WO2010138661A1 - Nanoparticulate anticancer compositions and methods for making the same - Google Patents

Nanoparticulate anticancer compositions and methods for making the same Download PDF

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Publication number
WO2010138661A1
WO2010138661A1 PCT/US2010/036304 US2010036304W WO2010138661A1 WO 2010138661 A1 WO2010138661 A1 WO 2010138661A1 US 2010036304 W US2010036304 W US 2010036304W WO 2010138661 A1 WO2010138661 A1 WO 2010138661A1
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dimethyl
chloride
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composition
pyrido
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PCT/US2010/036304
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French (fr)
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WO2010138661A8 (en
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David Slifer
Janine Keller
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Elan Pharma International Ltd.
Sanofi Advantis
Mcgurk, Simon, L.
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Publication of WO2010138661A1 publication Critical patent/WO2010138661A1/en
Publication of WO2010138661A8 publication Critical patent/WO2010138661A8/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/145—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates generally to nanoparticulate compositions of 3-(2,4-dichloro-phenyl)-l,6-dimethyl-l,9-dihydro-pyrido[2,3-b]indol-2-one, and in particular, a nanoparticulate composition useful in the treatment of cancer.
  • Bioavailability is the degree to which a 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 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-dichloro-phenyl)-l,6-dimethyl-l,9-dihydro- pyrido[2,3-b]indol-2-one. Poorly water soluble drugs tend to be eliminated from the gastrointestinal tract before being absorbed into the circulation. Moreover, poorly water soluble drugs tend to be unsafe for intravenous administration techniques, which are used primarily in conjunction with fully soluble drug substances.
  • an enhanced dissolution rate could allow for a larger dose to be absorbed, which could increase the efficacy of 3-(2,4-dichloro-phenyl)-l,6-dimethyl-l,9- dihydro-pyrido[2,3-b]indol-2-one.
  • an injectable nanop articulate formulation of 3-(2,4-dichloro-phenyl)-l,6-dimethyl-l,9-dihydro-pyrido[2,3-b]indol-2-one could eliminate the need for toxic co-solvents and enhance the efficacy of 3-(2,4-dichloro- phenyl)-l,6-dimethyl-l,9-dihydro-pyrido[2,3-b]indol-2-one treatment.
  • the present invention which relates to nanoparticulate compositions comprising 3-(2,4-dichloro- phenyl)-l,6-dimethyl-l,9-dihydro-pyrido[2,3-b]indol-2-one, addresses these concerns.
  • Nanoparticulate active agent compositions comprise particles of a poorly soluble therapeutic or diagnostic agent having adsorbed onto, or associated with, the surface thereof a non-crosslinked surface stabilizer.
  • the '684 patent does not describe nanoparticulate compositions of 3-(2,4-dichloro-phenyl)-l,6-dimethyl-l,9- dihydro-pyrido[2,3-b]indol-2-one.
  • Nanoparticulate active agent compositions are also described, for example, in U.S. Patent Nos. 5,298,262 for "Use of Ionic Cloud Point Modifiers to Prevent Particle Aggregation During Sterilization;" 5,302,401 for “Method to Reduce Particle Size Growth During Lyophilization;” 5,318,767 for “X-Ray Contrast Compositions Useful in Medical Imaging;” 5,326,552 for “Novel Formulation For Nanoparticulate X-Ray Blood Pool Contrast Agents Using High Molecular Weight Non- ionic Surfactants;” 5,328,404 for “Method of X-Ray Imaging Using Iodinated Aromatic Propanedioates;” 5,336,507 for “Use of Charged Phospholipids to Reduce Nanoparticle Aggregation;” 5,340,564 for “Formulations Comprising Olin 10-G to Prevent Particle Aggregation and Increase Stability;” 5,346,702 for "Use of Non-S.
  • Amorphous small particle compositions are described, for example, in U.S. Patent Nos. 4,783,484 for "Particulate Composition and Use Thereof as Antimicrobial Agent;” 4,826,689 for “Method for Making Uniformly Sized Particles from Water-Insoluble Organic Compounds;” 4,997,454 for “Method for Making Uniformly-Sized Particles From Insoluble Compounds;” 5,741,522 for "Ultrasmall, Non- aggregated Porous Particles of Uniform Size for Entrapping Gas Bubbles Within and Methods;” and 5,776,496 for "Ultrasmall Porous Particles for Enhancing Ultrasound Back Scatter,” which are also incorporated by reference herein.
  • the present invention relates, in certain aspects, to nanoparticulate 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 to methods for making and using the same.
  • the present invention relates to nanoparticulate compositions comprising 3-(2,4-dichloro-phenyl)-l,6-dimethyl-l,9-dihydro-pyrido[2,3-b]indol-2-one, as well as methods of making and using the same.
  • the composition comprises particles comprising 3-(2,4-dichloro-phenyl)-l,6-dimethyl-l,9-dihydro-pyrido[2,3-b]indol-2-one, wherein the particles have an effective average size of less than about 2000 nm.
  • the composition may also comprise at least one surface stabilizer adsorbed onto or associated with the surface of the drug particles.
  • the surface stabilizer is present in an amount sufficient to maintain 3-(2,4-dichloro-phenyl)-l,6-dimethyl-l,9-dihydro-pyrido[2,3- b]indol-2-one at an effective average particle size of less than 2000 nm, thereby maintaining the efficacy of the drug over a period of time.
  • the particle size of 3-(2,4- dichloro-phenyl)-l,6-dimethyl-l,9-dihydro-pyrido[2,3-b]indol-2-one nanoparticles can be manipulated to give the desirable blood profile and duration of action when administered.
  • the composition may further comprise other excipients such as aggregation reducing agents, pH modifying agents, and the like.
  • the nanoparticulate composition is an injectable formulation.
  • the nanoparticulate composition is an intraperitoneal or intramuscular formulation.
  • a preferred dosage form of the invention is a formulation suitable for intravenous administration.
  • a method for making a nanoparticulate 3-(2,4-dichloro-phenyl)-l,6-dimethyl-l,9-dihydro- pyrido[2,3-b]indol-2-one composition comprises the step of contacting 3-(2,4-dichloro- phenyl)-l,6-dimethyl-l,9-dihydro-pyrido[2,3-b]indol-2-one with at least one surface stabilizer and optionally with additional excipients for a period of time and under conditions sufficient to provide a nanoparticulate 3-(2,4-dichloro-phenyl)-l,6-dimethyl- l,9-dihydro-pyrido[2,3-b]indol-2-one composition having an effective average particle size of less than about 2000 nm.
  • Additional aspects of the present invention are directed to methods of treating cancer comprising administering an effective amount of a nanoparticulate composition comprising 3-(2,4-dichloro-phenyl)- 1 ,6-dimethyl- 1 ,9-dihydro-pyrido[2,3- b]indol-2-one to a subject in need thereof.
  • Another aspect of the present invention is the use of a nanoparticulate composition comprising 3-(2,4-dichloro-phenyl)- 1 ,6-dimethyl- 1 ,9-dihydro-pyrido[2,3- b]indol-2-one in the treatment of cancers.
  • pill refers to a state of matter which is characterized by the presence of discrete particles, pellets, beads or granules irrespective of their size, shape or morphology.
  • nanoparticulate refers to a composition in which the effective average particle size of the particles therein is less than about 2000 nm (2 microns).
  • the terms "conventional” or “non-nanoparticulate” active agent shall mean an active agent, such as 3-(2,4-dichloro-phenyl)-l,6-dimethyl-l,9- dihydro-pyrido[2,3-b]indol-2-one, which is solubilized or which has an effective average particle size of greater than about 2000 nm.
  • an effective average particle size describes a population of particles in a composition in which at least 50% of the particles are less than a specified size. Accordingly, "effective average particle size of less than about 2000 nm” means that at least 50% of the particles therein are less than about 2000 nm.
  • D50 refers to a particle size below which 50% of the particles in a composition are less than that particle size.
  • D90 refers to the particle size below which 90% of the particles in a composition are less than that particle size.
  • stable refers to, but is not limited to, one or more of the following parameters: (1) the particles do not appreciably flocculate or agglomerate due to interparticle attractive forces or otherwise significantly increase in particle size over time; (2) the physical structure of the particles is not altered over time, such as by conversion from an amorphous phase to a crystalline phase; (3) the particles are chemically stable; and/or (4) where the active ingredient has not been subject to a heating step at or above the melting point of the active agent in the preparation of the particles of the present invention.
  • a 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/ml, or less than about 1 mg/ml.
  • a therapeutically effective amount means the dosage that provides the specific pharmacological response for which the active agent is administered in a significant number of subjects in need of the relevant treatment. It is emphasized that a therapeutically effective amount of the active agent that is administered to a particular subject in a particular instance will not always be effective in treating the conditions described herein, even though such dosage is deemed to be a therapeutically effective amount by those of skill in the art.
  • the terms "sterilize” or “sterilized” as used in the present application generally means to inactivate biological contaminants present in the product. In typical pharmaceutical applications, autoclaving the pharmaceutical product, exposure to at least a 25 kGray dose of irradiation, or sterile filtering through a 0.2 micron sieve sterilizes the pharmaceutical product.
  • the composition comprises particles of 3- (2,4-dichloro-phenyl)-l,6-dimethyl-l,9-dihydro-pyrido[2,3-b]indol-2-one having an effective average particle size of less than about 2000 nm and at least one surface stabilizer adsorbed on the surface of the particles.
  • nanoparticulate particles of 3-(2,4-dichloro-phenyl)-l ,6-dimethyl- l,9-dihydro-pyrido[2,3-b]indol-2-one described herein may exist in a crystalline phase, an amorphous phase, a semi-crystalline phase, or a mixture thereof.
  • the surface stabilizers are preferably adsorbed onto or associated with the surface of the 3-(2,4-dichloro-phenyl)-l,6-dimethyl-l,9-dihydro-pyrido[2,3-b]indol- 2-one particles.
  • Surface stabilizers useful herein may physically adhere on, adsorb on, or associate with the surface of the nanoparticulate active agent but may not chemically react with the active agent particles.
  • the molecules of the surface stabilizer are essentially free of intermolecular cross-linkages.
  • the compositions of the present invention may comprise two or more surface stabilizers.
  • compositions comprising nanoparticulate 3-(2,4-dichloro-phenyl)-l,6-dimethyl-l,9-dihydro-pyrido[2,3-b]indol-2- one particles, at least one surface stabilizer and optionally additional excipients, such as aggregation reducing agents, pH modifying agents, and the like.
  • the present invention also includes nanoparticulate 3- (2,4-dichloro-phenyl)-l,6-dimethyl-l,9-dihydro-pyrido[2,3-b]indol-2-one compositions together with one or more non-toxic physiologically acceptable carriers, adjuvants, or vehicles, collectively referred to as carriers.
  • the compositions may be formulated, for example, for parenteral administration (e.g., intravenous, intramuscular, intrathecal, or subcutaneous), intracisternal administration, intravaginal administration, intraperitoneal administration, local administration and the like.
  • an effective average particle size of less than about 2000 nm it is meant that at least 50% of the active agent particles have a particle size less than the effective average, by weight (or by other suitable measurement techniques, such as by volume, number, etc.).
  • the "effective average" particle size can be, for example, less than about 2000 nm, 1900 nm, 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 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, when measured by techniques well known to those skilled in the art.
  • 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 particles have a particle size of less than the effective average, i.e., less than about 2000 nm, 1900 nm, 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 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
  • compositions of the invention comprise 3-(2,4-dichloro-phenyl)-l,6- dimethyl-l,9-dihydro-pyrido[2,3-b]indol-2-one particles having an effective average particle size of less than about 2 microns.
  • the 3- (2,4-dichloro-phenyl)-l,6-dimethyl-l,9-dihydro-pyrido[2,3-b]indol-2-one particles have an effective average particle size of less than about 1900 nm, less than about 1800 nm, less than about 1700 nm, less than about 1600 nm, less than about 1500 nm, less than about 1400 nm, less than about 1300 nm, less than about 1200 nm, less than about 1100 nm, less than about 1000 nm, less than about 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
  • compositions of the invention are in an injectable dosage form and the 3-(2,4-dichloro-phenyl)-l,6-dimethyl- l,9-dihydro-pyrido[2,3-b]indol-2-one particles 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 can comprise 3-(2,4-dichloro-phenyl)-l,6-dimethyl-l,9-dihydro- pyrido[2,3-b]indol-2-one having an effective average particle size of greater than about 1 micron, up to about 2 microns. If the "effective average particle size" is less than about 600 nm, then at least about 50% of the 3-(2,4-dichloro-phenyl)-l,6-dimethyl-l,9-dihydro- pyrido[2,3-b]indol-2-one particles have a size of less than about 600 nm, when measured by the above-noted techniques. The same is true for the other particle sizes referenced above.
  • 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 3-(2,4- dichloro-phenyl)-l,6-dimethyl-l,9-dihydro-pyrido[2,3-b]indol-2-one particles have a particle size less than the effective average, i.e., 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
  • 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 of less than 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, 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 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
  • compositions of the invention may 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.
  • the surface stabilizers especially useful herein preferably do not chemically react with the active agent particles or itself.
  • individual molecules of the auxiliary surface stabilizer are essentially free of intermolecular cross-linkages.
  • Two or more surface stabilizers can be employed in the compositions and methods of the invention.
  • Suitable surface stabilizers can preferably be selected from known organic and inorganic pharmaceutical excipients. Such excipients include various polymers, low molecular weight oligomers, natural products, and surfactants. Preferred surface stabilizers include nonionic, anionic, cationic and zwitterionic compounds or surfactants.
  • nonionic stabilizers including but not limited to, albumin, dextran, gum acacia, tragacanth, glycerol monostearate, cetostearyl alcohol, cetomacrogol emulsifying wax, sorbitan esters, polyoxyethylene alkyl ethers (e.g., macrogol ethers such as cetomacrogol 1000), polyethylene alkyl esters, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters (e.g.
  • Tweens ® such as e.g., Tween 20 ® and Tween 80 ® (ICI Speciality Chemicals)); polyethylene glycols (e.g., Carbowaxs 3550 ® and 934 ® (Union Carbide)), polyoxyethylene stearates, methylcellulose, hydroxyethylcellulose, hydroxypropyl celluloses (e.g., HPC, HPC-SL, and HPC-L), hydroxypropyl methylcellulose (HPMC), hydroxypropylmethyl-cellulose phthalate, noncrystalline cellulose, triethanolamine, polyvinyl alcohol (PVA), polyvinylpyrrolidone (PVP), 4-(l,l,3,3-tetramethylbutyl)- phenol polymer with ethylene oxide and formaldehyde (also known as tyloxapol, superione, and triton), poloxamers (e.g., Pluronics F68 ® and F 108 ® ,
  • Preferred nonionic stabilizers include, but are not limited to, Hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose grade HPC-SL, Polyvinylpyrrolidones, Kollidone Kl 2 (BASF) or Plasdone® C- 12 (ISP Technologies, Inc.) Kollidone Kl 7 (BASF) - Plasdone® C- 17 (ISP Technologies, Inc). Kollidone K29/32 (BASF)- Plasdone® C-29/32 (ISP Technologies, Inc.
  • copolymer of vinylpyrrolidone and vinyl acetate - Copovidone sold under the tradename Plasdone® S-630 (ISP Technologies, Inc), distearyl palmitate glyceryl, polyoxyethylene sorbitan fatty acid esters such as polyoxyethylene 20 sorbitan monolaurate, polysorbate 20 a.k.a. Tween® 20 by ICI Americas, polyoxyethylene 20 sorbitan monopalmitate, polysorbate 40" a.k.a. Tween® 40 by ICI Americas, polyoxyethylene 20 sorbitan monooleate, polysortbate 80 a.k.a. Tween® 80 by ICI Americas, macrogol 15 hydroxystearate - Solutol® 15 BASF, Tyloxapol and Cremaphor.
  • Plasdone® S-630 ISP Technologies, Inc
  • distearyl palmitate glyceryl polyoxyethylene sorbitan fatty acid esters such as polyoxyethylene 20 sorbitan monol
  • anionic stabilizers including but 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 dodecylsulfate, Duponol P ® , which is a sodium lauryl sulfate (DuPont), carboxymethylcellulose calcium, carboxymethylcellulose sodium, dialkylesters of sodium sulfosuccinic acid (e.g.
  • Aerosol OT ® which is a dioctyl ester of sodium sulfosuccinic acid (DOSS) (American Cyanamid)
  • Triton X-200 ® which is an alkyl aryl polyether sulfonate (Union Carbide).
  • Salt forms of bile acids are also useful as anionic stabilizers, such as sodium deoxycholate, sodium cholate, sodium chenodeoxycholate, sodium dehydrocholate, disuccinylursodeoxycholic acid bisodic salt, sodium hyodeoxycholate, sodium ursodeoxy cholate.
  • Preferred anionic stabilizers include, but are not limited to, dioctyl sodium succinate (DOSS) sodium lauryl sulfate (SLS) a.k.a. sodium dodecyl sulfate (SDS) and sodium deoxycholate.
  • DOSS dioctyl sodium succinate
  • SLS sodium lauryl sulfate
  • SDS sodium dodecyl sulfate
  • deoxycholate sodium deoxycholate
  • Examples of useful cationic surface stabilizers include but are not limited to polymers, biopolymers, poly-n-methylpyridinium, anthryul pyridinium chloride, cationic phospholipids, chitosan, polylysine, polyvinylimidazole, polybrene, polymethylmethacrylate trimethylammoniumbromide bromide (PMMTMABr), hexyldesyltrimethylammonium bromide (HDMAB), and polyvinylpyrrolidone-2- dimethylaminoethyl methacrylate dimethyl sulfate.
  • polymers biopolymers, poly-n-methylpyridinium, anthryul pyridinium chloride, cationic phospholipids, chitosan, polylysine, polyvinylimidazole, polybrene, polymethylmethacrylate trimethylammoniumbromide bromide (PMMTMABr), hexyldesyltrimethylam
  • cationic stabilizers include, but are not limited to, cationic lipids, sulfonium, phosphonium, and quarternary ammonium compounds, such as stearyltrimethylammonium chloride, benzyl-di(2-chloroethyl)ethylammonium bromide, coconut trimethyl ammonium chloride or bromide, coconut methyl dihydroxyethyl ammonium chloride or bromide, dodecyl trimethyl ammonium bromide, decyl triethyl ammonium chloride, decyl dimethyl hydroxyethyl ammonium chloride or bromide, C 12- 15 dimethyl hydroxyethyl ammonium chloride or bromide, coconut dimethyl hydroxyethyl ammonium chloride or bromide, myristyl trimethyl ammonium methyl sulphate, lauryl dimethyl benzyl ammonium chloride or bromide, lauryl dimethyl (stearyltrimethyl
  • ⁇ dimethyl-benzyl ammonium chloride N-tetradecylidmethylbenzyl ammonium chloride monohydrate, dimethyl didecyl ammonium chloride, N-alkyl and (C 12-14 ) dimethyl 1- napthylmethyl ammonium chloride, trimethylammonium halide, alkyl- trimethylammonium salts and dialkyl-dimethylammonium salts, lauryl trimethyl ammonium chloride, ethoxylated alkyamidoalkyldialkylammonium salt and/or an ethoxylated trialkyl ammonium salt, dialkylbenzene dialkylammonium chloride, N- didecyldimethyl ammonium chloride, N-tetradecyldimethylbenzyl ammonium, chloride monohydrate, N-alkyl(Ci2-i4) dimethyl 1-naphthylmethyl ammonium chloride and dodecyldimethylbenzyl ammonium chlor
  • Such exemplary cationic surface stabilizers and other useful cationic surface stabilizers are described in J. Cross and E. Singer, Cationic Surfactants: Analytical and Biological Evaluation (Marcel Dekker, 1994); P. and D. Rubingh (Editor), Cationic Surfactants: Physical Chemistry (Marcel Dekker, 1991); and J. Richmond, Cationic Surfactants: Organic Chemistry, (Marcel Dekker, 1990).
  • nonpolymeric primary stabilizers are any nonpolymeric compound, such benzalkonium chloride, a carbonium compound, a phosphonium compound, an oxonium compound, a halonium compound, a cationic organometallic compound, a quarternary phosphorous compound, a pyridinium compound, an anilinium compound, an immonium compound, a hydroxylammonium compound, a primary ammonium compound, a secondary ammonium compound, a tertiary ammonium compound, and quarternary ammonium compounds of the formula NR 1 R 2 R 3 R 4 ⁇ .
  • benzalkonium chloride a carbonium compound, a phosphonium compound, an oxonium compound, a halonium compound, a cationic organometallic compound, a quarternary phosphorous compound, a pyridinium compound, an anilinium compound, an immonium compound, a hydroxylammonium compound, a primary ammoni
  • Such compounds include, but are not limited to, behenalkonium chloride, benzethonium chloride, cetylpyridinium chloride, behentrimonium chloride, lauralkonium chloride, cetalkonium chloride, cetrimonium bromide, cetrimonium chloride, cethylamine hydrofluoride, chlorallylmethenamine chloride (Quaternium-15), distearyldimonium chloride (Quaternium-5), dodecyl dimethyl ethylbenzyl ammonium chloride(Quaternium-14), Quaternium-22, Quaternium-26, Quaternium-18 hectorite, dimethylaminoethylchloride hydrochloride, cysteine hydrochloride, diethanolammonium POE (10) oletyl ether phosphate, diethanolammonium POE (3)oleyl ether phosphate, tallow alkonium chloride, dimethyl dioctadecylammoni
  • Examples of zwitterionic stabilizers include but are not limited to proteins, phospholipids, zwitterionic polymers and zwitterionic surfactant molecules.
  • proteins albumin including but not limited to human serum albumin and bovine serum albumin, gelatin, casein, lysozyme.
  • phospholipids include phosphotidylcholine, lecithin.
  • the proteins and peptides are zwitteronic may morph into cationic or anionic depending on the pH of the medium they are exposed to. In this embodiment, it should be understood that in the considered pH range, these are molecules are zwitterionic.
  • compositions according to the invention may also comprise one or more aggregation reducing agents, binding agents, bulking agents, filling agents, lubricating agents, suspending agents, preservatives, pH modifying agents, wetting agents, disintegrants, effervescent agents, crystal growth inhibitors, free radical scavenger agents, redispersion agents, and other excipients.
  • excipients are known in the art.
  • the composition may also comprise isotonic agents, such as sugars, sodium chloride, and the like, and agents for use in delaying the absorption of the injectable pharmaceutical form, such as aluminum monostearate and gelatin.
  • isotonic agents such as sugars, sodium chloride, and the like
  • agents for use in delaying the absorption of the injectable pharmaceutical form such as aluminum monostearate and gelatin.
  • compositions suitable for parenteral injection may comprise, for example, physiologically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions and sterile powders for reconstitution into sterile injectable solutions or dispersions.
  • aqueous and nonaqueous carriers examples include water, ethanol, sodium chloride, Ringer's solution, lactated Ringer's solution, stabilizer solutions, tonicity enhancers (sucrose, dextrose, mannitol, etc.), polyols (propyleneglycol, polyethylene-glycol, glycerol, and the like), suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate.
  • suitable aqueous and nonaqueous carriers including water, ethanol, sodium chloride, Ringer's solution, lactated Ringer's solution, stabilizer solutions, tonicity enhancers (sucrose, dextrose, mannitol, etc.), polyols (propyleneglycol, polyethylene-glycol, glycerol, and the like), suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate.
  • Examples of aggregation reducing agents include sugars, sugar alcohols and buffers.
  • Exemplary sugars and sugar alcohols includes, but are not limited to, sucrose, fructose, glucose, erythritol, isomalt, mannitol, sorbitol, xylitol, sorbitol, and dextrose.
  • Any pH modifying agent system suitable for LV. or LM. administration may be used, such as but not limited to a phosphate buffer, an acetate buffer or a citrate buffer.
  • the buffer is a potassium phosphate buffer, a sodium phosphate buffer, or a sodium acetate buffer.
  • filling agents include lactose monohydrate, lactose anhydrous, and various starches
  • binding agents include various celluloses and cross-linked polyvinylpyrrolidone, microcrystalline cellulose, such as Avicel ® PHlOl and Avicel ® PH 102, microcrystalline cellulose, and silicif ⁇ ed microcrystalline cellulose (ProSolv SMCCTM).
  • Suitable lubricants including agents that act on the flowability of the powder to be compressed, may include colloidal silicon dioxide, such as Aerosil ® 200, talc, stearic acid, magnesium stearate, calcium stearate, and silica gel.
  • colloidal silicon dioxide such as Aerosil ® 200, talc, stearic acid, magnesium stearate, calcium stearate, and silica gel.
  • preservatives include potassium sorbate, methylparaben, propylparaben, benzoic acid and its salts, other esters of parahydroxybenzoic acid such as butylparaben, alcohols such as ethyl or benzyl alcohol, phenolic compounds such as phenol, or quaternary compounds such as benzalkonium chloride.
  • Exemplary pH adjusting agents are sodium hydroxide and hydrochloric acid, and an exemplary liquid carrier is sterile water for injection.
  • Other useful preservatives, pH adjusting agents, and liquid carriers are well-known in the art.
  • Suitable diluents include pharmaceutically acceptable inert fillers, such as microcrystalline cellulose, lactose, dibasic calcium phosphate, saccharides, and/or mixtures of any of the foregoing.
  • examples of diluents include microcrystalline cellulose, such as Avicel ® PHlOl and Avicel ® PH 102; lactose such as lactose monohydrate, lactose anhydrous, and Pharmatose ® DCL21; dibasic calcium phosphate such as Emcompress ® ; mannitol; starch; sorbitol; sucrose; and glucose.
  • Suitable disintegrants include lightly crosslinked polyvinyl pyrrolidone, corn starch, potato starch, maize starch, and modified starches, croscarmellose sodium, cross-povidone, sodium starch glycolate, and mixtures thereof.
  • effervescent agents include effervescent couples such as an organic acid and a carbonate or bicarbonate.
  • Suitable organic acids include, for example, citric, tartaric, malic, fumaric, adipic, succinic, and alginic acids and anhydrides and acid salts.
  • Suitable carbonates and bicarbonates include, for example, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, magnesium carbonate, sodium glycine carbonate, L-lysine carbonate, and arginine carbonate.
  • sodium bicarbonate component of the effervescent couple may be present.
  • the pH of the composition for IV or IM administration is a buffered formulation that is at a pH that is suitably high enough to reduce aggregation.
  • the compositions of the invention have a pH level of about pH 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 10.7, 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, about 12.5, about 12.6, about 12.7, about 12.
  • the pH of the formulation of the invention is in a range selected from the group consisting of pH about 9.0- about 10.0, about 10.0- about 11.0, about 11.0- about 12.0, about 12.0- about 14.0. In another embodiment, the pH of the formulation is in the range of pH about 9.5 - about 11.0. In yet another embodiment, the pH of the formulation is in the range of pH about 7.0 - about 9.5.
  • the relative amounts of 3-(2,4-dichloro-phenyl)-l ,6-dimethyl-l ,9- dihydro-pyrido[2,3-b]indol-2-one and one or more surface stabilizers can vary widely.
  • the optimal amount of the individual components depends, for example, upon physical and chemical attributes of the surface stabilizer(s) and 3-(2,4-dichloro-phenyl)-l,6- dimethyl-l,9-dihydro-pyrido[2,3-b]indol-2-one selected, such as the hydrophilic lipophilic balance (HLB), melting point, and the surface tension of water solutions of the stabilizer, etc.
  • HLB hydrophilic lipophilic balance
  • the concentration of the 3-(2,4-dichloro-phenyl)-l,6- dimethyl-l,9-dihydro-pyrido[2,3-b]indol-2-one can 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-dichloro-phenyl)-l,6-dimethyl-l,9-dihydro- pyrido[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 from a dose and cost efficiency standpoint.
  • the concentration of surface stabilizer can vary from about 0.5% to about 99.999%, from about 5.0% to about 99.9%, or from about 10% to about 99.5%, by weight, based on the total combined dry weight of the 3-(2,4-dichloro-phenyl)- l,6-dimethyl-l,9-dihydro-pyrido[2,3-b]indol-2-one and at least one surface stabilizer, not including other excipients.
  • Certain embodiments of the invention may include nanoparticulate 3- (2,4-dichloro-phenyl)-l,6-dimethyl-l,9-dihydro-pyrido[2,3-b]indol-2-one compositions together with one or more non-toxic physiologically acceptable excipients, carriers, adjuvants, or vehicles, etc.
  • the excipient may be present in an amount from about 1 to about 50, about 1 to about 40, about 1 to about 30, about 1 to about 20, about 1 to about 15, about 1 to about 10, or about 1 to about 5, as measured by % w/w of the composition.
  • Exemplary preservatives useful in certain embodiments of the invention include, without limitation, methylparaben (about 0.18% based on % w/w), propylparaben (about 0.02% based on % w/w), phenol (about 0.5% based on % w/w), and benzyl alcohol (up to 2% v/v).
  • compositions of the invention may comprise, in addition to 3-(2,4-dichloro-phenyl)-l,6-dimethyl-l,9-dihydro-pyrido[2,3- b]indol-2-one, one or more compounds useful in treating cancer.
  • alkylating agents such as alkylsulphonates (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; intercalating agents, antineoplastic antimetabolites, folate antagonists or methotrexate; purine synthesis inhibitors; purine analogues, such as mercaptopurine or 6-thioguanine; pyrimidine synthesis inhibitors, aromatase inhibitors, capecitabine or pyrimidine analogues, such as fluorouracil, gemcitabine,
  • alkylating agents such as al
  • nanoparticulate active agent compositions of the invention are proposed to have an unexpectedly rapid dissolution profile. Rapid dissolution of 3-(2,4-dichloro-phenyl)- 1 ,6-dimethyl- 1 ,9- dihydro-pyrido[2,3-b]indol-2-one is preferable, as faster dissolution generally leads to faster onset of action and greater bioavailability.
  • Additional advantages of a nanoparticulate active agent formulation include, without limitations, (1) a decrease in the frequency of dosing and/or prolonged therapeutic levels of drug following dosing; (2) smaller doses of 3-(2,4-dichloro-phenyl)- l,6-dimethyl-l,9-dihydro-pyrido[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 C max and AUC profiles; (6) bioadhesive 3-(2,4-dichloro-phenyl)-l,6- dimethyl-l,9-dihydro-pyrido[2,3-b]indol-2-one formulations, which can coat the desired site of application and be retained for a period of time, thereby increasing the efficacy of the drug as
  • compositions of the invention preferably have a dissolution profile in which within about 5 minutes at least about 20% of the 3-(2,4-dichloro-phenyl)-l,6-dimethyl-l,9-dihydro-pyrido[2,3-b]indol-2- one is dissolved. In other embodiments of the invention, at least about 30% or at least about 40% of the 3-(2,4-dichloro-phenyl)-l,6-dimethyl-l,9-dihydro-pyrido[2,3-b]indol-2- one is dissolved within about 5 minutes.
  • 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)-l,6-dimethyl-l,9-dihydro- pyrido[2,3-b]indol-2-one is dissolved within about 10 minutes.
  • at least about 70%, at least about 80%, at least about 90%, or at least about 100% of the 3-(2,4-dichloro-phenyl)-l,6-dimethyl-l,9- dihydro-pyrido[2,3-b]indol-2-one is dissolved within about 20 minutes.
  • Dissolution is preferably measured in a medium which is discriminating. Such a dissolution medium will produce two very different dissolution curves for two products having very different dissolution profiles in gastric juices; i.e., the dissolution medium is predictive of in vivo dissolution of a composition.
  • An exemplary dissolution medium is an aqueous medium containing the surfactant sodium lauryl sulfate at 0.025 M. Determination of the amount dissolved can be carried out by spectrophotometry. The rotating blade method (European Pharmacopoeia) can be used to measure dissolution.
  • the nanoparticulate particles of the composition redisperse so that the particles have an effective average particle size of less than about 2000 nm. This is significant because, if the particles did not redisperse so that they have an effective average particle size of less than about 2000 nm, the composition may lose benefits afforded by formulating 3-(2,4-dichloro-phenyl)-l,6-dimethyl-l,9- dihydro-pyrido[2,3-b]indol-2-one therein into a nanoparticulate form.
  • nanoparticulate compositions benefit from the small size of the particles comprising 3- (2,4-dichloro-phenyl)-l,6-dimethyl-l,9-dihydro-pyrido[2,3-b]indol-2-one. If the particles do not redisperse into small particle sizes upon administration, then "clumps" or agglomerated particles may be formed, owing to the extremely high surface free energy of the nanoparticulate system and the thermodynamic driving force to achieve an overall reduction in free energy. With the formation of such agglomerated particles, the bioavailability of the dosage form may fall well below that observed with the liquid dispersion form of the nanoparticulate composition.
  • the stabilizer hinders the flocculation and/or agglomeration of the 3-(2,4- dichloro-phenyl)-l,6-dimethyl-l,9-dihydro-pyrido[2,3-b]indol-2-one particles by functioning as a mechanical or steric barrier between the particles, minimizing the close, interparticle approach necessary for agglomeration and flocculation.
  • nanometer scale particles are intrinsically unstable in the absence of stabilization. The presence of a surface stabilizer adsorbed on the surface of the particles ensures that a small particle size is maintained. Thus, the claimed interaction between the surface stabilizer and the particle surface allows the small particle size to be maintained, due to the fact that particles are prevented from coming close enough together to aggregate.
  • the redispersed particles of the invention (redispersed in water, a biorelevant media, or any other suitable liquid media) have an effective average particle size of less than about 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 in diameter, as measured by light-scattering methods
  • Redispersibility can be tested using any suitable means known in the art. See e.g., the example sections of U.S. Patent No. 6,375,986 for "Solid Dose Nanoparticulate Compositions Comprising a Synergistic Polymeric Surface Stabilizer and Sulfosuccinate," incorporated herein by reference.
  • 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.
  • routes 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.
  • injectable nanoparticulate 3-(2,4-dichloro-phenyl)-l,6-dimethyl-l,9-dihydro-pyrido[2,3-b]indol-2- one formulations that can comprise high concentrations in low injection volumes, with rapid dissolution upon administration, which can be infused more rapidly than conventional formulations.
  • composition of the instant invention may be formulated in a powder or solid form for reconstitution prior to injectable administration, such as by lyophilization.
  • Exemplary preservatives useful with injectable formulations of the invention include, without limitation, methylparaben (about 0.18% based on % w/w), propylparaben (about 0.02% based on % w/w), phenol (about 0.5% based on % w/w), and benzyl alcohol (up to 2% v/v).
  • An exemplary pH adjusting agent is sodium hydroxide
  • an exemplary liquid carrier is sterile water for injection.
  • Other useful preservatives, pH adjusting agents, and liquid carriers are well-known in the art.
  • compositions suitable for parenteral injection may comprise physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions.
  • suitable aqueous and non-aqueous carriers, diluents, solvents, or vehicles including water, ethanol, polyols (propyleneglycol, polyethylene-glycol, glycerol, and the like), suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate.
  • Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
  • the nanoparticulate 3-(2,4- dichloro-phenyl)-l,6-dimethyl-l,9-dihydro-pyrido[2,3-b]indol-2-one composition is free of polysorbate, ethanol, or a combination thereof.
  • the compositions of the invention may provide a high concentration in a small volume to be injected.
  • compositions of the invention can be administered, for example, in a bolus injection or with a slow infusion over a suitable period of time.
  • the nanoparticulate 3-(2,4- dichloro-phenyl)-l,6-dimethyl-l,9-dihydro-pyrido[2,3-b]indol-2-one compositions are formulated as a subcutaneous or intramuscular depot.
  • the depot is preferably formulated to release 3-(2,4-dichloro-phenyl)-l,6-dimethyl-l,9-dihydro-pyrido[2,3-b]indol-2-one over a period from about one week to about four weeks.
  • the injectable depot nanoparticulate 3-(2,4-dichloro-phenyl)-l,6-dimethyl-l,9- dihydro-pyrido[2,3-b]indol-2-one composition provides therapeutic levels of drug for up to about one week, up to about two weeks, up to about three weeks, or up about four weeks.
  • nanoparticulate active agent compositions can be made using methods known in the art such as, for example, milling, homogenization, and precipitation techniques. Exemplary methods of making nanoparticulate active agent compositions are generally described in U.S. Patent No. 5,145,684 ("the '684 patent"), the contents of which are incorporated by reference herein.
  • the '684 patent describes nanoparticles of poorly soluble therapeutic or diagnostic agents having adsorbed onto or associated with the surface thereof a non-crosslinked surface stabilizer.
  • particles comprising 3-(2,4- dichloro-phenyl)-l,6-dimethyl-l,9-dihydro-pyrido[2,3-b]indol-2-one may be dispersed in a liquid dispersion medium in which the 3-(2,4-dichloro-phenyl)-l,6-dimethyl-l,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 effective average particle size.
  • the dispersion medium can be, for example, water, safflower oil, ethanol, t- butanol, glycerin, polyethylene glycol (PEG), hexane, or glycol.
  • a preferred dispersion medium is water.
  • the particles can be reduced in size in the presence of at least one surface stabilizer.
  • the particles comprising 3-(2,4-dichloro-phenyl)-l,6-dimethyl-l,9- dihydro-pyrido[2,3-b]indol-2-one can be contacted with one or more surface stabilizers after attrition.
  • Other compounds, such as a diluent, aggregation reducing agents, pH buffers, etc. can be added to the composition during the size reduction process.
  • Dispersions can be manufactured continuously or in a batch mode. One skilled in the art would understand that it may be the case that, following milling, not all particles may be reduced to the desired size. In such an event, the particles of the desired size may be separated and used in the practice of the present invention.
  • the grinding media can comprise particles that are preferably substantially spherical in shape, e.g., beads, consisting essentially of polymeric resin or glass or Zirconium Silicate or other suitable compositions.
  • the grinding media can comprise a core having a coating of a polymeric resin adhered thereon.
  • suitable polymeric resins are chemically and physically inert, substantially free of metals, solvent, and monomers, and of sufficient hardness and friability to enable them to avoid being chipped or crushed during grinding.
  • Suitable polymeric resins include crosslinked polystyrenes, such as polystyrene crosslinked with divinylbenzene; styrene copolymers; polycarbonates; polyacetals, such as Delrin® (E.I. du Pont de Nemours and Co.); vinyl chloride polymers and copolymers; polyurethanes; polyamides; poly(tetrafluoroethylenes), e.g., Teflon® (E.I.
  • du Pont de Nemours and Co. and other fluoropolymers
  • high density polyethylenes polypropylenes
  • cellulose ethers and esters such as cellulose acetate
  • polyhydroxymethacrylate polyhydroxyethyl acrylate
  • silicone-containing polymers such as polysiloxanes and the like.
  • the polymer can be biodegradable.
  • biodegradable polymers include poly(lactides), poly(glycolide) copolymers of lactides and glycolide, polyanhydrides, poly(hydroxyethyl methacylate), poly(imino carbonates), poly(N- acylhydroxyproline)esters, poly(N-palmitoyl hydroxyproline) esters, ethylene-vinyl acetate copolymers, poly(orthoesters), poly(caprolactones), and poly(phosphazenes).
  • contamination from the media itself advantageously can metabolize in vivo into biologically acceptable products that can be eliminated from the body.
  • the grinding media preferably ranges in size from about 0.01 to about 3 mm.
  • the grinding media is preferably from about 0.02 to about 2 mm, and more preferably from about 0.03 to about 1 mm in size.
  • the polymeric resin can have a density from about 0.8 to about 3.0 g/cm .
  • solid or powder forms of nanoparticulate active agent dispersions can also be prepared by lyophilizing the liquid nanoparticulate active agent dispersion following particle size reduction.
  • lyophilization step water is removed from the nanoparticulate active agent formulations after the dispersion is frozen and placed under vacuum, allowing the ice to change directly from solid to vapor without passing through a liquid phase.
  • the lyophilization process consists of four interdependent processes: freezing, sublimation, the primary drying step, and desorption, which is the secondary drying step.
  • Many lyophilizers can be used to achieve the lyophilization step of nanoparticulate active agent dispersions.
  • Suitable lyophilization 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), all of which are incorporated herein by reference.
  • the nanoparticulate active agent dispersion is placed in a suitable vessel and frozen to a temperature of between about -5° C. to about -100° C.
  • the frozen dispersion is then subjected to reduced pressure for a period of up to about 48 hours.
  • the combination of parameters such as temperature, pressure, dispersion media, and batch size will impact the time required for the lyophilization process.
  • the frozen solvent is removed by sublimation yielding a solid, porous, immediate release solid dosage form having the nanoparticulate active agent distributed throughout.
  • 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 making a sterilized nanoparticulate 3-(2,4-dichloro-phenyl)- 1 ,6-dimethyl- 1 ,9-dihydro-pyrido[2,3- b]indol-2-one composition
  • a method for making a sterilized nanoparticulate 3-(2,4-dichloro-phenyl)- 1 ,6-dimethyl- 1 ,9-dihydro-pyrido[2,3- b]indol-2-one composition comprising the steps of: mixing 3-(2,4-dichloro-phenyl)-l,6- dimethyl-l,9-dihydro-pyrido[2,3-b]indol-2-one, at least one excipient, and at least one surface stabilizer in an aqueous medium containing milling media for a period of time and under conditions sufficient to provide a dispersion of particles of 3-(2,4-dichloro-
  • the solid nanoparticulate active agent particles are subjected to gamma radiation at ambient temperature, which remains relatively constant during the period of irradiation.
  • Gamma radiation is applied in an amount sufficient to expose the pharmaceutical product to at least 25 kGray of irradiation.
  • the total amount of gamma radiation that the solid nanoparticulate active agent is exposed to has been experimentally verified to: (1) render the active agent composition sterile, and (2) maintain the integrity of the nanoparticulate active agent composition.
  • the application of the gamma radiation does not significantly degrade the active agent or reduce the active agent's efficacy. In this way, it is possible to provide products which meet cGMP requirements for sterile products without harming the active agent.
  • the gamma radiation is applied in 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.
  • the nanoparticulate active agent compositions can be moist heat sterilized without producing significant active agent particle size growth.
  • the heat sterilization process destroys substantially all of the microbial and viral contamination in the dispersion, such as microbes, mycoplasma, yeast, viruses, and mold.
  • the microbial contamination which is to be destroyed is generally that of bacteria, mycoplasma, yeast and mold contamination.
  • the moist heat sterilization step (1) results in minimal, if any, increase in active agent particle size on storage, (2) maintains the chemical integrity of the nanoparticulate active agent, and (3) shows generally acceptable impurity concentrations for the active agent composition following heat sterilization.
  • the moist heat sterilization process does not significantly degrade the active agent, or reduce the active agent's efficacy.
  • the present invention enables products to meet cGMP requirements for sterile products without harming the active agent.
  • the nanoparticulate active agent composition exhibits unexpected overall stability, maintains the pre-sterilized physical and chemical properties, while meeting cGMP requirements for sterility. It is particularly unexpected that moist heat sterilization of the active agent dispersion does not significantly alter the particle size of the active agent. This is significant because if the sterilized product formed aggregates or large crystals, the dispersion would lose the benefits afforded by being formulated into a nanoparticulate active agent composition.
  • the technique of heat sterilization is well known to one skilled in the art.
  • the heat sterilization is performed at approximately 121°C for at least 10 minutes, at least 15 minutes, at least 20 minutes, at least 25 minutes, or at least 30 minutes. More preferably, the heat sterilization is perform at approximately 121°C for approximately 20 minutes, approximately 21 minutes, or approximately 26 minutes.
  • One aspect of the invention is that upon reconstitution or redispersion after sterilization, 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 a retention of particle size, pH, osmolality, assay, and stabilizer concentration following redispersion of the solid in a liquid media.
  • a manufacturing process of the present invention that is similar to typical known manufacturing processes for sterile suspensions.
  • a typical sterile suspension manufacturing process flowchart is as follows:
  • Some of the processing may be dependent upon the method of particle size reduction and/or method of sterilization. For example, media conditioning is not required for a milling method that does not use media. If terminal sterilization is not feasible due to chemical and/or physical instability, aseptic processing can be used.
  • the present invention also provides methods comprising the administration to a subject in need thereof an effective amount of a nanoparticulate composition comprising 3-(2,4-dichloro-phenyl)-l,6-dimethyl-l,9- dihydro-pyrido[2,3-b]indol-2-one.
  • a nanoparticulate composition comprising 3-(2,4-dichloro-phenyl)-l,6-dimethyl-l,9- dihydro-pyrido[2,3-b]indol-2-one.
  • the term "subject” is used to mean an animal, preferably a mammal, including a human.
  • patient and “subject” may be used interchangeably.
  • certain embodiments of the invention are directed to appropriate dosage forms useful in the administration of 3-(2,4-dichloro-phenyl)-l,6- dimethyl-l,9-dihydro-pyrido[2,3-b]indol-2-one to a subject.
  • Certain aspects of the invention are directed to methods comprising the administration of an effective amount of a nanoparticulate composition comprising 3- (2,4-dichloro-phenyl)-l,6-dimethyl-l,9-dihydro-pyrido[2,3-b]indol-2-one to a subject in need thereof. According to certain aspects of the invention, there are provided methods for the treatment of cancer.
  • nanoparticulate 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.
  • nanoparticulate 3-(2,4-dichloro-phenyl)-l,6-dimethyl-l,9-dihydro-pyrido[2,3-b]indol-2- one compositions of the invention may be used in the treatment of solid tumours, both primary and metastatic solid tumours, carcinomas and cancers, in particular: breast cancer; lung cancer; cancer of the small intestine, cancer of the colon and of the rectum; cancer of the respiratory tract, of the oropharynx and of the hypopharynx; cancer of the oesophagus; liver cancer, stomach cancer, cancer of the bile ducts, cancer of the gall bladder, cancer of the pancreas; cancers of the urinary tract, including kidney, urothelium and bladder; cancers of the female genital tract, including cancer of the uterus, cervix and ovaries, choriocarcinoma and trophoblastic cancer; cancers of the male genital tract, including cancer of the prostate
  • compositions of the invention may also be administered in conjunction with one or more additional active agents.
  • additional active agents preferably include those useful for treatment of cancer as well as those agents useful for treating the adverse events that may be associated with 3-(2,4-dichloro- phenyl)-l,6-dimethyl-l,9-dihydro-pyrido[2,3-b]indol-2-one treatment.
  • Such active agents are preferably present in a manner, as determined by one skilled in the art, such that they do not interfere with therapeutic effect(s) of 3-(2,4-dichloro-phenyl)-l,6- dimethyl- 1 ,9-dihydro-pyrido[2,3-b]indol-2-one.
  • the nanoparticulate compositions of the present invention may exhibit increased bioavailability, and may require the administration of smaller doses of 3-(2,4-dichloro- phenyl)-l,6-dimethyl-l,9-dihydro-pyrido[2,3-b]indol-2-one, as compared to prior conventional, non-nanoparticulate compositions which comprise 3-(2,4-dichloro-phenyl)- l,6-dimethyl-l,9-dihydro-pyrido[2,3-b]indol-2-one.
  • a nanoparticulate composition may have a bioavailability that is about 50% greater than 3-(2,4-dichloro-phenyl)-l,6-dimethyl-l,9-dihydro-pyrido[2,3-b]indol-2-one when administered in a conventional dosage form.
  • 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 3-(2,4-dichloro- phenyl)-l,6-dimethyl-l,9-dihydro-pyrido[2,3-b]indol-2-one when administered in a non- nanoparticulate dosage form.
  • a nanoparticulate composition of the present invention may exhibit, for example, a C max for 3-(2,4- dichloro-phenyl)-l,6-dimethyl-l,9-dihydro-pyrido[2,3-b]indol-2-one contained therein which is at least about 50% of the C max for the same 3-(2,4-dichloro-phenyl)-l,6- dimethyl-l,9-dihydro-pyrido[2,3-b]indol-2-one when delivered at the same dosage by a non-nanoparticulate composition.
  • the nanoparticulate composition of the present invention may exhibit, for example, a C max 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 100%, at least about 200%, at least about 300%, at least about 400%, at least about 500%, at least about 600%, at least about 700%, at least about 800%, at least about 900%, at least about 1000%, at least about 1100%, at least about 1200%, at least about 1300%, at least about 1400%, at least about 1500%, at least about 1600%, at least about 1700%, at least about 1800%, or at least about 1900% greater than the C max for the same 3-(2,4-dichloro-phenyl)-l,6-dimethyl-l,9-dihydro-pyrido[2,3- b]indol
  • a nanoparticulate composition of the present invention may exhibit, for example, an AUC for 3-(2,4- dichloro-phenyl)-l,6-dimethyl-l,9-dihydro-pyrido[2,3-b]indol-2-one contained therein which is at least about 25% greater than the AUC for the same 3-(2,4-dichloro-phenyl)- l,6-dimethyl-l,9-dihydro-pyrido[2,3-b]indol-2-one when delivered at the same dosage by a non-nanoparticulate composition.
  • the nanoparticulate composition of the present invention may exhibit, for example, an AUC 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%, 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 5 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 850%, at least about 900%, at least about 950%, at least about 1000%, at least about 1050%, at least about 1100%, at least about 1150%, or
  • DPC Drug Particle Count
  • the manufacturing process was as follows: The stabilizers (polyvinylpyrolidone and sodium deoxycholate) and some of the sucrose were dissolved in sterile water for injection and further filtered through a sterilizing grade 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% PVP kl2, 1.4% NaDOC, 8.0% Sucrose and 60.6% SWFI - %w/w. The slurry was then milled with high energy in the presence of PolyMill® 500 to reduce the particle size of the drug to a sufficiently small size.
  • the NanoCrystal® Colloidal Dispersion® was harvested from the milling equipment through a 5 ⁇ m capsule filter. Separate to the harvesting step a separate solution of the remaining sucrose, TRIS and SWFI was manufactured and passed through a sterilizing grade filter. This solution was mixed with the harvested dispersion to create the preferred composition mentioned above. The preferred composition was further pH adjusted with hydrochloric acid to bring the pH to -8.0. The resulting composition was filled into vials and autoclaved at 121 0 C for approximately 21 minutes.
  • This composition was prepared in a similar manner to Example 1 with the exception that it was not buffered with TRIS. Despite not being buffered, the formulation was able to withstand autoclaving at 121 0 C for approximately 26 minutes.
  • This composition was prepared in a similar manner to Example 1 with the exception that it was buffered with TRIS and the pH was adjusted to approximately pH 10. This formulation was able to withstand autoclaving at 121°C for approximately 26 minutes.
  • This composition was prepared in a similar manner to Example 1 with the exception that the formulation was milled without sucrose or sorbitol and sorbitol was added during the harvest step. It was buffered with TRIS and pH adjusted to approximately 9.5. This formulation was able to withstand autoclaving at 121°C for approximately 26 minutes.
  • This composition was prepared in a similar manner to Example 1 with the exception that the formulation was milled without sucrose or sorbitol and Tween 80 was used as the primary stabilizer instead of PVP kl2. It was not buffered with TRIS, nor pH adjusted. This formulation was unable to withstand autoclaving at 121 0 C for approximately 20 minutes.
  • This composition was prepared in a similar manner to Example 1 with the exception that the formulation was milled without sucrose, but sucrose was added during the harvest step.
  • the primary and secondary stabilizers , PVP and NaDOC, were lower than the preferred system by 5 mg and 0.5 mg respectively. It was not buffered with TRIS, nor pH adjusted. This formulation was unable to withstand autoclaving at 121 0 C for approximately 20 minutes.

Abstract

Described are injectable formulations of particulate 3-(2,4-dichloro-phenyl)-l,6- dimethyl-l,9-dihydro-pyrido[2,3-b]indol-2-one that produce a prolonged duration of action upon administration, and methods of making and using such formulations. The injectable formulations comprise particulate 3-(2,4-dichloro-phenyl)-l,6-dimethyl-l,9- dihydro-pyrido[2,3-b]indol-2-one.

Description

NANOPARTICULATE ANTICANCER COMPOSITIONS AND METHODS FOR MAKING THE SAME
CROSS REFERENCE TO RELATED APPLICATION
[0001] This application claims priority to U.S. Provisional Patent Application No. 61/181,638, filed May 27, 2009 and French Patent Application No. 1002210, filed May 26, 2010. The contents of these applications are incorporated herein by reference in its entirety.
FIELD OF THE INVENTION
[0002] The present invention relates generally to nanoparticulate compositions of 3-(2,4-dichloro-phenyl)-l,6-dimethyl-l,9-dihydro-pyrido[2,3-b]indol-2-one, and in particular, a nanoparticulate composition useful in the treatment of cancer.
BACKGROUND OF THE INVENTION
[0003] The following discussion of the background of the invention is merely provided to aid the reader in understanding the invention and is not admitted to describe or constitute prior art to the invention.
A. Background of 3-(2,4-Dichloro-phenyl)-l,6-dimethyl-l,9-dihydro-pyrido[2,3- b]indol-2-one
[0004] 3-(2,4-Dichloro-phenyl)- 1 ,6-dimethyl- 1 ,9-dihydro-pyrido[2,3-b]indol-2- one, which has been shown to be particularly potent as an anticancer agent, has the structure of Formula (I):
Figure imgf000002_0001
[0005] The preparation, physical properties and beneficial pharmacological properties of 3-(2,4-dichloro-phenyl)-l ,6-dimethyl-l ,9-dihydro-pyrido[2,3-b]indol-2-one are described in, for example, WO 2004/041817 (also U.S. Patent No. 7,390,818), hereby incorporated by reference. The limited solubility of 3-(2,4-dichloro-phenyl)-l ,6- dimethyl-l, 9-dihydro-pyrido[2,3-b]indol-2-one in aqueous solutions presents difficulties in the administration and formulation of the drug and can lead to poor bioavailability.
[0006] Bioavailability is the degree to which a 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 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-dichloro-phenyl)-l,6-dimethyl-l,9-dihydro- pyrido[2,3-b]indol-2-one. Poorly water soluble drugs tend to be eliminated from the gastrointestinal tract before being absorbed into the circulation. Moreover, poorly water soluble drugs tend to be unsafe for intravenous administration techniques, which are used primarily in conjunction with fully soluble drug substances.
[0007] While the high therapeutic value of 3-(2,4-dichloro-phenyl)- 1 ,6- dimethyl-l, 9-dihydro-pyrido[2,3-b]indol-2-one is recognized in the art, poorly water soluble compounds such as 3-(2,4-dichloro-phenyl)-l,6-dimethyl-l,9-dihydro-pyrido[2,3- b]indol-2-one are limited in their bioavailability upon oral administration and can be difficult to formulate as safe and effective products for other types of administration. Thus, there exists a need for formulations comprising 3-(2,4-dichloro-phenyl)-l,6- dimethyl-l,9-dihydro-pyrido[2,3-b]indol-2-one suitable for injectable administration, such as intravenous administration. An improvement in dissolution rate would enhance the bioavailability of 3-(2,4-dichloro-phenyl)-l,6-dimethyl-l,9-dihydro-pyrido[2, 3- b]indol-2-one, allowing a smaller dose to provide effective in vivo blood levels of the active agent. In addition, an enhanced dissolution rate could allow for a larger dose to be absorbed, which could increase the efficacy of 3-(2,4-dichloro-phenyl)-l,6-dimethyl-l,9- dihydro-pyrido[2,3-b]indol-2-one. Moreover, an injectable nanop articulate formulation of 3-(2,4-dichloro-phenyl)-l,6-dimethyl-l,9-dihydro-pyrido[2,3-b]indol-2-one could eliminate the need for toxic co-solvents and enhance the efficacy of 3-(2,4-dichloro- phenyl)-l,6-dimethyl-l,9-dihydro-pyrido[2,3-b]indol-2-one treatment. The present invention, which relates to nanoparticulate compositions comprising 3-(2,4-dichloro- phenyl)-l,6-dimethyl-l,9-dihydro-pyrido[2,3-b]indol-2-one, addresses these concerns.
B. Background of Nanoparticulate Active Agent Compositions
[0008] Nanoparticulate active agent compositions, first described in U.S. Patent No. 5,145,684 ("the '684 patent"), hereby incorporated by reference, comprise particles of a poorly soluble therapeutic or diagnostic agent having adsorbed onto, or associated with, the surface thereof a non-crosslinked surface stabilizer. The '684 patent does not describe nanoparticulate compositions of 3-(2,4-dichloro-phenyl)-l,6-dimethyl-l,9- dihydro-pyrido[2,3-b]indol-2-one.
[0009] Methods of making nanoparticulate active agent compositions are described in, for example, U.S. Patent No. 5,518,187 for "Method of Grinding Pharmaceutical Substances;" U.S. Patent No. 5,718,388 for "Continuous Method of Grinding Pharmaceutical Substances;" U.S. Patent No. 5,862,999 for "Method of Grinding Pharmaceutical Substances;" U.S. Patent No. 5,665,331 for "Co- Microprecipitation of Nanoparticulate Pharmaceutical Agents with Crystal Growth Modifiers;" U.S. Patent No. 5,662,883 for "Co-Microprecipitation of Nanoparticulate Pharmaceutical Agents with Crystal Growth Modifiers;" U.S. Patent No. 5,560,932 for "Microprecipitation of Nanoparticulate Pharmaceutical Agents;" U.S. Patent No. 5,543,133 for "Process of Preparing X-Ray Contrast Compositions Containing Nanoparticles;" U.S. Patent No. 5,534,270 for "Method of Preparing Stable Drug Nanoparticles;" U.S. Patent No. 5,510,118 for "Process of Preparing Therapeutic Compositions Containing Nanoparticles;" and U.S. Patent No. 5,470,583 for "Method of Preparing Nanoparticle Compositions Containing Charged Phospholipids to Reduce Aggregation," all of the above patents are incorporated by reference, as are all the earlier aforementioned patents.
[0010] Nanoparticulate active agent compositions are also described, for example, in U.S. Patent Nos. 5,298,262 for "Use of Ionic Cloud Point Modifiers to Prevent Particle Aggregation During Sterilization;" 5,302,401 for "Method to Reduce Particle Size Growth During Lyophilization;" 5,318,767 for "X-Ray Contrast Compositions Useful in Medical Imaging;" 5,326,552 for "Novel Formulation For Nanoparticulate X-Ray Blood Pool Contrast Agents Using High Molecular Weight Non- ionic Surfactants;" 5,328,404 for "Method of X-Ray Imaging Using Iodinated Aromatic Propanedioates;" 5,336,507 for "Use of Charged Phospholipids to Reduce Nanoparticle Aggregation;" 5,340,564 for "Formulations Comprising Olin 10-G to Prevent Particle Aggregation and Increase Stability;" 5,346,702 for "Use of Non-Ionic Cloud Point Modifiers to Minimize Nanoparticulate Aggregation During Sterilization;" 5,349,957 for "Preparation and Magnetic Properties of Very Small Magnetic-Dextran Particles;" 5,352,459 for "Use of Purified Surface Modifiers to Prevent Particle Aggregation During Sterilization;" 5,399,363 and 5,494,683, both for "Surface Modified Anticancer Nanoparticles;" 5,401,492 for "Water Insoluble Non-Magnetic Manganese Particles as Magnetic Resonance Enhancement Agents;" 5,429,824 for "Use of Tyloxapol as a Nanoparticulate Stabilizer;" 5,447,710 for "Method for Making Nanoparticulate X-Ray Blood Pool Contrast Agents Using High Molecular Weight Non-ionic Surfactants;" 5,451,393 for "X-Ray Contrast Compositions Useful in Medical Imaging;" 5,466,440 for "Formulations of Oral Gastrointestinal Diagnostic X-Ray Contrast Agents in Combination with Pharmaceutically Acceptable Clays;" 5,470,583 for "Method of Preparing Nanoparticle Compositions Containing Charged Phospholipids to Reduce Aggregation;" 5,472,683 for "Nanoparticulate Diagnostic Mixed Carbamic Anhydrides as X-Ray Contrast Agents for Blood Pool and Lymphatic System Imaging;" 5,500,204 for "Nanoparticulate Diagnostic Dimers as X-Ray Contrast Agents for Blood Pool and Lymphatic System Imaging;" 5,518,738 for "Nanoparticulate NSAID Formulations;" 5,521,218 for "Nanoparticulate Iododipamide Derivatives for Use as X-Ray Contrast Agents;" 5,525,328 for "Nanoparticulate Diagnostic Diatrizoxy Ester X-Ray Contrast Agents for Blood Pool and Lymphatic System Imaging;" 5,543,133 for "Process of Preparing X-Ray Contrast Compositions Containing Nanoparticles;" 5,552,160 for "Surface Modified NSAID Nanoparticles;" 5,560,931 for "Formulations of Compounds as Nanoparticulate Dispersions in Digestible Oils or Fatty Acids;" 5,565,188 for "Polyalkylene Block Copolymers as Surface Modifiers for Nanoparticles;" 5,569,448 for "Sulfated Non-ionic Block Copolymer Surfactant as Stabilizer Coatings for Nanoparticle Compositions;" 5,571,536 for "Formulations of Compounds as Nanoparticulate Dispersions in Digestible Oils or Fatty Acids;" 5,573,749 for "Nanoparticulate Diagnostic Mixed Carboxylic Anydrides as X-Ray Contrast Agents for Blood Pool and Lymphatic System Imaging;" 5,573,750 for "Diagnostic Imaging X-Ray Contrast Agents;" 5,573,783 for "Redispersible Nanoparticulate Film Matrices With Protective Overcoats;" 5,580,579 for "Site-specific Adhesion Within the GI Tract Using Nanoparticles Stabilized by High Molecular Weight, Linear Poly(ethylene Oxide) Polymers;" 5,585,108 for "Formulations of Oral Gastrointestinal Therapeutic Agents in Combination with Pharmaceutically Acceptable Clays;" 5,587,143 for "Butylene Oxide- Ethylene Oxide Block Copolymers Surfactants as Stabilizer Coatings for Nanoparticulate Compositions;" 5,591,456 for "Milled Naproxen with Hydroxypropyl Cellulose as Dispersion Stabilizer;" 5,593,657 for "Novel Barium Salt Formulations Stabilized by Non-ionic and Anionic Stabilizers;" 5,622,938 for "Sugar Based Surfactant for Nanocrystals;" 5,628,981 for "Improved Formulations of Oral Gastrointestinal Diagnostic X-Ray Contrast Agents and Oral Gastrointestinal Therapeutic Agents;" 5,643,552 for "Nanoparticulate Diagnostic Mixed Carbonic Anhydrides as X-Ray Contrast Agents for Blood Pool and Lymphatic System Imaging;" 5,718,388 for "Continuous Method of Grinding Pharmaceutical Substances;" 5,718,919 for "Nanoparticles Containing the R(-)Enantiomer of Ibuprofen;" 5,747,001 for Formulations of Human Immunodeficiency Virus (HIV) Protease Inhibitors Using Cellulosic Surface Stabilizers;" 6,068,858 for "Methods of Making Nanocrystalline Formulations of Human Immunodeficiency Virus (HIV) Protease Inhibitors Using Cellulosic Surface Stabilizers;" 6,153,225 for "Injectable Formulations of Nanoparticulate Naproxen;" 6,165,506 for "New Solid Dose Form of Nanoparticulate Naproxen;" 6,221,400 for "Methods of Treating Mammals Using Nanocrystalline Formulations of Human Immunodeficiency Virus (HIV) Protease Inhibitors;" 6,264,922 for "Nebulized Aerosols Containing Nanoparticle Dispersions;" 6,267,989 for "Methods for Preventing Crystal Growth and Particle Aggregation in Nanoparticle Compositions;" 6,270,806 for "Use of PEG- Derivatized Lipids as Surface Stabilizers for Nanoparticulate Compositions;" 6,316,029 for "Rapidly Disintegrating Solid Oral Dosage Form," 6,375,986 for "Solid Dose Nanoparticulate Compositions Comprising a Synergistic Combination of a Polymeric Surface Stabilizer and Dioctyl Sodium Sulfosuccinate;" 6,428,814 for "Bioadhesive Nanoparticulate Compositions Having Cationic Surface Stabilizers;" 6,431,478 for "Small Scale Mill;" and 6,432,381 for "Methods for Targeting Drug Delivery to the Upper and/or Lower Gastrointestinal Tract," all of which are specifically incorporated by reference. In addition, U.S. Patent Application Publication No. 20020012675 Al, published on January 31, 2002, for "Controlled Release Nanoparticulate Compositions," describes nanoparticulate compositions, and is specifically incorporated by reference, as are all the earlier aforementioned patents.
[0011] Amorphous small particle compositions are described, for example, in U.S. Patent Nos. 4,783,484 for "Particulate Composition and Use Thereof as Antimicrobial Agent;" 4,826,689 for "Method for Making Uniformly Sized Particles from Water-Insoluble Organic Compounds;" 4,997,454 for "Method for Making Uniformly-Sized Particles From Insoluble Compounds;" 5,741,522 for "Ultrasmall, Non- aggregated Porous Particles of Uniform Size for Entrapping Gas Bubbles Within and Methods;" and 5,776,496 for "Ultrasmall Porous Particles for Enhancing Ultrasound Back Scatter," which are also incorporated by reference herein.
[0012] The present invention relates, in certain aspects, to nanoparticulate 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 to methods for making and using the same.
SUMMARY OF THE INVENTION
[0013] The present invention relates to nanoparticulate compositions comprising 3-(2,4-dichloro-phenyl)-l,6-dimethyl-l,9-dihydro-pyrido[2,3-b]indol-2-one, as well as methods of making and using the same.
[0014] In one aspect of the invention, the composition comprises particles comprising 3-(2,4-dichloro-phenyl)-l,6-dimethyl-l,9-dihydro-pyrido[2,3-b]indol-2-one, wherein the particles have an effective average size of less than about 2000 nm. The composition may also comprise at least one surface stabilizer adsorbed onto or associated with the surface of the drug particles. The surface stabilizer is present in an amount sufficient to maintain 3-(2,4-dichloro-phenyl)-l,6-dimethyl-l,9-dihydro-pyrido[2,3- b]indol-2-one at an effective average particle size of less than 2000 nm, thereby maintaining the efficacy of the drug over a period of time. The particle size of 3-(2,4- dichloro-phenyl)-l,6-dimethyl-l,9-dihydro-pyrido[2,3-b]indol-2-one nanoparticles can be manipulated to give the desirable 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 modifying agents, and the like.
[0015] Further aspects of the present invention relate to dosage forms made from the compositions of the present invention. In another embodiment, the nanoparticulate composition is an injectable formulation. In another embodiment, the nanoparticulate composition is an intraperitoneal or intramuscular formulation. A preferred dosage form of the invention is a formulation suitable for intravenous administration.
[0016] Further aspects of the invention are directed to methods of making compositions according to the invention. According to one aspect of the invention, a method for making a nanoparticulate 3-(2,4-dichloro-phenyl)-l,6-dimethyl-l,9-dihydro- pyrido[2,3-b]indol-2-one composition comprises the step of contacting 3-(2,4-dichloro- phenyl)-l,6-dimethyl-l,9-dihydro-pyrido[2,3-b]indol-2-one with at least one surface stabilizer and optionally with additional excipients for a period of time and under conditions sufficient to provide a nanoparticulate 3-(2,4-dichloro-phenyl)-l,6-dimethyl- l,9-dihydro-pyrido[2,3-b]indol-2-one composition having an effective average particle size of less than about 2000 nm.
[0017] Additional aspects of the present invention are directed to methods of treating cancer comprising administering an effective amount of a nanoparticulate composition comprising 3-(2,4-dichloro-phenyl)- 1 ,6-dimethyl- 1 ,9-dihydro-pyrido[2,3- b]indol-2-one to a subject in need thereof. [0018] Another aspect of the present invention is the use of a nanoparticulate composition comprising 3-(2,4-dichloro-phenyl)- 1 ,6-dimethyl- 1 ,9-dihydro-pyrido[2,3- b]indol-2-one in the treatment of cancers.
[0019] Both the foregoing general description and the following detailed description are exemplary and explanatory, and are intended to provide further explanation of the invention as claimed. Other objects, advantages, and novel features will be readily apparent to those skilled in the art from the following detailed description of the invention.
DETAILED DESCRIPTION OF THE INVENTION
A. Definitions
[0020] As employed above and throughout the disclosure, the following terms, unless otherwise indicated, shall be understood to have the following meanings.
[0021] As used herein, "about" will be understood by persons of ordinary skill in the art and will vary to some extent according to the context in which it is used. If there are uses of the term which are not clear to persons of ordinary skill in the art given the context in which it is used, "about" will mean plus or minus up to 10% of the particular term.
[0022] As used herein, "particulate" refers to a state of matter which is characterized by the presence of discrete particles, pellets, beads or granules irrespective of their size, shape or morphology.
[0023] As used herein, "nanoparticulate" refers to a composition in which the effective average particle size of the particles therein is less than about 2000 nm (2 microns).
[0024] As used herein, the terms "conventional" or "non-nanoparticulate" active agent shall mean an active agent, such as 3-(2,4-dichloro-phenyl)-l,6-dimethyl-l,9- dihydro-pyrido[2,3-b]indol-2-one, which is solubilized or which has an effective average particle size of greater than about 2000 nm. [0025] As used herein, "an effective average particle size" describes a population of particles in a composition in which at least 50% of the particles are less than a specified size. Accordingly, "effective average particle size of less than about 2000 nm" means that at least 50% of the particles therein are less than about 2000 nm.
[0026] As used herein, "D50" refers to a particle size below which 50% of the particles in a composition are less than that particle size. Similarly, "D90" refers to the particle size below which 90% of the particles in a composition are less than that particle size.
[0027] As used herein with reference to stable particles, "stable" refers to, but is not limited to, one or more of the following parameters: (1) the particles do not appreciably flocculate or agglomerate due to interparticle attractive forces or otherwise significantly increase in particle size over time; (2) the physical structure of the particles is not altered over time, such as by conversion from an amorphous phase to a crystalline phase; (3) the particles are chemically stable; and/or (4) where the active ingredient has not been subject to a heating step at or above the melting point of the active agent in the preparation of the particles of the present invention.
[0028] As used herein, "a 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/ml, or less than about 1 mg/ml.
[0029] As used herein, "a therapeutically effective amount" means the dosage that provides the specific pharmacological response for which the active agent is administered in a significant number of subjects in need of the relevant treatment. It is emphasized that a therapeutically effective amount of the active agent that is administered to a particular subject in a particular instance will not always be effective in treating the conditions described herein, even though such dosage is deemed to be a therapeutically effective amount by those of skill in the art.
[0030] As used herein, the term "active agent," unless otherwise indicated, refers to 3-(2,4-dichloro-phenyl)- 1 ,6-dimethyl- 1 ,9-dihydro-pyrido[2,3-b]indol-2-one. [0031] The terms "sterilize" or "sterilized" as used in the present application generally means to inactivate biological contaminants present in the product. In typical pharmaceutical applications, autoclaving the pharmaceutical product, exposure to at least a 25 kGray dose of irradiation, or sterile filtering through a 0.2 micron sieve sterilizes the pharmaceutical product.
B. Nanoparticulate Active Agent Compositions
[0032] In one aspect of the invention, the composition comprises particles of 3- (2,4-dichloro-phenyl)-l,6-dimethyl-l,9-dihydro-pyrido[2,3-b]indol-2-one having an effective average particle size of less than about 2000 nm and at least one surface stabilizer adsorbed on the surface of the particles.
[0033] The nanoparticulate particles of 3-(2,4-dichloro-phenyl)-l ,6-dimethyl- l,9-dihydro-pyrido[2,3-b]indol-2-one described herein may exist in a crystalline phase, an amorphous phase, a semi-crystalline phase, or a mixture thereof.
[0034] The surface stabilizers are preferably adsorbed onto or associated with the surface of the 3-(2,4-dichloro-phenyl)-l,6-dimethyl-l,9-dihydro-pyrido[2,3-b]indol- 2-one particles. Surface stabilizers useful herein may physically adhere on, adsorb on, or associate with the surface of the nanoparticulate active agent but may not chemically react with the active agent particles. The molecules of the surface stabilizer are essentially free of intermolecular cross-linkages. In another embodiment, the compositions of the present invention may comprise two or more surface stabilizers.
[0035] In certain aspects, the invention provides compositions comprising nanoparticulate 3-(2,4-dichloro-phenyl)-l,6-dimethyl-l,9-dihydro-pyrido[2,3-b]indol-2- one particles, at least one surface stabilizer and optionally additional excipients, such as aggregation reducing agents, pH modifying agents, and the like.
[0036] In other aspects, the present invention also includes nanoparticulate 3- (2,4-dichloro-phenyl)-l,6-dimethyl-l,9-dihydro-pyrido[2,3-b]indol-2-one compositions together with one or more non-toxic physiologically acceptable carriers, adjuvants, or vehicles, collectively referred to as carriers. [0037] The compositions may be formulated, for example, for parenteral administration (e.g., intravenous, intramuscular, intrathecal, or subcutaneous), intracisternal administration, intravaginal administration, intraperitoneal administration, local administration and the like.
C. Particle Size
[0038] As used herein, by "an effective average particle size of less than about 2000 nm" it is meant that at least 50% of the active agent particles have a particle size less than the effective average, by weight (or by other suitable measurement techniques, such as by volume, number, etc.). The "effective average" particle size can be, for example, less than about 2000 nm, 1900 nm, 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 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, when measured by techniques well known to those skilled in the art. Such techniques include, for example, sedimentation field flow fractionation, photon correlation spectroscopy, light scattering, and disk centrifugation.
[0039] 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 particles have a particle size of less than the effective average, i.e., less than about 2000 nm, 1900 nm, 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 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.
[0040] Compositions of the invention comprise 3-(2,4-dichloro-phenyl)-l,6- dimethyl-l,9-dihydro-pyrido[2,3-b]indol-2-one particles having an effective average particle size of less than about 2 microns. In other embodiments of the invention, the 3- (2,4-dichloro-phenyl)-l,6-dimethyl-l,9-dihydro-pyrido[2,3-b]indol-2-one particles have an effective average particle size of less than about 1900 nm, less than about 1800 nm, less than about 1700 nm, less than about 1600 nm, less than about 1500 nm, less than about 1400 nm, less than about 1300 nm, less than about 1200 nm, less than about 1100 nm, less than about 1000 nm, less than about 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, as measured by light-scattering methods, microscopy, or other appropriate methods.
[0041] In another embodiment of the invention, the compositions of the invention are in an injectable dosage form and the 3-(2,4-dichloro-phenyl)-l,6-dimethyl- l,9-dihydro-pyrido[2,3-b]indol-2-one particles 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 can comprise 3-(2,4-dichloro-phenyl)-l,6-dimethyl-l,9-dihydro- pyrido[2,3-b]indol-2-one having an effective average particle size of greater than about 1 micron, up to about 2 microns. If the "effective average particle size" is less than about 600 nm, then at least about 50% of the 3-(2,4-dichloro-phenyl)-l,6-dimethyl-l,9-dihydro- pyrido[2,3-b]indol-2-one particles have a size of less than about 600 nm, when measured by the above-noted techniques. The same is true for the other particle sizes referenced above. [0042] In certain 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 3-(2,4- dichloro-phenyl)-l,6-dimethyl-l,9-dihydro-pyrido[2,3-b]indol-2-one particles have a particle size less than the effective average, i.e., 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. 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 of less than 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, 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 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.
D. Surface Stabilizers
[0043] The choice of a surface stabilizer for 3-(2,4-dichloro-phenyl)- 1 ,6- dimethyl-l,9-dihydro-pyrido[2,3-b]indol-2-one is non-trivial and requires experimentation to realize a desirable formulation. Combinations of more than one surface stabilizer can be used in the invention.
[0044] The compositions of the invention may 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. The surface stabilizers especially useful herein preferably do not chemically react with the active agent particles or itself. Preferably, individual molecules of the auxiliary surface stabilizer are essentially free of intermolecular cross-linkages.
[0045] Two or more surface stabilizers can be employed in the compositions and methods of the invention.
[0046] Suitable surface stabilizers can preferably be selected from known organic and inorganic pharmaceutical excipients. Such excipients include various polymers, low molecular weight oligomers, natural products, and surfactants. Preferred surface stabilizers include nonionic, anionic, cationic and zwitterionic compounds or surfactants.
[0047] Examples of useful nonionic stabilizers, including but not limited to, albumin, dextran, gum acacia, tragacanth, glycerol monostearate, cetostearyl alcohol, cetomacrogol emulsifying wax, sorbitan esters, polyoxyethylene alkyl ethers (e.g., macrogol ethers such as cetomacrogol 1000), polyethylene alkyl esters, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters (e.g. , the commercially available Tweens® such as e.g., Tween 20® and Tween 80® (ICI Speciality Chemicals)); polyethylene glycols (e.g., Carbowaxs 3550® and 934® (Union Carbide)), polyoxyethylene stearates, methylcellulose, hydroxyethylcellulose, hydroxypropyl celluloses (e.g., HPC, HPC-SL, and HPC-L), hydroxypropyl methylcellulose (HPMC), hydroxypropylmethyl-cellulose phthalate, noncrystalline cellulose, triethanolamine, polyvinyl alcohol (PVA), polyvinylpyrrolidone (PVP), 4-(l,l,3,3-tetramethylbutyl)- phenol polymer with ethylene oxide and formaldehyde (also known as tyloxapol, superione, and triton), poloxamers (e.g., Pluronics F68® and F 108®, which are block copolymers of ethylene oxide and propylene oxide); poloxamines (e.g., Tetronic 908®, also known as Poloxamine 908®, which is a tetrafunctional block copolymer derived from sequential addition of propylene oxide and ethylene oxide to ethylenediamine (BASF Wyandotte Corporation, Parsippany, N.J.)); Tetronic 1508® (T-1508) (BASF Wyandotte Corporation), alkyl phenol ethylene 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.); p-isononylphenoxypoly-(glycidol), also known as Olin-IOG® or Surfactant 10-G® (Olin Chemicals, Stamford, CT); Crodestas SL-40® (Croda, Inc.); and SA9OHCO, which is Cl8H37CH2C(O)N(CH3)-CH2(CHOH)4(CH2OH)2 (Eastman Kodak Co.); decanoyl-N-methylglucamide; n-decyl β-D-glucopyranoside; n-decyl β-D- maltopyranoside; n-dodecyl β-D-glucopyranoside; n-dodecyl β-D-maltoside; heptanoyl- N-methylglucamide; n-heptyl-β-D-glucopyranoside; n-heptyl β-D-thioglucoside; n-hexyl β-D-glucopyranoside; nonanoyl-N-methylglucamide; n-noyl β-D-glucopyranoside; octanoyl-N-methylglucamide; n-octyl-β-D-glucopyranoside; octyl β-D- thioglucopyranoside; 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 vinyl pyrrolidone and vinyl acetate (an example would be Plasdone S-630, ISP).
[0048] Preferred nonionic stabilizers include, but are not limited to, Hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose grade HPC-SL, Polyvinylpyrrolidones, Kollidone Kl 2 (BASF) or Plasdone® C- 12 (ISP Technologies, Inc.) Kollidone Kl 7 (BASF) - Plasdone® 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 tradename Pluronics® by BASF (sold as Lutrols® in EU), specifically Pluronic® F 68 a.k.a. poloxamer 188, Pluronic® F 108 a.k.a. poloxamer 338, Pluronic® F 127 a.k.a poloxamer. 407, copolymer of vinylpyrrolidone and vinyl acetate - Copovidone sold under the tradename Plasdone® S-630 (ISP Technologies, Inc), distearyl palmitate glyceryl, polyoxyethylene sorbitan fatty acid esters such as polyoxyethylene 20 sorbitan monolaurate, polysorbate 20 a.k.a. Tween® 20 by ICI Americas, polyoxyethylene 20 sorbitan monopalmitate, polysorbate 40" a.k.a. Tween® 40 by ICI Americas, polyoxyethylene 20 sorbitan monooleate, polysortbate 80 a.k.a. Tween® 80 by ICI Americas, macrogol 15 hydroxystearate - Solutol® 15 BASF, Tyloxapol and Cremaphor.
[0049] Examples of useful anionic stabilizers, including but 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 dodecylsulfate, Duponol P®, which is a sodium lauryl sulfate (DuPont), carboxymethylcellulose calcium, carboxymethylcellulose sodium, dialkylesters of sodium sulfosuccinic acid (e.g. , Aerosol OT®, which is a dioctyl ester of sodium sulfosuccinic acid (DOSS) (American Cyanamid)), Triton X-200®, which is an alkyl aryl polyether sulfonate (Union Carbide). Salt forms of bile acids are also useful as anionic stabilizers, such as sodium deoxycholate, sodium cholate, sodium chenodeoxycholate, sodium dehydrocholate, disuccinylursodeoxycholic acid bisodic salt, sodium hyodeoxycholate, sodium ursodeoxy cholate.
[0050] Preferred anionic stabilizers include, but are not limited to, dioctyl sodium succinate (DOSS) sodium lauryl sulfate (SLS) a.k.a. sodium dodecyl sulfate (SDS) and sodium deoxycholate.
[0051] Examples of useful cationic surface stabilizers include but are not limited to polymers, biopolymers, poly-n-methylpyridinium, anthryul pyridinium chloride, cationic phospholipids, chitosan, polylysine, polyvinylimidazole, polybrene, polymethylmethacrylate trimethylammoniumbromide bromide (PMMTMABr), hexyldesyltrimethylammonium bromide (HDMAB), and polyvinylpyrrolidone-2- dimethylaminoethyl methacrylate dimethyl sulfate.
[0052] Other useful cationic stabilizers include, but are not limited to, cationic lipids, sulfonium, phosphonium, and quarternary ammonium compounds, such as stearyltrimethylammonium chloride, benzyl-di(2-chloroethyl)ethylammonium bromide, coconut trimethyl ammonium chloride or bromide, coconut methyl dihydroxyethyl ammonium chloride or bromide, dodecyl trimethyl ammonium bromide, decyl triethyl ammonium chloride, decyl dimethyl hydroxyethyl ammonium chloride or bromide, C12- 15 dimethyl hydroxyethyl ammonium chloride or bromide, coconut dimethyl hydroxyethyl ammonium chloride or bromide, myristyl trimethyl ammonium methyl sulphate, lauryl dimethyl benzyl ammonium chloride or bromide, lauryl dimethyl (ethenoxy)4 ammonium chloride or bromide, N-alkyl (C12-i8)dimethylbenzyl ammonium chloride, N-alkyl (C14. ^dimethyl-benzyl ammonium chloride, N-tetradecylidmethylbenzyl ammonium chloride monohydrate, dimethyl didecyl ammonium chloride, N-alkyl and (C12-14) dimethyl 1- napthylmethyl ammonium chloride, trimethylammonium halide, alkyl- trimethylammonium salts and dialkyl-dimethylammonium salts, lauryl trimethyl ammonium chloride, ethoxylated alkyamidoalkyldialkylammonium salt and/or an ethoxylated trialkyl ammonium salt, dialkylbenzene dialkylammonium chloride, N- didecyldimethyl ammonium chloride, N-tetradecyldimethylbenzyl ammonium, chloride monohydrate, N-alkyl(Ci2-i4) dimethyl 1-naphthylmethyl ammonium chloride and dodecyldimethylbenzyl ammonium chloride, dialkyl benzenealkyl ammonium chloride, lauryl trimethyl ammonium chloride, alkylbenzyl methyl ammonium chloride, alkyl benzyl dimethyl ammonium bromide, C12, C15, C17 trimethyl ammonium bromides, dodecylbenzyl triethyl ammonium chloride, poly-diallyldimethylammonium chloride (DADMAC), dimethyl ammonium chlorides, alkyldimethylammonium halogenides, tricetyl methyl ammonium chloride, decyltrimethylammonium bromide, dodecyltriethylammonium bromide, tetradecyltrimethylammonium bromide, methyl trioctylammonium chloride (ALIQUAT 336™), POLYQUAT 10™, tetrabutylammonium bromide, benzyl trimethylammonium bromide, choline esters (such as choline esters of fatty acids), benzalkonium chloride, stearalkonium chloride compounds (such as stearyltrimonium chloride and Di-stearyldimonium chloride), cetyl pyridinium bromide or chloride, halide salts of quaternized polyoxyethylalkylamines, MIRAPOL™ and ALKAQUAT™ (Alkaril Chemical Company), alkyl pyridinium salts; amines, such as alkylamines, dialkylamines, alkanolamines, polyethylenepolyamines, N,N-dialkylaminoalkyl acrylates, and vinyl pyridine, amine salts, such as lauryl amine acetate, stearyl amine acetate, alkylpyridinium salt, and alkylimidazolium salt, and amine oxides; imide azolinium salts; protonated quaternary acrylamides; methylated quaternary polymers, such as poly[diallyl dimethylammonium chloride] and poly-[N-methyl vinyl pyridinium chloride]; and cationic guar.
[0053] Such exemplary cationic surface stabilizers and other useful cationic surface stabilizers are described in J. Cross and E. Singer, Cationic Surfactants: Analytical and Biological Evaluation (Marcel Dekker, 1994); P. and D. Rubingh (Editor), Cationic Surfactants: Physical Chemistry (Marcel Dekker, 1991); and J. Richmond, Cationic Surfactants: Organic Chemistry, (Marcel Dekker, 1990). [0054] Particularly preferred nonpolymeric primary stabilizers are any nonpolymeric compound, such benzalkonium chloride, a carbonium compound, a phosphonium compound, an oxonium compound, a halonium compound, a cationic organometallic compound, a quarternary phosphorous compound, a pyridinium compound, an anilinium compound, an immonium compound, a hydroxylammonium compound, a primary ammonium compound, a secondary ammonium compound, a tertiary ammonium compound, and quarternary ammonium compounds of the formula NR1R2R3R4^. For compounds of the formula NR1R2R3R4^:
(i) none of R1-R4 are CH3;
(ii) one OfR1-R4 is CH3;
(iii) three of R1-R4 are CH3;
(iv) all OfR1-R4 are CH3;
(v) two Of R1-R4 are CH3, one OfR1-R4 is CeHsCH2, and one OfR1-R4 is an alkyl chain of seven carbon atoms or less;
(vi) two Of R1-R4 are CH3, one OfR1-R4 is CeH5CH2, and one OfR1-R4 is an alkyl chain of nineteen carbon atoms or more;
(vii) two Of R1-R4 are CH3 and one OfR1-R4 is the group CeH5(CH2)n, where n>l;
(viii) two Of R1-R4 are CH3, one OfR1-R4 is CeH5CH2, and one OfR1-R4 comprises at least one heteroatom;
(ix) two Of R1-R4 are CH3, one OfR1-R4 is CeH5CH2, and one OfR1-R4 comprises at least one halogen;
(x) two Of R1-R4 are CH3, one OfR1-R4 is CeH5CH2, and one OfR1-R4 comprises at least one cyclic fragment;
(xi) two Of R1-R4 are CH3 and one OfR1-R4 is a phenyl ring; or
(xii) two OfR1-R4 are CH3 and two OfR1-R4 are purely aliphatic fragments.
[0055] Such compounds include, but are not limited to, behenalkonium chloride, benzethonium chloride, cetylpyridinium chloride, behentrimonium chloride, lauralkonium chloride, cetalkonium chloride, cetrimonium bromide, cetrimonium chloride, cethylamine hydrofluoride, chlorallylmethenamine chloride (Quaternium-15), distearyldimonium chloride (Quaternium-5), dodecyl dimethyl ethylbenzyl ammonium chloride(Quaternium-14), Quaternium-22, Quaternium-26, Quaternium-18 hectorite, dimethylaminoethylchloride hydrochloride, cysteine hydrochloride, diethanolammonium POE (10) oletyl ether phosphate, diethanolammonium POE (3)oleyl ether phosphate, tallow alkonium chloride, dimethyl dioctadecylammoniumbentonite, stearalkonium chloride, domiphen bromide, denatonium benzoate, myristalkonium chloride, laurtrimonium chloride, ethylenediamine dihydrochloride, guanidine hydrochloride, pyridoxine HCl, iofetamine hydrochloride, meglumine hydrochloride, methylbenzethonium chloride, myrtrimonium bromide, oleyltrimonium chloride, polyquaternium-1, procainehydrochloride, cocobetaine, stearalkonium bentonite, stearalkoniumhectonite, stearyl trihydroxyethyl propylenediamine dihydrofluoride, tallowtrimonium chloride, and hexadecyltrimethyl ammonium bromide.
[0056] Examples of zwitterionic stabilizers include but are not limited to proteins, phospholipids, zwitterionic polymers and zwitterionic surfactant molecules. Examples of proteins albumin, including but not limited to human serum albumin and bovine serum albumin, gelatin, casein, lysozyme. Examples of phospholipids include phosphotidylcholine, lecithin. The proteins and peptides are zwitteronic may morph into cationic or anionic depending on the pH of the medium they are exposed to. In this embodiment, it should be understood that in the considered pH range, these are molecules are zwitterionic.
[0057] Most of these surface stabilizers are known pharmaceutical excipients and are described in detail in the Handbook of Pharmaceutical Excipients, published jointly by the American Pharmaceutical Association and The Pharmaceutical Society of Great Britain (The Pharmaceutical Press, 5th ed., 2005), specifically incorporated by reference. The surface stabilizers are commercially available and/or can be prepared by techniques known in the art.
E. Other Pharmaceutical Ingredients
[0058] Pharmaceutical compositions according to the invention may also comprise one or more aggregation reducing agents, binding agents, bulking agents, filling agents, lubricating agents, suspending agents, preservatives, pH modifying agents, wetting agents, disintegrants, effervescent agents, crystal growth inhibitors, free radical scavenger agents, redispersion agents, and other excipients. Such excipients are known in the art.
[0059] Prevention of the growth of microorganisms may be ensured by the addition of various antibacterial and antifungal agents, such as, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like.
[0060] 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 delaying the absorption of the injectable pharmaceutical form, such as aluminum monostearate and gelatin.
[0061] Compositions suitable for parenteral injection may comprise, for example, physiologically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions and sterile powders for reconstitution into sterile injectable solutions or dispersions. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents, or vehicles including water, ethanol, sodium chloride, Ringer's solution, lactated Ringer's solution, stabilizer solutions, tonicity enhancers (sucrose, dextrose, mannitol, etc.), polyols (propyleneglycol, polyethylene-glycol, glycerol, and the like), suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate. A number of fluids which may be suitable are referenced in Remington 's Pharmaceutical Sciences, 17th edition, published by Mack Publishing Co., page 1543.
[0062] Examples of aggregation reducing agents include sugars, sugar alcohols and buffers. Exemplary sugars and sugar alcohols includes, but are not limited to, sucrose, fructose, glucose, erythritol, isomalt, mannitol, sorbitol, xylitol, sorbitol, and dextrose. Any pH modifying agent system suitable for LV. or LM. administration may be used, such as but not limited to a phosphate buffer, an acetate buffer or a citrate buffer. In some embodiments, the buffer is a potassium phosphate buffer, a sodium phosphate buffer, or a sodium acetate buffer. [0063] Examples of filling agents include lactose monohydrate, lactose anhydrous, and various starches; examples of binding agents include various celluloses and cross-linked polyvinylpyrrolidone, microcrystalline cellulose, such as Avicel® PHlOl and Avicel® PH 102, microcrystalline cellulose, and silicifϊed microcrystalline cellulose (ProSolv SMCC™).
[0064] Suitable lubricants, including agents that act on the flowability of the powder to be compressed, may include colloidal silicon dioxide, such as Aerosil® 200, talc, stearic acid, magnesium stearate, calcium stearate, and silica gel.
[0065] Examples of preservatives include potassium sorbate, methylparaben, propylparaben, benzoic acid and its salts, other esters of parahydroxybenzoic acid such as butylparaben, alcohols such as ethyl or benzyl alcohol, phenolic compounds such as phenol, or quaternary compounds such as benzalkonium chloride. Exemplary pH adjusting agents are sodium hydroxide and hydrochloric acid, and an exemplary liquid carrier is sterile water for injection. Other useful preservatives, pH adjusting agents, and liquid carriers are well-known in the art.
[0066] Suitable diluents include pharmaceutically acceptable inert fillers, such as microcrystalline cellulose, lactose, dibasic calcium phosphate, saccharides, and/or mixtures of any of the foregoing. Examples of diluents include microcrystalline cellulose, such as Avicel® PHlOl and Avicel® PH 102; lactose such as lactose monohydrate, lactose anhydrous, and Pharmatose® DCL21; dibasic calcium phosphate such as Emcompress®; mannitol; starch; sorbitol; sucrose; and glucose.
[0067] Suitable disintegrants include lightly crosslinked polyvinyl pyrrolidone, corn starch, potato starch, maize starch, and modified starches, croscarmellose sodium, cross-povidone, sodium starch glycolate, and mixtures thereof.
[0068] 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.
F. pH of the Composition
[0069] The pH of the composition for IV or IM administration is a buffered formulation that is at a pH that is suitably high enough to reduce aggregation. The compositions of the invention have a pH level of about pH 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 10.7, 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, 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 about 9.0- about 10.0, about 10.0- about 11.0, about 11.0- about 12.0, about 12.0- about 14.0. In another embodiment, the pH of the formulation is in the range of pH about 9.5 - about 11.0. In yet another embodiment, the pH of the formulation is in the range of pH about 7.0 - about 9.5.
G. Concentration of Composition
[0070] The relative amounts of 3-(2,4-dichloro-phenyl)-l ,6-dimethyl-l ,9- dihydro-pyrido[2,3-b]indol-2-one and one or more surface stabilizers can vary widely. The optimal amount of the individual components depends, for example, upon physical and chemical attributes of the surface stabilizer(s) and 3-(2,4-dichloro-phenyl)-l,6- dimethyl-l,9-dihydro-pyrido[2,3-b]indol-2-one selected, such as the hydrophilic lipophilic balance (HLB), melting point, and the surface tension of water solutions of the stabilizer, etc. [0071] Preferably, the concentration of the 3-(2,4-dichloro-phenyl)-l,6- dimethyl-l,9-dihydro-pyrido[2,3-b]indol-2-one can 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-dichloro-phenyl)-l,6-dimethyl-l,9-dihydro- pyrido[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 from a dose and cost efficiency standpoint.
[0072] Preferably, the concentration of surface stabilizer can vary from about 0.5% to about 99.999%, from about 5.0% to about 99.9%, or from about 10% to about 99.5%, by weight, based on the total combined dry weight of the 3-(2,4-dichloro-phenyl)- l,6-dimethyl-l,9-dihydro-pyrido[2,3-b]indol-2-one and at least one surface stabilizer, not including other excipients.
[0073] Certain embodiments of the invention may include nanoparticulate 3- (2,4-dichloro-phenyl)-l,6-dimethyl-l,9-dihydro-pyrido[2,3-b]indol-2-one compositions together with one or more non-toxic physiologically acceptable excipients, carriers, adjuvants, or vehicles, etc. Preferably, the excipient may be present in an amount from about 1 to about 50, about 1 to about 40, about 1 to about 30, about 1 to about 20, about 1 to about 15, about 1 to about 10, or about 1 to about 5, as measured by % w/w of the composition.
[0074] Exemplary preservatives useful in certain embodiments of the invention include, without limitation, methylparaben (about 0.18% based on % w/w), propylparaben (about 0.02% based on % w/w), phenol (about 0.5% based on % w/w), and benzyl alcohol (up to 2% v/v).
H. Additional Anticancer Compounds
[0075] In certain embodiments, the compositions of the invention may comprise, in addition to 3-(2,4-dichloro-phenyl)-l,6-dimethyl-l,9-dihydro-pyrido[2,3- b]indol-2-one, one or more compounds useful in treating cancer. Representative examples include, but are not limited to, alkylating agents, such as alkylsulphonates (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; intercalating agents, antineoplastic antimetabolites, folate antagonists or methotrexate; purine synthesis inhibitors; purine analogues, such as mercaptopurine or 6-thioguanine; pyrimidine synthesis inhibitors, aromatase inhibitors, capecitabine or pyrimidine analogues, such as fluorouracil, gemcitabine, cytarabine and cytosine arabinoside; brequinar; topoisomerase inhibitors, such as camptothecin or etoposide; anticancer hormonal agonists and antagonists, including tamoxifen; kinase inhibitors, imatinib; growth factor inhibitors; antiinflammatories, such as pentosan polysulphate, corticosteroids, prednisone or dexamethasone; antitopoisomerases, 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.
I. Characteristics of Nanoparticulate Active Agent Compositions
[0076] According to certain aspects of the invention, nanoparticulate active agent compositions of the invention are proposed to have an unexpectedly rapid dissolution profile. Rapid dissolution of 3-(2,4-dichloro-phenyl)- 1 ,6-dimethyl- 1 ,9- dihydro-pyrido[2,3-b]indol-2-one is preferable, as faster dissolution generally leads to faster onset of action and greater bioavailability. To improve the dissolution profile and bioavailability of 3-(2,4-dichloro-phenyl)-l,6-dimethyl-l,9-dihydro-pyrido[2,3-b]indol-2- one, it would be useful to increase the drug's dissolution so that it could attain a level close to 100% dissolved.
[0077] Additional advantages of a nanoparticulate active agent formulation include, without limitations, (1) a decrease in the frequency of dosing and/or prolonged therapeutic levels of drug following dosing; (2) smaller doses of 3-(2,4-dichloro-phenyl)- l,6-dimethyl-l,9-dihydro-pyrido[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 AUC profiles; (6) bioadhesive 3-(2,4-dichloro-phenyl)-l,6- dimethyl-l,9-dihydro-pyrido[2,3-b]indol-2-one formulations, which can coat the desired site of application and be retained for a period of time, thereby increasing the efficacy of the drug as well as eliminating or decreasing the frequency of dosing; (7) high redispersibility of the nanoparticulate 3-(2,4-dichloro-phenyl)-l,6-dimethyl-l,9-dihydro- pyrido[2,3-b]indol-2-one particles present in the compositions of the invention following administration; (8) low viscosity liquid nanoparticulate 3-(2,4-dichloro-phenyl)-l,6- dimethyl-l,9-dihydro-pyrido[2,3-b]indol-2-one dosage forms can be made; (9) the nanoparticulate 3-(2,4-dichloro-phenyl)-l,6-dimethyl-l,9-dihydro-pyrido[2,3-b]indol-2- one compositions can be used in conjunction with other active agents; (10) the nanoparticulate 3-(2,4-dichloro-phenyl)-l,6-dimethyl-l,9-dihydro-pyrido[2,3-b]indol-2- one compositions can be sterile filtered; (11) the nanoparticulate 3-(2,4-dichloro-phenyl)- l,6-dimethyl-l,9-dihydro-pyrido[2,3-b]indol-2-one compositions can be autoclaved; (12) the nanoparticulate 3-(2,4-dichloro-phenyl)-l,6-dimethyl-l,9-dihydro-pyrido[2,3-b]indol- 2-one compositions are suitable for parenteral administration; and (13) the nanoparticulate 3-(2,4-dichloro-phenyl)-l,6-dimethyl-l,9-dihydro-pyrido[2,3-b]indol-2- one compositions do not require organic solvents or pH extremes.
[0078] According to certain embodiments of the invention, compositions of the invention preferably have a dissolution profile in which within about 5 minutes at least about 20% of the 3-(2,4-dichloro-phenyl)-l,6-dimethyl-l,9-dihydro-pyrido[2,3-b]indol-2- one is dissolved. In other embodiments of the invention, at least about 30% or at least about 40% of the 3-(2,4-dichloro-phenyl)-l,6-dimethyl-l,9-dihydro-pyrido[2,3-b]indol-2- one is dissolved within about 5 minutes. In yet other embodiments of the invention, preferably at least about 40%, at least about 50%, at least about 60%, at least about 70%, or at least about 80% of the 3-(2,4-dichloro-phenyl)-l,6-dimethyl-l,9-dihydro- pyrido[2,3-b]indol-2-one is dissolved within about 10 minutes. Finally, in another embodiment of the invention, preferably at least about 70%, at least about 80%, at least about 90%, or at least about 100% of the 3-(2,4-dichloro-phenyl)-l,6-dimethyl-l,9- dihydro-pyrido[2,3-b]indol-2-one is dissolved within about 20 minutes.
[0079] Dissolution is preferably measured in a medium which is discriminating. Such a dissolution medium will produce two very different dissolution curves for two products having very different dissolution profiles in gastric juices; i.e., the dissolution medium is predictive of in vivo dissolution of a composition. An exemplary dissolution medium is an aqueous medium containing the surfactant sodium lauryl sulfate at 0.025 M. Determination of the amount dissolved can be carried out by spectrophotometry. The rotating blade method (European Pharmacopoeia) can be used to measure dissolution.
[0080] In one embodiment of the invention, the nanoparticulate particles of the composition redisperse so that the particles have an effective average particle size of less than about 2000 nm. This is significant because, if the particles did not redisperse so that they have an effective average particle size of less than about 2000 nm, the composition may lose benefits afforded by formulating 3-(2,4-dichloro-phenyl)-l,6-dimethyl-l,9- dihydro-pyrido[2,3-b]indol-2-one therein into a nanoparticulate form. This is because nanoparticulate compositions benefit from the small size of the particles comprising 3- (2,4-dichloro-phenyl)-l,6-dimethyl-l,9-dihydro-pyrido[2,3-b]indol-2-one. If the particles do not redisperse into small particle sizes upon administration, then "clumps" or agglomerated particles may be formed, owing to the extremely high surface free energy of the nanoparticulate system and the thermodynamic driving force to achieve an overall reduction in free energy. With the formation of such agglomerated particles, the bioavailability of the dosage form may fall well below that observed with the liquid dispersion form of the nanoparticulate composition.
[0081] While applicants do not wish to be bound by theoretical mechanisms, it is believed that the stabilizer hinders the flocculation and/or agglomeration of the 3-(2,4- dichloro-phenyl)-l,6-dimethyl-l,9-dihydro-pyrido[2,3-b]indol-2-one particles by functioning as a mechanical or steric barrier between the particles, minimizing the close, interparticle approach necessary for agglomeration and flocculation. [0082] It should be recognized that nanometer scale particles are intrinsically unstable in the absence of stabilization. The presence of a surface stabilizer adsorbed on the surface of the particles ensures that a small particle size is maintained. Thus, the claimed interaction between the surface stabilizer and the particle surface allows the small particle size to be maintained, due to the fact that particles are prevented from coming close enough together to aggregate.
[0083] In other embodiments of the invention, the redispersed particles of the invention (redispersed in water, a biorelevant media, or any other suitable liquid media) have an effective average particle size of less than about 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 in diameter, as measured by light-scattering methods, microscopy, or other appropriate methods. Such methods suitable for measuring effective average particle size are known to a person of ordinary skill in the art.
[0084] Redispersibility can be tested using any suitable means known in the art. See e.g., the example sections of U.S. Patent No. 6,375,986 for "Solid Dose Nanoparticulate Compositions Comprising a Synergistic Polymeric Surface Stabilizer and Sulfosuccinate," incorporated herein by reference.
J. Pharmaceutical Formulations
[0085] 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. [0086] Dosage forms that are preferably sterile include, but are not limited to, injectable dosage forms.
[0087] In one embodiment of the invention, provided are injectable nanoparticulate 3-(2,4-dichloro-phenyl)-l,6-dimethyl-l,9-dihydro-pyrido[2,3-b]indol-2- one formulations that can comprise high concentrations in low injection volumes, with rapid dissolution upon administration, which can be infused more rapidly than conventional formulations.
[0088] The composition of the instant invention may be formulated in a powder or solid form for reconstitution prior to injectable administration, such as by lyophilization.
[0089] Exemplary preservatives useful with injectable formulations of the invention include, without limitation, methylparaben (about 0.18% based on % w/w), propylparaben (about 0.02% based on % w/w), phenol (about 0.5% based on % w/w), and benzyl alcohol (up to 2% v/v). An exemplary pH adjusting agent is sodium hydroxide, and an exemplary liquid carrier is sterile water for injection. Other useful preservatives, pH adjusting agents, and liquid carriers are well-known in the art.
[0090] Compositions suitable for parenteral injection may comprise 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 and non-aqueous carriers, diluents, solvents, or vehicles including water, ethanol, polyols (propyleneglycol, polyethylene-glycol, glycerol, and the like), suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
[0091] In certain embodiments of the invention, the nanoparticulate 3-(2,4- dichloro-phenyl)-l,6-dimethyl-l,9-dihydro-pyrido[2,3-b]indol-2-one composition, including an injectable composition, is free of polysorbate, ethanol, or a combination thereof. In addition, when formulated into an injectable formulation, the compositions of the invention may provide a high concentration in a small volume to be injected. Injectable 3-(2,4-dichloro-phenyl)-l ,6-dimethyl-l ,9-dihydro-pyrido[2,3-b]indol-2-one compositions of the invention can be administered, for example, in a bolus injection or with a slow infusion over a suitable period of time.
[0092] In certain embodiments of the invention, the nanoparticulate 3-(2,4- dichloro-phenyl)-l,6-dimethyl-l,9-dihydro-pyrido[2,3-b]indol-2-one compositions are formulated as a subcutaneous or intramuscular depot. The depot is preferably formulated to release 3-(2,4-dichloro-phenyl)-l,6-dimethyl-l,9-dihydro-pyrido[2,3-b]indol-2-one over a period from about one week to about four weeks. In other embodiments of the invention, the injectable depot nanoparticulate 3-(2,4-dichloro-phenyl)-l,6-dimethyl-l,9- dihydro-pyrido[2,3-b]indol-2-one composition provides therapeutic levels of drug for up to about one week, up to about two weeks, up to about three weeks, or up about four weeks.
K. Methods of Making Nanoparticulate 3-(2,4-Dichloro-phenyl)-l,6-dimethyl- 1 ,9-dihydro-pyrido [2,3-b] indol-2-one Formulations
[0093] According to certain aspects of the invention, nanoparticulate active agent compositions can be made using methods known in the art such as, for example, milling, homogenization, and precipitation techniques. Exemplary methods of making nanoparticulate active agent compositions are generally described in U.S. Patent No. 5,145,684 ("the '684 patent"), the contents of which are incorporated by reference herein. The '684 patent describes nanoparticles of poorly soluble therapeutic or diagnostic agents having adsorbed onto or associated with the surface thereof a non-crosslinked surface stabilizer.
[0094] In one embodiment of the invention, particles comprising 3-(2,4- dichloro-phenyl)-l,6-dimethyl-l,9-dihydro-pyrido[2,3-b]indol-2-one may be dispersed in a liquid dispersion medium in which the 3-(2,4-dichloro-phenyl)-l,6-dimethyl-l,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 effective average particle size. The dispersion medium can be, for example, water, safflower oil, ethanol, t- butanol, glycerin, polyethylene glycol (PEG), hexane, or glycol. A preferred dispersion medium is water. The particles can be reduced in size in the presence of at least one surface stabilizer. The particles comprising 3-(2,4-dichloro-phenyl)-l,6-dimethyl-l,9- dihydro-pyrido[2,3-b]indol-2-one can be contacted with one or more surface stabilizers after attrition. Other compounds, such as a diluent, aggregation reducing agents, pH buffers, etc., can be added to the composition during the size reduction process. Dispersions can be manufactured continuously or in a batch mode. One skilled in the art would understand that it may be the case that, following milling, not all particles may be reduced to the desired size. In such an event, the particles of the desired size may be separated and used in the practice of the present invention.
[0095] The grinding media can comprise particles that are preferably substantially spherical in shape, e.g., beads, consisting essentially of polymeric resin or glass or Zirconium Silicate or other suitable compositions. Alternatively, the grinding media can comprise a core having a coating of a polymeric resin adhered thereon.
[0096] In general, suitable polymeric resins are chemically and physically inert, substantially free of metals, solvent, and monomers, and of sufficient hardness and friability to enable them to avoid being chipped or crushed during grinding. Suitable polymeric resins include crosslinked polystyrenes, such as polystyrene crosslinked with divinylbenzene; styrene copolymers; polycarbonates; polyacetals, such as Delrin® (E.I. du Pont de Nemours and Co.); vinyl chloride polymers and copolymers; polyurethanes; polyamides; poly(tetrafluoroethylenes), e.g., Teflon® (E.I. du Pont de Nemours and Co.), and other fluoropolymers; high density polyethylenes; polypropylenes; cellulose ethers and esters such as cellulose acetate; polyhydroxymethacrylate; polyhydroxyethyl acrylate; and silicone-containing polymers such as polysiloxanes and the like. The polymer can be biodegradable. Exemplary biodegradable polymers include poly(lactides), poly(glycolide) copolymers of lactides and glycolide, polyanhydrides, poly(hydroxyethyl methacylate), poly(imino carbonates), poly(N- acylhydroxyproline)esters, poly(N-palmitoyl hydroxyproline) esters, ethylene-vinyl acetate copolymers, poly(orthoesters), poly(caprolactones), and poly(phosphazenes). For biodegradable polymers, contamination from the media itself advantageously can metabolize in vivo into biologically acceptable products that can be eliminated from the body.
[0097] The grinding media preferably ranges in size from about 0.01 to about 3 mm. For fine grinding, the grinding media is preferably from about 0.02 to about 2 mm, and more preferably from about 0.03 to about 1 mm in size.
[0098] The polymeric resin can have a density from about 0.8 to about 3.0 g/cm .
[0099] According to an embodiment of the invention, solid or powder forms of nanoparticulate active agent dispersions can also be prepared by lyophilizing the liquid nanoparticulate active agent dispersion following particle size reduction.
[0100] In the lyophilization step, water is removed from the nanoparticulate active agent formulations after the dispersion is frozen and placed under vacuum, allowing the ice to change directly from solid to vapor without passing through a liquid phase. The lyophilization process consists of four interdependent processes: freezing, sublimation, the primary drying step, and desorption, which is the secondary drying step. Many lyophilizers can be used to achieve the lyophilization step of nanoparticulate active agent dispersions.
[0101] Suitable lyophilization 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), all of which are incorporated herein by reference. Typically, the nanoparticulate active agent dispersion is placed in a suitable vessel and frozen to a temperature of between about -5° C. to about -100° C. The frozen dispersion is then subjected to reduced pressure for a period of up to about 48 hours. The combination of parameters such as temperature, pressure, dispersion media, and batch size will impact the time required for the lyophilization process. Under conditions of reduced temperature and pressure, the frozen solvent is removed by sublimation yielding a solid, porous, immediate release solid dosage form having the nanoparticulate active agent distributed throughout.
[0102] Following sterilization, the lyophilized solid form can be reconstituted into a liquid dosage form, such as injectable compositions, etc.
[0103] One embodiment of the invention comprises a method for making a sterilized nanoparticulate 3-(2,4-dichloro-phenyl)- 1 ,6-dimethyl- 1 ,9-dihydro-pyrido[2,3- b]indol-2-one composition comprising the steps of: mixing 3-(2,4-dichloro-phenyl)-l,6- dimethyl-l,9-dihydro-pyrido[2,3-b]indol-2-one, at least one excipient, and at least one surface stabilizer in an aqueous medium containing milling media for a period of time and under conditions sufficient to provide a dispersion of particles of 3-(2,4-dichloro- phenyl)-l,6-dimethyl-l,9-dihydro-pyrido[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 surface of the particles; removing the milling media from the dispersion; lyophilizing the dispersion to form a lyo; and sterilizing the lyo to produce a sterilized 3-(2,4- dichloro-phenyl)-l,6-dimethyl-l,9-dihydro-pyrido[2,3-b]indol-2-one composition.
[0104] According to an embodiment of the invention, the solid nanoparticulate active agent particles are subjected to gamma radiation at ambient temperature, which remains relatively constant during the period of irradiation. Gamma radiation is applied in an amount sufficient to expose the pharmaceutical product to at least 25 kGray of irradiation. The total amount of gamma radiation that the solid nanoparticulate active agent is exposed to has been experimentally verified to: (1) render the active agent composition sterile, and (2) maintain the integrity of the nanoparticulate active agent composition. The application of the gamma radiation does not significantly degrade the active agent or reduce the active agent's efficacy. In this way, it is possible to provide products which meet cGMP requirements for sterile products without harming the active agent.
[0105] In a preferred aspect of the invention, the gamma radiation is applied in 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.
[0106] In another embodiment of the invention, the nanoparticulate active agent compositions can be moist heat sterilized without producing significant active agent particle size growth. The heat sterilization process destroys substantially all of the microbial and viral contamination in the dispersion, such as microbes, mycoplasma, yeast, viruses, and mold. The microbial contamination which is to be destroyed is generally that of bacteria, mycoplasma, yeast and mold contamination. The moist heat sterilization step: (1) results in minimal, if any, increase in active agent particle size on storage, (2) maintains the chemical integrity of the nanoparticulate active agent, and (3) shows generally acceptable impurity concentrations for the active agent composition following heat sterilization. The moist heat sterilization process does not significantly degrade the active agent, or reduce the active agent's efficacy. The present invention enables products to meet cGMP requirements for sterile products without harming the active agent.
[0107] Surprisingly, following sterilization the nanoparticulate active agent composition exhibits unexpected overall stability, maintains the pre-sterilized physical and chemical properties, while meeting cGMP requirements for sterility. It is particularly unexpected that moist heat sterilization of the active agent dispersion does not significantly alter the particle size of the active agent. This is significant because if the sterilized product formed aggregates or large crystals, the dispersion would lose the benefits afforded by being formulated into a nanoparticulate active agent composition.
[0108] The requirement of sterility can be problematic for formulations of nanoparticulate drugs, as heat sterilization can result in solubilization and subsequent recrystallization of the component drug particles. Aggregation of nanoparticle compositions upon heating is directly related to the precipitation of the surface stabilizer at temperatures above the cloud point of the surface stabilizer. At this point, the bound surface stabilizer molecules are likely to dissociate from the nanoparticles and precipitate, leaving the nanoparticles unprotected. The unprotected nanoparticles then aggregate into clusters of particles. Such particle size growth results in a loss of the pharmaceutical benefits afforded by formulating the active agent in a nanoparticulate dosage form, such as a faster onset of activity, reduced toxicity, and a lower dosage of active agent. It was unexpectedly discovered that the active agent, in combination with at least one surface stabilizer, can be successfully heat sterilized, producing sterile compositions having an effective average particle size of less than about 2000 nm, with minimal or no degradation of the active agent.
[0109] The technique of heat sterilization is well known to one skilled in the art. In a preferred embodiment, the heat sterilization is performed at approximately 121°C for at least 10 minutes, at least 15 minutes, at least 20 minutes, at least 25 minutes, or at least 30 minutes. More preferably, the heat sterilization is perform at approximately 121°C for approximately 20 minutes, approximately 21 minutes, or approximately 26 minutes.
[0110] One aspect of the invention is that upon reconstitution or redispersion after sterilization, 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 a retention of particle size, pH, osmolality, assay, and stabilizer concentration following redispersion of the solid in a liquid media.
[0111] In other embodiments, employed is a manufacturing process of the present invention that is similar to typical known manufacturing processes for sterile suspensions. A typical sterile suspension manufacturing process flowchart is as follows:
Compounding
Particle size Reduction
Vial Filling Lyophilization and/or Terminal Sterilization or Autoclaving
[0112] Some of the processing may be dependent upon the method of particle size reduction and/or method of sterilization. For example, media conditioning is not required for a milling method that does not use media. If terminal sterilization is not feasible due to chemical and/or physical instability, aseptic processing can be used.
L. Methods of Treatment
[0113] In certain embodiments, the present invention also provides methods comprising the administration to a subject in need thereof an effective amount of a nanoparticulate composition comprising 3-(2,4-dichloro-phenyl)-l,6-dimethyl-l,9- dihydro-pyrido[2,3-b]indol-2-one. As used herein, the term "subject" is used to mean an animal, preferably a mammal, including a human. The terms "patient" and "subject" may be used interchangeably. Thus, certain embodiments of the invention are directed to appropriate dosage forms useful in the administration of 3-(2,4-dichloro-phenyl)-l,6- dimethyl-l,9-dihydro-pyrido[2,3-b]indol-2-one to a subject.
[0114] Certain aspects of the invention are directed to methods comprising the administration of an effective amount of a nanoparticulate composition comprising 3- (2,4-dichloro-phenyl)-l,6-dimethyl-l,9-dihydro-pyrido[2,3-b]indol-2-one to a subject in need thereof. According to certain aspects of the invention, there are provided methods for the treatment of cancer.
[0115] Other aspects of the invention are directed to the use of a nanoparticulate 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.
[0116] 3-(2,4-Dichloro-phenyl)-l,6-dimethyl-l,9-dihydro-pyrido[2,3-b]indol-2- one displays in vitro and in vivo activity indicating that it is a strong inhibitor of the proliferation of tumour cells, and, as such, can be used in the treatment of or prevention from diseases caused or exacerbated by the proliferation of tumour cells. In particular, nanoparticulate 3-(2,4-dichloro-phenyl)-l,6-dimethyl-l,9-dihydro-pyrido[2,3-b]indol-2- one compositions of the invention may be used in the treatment of solid tumours, both primary and metastatic solid tumours, carcinomas and cancers, in particular: breast cancer; lung cancer; cancer of the small intestine, cancer of the colon and of the rectum; cancer of the respiratory tract, of the oropharynx and of the hypopharynx; cancer of the oesophagus; liver cancer, stomach cancer, cancer of the bile ducts, cancer of the gall bladder, cancer of the pancreas; cancers of the urinary tract, including kidney, urothelium and bladder; cancers of the female genital tract, including cancer of the uterus, cervix and ovaries, choriocarcinoma and trophoblastic cancer; cancers of the male genital tract, including cancer of the prostate, seminal vesicles and testicles, tumours of the germinal cells; cancers of the endocrine glands, including cancer of the thyroid, pituitary gland and adrenal glands; skin cancers, including haemangiomas, melanomas and sarcomas, including Kaposi's sarcoma; tumours of the brain, nerves, eyes and meninges, including astrocytomas, gliomas, glioblastomas, retinoblastomas, neurinomas, neuroblastomas, schwannomas and meningiomas; solid tumours resulting from haematopoietic malignant tumours, including leukaemias, chloromas, plasmacytomas, fungoid mycosis, T-cell lymphoma or leukaemia, non-Hodgkin's lymphoma, malignant haemopathies and myelomas.
[0117] In certain embodiments, the compositions of the invention may also be administered in conjunction with one or more additional active agents. These other active agents preferably include those useful for treatment of cancer as well as those agents useful for treating the adverse events that may be associated with 3-(2,4-dichloro- phenyl)-l,6-dimethyl-l,9-dihydro-pyrido[2,3-b]indol-2-one treatment. Such active agents are preferably present in a manner, as determined by one skilled in the art, such that they do not interfere with therapeutic effect(s) of 3-(2,4-dichloro-phenyl)-l,6- dimethyl- 1 ,9-dihydro-pyrido[2,3-b]indol-2-one.
[0118] In human therapy, it is important to provide 3-(2,4-dichloro-phenyl)-l,6- dimethyl-l,9-dihydro-pyrido[2,3-b]indol-2-one dosage forms that deliver the required therapeutic amount of the drug in vivo, and that renders the drug bioavailable in a constant manner. [0119] In addition to allowing for a smaller solid dosage form size, the nanoparticulate compositions of the present invention may exhibit increased bioavailability, and may require the administration of smaller doses of 3-(2,4-dichloro- phenyl)-l,6-dimethyl-l,9-dihydro-pyrido[2,3-b]indol-2-one, as compared to prior conventional, non-nanoparticulate compositions which comprise 3-(2,4-dichloro-phenyl)- l,6-dimethyl-l,9-dihydro-pyrido[2,3-b]indol-2-one. In one embodiment of the invention, a nanoparticulate composition may have a bioavailability that is about 50% greater than 3-(2,4-dichloro-phenyl)-l,6-dimethyl-l,9-dihydro-pyrido[2,3-b]indol-2-one when administered in a conventional dosage form. In other embodiments, 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 3-(2,4-dichloro- phenyl)-l,6-dimethyl-l,9-dihydro-pyrido[2,3-b]indol-2-one when administered in a non- nanoparticulate dosage form.
[0120] In an embodiment of the present invention, a nanoparticulate composition of the present invention may exhibit, for example, a Cmax for 3-(2,4- dichloro-phenyl)-l,6-dimethyl-l,9-dihydro-pyrido[2,3-b]indol-2-one contained therein which is at least about 50% of the Cmax for the same 3-(2,4-dichloro-phenyl)-l,6- dimethyl-l,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 nanoparticulate composition of the present invention may exhibit, 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 100%, at least about 200%, at least about 300%, at least about 400%, at least about 500%, at least about 600%, at least about 700%, at least about 800%, at least about 900%, at least about 1000%, at least about 1100%, at least about 1200%, at least about 1300%, at least about 1400%, at least about 1500%, at least about 1600%, at least about 1700%, at least about 1800%, or at least about 1900% greater than the Cmax for the same 3-(2,4-dichloro-phenyl)-l,6-dimethyl-l,9-dihydro-pyrido[2,3- b]indol-2-one when delivered at the same dosage by a non-nanoparticulate composition.
[0121] In an embodiment of the present invention, a nanoparticulate composition of the present invention may exhibit, for example, an AUC for 3-(2,4- dichloro-phenyl)-l,6-dimethyl-l,9-dihydro-pyrido[2,3-b]indol-2-one contained therein which is at least about 25% greater than the AUC for the same 3-(2,4-dichloro-phenyl)- l,6-dimethyl-l,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 nanoparticulate composition of the present invention may exhibit, for example, an AUC 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%, 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 5 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 850%, at least about 900%, at least about 950%, at least about 1000%, at least about 1050%, at least about 1100%, at least about 1150%, or at least about 1200% greater than the AUC for the same 3-(2,4-dichloro- phenyl)-l,6-dimethyl-l,9-dihydro-pyrido[2,3-b]indol-2-one when delivered at the same dosage by a non-nanoparticulate composition.
M. Examples
[0122] Examples have been set forth below for purposes of illustration and to describe the best mode of the invention at the present time. The scope of the invention is not to be in any way limited by the examples set forth herein.
[0123] Drug Particle Count (DPC) Test: This microscopic test was performed for the purpose of enumerating undissolved particles within specific size ranges that are unintentionally present in the formulation intended for IV administration. The entire vial contents, 5ml volume for this system, was filtered through a 5.0μm membrane filter and the particles captured on the filter were manually enumerated with the use of a compound microscope. A circular diameter graticule provided comparisons for particle sizing. The result is reported on a particle count per container basis. EXAMPLE 1: Example of a composition according to the invention
Figure imgf000040_0001
[0124] The manufacturing process was as follows: The stabilizers (polyvinylpyrolidone and sodium deoxycholate) and some of the sucrose were dissolved in sterile water for injection and further filtered through a sterilizing grade 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% PVP kl2, 1.4% NaDOC, 8.0% Sucrose and 60.6% SWFI - %w/w. The slurry was then milled with high energy in the presence of PolyMill® 500 to reduce the particle size of the drug to a sufficiently small size. Post milling, the NanoCrystal® Colloidal Dispersion® was harvested from the milling equipment through a 5μm capsule filter. Separate to the harvesting step a separate solution of the remaining sucrose, TRIS and SWFI was manufactured and passed through a sterilizing grade filter. This solution was mixed with the harvested dispersion to create the preferred composition mentioned above. The preferred composition was further pH adjusted with hydrochloric acid to bring the pH to -8.0. The resulting composition was filled into vials and autoclaved at 1210C for approximately 21 minutes.
EXAMPLE 2: Example of a composition according to the invention
Figure imgf000040_0002
Figure imgf000041_0001
[0125] This composition was prepared in a similar manner to Example 1 with the exception that it was not buffered with TRIS. Despite not being buffered, the formulation was able to withstand autoclaving at 1210C for approximately 26 minutes.
EXAMPLE 3: Example of a composition according to the invention
Figure imgf000041_0002
[0126] This composition was prepared in a similar manner to Example 1 with the exception that it was buffered with TRIS and the pH was adjusted to approximately pH 10. This formulation was able to withstand autoclaving at 121°C for approximately 26 minutes.
EXAMPLE 4: Example of a composition according to the invention
Figure imgf000041_0003
Figure imgf000042_0001
[0127] This composition was prepared in a similar manner to Example 1 with the exception that the formulation was milled without sucrose or sorbitol and sorbitol was added during the harvest step. It was buffered with TRIS and pH adjusted to approximately 9.5. This formulation was able to withstand autoclaving at 121°C for approximately 26 minutes.
EXAMPLE 5: Example of a composition according to the invention
Figure imgf000042_0002
[0128] This composition was prepared in a similar manner to Example 1 with the exception that the formulation was milled without sucrose or sorbitol and Tween 80 was used as the primary stabilizer instead of PVP kl2. It was not buffered with TRIS, nor pH adjusted. This formulation was unable to withstand autoclaving at 1210C for approximately 20 minutes.
EXAMPLE 6: Example of a composition according to the invention
Figure imgf000042_0003
[0129] This composition was prepared in a similar manner to Example 1 with the exception that the formulation was milled without sucrose, but sucrose was added during the harvest step. The primary and secondary stabilizers , PVP and NaDOC, were lower than the preferred system by 5 mg and 0.5 mg respectively. It was not buffered with TRIS, nor pH adjusted. This formulation was unable to withstand autoclaving at 1210C for approximately 20 minutes.
Figure imgf000044_0001
TNTC - too numerous to count, NT - not tested
[0130] All publications, patent applications, patents, and other references mentioned herein are expressly incorporated by reference in their entirety, including all formulas and figures, to the same extent as if each were incorporated by reference individually. In case of conflict, the present specification, including definitions, will control. Other embodiments are set forth within the following claims.

Claims

We claim:
1. A nanoparticulate composition comprising:
(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.
2. The composition of claim 1, wherein the 3-(2,4-dichloro-phenyl)-l,6- dimethyl-l,9-dihydro-pyrido[2,3-b]indol-2-one is in a crystalline phase, an amorphous phase, a semi-crystalline phase, or any mixture thereof.
3. The composition of claim 1 or claim 2, wherein the particles of 3 -(2,4- dichloro-phenyl)-l,6-dimethyl-l,9-dihydro-pyrido[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. The composition of any one of claims 1-3, wherein the composition is formulated for administration by parenteral, intracisternal, intravaginal, intraperitoneal or local administration.
5. The composition of claim 4, wherein the parenteral injection is selected from the group consisting of an intravenous injection, an intramuscular injection and a subcutaneous injection.
6. The composition of claim 5, wherein the particles of 3-(2,4-dichloro- phenyl)-l,6-dimethyl-l,9-dihydro-pyrido[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.
7. The composition of any one of claims 1-6, wherein the composition is sterile.
8. The composition of any one of claims 1-7, wherein the composition further comprises one or more pharmaceutically acceptable excipients, carriers, antibacterial agents, antifungal agents, or any combination thereof.
9. The composition of claim 8, wherein the pharmaceutically acceptable excipient is selected from the group consisting of an aggregation reducing agent, a binding agent, a filling agent, a bulking agent, a lubricating agent, a suspending agent, a preservative, a pH modifying agent, a wetting agent, a disintegrant, a crystal growth inhibitor, a free radical scavenger agent, a redispersion agent, and an effervescent agent.
10. The composition of any one of claims 1 -9, wherein the composition comprises two or more surface stabilizers.
11. The composition of any one of claims 1-10, wherein the surface stabilizer is selected from the group consisting of a nonionic surface stabilizer, an ionic surface stabilizer, an anionic surface stabilizer, a cationic surface stabilizer, and a zwitterionic surface stabilizer.
12. The composition of any one of claims 1-11, wherein the surface stabilizer is selected from the group consisting of dextran, gum acacia, tragacanth, glycerol monostearate, cetostearyl alcohol, cetomacrogol emulsifying wax, sorbitan esters, polyoxyethylene alkyl ethers, polyethylene alkyl esters, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, polyethylene glycols, polyoxyethylene stearates, methylcellulose, hydroxyethylcellulose, hydroxypropyl celluloses, hydroxypropyl methylcellulose, hydroxypropylmethyl-cellulose phthalate, noncrystalline cellulose, triethanolamine, polyvinyl alcohol, polyvinylpyrrolidone, 4- (l,l,3,3-tetramethylbutyl)-phenol polymer with ethylene oxide and formaldehyde, poloxamers, poloxamines, Tetronic 1508®, alkyl phenol ethylene oxide, Crodestas F- 110®, p-isononylphenoxypoly-Cglycidol), Crodestas SL-40®, SA9OHCO, decanoyl-N- methylglucamide, n-decyl β-D-glucopyranoside, n-decyl β-D-maltopyranoside, n- dodecyl β-D-glucopyranoside, n-dodecyl β-D-maltoside, heptanoyl-N-methylglucamide, n-heptyl-β-D-glucopyranoside, n-heptyl β-D-thioglucoside, n-hexyl β-D-glucopyranoside, nonanoyl-N-methylglucamide, n-noyl β-D-glucopyranoside, octanoyl-N- methylglucamide, n-octyl-β-D-glucopyranoside, octyl β-D-thioglucopyranoside, lysozyme, PEG-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 oxide and propylene oxide, copolymer of vinylpyrrolidone and vinyl acetate, distearyl palmitate glyceryl, polyoxyethylene sorbitan fatty acid esters, macrogol 15 hydroxystearate, oleic acid, stearic acid, palmitic acid, lauric acid, myristic acid, calcium stearate, sodium dodecylsulfate, sodium lauryl sulfate, carboxymethylcellulose calcium, carboxymethylcellulose sodium, dialkylesters of sodium sulfosuccinic acid, dioctyl ester of sodium sulfosuccinic acid, an 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, anthryul pyridinium chloride, cationic phospholipids, chitosan, polylysine, polyvinylimidazole, polybrene, polymethylmethacrylate trimethylammoniumbromide bromide (PMMTMABr), hexyldesyltrimethylammonium bromide (HDMAB), and polyvinylpyrrolidone-2- dimethylaminoethyl methacrylate dimethyl sulfate, cationic lipids, sulfonium, phosphonium, stearyltrimethylammonium chloride, benzyl-di(2- chloroethyl)ethylammonium bromide, coconut trimethyl ammonium chloride or bromide, coconut methyl dihydroxyethyl ammonium chloride or bromide, dodecyl trimethyl ammonium bromide, decyl triethyl ammonium chloride, decyl dimethyl hydroxyethyl ammonium chloride or bromide, C12_15dimethyl hydroxyethyl ammonium chloride or bromide, coconut dimethyl hydroxyethyl ammonium chloride or bromide, myristyl trimethyl ammonium methyl sulphate, lauryl dimethyl benzyl ammonium chloride or bromide, lauryl dimethyl (ethenoxy)4 ammonium chloride or bromide, N-alkyl (C12- i8)dimethylbenzyl ammonium chloride, N-alkyl (C14_i8)dimethyl-benzyl ammonium chloride, N-tetradecylidmethylbenzyl ammonium chloride monohydrate, dimethyl didecyl ammonium chloride, N-alkyl and (C12-I4) dimethyl 1-napthylmethyl ammonium chloride, trimethylammonium halide, alkyl-trimethylammonium salts and dialkyl- dimethylammonium salts, lauryl trimethyl ammonium chloride, ethoxylated alkyamidoalkyldialkylammonium salt and/or an ethoxylated trialkyl ammonium salt, dialkylbenzene dialkylammonium chloride, N-didecyldimethyl ammonium chloride, N- tetradecyldimethylbenzyl ammonium, chloride monohydrate, N-alkyl(Ci2-i4) dimethyl 1- naphthylmethyl ammonium chloride and dodecyldimethylbenzyl ammonium chloride, dialkyl benzenealkyl ammonium chloride, lauryl trimethyl ammonium chloride, alkylbenzyl methyl ammonium chloride, alkyl benzyl dimethyl ammonium bromide, C12, C15, C17 trimethyl ammonium bromides, dodecylbenzyl triethyl ammonium chloride, poly-diallyldimethylammonium chloride (DADMAC), dimethyl ammonium chlorides, alkyldimethylammonium halogenides, tricetyl methyl ammonium chloride, decyltrimethylammonium bromide, dodecyltriethylammonium bromide, tetradecyltrimethylammonium bromide, methyl trioctylammonium chloride, POLYQUAT 10™, tetrabutylammonium bromide, benzyl trimethylammonium bromide, choline esters (such as choline esters of fatty acids), benzalkonium chloride, stearalkonium chloride compounds (such as stearyltrimonium chloride and Di- stearyldimonium chloride), cetyl pyridinium bromide or chloride, halide salts of quaternized polyoxyethylalkylamines, MIRAPOL™ and ALKAQUAT™, alkyl pyridinium salts, alkylamines, dialkylamines, alkanolamines, polyethylenepolyamines, N,N-dialkylaminoalkyl acrylates, vinyl pyridine, lauryl amine acetate, stearyl amine acetate, alkylpyridinium salt, and alkylimidazolium salt, amine oxides, imide azolinium salts, protonated quaternary acrylamides, methylated quaternary polymers, poly[diallyl dimethylammonium chloride], poly-[N-methyl vinyl pyridinium chloride], cationic guar, benzalkonium chloride, a carbonium compound, a phosphonium compound, an oxonium compound, a halonium compound, a cationic organometallic compound, a quarternary phosphorous compound, a pyridinium compound, an anilinium compound, an immonium compound, a hydroxylammonium compound, a primary ammonium compound, a secondary ammonium compound, a tertiary ammonium compound, quarternary ammonium compounds of the formula NR1R2R3R4^, behenalkonium chloride, benzethonium chloride, cetylpyridinium chloride, behentrimonium chloride, lauralkonium chloride, cetalkonium chloride, cetrimonium bromide, cetrimonium chloride, cethylamine hydrofluoride, chlorallylmethenamine chloride, distearyldimonium chloride, dodecyl dimethyl ethylbenzyl ammonium chloride, Quaternium-22, Quaternium-26, Quaternium-18 hectorite, dimethylaminoethylchloride hydrochloride, cysteine hydrochloride, diethanolammonium POE (10) oletyl ether phosphate, diethanolammonium POE (3)oleyl ether phosphate, tallow alkonium chloride, dimethyl dioctadecylammoniumbentonite, stearalkonium chloride, domiphen bromide, denatonium benzoate, myristalkonium chloride, laurtrimonium chloride, ethylenediamine dihydrochloride, guanidine hydrochloride, pyridoxine HCl, iofetamine hydrochloride, meglumine hydrochloride, methylbenzethonium chloride, myrtrimonium bromide, oleyltrimonium chloride, polyquaternium-1, procainehydrochloride, cocobetaine, stearalkonium bentonite, stearalkoniumhectonite, stearyl trihydroxyethyl propylenediamine dihydrofluoride, tallowtrimonium chloride, hexadecyltrimethyl ammonium bromide, proteins, phospholipids, zwitterionic polymers and zwitterionic surfactant molecules, human serum albumin, bovine serum albumin, gelatin, casein, lysozyme, phosphotidylcholine, and lecithin.
13. The composition of any one of claims 1-12, 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, 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 10.7, 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, 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.
14. The composition of claim 13, 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 12.0, and about 12.0 to about 14.0.
15. The composition of claim 13, wherein the pH of the composition is in the range of about 9.5 to about 11.0.
16. The composition of claim 13, wherein the pH of the composition is in the range of about 7.0 to about 9.5.
17. The composition of any of claims 1-16, wherein:
(a) the concentration of the 3-(2,4-dichloro-phenyl)-l,6-dimethyl-l,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, based on the total combined weight of 3-(2,4-dichloro-phenyl)-l,6-dimethyl-l,9- dihydro-pyrido[2,3-b]indol-2-one and at least one surface stabilizer, not including other excipients.
18. The composition of any one of claims 1-17, wherein the composition comprises an additional anti-cancer active agent.
19. The composition of claim 18, wherein the additional anti-cancer 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, intercalating agents, antineoplastic antimetabolites, folate antagonists, methotrexate, purine synthesis inhibitors, purine analogues, mercaptopurine, 6-thioguanine, pyrimidine synthesis inhibitors, aromatase inhibitors, capecitabine or pyrimidine analogues, fluorouracil, gemcitabine, cytarabine, cytosine arabinoside, brequinar, topoisomerase inhibitors, camptothecin, etoposide, anticancer hormonal agonists and antagonists, tamoxifen, kinase inhibitors, imatinib, growth factor inhibitors, antiinflammatories, pentosan polysulphate, corticosteroids, prednisone, dexamethasone, antitopoisomerases, etoposide, anthracyclines, doxorubicin, bleomycin, mitomycin, mithramycin, anticancer metal complexes, platinum complexes, cisplatin, carboplatin, oxaliplatin, interferon-alpha, triphenyl thiophosphoramide, altretamine, antiangiogenic agents, thalidomide, immunotherapy adjuvants, and vaccines.
20. A method for making a nanoparticulate 3-(2,4-dichloro-phenyl)- 1 ,6- dimethyl-l,9-dihydro-pyrido[2,3-b]indol-2-one composition comprising contacting 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 period of time and under conditions sufficient to provide a nanoparticulate 3-(2,4-dichloro-phenyl)-l,6-dimethyl-l,9-dihydro-pyrido[2,3- b]indol-2-one composition having an effective average particle size of less than about 400 nm.
21. The method of claim 20, wherein contacting comprises milling, homogenization precipitation, or any combination thereof.
22. A method for making a sterile nanoparticulate 3-(2,4-dichloro-phenyl)- 1 ,6-dimethyl- 1 ,9-dihydro-pyrido[2,3-b]indol-2-one composition comprising:
(a) contacting 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 and at least one excipient for a period of time and under conditions sufficient to provide a nanoparticulate 3-(2,4- dichloro-phenyl)-l,6-dimethyl-l,9-dihydro-pyrido[2,3-b]indol-2-one dispersion having an effective average particle size of less than about 400 nm;
(b) lyophilizing the dispersion to form a lyo; and
(c) sterilizing the lyo to produce a sterile nanoparticulate 3-(2,4-dichloro- phenyl)-l ,6-dimethyl-l ,9-dihydro-pyrido[2,3-b]indol-2-one composition.
23. The method of claim 22, wherein the sterilization comprises gamma radiation at ambient temperature.
24. The method of claim 23, wherein the gamma radiation is applied in a range of between about 5 kGray and about 50 kGray.
25. The method of claim 22, wherein the sterilization comprises autoclave.
26. A method for treating cancer comprising administrating to a subject in need thereof an effective amount of a nanoparticulate 3-(2,4-dichloro-phenyl)-l,6- dimethyl-l,9-dihydro-pyrido[2,3-b]indol-2-one composition, 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.
27. The method of claim 26, wherein the cancer is selected from the group consisting of breast cancer; lung cancer, cancer of the small intestine, cancer of the colon and of the rectum, cancer of the respiratory tract, of the oropharynx or of the hypopharynx, cancer of the oesophagus, liver cancer, stomach cancer, cancer of the bile ducts, cancer of the gall bladder, cancer of the pancreas, cancers of the urinary tract, cancers of the female genital tract, choriocarcinoma or trophoblastic cancer, cancers of the male genital tract, cancers of the endocrine glands, skin cancers, tumours of the brain, nerves, eyes and meninges, and solid tumours resulting from haematopoietic malignant tumours.
28. The method of claim 26 or claim 27, wherein the method further comprises administering to the subject one or more additional active agents.
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