US20050233001A1 - Nanoparticulate megestrol formulations - Google Patents

Nanoparticulate megestrol formulations Download PDF

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US20050233001A1
US20050233001A1 US11093149 US9314905A US2005233001A1 US 20050233001 A1 US20050233001 A1 US 20050233001A1 US 11093149 US11093149 US 11093149 US 9314905 A US9314905 A US 9314905A US 2005233001 A1 US2005233001 A1 US 2005233001A1
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megestrol
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nanoparticulate
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Douglas Hovey
John Pruitt
Tuula Ryde
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Alkermes Pharma Ireland Ltd
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Elan Pharma International Ltd
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    • AHUMAN NECESSITIES
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    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/14Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/56Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives, e.g. steroids
    • A61K31/57Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane, progesterone
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/56Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives, e.g. steroids
    • A61K31/57Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane, progesterone
    • A61K31/573Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane, progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K45/00Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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    • A61K47/00Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/20Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K47/00Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K47/00Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K47/30Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/34Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
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    • A61K47/36Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
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    • A61K47/30Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/42Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein
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    • A61K9/0087Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0095Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
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    • A61K9/08Solutions
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    • A61K9/141Intimate 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
    • A61K9/145Intimate 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
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    • A61K9/141Intimate 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
    • A61K9/146Intimate 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
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    • A61K9/51Nanocapsules; Nanoparticles
    • A61K9/5107Excipients; Inactive ingredients
    • A61K9/5123Organic compounds, e.g. fats, sugars
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    • A61K9/513Organic macromolecular compounds; Dendrimers
    • A61K9/5138Organic macromolecular compounds; Dendrimers obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K9/50Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51Nanocapsules; Nanoparticles
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    • A61K9/513Organic macromolecular compounds; Dendrimers
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    • AHUMAN NECESSITIES
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    • A61K9/50Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51Nanocapsules; Nanoparticles
    • A61K9/5107Excipients; Inactive ingredients
    • A61K9/513Organic macromolecular compounds; Dendrimers
    • A61K9/5169Proteins, e.g. albumin, gelatin

Abstract

The present invention is directed to nanoparticulate compositions comprising megestrol. The megestrol particles of the composition have an effective average particle size of less than about 2000 nm.

Description

  • This application is a continuation-in-part of application Ser. No. 10/412,669 filed Apr. 14, 2003, which claims the priority benefit of U.S. provisional patent application Ser. No. 60/371,680, filed Apr. 12, 2002, and U.S. provisional patent application No. 60/430,348, filed Dec. 3, 2002.
  • FIELD OF THE INVENTION
  • The present invention relates to a nanoparticulate composition comprising megestrol and preferably at least one surface stabilizer associated with the surface of the drug. The nanoparticulate megestrol particles have an effective average particle size of less than about 2000 nm.
  • BACKGROUND OF THE INVENTION
  • A. Background Regarding Nanoparticulate Compositions
  • Nanoparticulate compositions, first described in U.S. Pat. No. 5,145,684 (“the '684 patent”), are particles consisting of a poorly soluble therapeutic or diagnostic agent having adsorbed onto the surface thereof a non-crosslinked surface stabilizer. The '684 patent does not describe nanoparticulate compositions of megestrol.
  • Methods of making nanoparticulate compositions are described, for example, in U.S. Pat. Nos. 5,518,187 and 5,862,999, both for “Method of Grinding Pharmaceutical Substances;” U.S. Pat. No. 5,718,388, for “Continuous Method of Grinding Pharmaceutical Substances;” and U.S. Pat. No. 5,510,118 for “Process of Preparing Therapeutic Compositions Containing Nanoparticles.”
  • Nanoparticulate compositions are also described, for example, in U.S. Pat. No. 5,298,262 for “Use of Ionic Cloud Point Modifiers to Prevent Particle Aggregation During Sterilization;” U.S. Pat. No. 5,302,401 for “Method to Reduce Particle Size Growth During Lyophilization;” U.S. Pat. No. 5,318,767 for “X-Ray Contrast Compositions Useful in Medical Imaging;” U.S. Pat. No. 5,326,552 for “Novel Formulation For Nanoparticulate X-Ray Blood Pool Contrast Agents Using High Molecular Weight Non-ionic Surfactants;” U.S. Pat. No. 5,328,404 for “Method of X-Ray Imaging Using Iodinated Aromatic Propanedioates;” U.S. Pat. No. 5,336,507 for “Use of Charged Phospholipids to Reduce Nanoparticle Aggregation;” U.S. Pat. No. 5,340,564 for “Formulations Comprising Olin 10-G to Prevent Particle Aggregation and Increase Stability;” U.S. Pat. No. 5,346,702 for “Use of Non-Ionic Cloud Point Modifiers to Minimize Nanoparticulate Aggregation During Sterilization;” U.S. Pat. No. 5,349,957 for “Preparation and Magnetic Properties of Very Small Magnetic-Dextran Particles;” U.S. Pat. No. 5,352,459 for “Use of Purified Surface Modifiers to Prevent Particle Aggregation During Sterilization;” U.S. Pat. No. 5,399,363 and U.S. Pat. No. 5,494,683, both for “Surface Modified Anticancer Nanoparticles;” U.S. Pat. No. 5,401,492 for “Water Insoluble Non-Magnetic Manganese Particles as Magnetic Resonance Enhancement Agents;” U.S. Pat. No. 5,429,824 for “Use of Tyloxapol as a Nanoparticulate Stabilizer;” U.S. Pat. No. 5,447,710 for “Method for Making Nanoparticulate X-Ray Blood Pool Contrast Agents Using High Molecular Weight Non-ionic Surfactants;” U.S. Pat. No. 5,451,393 for “X-Ray Contrast Compositions Useful in Medical Imaging;” U.S. Pat. No. 5,466,440 for “Formulations of Oral Gastrointestinal Diagnostic X-Ray Contrast Agents in Combination with Pharmaceutically Acceptable Clays;” U.S. Pat. No. 5,470,583 for “Method of Preparing Nanoparticle Compositions Containing Charged Phospholipids to Reduce Aggregation;” U.S. Pat. No. 5,472,683 for “Nanoparticulate Diagnostic Mixed Carbamic Anhydrides as X-Ray Contrast Agents for Blood Pool and Lymphatic System Imaging;” U.S. Pat. No. 5,500,204 for “Nanoparticulate Diagnostic Dimers as X-Ray Contrast Agents for Blood Pool and Lymphatic System Imaging;” U.S. Pat. No. 5,518,738 for “Nanoparticulate NSAID Formulations;” U.S. Pat. No. 5,521,218 for “Nanoparticulate Iododipamide Derivatives for Use as X-Ray Contrast Agents;” U.S. Pat. No. 5,525,328 for “Nanoparticulate Diagnostic Diatrizoxy Ester X-Ray Contrast Agents for Blood Pool and Lymphatic System Imaging;” U.S. Pat. No. 5,543,133 for “Process of Preparing X-Ray Contrast Compositions Containing Nanoparticles;” U.S. Pat. No. 5,552,160 for “Surface Modified NSAID Nanoparticles;” U.S. Pat. No. 5,560,931 for “Formulations of Compounds as Nanoparticulate Dispersions in Digestible Oils or Fatty Acids;” U.S. Pat. No. 5,565,188 for “Polyalkylene Block Copolymers as Surface Modifiers for Nanoparticles;” U.S. Pat. No. 5,569,448 for “Sulfated Non-ionic Block Copolymer Surfactant as Stabilizer Coatings for Nanoparticle Compositions;” U.S. Pat. No. 5,571,536 for “Formulations of Compounds as Nanoparticulate Dispersions in Digestible Oils or Fatty Acids;” U.S. Pat. No. 5,573,749 for “Nanoparticulate Diagnostic Mixed Carboxylic Anydrides as X-Ray Contrast Agents for Blood Pool and Lymphatic System Imaging;” U.S. Pat. No. 5,573,750 for “Diagnostic Imaging X-Ray Contrast Agents;” U.S. Pat. No. 5,573,783 for “Redispersible Nanoparticulate Film Matrices With Protective Overcoats;” U.S. Pat. No. 5,580,579 for “Site-specific Adhesion Within the GI Tract Using Nanoparticles Stabilized by High Molecular Weight, Linear Poly(ethylene Oxide) Polymers;” U.S. Pat. No. 5,585,108 for “Formulations of Oral Gastrointestinal Therapeutic Agents in Combination with Pharmaceutically Acceptable Clays;” U.S. Pat. No. 5,587,143 for “Butylene Oxide-Ethylene Oxide Block Copolymers Surfactants as Stabilizer Coatings for Nanoparticulate Compositions;” U.S. Pat. No. 5,591,456 for “Milled Naproxen with Hydroxypropyl Cellulose as Dispersion Stabilizer;” U.S. Pat. No. 5,593,657 for “Novel Barium Salt Formulations Stabilized by Non-ionic and Anionic Stabilizers;” U.S. Pat. No. 5,622,938 for “Sugar Based Surfactant for Nanocrystals;” U.S. Pat. No. 5,628,981 for “Improved Formulations of Oral Gastrointestinal Diagnostic X-Ray Contrast Agents and Oral Gastrointestinal Therapeutic Agents;” U.S. Pat. No. 5,643,552 for “Nanoparticulate Diagnostic Mixed Carbonic Anhydrides as X-Ray Contrast Agents for Blood Pool and Lymphatic System Imaging;” U.S. Pat. No. 5,718,388 for “Continuous Method of Grinding Pharmaceutical Substances;” U.S. Pat. No. 5,718,919 for “Nanoparticles Containing the R(−)Enantiomer of Ibuprofen;” U.S. Pat. No. 5,747,001 for “Aerosols Containing Beclomethasone Nanoparticle Dispersions;” U.S. Pat. No. 5,834,025 for “Reduction of Intravenously Administered Nanoparticulate Formulation Induced Adverse Physiological Reactions;” U.S. Pat. No. 6,045,829 “Nanocrystalline Formulations of Human Immunodeficiency Virus (HIV) Protease Inhibitors Using Cellulosic Surface Stabilizers;” U.S. Pat. No. 6,068,858 for “Methods of Making Nanocrystalline Formulations of Human Immunodeficiency Virus (HIV) Protease Inhibitors Using Cellulosic Surface Stabilizers;” U.S. Pat. No. 6,153,225 for “Injectable Formulations of Nanoparticulate Naproxen;” U.S. Pat. No. 6,165,506 for “New Solid Dose Form of Nanoparticulate Naproxen;” U.S. Pat. No. 6,221,400 for “Methods of Treating Mammals Using Nanocrystalline Formulations of Human Innunodeficiency Virus (HIV) Protease Inhibitors;” U.S. Pat. No. 6,264,922 for “Nebulized Aerosols Containing Nanoparticle Dispersions;” U.S. Pat. No. 6,267,989 for “Methods for Preventing Crystal Growth and Particle Aggregation in Nanoparticle Compositions;” U.S. Pat. No. 6,270,806 for “Use of PEG-Derivatized Lipids as Surface Stabilizers for Nanoparticulate Compositions;” U.S. Pat. No. 6,316,029 for “Rapidly Disintegrating Solid Oral Dosage Form,” U.S. Pat. No. 6,375,986 for “Solid Dose Nanoparticulate Compositions Comprising a Synergistic Combination of a Polymeric Surface Stabilizer and Dioctyl Sodium Sulfosuccinate,” U.S. Pat. No. 6,428,814 for “Bioadhesive Nanoparticulate Compositions Having Cationic Surface Stabilizers;” U.S. Pat. No. 6,431,478 for “Small Scale Mill;” and U.S. Pat. No. 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 No. 20020012675 A1, published on Jan. 31, 2002, for “Controlled Release Nanoparticulate Compositions,” describes nanoparticulate compositions, and is specifically incorporated by reference.
  • Amorphous small particle compositions are described, for example, in U.S. Pat. No. 4,783,484 for “Particulate Composition and Use Thereof as Antimicrobial Agent;” U.S. Pat. No. 4,826,689 for “Method for Making Uniformly Sized Particles from Water-Insoluble Organic Compounds;” U.S. Pat. No. 4,997,454 for “Method for Making Uniformly-Sized Particles From Insoluble Compounds;” U.S. Pat. No. 5,741,522 for “Ultrasmall, Non-aggregated Porous Particles of Uniform Size for Entrapping Gas Bubbles Within and Methods;” and U.S. Pat. No. 5,776,496, for “Ultrasmall Porous Particles for Enhancing Ultrasound Back Scatter.”
  • B. Background Regarding Megestrol
  • Megestrol acetate, also known as 17α-acetyloxy-6-methylpregna-4,6-diene-3,20-dione, is a synthetic progestin with progestational effects similar to those of progesterone. It is used in abortion, endometriosis, and menstrual disorders. It is also used in a variety of situations including treatment of breast cancer, contraception, and hormone replacement therapy in post-menopausal women. Megestrol acetate is also frequently prescribed as an appetite enhancer for patients in a wasting state, such as HIV wasting, cancer wasting, or anorexia. In combination with ethynyl estradiol it acts as an oral contraceptive. It is also administered to subjects after castration.
  • Megestrol acetate is marketed by Par Pharmaceuticals, Inc. and under the brand name Megace® by Bristol Myers Squibb Co. Typical commercial formulations are relatively large volume. For example, Par Pharmaceuticals, Inc. megestrol acetate oral suspension contains 40 mg of micronized megestrol acetate per ml, and the package insert recommends an initial adult dosage of megestrol acetate oral suspension of 800 mg/day (20 mL/day). The commercial formulations of megestrol acetate are highly viscous suspensions, which have a relatively long residence time in the mouth and any tubing. Highly viscous substances are not well accepted by patient populations, particularly patients suffering wasting and those that are intubated.
  • U.S. Pat. No. 6,028,065 for “Flocculated Suspension of Megestrol Acetate,” assigned to Pharmaceutical Resources, Inc. (Spring Valley, N.Y.), describes oral pharmaceutical micronized megestrol acetate compositions in the form of a stable flocculated suspension in water. The compositions comprise at least one compound selected from the group consisting of polyethylene glycol, propylene glycol, glycerol, and sorbitol; and a surfactant, wherein polysorbate and polyethylene glycol are not simultaneously present. U.S. Pat. No. 6,268,356, also for “Flocculated Suspension of Megestrol Acetate,” and assigned to Pharmaceutical Resources, Inc., describes methods of treating a neoplastic condition comprising administering the composition of U.S. Pat. No. 6,028,065.
  • Another company that has developed a megestrol formulation is Eurand (Milan, Italy). Eurand's formulation is a modified form of megestrol acetate having increased bioavailability. Eurand structurally modifies poorly soluble drugs to increase their bioavailability. See www.eurand.com. For megestrol acetate, Eurand uses its' “Biorise” process, in which a New Physical Entity (NPE) is created by physically breaking down megestrol's crystal lattice. This results in drug nanocrystals and/or amorphous drug, which are then stabilized with biologically inert carriers. Eurand uses three types of carriers: swellable microparticles, composite swellable microparticles, and cyclodextrins. See e.g., http://www.eurand.com/page.php?id=39. Such a delivery system can be undesirable, as “breaking down” an active agent's crystalline structure can modify the activity of the active agent. A drug delivery system which does not alter the structure of the active agent is preferable.
  • Among the progestins, megestrol acetate is one of the few that can be administered orally because of its reduced first-pass (hepatic) metabolism, compared to the parent hormone. In addition, it is claimed to be superior to 19-nor compounds as an antifertility agent because it has less effect on the endometrium and vagina. See Stedman's Medical Dictionary, 25th Ed., page 935 (Williams & Wilkins, MD 1990).
  • There is a need in the art for megestrol formulations which exhibit increased bioavailability, less variability, and/or less viscosity as compared to conventional microparticulate megestrol formulations. The present invention satisfies these needs.
  • SUMMARY OF THE INVENTION
  • The invention relates to nanoparticulate megestrol compositions. The compositions comprise megestrol and preferably at least one surface stabilizer associated with the surface of the megestrol particles. The nanoparticulate megestrol particles have an effective average particle size of less than about 2000 nm.
  • Another aspect of the invention is directed to pharmaceutical compositions comprising a nanoparticulate megestrol composition of the invention. The pharmaceutical compositions preferably comprise megestrol, at least one surface stabilizer, and a pharmaceutically acceptable carrier, as well as any desired excipients.
  • This invention further discloses a method of making a nanoparticulate megestrol composition according to the invention. Such a method comprises contacting megestrol particles and at least one surface stabilizer for a time and under conditions sufficient to provide a nanoparticulate megestrol composition. The one or more surface stabilizers can be contacted with megestrol either before, during, or after size reduction of the megestrol.
  • The present invention is also directed to methods of treatment using the nanoparticulate compositions of the invention for conditions such as endometriosis, dysmenorrhea, hirsutism, uterine bleeding, neoplastic diseases, methods of appetite enhancement, contraception, hormone replacement therapy, and treating patients following castration. Such methods comprises administering to a subject a therapeutically effective amount of a nanoparticulate megestrol composition according to the invention.
  • Finally, the present invention is directed to megestrol acetate compositions with improved physical (viscosity) and pharmacokinetic profiles (such as less variability) over traditional forms of megestrol acetate.
  • 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.
  • BRIEF DESCRIPTION OF THE DRAWINGS
  • FIG. 1: Illustrates viscosity in units of mPa s as a function of concentration. Circles indicate the experimental values and the line illustrates the expected trend;
  • FIG. 2: Illustrates viscosity in units of Pa s as a function of shear rate for two commercial samples, Bristol Myers Squibb and Par Pharmaceuticals, both at an active concentration of 40 mg/mL; and
  • FIG. 3: Shows a photograph of, from left to right, a nanoparticulate dispersion of megestrol acetate, a commercial sample of megestrol acetate marketed by Par Pharmaceuticals, and a commercial sample of megestrol acetate marketed by Bristol Myers Squibb.
  • FIG. 4: The figure graphically shows the comparative bioavailability (via plasma concentration (ng/mL)) of several nanoparticulate megestrol compositions (575 mg/5 ml, 625 mg/5 ml and 675 mg/5 ml) versus a conventional megestrol acetate marketed by Bristol Myers Squibb.
  • FIG. 5: The figure graphically shows on a natural log scale the comparative bioavailability (via plasma concentration (ng/mL)) of several nanoparticulate megestrol compositions (575 mg/5 ml, 625 mg/5 ml and 675 mg/5 ml) versus a conventional megestrol acetate marketed by Bristol Myers Squibb.
  • DETAILED DESCRIPTION OF THE INVENTION
  • The present invention is directed to nanoparticulate compositions comprising megestrol particles having an effective average particle size of less than about 2 microns. The compositions comprise megestrol and preferably at least one surface stabilizer associated with the surface of the drug.
  • As taught in the '684 patent, not every combination of surface stabilizer and active agent will result in a stable nanoparticulate composition. It was surprisingly discovered that stable nanoparticulate megestrol compositions can be made.
  • For example, nanoparticulate megestrol compositions with hydroxypropyl methylcellulose (HPMC) and sodium lauryl sulfate (SLS) as surface stabilizers remained stable in an electrolyte solution mimicking the physiological pH of the stomach. Nanoparticulate megestrol compositions comprising HPMC and SLS are stable for several weeks at temperatures up to 40° C. with only minimal particle size growth. In addition, nanoparticulate megestrol compositions with hydroxypropylcellulose (HPC) and dioctyl sodium sulfosuccinate (DOSS) as surface stabilizers, HPMC and DOSS as surface stabilizers, polyvinylpyrrolidone (PVP) and DOSS as surface stabilizers, and Plasdone® S630 and DOSS as surface stabilizers were stable in electrolyte fluids and exhibited acceptable physical stability at 5° C. for 4 weeks. (Plasdone® S630 (ISP) is a random copolymer of vinyl acetate and vinyl pyrrolidone.) Moreover, the nanoparticulate megestrol/HPMC/SLS and nanoparticulate megestrol/HPMC/DOSS compositions also exhibited acceptable physical stability at 25° C. and 40° C. for 4 weeks.
  • Advantages of the nanoparticulate megestrol compositions of the invention include, but are not limited to: (1) low viscosity liquid nanoparticulate megestrol dosage forms; (2) for liquid nanoparticulate megestrol compositions having a low viscosity—better subject compliance due to the perception of a lighter formulation which is easier to consume and digest; (3) for liquid nanoparticulate megestrol compositions having a low viscosity—ease of dispensing because one can use a cup or a syringe; (4) faster onset of action; (5) smaller doses of megestrol required to obtain the same pharmacological effect as compared to conventional microcrystalline forms of megestrol; (6) increased bioavailability as compared to conventional microcrystalline forms of megestrol; (7) substantially similar pharmacokinetic profiles of the nanoparticulate megestrol compositions when administered in the fed versus the fasted state; (8) bioequivalency of the nanoparticulate megestrol compositions when administered in the fed versus the fasted state; (9) redispersibility of the nanoparticulate megestrol particles present in the compositions of the invention following administration; (10) bioadhesive nanoparticulate megestrol compositions; (11) improved pharmacokinetic profiles, such as more rapid megestrol absorption, greater megestrol absorption, and longer megestrol dose retention in the blood following administration; (12) the nanoparticulate megestrol compositions can be used in conjunction with other active agents; (13) the nanoparticulate megestrol compositions preferably exhibit an increased rate of dissolution as compared to conventional microcrystalline forms of megestrol; (14) improved performance characteristics for oral, intravenous, subcutaneous, or intramuscular injection, such as higher dose loading and smaller tablet or liquid dose volumes; (15) the nanoparticulate megestrol compositions are suitable for parenteral administration; (16) the nanoparticulate megestrol compositions can be sterile filtered; and (17) the nanoparticulate megestrol compositions do not require organic solvents or pH extremes.
  • The present invention is described herein using several definitions, as set forth below and throughout the application.
  • “About” will be understood by persons of ordinary skill in the art and will vary to some extent on the context in which the term is used. If there are uses of the term which are not clear to persons of ordinary skill in the art given the context in which it is used, “about” will mean up to plus or minus 10% of the particular term.
  • As used herein with reference to stable drug particles, “stable” means that the megestrol particles do not appreciably flocculate or agglomerate due to interparticle attractive forces or otherwise increase in particle size.
  • “Conventional active agents or drugs” refers to non-nanoparticulate compositions of active agents or solubilized active agents or drugs. Non-nanoparticulate active agents have an effective average particle size of greater than about 2 microns.
  • A. Preferred Characteristics of the Nanoparticulate Megestrol Compositions of the Invention
  • 1. Low Viscosity
  • Typical commercial formulations of megestrol, such as Megace®, are relatively large volume, highly viscous substances that are not well accepted by patient populations, particularly subjects suffering from wasting. “Wasting” is a condition in which a subject finds it difficult to eat because, for example, food makes the subject nauseous. A highly viscous medicine is not compatible with treating such a condition, as frequently the highly viscous substance can cause additional nausea.
  • Moreover, viscous solutions can be problematic in parenteral administration because these solutions require a slow syringe push and can stick to tubing. In addition, conventional formulations of poorly water-soluble active agents, such as megestrol, tend to be unsafe for intravenous administration techniques, which are used primarily in conjunction with highly water-soluble substances.
  • Liquid dosage forms of the nanoparticulate megestrol compositions of the invention provide significant advantages over conventional liquid megestrol dosage forms. The low viscosity and silky texture of liquid dosage forms of the nanoparticulate megestrol compositions of the invention results in advantages in both preparation and use. These advantages include, for example: (1) better subject compliance due to the perception of a lighter formulation which is easier to consume and digest; (2) ease of dispensing because one can use a cup or a syringe; (3) potential for formulating a higher concentration of megestrol resulting in a smaller dosage volume and thus less volume for the subject to consume; and (4) easier overall formulation concerns.
  • Liquid megestrol dosage forms which are easier to consume are especially important when considering juvenile patients, terminally ill patients, and patients suffering from gastrointestinal tract dysfunction or other conditions where nausea and vomiting are symptoms. For example, patients suffering from cancer or AIDS-related complications are commonly hypermetabolic and, at various stages of disease, exhibit gastrointestinal dysfunction. Additionally, drugs used to treat these conditions often cause nausea and vomiting. Viscous or gritty formulations, and those that require a relatively large dosage volume, are not well tolerated by patient populations suffering from wasting associated with these diseases because the formulations can exacerbate nausea and encourage vomiting.
  • The viscosities of liquid dosage forms of nanoparticulate megestrol according to the invention are preferably less than about 1/200, less than about 1/175, less than about 1/150, less than about 1/125, less than about 1/100, less than about 1/75, less than about 1/50, or less than about 1/25 of existing commercial liquid oral megestrol acetate compositions, e.g. Megace®, at about the same concentration per ml of megestrol.
  • Typically the viscosity of liquid nanoparticulate megestrol dosage forms of the invention is from about 175 mPa s to about 1 mPa s, from about 150 mPa s to about 1 mPa, from about 125 mPa s to about 1 mPa s, from about 100 mPa s to about 1 mPa s, from about 75 mPa s to about 1 mPa s, from about 50 mPa s to about 1 mPa s, from about 25 mPa s to about 1 mPa s, from about 15 mPa s to about 1 mPa s, or from about 5 mPa s to about 1 mPa s. Such a viscosity is much more attractive for subject consumption and may lead to better overall subject compliance.
  • Viscosity is concentration and temperature dependent. Typically, a higher concentration results in a higher viscosity, while a higher temperature results in a lower viscosity. Viscosity as defined above refers to measurements taken at about 20° C. (The viscosity of water at 20° C. is 1 mPa s.) The invention encompasses equivalent viscosities measured at different temperatures.
  • A viscosity of 1.5 mPa s for a nanoparticulate megestrol dispersion having a concentration of 30 mg/mL, measured at 20° C., was obtained by the inventors. An equivalent viscosity at 4% active agent concentration would be 1.7 mPa s. Higher and lower viscosities can be obtained by varying the temperature and concentration of megestrol.
  • Another important aspect of the invention is that the nanoparticulate megestrol compositions of the invention are not turbid. “Turbid,” as used herein refers to the property of particulate matter that can be seen with the naked eye or that which can be felt as “gritty.” The nanoparticulate megestrol compositions of the invention can be poured out of or extracted from a container as easily as water, whereas a conventional standard commercial (i.e., non-nanoparticulate or solubilized) megestrol liquid dosage form exhibits notably more “sluggish” characteristics.
  • The liquid formulations of this invention can be formulated for dosages in any volume but preferably equivalent or smaller volumes than existing commercial formulations.
  • 2. Fast Onset of Activity
  • The use of conventional formulations of megestrol is not ideal due to delayed onset of action. In contrast, the nanoparticulate megestrol compositions of the invention exhibit faster therapeutic effects.
  • Preferably, following administration the nanoparticulate megestrol compositions of the invention have a Tmax of less than about 5 hours, less than about 4.5 hours, less than about 4 hours, less than about 3.5 hours, less than about 3 hours, less than about 2.75 hours, less than about 2.5 hours, less than about 2.25 hours, less than about 2 hours, less than about 1.75 hours, less than about 1.5 hours, less than about 1.25 hours, less than about 1.0 hours, less than about 50 minutes, less than about 40 minutes, less than about 30 minutes, less than about 25 minutes, less than about 20 minutes, less than about 15 minutes, or less than about 10 minutes.
  • 3. Increased Bioavailability
  • The nanoparticulate megestrol compositions of the invention preferably exhibit increased bioavailability and require smaller doses as compared to prior conventional megestrol compositions administered at the same dose.
  • Any drug, including megestrol, can have adverse side effects. Thus, lower doses of megestrol which can achieve the same or better therapeutic effects as those observed with larger doses of conventional megestrol compositions are desired. Such lower doses can be realized with the nanoparticulate megestrol compositions of the invention because the greater bioavailability observed with the nanoparticulate megestrol compositions as compared to conventional drug formulations means that smaller doses of drug are required to obtain the desired therapeutic effect. Specifically, a once a day dose of about 375 mg/5 mL (75 mg/mL) of a nanoparticulate megestrol acetate composition is considered equivalent to an 800 mg dose of Megace®.
  • Administration of nanoparticulate megestrol formulations of the present invention can exhibit bioavailability, as determined by AUC0-t, in an amount of about 3000 ng hr/ml to about 15,000 ng hr/ml, wherein Cmax is about 300 ng/ml to about 1400 ng/ml, 1500 ng/ml, 1600 ng/ml, 1645 ng/ml or 1700 ng/ml in a fed human subject and AUC0-t in an amount of about 2000 ng hr/ml to about 9000 ng hr/ml, wherein Cmax is about 300 ng/ml to about 2000 ng/ml in a fasted human subject. Preferably, nanoparticulate megestrol formulations of the present invention exhibit comparable bioavailability in a range of between about 75 and about 130%, more preferably between about 80% and about 125%, of the specified therapeutic parameter (e.g., AUC0-t or Cmax).
  • 4. The Pharmacokinetic Profiles of the Nanoparticulate Megestrol Compositions of the Invention are not Substantially Affected by the Fed or Fasted State of the Subject Ingesting the Compositions
  • The invention encompasses nanoparticulate megestrol compositions wherein the pharmacokinetic profile of the megestrol is not substantially affected by the fed or fasted state of a subject ingesting the composition. This means that there is no substantial difference in the quantity of megestrol absorbed or the rate of megestrol absorption when the nanoparticulate megestrol compositions are administered in the fed versus the fasted state. Thus, the invention encompasses nanoparticulate megestrol compositions that can substantially eliminate the effect of food on the pharmacokinetics of megestrol.
  • The difference in absorption of the nanoparticulate megestrol composition of the invention, when administered in the fed versus the fasted state, is less than about 35%, less than about 30%, less than about 25%, less than about 20%, less than about 15%, less than about 10%, less than about 5%, or less than about 3%. This is an especially important feature in treating patients with difficulty in maintaining a fed state.
  • In addition, preferably the difference in the rate of absorption (i.e., Tmax) of the nanoparticulate megestrol compositions of the invention, when administered in the fed versus the fasted state, is less than about 100%, less than about 90%, less than about 80%, less than about 70%, less than about 60%, less than about 50%, less than about 40%, less than about 30%, less than about 20%, less than about 15%, less than about 10%, less than about 5%, less than about 3%, or essentially no difference.
  • Benefits of a dosage form which substantially eliminates the effect of food include an increase in subject convenience, thereby increasing subject compliance, as the subject does not need to ensure that they are taking a dose either with or without food.
  • 5. Redispersibility Profiles of the Nanoparticulate Megestrol Compositions of the Invention
  • An additional feature of the nanoparticulate megestrol compositions of the invention is that the compositions redisperse such that the effective average particle size of the redispersed megestrol particles is less than about 2 microns. This is significant, as if upon administration the nanoparticulate megestrol particles present in the compositions of the invention did not redisperse to a substantially nanoparticulate particle size, then the dosage form may lose the benefits afforded by formulating megestrol into a nanoparticulate particle size.
  • This is because nanoparticulate megestrol compositions benefit from the small particle size of megestrol; if the nanoparticulate megestrol particles do not redisperse into the small particle sizes upon administration, then “clumps” or agglomerated megestrol particles are formed. With the formation of such agglomerated particles, the bioavailability of the dosage form may fall.
  • Preferably, the redispersed megestrol particles of the invention have an effective average particle size, by weight, of less than about 2 microns, less than about 1900 nm, less than about 1800 nm, less than about 1700 nm, less than about 1600 nm, less than about 1500 nm, less than about 1400 nm, less than about 1300 nm, less than about 1200 nm, less than about 1100 nm, less than about 1000 nm, less than about 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, as measured by light-scattering methods, microscopy, or other appropriate methods.
  • Moreover, the nanoparticulate megestrol compositions of the invention exhibit dramatic redispersion of the nanoparticulate megestrol particles upon administration to a mammal, such as a human or animal, as demonstrated by reconstitution in a biorelevant aqueous media. Such biorelevant aqueous media can be any aqueous media that exhibit the desired ionic strength and pH, which form the basis for the biorelevance of the media. The desired pH and ionic strength are those that are representative of physiological conditions found in the human body. Such biorelevant aqueous media can be, for example, aqueous electrolyte solutions or aqueous solutions of any salt, acid, or base, or a combination thereof, which exhibit the desired pH and ionic strength.
  • Biorelevant pH is well known in the art. For example, in the stomach, the pH ranges from slightly less than 2 (but typically greater than 1) up to 4 or 5. In the small intestine the pH can range from 4 to 6, and in the colon it can range from 6 to 8. Biorelevant ionic strength is also well known in the art. Fasted state gastric fluid has an ionic strength of about 0.1M while fasted state intestinal fluid has an ionic strength of about 0.14. See e.g., Lindahl et al., “Characterization of Fluids from the Stomach and Proximal Jejunum in Men and Women,” Pharm. Res., 14 (4): 497-502 (1997).
  • It is believed that the pH and ionic strength of the test solution is more critical than the specific chemical content. Accordingly, appropriate pH and ionic strength values can be obtained through numerous combinations of strong acids, strong bases, salts, single or multiple conjugate acid-base pairs (i.e., weak acids and corresponding salts of that acid), monoprotic and polyprotic electrolytes, etc.
  • Representative electrolyte solutions can be, but are not limited to, HCl solutions, ranging in concentration from about 0.001 to about 0.1 M, and NaCl solutions, ranging in concentration from about 0.001 to about 0.1 M, and mixtures thereof. For example, electrolyte solutions can be, but are not limited to, about 0.1 M HCl or less, about 0.01 M HCl or less, about 0.001 M HCl or less, about 0.1 M NaCl or less, about 0.01 M NaCl or less, about 0.001 M NaCl or less, and mixtures thereof. Of these electrolyte solutions, 0.01 M HCl and/or 0.1 M NaCl, are most representative of fasted human physiological conditions, owing to the pH and ionic strength conditions of the proximal gastrointestinal tract.
  • Electrolyte concentrations of 0.001 M HCl, 0.01 M HCl, and 0.1 M HCl correspond to pH 3, pH 2, and pH 1, respectively. Thus, a 0.01 M HCl solution simulates typical acidic conditions found in the stomach. A solution of 0.1 M NaCl provides a reasonable approximation of the ionic strength conditions found throughout the body, including the gastrointestinal fluids, although concentrations higher than 0.1 M may be employed to simulate fed conditions within the human GI tract.
  • Exemplary solutions of salts, acids, bases or combinations thereof, which exhibit the desired pH and ionic strength, include but are not limited to phosphoric acid/phosphate salts+sodium, potassium and calcium salts of chloride, acetic acid/acetate salts+sodium, potassium and calcium salts of chloride, carbonic acid/bicarbonate salts+sodium, potassium and calcium salts of chloride, and citric acid/citrate salts+sodium, potassium and calcium salts of chloride.
  • 6. Bioadhesive Nanoparticulate Megestrol Compositions
  • Bioadhesive nanoparticulate megestrol compositions of the invention comprise at least one cationic surface stabilizer, which are described in more detail below. Bioadhesive formulations of megestrol exhibit exceptional bioadhesion to biological surfaces, such as mucous.
  • In the case of bioadhesive nanoparticulate megestrol compositions, the term “bioadhesion” is used to describe the adhesion between the nanoparticulate megestrol compositions and a biological substrate (i.e. gastrointestinal mucin, lung tissue, nasal mucosa, etc.). See e.g., U.S. Pat. No. 6,428,814 for “Bioadhesive Nanoparticulate Compositions Having Cationic Surface Stabilizers,” which is specifically incorporated by reference.
  • The bioadhesive megestrol compositions of the invention are useful in any situation in which it is desirable to apply the compositions to a biological surface. The bioadhesive megestrol compositions coat the targeted surface in a continuous and uniform film which is invisible to the naked human eye.
  • A bioadhesive nanoparticulate megestrol composition slows the transit of the composition, and some megestrol particles would also most likely adhere to tissue other than the mucous cells and therefore give a prolonged exposure to megestrol, thereby increasing absorption and the bioavailability of the administered dosage.
  • 7. Pharmacokinetic Profiles of the Nanoparticulate Megestrol Compositions of the Invention
  • The present invention also provides compositions of nanoparticulate megestrol having a desirable pharmacokinetic profile when administered to mammalian subjects. The desirable pharmacokinetic profile of the nanoparticulate megestrol compositions comprise the parameters: (1) that the Tmax of megestrol, when assayed in the plasma of the mammalian subject, is less than about 5 hours; and (2) a Cmax of megestrol is greater than about 30 ng/ml. Preferably, the Tmax parameter of the pharmacokinetic profile is not greater than about 3 hours. Most preferably, the Tmax parameter of the pharmacokinetic profile is not greater than about 2 hours.
  • The desirable pharmacokinetic profile, as used herein, is the pharmacokinetic profile measured after the initial dose of megestrol. For example, in a subject receiving 40 mg of megestrol four times a day, the Tmax and Cmax after the initial dose must be less than about 5 hours and greater than about 30 ng/ml, respectively. The compositions can be formulated in any way as described below.
  • Current formulations of megestrol include oral suspensions and tablets. According to the package insert of Megace®, the pharmacokinetic profile of the oral suspension contains parameters such that the median Tmax is 5 hours and the mean Cmax is 753 ng/ml. Further, the Tmax and Cmax for the Megace® 40 mg tablet, after the initial dose, is 2.2 hours and 27.6 ng/ml, respectively. Physicians Desk Reference, 55th Ed., 2001. The nanoparticulate megestrol compositions of the invention simultaneously improve upon at least the Tmax and Cmax parameters of the pharmacokinetic profile of megestrol.
  • In one embodiment, a threshold blood plasma concentration of megestrol of about 700 ng/ml is attained in less than about 5 hours after administration of the formulation, and preferably not greater than about 3 hours.
  • Preferably, the Tmax of an administered dose of a nanoparticulate megestrol composition is less than that of a conventional standard commercial non-nanoparticulate megestrol composition, administered at the same dosage. In addition, preferably the Cmax of a nanoparticulate megestrol composition is greater than the Cmax of a conventional standard commercial non-nanoparticulate megestrol composition, administered at the same dosage.
  • A preferred nanoparticulate megestrol composition of the invention exhibits in comparative pharmacokinetic testing with a standard commercial formulation of megestrol, such as Megace® oral suspension or tablet from Bristol Myers Squibb, a Tmax which is less than about 100%, less than about 90%, less than about 80%, less than about 70%, less than about 60%, less than about 50%, less than about 40%, less than about 30%, less than about 25%, less than about 20%, less than about 15%, or less than about 10% of the Tmax exhibited by the standard commercial formulation of megestrol.
  • A preferred nanoparticulate megestrol composition of the invention exhibits in comparative pharmacokinetic testing with a standard commercial formulation of megestrol, such as Megace® oral suspension or tablet from Bristol Myers Squibb, a Cmax which is greater than about 5%, greater than about 10%, greater than about 15%, greater than about 20%, greater than about 30%, greater than about 40%, greater than about 50%, greater than about 60%, greater than about 70%, greater than about 80%, greater than about 90%, greater than about 100%, greater than about 110%, greater than about 120%, greater than about 130%, greater than about 140%, greater than about 150%, greater than about 200%, greater than about 500% or greater than about 800% than the Cmax exhibited by the standard commercial formulation of megestrol.
  • There is no critical upper limit of blood plasma concentration so long as the dosage amounts set out below are not significantly exceeded. A suitable dose of megestrol, administered according to the method of the invention, is typically in the range of about 1 mg/day to about 1000 mg/day, or from about 40 mg/day to about 800 mg/day. In one embodiment, a nanoparticulate megestrol composition is administered at a dose of 575 mg/day. In other embodiments, the nanoparticulate megestrol composition is administered at doses of 625 mg/day or 675 mg/day. Preferably, the therapeutically effective amount of the nanoparticulate megestrol compositions of the invention is about ⅙, ⅕, ¼, ⅓, ½, ⅔, ¾ or ⅚ of the therapeutically effective amount of existing commercial megestrol formulations.
  • Any standard pharmacokinetic protocol can be used to determine blood plasma concentration profile in humans following administration of a nanoparticulate megestrol composition, and thereby establish whether that composition meets the pharmacokinetic criteria set-out-herein. For example, a randomized single-dose crossover study can be performed using a group of healthy adult human subjects. The number of subjects should be sufficient to provide adequate control of variation in a statistical analysis, and is typically about 10 or greater, although for certain purposes a smaller group can suffice. Each subject receives by oral administration at time zero a single dose (e.g., 300 mg) of a test formulation of megestrol, normally at around 8 am following an overnight fast. The subjects continue to fast and remain in an upright position for about 4 hours after administration of the megestrol formulation. Blood samples are collected from each subject prior to administration (e.g., 15 minutes) and at several intervals after administration. For the present purpose it is preferred to take several samples within the first hour, and to sample less frequently thereafter. Illustratively, blood samples could be collected at 15, 30, 45, 60, and 90 minutes after administration, then every hour from 2 to 10 hours after administration. Additional blood samples may also be taken later, for example at 12 and 24 hours after administration. If the same subjects are to be used for study of a second test formulation, a period of at least 7 days should elapse before administration of the second formulation. Plasma is separated from the blood samples by centrifugation and the separated plasma is analyzed for megestrol by a validated high performance liquid chromatography (HPLC) procedure, such as for example Garver et al., J. Pharm. Sci. 74(6):664-667 (1985), the entirety of which is hereby incorporated by reference. Plasma concentrations of megestrol referenced herein are intended to mean total megestrol concentrations including both free and bound megestrol.
  • Any formulation giving the desired pharmacokinetic profile is suitable for administration according to the present methods. Exemplary types of formulations giving such profiles are liquid dispersions and solid dose forms of nanoparticulate megestrol. Dispersions of megestrol have proven to be stable at temperatures up to 50° C. If the liquid dispersion medium is one in which the nanoparticulate megestrol has very low solubility, the nanoparticulate megestrol particles are present as suspended particles. The smaller the megestrol particles, the higher the probability that the formulation will exhibit the desired pharmacokinetic profile.
  • 8. Combination Pharmacokinetic Profile Compositions
  • In yet another embodiment of the invention, a first nanoparticulate megestrol composition providing a desired pharmacokinetic profile is co-administered, sequentially administered, or combined with at least one other megestrol composition that generates a desired different pharmacokinetic profile. More than two megestrol compositions can be co-administered, sequentially administered, or combined. While the first megestrol composition has a nanoparticulate particle size, the additional one or more megestrol compositions can be nanoparticulate, solubilized, or have a conventional microparticulate particle size.
  • For example, a first megestrol composition can have a nanoparticulate particle size, conferring a short Tmax and typically a higher Cmax. This first megestrol composition can be combined, co-administered, or sequentially administered with a second composition comprising: (1) megestrol having a larger (but still nanoparticulate as defined herein) particle size, and therefore exhibiting slower absorption, a longer Tmax and typically a lower Cmax; or (2) a microparticulate or solubilized megestrol composition, exhibiting a longer Tmax, and typically a lower Cmax.
  • The second, third, fourth, etc., megestrol compositions can differ from the first, and from each other, for example: (1) in the effective average particle sizes of megestrol; or (2) in the dosage of megestrol. Such a combination composition can reduce the dose frequency required.
  • If the second megestrol composition has a nanoparticulate particle size, then preferably the megestrol particles of the second composition have at least one surface stabilizer associated with the surface of the drug particles. The one or more surface stabilizers can be the same as or different from the surface stabilizer(s) present in the first megestrol composition.
  • Preferably where co-administration of a “fast-acting” formulation and a “longer-lasting” formulation is desired, the two formulations are combined within a single composition, for example a dual-release composition.
  • 9. Combination Active Agent Compositions
  • The invention encompasses the nanoparticulate megestrol compositions of the invention formulated or co-administered with one or more non-megestrol active agents, which are either conventional (solubilized or microparticulate) or nanoparticulate. Methods of using such combination compositions are also encompassed by the invention. The non-megestrol active agents can be present in a crystalline phase, an amorphous phase, a semi-crystalline phase, a semi-amorphous phase, or a mixture thereof.
  • The compound to be administered in combination with a nanoparticulate megestrol composition of the invention can be formulated separately from the nanoparticulate megestrol composition or co-formulated with the nanoparticulate megestrol composition. Where a nanoparticulate megestrol composition is co-formulated with a second active agent, the second active agent can be formulated in any suitable manner, such as immediate-release, rapid-onset, sustained-release, or dual-release form.
  • If the non-megestrol active agent has a nanoparticulate particle size i.e., a particle size of less than about 2 microns, then preferably it will have one or more surface stabilizers associated with the surface of the active agent. In addition, if the active agent has a nanoparticulate particle size, then it is preferably poorly soluble and dispersible in at least one liquid dispersion media. By “poorly soluble” it is meant that the active agent has a solubility in a liquid dispersion media 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. Useful liquid dispersion medias include, but are not limited to, water, aqueous salt solutions, safflower oil, and solvents such as ethanol, t-butanol, hexane, and glycol.
  • Such non-megestrol active agents can be, for example, a therapeutic agent. A therapeutic agent can be a pharmaceutical agent, including biologics. The active agent can be selected from a variety of known classes of drugs, including, for example, amino acids, proteins, peptides, nucleotides, anti-obesity drugs, central nervous system stimulants, carotenoids, corticosteroids, elastase inhibitors, anti-fungals, oncology therapies, anti-emetics, analgesics, cardiovascular agents, anti-inflammatory agents, such as NSAIDs and COX-2 inhibitors, anthelmintics, anti-arrhythmic agents, antibiotics (including penicillins), anticoagulants, antidepressants, antidiabetic agents, antiepileptics, antihistamines, antihypertensive agents, antimuscarinic agents, antimycobacterial agents, antineoplastic agents, immunosuppressants, antithyroid agents, antiviral agents, anxiolytics, sedatives (hypnotics and neuroleptics), astringents, alpha-adrenergic receptor blocking agents, beta-adrenoceptor blocking agents, blood products and substitutes, cardiac inotropic agents, contrast media, corticosteroids, cough suppressants (expectorants and mucolytics), diagnostic agents, diagnostic imaging agents, diuretics, dopaminergics (antiparkinsonian agents), haemostatics, immunological agents, lipid regulating agents, muscle relaxants, parasympathomimetics, parathyroid calcitonin and biphosphonates, prostaglandins, radio-pharmaceuticals, sex hormones (including steroids), anti-allergic agents, stimulants and anoretics, sympathomimetics, thyroid agents, vasodilators, and xanthines.
  • A description of these classes of active agents and a listing of species within each class can be found in Martindale's The Extra Pharmacopoeia, 31st Edition (The Pharmaceutical Press, London, 1996), specifically incorporated by reference. The active agents are commercially available and/or can be prepared by techniques known in the art.
  • Exemplary nutraceuticals and dietary supplements are disclosed, for example, in Roberts et al., Nutraceuticals: The Complete Encyclopedia of Supplements, Herbs, Vitamins, and Healing Foods (American Nutraceutical Association, 2001), which is specifically incorporated by reference. Dietary supplements and nutraceuticals are also disclosed in Physicians' Desk Reference for Nutritional Supplements, 1 st Ed. (2001) and The Physicians' Desk Referencefor Herbal Medicines, 1st Ed. (2001), both of which are also incorporated by reference. A nutraceutical or dietary supplement, also known as a phytochemical or functional food, is generally any one of a class of dietary supplements, vitamins, minerals, herbs, or healing foods that have medical or pharmaceutical effects on the body.
  • Exemplary nutraceuticals or dietary supplements include, but are not limited to, lutein, folic acid, fatty acids (e.g., DHA and ARA), fruit and vegetable extracts, vitamin and mineral supplements, phosphatidylserine, lipoic acid, melatonin, glucosamine/chondroitin, Aloe Vera, Guggul, glutamine, amino acids (e.g., arginine, iso-leucine, leucine, lysine, methionine, phenylanine, threonine, tryptophan, and valine), green tea, lycopene, whole foods, food additives, herbs, phytonutrients, antioxidants, flavonoid constituents of fruits, evening primrose oil, flax seeds, fish and marine animal oils, and probiotics. Nutraceuticals and dietary supplements also include bio-engineered foods genetically engineered to have a desired property, also known as “pharmafoods.”
  • 10. Sterile Filtered Nanoparticulate Megestrol Compositions
  • The nanoparticulate megestrol compositions of the invention can be sterile filtered. This obviates the need for heat sterilization, which can harm or degrade megestrol, as well as result in crystal growth and particle aggregation.
  • Sterile filtration can be difficult because of the required small particle size of the composition. Filtration is an effective method for sterilizing homogeneous solutions when the membrane filter pore size is less than or equal to about 0.2 microns (200 nm) because a 0.2 micron filter is sufficient to remove essentially all bacteria. Sterile filtration is normally not used to sterilize conventional suspensions of micron-sized megestrol because the megestrol particles are too large to pass through the membrane pores.
  • A sterile nanoparticulate megestrol dosage form is particularly useful in treating immunocompromised patients, infants or juvenile patients, and the elderly, as these patient groups are the most susceptible to infection caused by a non-sterile liquid dosage form.
  • Because the nanoparticulate megestrol compositions of the invention can be sterile filtered, and because the compositions can have a very small megestrol effective average particle size, the compositions are suitable for parenteral administration.
  • 11. Miscellaneous Benefits of the Nanoparticulate Megestrol Compositions of the Invention
  • The nanoparticulate megestrol compositions preferably exhibit an increased rate of dissolution as compared to conventional microcrystalline forms of megestrol. In addition, the compositions of the invention exhibit improved performance characteristics for oral, intravenous, subcutaneous, or intramuscular injection, such as higher dose loading and smaller tablet or liquid dose volumes. Moreover, the nanoparticulate megestrol compositions of the invention do not require organic solvents or pH extremes.
  • Another benefit of the nanoparticulate megestrol compositions of the invention is that is was surprisingly discovered that upon administration, nanoparticulate compositions of megestrol acetate reach therapeutic blood levels within one dose. This is in dramatic contrast to the current commercially available megestrol acetate composition (Megace® by Bristol Myers Squibb Co.), which requires multiple doses, administered over several days to a week, to build up to a therapeutic level of drug in the blood stream.
  • B. Compositions
  • The invention provides compositions comprising nanoparticulate megestrol particles and preferably at least one surface stabilizer. The one or more surface stabilizers are preferably associated with the surface of the megestrol particles. Surface stabilizers useful herein preferably do not chemically react with the megestrol particles or itself. Individual molecules of the surface stabilizer are essentially free of intermolecular cross-linkages.
  • The present invention also includes nanoparticulate megestrol compositions together with one or more non-toxic physiologically acceptable carriers, adjuvants, or vehicles, collectively referred to as carriers. The compositions can be formulated for parenteral injection (e.g., intravenous, intramuscular, or subcutaneous), oral administration in solid, liquid, or aerosol form, vaginal, nasal, rectal, ocular, local (powders, ointments or drops), buccal, intracisternal, intraperitoneal, or topical administration, and the like.
  • 1. Megestrol Particles
  • As used herein the term megestrol, which is the active ingredient in the composition, is used to mean megestrol, megestrol acetate (17α-acetyloxy-6-methylpregna-4,6-diene-3,20-dione), or a salt thereof. The megestrol particles can be present in a crystalline phase, an amorphous phase, a semi-crystalline phase, a semi-amorphous phase, or a mixture thereof.
  • Megestrol acetate is well known in the art and is readily recognized by one of ordinary skill. Generally, megestrol is used for treating breast cancer, endometrial cancer and, less frequently, prostate cancer. Megestrol is also frequently used as an appetite stimulant for patients in a wasting state, such as HIV wasting, cancer wasting, and anorexia. Megestrol may be used for other indications where progestins are typically used, such as hormone replacement therapy in post-menopausal women and oral contraception. Further, megestrol may be used for ovarian suppression in several conditions such as endometriosis, hirsutism, dysmenorrhea, and uterine bleeding, as well as uterine cancer, cervical cancer, and renal cancer. Megestrol is also used in patients following castration.
  • 2. Surface Stabilizers
  • The choice of a surface stabilizer for megestrol is non-trivial. Accordingly, the present invention is directed to the surprising discovery that nanoparticulate megestrol compositions can be made.
  • Combinations of more than one surface stabilizer can be used in the invention. Preferred surface stabilizers include, but are not limited to, hydroxypropyl methylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, random copolymers of vinyl pyrrolidone and vinyl acetate, sodium lauryl sulfate, dioctylsulfosuccinate or a combination thereof. Preferred primary surface stabilizers include, but are not limited to, hydroxypropyl methylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, random copolymers of vinyl pyrrolidone and vinyl acetate, or a combination thereof. Preferred secondary surface stabilizers include, but are not limited to, sodium lauryl sulfate and dioctylsulfosuccinate.
  • Other surface stabilizers which can be employed in the invention include, but are not limited to, known organic and inorganic pharmaceutical excipients. Such excipients include various polymers, low molecular weight oligomers, natural products, and surfactants. Surface stabilizers include nonionic, cationic, ionic, and zwitterionic surfactants.
  • Representative examples of surface stabilizers include hydroxypropyl methylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, sodium lauryl sulfate, dioctylsulfosuccinate, gelatin, casein, lecithin (phosphatides), dextran, gum acacia, cholesterol, tragacanth, stearic acid, benzalkonium chloride, calcium stearate, glycerol monostearate, cetostearyl alcohol, cetomacrogol emulsifying wax, sorbitan esters, polyoxyethylene alkyl ethers (e.g., macrogol ethers such as cetomacrogol 1000), polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters (e.g., the commercially available Tweens® such as e.g., Tween 20® and Tween 80® (ICI Specialty Chemicals)); polyethylene glycols (e.g., Carbowaxs 3550® and 934® (Union Carbide)), polyoxyethylene stearates, colloidal silicon dioxide, phosphates, carboxymethylcellulose calcium, carboxymethylcellulose sodium, methylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose phthalate, noncrystalline cellulose, magnesium aluminium silicate, triethanolamine, polyvinyl alcohol (PVA), 4-(1,1,3,3-tetramethylbutyl)-phenol polymer with ethylene oxide and formaldehyde (also known as tyloxapol, superione, and triton), poloxamers (e.g., Pluronics F68® and F108®, which are block copolymers of ethylene oxide and propylene oxide); poloxamines (e.g., Tetronic 908®, also known as Poloxamine 908®, which is a tetrafunctional block copolymer derived from sequential addition of propylene oxide and ethylene oxide to ethylenediamine (BASF Wyandotte Corporation, Parsippany, N.J.)); Tetronic 1508® (T-1508) (BASF Wyandotte Corporation), Tritons X-200®, which is an alkyl aryl polyether sulfonate (Rohm and Haas); Crodestas F-110®, which is a mixture of sucrose stearate and sucrose distearate (Croda Inc.); p-isononylphenoxypoly-(glycidol), also known as Olin-lOG® or Surfactant 110-G® (Olin Chemicals, Stamford, Conn.); Crodestas SL-40® (Croda, Inc.); and SA90HCO, which is C18H37CH2(CON(CH3)—CH2(CHOH)4(CH2OH)2 (Eastman Kodak Co.); decanoyl-N-methylglucamide; n-decyl β-D-glucopyranoside; n-decyl β-D-maltopyranoside; n-dodecyl β-D-glucopyranoside; n-dodecyl β-D-maltoside; heptanoyl-N-methylglucamide; n-heptyl-β-D-glucopyranoside; n-heptyl β-D-thioglucoside; n-hexyl β-D-glucopyranoside; nonanoyl-N-methylglucamide; n-noyl β-D-glucopyranoside; octanoyl-N-methylglucamide; n-octyl-β-D-glucopyranoside; octyl β-D-thioglucopyranoside; PEG-phospholipid, PEG-cholesterol, PEG-cholesterol derivative, PEG-vitamin A, PEG-vitamin E, lysozyme, random copolymers of vinyl pyrrolidone and vinyl acetate, and the like.
  • Examples of useful cationic surface stabilizers include, but are not limited to, polymers, biopolymers, polysaccharides, cellulosics, alginates, phospholipids, and nonpolymeric compounds, such as zwitterionic stabilizers, poly-n-methylpyridinium, anthryul pyridinium chloride, cationic phospholipids, chitosan, polylysine, polyvinylimidazole, polybrene, polymethylnethacrylate trimethylammoniumbromide bromide (PMMTMABr), hexyldesyltrimethylammonium bromide (HDMAB), and polyvinylpyrrolidone-2-dimethylaminoethyl methacrylate dimethyl sulfate.
  • Other useful cationic stabilizers include, but are not limited to, cationic lipids, sulfonium, phosphonium, and quarternary ammonium compounds, such as stearyltrimethylammonium chloride, benzyl-di(2-chloroethyl)ethylammonium bromide, coconut trimethyl ammonium chloride or bromide, coconut methyl dihydroxyethyl ammonium chloride or bromide, decyl triethyl ammonium chloride, decyl dimethyl hydroxyethyl ammonium chloride or bromide, 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 (C12-18)dimethylbenzyl ammonium chloride, N-alkyl (C14-18)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(C12-14) 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 ALKAQUA™ (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.
  • 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).
  • 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 ammonium compound, a hydroxylammonium compound, a primary ammonium compound, a secondary ammonium compound, a tertiary ammonium compound, and quartemary ammonium compounds of the formula NR1R2R3R4 (+). For compounds of the formula NR1R2R3R4 (+):
      • (i) none of R1-R4 are CH3;
      • (ii) one of R1-R1 is CH3;
      • (iii) three of R1-R4 are CH3;
      • (iv) all of R1-R4 are CH3;
      • (v) two of R1-R4 are CH3, one of R1-R4 is C6H5CH2, and one of R1-R4 is an alkyl chain of seven carbon atoms or less;
      • (vi) two of R1-R4 are CH3, one of R1-R4 is C6H5CH2, and one of R1-R4 is an alkyl chain of nineteen carbon atoms or more;
      • (vii) two of R1-R4 are CH3 and one of R1-R4 is the group C6H5(CH2)n, where n>1;
      • (viii) two of R1-R4 are CH3, one of R1-R4 is C6H5CH2, and one of R1-R4 comprises at least one heteroatom;
      • (ix) two of R1-R4 are CH3, one of R1-R4 is C6H5CH2, and one of R1-R4 comprises at least one halogen;
      • (x) two of R1-R4 are CH3, one of R1-R4 is C6H5CH2, and one of R1-R4 comprises at least one cyclic fragment;
      • (xi) two of R1-R4 are CH3 and one of R1-R4 is a phenyl ring; or
      • (xii) two of R1-R4 are CH3 and two of R1-R4 are purely aliphatic fragments.
  • 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 (Quatemium-15), distearyldimonium chloride (Quatemium-5), dodecyl dimethyl ethylbenzyl ammonium chloride(Quatemium-14), Quatemium-22, Quaternium-26, Quatemium-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.
  • Most of these surface stabilizers are known pharmaceutical excipients and are described in detail in the Handbook of Pharmaceutical Excipients, published jointly by the American Pharmaceutical Association and The Pharmaceutical Society of Great Britain (The Pharmaceutical Press, 2000), specifically incorporated by reference. The surface stabilizers are commercially available and/or can be prepared by techniques known in the art.
  • 3. Other Pharmaceutical Excipients
  • Pharmaceutical megestrol compositions according to the invention may also comprise one or more binding agents, filling agents, lubricating agents, suspending agents, sweeteners, flavoring agents, preservatives, buffers, wetting agents, disintegrants, effervescent agents, and other excipients. Such excipients are known in the art.
  • Examples of filling agents are lactose monohydrate, lactose anhydrous, and various starches; examples of binding agents are various celluloses and cross-linked polyvinylpyrrolidone, microcrystalline cellulose, such as Avicel® PH101 and Avicel® PH102, microcrystalline cellulose, and silicified microcrystalline cellulose (ProSolv SMCC™).
  • Suitable lubricants, including agents that act on the flowability of the powder to be compressed, are colloidal silicon dioxide, such as Aerosil® 200, talc, stearic acid, magnesium stearate, calcium stearate, and silica gel.
  • Examples of sweeteners are any natural or artificial sweetener, such as sucrose, xylitol, sodium saccharin, cyclamate, aspartame, and acsulfame. Examples of flavoring agents are Magnasweet® (trademark of MAFCO), bubble gum flavor, and fruit flavors, and the like.
  • Examples of preservatives are potassium sorbate, methylparaben, propylparaben, benzoic acid and its salts, other esters of parahydroxybenzoic acid such as butylparaben, alcohols such as ethyl or benzyl alcohol, phenolic compounds such as phenol, or quarternary compounds such as benzalkonium chloride.
  • Suitable diluents include pharmaceutically acceptable inert fillers, such as microcrystalline cellulose, lactose, dibasic calcium phosphate, saccharides, and/or mixtures of any of the foregoing. Examples of diluents include microcrystalline cellulose, such as Avicel® PH101 and Avicel® PH102; 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.
  • Examples of effervescent agents are effervescent couples such as an organic acid and a carbonate or bicarbonate. Suitable organic acids include, for example, citric, tartaric, malic, fumaric, adipic, succinic, and alginic acids and anhydrides and acid salts. Suitable carbonates and bicarbonates include, for example, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, magnesium carbonate, sodium glycine carbonate, L-lysine carbonate, and arginine carbonate. Alternatively, only the sodium bicarbonate component of the effervescent couple may be present.
  • 4. Nanoparticulate Megestrol or Active Agent Particle Size
  • As used herein, particle size is determined on the basis of the weight average particle size as measured by conventional particle size measuring 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.
  • The compositions of the invention comprise nanoparticulate megestrol particles which have an effective average particle size of less than about 2000 nm (i.e., 2 microns). In other embodiments of the invention, the megestrol 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 600 nm, less than about 500 nm, less than about 400 nm, less than about 300 nm, less than about 250=n, 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 the above techniques.
  • If the nanoparticulate megestrol composition additionally comprises one or more non-megestrol nanoparticulate active agents, then such active agents have an effective average particle size of less than about 2000 nm (i.e., 2 microns). In other embodiments of the invention, the nanoparticulate non-megestrol active agents can 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 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, as measured by light-scattering methods, microscopy, or other appropriate methods.
  • By “an effective average particle size of less than about 2000 nm” it is meant that at least 50% of the nanoparticulate megestrol or nanoparticulate non-megestrol active agent particles have a particle size of less than about 2000 nm, by weight, when measured by the above-noted techniques. Preferably, at least about 70%, about 90%, about 95%, or about 99% of the nanoparticulate megestrol or nanoparticulate non-megestrol 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, etc.
  • If the nanoparticulate megestrol composition is combined with a conventional or microparticulate megestrol composition or non-megestrol active agent composition, then such a composition is either solubilized or has an effective average particle size of greater than about 2 microns. By “an effective average particle size of greater than about 2 microns” it is meant that at least 50% of the conventional megestrol or non-megestrol active agent particles have a particle size of greater than about 2 microns, by weight, when measured by the above-noted techniques. In other embodiments of the invention, at least about 70%, about 90%, about 95%, or about 99% of the conventional megestrol or non-megestrol active agent particles have a particle size greater than about 2 microns.
  • 5. Concentration of Nanoparticulate Megestrol and Surface Stabilizers
  • The relative amounts of nanoparticulate megestrol and one or more surface stabilizers can vary widely. The optimal amount of the individual components can depend, for example, the hydrophilic lipophilic balance (HLB), melting point, and the surface tension of water solutions of the stabilizer, etc.
  • The concentration of megestrol 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 dry weight of the megestrol and at least one surface stabilizer, not including other excipients.
  • The concentration of the at least one 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 megestrol and at least one surface stabilizer, not including other excipients.
  • If a combination of two or more surface stabilizers is employed in the composition, the concentration of the at least one primary surface stabilizer can vary from about 0.01% to about 99.5%, from about 0.1% to about 95%, or from about 0.5% to about 90%, by weight, based on the total combined dry weight of the megestrol, at least one primary surface stabilizer, and at least one secondary surface stabilizer, not including other excipients. In addition, the concentration of the at least one secondary surface stabilizer can vary from about 0.01% to about 99.5%, from about 0.1% to about 95%, or from about 0.5% to about 90%, by weight, based on the total combined dry weight of the megestrol, at least one primary surface stabilizer, and at least one secondary surface stabilizer, not including other excipients.
  • C. Methods of Making Nanoparticulate Megestrol Compositions
  • The nanoparticulate megestrol compositions can be made using, for example, milling, homogenization, or precipitation techniques. Exemplary methods of making nanoparticulate compositions are described in the '684 patent.
  • Methods of making nanoparticulate compositions are also described in U.S. Pat. No. 5,518,187 for “Method of Grinding Pharmaceutical Substances;” U.S. Pat. No. 5,718,388 for “Continuous Method of Grinding Pharmaceutical Substances;” U.S. Pat. No. 5,862,999 for “Method of Grinding Pharmaceutical Substances;” U.S. Pat. No. 5,665,331 for “Co-Microprecipitation of Nanoparticulate Pharmaceutical Agents with Crystal Growth Modifiers;” U.S. Pat. No. 5,662,883 for “Co-Microprecipitation of Nanoparticulate Pharmaceutical Agents with Crystal Growth Modifiers;” U.S. Pat. No. 5,560,932 for “Microprecipitation of Nanoparticulate Pharmaceutical Agents;” U.S. Pat. No. 5,543,133 for “Process of Preparing X-Ray Contrast Compositions Containing Nanoparticles;” U.S. Pat. No. 5,534,270 for “Method of Preparing Stable Drug Nanoparticles;” U.S. Pat. No. 5,510,118 for “Process of Preparing Therapeutic Compositions Containing Nanoparticles;” and U.S. Pat. No. 5,470,583 for “Method of Preparing Nanoparticle Compositions Containing Charged Phospholipids to Reduce Aggregation,” all of which are specifically incorporated by reference.
  • The resultant nanoparticulate megestrol compositions can be utilized in solid or liquid dosage formulations, such as controlled release formulations, solid dose fast melt formulations, aerosol formulations, lyophilized formulations, tablets, capsules, etc.
  • 1. Milling to Obtain Nanoparticulate Megestrol Dispersions
  • Milling megestrol to obtain a nanoparticulate megestrol dispersion comprises dispersing megestrol particles in a liquid dispersion medium in which megestrol is poorly soluble, followed by applying mechanical means in the presence of grinding media to reduce the particle size of megestrol 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.
  • The megestrol particles can be reduced in size in the presence of at least one surface stabilizer. Alternatively, the megestrol particles can be contacted with one or more surface stabilizers after attrition. Other compounds, such as a diluent, can be added to the megestrol/surface stabilizer composition either before, during, or after the size reduction process. Dispersions can be manufactured continuously or in a batch mode.
  • 2. Precipitation to Obtain Nanoparticulate Megestrol Compositions
  • Another method of forming the desired nanoparticulate megestrol composition is by microprecipitation. This is a method of preparing stable dispersions of poorly soluble active agents in the presence of one or more surface stabilizers and one or more colloid stability enhancing surface active agents free of any trace toxic solvents or solubilized heavy metal impurities. Such a method comprises, for example: (1) dissolving megestrol in a suitable solvent; (2) adding the formulation from step (1) to a solution comprising at least one surface stabilizer; and (3) precipitating the formulation from step (2) using an appropriate non-solvent. The method can be followed by removal of any formed salt, if present, by dialysis or diafiltration and concentration of the dispersion by conventional means.
  • 3. Homogenization to Obtain Nanoparticulate Megestrol Compositions
  • Exemplary homogenization methods of preparing nanoparticulate active agent compositions are described in U.S. Pat. No. 5,510,118, for “Process of Preparing Therapeutic Compositions Containing Nanoparticles.”
  • Such a method comprises dispersing megestrol particles in a liquid dispersion medium, followed by subjecting the dispersion to homogenization to reduce the particle size of the megestrol to the desired effective average particle size. The megestrol particles can be reduced in size in the presence of at least one surface stabilizer. Alternatively, the megestrol particles can be contacted with one or more surface stabilizers either before or after attrition. Other compounds, such as a diluent, can be added to the megestrol/surface stabilizer composition either before, during, or after the size reduction process. Dispersions can be manufactured continuously or in a batch mode.
  • D. Methods of Using Nanoparticulate Megestrol Formulations of the Invention
  • 1. Applications of the Nanoparticulate Compositions of the Invention
  • The nanoparticulate megestrol compositions of the invention may be used as an appetite stimulant to treat wasting conditions or cachexia. As used herein, the term “wasting” is used to mean a condition where the patient is losing body mass as a side effect of a disease progression, a disease treatment, or other condition. Examples of conditions where wasting is prevalent include, but are not limited to, HIV or AIDS, cancer, cachexia and anorexia.
  • Additional conditions where the nanoparticulate megestrol compositions of the invention may be used include, but are not limited to, neoplastic diseases where the disease normally regresses or the patient's symptoms are normally reduced in response to megestrol, or any other progestin.
  • The nanoparticulate megestrol compositions of the invention may also be used to treat conditions such as breast cancer, endometrial cancer, uterine cancer, cervical cancer, prostate cancer, and renal cancer. As used herein, the term “cancer” is used as one of ordinary skill in the art would recognize the term. Examples of cancers include, but are not limited to, neoplasias (or neoplasms), hyperplasias, dysplasias, metaplasias, and hypertrophies. The neoplasms may be benign or malignant, and they may originate from any cell type, including but not limited to epithelial cells of various origin, muscle cells, and endothelial cells.
  • The present invention also provides methods of hormone replacement therapy in post-menopausal women, or in subjects after castration, comprising administering a nanoparticulate megestrol composition of the invention. Further, the compositions of the present invention may be used for ovarian suppression in several situations such as endometriosis, hirsutism, dysmenorrhea, and uterine bleeding.
  • The present invention also provides methods of oral contraception comprising administering a nanoparticulate megestrol composition of the invention. In one embodiment, the compositions of the invention are administered in combination with estrogen or a synthetic estrogen.
  • 2. Dosage Forms of the Invention
  • The nanoparticulate megestrol compositions of the invention can be administered to a subject via any conventional means including, but not limited to, orally, rectally, ocularly, parenterally (e.g., intravenous, intramuscular, or subcutaneous), intracistemally, pulmonary, intravaginally, intraperitoneally, locally (e.g., powders, ointments or drops), or as a buccal or nasal spray. As used herein, the term “subject” is used to mean an animal, preferably a mammal, including a human or non-human. The terms patient and subject may be used interchangeably.
  • Moreover, the nanoparticulate megestrol compositions of the invention can be formulated into any suitable dosage form, including but not limited to liquid dispersions, gels, aerosols, ointments, creams, controlled release formulations, fast melt formulations, lyophilized formulations, tablets, capsules, delayed release formulations, extended release formulations, pulsatile release formulations, and mixed immediate release and controlled release formulations.
  • Nanoparticulate megestrol compositions suitable for parenteral injection may comprise physiologically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents, or vehicles including water, ethanol, polyols (propyleneglycol, polyethylene-glycol, glycerol, and the like), suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
  • The nanoparticulate megestrol compositions may also contain adjuvants such as preserving, wetting, emulsifying, and dispensing agents. Prevention of the growth of microorganisms can be ensured by various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like. Prolonged absorption of the injectable pharmaceutical form can be brought about by the use of agents delaying absorption, such as aluminum monostearate and gelatin.
  • Solid dosage forms for oral administration include, but are not limited to, capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active agent is admixed with at least one of the following: (a) one or more inert excipients (or carriers), such as sodium citrate or dicalcium phosphate; (b) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and silicic acid; (c) binders, such as carboxymethylcellulose, alignates, gelatin, polyvinylpyrrolidone, sucrose, and acacia; (d) humectants, such as glycerol; (e) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (f) solution retarders, such as paraffin; (g) absorption accelerators, such as quaternary ammonium compounds; (h) wetting agents, such as cetyl alcohol and glycerol monostearate; (i) adsorbents, such as kaolin and bentonite; and (j) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. For capsules, tablets, and pills, the dosage forms may also comprise buffering agents.
  • Liquid nanoparticulate megestrol dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs. In addition to megestrol, the liquid dosage forms may comprise inert diluents commonly used in the art, such as water or other solvents, solubilizing agents, and emulsifiers. Exemplary emulsifiers are ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butyleneglycol, dimethylformamide, oils, such as cottonseed oil, groundnut oil, corn germ oil, olive oil, castor oil, and sesame oil, glycerol, tetrahydrofurfuryl alcohol, polyethyleneglycols, fatty acid esters of sorbitan, or mixtures of these substances, and the like.
  • Besides such inert diluents, the composition can also include adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • 3. Dosage Quantities for the Nanoparticulate Megestrol Compositions of the Invention
  • The present invention provides a method of achieving therapeutically effective plasma levels of megestrol in a subject at a lower dose than the standard commercial formulations. This can permit smaller dosing volumes depending on the megestrol concentration chosen. Such a method comprises orally administering to a subject an effective amount of a nanoparticulate megestrol composition.
  • The nanoparticulate megestrol composition, when tested in fasting subjects in accordance with standard pharmacokinetic practice, produces a maximum blood plasma concentration profile of megestrol of greater than about 30 ng/ml in less than about 5 hours after the initial dose of the composition.
  • As used herein, the phrase “maximum plasma concentration” is interpreted as the maximum plasma concentration that megestrol will reach in fasting subjects.
  • A suitable dose of megestrol, administered according to the method of the invention, is typically in the range of about 1 mg/day to about 1000 mg/day, or from about 40 mg/day to about 800 mg/day. Preferably, the therapeutically effective amount of the megestrol of this invention is about ⅙, about ⅕, about ¼, about ⅓rd, or about ½ of the therapeutically effective amount of existing commercial megestrol formulations, e.g., Megace®.
  • “Therapeutically effective amount” as used herein with respect to a drug dosage, shall mean that dosage that provides the specific pharmacological response for which the drug is administered in a significant number of subjects in need of such treatment. It is emphasized that “therapeutically effective amount,” administered to a particular subject in a particular instance will not always be effective in treating the diseases described herein, even though such dosage is deemed a “therapeutically effective amount” by those skilled in the art. It is to be further understood that drug dosages are, in particular instances, measured as oral dosages, or with reference to drug levels as measured in blood.
  • One of ordinary skill will appreciate that effective amounts of megestrol can be determined empirically and can be employed in pure form or, where such forms exist, in pharmaceutically acceptable salt, ester, or prodrug form. Actual dosage levels of megestrol in the nanoparticulate compositions of the invention may be varied to obtain an amount of megestrol that is effective to obtain a desired therapeutic response for a particular composition and method of administration. The selected dosage level therefore depends upon the desired therapeutic effect, the route of administration, the potency of the administered megestrol, the desired duration of treatment, and other factors.
  • Dosage unit compositions may contain such amounts of such submultiples thereof as may be used to make up the daily dose. It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors: the type and degree of the cellular or physiological response to be achieved; activity of the specific agent or composition employed; the specific agents or composition employed; the age, body weight, general health, sex, and diet of the patient; the time of administration, route of administration, and rate of excretion of the agent; the duration of the treatment; drugs used in combination or coincidental with the specific agent; and like factors well known in the medical arts.
  • The following examples are given to illustrate the present invention. It should be understood, however, that the invention is not to be limited to the specific conditions or details described in these examples. Throughout the specification, any and all references to a publicly available document, including a U.S. patent, are specifically incorporated by reference.
  • In the examples that follow, the value for D50 is the particle size below which 50% of the megestrol particles fall. Similarly, D90 is the particle size below which 90% of the megestrol particles fall.
  • The formulations in the examples that follow were also investigated using a light microscope. Here, “stable” nanoparticulate dispersions (uniform Brownian motion) were readily distinguishable from “aggregated” dispersions (relatively large, nonuniform particles without motion). Stable, as known in the art and used herein, means the particles don't substantially aggregate or ripen (increase in fundamental particle size).
  • EXAMPLE 1
  • The purpose of this example was to describe preparation of nanoparticulate dispersions of megestrol acetate.
  • Formulations 1, 2, 3, 4 and 5, shown in Table 1, were milled under high energy milling conditions using a NanoMill® (Elan Drug Delivery, Inc.) (see e.g., WO 00/72973 for “Small-Scale Mill and Method Thereof”) and a Dyno®-Mill (Willy Bachofen AG).
    TABLE 1
    Identity
    Identity and and
    Quantity Quantity
    Quantity of Primary of Secondary
    of Surface Surface Mean D90
    Formulation Megestrol Stabilizer Stabilizer (nm) (nm)
    1 5% 1% HPC-SL 0.05% DOSS 167 224
    2 5% 1% HPMC 0.05% DOSS 156 215
    3 5% 1% PVP 0.05% DOSS 167 226
    4 5% 1% Plasdone ® 0.05% DOSS 164 222
    S630*
    5 5% 1% HPMC 0.05% SLS 148 208

    *Plasdone ® S630 (ISP) is a random copolymer of vinyl acetate and vinyl pyrrolidone.
  • Formulations 1-5 showed small, well-dispersed particles using the Horiba La-910 Laser Scattering Particle Size Distribution Analyzer (Horiba Instruments, Irvine, Calif.) and light microscopy. Formulations 1-5 were stable in electrolyte fluids and had acceptable physical stability at 5° C. for 4 weeks. Electrolyte fluids are representative of physiological conditions found in the human body. Formulations 1, 2, 3, and 4 also exhibited acceptable stability at 25° C. and 40° C. for 4 weeks. Formulation 5 exhibited acceptable stability at 40° C. for at least 3 weeks.
  • EXAMPLE 2
  • This example compares the pharmacokinetic parameters of nanoparticulate megestrol acetate formulations of the present invention with conventional microparticulate formulations of megestrol acetate.
  • Twelve male beagles, at least twelve months of age, were divided into 2 groups based on whether they were fasting or being fed. The dogs were acclimated for thirteen days prior to dosing. The animals weighed approximately 11.4 to 14.3 kg at the time of dosing, and the dose was adjusted to 10 mg/kg. Water was available ad libitum. The animals were fasted (food only) for twelve to sixteen hours prior to dosing on day 1. On day 1, each dog was administered a formulation by gavage. Following dosing, the gavage tube was flushed with 18 ml of water. In the fed study, the animals were fed a high fat meal about 1 hour prior to dosing.
  • The dogs were subdivided into four groups, with each group receiving either Formulation-A (nanoparticulate megestrol dispersion #1, comprising 4.0% megestrol acetate, 0.8% HPMC, and 0.4% DOSS), Formulation B (nanoparticulate megestrol dispersion #2, comprising 4.0% megestrol acetate, 0.8% HPMC, and 0.04% SLS), Formulation C (suspension of microparticulate megestrol acetate, Par Pharmaceutical, Inc., New York) or Formulation D (Megace® Oral Suspension, which is a suspension of microparticulate megestrol acetate). Each formulation was adjusted to administer a dose of 10 mg/kg of megestrol acetate to the subject.
  • Prior to dosing, blood samples were taken from each subject. Blood samples were then collected from each subject at 15 and 30 minutes, as well as 1, 2, 3, 4, 6, 8, 24, 48, and 72 hours after dosing and centrifuged. Plasma was then separated and diluted when necessary, and subsequently analyzed for megestrol acetate by HPLC.
  • Tables 2 and 3 summarize the pharmacokinetic data of the four formulations administered to fasted dogs and fed dogs, respectively.
    TABLE 2
    Summary of Pharmacokinetic Data in Fasted Dogs
    Formulation A n = 3 Formulation B n = 3 Formulation C n = 3 Formulation D n = 3
    Parameters (Mean ± SD) (Mean ± SD) (Mean ± SD) (Mean ± SD)
    AUC0-t 37774.23 ± 11648.60 21857.68 ± 10737.53 17395.95 ± 10428.73 10094.30 ± 1990.89
    AUC0-inf 49408.88 ± 3392.80  27863.56 ± 15279.16  6948.48±* 12007.13 ± 1923.80 
    Cmax 2209.74 ± 351.54  1563.02 ± 787.37   484.98 ± 321.70 339.92 ± 175.86
    Tmax 0.83 ± 0.29 0.50 ± 0.00   18.67 ± 9.24 2.67 ± 0.58
    t1/2 42.01 ± 33.81 30.09 ± 19.37   26.57±* 25.59 ± 7.11 
    Kel 0.025 ± 0.018 0.032 ± 0.024   0.026±* 0.028 ± 0.007

    AUC0-t (ng · hr/ml) = Area under the curve from time zero to the last measurable concentration;

    AU0-inf (ng · hr/ml) = Area under the curve from time zero to infinity;

    Cmax (ng/ml) = Maximum plasma concentration;

    Tmax (hr) = Time to occurrence of Cmax;

    t1/2 (hr) = Apparent elimination half-life;

    Kel (1/hr) = elimination rate constant;

    *n = 1.
  • TABLE 3
    Summary of Pharmacokinetic Data in Fed Dogs
    Formulation A Formulation B Formulation C Formulation D
    n = 3 n = 3 n = 3 n = 3
    Parameters (Mean ± SD) (Mean ± SD) (Mean ± SD) (Mean ± SD)
    AUC0-t 48543.56 ± 11608.55 36687.92 ± 12016.26 27332.11 ± 6488.79  31397.16 ± 5823.79
    AUC0-inf 61734.90 ± 4918.52  42787.74 ± 14630.92 31720.98 ± 5580.32  40218.66 ± 8649.33*
    Cmax 3777.34 ± 2489.41 2875.82 ± 1334.32 2180.73 ± 406.28   2577.83 ± 665.31
    Tmax 1.67 ± 2.02 3.00 ± 4.33 1.00 ± 0.00   0.83 ± 0.29
    T1/2 34.35 ± 12.10 26.67 ± 7.80  26.16 ± 10.88   36.60 ± 9.62*
    Kel 0.022 ± 0.009 0.028 ± 0.010 0.31 ± 0.16   0.20 ± 0.005

    AUC0-t (ng · hr/ml) = Area under the curve from time zero to the last measurable concentration;

    AUC0-inf (ng · hr/ml) = Area under the curve from time zero to infinity;

    Cmax (ng/ml) = Maximum plasma concentration;

    Tmax (hr) = Time to occurrence of Cmax;

    t1/2 (hr) = Apparent elimination half-life;

    Kel (1/hr) = elimination rate constant;

    *n = 2.
  • The results in the fasted dogs show that the nanoparticulate megestrol formulations (Formulations A and B) showed dramatically superior bioavailability, as evidenced by the superior AUC and Cmax results, as compared to the conventional microparticulate megestrol formulations (Formulations C and D). Formulation A, with a Cmax of 2210, had a maximum concentration more than 4½ times that of Formulation C (485), and a maximum concentration more than 6½ times that of Formulation D (340). Formulation B, with a Cmax of 1563, had a maximum concentration more than 3.2 times that of Formulation C (485), and a maximum concentration more than 4.6 times that of Formulation D (340). Also, Formulation A, with an AUC of 49,409 ng hr/mL, had an oral bioavailability more than 7 times that of Formulation C (6948 ng hr/mL) and an oral bioavailability of more than 4 times that of Formulation D (12007 ng hr/mL). Formulation B, with an AUC of 27,864 ng hr/mL, had an oral bioavailability more than 4 times that of Formulation C (6949 ng hr/mL) and an oral bioavailability more than 2 times that of Formulation D (12,007 ng hr/mL).
  • In addition, in the fasted dogs the nanoparticulate megestrol formulations (Formulations A and B) showed dramatically superior faster onset of action, as evidenced by the superior Tmax results, as compared to the conventional microparticulate megestrol formulations (Formulations C and D). Formulation A, with a Tmax of 0.83 hr, reached a maximum concentration of megestrol in less than 1/20th the time of Formulation C (18.67 hr), and in less than ⅓rd the time of Formulation D (2.67 hr). Formulation B, with a Tmax of 0.50 hr, reached a maximum concentration in less than 1/37th the time of Formulation C (18.67 hr), and in less than ⅕th the time of Formulation D (2.67 hr).
  • Similarly, the results in the fed dogs show that the nanoparticulate megestrol formulations (Formulations A and B) showed dramatically superior bioavailability, as evidenced by the superior AUC and Cmax results, as compared to the conventional microparticulate megestrol formulations (Formulations C and D). Formulation A, with a Cmax of 3777, had a maximum concentration of about more than 1.7 times that of Formulation C (2181), and a maximum concentration of about more than 1.5 times that of Formulation D (2578). Formulation B, with a Cmax of 2876, had a maximum concentration of about more than 1.3 times that of Formulation C (2181), and a maximum concentration of about more than 1.1 times that of Formulation D (2578). Formulation A, with an AUC of 61,735 ng hr/mL, had an oral bioavailability of more than 1.9 times that of Formulation C (31721 ng hr/mL) and more than 1.5 times that of Formulation D (40219 ng hr/mL). Formulation B, with an AUC of 42788 ng hr/mL, had an oral bioavailability of more than 1.3 times that of Formulation C (31721 ng hr/mL) and an oral bioavailability of more than 1.1 times that of Formulation D (40218 ng hr/nL).
  • EXAMPLE 3
  • This example demonstrates the physical stability of megestrol acetate dispersions at various concentrations and with the addition of sucrose, flavoring, and preservatives.
  • Megestrol acetate was milled under high energy milling conditions using a NanoMill™2 System (Elan Drug Delivery, Inc.) in the presence of a preservative/buffer system consisting of sodium benzoate, citric acid monohydrate, and sodium citrate dihydrate. After milling, the resulting dispersion was diluted with water, sucrose, flavoring, and additional preservative/buffer to prepare dispersions containing 3% (w/w), 5% (w/w), or 9% (w/w) megestrol acetate. The resulting formulations are shown in Table 4. The physical stability of the formulations was then monitored at 25° C., 40° C., and 50° C.
    TABLE 4
    Formulation Summary
    Concentrated Diluted, Flavored Dispersions
    Nanoparticle Formulation E Formulation F Formulation G
    Dispersion 3% Dispersion 5% Dispersion 9% Dispersion
    API and Excipients g/kg g/kg g/kg g/kg
    Megestrol Acetate, USP 325.000 30.000 50.000 90.000
    Hydroxypropyl Methylcellulose, USP 65.000 6.000 10.000 18.000
    Docusate Sodium, USP 3.250 0.300 0.500 0.900
    Sodium Benzoate, USP 1.214 1.826 1.777 1.681
    Sodium Citrate Dihydrate, USP 0.910 0.091 0.089 0.084
    Citric Acid Monohydrate, USP 0.061 1.369 1.333 1.260
    Sucrose, USP 50.000 50.000 50.000
    Natural and Artificial Lemon Flavor 0.400 0.400 0.400
    Artificial Lime Flavor 0.400 0.400 0.400
    Purified Water, USP 604.600 909.614 885.500 837.280

    API = active pharmaceutical ingredient
  • Particle size measurements (Table 5) were used to assess the physical stability. The results show almost no increase in the mean particle size at either 25° C. or 40° C., and only a slight increase in the mean particle size at 50° C. 126 days of stability measurements were obtained for the 5% and 9% dispersions and 33 days of stability were obtained for the 3% dispersion, which was prepared at a later date.
    TABLE 5
    Mean particle size (nm)
    3% Dispersion 5% Dispersion 9% Dispersion
    25° C. 40° C. 50° C. 25° C. 40° C. 50° C. 25° C. 40° C. 50° C.
     0 days 148 148 148 169 169 169 169 169 169
     30 days 172 171 187 172 170 179
     33 days 141 144 173
    126 days 171 174 188 168 175 182
  • EXAMPLE 4
  • The purpose of this Example was to demonstrate the improved viscosity characteristics of the dispersions of this invention.
  • The viscosities of three formulations of this invention (E, F, and G as described in Example 3) and two conventional commercial formulations (Formulations C and D as described in Example 2) were determined using a rheometer (model CVO-50, Bohlin Instruments). The measurements were performed at a temperature of 20° C. using a double gap (40/50) geometry.
  • The viscosities of the Formulations of this invention were found to be nearly Newtonian (i.e., the viscosity being independent of shear rate), and were 1.5, 2.0, and 3.5 mPa s for the 30, 50, and 90 mg/mL concentrations, respectively.
  • The viscosity dependence on concentration is illustrated in FIG. 1.
  • The commercial formulations C and D were shear thinning in nature. Such samples cannot be characterized by a single viscosity but rather a series of viscosities measured at different shear rates. This is most conveniently illustrated as viscosity—shear rate curves as shown in FIG. 2.
  • The commercial samples and the three formulations of this invention are compared in Table 6 below. Viscosities are in units of mPa s.
    TABLE 6
    Shear Rates of Commercial Megestrol Formulations (D and C) and the
    Nanoparticulate Megestrol Formulations of the Invention (E, F, & G)
    Commercial Samples Formulations E, F, & G
    Shear Rate Formulation D Formulation C (E) 30 mg/mL (F) 50 mg/mL (G) 90 mg/mL
    s−1 (mPa s) (mPa s) (mPa s) (mPa s) (mPa s)
    0.1 4010 2860 1.5 2.0 3.5
    1 929 723
    10 215 183
    100 49.9 46.3

    * These samples were not measured at the 0.1 and 1 s−1 shear rates (the shear range was ca 2 to 100 s−1) but the assessment that these exhibit Newtonian flow properties justifies the entries.
  • EXAMPLE 5
  • The purpose of this Example was to visually demonstrate the difference between the viscosity characteristics of liquid megestrol formulations of the invention as compared to conventional liquid megestrol formulations.
  • A sample of a 50 mg/mL nanoparticulate dispersion of megestrol acetate and two conventional commercial formulations at 40 mg/mL (Formulations C and D as described in Example 2) were each placed in a vial, which was then shaken. Attached as FIG. 3 is a photograph of the thee vials, which from left to right are the nanoparticulate megestrol acetate dispersion, Formulation C, and Formulation D.
  • The vial with the nanoparticulate dispersion shows a thin, silky, almost shear film coating the vial. In contrast, the vials containing the two commercial formulations show a gritty residue coating. Such a gritty residue is the same residue which coats a patient's mouth and throat upon administration. Such a coating is highly unpleasant, particularly for patients suffering from wasting (i.e., unable to eat). Thus, FIG. 3 visually demonstrates the appeal of a liquid oral nanoparticulate megestrol formulation of the invention as compared to conventional commercial liquid oral megestrol formulations.
  • EXAMPLE 6
  • The purpose of this example was to prepare nanoparticulate compositions of megestrol acetate using various surface stabilizers.
  • 5% megestrol acetate (Par Pharmaceuticals, Inc.) was combined with 1.25% of various surface stabilizers: tyloxapol (Sterling Organics), Tween 80 (Spectrum Quality Products), Pluronic F-108 (BASF), Plasdone S-630 (ISP), hydroxypropylmethylcellulose (HPMC) (Shin Etsu), hydroxypropylcellulose (HPC-SL) (Nippon Soda Co., Ltd.), Kollidon K29/32 (polyvinylpyrrolidone) (ISP), or lysozyme (Fordras).
  • For each combination of megestrol acetate and surface stabilizer, the surface stabilizer was first dissolved in 7.875 g water for injection (WFI) (Abbott Laboratories, Inc.), followed by the addition of the milling media, PolyMill™-500 (Dow Chemical, Co.), and 0.42 g megestrol.
  • The slurries were charged into each of eight 18 cc NanoMill® (Elan Drug Delivery) chambers and milled for 30 min. Upon completion of milling the dispersions were harvested with a 26 gauge needle yielding the following particle sizes shown in Table 7.
  • All particle size distribution analyses were conducted on a Horiba LA-910 Laser Light Scattering Particle Size Distribution Analyzer (Horiba Instruments, Irvine, Calif.). RO-water was utilized as the liquid dispersing medium and a flow-through sample cell was used for all measurements. All samples were assayed in 150 cc liquid medium.
    TABLE 7
    Megestrol
    Conc. Surface Stabilizer/Conc. Mean Particle Size
    5% tyloxapol; 1.25%  214 nm
    5% Tween 80; 1.25%  210 nm
    5% Pluronic F-108; 1.25%  459 nm
    5% Plasdone S-630; 1.25%  292 nm
    5% HPMC; 1.25%  314 nm
    5% HPC-SL; 1.25%  623 nm
    5% PVP K29/32; 1.25% 24816 nm
    5% lysozyme; 1.25%  179 nm
  • The results show that tyloxapol, Tween 80, and lysozyme produced small particles without substantial aggregation. Pluronic F-108, Plasdone S-630, HPMC, HPC-SL, and K29/32 had larger particle sizes, indicating that aggregation was occurring. Thus, at the particular concentration of drug and surface stabilizer, using the described milling method, Pluronic F-108, Plasdone S-630, HPMC, HPC-SL, and K29/32 were not preferable surface stabilizers. These surface stabilizers may be useful in nanoparticulate compositions of megestrol at different drug or surface stabilizer concentrations, or when used in conjunction with another surface stabilizer.
  • EXAMPLE 7
  • The purpose of this example was to prepare nanoparticulate compositions of megestrol acetate using various surface stabilizers.
  • Megestrol acetate (Par Pharmaceuticals, Inc.) and various surface stabilizers, as shown in Table 8, were combined and milled, followed by determination of the particle size and stability of the resulting composition. Materials were obtained as in Example 6.
  • All of the samples were milled using a Dyno®-Mill (Model KDL-Series, Willy Bachofen A G, Basel, Switzerland) equipped with a 150 cc stainless steel batch chamber. Cooling water (approximate temperature 5° C.) was circulated through the mill and chamber during operation.
  • All particle size distribution analyses were conducted on a Horiba LA-910 Laser Light Scattering Particle Size Distribution Analyzer (Horiba Instruments, Irvine, Calif.), as described above in Example 6.
  • Qualitative microscopic assessments of the formulations were performed using a Leica light microscope (Type 301-371.010). Sample preparation involved diluting the product dispersions in RO-water and dispensing about 10 μL onto a glass slide. Oil immersion was utilized in conjunction with 1000× magnification.
  • The physical stability was assessed by storing the dispersion is 20 ml glass scintillation vials in a temperature/humidity controlled chamber at either 5° C., (25° C./60% RH), (40° C./75% RH), (50° C./75% RH), or 55° C. Samples were taken at varying time intervals and the particle size was analyzed.
  • For all formulations, the surface stabilizer(s) was first dissolved in WFI (Abbott Laboratories, Inc.) (75.0 g for Exp. Nos. 1, 2, 3, 7, and 8; 75.2 g for Exp. Nos. 4 and 9; 74.9 g for Exp. Nos. 5 and 6; 70.3 g for Exp. Nos. 10 and 11), followed by combining the surface stabilizer solution megestrol acetate and PolyMill™ 500 polymeric grinding media. This mixture was then added to the appropriate milling chamber, milled for the time period shown in Table 8, followed by harvesting and vacuum filtering of the megestrol acetate dispersion.
    TABLE 8
    Surface Mean
    Exp. Megestrol Stabilizer(s) and Particle
    No. Conc. Conc. Milling Time Size Stability
    1  5% 1.25% lysozyme 20 min. 209 nm The sample showed substantial aggregation after incubation in normal saline
    for 30 minutes as determined by optical microscopy
    2  5% 1.25% Tween 80 75 min. 157 nm Upon storage at 5° C. for 15 days the sample grew to a mean diameter of 577 nm.
    3  5% 1.25% tyloxapol  2 hrs. 208 nm Optical microscopoy revealed the presence of elongated “needle-like”
    crystals.
    4  5% 1% Pluronic F127  2 hrs. 228 nm Upon storage at 25° C. for 5 days the sample grew to a mean diameter of 308 nm.
    5  5% 1.25% HPMC 75 min. 161 nm Upon storage at 40° C. for 19 days, the sample grew to a mean diameter of
    0.0625% SLS1 171 nm. Incubation for 30 minutes at 40° C. in 0.01 N HCl or normal saline
    resulted in particle sizes of 164 nm and 209 nm, respectively.
    6  5% 1.25% HPC-SL, 60 min. 167 nm Upon storage at 40° C. for 15 days, the sample grew to a mean diameter of
    0.05% SLS 194 nm. Incubation for 30 minutes at 40° C. in 0.01 N HCl or normal saline
    resulted in particle sizes of 183 nm and 179 nm, respectively.
    7  5% 1.25% HPMC 45 min. 185 nm Upon storage at 40° C. for 6 days, the sample grew to a mean diameter of 313 nm.
    Incubation for 30 minutes at 40° C. in 0.01 N HCl or normal saline
    resulted in particle sizes of 2041 nm and 1826 nm, respectively. Optical
    microscopy revealed aggregation in both the saline and HCl samples.
    8  5% 1.25% HPC-SL 45 min. 176 nm Upon storage at 40° C. for 6 days, the sample grew to a mean diameter of 244 nm.
    Incubation for 30 minutes at 40° C. in 0.01 N HCl or normal saline
    resulted in particle sizes of 873 nm and 524 nm, respectively. Optical
    microscopy revealed aggregation in both the saline and HCl samples.
    9  5% 1% HPMC 70 min. 152 nm Incubation for 30 minutes at 40° C. in 0.01 N HCl or normal saline resulted in
    0.05% SLS particle sizes of 155 nm and 539 nm, respectively. Optical microscopy
    confirmed that aggregation was present in the sample incubated in saline.
    10 10% 2% HPMC 70 min. 150 nm Following harvesting the sample was diluted to 4% API by adding WFI.
    0.1% DOSS2 Upon storage at 40° C. for 40 days, the sample had a mean diameter of 146 nm. Optical
    microscopy revealed small, well dispersed particles.
    11 10% 2% HPMC 70 min. 146 nm Upon storage at 40° C. for 19 days, the sample had a mean diameter of 149 nm.
    0.1% SLS Optical microscopy revealed small, well dispersed particles.
    12 10% 4% lysozyme 60 min. 108 nm Upon storage at 40° C. for 9 days the sample had a mean diameter of 124 nm.
    Optical microscopy revealed small, well dispersed particles.

    1Sodium lauryl sulfate (Spectrum Quality Products)

    2Dioctyl Sodium Sulfosuccinate (Cytec)
  • The results shown in Table 8 indicate that the use of lysozyme (Exp. No. 1) as a surface stabilizer resulted in small well dispersed particles with a mean particle size of 209 nm, but the formulation showed aggregation when diluted into a normal saline solution. A megestrol acetate/tyloxapol sample was also stable at higher drug and stabilizer concentrations (Exp. No. 12).
  • Tween 80, tyloxapol, and Pluronic F127 (Exp. Nos. 2, 3, and 4) were effective primary surface stabilizers and produced well-dispersed particles without significant aggregation. Stability measurements, however, revealed rapid crystal growth for all three stabilizers. 5% megestrol acetate/1.25% Tween 80 grew from 157 nm to 577 nm after 15 days at 5° C. 5% megestrol acetate/1.25% tyloxapol showed needle-like crystals when observed under optical microscopy. 5% megestrol acetate/1.25% Pluronic F127 grew from 228 nm to 308 nm after 5 days at 25° C. Because of the rapid crystal growth observed, Tween 80, tyloxapol, and Pluronic F127 were deemed not suitable surface stabilizers at the described drug/surface stabilizer concentrations prepared under the conditions described above.
  • The HPC-SL formulation (Exp. No. 8) showed substantial aggregation indicating that a secondary charged stabilizer would be needed. SLS was added (Exp. No. 6) and the new formulation grew from 167 to 194 nm after storage at 40° C. for 15 days and did not show any substantial aggregation upon incubation in either 0.01N HCl or normal saline. The SLS appeared effective at preventing the aggregation but the sample showed some particle size growth.
  • The HPMC formulation (Exp. No. 7) showed substantial aggregation indicating that a secondary charged stabilizer would be needed. SLS was added (Exp. Nos. 5 and 11), and the new formulations showed only minimal growth from 161 nm to 171 nm (Exp. No. 5), and from 146 to 149 nm (Exp. No. 11), after storage at 40° C. for 19 days. In addition, the composition of Exp. No. 5 did not show any substantial aggregation upon incubation in either 0.01N HCl or normal saline. The SLS was effective at preventing the aggregation without causing significant crystal growth.
  • An attempt was made to reduce the concentration of the primary and secondary stabilizers (Exp. No. 9) and resulted in a post-milling mean diameter of 152 nm. Incubation for 30 minutes at 40° C. in normal saline resulted in particle sizes of 539 nm. Optical microscopy confirmed that aggregation was present in the sample incubated in saline.
  • Docusate sodium (DOSS) was tried as a secondary stabilizer (Exp. No. 10) and resulted in well-dispersed particles with a mean diameter of 150 nm. Upon storage at 40° C. for 40 days, the sample had a mean diameter of 146 nm. Optical microscopy revealed small, well-dispersed particles. DOSS seemed to result in even less particle size growth than SLS.
  • EXAMPLE 8
  • The purpose of this example was to prepare nanoparticulate compositions of megestrol acetate using various surface stabilizers and further including preservatives or excipients.
  • The materials and methods were the same as in Example 7, except that for several of the examples different sources of megestrol acetate were used (See Table 9). In addition, for Exp. Nos. 5, a NanoMill® milling system (Elan Drug Delivery) was used. Several different combinations of megestrol acetate, surface stabilizer(s), and one or more preservatives or excipients were prepared, following by testing the compositions for particle size and stability.
  • The surface stabilizer(s) and one or more preservatives were first dissolved in WFI, followed by combining the solution with megestrol acetate and the grinding media. This mixture was then added to the milling chamber and milled for the time period set forth in Table 9, below.
  • For several of the experiments, following milling the megestrol acetate dispersion was combined with a flavored suspension. The stability of the resultant composition was then evaluated.
  • The formulation details and results are shown in Table 9, below.
    TABLE 9
    Surface Mean
    Megestrol Stabilizer(s) Preservatives/ Milling Particle
    Exp. Conc. and Conc. Excipients Time Size Stability
    1   10% 2% HPMC Sodium Benzoate   75 min 146 nm After milling a flavored suspension was prepared by adding sucrose
    0.1% DOSS (0.4 g), Sodium (2.5 g), xanthan gum (0.113 g), glycerol (13.75 g), lemon flavor
    Citrate Dihydrate (0.1 g), WFI (18.6 g), and 20.0 g of the milled dispersion. Upon
    (20 mg) storage at 40° C. for 24 days, the sample showed aggregation with a
    Citric Acid mean diameter of 837 nm. Incubation for 30 minutes at 40° C. in
    Monohydrate 0.01 N HCl or normal saline resulted in particle sizes of 206 nm and
    (0.3 g) 3425 nm, respectively. Optical microscopy confirmed that the
    sample incubated in saline had aggregated.
    2   25% 5% HPMC Sodium Benzoate   95 min. See right 16 g of the milled drug dispersion was combined with sucrose (5 g),
    0.05% DOSS (0.11 g) column. lime flavor (80 mg), and WFI (78.9 g). The diluted drug dispersion
    Citric Acid had a mean diameter of 192. After 6 days at 55° C. the particles had
    Monohydrate a mean diameter of 10 microns, indicating substantial aggregation
    (0.08 g)
    3   25% 5% HPMC, Sodium Benzoate   95 min. See right 16 g of the milled drug dispersion was combined with sucrose (5 g),
    0.15% DOSS (0.11 g) column. lime flavor (80 mg), and WFI (78.9 g). The diluted drug dispersion
    Citric Acid had a mean diameter of 173 nm. After 12 days at 55° C. the particles
    Monohydrate had a mean diameter of 295 nm.
    (0.08 g)
    4 32.5%1 6.5% HPMC Sodium Benzoate 15.5 hrs 160 nm Upon storage at 50° C. for 44 days, the mean diameter was 190 nm.
    0.33% DOSS (13.07 g)
    Sodium Citrate
    Dihydrate (0.65 g)
    Citric Acid
    Monohydrate (9.8 g)
    5 32.5% 6.5% HPMC Sodium Benzoate   12 hrs 147 nm Upon storage at 50° C. for 44 days the mean diameter was 178 nm.
    0.33% DOSS (9.71 g)
    Sodium Citrate
    Dihydrate (0.49 g)
    Citric Acid
    Monohydrate
    (7.28 g)

    1Pharmacia

    2Pharmabios
  • In Exp. No. 1 of Table 9, a sweetened, flavored dispersion was prepared by mimicking the current commercial formulation of megestrol acetate that contains sucrose, xanthan gum, glycerol, lemon and lime flavors, and is preserved and buffered with sodium benzoate and citric acid. Upon storage at 40° C. for 24 days the sample showed aggregation with a mean diameter of 837 nm. Incubation for 30 minutes at 40° C. in 0.01N HCl or normal saline resulted in particle sizes of 206 nm and 3425 μm, respectively. Optical microscopy confirmed that the sample incubated in saline had aggregated. The aggregation upon storage indicated that this particular combination of drug and surface stabilizer, at the concentrations used and methodology employed to make the compositions, would not be an effective formulation.
  • For Exp. Nos. 4 and 5, the formulation was scaled-up iu a NanoMill™-2 system to determine if the scale-up would effect the physical stability. Two different sources of megestrol acetate were tested: Pharmacia and Pharmabios. The product of Exp. No. 4 had a mean diameter of 160 nm without ultrasound. Upon storage at 50° C. for 44 days the mean diameter was 190 nm. The composition of Exp. No. 5 had a post-milling mean diameter of 147 nm without ultrasound. Upon storage at 50° C. for 44 days the mean diameter was 178 nm. Both sources of active agent milled effectively and showed little particle size growth even at 50° C.
  • The results of Examples 6 and 7 showed that high energy milling with polymeric attrition media could be used to produce stable nanoparticulate colloidal dispersions of megestrol acetate suitable for oral administration to animals or humans. The primary stabilizer HPMC required the presence of DOSS or SLS to prevent aggregation at the concentrations of drug and stabilizer tested (other combinations of drug and HPMC concentrations may result in a stable composition without the addition of a second surface stabilizer). In general, average particle sizes of less than about 160 nm could be obtained. Tests conducted with two sources of megestrol acetate revealed that both sources milled effectively and exhibited excellent physical stability.
  • Based on mean particle size, physical stability, and the pre-clinical dog study, the best nanoparticulate megestrol acetate formulation for commercial development, based on the results of the data given in the examples, consisted of 32.5% megestrol acetate, 6.5% HPMC, and 0.325% DOSS (i.e., a drug:HPMC ratio of 1:5 and a drug:DOSS ratio of 1:100. The formulation milled effectively in the presence of preserved water (0.2% sodium benzoate, 0.01% sodium citrate dihydrate, and 0.15% citric acid monohydrate). Upon dilution with preserved water, flavors, and sucrose none of the dispersions showed severe aggregation, except for the dispersions containing xanthan gum (data not shown) or low levels of DOSS. The alcohol-based flavors did not effect the physical stability nor did several freeze-thaw cycles (data not shown).
  • EXAMPLE 9
  • This example compares the pharmacokinetic parameters of nanoparticulate megestrol acetate formulations of the invention with a conventional microparticulate formulation of megestrol acetate. Results were obtained from a fasted study group consisting of 36 male subjects, 18 years of age or older. For a fed study group, results from 32 subjects were analyzed.
  • Subjects in the fasted study group and the fed study group were administered study drugs in four successive periods. Treatment A (1×150 mg drug as 5 ml of a 3% megestrol acetate nanoparticulate formulation) was administered in the first period. Reference Treatment B (1×800 mg drug as 20 ml of a 4% megestrol acetate Megace® Oral Suspension) was administered in the second period. Treatment C (1×250 mg drug as 5 ml of a 5% megestrol acetate nanoparticulate formulation) was administered in the third period. Treatment D (1×450 mg drug as 5 ml of a 9% megestrol acetate nanoparticulate formulation) was administered in the fourth period. The formulations of Treatments A, C, and D are listed in Table 10 below, with particle size information (microns) provided in Table 11.
  • In each period, subjects were confined from at least 10 hours prior to drug administration to after the last sample collection. In the fasted study group, no food was consumed from at least 10 hours before dosing to at least 4 hours after dosing. In the fed study group, a high-calorie breakfast (containing about 800 to 1000 calories, approximately 50% of which were from fat) was served within 30 minutes prior to dosing; dosing occurred within 5 minutes after the breakfast was completed. A controlled meal was served to both groups after 4 hours after dosing, and standard meals were served at appropriate times thereafter. The meals in all four periods were identical. Subjects in the fasted study group were not allowed fluid intake from 1 hour before dosing to 1 hour after. Subjects in the fed study group were also not allowed fluid intake during this period except for fluids provided with the high-calorie breakfast. Water was provided ad libitum to both study groups at all other times.
  • Blood samples were obtained before dosing, at half-hourly intervals in the 6 hours following dosing, and at 7, 8, 12, 16, 20, 24, 36, 48, 72, and 96 hours after dosing. Megestrol acetate in plasma samples was then determined.
  • Table 12 below summarizes pharmacokinetic data for the fasted study group, and Table 13 below summarizes pharmacokinetic data for the fed study group.
  • Treatments A, C, and D in fasting subjects produced dose-normalized values for AUC0-t and AUC0-inf that were approximately twice those of Reference Treatment B. Maximum dose-normalized megestrol acetate concentrations in Treatments A, C, and D were approximately 9 to 12 times that of Reference Treatment B. The maximum megestrol acetate concentration for the 150 mg-dose of Treatment A was approximately twice that of the 800 mg-dose of reference Treatment B. Moreover, comparable values of AUC0-t and AUC0-inf were observed for the 450 mg-dose of Treatment D and the 800 mg-dose of Reference Treatment B.
  • Treatments A, C, and D in fed subjects produced dose-normalized values for AUC0-t and AUC0-inf that were approximately 8 to 10% greater than those of Reference Treatment B. Maximum dose-normalized megestrol acetate concentrations in Treatments A, C, and D were approximately 38 to 46% greater than that of Reference Treatment B. Megestrol acetate onset for Treatments A, C, and D was comparable to Reference Treatment B.
  • Nanoparticulate megestrol acetate formulations, therefore, exhibited superior oral bioavailability, relative to the Megace® Oral Suspension, in fasting and fed human subjects.
    TABLE 10
    Formulations for Megestrol Acetate Oral Suspension 3, 5% and 9%
    Strengths
    3% w/w 5% w/w 9% w/w
    Ingredients (30 mg/mL) (50 mg/mL) (90 mg/mL)
    Megestrol Acetate 3.000 5.000 9.000
    Hydroxypropyl 0.600 1.000 1.800
    Methylcellulose
    Docusate Sodium 0.030 0.050 0.090
    Sodium Benzoate 0.183 0.178 0.168
    Sodium Citrate Dihydrate 0.009 0.009 0.008
    Citric Acid Monohydrate 0.137 0.133 0.126
    Sucrose 5.000 5.000 5.000
    Natural and Artificial Lemon 0.040 0.040 0.040
    Flavor
    Artificial Lime Flavor 0.040 0.040 0.040
    Purified Water 90.961 88.550 83.727
    TOTAL 100.000 100.000 100.000
  • TABLE 11
    Particle Size Data for the Megestrol Acetate Oral Suspensions*
    Strength 30 mg/g Strength 50 mg/g Strength 90 mg/g
    d(0.1) d(0.5) d(0.9) d(0.1) d(0.5) d(0.9) d(0.1) d(0.5) d(0.9)
    Initial 0.068 0.123 0.223 0.069 0.125 0.229 0.068 0.124 0.227
    ACC/1 0.070 0.129 0.237 0.070 0.127 0.231 0.070 0.127 0.230
    month
    ACC/2 0.070 0.127 0.231 0.070 0.127 0.233 0.073 0.126 0.221
    months
    ACC/3 0.070 0.129 0.237 0.070 0.128 0.235 0.070 0.128 0.234
    months
    RT 3 0.070 0.128 0.237 0.073 0.128 0.224 0.067 0.121 0.223
    months

    *All particle sizes are given in microns. “d(0.1)” means distribution of smallest 10% of the particles, i.e., d(0.1) 10 μm means 10% of the particles are less than 10%. Similarly, “d (0.5)” means distribution of the smallest 50% of the particles, and “d(0.9)” means distribution of the smallest 90% of the particles. Thus, d(0.9) means that 90% of the particles are less than XX μm.
  • TABLE 12
    Summary of Pharmacokinetic Data in Fasted Human Subjects*
    Treatment A Ref. Treatment B Treatment C Treatment D
    Parameters (Mean ± SD) (Mean ± SD) (Mean ± SD) (Mean ± SD)
    AUC0-t 2800 ± 900  7000 ± 5000 4700 ± 1800 8500 ± 3200
    AUC0-inf 3100 ± 1000 9000 ± 9000 5200 ± 2100 9000 ± 4000
    Cmax 410 ± 120 190 ± 110 650 ± 200 950 ± 270
    Tmax 1.7 ± 0.9 6 ± 6 1.6 ± 1.0 1.7 ± 1.1
    t1/2 35 ± 13 31 ± 19 34 ± 10 34 ± 12
    Kel 0.023 ± 0.011 0.026 ± 0.009 0.022 ± 0.008 0.023 ± 0.008

    AUC0-t (ng · hr/ml) = Area under the curve from time zero to the last measurable concentration;

    AUC0-inf (ng · hr/ml) = Area under the curve from time zero to infinity;

    Cmax (ng/ml) = Maximum plasma concentration;

    Tmax (hr) = Time to occurrence of Cmax;

    t1/2 (hr) = Apparent elimination half-life;

    Kel (1/hr) = Elimination rate constant;

    *n = 36.
  • TABLE 13
    Summary of Pharmacokinetic Data in Fed Human Subjects*
    Treatment A Ref. Treatment B Treatment C Treatment D
    Parameters (Mean ± SD) (Mean ± SD) (Mean ± SD) (Mean ± SD)
    AUC0-t 3500 ± 1100 17000 ± 5000  5700 ± 1600 10500 ± 3000 
    AUC0-inf 3900 ± 1300 19000 ± 6000  6300 ± 2000 12000 ± 4000 
    Cmax 380 ± 140 1400 ± 400  590 ± 170 1080 ± 290 
    Tmax 3.8 ± 3.5 3.9 ± 0.9 3.4 ± 1.7 3.2 ± 1.7
    t1/2 35 ± 12 33 ± 9  35 ± 10 38 ± 12
    Kel 0.023 ± 0.013 0.023 ± 0.007 0.023 ± 0.009 0.021 ± 0.008

    AUC0-t (ng · hr/ml) = Area under the curve from time zero to the last measurable concentration;

    AUC0-inf (ng · hr/ml) = Area under the curve from time zero to infinity;

    Cmax (ng/ml) = Maximum plasma concentration;

    Tmax (hr) = Time to occurrence of Cmax;

    t1/2 (hr) = Apparent elimination half-life;

    Kel (1/hr) = Elimination rate constant;

    *n = 32.
  • EXAMPLE 10
  • This example compares the pharmacokinetic parameters of a nanoparticulate megestrol acetate formulations to a conventional microparticulate formulation of megestrol acetate (Megace® by Bristol Myers Squibb Co.). Results were obtained from a fasted study group consisting of 33 male subjects, 18 years of age or older.
  • The nanoparticulate megestrol acetate compositions were prepared as described in Example 10.
  • Subjects were administered study drugs in four successive periods. Treatment A (575 mg of nanoparticulate megestrol acetate formulation in 5 ml oral suspension) was administered in the first period. Reference Treatment B (800 mg of megestrol acetate (Megace® by Bristol Myers Squibb Co.) in 20 ml oral suspension) was administered in the second period. Treatment C (625 mg of nanoparticulate megestrol acetate formulation in 5 ml oral suspension) was administered in the third period. Treatment D (675 mg of nanoparticulate megestrol acetate formulation in 5 ml oral suspension) was administered in the fourth period.
  • Table 14 provides the formulations of Treatments A, C and D.
    TABLE 14
    Formulations of Nanoparticulate Megestrol Acetate Oral Suspensions
    115 mg/mL 125 mg/mL 135 mg/mL
    Dosage Conc. Conc. Conc.
    FINAL AMOUNTS Weight (g) (mg/mL) Weight (g) (mg/mL) Weight (g) (mg/mL)
    Megestrol Acetate 37,500.0 115.00 37,500.0 125.00 37,500.0 135.00
    HPMC 7,500.0 23.00 7,500.0 25.00 7,500.0 27.00
    Docusate Sodium 375.0 1.15 375.0 1.25 375.0 1.35
    Sodium Benzoate 530.4 1.63 481.4 1.60 439.7 1.58
    Sodium Citrate Dihydrate 26.5 0.08 24.0 0.08 22.0 0.08
    Citric Acid Monohydrate 397.8 1.22 361.1 1.20 329.8 1.19
    Sucrose 15,473.0 47.45 14,044.0 46.81 12,826.7 46.18
    Lemon Flavor 123.8 0.38 112.4 0.37 102.6 0.37
    Lime Flavor 123.8 0.38 112.4 0.37 102.6 0.37
    Water 277,080.1 251,489.7 229,690.5
    TOTAL (Weight, g) 339,130.4 312,000.0 288,888.9
    TOTAL (volume, L) 326.1 300.0 277.8
  • The nanoparticulate megestrol acetate formulations were prepared by milling a concentrated dispersion of the drug substance followed by dilution to yield the final products. Hydroxypropyl methylcellulose and docusate sodium were used as stabilizing agents. The formulations were processed in a NanoMill-10 horizontal media mill (Netzsch USA) for 20 hours. The attrition media used was 500 μm crosslinked polystyrene (PolyMill™-500). The dispersion further comprised 0.13% sodium benzoate, 0.01% sodium citrate dihydrate, and 0.1% citric acid monohydrate. Milled dispersion was diluted to final megestrol acetate concentrations of 115 mg/mL (575 mg/5 mL), 125 mg/mL (625 mg/5 mL) and 135 mg/mL (675 mg/5 mL). The final compositions additionally contained sweetening and flavoring agents.
  • Particle size determinations were performed on a Malvern Mastersizer 2000 instrument. The particle size distributions of the nanoparticulate megestrol acetate compositions are provided in Table 15.
    TABLE 15
    Concentration
    (mg/mL) Mean particle size (nm) 50% < (nm) 90% < (nm)
    115 144 130 234
    125 144 127 237
    135 145 131 236
  • In each period, subjects were confined from at least 11 hours prior to drug administration until after the 24.0 hour post-dose sample collection. After a supervised fast of at least 10 hours, subjects were fed a high-calorie meal containing about 800 to 1000 calories (approximately 150 calories from carbohydrates and 500-600 calories from fat). The meal consisted of two eggs fried in butter, two slices of toast with butter, two strips of bacon, approximately 128 g of hash brown potatoes and 200 ml of whole milk. The meals in all four periods were identical. The meal was completed within 30 minutes, and subjects were dosed 30 minutes after starting the meal.
  • The suspensions of Treatments A, B, C and D were administered via Slip Tip syringe directly into the mouth and swallowed. The syringe was rinsed three (3) times with approximately 5 ml (Treatments A, C and D) or 20 ml (Treatment B) of water. Following drug administration, approximately 225 ml (Treatments A, C and D) or 180 ml (Treatment B) of water was ingested.
  • For each period, a total of 24 blood samples were drawn from each subject. Blood samples were collected in EDTA blood tubes prior to drug administration and 0.250, 0.500, 0.750, 1.00, 1.50, 2.00, 2.50, 3.00, 3.50, 4.00, 4.50, 5.00, 5.50, 6.00, 8.00, 12.0, 16.0, 20.0, 24.0, 36.0, 48.0, 72.0 and 96.0 hours post-dose (1×7 nL for each sampling time).
  • Table 16 below summarizes the phammacokinetic data, while Table 17 provides the statistical comparisons of the treatments.
    TABLE 16
    Pharmacokinetic Parameters
    Test-1 (Megtestrol Acetate
    575 mg/5 mL Reference:
    (A)) (Megace 40 mg/mL (B))
    Parameters Mean ± SD CV (%) Mean ± SD Cv (%)
    AUCo-t (ng-h/mL) 13657.52 ± 3900.50 28.56 16896.21 ± 4942.51 29.25
    AUCo-inf (ng-h/mL) 14743.33 ± 4451.31 30.19 18274.06 ± 5623.07 30.77
    Cmax (ng/mL) 1420.73 ± 420.79 2962 1400.66 ± 350.57 25.03
    Tmax (h) 3.75 ± 1.57 41.85 3.88 ± 1.02 26.38
    Tmax* (h) 4.50 ± 1.00 4.50 ± 1.00
    Kel (h−1) 0.0224 ± 0.0062 27.44 0.0238 ± 0.0054 22.84
    T1/2 el (h) 32.78 ± 7.47 22.80 30.53 ± 6.66 21.80
    Test-2 (Megtestrol
    Acetate 625 mg/5 mL Test-3 (Megestrol
    (C)) Acetate 675 mg/5 mL (D))
    Parameters Mean ± SD CV (%) ± ± SD Cv (%)
    AUCo-t (ng-h/mL) 14682.37 ± 4844.60 33.00 15323.29 ± 4525.94 29.54
    AUCo-inf (ng-h/mL) 16081.76 ± 5563.09 34.59 16738.88 ± 5432.52 32.45
    Cmax (ng/mL) 1516.79 ± 389.01 25.65 1645.74 ± 455.71 27.69
    Tmax (h) 2.52 ± 1.60 63.52 3.13 ± 1.64 52.55
    Tmax* (h) 2.50 ± 3.50 3.50 ± 3.00
    Kel (h−1) 0.0211 ± 0.0055 26.21 0.0211 ± 0.0054 25.64
    T1/2 el (h) 34.75 ± 7.81 22.48 34.83 ± 8.12 23.30

    *Median and interquartile ranges are presented.

    AUCo-t (ng · h/ml) = Area under the curve from time zero to the last measurable concentration

    AUCo-inf (ng · h/ml) = Area under the curve from time zero to infinity

    Cmax (ng/ml) = Maximum plasma concentration

    Tmax (h) = Time to occurrence of Cmax

    t1/2 el (h) = elimination half-life

    Kel (1/h) = elimination rate constant
  • TABLE 17
    Treatment Comparisons
    Statistical 90% Geometric Intra-
    Analysis Treatment CL2 Subject
    (ANOVA) Comparisons Ratio1 Lower Upper Cv
    AUCo-t Megestrol Actate 575 mg/5 mL (A) vs 81.06% 78.20% 84.03% 8.82%
    Megace 40 mg/mL (B)
    Megestrol Actate 625 mg/5 mL (C) vs 86.29% 83.24% 89.45%
    Megace 40 mg/mL (B)
    Megestrol Actate 675 mg/5 mL (D) vs 90.63% 87.43% 93.95%
    Megace 40 mg/mL (B)
    AUCo-inf Megestral Actate 575 mg/5 mL (A) vs 80.92% 77.95% 84.00% 9.16%
    Megace 40 mg/mL (B)
    Megestrol Actate 625 mg/5 mL (C) vs 87.33% 84.12% 90.65%
    Megace 40 mg/mL (B)
    Megestrol Actate 675 mg/5 mL (D) vs 91.31% 87.96% 94.79%
    Megace 40 mg/mL (B)
    Cmax Megestrol Actate 575 mg/5 mL (A) vs 100.62% 94.10% 107.69% 16.51%
    Megace 40 mg/mL (B)
    Megestrol Actate 625 mg/5 mL (C) vs 108.18% 101.17% 115.69%
    Megace 40 mg/mL (B)
    Megestrol Actate 675 mg/5 mb (D) vs 116.72% 109.15% 124.82%
    Megace 40 mg/mL (B)

    1Calculated using least-squares means

    290% Geometric Confidence Interval using In-transformed data
  • Tables 16 and 17 demonstrate that Treatments A, C, and D produced similar pharmakinetics as Treatment B. FIGS. 4 and 5 show that Treatments A, C and D produce similar concentration-time curves as Treatment B.
  • It will be apparent to those skilled in the art that various modifications and variations can be made in the methods and compositions of the present invention without departing from the spirit or scope of the invention. Thus, it is intended that the present invention cover the modifications and variations of this invention provided they come within the scope of the appended claims and their equivalents.

Claims (85)

  1. 1. A megestrol nanoparticulate composition comprising:
    (a) particles of megestrol, megestrol acetate, or a salt thereof; and
    (b) associated with the surface thereof at least one surface stabilizer,
    wherein the megestrol particles have an effective average particle size of less than about 2000 nm.
  2. 2. The composition of claim 1, wherein the megestrol is selected from the group consisting of a crystalline phase, an amorphous phase, a semi-crystalline phase, a semi-amorphous phase, and mixtures thereof.
  3. 3. The composition of claim 1, wherein the effective average particle size of the nanoparticulate megestrol particles is selected from the group consisting of less than about 1900 nm, less than about 1800 nm, less than about 1700 nm, less than about 1600 nm, less than about 1500 nm, less than about 1400 nm, less than about 1300 nm, less than about 1200 nm, less than about 1100 nm, less than about 1000 nm, less than about 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 100 nm, less than about 75 nm, and less than about 50 nm.
  4. 4. The composition of claim 1, wherein the composition is formulated:
    (a) for administration selected from the group consisting of oral, pulmonary, rectal, opthalmic, colonic, parenteral, intracisternal, intravaginal, intraperitoneal, local, buccal, nasal, and topical administration;
    (b) into a dosage form selected from the group consisting of liquid dispersions, gels, aerosols, ointments, creams, controlled release formulations, fast melt formulations, lyophilized formulations, tablets, capsules, delayed release formulations, extended release formulations, pulsatile release formulations, and mixed immediate release and controlled release formulations; or
    (c) a combination thereof.
  5. 5. (canceled)
  6. 6. The composition of claim 1, wherein the composition further comprises one or more pharmaceutically acceptable excipients, carriers, or a combination thereof.
  7. 7. The composition of claim 1, wherein
    (a) the megestrol is present in an amount selected from the group consisting of from about 99.5% to about 0.001%, from about 95% to about 0.1%, and from about 90% to about 0.5%, by weight, based on the total combined weight of the megestrol and at least one surface stabilizer, not including other excipients; and
    (b) the at least one surface stabilizer is present in an amount selected from the group consisting of from about 0.5% to about 99.999%, from about 5.0% to about 95%, and from about 10% to about 99.5%, by weight, based on the total combined dry weight of the megestrol and at least one surface stabilizer, not including other excipients.
  8. 8. (canceled)
  9. 9. The composition of claim 1, comprising at least two surface stabilizers, including a primary and a secondary surface stabilizer.
  10. 10. The composition of claim 9, wherein:
    (a) at least one primary surface stabilizer is selected from the group consisting of hydroxypropyl methylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, and random copolymers of vinyl acetate and vinyl pyrrolidone;
    (b) the secondary surface stabilizer is selected from the group consisting of sodium lauryl sulfate and dioctyl sodium Sulfosuccinate, or
    (c) a combination thereof.
  11. 11. (canceled)
  12. 12. The composition of claim 9, wherein at least one secondary surface stabilizer is present in an amount selected from the group consisting of from about 0.01% to about 99%, from about 0.1% to about 95%, and from about 1% to about 90%, by weight, based on the total combined dry weight of the megestrol, at least one primary surface stabilizer, and at least one secondary surface stabilizer, not including other excipients.
  13. 13. The composition of claim 1, wherein the surface stabilizer is selected from the group consisting of an anionic surface stabilizer, a cationic surface stabilizer, an ionic surface stabilizer, and a zwitterionic surface stabilizer.
  14. 14. The composition of claim 13, wherein the at least one surface stabilizer is selected from the group consisting of cetyl pyridinium chloride, gelatin, casein, phosphatides, dextran, glycerol, gum acacia, cholesterol, tragacanth, stearic acid, benzalkonium chloride, calcium stearate, glycerol monostearate, cetostearyl alcohol, cetomacrogol emulsifying wax, sorbitan esters, polyoxyethylene alkyl ethers, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, polyethylene glycols, dodecyl trimethyl ammonium bromide, polyoxyethylene stearates, colloidal silicon dioxide, phosphates, sodium dodecylsulfate, carboxymethylcellulose calcium, hydroxypropyl celluloses, hydroxypropyl methylcellulose, carboxymethylcellulose sodium, methylcellulose, hydroxyethylcellulose, hydroxypropylmethyl-cellulose phthalate, noncrystalline cellulose, magnesium aluminum silicate, triethanolamine, polyvinyl alcohol, polyvinylpyrrolidone, 4-(1,1,3,3-tetramethylbutyl)-phenol polymer with ethylene oxide and formaldehyde, poloxamers; poloxamines, a charged phospholipid, dioctylsulfosuccinate, dialkylesters of sodium sulfosuccinic acid, sodium lauryl sulfate, alkyl aryl polyether sulfonates, mixtures of sucrose stearate and sucrose distearate, p-isononylphenoxypoly-(glycidol), decanoyl-N-methylglucamide; n-decyl β-D-glucopyranoside; n-decyl β-D-maltopyranoside; n-dodecyl β-D-glucopyranoside; n-dodecyl β-D-maltoside; heptanoyl-N-methylglucamide; n-heptyl-β-D-glucopyranoside; n-heptyl β-D-thioglucoside; n-hexyl β-D-glucopyranoside; nonanoyl-N-methylglucamide; n-noyl β-D-glucopyranoside; octanoyl-N-methylglucamide; n-octyl-β-D-glucopyranoside; octyl β-D-thioglucopyranoside; lysozyme, PEG-phospholipid, PEG-cholesterol, PEG-cholesterol derivative, PEG-vitamin A, PEG-vitamin E, random copolymers of vinyl acetate and vinyl pyrrolidone, cationic polymers, cationic biopolymers, cationic polysaccharides, cationic cellulosics, cationic alginate, cationic nonpolymeric compounds, cationic phospholipids, polymethylmethacrylate trimethylammonium bromide, polyvinylpyrrolidone-2-dimethylaminoethyl methacrylate dimethyl sulfate, hexadecyltrimethyl ammonium bromide, cationic lipids, sulfonium compounds, phosphonium compounds, quarternary ammonium compounds, benzyl-di(2-chloroethyl)ethylammonium bromide, coconut trimethyl ammonium chloride, coconut trimethyl ammonium bromide, coconut methyl dihydroxyethyl ammonium chloride, coconut methyl dihydroxyethyl ammonium bromide, decyl triethyl ammonium chloride, decyl dimethyl hydroxyethyl ammonium chloride, decyl dimethyl hydroxyethyl ammonium chloride bromide, C12-15dimethyl hydroxyethyl ammonium chloride, C12-15dimethyl hydroxyethyl ammonium chloride bromide, coconut dimethyl hydroxyethyl ammonium chloride, coconut dimethyl hydroxyethyl ammonium bromide, myristyl trimethyl ammonium methyl sulphate, lauryl dimethyl benzyl ammonium chloride, lauryl dimethyl benzyl ammonium bromide, lauryl dimethyl (ethenoxy)4 ammonium chloride, lauryl dimethyl (ethenoxy)4 ammonium bromide, N-alkyl (C12-18)dimethylbenzyl ammonium chloride, N-alkyl (C14-18)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, dialkyl-dimethylammonium salts, lauryl trimethyl ammonium chloride, ethoxylated alkyamidoalkyldialkylammonium salt, an ethoxylated trialkyl ammonium salt, dialkylbenzene dialkylammonium chloride, N-didecyldimethyl ammonium chloride, N-tetradecyldimethylbenzyl ammonium, chloride monohydrate, N-alkyl (C12-14) dimethyl 1-naphthylmethyl ammonium chloride, dodecyldimethylbenzyl ammonium chloride, dialkyl benzenealkyl ammonium chloride, lauryl trimethyl ammonium chloride, alkylbenzyl methyl ammonium chloride, alkyl benzyl dimethyl ammonium bromide, C12 trimethyl ammonium bromides, C15 trimethyl ammonium bromides, C17 trimethyl ammonium bromides, dodecylbenzyl triethyl ammonium chloride, poly-diallyldimethylammonium chloride (DADMAC), dimethyl ammonium chlorides, alkyldimethylammonium halogenides, tricetyl methyl ammonium chloride, decyltrimethylammonium bromide, dodecyltriethylammonium bromide, tetradecyltrimethylammonium bromide, methyl trioctylammonium chloride, POLYQUAT 10™, tetrabutylammonium bromide, benzyl trimethylammonium bromide, choline esters, benzalkonium chloride, stearalkonium chloride compounds, cetyl pyridinium bromide, cetyl pyridinium chloride, halide salts of quaternized polyoxyethylalkylamines, MIRAPOL™, ALKAQUAT™, alkyl pyridinium salts; amines, amine salts, amine oxides, imide azolinium salts, protonated quatemary acrylamides, methylated quaternary polymers, lysozyme, and cationic guar.
  15. 15-16. (canceled)
  16. 17. The composition of claim 13, wherein the composition is bioadhesive.
  17. 18. The composition of claim 1, wherein the amount of megestrol is selected from the group consisting of 3 percent by weight, 5 percent by weight, and 9 percent by weight.
  18. 19. The composition of claim 18, additionally comprising hydroxypropyl methyl cellulose and dioctyl sodium sulfosuccinate as surface stabilizers.
  19. 20. The composition of claim 1, further comprising a megestrol composition having an effective average particle size of greater than about 2 microns.
  20. 21. The composition of claim 1, additionally comprising at least one additional nanoparticulate megestrol composition having an effective average particle size of less than about 2 microns, wherein said additional nanoparticulate megestrol composition has an effective average particle size which is different than the effective average particle size of the nanoparticulate megestrol composition of claim 1.
  21. 22. The composition of claim 1, additionally comprising at least one non-megestrol active agent.
  22. 23. The composition of claim 22, wherein said active agent is selected from the group consisting of amino acids, proteins, peptides, nucleotides, anti-obesity drugs, nutraceuticals, dietary supplements, central nervous symptom stimulants, carotenoids, corticosteroids, elastase inhibitors, anti-fungals, alkylxanthine, oncology therapies, anti-emetics, analgesics, opioids, antipyretics, cardiovascular agents, anti-inflammatory agents, anthelmintics, anti-arrhythmic agents, antibiotics, anticoagulants, antidepressants, antidiabetic agents, antiepileptics, antihistamines, antihypertensive agents, antimuscarinic agents, antimycobacterial agents, antineoplastic agents, immunosuppressants, antithyroid agents, antiviral agents, anxiolytics, sedatives, astringents, alpha-adrenergic receptor blocking agents, beta-adrenoceptor blocking agents, blood products, blood substitutes, cardiac inotropic agents, contrast media, corticosteroids, cough suppressants, diagnostic agents, diagnostic imaging agents, diuretics, dopaminergics, haemostatics, immunological agents, lipid regulating agents, muscle relaxants, parasympathomimetics, parathyroid calcitonin and biphosphonates, prostaglandins, radio-pharmaceuticals, sex hormones, anti-allergic agents, stimulants, anoretics, sympathomimetics, thyroid agents, vasodilators, vasomodulator, xanthines, Mu receptor antagonists, Kappa receptor antagonists, non-narcotic analgesics, monoamine uptake inhibitors, adenosine regulating agents, cannabinoid derivatives, Substance P antagonists, neurokinin-1 receptor antagonists, and sodium channel blockers.
  23. 24. The composition of claim 23, wherein said nutraceutical is selected from the group consisting of lutein, folic acid, fatty acids, fruit extracts, vegetable extracts, vitamin supplements, mineral supplements, phosphatidylserine, lipoic acid, melatonin, glucosamine/chondroitin, Aloe Vera, Guggul, glutamine, amino acids, green tea, lycopene, whole foods, food additives, herbs, phytonutrients, antioxidants, flavonoid constituents of fruits, evening primrose oil, flax seeds, fish oils, marine animal oils, and probiotics.
  24. 25. The composition of claim 22, wherein at least one non-megestrol active agent has an effective average particle size of less than about 2 microns.
  25. 26. The composition of claim 22, wherein at least one non-megestrol active agent has an effective average particle size of greater than about 2 microns.
  26. 27. The composition of claim 1, wherein:
    (a) upon administration the composition redisperses such that the megestrol particles have a particle size selected from the group consisting of less than about 2 microns, less than about 1900 nm, less than about 1800 nm, less than about 1700 nm, less than about 1600 nm, less than about 1500 nm, less than about 1400 nm, less than about 1300 nm, less than about 1200 nm, less than about 1100 nm, less than about 1000 nm, less than about 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, and less than about 50 nm;
    (b) the composition redisperses in a biorelevant media such that the megestrol particles have a particle size selected from the group consisting of less than about 2 microns, less than about 1900 nm, less than about 1800 nm, less than about 1700 nm, less than about 1600 nm, less than about 1500 nm, less than about 1400 nm, less than about 1300 nm, less than about 1200 nm, less than about 1100 nm, less than about 1000 nm, less than about 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, and less than about 50 nm, or
    (c) a combination thereof.
  27. 28. (canceled)
  28. 29. The composition of claim 1, wherein the composition does not produce significantly different absorption levels when administered under fed as compared to fasting conditions.
  29. 30. The composition of claim 1, wherein:
    (a) the difference in absorption of the nanoparticulate megestrol composition, when administered in the fed versus the fasted state, is selected from the group consisting of less than about 100%, less than about 90%, less than about 80%, less than about 70%, less than about 60%, less than about 50%, less than about 40%, less than about 35%, less than about 30%, less than about 25%, less than about 20%, less than about 15%, less than about 10%, less than about 5%, and less than about 3%;
    (b) the difference in the Tmax for the nanoparticulate megestrol composition, when administered in the fed versus the fasted state, is less than about 100%, less than about 90%, less than about 80%, less than about 70%, less than about 60%, less than about 50%, less than about 40%, less than about 30%, less than about 20%, less than about 15%, less than about 10%, less than about 5%, and less than about 3%; or
    (c) a combination thereof.
  30. 31. The composition of claim 1, wherein the composition does not produce significantly different rates of absorption (Tmax) when administered under fed as compared to fasting conditions.
  31. 32. (canceled)
  32. 33. The composition of claim 1, wherein upon administration:
    (a) the Tmax is less than that of a standard commercial non-nanoparticulate composition of megestrol, administered at the same dosage;
    (b) the Cmax of the composition is greater than the Cmax of a standard commercial non-nanoparticulate composition of megestrol administered at the same dosage, or
    (c) a combination thereof.
  33. 34. The composition of claim 1, wherein following administration the composition has a Tmax selected from the group consisting of less than about 5 hours, less than about 4.5 hours, less than about 4 hours, less than about 3.5 hours, less than about 3 hours, less than about 2.75 hours, less than about 2.5 hours, less than about 2.25 hours, less than about 2 hours, less than about 1.75 hours, less than about 1.5 hours, less than about 1.25 hours, less than about 1.0 hours, less than about 50 minutes, less than about 40 minutes, less than about 30 minutes, less than about 25 minutes, less than about 20 minutes, less than about 15 minutes, and less than about 10 minutes.
  34. 35. (canceled)
  35. 36. The composition of claim 34, wherein the composition exhibits a Tmax not greater than about 3 hours after administration.
  36. 37. The composition of claim 1, wherein in comparative pharmacokinetic testing with a standard commercial non-nanoparticulate composition of megestrol, administered at the same dosage, the nanoparticulate composition exhibits:
    (a) a Tmax selected from the group consisting of less than about 100%, less than about 90%, less than about 80%, less than about 70%, less than about 60%, less than about 50%, less than about 40%, less than about 30%, less than about 25%, less than about 20%, less than about 15%, and less than about 10% of the Tmax exhibited by the non-nanoparticulate composition of megestrol;
    (b) a Cmax selected from the group consisting of greater than about 5%, greater than about 10%, greater than about 15%, greater than about 20%, greater than about 30%, greater than about 40%, greater than about 50%, greater than about 60%, greater than about 70%, greater than about 80%, greater than about 90%, greater than about 100%, greater than about 110%, greater than about 120%, greater than about 130%, greater than about 140%, greater than about 150%, greater than about 200%, greater than about 500% and greater than about 800% than the Cmax exhibited by the non-nanoparticulate composition of megestrol; or
    (c) a combination thereof.
  37. 38. The composition of claim 1, wherein in comparative pharmacokinetic testing with a standard commercial formulation of megestrol, the composition exhibits a Tmax selected from the group consisting of not greater than about 50%, not greater than about 33%, and not greater than about 25% of the Tmax exhibited by the standard commercial megestrol formulation.
  38. 39-42. (canceled)
  39. 43. The composition of claim 1, wherein the therapeutically effective amount of the megestrol is selected from the group consisting of ⅙, ⅕, ¼, ⅓rd, or ½ of the therapeutically effective amount of a standard commercial megestrol formulation.
  40. 44. (canceled)
  41. 45. The composition of claim 1, wherein the composition is in a liquid oral dosage form, and the viscosity of the composition is selected from the group consisting of:
    (a) less than about 1/200, less than about 1/175, less than about 1/150, less than about 1/125, less than about 1/100, less than about 1/50, and less than about 1/25 of the viscosity of a standard commercial liquid oral megestrol formulation at about the same concentration per ml of megestrol;
    (b) from about 175 mPa s to about 1 mPa s, from about 150 mPa s to about 1 mPa, from about 125 mPa s to about 1 mPa s, from about 100 mPa s to about 1 mPa s, from about 75 mPa s to about 1 mPa s, from about 50 mPa s to about 1 mPa s, from about 25 mPa s to about 1 mPa s, from about 15 mPa s to about 1 mPa s, and from about 5 mPa s to about 1 mPa s; or
    (c) a combination thereof.
  42. 46. (canceled)
  43. 47. A liquid oral megestrol acetate composition having a viscosity less than the viscosity of a standard commercial megestrol formulation.
  44. 48. The composition of claim 47, wherein the amount of megestrol acetate per ml is equal to or greater than the amount of megestrol acetate per ml of a standard commercial liquid oral megestrol acetate formulation.
  45. 49. The composition of claim 48, wherein the viscosity is selected from the group consisting of:
    (a) less than about 1/200, less than about 1/175, less than about 1/150, less than about 1/125, less than about 1/100, less than about 1/50, and less than about 1/25 of a standard commercial liquid oral megestrol formulation at about the same concentration per ml of megestrol acetate;
    (b) from about 175 mPa s to about 1 mPa s, from about 150 mPa s to about 1 mPa, from about 125 mPa s to about 1 mPa s, from about 100 mPa s to about 1 mPa s, from about 75 mPa s to about 1 mPa s, from about 50 mPa s to about 1 mPa s, from about 25 mPa s to about 1 mPa s, from about 15 mPa s to about 1 mPa s, and from about 5 mPa s to about 1 mPa s; or
    (c) a combination thereof.
  46. 50. (canceled)
  47. 51. A megestrol acetate nanoparticulate composition comprising:
    (a) particles of megestrol acetate having an effective average particle size of less than about 2000 nm; and
    (b) associated with the surface thereof hydroxypropyl methylcellulose (HPMC) and dioctyl sodium sulfosuccinate (DOSS).
  48. 52. The composition of claim 51, wherein the ratio of megestrol acetate:HPMC is about 1 about 5 and the ratio of megestrol acetate:DOSS is about 1:about 100.
  49. 53. A method of making a nanoparticulate megestrol composition comprising contacting megestrol particles with at least one surface stabilizer for a time and under conditions sufficient to provide a nanoparticulate megestrol composition having an effective average particle size of less than about 2000 nm.
  50. 54-75. (canceled)
  51. 76. A method of treating a subject in need with a nanoparticulate megestrol formulation comprising administering to the subject an effective amount of a nanoparticulate composition comprising megestrol particles having at least one surface stabilizer associated with the surface thereof, wherein the megestrol particles have an effective average particle size of less than about 2000 nm.
  52. 77. The method of claim 76, wherein the condition to be treated is selected from the group consisting of neoplastic diseases, breast cancer, endometrial cancer, uterine cancer, cervical cancer, prostate cancer, renal cancer, hormone replacement therapy in post-menopausal women, endometriosis, hirsutism, dysmenorrhea, uterine bleeding, HIV wasting, cancer wasting, cachexia, anorexia, castration, and oral contraception.
  53. 78. The method of claim 76, wherein the nanoparticulate megestrol formulation is administered in the form of an oral suspension.
  54. 79. The method of claim 76, wherein a maximum blood plasma concentration of megestrol is attained in about 1 hour or less after administration of the nanoparticulate megestrol formulation in fasting subjects.
  55. 80. The method of claim 76, wherein a maximum blood plasma concentration of megestrol of at least about 700 ng/ml is obtained.
  56. 81. The method of claim 80, wherein the maximum blood plasma concentration of megestrol is at least about 700 ng/ml and is attained in less than 5 hours after administration of the nanoparticulate megestrol formulation.
  57. 82. The method of claim 76, wherein the maximum blood plasma concentration of megestrol is at least about 400 ng/ml and is attained in less than 5 hours after administration of the nanoparticulate megestrol formulation.
  58. 83. The method of claim 76, wherein the nanoparticulate megestrol formulation is administered in an amount providing from about 1 mg/day to about 1000 mg/day of megestrol.
  59. 84. The method of claim 83, wherein the nanoparticulate megestrol formulation is administered in an amount providing from about 40 mg/day to about 800 mg/day of megestrol.
  60. 85. The method of claim 83, wherein the nanoparticulate megestrol formulation is administered in an amount providing from about 500 mg/day to about 700 mg/day of megestrol.
  61. 86. The method of claim 76, wherein the amount of nanoparticulate megestrol formulation is 575 mg/day, 625 mg/day or 675 mg/day.
  62. 87. (canceled)
  63. 88. The method of claim 76, wherein the megestrol is selected from the group consisting of a crystalline phase, an amorphous phase, a semi-crystalline phase, a semi-amorphous phase, and mixtures thereof.
  64. 89. The method of claim 76, wherein the effective average particle size of the nanoparticulate megestrol particles is selected from the group consisting of less than about 1900 nm, less than about 1800 nm, less than about 1700 nm, less than about 1600 nm, less than about 1500 nm, less than about 1400 nm, less than about 1300 nm, less than about 1200 nm, less than about 1100 nm, less than about 1000 nm, less than about 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 100 nm, less than about 75 nm, and less than about 50 nm.
  65. 90. The method of claim 76, wherein the composition:
    (a) is formulated for administration selected from the group consisting of oral, pulmonary, rectal, opthalmic, colonic, parenteral, intracistemal, intravaginal, intraperitoneal, local, buccal, nasal, and topical administration;
    (b) further comprises one or more pharmaceutically acceptable excipients, carriers, or a combination thereof; or
    (c) a combination thereof.
  66. 91. (canceled)
  67. 92. The method of claim 76, wherein:
    (a) the megestrol is present in an amount selected from the group consisting of from about 99% to about 0.01%, from about 95% to about 0.5%, and from about 90% to about 0.5%, by weight, based on the total combined weight of the megestrol and at least one surface stabilizer, not including other excipients; and
    (b) the at least one surface stabilizer is present in an amount selected from the group consisting of from about 0.01% to about 99.5% by weight, from about 0.1% to about 95% by weight, and from about 0.5% to about 90% by weight based on the total combined dry weight of the megestrol and at least one surface stabilizer, not including other excipients.
  68. 93. (canceled)
  69. 94. The method of claim 76, comprising at least one primary surface stabilizer and at least one secondary surface stabilizer.
  70. 95. The method of claim 94, wherein:
    (a) the primary surface stabilizer is selected from the group consisting of hydroxypropyl methylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, and random copolymers of vinyl acetate and vinyl pyrrolidone;
    (b) the secondary surface stabilizer is selected from the group consisting of sodium lauryl sulfate and dioctyl sodium Sulfosuccinate; or
    (c) a combination thereof.
  71. 96. (canceled)
  72. 97. The method of claim 94, wherein the at least one secondary surface stabilizer is present in an amount selected from the group consisting of from about 0.01% to about 99%, from about 0.1% to about 95%, and from about 1% to about 90%, by weight, based on the total combined dry weight of the megestrol, at least one primary surface stabilizer, and at least one secondary surface stabilizer, not including other excipients.
  73. 98. The method of claim 76, wherein the surface stabilizer is selected from the group consisting of an anionic surface stabilizer, a cationic surface stabilizer, and an ionic surface stabilizer.
  74. 99. The method of claim 98, wherein the at least one surface stabilizer is selected from the group consisting of cetyl pyridinium chloride, gelatin, casein, phosphatides, dextran, glycerol, gum acacia, cholesterol, tragacanth, stearic acid, benzalkonium chloride, calcium stearate, glycerol monostearate, cetostearyl alcohol, cetomacrogol emulsifying wax, sorbitan esters, polyoxyethylene alkyl ethers, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, polyethylene glycols, dodecyl trimethyl ammonium bromide, polyoxyethylene stearates, colloidal silicon dioxide, phosphates, sodium dodecylsulfate, carboxymethylcellulose calcium, hydroxypropyl celluloses, hydroxypropyl methylcellulose, carboxymethylcellulose sodium, methylcellulose, hydroxyethylcellulose, hydroxypropylmethyl-cellulose phthalate, noncrystalline cellulose, magnesium aluminum silicate, triethanolamine, polyvinyl alcohol, polyvinylpyrrolidone, 4-(1,1,3,3-tetramethylbutyl)-phenol polymer with ethylene oxide and formaldehyde, poloxamers; poloxamines, a charged phospholipid, dioctylsulfosuccinate, dialkylesters of sodium sulfosuccinic acid, sodium lauryl sulfate, alkyl aryl polyether sulfonates, mixtures of sucrose stearate and sucrose distearate, p-isononylphenoxypoly-(glycidol), decanoyl-N-methylglucamide; n-decyl β-D-glucopyranoside; n-decyl β-D-maltopyranoside; n-dodecyl β-D-glucopyranoside; n-dodecyl β-D-maltoside; heptanoyl-N-methylglucamide; n-heptyl-β-D-glucopyranoside; n-heptyl β-D-thioglucoside; n-hexyl β-D-glucopyranoside; nonanoyl-N-methylglucamide; n-noyl β-D-glucopyranoside; octanoyl-N-methylglucamide; n-octyl-β-D-glucopyranoside; octyl β-D-thioglucopyranoside; lysozyme, PEG-phospholipid, PEG-cholesterol, PEG-cholesterol derivative, PEG-vitamin A, PEG-vitamin E, random copolymers of vinyl acetate and vinyl pyrrolidone, cationic polymers, cationic biopolymers, cationic polysaccharides, cationic cellulosics, cationic alginate, cationic nonpolymeric compounds, cationic phospholipids, benzalkonium chloride, polymethylmethacrylate trimethylammonium bromide, polyvinylpyrrolidone-2-dimethylaminoethyl methacrylate dimethyl sulfate, and hexadecyltrimethyl ammonium bromide, cationic lipids, sulfonium compounds, phosphonium compounds, quartemary ammonium compounds, benzyl-di(2-chloroethyl)ethylammonium bromide, coconut trimethyl ammonium chloride, coconut trimethyl ammonium bromide, coconut methyl dihydroxyethyl ammonium chloride, coconut methyl dihydroxyethyl ammonium bromide, decyl triethyl ammonium chloride, decyl dimethyl hydroxyethyl ammonium chloride, decyl dimethyl hydroxyethyl ammonium chloride bromide, C12-15dimethyl hydroxyethyl ammonium chloride, C12-15 dimethyl hydroxyethyl ammonium chloride bromide, coconut dimethyl hydroxyethyl ammonium chloride, coconut dimethyl hydroxyethyl ammonium bromide, myristyl trimethyl ammonium methyl sulphate, lauryl dimethyl benzyl ammonium chloride, lauryl dimethyl benzyl ammonium bromide, lauryl dimethyl (ethenoxy)4 ammonium chloride, lauryl dimethyl (ethenoxy)4 ammonium bromide, N-alkyl (C12-18)dimethylbenzyl ammonium chloride, N-alkyl (C14-18)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, dialkyl-dimethylammonium salts, lauryl trimethyl ammonium chloride, ethoxylated alkyamidoalkyldialkylammonium salt, an ethoxylated trialkyl ammonium salt, dialkylbenzene dialkylammonium chloride, N-didecyldimethyl ammonium chloride, N-tetradecyldimethylbenzyl ammonium, chloride monohydrate, N-alkyl(C12-14) dimethyl 1-naphthylmethyl ammonium chloride, dodecyldimethylbenzyl ammonium chloride, dialkyl benzenealkyl ammonium chloride, lauryl trimethyl ammonium chloride, alkylbenzyl methyl ammonium chloride, alkyl benzyl dimethyl ammonium bromide, C12 trimethyl ammonium bromides, C15 trimethyl ammonium bromides, C17 trimethyl ammonium bromides, dodecylbenzyl triethyl ammonium chloride, poly-diallyldimethylammonium chloride (DADMAC), dimethyl ammonium chlorides, alkyldimethylammonium halogenides, tricetyl methyl ammonium chloride, decyltrimethylammonium bromide, dodecyltriethylammonium bromide, tetradecyltrimethylammonium bromide, methyl trioctylammonium chloride, POLYQUAT 10™, tetrabutylammonium bromide, benzyl trimethylammonium bromide, choline esters, benzalkonium chloride, stearalkonium chloride compounds, cetyl pyridinium bromide, cetyl pyridinium chloride, halide salts of quaternized polyoxyethylalkylamines, MIRAPOL™, ALKAQUA™, alkyl pyridinium salts, amines, amine salts, amine oxides, imide azolinium salts, protonated quaternary acrylamides, methylated quaternary polymers, and cationic guar.
  75. 100-102. (canceled)
  76. 103. A therapeutic method comprising orally administering to a mammalian subject in need an effective amount of a composition comprising megestrol acetate formulated in such a way as to provide a blood plasma concentration profile, after an initial dose of said composition, with a Tmax of said megestrol acetate of less than 5 hours, and a Cmax of said megestrol acetate of at least 30 ng/ml.
  77. 104. The method of claim 103, wherein said Tmax of megestrol acetate is not greater than 3 hours.
  78. 105. The method of claim 103, wherein said subject is a human.
  79. 106. The method of claim 103, wherein said composition is an oral suspension.
  80. 107. The method of claim 103, wherein said composition is a tablet.
  81. 108. The method of claim 103, wherein said method is used to treat cachexia.
  82. 109. A method of providing megestrol to a fed human subject comprising administering a nanoparticulate megestrol formulation, wherein absorption comprises AUC0-t in an amount of about 3000 ng hr/ml to about 15,000 ng hr/ml.
  83. 110. The method of claim 109, wherein Cmax is about 300 ng/ml to about 1700 ng/ml.
  84. 111. A method of providing megestrol to a fasted human subject comprising administering a nanoparticulate megestrol formulation, wherein absorption comprises AUC0-t in an amount of about 2000 ng hr/ml to about 9000 ng hr/ml.
  85. 112. The method of claim 111, wherein Cmax is about 300 ng/ml to about 2000 ng/ml.
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US11980594 US20080171088A1 (en) 2002-04-12 2007-10-31 Nanoparticulate megestrol formulations
US12826557 US20100266705A1 (en) 2002-04-12 2010-06-29 Nanoparticulate megestrol formulations
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Cited By (22)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040105889A1 (en) * 2002-12-03 2004-06-03 Elan Pharma International Limited Low viscosity liquid dosage forms
US20050008707A1 (en) * 2002-04-12 2005-01-13 Elan Pharma International Ltd. Nanoparticulate megestrol formulations
US20060275372A1 (en) * 2005-06-03 2006-12-07 Elan Pharma International Limited Nanoparticulate imatinib mesylate formulations
US20060292214A1 (en) * 2005-06-03 2006-12-28 Elan Pharma International Limited Nanoparticulate acetaminophen formulations
US20070003615A1 (en) * 2005-06-13 2007-01-04 Elan Pharma International Limited Nanoparticulate clopidogrel and aspirin combination formulations
US20070003628A1 (en) * 2005-05-10 2007-01-04 Elan Pharma International Limited Nanoparticulate clopidogrel formulations
US20070042049A1 (en) * 2005-06-03 2007-02-22 Elan Pharma International, Limited Nanoparticulate benidipine compositions
US20070059371A1 (en) * 2005-06-09 2007-03-15 Elan Pharma International, Limited Nanoparticulate ebastine formulations
WO2008048018A1 (en) * 2006-10-19 2008-04-24 Lg Life Sciences Ltd. A pharmaceutically stable suspension of megestrol material
US20080102121A1 (en) * 1998-11-02 2008-05-01 Elan Pharma International Limited Compositions comprising nanoparticulate meloxicam and controlled release hydrocodone
WO2008073068A1 (en) 2005-06-08 2008-06-19 Elan Pharma International Limited Nanoparticulate and controlled release compositions comprising cefditoren
US20080317843A1 (en) * 2006-07-12 2008-12-25 Elan Corporation Plc Nanoparticulate formulations of modafinil
US20090238884A1 (en) * 2008-03-21 2009-09-24 Elan Pharma International Limited Compositions for site-specific delivery of imatinib and methods of use
US20100221327A1 (en) * 2005-06-15 2010-09-02 Elan Pharma International Limited Nanoparticulate azelnidipine formulations
US20100226989A1 (en) * 2002-04-12 2010-09-09 Elan Pharma International, Limited Nanoparticulate megestrol formulations
EP2279727A2 (en) 2005-09-15 2011-02-02 Elan Pharma International Limited Nanoparticulate aripiprazole formulations
US20110064803A1 (en) * 2005-05-10 2011-03-17 Elan Pharma International Limited. Nanoparticulate and controlled release compositions comprising vitamin k2
EP2343053A1 (en) 2006-05-30 2011-07-13 Elan Pharma International Limited Nanoparticulate posaconazole formulations
US8323641B2 (en) 2002-02-04 2012-12-04 Alkermes Pharma Ireland Limited Nanoparticulate compositions having lysozyme as a surface stabilizer
US9173854B2 (en) 2009-04-24 2015-11-03 Iceutica Pty Ltd. Formulation of diclofenac
US9192570B2 (en) 2013-12-20 2015-11-24 AntiOP, Inc. Intranasal naloxone compositions and methods of making and using same
US9345665B2 (en) 2009-05-27 2016-05-24 Alkermes Pharma Ireland Limited Reduction of flake-like aggregation in nanoparticulate active agent compositions

Families Citing this family (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7101576B2 (en) * 2002-04-12 2006-09-05 Elan Pharma International Limited Nanoparticulate megestrol formulations
EP1730751B1 (en) * 2004-03-12 2009-10-21 The Provost, Fellows And Scholars Of The College Of The Holy And Undivided Trinity Of Queen Elizabeth Near Dublin A magnetoresistive medium
WO2006109177A1 (en) * 2005-04-13 2006-10-19 Pfizer Products Inc. Injectable depot formulations and methods for providing sustained release of poorly soluble drugs comprising nanoparticles
US20080166411A1 (en) * 2006-04-10 2008-07-10 Pfizer Inc Injectable Depot Formulations And Methods For Providing Sustained Release Of Poorly Soluble Drugs Comprising Nanoparticles
US20070185066A1 (en) * 2005-12-20 2007-08-09 Verus Pharmaceuticals, Inc. Systems and methods for the delivery of corticosteroids
US20070249572A1 (en) * 2005-12-20 2007-10-25 Verus Pharmaceuticals, Inc. Systems and methods for the delivery of corticosteroids
US20070178050A1 (en) * 2005-12-20 2007-08-02 Verus Pharmaceuticals, Inc. Methods and systems for the delivery of corticosteroids having an increased lung depositon
US20070197486A1 (en) * 2005-12-20 2007-08-23 Verus Pharmaceuticals, Inc. Methods and systems for the delivery of corticosteroids
US20070160542A1 (en) * 2005-12-20 2007-07-12 Verus Pharmaceuticals, Inc. Methods and systems for the delivery of corticosteroids having an enhanced pharmacokinetic profile
US20070191327A1 (en) * 2006-02-15 2007-08-16 Verus Pharmaceuticals, Inc. Sterilization of corticosteroids with reduced mass loss
FR2945048B1 (en) * 2009-04-30 2013-07-05 Ondeo Ind Solutions Process for methanization from a liquid phase which is a by-product resulting from extraction of a main product obtained from a vegetable raw material
KR101378951B1 (en) * 2011-07-29 2014-03-31 재단법인 유타 인하 디디에스 및 신의료기술개발 공동연구소 Oral formulation comprising megestrol acetate powder with enhanced bioavailability, and method for preparing the same
WO2013032310A1 (en) * 2011-09-02 2013-03-07 재단법인 유타 인하 디디에스 및 신의료기술개발 공동연구소 Fast-dissolving megestrol tablet and method for preparing same
EP2780009A4 (en) 2011-11-17 2015-05-06 Univ Colorado Regents Methods and compositions for enhanced drug delivery to the eye and extended delivery formulations

Citations (80)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6432381B1 (en) *
US4783484A (en) * 1984-10-05 1988-11-08 University Of Rochester Particulate composition and use thereof as antimicrobial agent
US4826689A (en) * 1984-05-21 1989-05-02 University Of Rochester Method for making uniformly sized particles from water-insoluble organic compounds
US5145684A (en) * 1991-01-25 1992-09-08 Sterling Drug Inc. Surface modified drug nanoparticles
US5298262A (en) * 1992-12-04 1994-03-29 Sterling Winthrop Inc. Use of ionic cloud point modifiers to prevent particle aggregation during sterilization
US5302401A (en) * 1992-12-09 1994-04-12 Sterling Winthrop Inc. Method to reduce particle size growth during lyophilization
US5318767A (en) * 1991-01-25 1994-06-07 Sterling Winthrop Inc. X-ray contrast compositions useful in medical imaging
US5326552A (en) * 1992-12-17 1994-07-05 Sterling Winthrop Inc. Formulations for nanoparticulate x-ray blood pool contrast agents using high molecular weight nonionic surfactants
US5328404A (en) * 1993-03-29 1994-07-12 Sterling Winthrop Inc. Method of x-ray imaging using iodinated aromatic propanedioates
US5336507A (en) * 1992-12-11 1994-08-09 Sterling Winthrop Inc. Use of charged phospholipids to reduce nanoparticle aggregation
US5338732A (en) * 1991-06-18 1994-08-16 Bristol-Myers Squibb Company Megestrol acetate formulation
US5340564A (en) * 1992-12-10 1994-08-23 Sterling Winthrop Inc. Formulations comprising olin 10-G to prevent particle aggregation and increase stability
US5346702A (en) * 1992-12-04 1994-09-13 Sterling Winthrop Inc. Use of non-ionic cloud point modifiers to minimize nanoparticle aggregation during sterilization
US5349957A (en) * 1992-12-02 1994-09-27 Sterling Winthrop Inc. Preparation and magnetic properties of very small magnetite-dextran particles
US5352459A (en) * 1992-12-16 1994-10-04 Sterling Winthrop Inc. Use of purified surface modifiers to prevent particle aggregation during sterilization
US5399363A (en) * 1991-01-25 1995-03-21 Eastman Kodak Company Surface modified anticancer nanoparticles
US5401492A (en) * 1992-12-17 1995-03-28 Sterling Winthrop, Inc. Water insoluble non-magnetic manganese particles as magnetic resonance contract enhancement agents
US5429824A (en) * 1992-12-15 1995-07-04 Eastman Kodak Company Use of tyloxapole as a nanoparticle stabilizer and dispersant
US5449521A (en) * 1988-11-28 1995-09-12 Vectorpharma N.A. Inc. Supported drugs with increased dissolution rate, and a process for their preparation
US5466440A (en) * 1994-12-30 1995-11-14 Eastman Kodak Company Formulations of oral gastrointestinal diagnostic X-ray contrast agents in combination with pharmaceutically acceptable clays
US5472683A (en) * 1995-03-09 1995-12-05 Eastman Kodak Company Nanoparticulate diagnostic mixed carbamic anhydrides as X-ray contrast agents for blood pool and lymphatic system imaging
US5500204A (en) * 1995-02-10 1996-03-19 Eastman Kodak Company Nanoparticulate diagnostic dimers as x-ray contrast agents for blood pool and lymphatic system imaging
US5510118A (en) * 1995-02-14 1996-04-23 Nanosystems Llc Process for preparing therapeutic compositions containing nanoparticles
US5518187A (en) * 1992-11-25 1996-05-21 Nano Systems L.L.C. Method of grinding pharmaceutical substances
US5518738A (en) * 1995-02-09 1996-05-21 Nanosystem L.L.C. Nanoparticulate nsaid compositions
US5521218A (en) * 1995-05-15 1996-05-28 Nanosystems L.L.C. Nanoparticulate iodipamide derivatives for use as x-ray contrast agents
US5525328A (en) * 1994-06-24 1996-06-11 Nanosystems L.L.C. Nanoparticulate diagnostic diatrizoxy ester X-ray contrast agents for blood pool and lymphatic system imaging
US5534270A (en) * 1995-02-09 1996-07-09 Nanosystems Llc Method of preparing stable drug nanoparticles
US5543133A (en) * 1995-02-14 1996-08-06 Nanosystems L.L.C. Process of preparing x-ray contrast compositions containing nanoparticles
US5552160A (en) * 1991-01-25 1996-09-03 Nanosystems L.L.C. Surface modified NSAID nanoparticles
US5560932A (en) * 1995-01-10 1996-10-01 Nano Systems L.L.C. Microprecipitation of nanoparticulate pharmaceutical agents
US5560931A (en) * 1995-02-14 1996-10-01 Nawosystems L.L.C. Formulations of compounds as nanoparticulate dispersions in digestible oils or fatty acids
US5565188A (en) * 1995-02-24 1996-10-15 Nanosystems L.L.C. Polyalkylene block copolymers as surface modifiers for nanoparticles
US5569448A (en) * 1995-01-24 1996-10-29 Nano Systems L.L.C. Sulfated nonionic block copolymer surfactants as stabilizer coatings for nanoparticle compositions
US5571536A (en) * 1995-02-06 1996-11-05 Nano Systems L.L.C. Formulations of compounds as nanoparticulate dispersions in digestible oils or fatty acids
US5573783A (en) * 1995-02-13 1996-11-12 Nano Systems L.L.C. Redispersible nanoparticulate film matrices with protective overcoats
US5573749A (en) * 1995-03-09 1996-11-12 Nano Systems L.L.C. Nanoparticulate diagnostic mixed carboxylic anhydrides as X-ray contrast agents for blood pool and lymphatic system imaging
US5573750A (en) * 1995-05-22 1996-11-12 Nanosystems L.L.C. Diagnostic imaging x-ray contrast agents
US5580579A (en) * 1995-02-15 1996-12-03 Nano Systems L.L.C. Site-specific adhesion within the GI tract using nanoparticles stabilized by high molecular weight, linear poly (ethylene oxide) polymers
US5585108A (en) * 1994-12-30 1996-12-17 Nanosystems L.L.C. Formulations of oral gastrointestinal therapeutic agents in combination with pharmaceutically acceptable clays
US5587143A (en) * 1994-06-28 1996-12-24 Nanosystems L.L.C. Butylene oxide-ethylene oxide block copolymer surfactants as stabilizer coatings for nanoparticle compositions
US5591456A (en) * 1995-02-10 1997-01-07 Nanosystems L.L.C. Milled naproxen with hydroxypropyl cellulose as a dispersion stabilizer
US5593657A (en) * 1995-02-09 1997-01-14 Nanosystems L.L.C. Barium salt formulations stabilized by non-ionic and anionic stabilizers
US5605889A (en) * 1994-04-29 1997-02-25 Pfizer Inc. Method of administering azithromycin
US5622938A (en) * 1995-02-09 1997-04-22 Nano Systems L.L.C. Sugar base surfactant for nanocrystals
US5628981A (en) * 1994-12-30 1997-05-13 Nano Systems L.L.C. Formulations of oral gastrointestinal diagnostic x-ray contrast agents and oral gastrointestinal therapeutic agents
US5643552A (en) * 1995-03-09 1997-07-01 Nanosystems L.L.C. Nanoparticulate diagnostic mixed carbonic anhydrides as x-ray contrast agents for blood pool and lymphatic system imaging
US5662883A (en) * 1995-01-10 1997-09-02 Nanosystems L.L.C. Microprecipitation of micro-nanoparticulate pharmaceutical agents
US5665331A (en) * 1995-01-10 1997-09-09 Nanosystems L.L.C. Co-microprecipitation of nanoparticulate pharmaceutical agents with crystal growth modifiers
US5718388A (en) * 1994-05-25 1998-02-17 Eastman Kodak Continuous method of grinding pharmaceutical substances
US5718919A (en) * 1995-02-24 1998-02-17 Nanosystems L.L.C. Nanoparticles containing the R(-)enantiomer of ibuprofen
US5741522A (en) * 1991-07-05 1998-04-21 University Of Rochester Ultrasmall, non-aggregated porous particles of uniform size for entrapping gas bubbles within and methods
US5747001A (en) * 1995-02-24 1998-05-05 Nanosystems, L.L.C. Aerosols containing beclomethazone nanoparticle dispersions
US5834025A (en) * 1995-09-29 1998-11-10 Nanosystems L.L.C. Reduction of intravenously administered nanoparticulate-formulation-induced adverse physiological reactions
US5862999A (en) * 1994-05-25 1999-01-26 Nano Systems L.L.C. Method of grinding pharmaceutical substances
US6028065A (en) * 1998-04-20 2000-02-22 Pharmaceutical Resources, Inc. Flocculated suspension of megestrol acetate
US6034175A (en) * 1992-05-28 2000-03-07 Zeneca Limited Salts of peptides with carboxy-terminated polyesters
US6045829A (en) * 1997-02-13 2000-04-04 Elan Pharma International Limited Nanocrystalline formulations of human immunodeficiency virus (HIV) protease inhibitors using cellulosic surface stabilizers
US6068858A (en) * 1997-02-13 2000-05-30 Elan Pharma International Limited Methods of making nanocrystalline formulations of human immunodeficiency virus (HIV) protease inhibitors using cellulosic surface stabilizers
US6153225A (en) * 1998-08-13 2000-11-28 Elan Pharma International Limited Injectable formulations of nanoparticulate naproxen
US6165506A (en) * 1998-09-04 2000-12-26 Elan Pharma International Ltd. Solid dose form of nanoparticulate naproxen
US6165504A (en) * 1998-09-23 2000-12-26 Barr Laboratories, Inc. Methods for treating hot flashes and improving the quality of life of castrated prostatic cancer patients
US6264922B1 (en) * 1995-02-24 2001-07-24 Elan Pharma International Ltd. Nebulized aerosols containing nanoparticle dispersions
US6268356B1 (en) * 1998-04-20 2001-07-31 Pharmaceutical Resources, Inc. Flocculated suspension of megestrol acetate
US6267989B1 (en) * 1999-03-08 2001-07-31 Klan Pharma International Ltd. Methods for preventing crystal growth and particle aggregation in nanoparticulate compositions
US6270806B1 (en) * 1999-03-03 2001-08-07 Elan Pharma International Limited Use of peg-derivatized lipids as surface stabilizers for nanoparticulate compositions
US6316029B1 (en) * 2000-05-18 2001-11-13 Flak Pharma International, Ltd. Rapidly disintegrating solid oral dosage form
US20020012675A1 (en) * 1998-10-01 2002-01-31 Rajeev A. Jain Controlled-release nanoparticulate compositions
US20020028794A1 (en) * 2000-07-21 2002-03-07 Brubaker Greg Allen Megestrol acetate suspension
US6375986B1 (en) * 2000-09-21 2002-04-23 Elan Pharma International Ltd. Solid dose nanoparticulate compositions comprising a synergistic combination of a polymeric surface stabilizer and dioctyl sodium sulfosuccinate
US6428814B1 (en) * 1999-10-08 2002-08-06 Elan Pharma International Ltd. Bioadhesive nanoparticulate compositions having cationic surface stabilizers
US6431478B1 (en) * 1999-06-01 2002-08-13 Elan Pharma International Limited Small-scale mill and method thereof
US20020131988A1 (en) * 1999-12-16 2002-09-19 Foster Todd P. Pharmaceutical implant containing immediate-release and sustained-release components and method of administration
US20030045563A1 (en) * 2001-01-18 2003-03-06 Ping Gao Pharmaceutical composition having reduced tendency for drug crystallization
US20030108575A1 (en) * 2001-08-06 2003-06-12 Lu Guang Wei Stabilized oral suspension formulation
US20030157172A1 (en) * 2001-12-20 2003-08-21 Lu Guang Wei Pharmaceutical suspension for oral administration
US20030219490A1 (en) * 2002-04-12 2003-11-27 Elan Pharma International Ltd. Nanoparticulate megestrol formulations
US6656505B2 (en) * 2000-07-21 2003-12-02 Alpharma Uspd Inc. Method for forming an aqueous flocculated suspension
US6833373B1 (en) * 1998-12-23 2004-12-21 G.D. Searle & Co. Method of using an integrin antagonist and one or more antineoplastic agents as a combination therapy in the treatment of neoplasia
US20100226989A1 (en) * 2002-04-12 2010-09-09 Elan Pharma International, Limited Nanoparticulate megestrol formulations

Family Cites Families (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH0222227A (en) 1988-04-12 1990-01-25 Bristol Myers Co Treatment of aids cachexia with megestrol acetate
EP0644755B1 (en) 1992-06-10 1997-03-19 NanoSystems L.L.C. Surface modified nsaid nanoparticles
CA2152661C (en) * 1995-06-26 1999-06-29 Duane Leonhardt Improved disengaging means for hose couplings
WO1997010814A1 (en) 1995-09-18 1997-03-27 Vesifact Ag Propofol nanodispersions
FR2775435B1 (en) 1998-02-27 2000-05-26 Bioalliance Pharma Nanoparticles comprising at least one polymer and at least one compound capable of complexing one or more active principles
JP2002540080A (en) 1999-03-19 2002-11-26 パーカー ヒューズ インスティテュート Gerumikuro emulsion formulation
GB2355656B (en) 1999-08-17 2004-04-07 Galena As Pharmaceutical compositions for oral and topical administration
US6656504B1 (en) 1999-09-09 2003-12-02 Elan Pharma International Ltd. Nanoparticulate compositions comprising amorphous cyclosporine and methods of making and using such compositions
JP2001316274A (en) 2000-05-08 2001-11-13 Asahi Kasei Corp Tube feeding nutriment and method for producing the same
JP2003534376A (en) 2000-05-26 2003-11-18 ファルマシア・コーポレーション Use of celecoxib compositions for rapid pain relief
CA2412905A1 (en) 2000-06-16 2001-12-27 Rtp Pharma Inc. Improved injectable dispersions of propofol
CA2428785C (en) 2000-11-20 2011-04-26 Henry William Bosch Nanoparticulate compositions comprising a drug and copolymers of vinyl pyrrolidone and vinyl acetate as surface stabilizers
JP4223390B2 (en) 2001-06-05 2009-02-12 エラン・ファルマ・インターナショナル・リミテッド System and method for milling materials
WO2003002097A1 (en) 2001-06-29 2003-01-09 Eurand Pharmaceuticals Ltd Process of thermodynamical activation of water-insoluble drugs loaded into cross-linked polymers
US9101540B2 (en) * 2002-04-12 2015-08-11 Alkermes Pharma Ireland Limited Nanoparticulate megestrol formulations
EP1494649B1 (en) 2002-04-12 2012-01-04 Alkermes Pharma Ireland Limited Nanoparticulate megestrol formulations
CN1728982A (en) 2002-10-31 2006-02-01 阿尔扎公司 Pharmaceutical formulation providing an increased biovailability of hydrophobic drugs
US7879360B2 (en) 2003-11-05 2011-02-01 Elan Pharma International, Ltd. Nanoparticulate compositions having a peptide as a surface stabilizer

Patent Citations (90)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6432381B1 (en) *
US4826689A (en) * 1984-05-21 1989-05-02 University Of Rochester Method for making uniformly sized particles from water-insoluble organic compounds
US4997454A (en) * 1984-05-21 1991-03-05 The University Of Rochester Method for making uniformly-sized particles from insoluble compounds
US4783484A (en) * 1984-10-05 1988-11-08 University Of Rochester Particulate composition and use thereof as antimicrobial agent
US5449521A (en) * 1988-11-28 1995-09-12 Vectorpharma N.A. Inc. Supported drugs with increased dissolution rate, and a process for their preparation
US5399363A (en) * 1991-01-25 1995-03-21 Eastman Kodak Company Surface modified anticancer nanoparticles
US5145684A (en) * 1991-01-25 1992-09-08 Sterling Drug Inc. Surface modified drug nanoparticles
US5318767A (en) * 1991-01-25 1994-06-07 Sterling Winthrop Inc. X-ray contrast compositions useful in medical imaging
US5552160A (en) * 1991-01-25 1996-09-03 Nanosystems L.L.C. Surface modified NSAID nanoparticles
US5494683A (en) * 1991-01-25 1996-02-27 Eastman Kodak Company Surface modified anticancer nanoparticles
US5451393A (en) * 1991-01-25 1995-09-19 Eastman Kodak Company X-ray contrast compositions useful in medical imaging
US5338732A (en) * 1991-06-18 1994-08-16 Bristol-Myers Squibb Company Megestrol acetate formulation
US5776496A (en) * 1991-07-05 1998-07-07 University Of Rochester Ultrasmall porous particles for enhancing ultrasound back scatter
US5741522A (en) * 1991-07-05 1998-04-21 University Of Rochester Ultrasmall, non-aggregated porous particles of uniform size for entrapping gas bubbles within and methods
US6034175A (en) * 1992-05-28 2000-03-07 Zeneca Limited Salts of peptides with carboxy-terminated polyesters
US5518187A (en) * 1992-11-25 1996-05-21 Nano Systems L.L.C. Method of grinding pharmaceutical substances
US5349957A (en) * 1992-12-02 1994-09-27 Sterling Winthrop Inc. Preparation and magnetic properties of very small magnetite-dextran particles
US5346702A (en) * 1992-12-04 1994-09-13 Sterling Winthrop Inc. Use of non-ionic cloud point modifiers to minimize nanoparticle aggregation during sterilization
US5298262A (en) * 1992-12-04 1994-03-29 Sterling Winthrop Inc. Use of ionic cloud point modifiers to prevent particle aggregation during sterilization
US5302401A (en) * 1992-12-09 1994-04-12 Sterling Winthrop Inc. Method to reduce particle size growth during lyophilization
US5340564A (en) * 1992-12-10 1994-08-23 Sterling Winthrop Inc. Formulations comprising olin 10-G to prevent particle aggregation and increase stability
US5336507A (en) * 1992-12-11 1994-08-09 Sterling Winthrop Inc. Use of charged phospholipids to reduce nanoparticle aggregation
US5470583A (en) * 1992-12-11 1995-11-28 Eastman Kodak Company Method of preparing nanoparticle compositions containing charged phospholipids to reduce aggregation
US5429824A (en) * 1992-12-15 1995-07-04 Eastman Kodak Company Use of tyloxapole as a nanoparticle stabilizer and dispersant
US5352459A (en) * 1992-12-16 1994-10-04 Sterling Winthrop Inc. Use of purified surface modifiers to prevent particle aggregation during sterilization
US5447710A (en) * 1992-12-17 1995-09-05 Eastman Kodak Company Method of making nanoparticulate X-ray blood pool contrast agents using high molecular weight nonionic surfactants
US5401492A (en) * 1992-12-17 1995-03-28 Sterling Winthrop, Inc. Water insoluble non-magnetic manganese particles as magnetic resonance contract enhancement agents
US5326552A (en) * 1992-12-17 1994-07-05 Sterling Winthrop Inc. Formulations for nanoparticulate x-ray blood pool contrast agents using high molecular weight nonionic surfactants
US5328404A (en) * 1993-03-29 1994-07-12 Sterling Winthrop Inc. Method of x-ray imaging using iodinated aromatic propanedioates
US5605889A (en) * 1994-04-29 1997-02-25 Pfizer Inc. Method of administering azithromycin
US5862999A (en) * 1994-05-25 1999-01-26 Nano Systems L.L.C. Method of grinding pharmaceutical substances
US5718388A (en) * 1994-05-25 1998-02-17 Eastman Kodak Continuous method of grinding pharmaceutical substances
US5525328A (en) * 1994-06-24 1996-06-11 Nanosystems L.L.C. Nanoparticulate diagnostic diatrizoxy ester X-ray contrast agents for blood pool and lymphatic system imaging
US5587143A (en) * 1994-06-28 1996-12-24 Nanosystems L.L.C. Butylene oxide-ethylene oxide block copolymer surfactants as stabilizer coatings for nanoparticle compositions
US6432381B2 (en) * 1994-12-30 2002-08-13 Elan Pharma International Limited Methods for targeting drug delivery to the upper and/or lower gastrointestinal tract
US5585108A (en) * 1994-12-30 1996-12-17 Nanosystems L.L.C. Formulations of oral gastrointestinal therapeutic agents in combination with pharmaceutically acceptable clays
US5466440A (en) * 1994-12-30 1995-11-14 Eastman Kodak Company Formulations of oral gastrointestinal diagnostic X-ray contrast agents in combination with pharmaceutically acceptable clays
US5628981A (en) * 1994-12-30 1997-05-13 Nano Systems L.L.C. Formulations of oral gastrointestinal diagnostic x-ray contrast agents and oral gastrointestinal therapeutic agents
US5560932A (en) * 1995-01-10 1996-10-01 Nano Systems L.L.C. Microprecipitation of nanoparticulate pharmaceutical agents
US5662883A (en) * 1995-01-10 1997-09-02 Nanosystems L.L.C. Microprecipitation of micro-nanoparticulate pharmaceutical agents
US5665331A (en) * 1995-01-10 1997-09-09 Nanosystems L.L.C. Co-microprecipitation of nanoparticulate pharmaceutical agents with crystal growth modifiers
US5569448A (en) * 1995-01-24 1996-10-29 Nano Systems L.L.C. Sulfated nonionic block copolymer surfactants as stabilizer coatings for nanoparticle compositions
US5571536A (en) * 1995-02-06 1996-11-05 Nano Systems L.L.C. Formulations of compounds as nanoparticulate dispersions in digestible oils or fatty acids
US5593657A (en) * 1995-02-09 1997-01-14 Nanosystems L.L.C. Barium salt formulations stabilized by non-ionic and anionic stabilizers
US5534270A (en) * 1995-02-09 1996-07-09 Nanosystems Llc Method of preparing stable drug nanoparticles
US5518738A (en) * 1995-02-09 1996-05-21 Nanosystem L.L.C. Nanoparticulate nsaid compositions
US5622938A (en) * 1995-02-09 1997-04-22 Nano Systems L.L.C. Sugar base surfactant for nanocrystals
US5591456A (en) * 1995-02-10 1997-01-07 Nanosystems L.L.C. Milled naproxen with hydroxypropyl cellulose as a dispersion stabilizer
US5500204A (en) * 1995-02-10 1996-03-19 Eastman Kodak Company Nanoparticulate diagnostic dimers as x-ray contrast agents for blood pool and lymphatic system imaging
US5573783A (en) * 1995-02-13 1996-11-12 Nano Systems L.L.C. Redispersible nanoparticulate film matrices with protective overcoats
US5560931A (en) * 1995-02-14 1996-10-01 Nawosystems L.L.C. Formulations of compounds as nanoparticulate dispersions in digestible oils or fatty acids
US5510118A (en) * 1995-02-14 1996-04-23 Nanosystems Llc Process for preparing therapeutic compositions containing nanoparticles
US5543133A (en) * 1995-02-14 1996-08-06 Nanosystems L.L.C. Process of preparing x-ray contrast compositions containing nanoparticles
US5580579A (en) * 1995-02-15 1996-12-03 Nano Systems L.L.C. Site-specific adhesion within the GI tract using nanoparticles stabilized by high molecular weight, linear poly (ethylene oxide) polymers
US5565188A (en) * 1995-02-24 1996-10-15 Nanosystems L.L.C. Polyalkylene block copolymers as surface modifiers for nanoparticles
US5718919A (en) * 1995-02-24 1998-02-17 Nanosystems L.L.C. Nanoparticles containing the R(-)enantiomer of ibuprofen
US5747001A (en) * 1995-02-24 1998-05-05 Nanosystems, L.L.C. Aerosols containing beclomethazone nanoparticle dispersions
US6264922B1 (en) * 1995-02-24 2001-07-24 Elan Pharma International Ltd. Nebulized aerosols containing nanoparticle dispersions
US5472683A (en) * 1995-03-09 1995-12-05 Eastman Kodak Company Nanoparticulate diagnostic mixed carbamic anhydrides as X-ray contrast agents for blood pool and lymphatic system imaging
US5573749A (en) * 1995-03-09 1996-11-12 Nano Systems L.L.C. Nanoparticulate diagnostic mixed carboxylic anhydrides as X-ray contrast agents for blood pool and lymphatic system imaging
US5643552A (en) * 1995-03-09 1997-07-01 Nanosystems L.L.C. Nanoparticulate diagnostic mixed carbonic anhydrides as x-ray contrast agents for blood pool and lymphatic system imaging
US5521218A (en) * 1995-05-15 1996-05-28 Nanosystems L.L.C. Nanoparticulate iodipamide derivatives for use as x-ray contrast agents
US5573750A (en) * 1995-05-22 1996-11-12 Nanosystems L.L.C. Diagnostic imaging x-ray contrast agents
US5834025A (en) * 1995-09-29 1998-11-10 Nanosystems L.L.C. Reduction of intravenously administered nanoparticulate-formulation-induced adverse physiological reactions
US6045829A (en) * 1997-02-13 2000-04-04 Elan Pharma International Limited Nanocrystalline formulations of human immunodeficiency virus (HIV) protease inhibitors using cellulosic surface stabilizers
US6068858A (en) * 1997-02-13 2000-05-30 Elan Pharma International Limited Methods of making nanocrystalline formulations of human immunodeficiency virus (HIV) protease inhibitors using cellulosic surface stabilizers
US6221400B1 (en) * 1997-02-13 2001-04-24 Elan Pharma International Limited Methods of treating mammals using nanocrystalline formulations of human immunodeficiency virus (HIV) protease inhibitors
US6593320B2 (en) * 1998-04-20 2003-07-15 Pharmaceutical Resources Inc. Flocculated suspension of megestrol acetate
US6593318B2 (en) * 1998-04-20 2003-07-15 Pharmaceutical Resources Inc. Flocculated suspension of megestrol acetate
US6028065A (en) * 1998-04-20 2000-02-22 Pharmaceutical Resources, Inc. Flocculated suspension of megestrol acetate
US6268356B1 (en) * 1998-04-20 2001-07-31 Pharmaceutical Resources, Inc. Flocculated suspension of megestrol acetate
US6153225A (en) * 1998-08-13 2000-11-28 Elan Pharma International Limited Injectable formulations of nanoparticulate naproxen
US6165506A (en) * 1998-09-04 2000-12-26 Elan Pharma International Ltd. Solid dose form of nanoparticulate naproxen
US6165504A (en) * 1998-09-23 2000-12-26 Barr Laboratories, Inc. Methods for treating hot flashes and improving the quality of life of castrated prostatic cancer patients
US20020012675A1 (en) * 1998-10-01 2002-01-31 Rajeev A. Jain Controlled-release nanoparticulate compositions
US6833373B1 (en) * 1998-12-23 2004-12-21 G.D. Searle & Co. Method of using an integrin antagonist and one or more antineoplastic agents as a combination therapy in the treatment of neoplasia
US6270806B1 (en) * 1999-03-03 2001-08-07 Elan Pharma International Limited Use of peg-derivatized lipids as surface stabilizers for nanoparticulate compositions
US6267989B1 (en) * 1999-03-08 2001-07-31 Klan Pharma International Ltd. Methods for preventing crystal growth and particle aggregation in nanoparticulate compositions
US6431478B1 (en) * 1999-06-01 2002-08-13 Elan Pharma International Limited Small-scale mill and method thereof
US6428814B1 (en) * 1999-10-08 2002-08-06 Elan Pharma International Ltd. Bioadhesive nanoparticulate compositions having cationic surface stabilizers
US20020131988A1 (en) * 1999-12-16 2002-09-19 Foster Todd P. Pharmaceutical implant containing immediate-release and sustained-release components and method of administration
US6316029B1 (en) * 2000-05-18 2001-11-13 Flak Pharma International, Ltd. Rapidly disintegrating solid oral dosage form
US20020028794A1 (en) * 2000-07-21 2002-03-07 Brubaker Greg Allen Megestrol acetate suspension
US6656505B2 (en) * 2000-07-21 2003-12-02 Alpharma Uspd Inc. Method for forming an aqueous flocculated suspension
US6375986B1 (en) * 2000-09-21 2002-04-23 Elan Pharma International Ltd. Solid dose nanoparticulate compositions comprising a synergistic combination of a polymeric surface stabilizer and dioctyl sodium sulfosuccinate
US20030045563A1 (en) * 2001-01-18 2003-03-06 Ping Gao Pharmaceutical composition having reduced tendency for drug crystallization
US20030108575A1 (en) * 2001-08-06 2003-06-12 Lu Guang Wei Stabilized oral suspension formulation
US20030157172A1 (en) * 2001-12-20 2003-08-21 Lu Guang Wei Pharmaceutical suspension for oral administration
US20030219490A1 (en) * 2002-04-12 2003-11-27 Elan Pharma International Ltd. Nanoparticulate megestrol formulations
US20100226989A1 (en) * 2002-04-12 2010-09-09 Elan Pharma International, Limited Nanoparticulate megestrol formulations

Cited By (39)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20080102121A1 (en) * 1998-11-02 2008-05-01 Elan Pharma International Limited Compositions comprising nanoparticulate meloxicam and controlled release hydrocodone
US8652464B2 (en) 2002-02-04 2014-02-18 Alkermes Pharma Ireland Limited Method of treatment using nanoparticulate compositions having lysozyme as a surface stabilizer
US8323641B2 (en) 2002-02-04 2012-12-04 Alkermes Pharma Ireland Limited Nanoparticulate compositions having lysozyme as a surface stabilizer
US20050008707A1 (en) * 2002-04-12 2005-01-13 Elan Pharma International Ltd. Nanoparticulate megestrol formulations
US9040088B2 (en) 2002-04-12 2015-05-26 Alkermes Pharma Ireland Limited Nanoparticulate megestrol formulations
US20100266705A1 (en) * 2002-04-12 2010-10-21 Elan Pharma International Ltd. Nanoparticulate megestrol formulations
US20100226989A1 (en) * 2002-04-12 2010-09-09 Elan Pharma International, Limited Nanoparticulate megestrol formulations
US9101540B2 (en) * 2002-04-12 2015-08-11 Alkermes Pharma Ireland Limited Nanoparticulate megestrol formulations
US9107827B2 (en) 2002-04-12 2015-08-18 Alkermes Pharma Ireland Limited Nanoparticulate megestrol formulations
US9101549B2 (en) 2002-04-12 2015-08-11 Alkermes Pharma Ireland Limited Nanoparticulate megestrol formulations
US20080171088A1 (en) * 2002-04-12 2008-07-17 Elan Pharma International Ltd. Nanoparticulate megestrol formulations
US20080152585A1 (en) * 2002-04-12 2008-06-26 Elan Pharma International Ltd. Low viscosity liquid dosage forms
US20040105889A1 (en) * 2002-12-03 2004-06-03 Elan Pharma International Limited Low viscosity liquid dosage forms
US20070003628A1 (en) * 2005-05-10 2007-01-04 Elan Pharma International Limited Nanoparticulate clopidogrel formulations
US20110064803A1 (en) * 2005-05-10 2011-03-17 Elan Pharma International Limited. Nanoparticulate and controlled release compositions comprising vitamin k2
US20060292214A1 (en) * 2005-06-03 2006-12-28 Elan Pharma International Limited Nanoparticulate acetaminophen formulations
US20070042049A1 (en) * 2005-06-03 2007-02-22 Elan Pharma International, Limited Nanoparticulate benidipine compositions
US20060275372A1 (en) * 2005-06-03 2006-12-07 Elan Pharma International Limited Nanoparticulate imatinib mesylate formulations
WO2008073068A1 (en) 2005-06-08 2008-06-19 Elan Pharma International Limited Nanoparticulate and controlled release compositions comprising cefditoren
DE112006001606T5 (en) 2005-06-08 2009-07-09 Elan Pharma International Ltd., Athlone Nanoparticulate and having a controlled release composition comprising cefditoren
US20070059371A1 (en) * 2005-06-09 2007-03-15 Elan Pharma International, Limited Nanoparticulate ebastine formulations
US20070003615A1 (en) * 2005-06-13 2007-01-04 Elan Pharma International Limited Nanoparticulate clopidogrel and aspirin combination formulations
US20100221327A1 (en) * 2005-06-15 2010-09-02 Elan Pharma International Limited Nanoparticulate azelnidipine formulations
EP2279727A2 (en) 2005-09-15 2011-02-02 Elan Pharma International Limited Nanoparticulate aripiprazole formulations
EP2343053A1 (en) 2006-05-30 2011-07-13 Elan Pharma International Limited Nanoparticulate posaconazole formulations
US20080317843A1 (en) * 2006-07-12 2008-12-25 Elan Corporation Plc Nanoparticulate formulations of modafinil
WO2008048018A1 (en) * 2006-10-19 2008-04-24 Lg Life Sciences Ltd. A pharmaceutically stable suspension of megestrol material
US20090238884A1 (en) * 2008-03-21 2009-09-24 Elan Pharma International Limited Compositions for site-specific delivery of imatinib and methods of use
US9173854B2 (en) 2009-04-24 2015-11-03 Iceutica Pty Ltd. Formulation of diclofenac
US9180096B2 (en) 2009-04-24 2015-11-10 Iceutica Pty Ltd. Formulation of diclofenac
US9180095B2 (en) 2009-04-24 2015-11-10 Iceutica Pty Ltd. Formulation of diclofenac
US9186328B2 (en) 2009-04-24 2015-11-17 Iceutica Pty Ltd. Formulation of diclofenac
US9974748B2 (en) 2009-05-27 2018-05-22 Alkermes Pharma Ireland Limited Reduction of flake-like aggregation in nanoparticulate active agent compositions
US9345665B2 (en) 2009-05-27 2016-05-24 Alkermes Pharma Ireland Limited Reduction of flake-like aggregation in nanoparticulate active agent compositions
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US9289425B2 (en) 2013-12-20 2016-03-22 AntiOP, Inc. Intranasal naloxone compositions and methods of making and using same
US9192570B2 (en) 2013-12-20 2015-11-24 AntiOP, Inc. Intranasal naloxone compositions and methods of making and using same

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US20080171088A1 (en) 2008-07-17 application
US20150056287A1 (en) 2015-02-26 application
US20100266705A1 (en) 2010-10-21 application
US20150056286A1 (en) 2015-02-26 application
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