine, procarbazine, nitrogen mustards, chlormethine, melphalan, chlorambucil, cyclophosphamide, ifosfamide, nitrosoureas, carmustine, lomustine, semustine, streptozocin, antineoplastic alkaloids, vincristine, vinblastine, taxanes, paclitaxel, taxotere, antineoplastic antibiotics, actinomycin, intercalators, antineoplastic antimetabolites, folate antagonists, methotrexate, purine synthesis inhibitor, purine analogues, mercaptopurine, 6-thioguanine, pyrimidine synthesis inhibitors, aromatase inhibitors, capecitabine analogues or pyrimidines, fluorouracil, gemcitabine, cytarabine, cytosine arabinoside, descrine, topoisomerase inhibitors, camptothecin, etoposide, hormonal agonists and antagonists anticancer, tamoxifen, kinase inhibitors, imatinibe, growth factor inhibitors, anti-inflammatories, pentosan polysulfate, corticosteroids, prednisone, dexamethasone, antitopoisomerases, etoposide, anthracyclines, doxorubicin, bleomycin, mitomycin, mithramycin, anticancer metal complexes, platinum complexes, cisplatin , carboplatin, oxaliplatin, interferon-alpha, triphenyl thiophosphoramide, altretamine, anti-angiogenic agents, thalidomide, immunotherapy adjuvants, and vaccines. 19. Process for preparing a composition of 3- (2,4-dichloro-phenyl) -1,6-dimethyl-1,9-dihydro-pyrido [2,3-b] indol-2-one nanoparticle comprising contacting the particles of 3- (2,4-dichloro-phenyl) -1,6-dimethyl-1,9-dihydropyrido [2,3-b] indol-2-one with at least one surface stabilizer for a time and under conditions sufficient to form a composition of nanoparticles of 3- (2,4-dichlorophenyl) -1,6-dimethyl-1,9-dihydro-pyrido [2,3-b] indol-2-one having an average size effective particle less than about 400 nm. The method of claim 19, wherein the contacting comprises milling, homogenization precipitation or any combination thereof. A process for preparing a sterile composition of 3- (2,4-dichlorophenyl) -1,6-dimethyl-1,9-dihydro-pyrido [2,3-b] indol-2-one nanoparticles comprising the steps of (a) contacting the particles of 3- (2,4-dichloro-phenyl) -1,6-dimethyl-1,9-dihydropyrido [2,3-b] indol-2-one with at least a surface stabilizer and at least one excipient for a time and under conditions sufficient to form a dispersion of nanoparticles of 3- (2,4-dichloro-phenyl) -1,6-dimethyl-1,9-dihydropyrido [2, 3-b] indol-2-one having an average particle size effective at about 400 nm; (b) lyophilizing the dispersion to form a lyophilizate; and (c) sterilizing the lyophilizate to produce a sterile composition of 3- (2,4-dichloro-phenyl) -1,6-dimethyl-1,9-dihydropyrido [2,3-b] indol-2-one nanoparticles . The method of claim 21, wherein the sterilization comprises gamma radiation at room temperature. 23. The method of claim 22, wherein the gamma radiation is applied in a range from about 5 kGray to about 50 kGray. 24. The method of claim 23, wherein the sterilization comprises autoclaving. 25. Composition of 3- (2,4-dichloro-phenyl) -1,6-dimethyl-1,9-dihydropyrido [2,3-b] indol-2-one nanoparticles, wherein the composition comprises (a) particles of 3- (2,4-dichloro-phenyl) -1,6-dimethyl-1,9-dihydro-pyrido [2,3-b] indol-2-one having an effective average particle size of less than about 400 nm; and (b) at least one surface stabilizer as a medicament for the treatment of cancer. 26. The use of claim 25, wherein the cancer is selected from the group consisting of breast cancer; lung cancer, cancer of the small intestine, cancer of the colon and rectum, cancer of the respiratory tract, oropharynx or hypopharynx, cancer of the esophagus, cancer of the liver, stomach cancer, primary bile duct cancer, gallbladder cancer, pancreatic cancer, urinary tract cancers, female genital cancers, choriocarcinoma or trophoblastic cancer, cancer of the bile male genital tract, cancers of the endocrine glands, skin cancers, brain tumors, nerves, eyes and meninges, and solid tumors resulting from hematopoietic malignancies.