HK1133182A

HK1133182A - Sterilized nanoparticulate glucocorticosteroid formulations

Info

Publication number: HK1133182A
Application number: HK09110975.9A
Authority: HK
Inventors: Jack Michael Shaw; David Slifer; Steven B. Ruddy; John Pruitt; Raj Kewalramani
Original assignee: Elan Pharma International Ltd.
Priority date: 2006-01-27
Filing date: 2007-01-24
Publication date: 2010-03-19

Description

Sterilized nanoparticulate glucocorticoid formulations

Technical Field

The present invention relates generally to sterile compositions for the prevention and long term treatment of asthma in adult and pediatric patients and the alleviation of the symptoms of allergic conjunctivitis and seasonal allergic rhinitis in adult and pediatric patients. The sterile composition comprises a glucocorticoid. The invention also relates to pharmaceutical compositions of glucocorticoids for parenteral, inhalation and topical administration in the treatment of various inflammatory and allergic diseases.

Background

A.Background on glucocorticoids

Glucocorticoids have been shown to be effective as prophylactic therapies in the maintenance treatment of asthma, treating nasal symptoms of seasonal and perennial allergic and non-allergic rhinitis in both adult and pediatric patients, and relieving signs and symptoms of seasonal allergic conjunctivitis.

U.S. Pat. No. 6,392,036 to Karlsson et al, "Dry Heat Sterilization of glucocorticoids" refers to the Sterilization of Dry powders containing glucocorticoids. The process involves dry heat treating the powder at a temperature of 100-. This process is disclosed for sterilizing budesonide powders followed by aseptic addition of liquids and excipients to produce the product, pramipexole (Pulmicort respulles). The patent also indicates that sterilization in the presence of water (i.e., moist heat sterilization) is an unacceptable sterilization method because the particles agglomerate. Furthermore, ethylene oxide is an unacceptable sterilization process because of the toxic residue produced. Moreover, beta and gamma irradiation as a sterilization process for micronized budesonide showed significant chemical degradation at low irradiation exposure levels.

U.S. Pat. No. 6,464,958 to Bernini et al, "Process for the preparation of the Suspensions of Drug Particles for Inhalation Delivery," refers to the Process of preparing therapeutically acceptable sterile micronised beclomethasone dipropionate using gamma irradiation. This document discloses that beclometasone dipropionate remains chemically stable when exposed to gamma irradiation of 2-9KGy under specific conditions. Irradiation was carried out in a polyethylene container, Polikem bag, which had been air-replaced with nitrogen and sealed in two oxygen-resistant materials. The sterilized micronized beclomethasone dipropionate is processed in an aseptic manner using a turbo-emulsifier, wherein the aqueous content and excipients are pre-sterilized by steam sterilization using a steam jacket.

European patent application No. EP 1454636A 1 "Sterilization of glucocorticosteroids Drug Particles for Pulmonary administration" to Gentile et al, refers to a process for steam Sterilization of glucocorticosteroids which comprises heating a mixture of micronized glucocorticosteroids and water at a temperature in the range of 100-130 ℃. The glucocorticoid/water ratio is selected to be in the range of 3:100 to 10: 100. Preferably the glucocorticoid is beclomethasone or beclomethasone dipropionate. Preferably sterilized at 121 ℃ for 20 minutes. The impurity distribution of the sterilized glucocorticoid suspension of the invention has no significant difference with the distribution of the non-sterilized glucocorticoid.

U.S. patent No. 6,039,932 to Govind et al, "Medicinal inhalation Aerosol Formulations Containing Budesonide", describes a propellant-based glucocorticoid formulation. Preferred surfactants required include oleic acid, sorbitan oleate and lecithin.

International patent application WO 98/00111 to Waldrep et al, "High Dose Liposomal Aerosol Formulations" refers to High dose budesonide-liposome Aerosol compositions comprising up to about 12.5mg/ml budesonide in up to about 187.5mg dilauroylphosphatidylcholine/ml. Other phospholipids that may be used in carrying out the process may be selected from egg yolk phosphatidylcholine, hydrogenated soy phosphatidylcholine, dilauroyl phosphatidylcholine, dimyristoyl phosphatidylcholine, dioleoyl phosphatidylcholine and dipalmitoyl phosphatidylcholine.

U.S. Pat. No. 5,091,188 to Haynes, "phosphatized-coated microcystals: injectable pharmaceutical compositions of water-insoluble drugs "mention injectable pharmaceutical composition formulations that can be placed in a syringe, consisting of a suspension of solid particles of water-insoluble pharmaceutical active substance of the order of about 50nm to about 10,000nm, said particles being coated with a layer of a film-forming amphiphilic lipid (phospholipid). The compositions are also described for inhalation and ocular administration. The particle size of the drug is reduced in the presence of phospholipids by processes including sonication or high shear.

U.S. patent No. 6,863,865 to McAffer et al, "Sterilization of pharmaceuticals," discloses successful Sterilization of glucocorticoid (budesonide) formulations (also described as high temperature short time Sterilization, "HTST Sterilization") with rapid increase to high temperature, maintenance, and then rapid return to ambient temperature. The HTST sterilization cycle does not cause an increase in the level of impurities in the budesonide formulation and the physical properties of the formulation are not altered.

Verrecchia, U.S. Pat. No. 6,139,870 "Stabilized nanoparticles of filtered particles under sterile conditions" discloses the sterile filtration of nanoparticulate suspensions comprising a hydrophobic, water-insoluble and water-non-dispersible polymer or copolymer emulsified in an aqueous phase containing phospholipids and oleates. Nanoparticles comprise drugs (with emphasis on the "taxane family") and injectable compositions.

U.S. Pat. No. 5,922,355 to Parikh et al, "Composition and method of preparing Water-insoluble substances particles" discloses a probe sonication technique in which a poorly water-soluble drug is combined with one or more surface modifiers or surfactants and natural or synthetic phospholipids to prepare submicron particle sizes. The surface modifying agent or surfactant and phospholipid are combined to produce a final particle size that is at least half smaller than the phospholipid alone. The phospholipid may be phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, phosphatidylglycerol, phosphatidic acid, lysophospholipid, egg yolk or soybean phospholipid (naturally, partially or fully hydrogenated).

U.S. Pat. No. 5,858,410 to Muller et al, "Pharmaceutical nanosuspensions for Pharmaceutical administration as systems with increased saturation solubility and dissolution rate" discloses the preparation of Pharmaceutical carrier particles comprising at least one sparingly soluble therapeutic compound in the size range of 10-1000 nm. Naturally occurring surfactants include phospholipids (stabilization of the system with lecithin, phospholipids, sphingomyelin, sterols, egg yolk lecithin, soy lecithin, and hydrogenated lecithin, along with other dispersion stabilizers such as poloxamers, mono-and diglycerides, poloxamines, sugar alcohols, alkyl phenols). The drugs described in the patent include corticosteroids (such as aldosterone, triamcinolone, and dexamethasone). Muller the apparatus used to prepare the small particles was a Microfluidizer or Nanojet, a process that produces a high shear liquid in a jet.

U.S. Pat. No. 5,993,781 to Snell et al, "Fluticasone PropioninateNeebulizable Formulations" mentions sterilization of bulk suspensions of Fluticasone propionate by steam.

European patent application No. EP 1310243A 1 "Novelformulation" to Santesson et al, mentions a metered unit dose containing 32 μ g of budesonide prepared as fine particles suspended in an aqueous medium having a pH in the range of 3.5-5.0. Preferably the formulation comprises about 0.005-0.1% w/w chelating agent EDTA.

U.S. Pat. No. 5,914,122 "Stable budesonide Solutions, Method of Preparing the same And Use of the Solutions of the enema And Pharmaceutical Foams" to Otterbeck et al states that the stability of the budesonide Solutions is critically dependent on the pH (requiring a pH < 6). Budesonide stability is enhanced in the presence of EDTA or cyclodextrin.

U.S. published patent application No. 2002/0037257A 1 "Budesonide Particles and Pharmaceutical Compositions containing them" to Fraser et al emphasizes having BET values of 1-4.5m²Crystalline budesonide particles with smooth surface in gThe importance of the granule. The process uses a supercritical fluid.

B.Background on nanoparticle compositions

The nanoparticulate compositions first described in U.S. Pat. No. 5,145,684 ("the' 684 patent") are particles comprised of a poorly soluble therapeutic or diagnostic agent having a non-crosslinked surface stabilizer adsorbed on or associated with the surface.

Methods for Preparing nanoparticle Compositions are described, for example, in U.S. Pat. Nos. 5,518,187 and 5,862,999, both of which are "Method of Grinding Pharmaceutical substatics", U.S. Pat. No. 5,718,388 "Continuous Method of Grinding Pharmaceutical substatics", and U.S. Pat. No. 5,510,118 "Process of Grinding Pharmaceutical Compositions" for connecting nanoparticles.

Nanoparticle Compositions are also described in, For example, U.S. Pat. No. 5,298,262 "Use of Ionic cloud Point modulators to Present Particle Aggregation catalysis during sterilization", 5,302,401 "Method to Reduce Particle Growth during lyophilization", 5,318,767 "X-Ray control Compositions Using Medical Imaging", 5,326,552 "Novel Formulation nanoparticles Imaging X-Ray Contrast Compositions Using High Molecular weight ligand Imaging, High Molecular weight nanoparticle Imaging Method to Reduce the Use of nanoparticles of Iodinated phospholipid particles (Use of nanoparticles of Iodinated particles of nanoparticles of iodine ligand 3)" methods of reducing the Use of nanoparticles of Iodinated particles of malonic acid nanoparticles of specific Compositions Using iodine binding Agents (methods of Iodinated nanoparticles of specific binding Agents of specific, 5,340,564 "Formulations containing Olin 10-G to Prevent Particle Aggregation and Increase solubility", 5,346,702 "Use of Non-Ionic Cloud Point modifier to minimize nanoparticle Aggregation During Sterilization", 5,349,957 "preparation and Magnetic Properties of Small Magnetic Dextran Particles", 5,352,459 "Use of Purified Surface modifier to Prevent nanoparticle Aggregation During Sterilization", 5,352,459 "Non-Magnetic modifier to modify nanoparticle Aggregation During Magnetic stabilization", 5,494,683 "Non-Magnetic modifier to Prevent Particle Aggregation, No. 5, No. 57" Non-Magnetic modifier to Prevent Particle Aggregation, No. 5,401,492 "anti-cancer Particles" U.S. Pat. No. 5,429,824 "Use of Tyloxapol as a nanoparticulase Stabilizer (Use of Tyloxapol as Nanoparticle stabilizer)", 5,447,710 "Method for labeling Nanoparticulate X-Ray Blood Pool Agents Using high Molecular Weight Non-ionic Surfactants", 5,451,393 "X-Ray Contrast Compositions Using Medical Imaging (X-Ray Contrast composition for Medical Imaging)", 3632 "Formulations of organic Contrast Agents X-Ray Contrast Compositions in Combination with binding nanoparticles of nanoparticles binding nanoparticles of phospholipid 2" (Method for reducing the Aggregation of nanoparticles of lipid Contrast medium) and "Method for reducing the Aggregation of nanoparticles of lipid Contrast medium" (Method for Oral diagnostic X-Ray Contrast composition for Medical Imaging) ", and" Method for Preparing nanoparticles of lipid Contrast medium for Use of nanoparticles of lipid Contrast medium "(Method for reducing the Aggregation of nanoparticles of lipid particles of nanoparticles of lipid Contrast medium (viscosity of lipid Contrast medium) using the Method for reducing the Aggregation of nanoparticles of lipid particles of lipid Contrast medium (viscosity of lipid Contrast medium) and" Method for reducing the Aggregation of nanoparticles of lipid Contrast medium Nanoparticle Diagnostic mixed carbamates of X-Ray Contrast Agents for blood Pool and Lymphatic System Imaging), "5,500,204" nanoparticle Diagnostic Dimers as X-Ray Contrast Agents for blood Pool and Lymphatic System Imaging), "5,518,738" nanoparticle Diagnostic NSAID Formulations for Use in blood Pool and Lymphatic System Imaging, "5,521,218" nanoparticle Diagnostic as X-Ray Contrast Agents for Use in X-Ray Contrast Agents, "5,525,328" nanoparticle Diagnostic conjugates X-Ray Contrast Agents for blood Pool and Lymphatic System Imaging "(nanoparticle Diagnostic X-Ray Contrast agent for Use in X-Ray Contrast Agents)," 5,525,328 "nanoparticle Diagnostic reagents X-Ray Contrast Agents for blood Pool and Lymphatic System Imaging" (nanoparticle Diagnostic mixed carbamate for Use in blood Pool and Lymphatic System Imaging), "and" nanoparticle Diagnostic reagent for Use in blood Pool and Lymphatic System Imaging "(nanoparticle Diagnostic reagent for Use in Lymphatic System Imaging) and" nanoparticle Diagnostic reagent for Use in blood Pool and Lymphatic System Imaging "nanoparticle Diagnostic mixed carbamate for Use in blood Pool and Lymphatic System (nanoparticle Diagnostic Imaging procedure for Use in blood Pool and Lymphatic System (nanoparticle Diagnostic reagent for Use in Lymphatic System Imaging)" and "nanoparticle Diagnostic reagent for Use in blood Pool and Lymphatic System Imaging (Contrast agent for Use in blood Pool Imaging of blood Pool and Lymphatic System (Contrast System Imaging) and lymph System Imaging, 5,552,160 "Surface modified NSAIDs Nanoparticulates", 5,560,931 "Formulations of Compounds as Nanoparticulate Dispersions in digestible Oils or Fatty Acids", 5,565,188 "Polyalkylene Block copolymers as Nanoparticulate Surface modifying Agents", 5,569,448 "Surface Non-ionic Block copolymer surfactant Coatings for Nanoparticulate compositions (Non-ionic Block copolymer surfactants as Stabilizer coating for Nanoparticulate compositions", 5,571,536 "Formulations of Nanoparticles composites derivatives for Nanoparticulate compositions" or mixed Nanoparticles of Compounds as Nanoparticulate Dispersions in Nanoparticulate systems (injectable Nanoparticles for Nanoparticulate Dispersions or injectable Nanoparticles in Nanoparticulate systems) "Diagnostic reagent for Nanoparticulate compositions" and Diagnostic reagent for Nanoparticulate compositions "or Diagnostic reagent for Nanoparticulate compositions" for Nanoparticulate Dispersions "or mixed Nanoparticles of Nanoparticulate Dispersions" for Nanoparticulate Dispersions "Formulations in Nanoparticulate systems" for Nanoparticulate compositions "or for Nanoparticulate Dispersions (injectable Nanoparticles for Nanoparticulate Dispersions" in Nanoparticulate systems for the diagnosis of Nanoparticulate systems Carboxylic acid anhydrides), "5,573,750" Diagnostic Imaging X-ray contrast Agents, "5,573,783" redispersable anisotropic Film materials With Protective coatings, "5,580,579" Site-specific additive With the GI Tract transporting Nanoparticles Stabilized by High molecular weight Nanoparticles, Linear polymer (Ethylene Oxide) Polymers (Site-specific adhesion in the GI Tract With Nanoparticles Stabilized by High molecular weight Linear Poly (oxyethylene) Polymers), "5,585,108" formulation of organic synergistic Agents With Nanoparticles Stabilized by High molecular weight Linear Poly (oxyethylene) Polymers, "orally administered surfactant Copolymers" of oxidized Nanoparticles Stabilized by polymeric Nanoparticles, oxygen-Stabilized Copolymers of organic polymeric compounds (Ethylene Oxide) as active Nanoparticles in a Gastrointestinal Tract, etc. "(oxygen-Stabilized clay-Stabilized Copolymers," 3-modified Copolymers of organic polymeric compounds (modified Polymers) as active Nanoparticles in a Gastrointestinal Tract, 3-modified Copolymers of organic polymeric compounds (modified Polymers) as active Nanoparticles, coating of a Pharmaceutically Acceptable surfactant in a Gastrointestinal Tract, 5-modified copolymer (Ethylene Oxide-modified Copolymers) as active Nanoparticles in a Therapeutic composition, etc.) ", 5,591,456 "Milled Naprox with Hydroxypropyl Cellulose as Dispersion Stabilizer", 5,593,657 "Novelbarum Salt Formulations stabilizing and Anionic Stabilizers", 5,622,938 "sugar based Surfactant for Nanocrystals", 5,628,981 "Improved Formulations of organic Contrast X-Ray Contrast Agents and organic Contrast media additives for Oral Gastrointestinal Diagnostic X-Ray Contrast Agents and Oral Gastrointestinal Contrast Agents", 5,643,552 "Contrast medium compositions for Continuous Imaging of lymph Contrast medium and Oral gastric Contrast medium and lymph tissue systems" (modified formulation of Oral Gastrointestinal Diagnostic reagent for Gastrointestinal Contrast medium and Oral Contrast medium) and Method for Continuous Imaging of lymph tissue nanoparticles using a Continuous Grinding System of nanoparticles and lymph tissue nanoparticles (reagent for Imaging nanoparticles) and a Continuous Imaging System of lymph tissue and lymph tissue System (reagent for Imaging nanoparticles of nanophase nanoparticles), 5,718,919 "nanoparticles Containing the R (-) Enantiomer of Ibuprofen", 5,747,001 "Aerosols Containing beclomethasone nanoparticle Dispersions", 5,834,025 "Reduction of introduced Administered nanoparticles expressing Induced additive Physiological Reactions", 6,045,829 "nanoparticles Formulations of Human Immunodeficiency Virus (HIV) Protease preparation, and" nanoparticles of Human Immunodeficiency Virus (HIV) Protease preparation "method of stabilizing nanoparticles of Human Immunodeficiency Virus (HIV) Using cellulose Surface stabilizer" (see: Methods of preparing nanoparticle formulation of injectable nanoparticles of HIV Protease inhibitor (see 7) Using cellulose Surface stabilizer) ", method of preparing nanoparticle formulation of stabilizing nanoparticles of Human Immunodeficiency Virus (see 36) Protease preparation (see 7) and" method of stabilizing nanoparticles of HIV Protease preparation Using cellulose Surface stabilizer (see 7) and "method of stabilizing nanoparticles of HIV Protease preparation" method of stabilizing nanoparticles of Using Protease preparation (see 36) Using cellulose Surface stabilizer (see 7) method of stabilizing Protease preparation (see 3) of Human Immunodeficiency Virus (see 3) preparation of nanoparticles of stabilizing Protease preparation (see 3) and (see 3) method of stabilizing HIV Protease preparation of stabilizing nanoparticles of Human Immunodeficiency Virus (see 3) preparation of Human Immunodeficiency Virus (see 3) preparation of nanoparticles of Human Immunodeficiency Virus (see 3) preparation of stabilizing Protease preparation of Human Immunodeficiency Virus (see 3) preparation of Human Immunodeficiency Virus (see) preparation of stabilizing nanoparticles of stabilizing Protease preparation of Human Immunodeficiency Virus) preparation of Human Immunodeficiency Virus (see 3) preparation of stabilizing nanoparticles of Human Immunodeficiency Virus (see) preparation of stabilizing protein preparation of nanoparticles of Human Immunodeficiency Virus (see 3) preparation of nanoparticles of Human Immunodeficiency Virus (, 6,165,506 "New Solid formulation of Nanoparticulate Naprox", 6,221,400 "Methods of treating mammals with Nanocrystallite Formulations of Human Immunodeficiency Virus (HIV) Protease Inhibitors", 6,264,922 "atomized Aerosol Containing Nanoparticle Dispersion", 6,267,989 "Methods for preparing nanoparticles Growth and nanoparticles Aggregation in nanoparticles Compositions" Oral Solid formulation of nanoparticles dissolution stabilization of nanoparticles composition ", 6,270,806" PEG-Dezeware Synthesis composition "(method of stabilizing nanoparticles composition for preventing crystal Growth and Particle Aggregation), and" Oral Solid formulation of nanoparticles composition "(Synergistic composition 6,375,986) Oral Solid formulation of nanoparticles composition, nanoparticles dissolution stabilization of nanoparticles composition (nanoparticles composition) and nanoparticles dissolution composition (nanoparticles dissolution composition) Containing nanoparticles composition of nanoparticles composition", 6,270,806 "PEG-Dezeware composition of nanoparticles composition" Oral Solid formulation of nanoparticles composition (nanoparticles dissolution stabilization of nanoparticles composition) ", and" Oral Solid formulation of nanoparticles composition (nanoparticles dissolution stabilization of nanoparticles composition ", and" Oral Solid formulation of nanoparticles composition (nanoparticles composition of nanoparticles composition) ", and" Oral Solid formulation of nanoparticles composition (composition of nanoparticles of lipid of the composition of the invention Solid dose nanoparticle Compositions of a Surface Stabilizer and Dioctyl sodium sulfosuccinate ', 6,428,814 "Bioadhesive nanoparticle Compositions having a cationic Surface Stabilizer ', 6,431,478" Small Scale Mill "and 6,432,381" Methods for Targeting Drug Delivery to the Upper and/or lower gastrointestinal Tract ", 6,592,903" Nanoparticulate Dispersion synthetic combination of a Polymeric Surface Stabilizer and Dioctyl sodium sulfosuccinate ', 3656 "sanitary nanoparticle Dispersions (particulate Compositions) Comprising a synergistic combination of a Polymeric Surface Stabilizer and Dioctyl sodium sulfosuccinate", and "nonadhesive nanoparticle dispersion", a sanitary nanoparticle dispersion of a particulate composition (particulate composition) Comprising a cationic Surface Stabilizer and Dioctyl sodium sulfosuccinate ", a" biological surfactant dispersion of a biological surfactant and a "biological surfactant dispersion", a "biological surfactant dispersion of a biological surfactant and a" biological surfactant dispersion ", and a" biological surfactant dispersion of a biological surfactant dispersion ", a" biological surfactant dispersion of a biological surfactant and a "biological surfactant dispersion of a" and a biological surfactant dispersion of a "biological surfactant dispersion of a" and a biological surfactant dispersion of a "biological surfactant dispersion of a biological surfactant dispersion, 6,745,962 "Small Scale Mill and Method of nanoparticles therapeutics", 6,811,767 "Liquid droplet suspensions of Nanoparticulate drugs" and 6,908,626 "Compositions having a combination of immediate release and controlled release characteristics", 6,969,529 "Nanoparticulate Compositions of nanoparticles of vinyl pyrrolidone and vinyl acetate as surface stabilizers", 6,976,647 "System and Method for Mill coatings (systems and methods for grinding Materials)", 6,991,191 "Small Scale Mill and Method of nanoparticles Using the methods of nanoparticles grinding the nanoparticles of progesterone (methods for nanoparticles of progesterone, methods of nanoparticles of progesterone (methods of Using the methods of nanoparticles of progesterone)", 6,991,191 "all incorporated by the methods of nanoparticles of pharmaceuticals (methods of nanoparticles of the invention" (methods of nanoparticles of the invention).

Furthermore, U.S. patent publication No. 20060246142 "Nanoparticulate pharmaceutical Formulations", U.S. patent publication No. 20060246141 "Nanoparticulate lipase inhibitor Formulations", U.S. patent publication No. 20060216353 "Nanoparticulate therapeutic and antihistaminic Formulations", U.S. patent publication No. 20060210639 "Nanoparticulate biospirtant Formulations", U.S. patent publication No. 20060210638 "Injectable Formulations of Nanoparticulate therapeutic Formulations", U.S. patent publication No. 20060204588 "Injectable Formulations of nanoparticles of antimicrobial aerosols, or Injectable nanoparticles of Nanoparticulate Formulations", and "Injectable Formulations of Nanoparticulate immunosuppressive compounds", U.S. patent publication No. 20060204588 "Nanoparticulate therapeutic Formulations of nanoparticles of Nanoparticulate therapeutic aerosols, or Nanoparticulate Formulations thereof", and "Injectable Formulations of Nanoparticulate salts", or Nanoparticulate Formulations thereof ", and" Injectable Formulations of Nanoparticulate salts of nanoparticles of antimicrobial compounds ", and" Injectable Formulations of Nanoparticulate salts of nanoparticles of antimicrobial compounds ", and" or "Injectable Formulations thereof", and "Nanoparticulate Formulations thereof, U.S. patent publication No. 20060193920 "nanoparticulates complexes of Mitogen-activated (MAP) kinase inhibitors," U.S. patent publication No. 20060188566 "nanoparticulates complexes of docetaxel and analogs thereof," U.S. patent publication No. 20060165806 "nanoparticulates reagent formulations," U.S. patent publication No. 20060159767 "nanoparticulates biological reagent formulations," U.S. patent publication No. 20060159766 "nanoparticulates reagent formulations," U.S. patent publication No. 392 "nanoparticulates reagent formulations," U.S. patent publication No. 20060121112 "nanoparticulates reagent formulations," U.S. patent publication No. 392 "nanoparticulates reagent formulations," and nanoparticulates reagent formulations, U.S. patent publication No. 20020012675A 1 "Controlled release nanoparticles Compositions", U.S. patent publication No. 20040195413A 1 "Compositions and Methods for Milling materials", U.S. patent publication No. 20040173696A 1 "Milling microparticles Compositions of nanoparticles candidate compounds", U.S. patent publication No. 20050276974 "nanoparticles fiber Formulations", U.S. patent publication No. 20050238725 "nanoparticles Compositions and Methods for providing nanoparticles to nanoparticles candidate Compositions", U.S. patent publication No. 20050233001 "nanoparticles Compositions with peptides as Surface stabilizers", U.S. patent publication No. 20050233001 "nanoparticles Compositions of nanoparticles Active compounds", U.S. patent publication No. 24 "nanoparticles Compositions with peptides as Surface stabilizers", U.S. patent publication No. 20050233001 "nanoparticles Compositions of nanoparticles Active compounds (nanoparticles Active agents), and Methods for targeting nanoparticles of nanoparticles Using nanoparticles 20050147664" targeted Compositions of nanoparticles and Methods for Delivery of nanoparticles Using nanoparticles of nanoparticles Active compounds (nanoparticles Active agents for Delivery of nanoparticles) described in U.S. patent publication No. 3925 "Compositions of nanoparticles Active compounds (nanoparticles Active agents (nanoparticles Active Compositions of nanoparticles and Methods for Delivery of nanoparticles of Active compounds of nanoparticles of Active agents of nanoparticles of Active agents of nanoparticles of Active Compositions of nanoparticles of Active agents of, U.S. patent publication No. 20050063913 "Novel Metaxalone Compositions", U.S. patent publication No. 20050042177 "Novel Compositions of Sildenafil free Base", U.S. patent publication No. 20050031691 "Gel Stabilized Nanoparticulate Active Compositions", U.S. patent publication No. 20050019412 "Novel Glipidizide Compositions", U.S. patent publication No. 20050004049 "Novel grid of Nanoparticulate Compositions", U.S. patent publication No. 20040258758 "Nanoparticulate Tomatoformulations", U.S. patent publication No. 20040258757 "Liquid of nanoparticles of Stable nanoparticles of Fluorosilicone Formulations", U.S. patent publication No. 3625 "Nanoparticulate Formulations", U.S. patent publication No. 3 "New Compositions of nanoparticles of Fluorosilicone Formulations", U.S. patent publication No. 3 "Nanoparticulate Active Compositions", U.S. patent publication No. 3625 "Nanoparticulate Formulations of nanoparticles of Fluorosilicone Active Compositions", U.S. patent publication No. 3 "Nanoparaldehyde Active Compositions of Silicodextrin Compositions", U.S. 5 "nanoparticles of Fluorosilicone Formulations", U.S. patent publication No. 3 (New Formulations of Lipolanzapine Active Compositions ", U.S. 3,, U.S. patent publication No. 20040156895 "Solid Dosage Forms compounding pullulans", U.S. patent publication No. 20040156872 "Novel Nimesulide Compositions", U.S. patent publication No. 20040141925 "Novel triamcinolone Compositions", U.S. patent publication No. 20040115134 "Novel Nifedipine Compositions", U.S. patent publication No. 20040105889 "Low Viscosity Liquid Dosage Forms", U.S. patent publication No. 20040105778 "Gamma Irradiation of Solid Nanoparticulate Agents", U.S. patent publication No. 20040101566 "Novel Nanzoxide Compositions", U.S. patent publication No. 20040057905 "Nanocomposition Compositions", U.S. patent publication No. 3663 "Nanoconazole Compositions", U.S. patent publication No. 8678 "Nanocomposition Compositions", and methods for producing Nanocomposition nanoparticles of nanoparticles, U.S. patent publication No. 20040033202 "Nanoparticulated Sterol Formulations and non-Sterol Combinations (Nanoparticulate Sterol formulation and New Sterol combination)", U.S. patent publication No. 20040018242 "Nanoparticulated Nystatin Formulations (Nanoparticulate Nystatin formulation)", U.S. patent publication No. 20040015134 "Drug Delivery Systems and Methods", U.S. patent publication No. 20030232796 "Nanoparticulated Polycosanol Formulations & non-fine Polycosanol Combinations (Nanoparticulate Polyeicosanol formulation and New Polyeicosanonol combination)", U.S. patent publication No. 20030215502 "Fast Dissolving microparticles modified Reduced Friabilogical composition (MAP Kinase) as Nanoparticulate surfactant composition (Nanoparticulate surfactant formulation and New Polyeicosanolytic composition)", U.S. patent publication No. 20030185869 "Nanoparticulate Sterol formulation and New Polyeicosanomer surfactant composition", and Nanoparticulate surfactant composition (Nanoparticulate surfactant) Having Surface stabilizing protein of Nanoparticulate surfactant composition (Nanoparticulate surfactant of Nanoparticulate Polycosanol) as Nanoparticulate surfactant composition, Nanoparticulate surfactant composition (Nanoparticulate surfactant of Nanoparticulate surfactant) and Nanoparticulate surfactant composition of Nanoparticulate surfactant, U.S. patent publication No. 20030137067 "composition of Immediate Release and Controlled Release characteristics", U.S. patent publication No. 20030108616 "Nanoparticulate Compositions of Wet Milling of Vinyl Pyrrolidone and Vinyl Acetate copolymers (Nanoparticulate composition comprising Vinyl Pyrrolidone and Vinyl Acetate copolymer as Surface stabilizer)", U.S. patent publication No. 20030095928 "Nanoparticulate Instrument", U.S. patent publication No. 20030087308 "Method for high-throughput Screening Using Small Scale metals and micro-fluidic System" U.S. patent publication No. 56 "Drug Delivery System and Method for delivering materials" and Method for Wet Milling of materials (for high throughput Screening System and Method Using Small Scale) and "Method for Wet Milling of materials" (for high throughput Screening Method Using Small Millipodes and micro-fluidic System) "and U.S. patent publication No. 20010053664" Method for Wet Milling of materials (composition of Compositions with Immediate Release and Controlled Release characteristics) ", U.S. patent publication No. 20030108616" and Method for Wet Milling of materials (for high throughput Screening System and Method for Wet Milling of materials "(US patent publication No. 56" Method for high throughput Screening System and Method for Wet Milling of materials and Method for grinding System and Method for Wet Milling of materials) ", and Method for Wet Milling of materials (US patent publication No. 7 & supplement and Method for Wet Milling System for Wet Milling of materials The nanoparticulate active agent compositions described above are specifically incorporated herein by reference.

Amorphous small particle compositions are described, for example, in U.S. Pat. No. 4,783,484 "Particulate Composition and Use of the same as an Antimicrobial Agent", U.S. Pat. No. 4,826,689 "Method for Making Uniform Particles From Water-Insoluble Organic Compounds", 4,997,454 "Method for Making Uniform Particles From Particles of Uniform Size using an Insoluble Organic Compound", 5,741,522 "ultrasonic", Non-aggregate Particles of Uniform Size for Making Uniform Particles From Insoluble Compounds ", and" ultrasonic reinforcing Porous Particles and Method for reinforcing Porous Particles for Use in ultrasonic Back scattering "(ultra-small, Non-aggregated Uniform Particles and Method for capturing internal bubbles)" U.S. Pat. No. 5,776,496 "for reinforcing Porous Particles.

Nanoparticulate glucocorticoids are described, for example, in U.S. Pat. No. 6,264,922, "Aerosol compositions Containing nanoparticle Dispersions", U.S. Pat. No. 5,747,001, "Aerosol compositions Containing Beclomethasone Nanoparticulate Dispersions", U.S. Pat. No. 20040208833A 1, "Novel Fluticasone formulations", U.S. Pat. No. 20040057905A 1, "Nanoparticulate Betacroline Diproprione formulations", U.S. Pat. No. 20040141925 "Notrimolone formulations", and U.S. Pat. No. 20030129242 "Boraxacuminate formulations", as Sterile nanoparticles of.

C.Background on Sterilization of Nanoparticulate active agent compositions

There are several effective methods for sterilizing drugs: heat sterilization, sterile filtration, ethylene oxide exposure and gamma irradiation.

1. Thermal sterilization of nanoparticulate active agent compositions

One of the problems encountered with thermal sterilization of nanoparticulate active agent compositions is dissolution and subsequent recrystallization of the constituent active agent particles. This process results in an increase in the size distribution of the active agent particles. Where the nanoparticle active agent formulation includes a surface stabilizer having a cloud point below the sterilization temperature (typically about 121 ℃), the surface stabilizer may desorb or dissociate from the nanoparticle active agent surface and precipitate from solution at or below the sterilization temperature. Thus, some nanoparticulate active agent formulations also exhibit particle agglomeration after exposure to elevated temperatures during thermal sterilization.

Crystal growth and particle aggregation are highly undesirable in the preparation of nanoparticulate active agents for several reasons. The presence of large crystals in nanoparticulate active agent compositions can lead to undesirable side effects, particularly when prepared in injectable formulations. This is also true of particle aggregation, as injectable formulations preferably have an effective average particle size greater than about 250 nm. Larger particles, such as particles larger than 2 microns in size, formed by particle aggregation and recrystallization, can interfere with blood flow, leading to pulmonary embolism and death.

In addition, for injectable and oral formulations, the presence of large crystals (and therefore multiple particle sizes) and/or particle aggregation can alter the pharmacokinetic profile of a given active agent. For oral formulations, the presence of large crystals or aggregates produces a variable bioavailability profile because smaller particles dissolve faster than larger aggregates or larger crystal particles. The faster the dissolution rate, the greater the bioavailability, and the lower the dissolution rate, the lower the bioavailability. This is because bioavailability is proportional to the surface area of the administered drug and, therefore, increases as the particle size of the dispersant decreases { see U.S. patent No. 5,662,833).

For compositions with a wide variety of particle sizes, bioavailability becomes very variable and unstable, making it difficult to determine the dose. Moreover, the quality of the nanoparticle composition is not stable because such crystal growth and particle aggregation are uncontrollable and unpredictable. For intravenously injected microparticle formulations, the presence of large crystals or aggregates, in addition to the embolization effects (embolyticefects) described above, can induce immune system responses that result in macrophages transporting larger particles to the liver or spleen and metabolism.

Particle size is also critical for inhaled microparticle compositions of poorly water soluble therapeutic agents, as particle size determines the site of delivery and pharmacokinetic distribution. Pulmonary drug delivery is accomplished by inhalation of the aerosol through the mouth and throat. Particles having an aerodynamic diameter greater than about 5 microns generally do not reach the lungs; instead, they are easily affected in the back of the throat, swallowed, and may be absorbed orally. Particles of about 2 to about 5 microns in diameter are small enough to reach the upper-middle lung region (conducting airways), but too large to reach the alveoli. Smaller particles, i.e., from about 0.5 to about 2 microns, are able to reach the alveolar region. Particles smaller than about 0.5 microns in diameter may also be deposited in the alveolar region by sedimentation, but very small particles may be exhaled.

As described in u.s.20020102294 a1, conventional techniques are very inefficient in delivering drugs to the lungs for a variety of reasons. For example, it has been reported that ultrasonic nebulization of a suspension containing fluorescein and latex drug spheres (representing insoluble drug particles) results in only 1% particle aerosolization, whereas air jet nebulization results in only a portion of the particles aerosolization. Susan l.tiano, "functional testing Used to ratio assembly Performance of a Model respiratory solution or a Suspension in a Nebulizer (functional test for rational assessment of the Performance of a Model respiratory solution or Suspension in a Nebulizer)," Disservation assays International, 56/12-B, p.6578 (1995). Another problem encountered with aerosolized liquid formulations is the long time (4-20min) required to administer a therapeutic dose. Long dosing times are required because conventional or non-nanoparticulate liquid formulations for nebulization are very dilute micronized drug solutions or suspensions. Prolonged administration times are disadvantageous because they reduce patient compliance and make it difficult to control the administered dose, particularly in pediatric patients. Finally, aerosol formulations of micronized drug are not suitable for deep lung delivery of water-insoluble compounds because the droplets required to reach the alveolar region (0.5-2 microns) are too small to fit in micronized drug crystals, typically 2-3 microns or more in diameter.

Conventional pressurized metered dose inhalers (pmdis) are also ineffective at delivering drugs to the lungs. In most cases, pMDI consists of a suspension of the micronized drug in a halogenated hydrocarbon such as chlorofluorocarbon (CFC) or Hydrofluorocarbon (HFA). Actuation of the pMDI results in the delivery of a metered dose of drug and propellant, both of which exit the device at high speed due to the pressure of the propellant. The high velocity and momentum of the drug particles results in a high degree of oropharyngeal impaction and wear on the devices used to deliver the drug. These losses result in variability in therapeutic agent levels and poor control of therapy. In addition, deposition of drugs intended for local administration to the conducting airways (e.g., corticosteroids) in the oropharynx can lead to systemic absorption with undesirable side effects. Additionally, conventional micronization (air jet milling) of pure drug substances can reduce the drug particle size to not less than about 2-3 microns. Thus, the micropowder materials commonly used in pMDI are inherently unsuitable for delivery to the alveolar region, which is not expected to deposit below the central bronchiolar region of the lung.

Delivery of dry powders to the lung with micronized drugs is also problematic. In the dry powder form, the fine powder substance tends to generate significant interparticle electrostatic attraction, which prevents the powder from flowing smoothly, often making it difficult to disperse. Thus, two key issues with dry powder pulmonary delivery are the ability of the device to accurately meter the intended dose and the ability of the device to completely disperse the micropowder particles. For many devices and formulations, the degree of dispersion depends on the patient's rate of inhalation, which itself can vary, leading to variability in the delivered dose.

Drugs may also be delivered to the nasal mucosa with aqueous, propellant-based or dry powders. However, absorption of poorly water soluble drugs can be problematic because mucociliary clearance transports the deposited particles from the nasal mucosa to the throat, where they are swallowed. Complete clearance is usually achieved in about 15 to 20 minutes. Thus, poorly water soluble drugs that do not dissolve in this time have not been available to exert local or systemic activity.

At temperatures above the cloud point of the surface stabilizer, aggregation of the nanoparticulate active agent composition upon heating is directly related to precipitation of the surface stabilizer. At this point, the bound surface stabilizer molecules may dissociate and precipitate from the nanoparticles leaving them unprotected. The unprotected nanoparticles then aggregate into clusters. Several approaches have been proposed in the prior art to prevent such crystal growth and particle aggregation after thermal sterilization, including the addition of cloud point modifiers or crystal growth modifiers to the nanoparticulate active agent compositions and the purification of surface stabilizers. For example, U.S. patent No. 5,298,262 describes the use of anionic or cationic cloud point modifiers in nanoparticle active agent compositions, and U.S. patent No. 5,346,702 describes nanoparticle active agent compositions having a nonionic surface stabilizer and a nonionic cloud point modifier. Cloud point modifiers enable thermal sterilization of nanoparticulate active agent compositions with low aggregation of the resulting particles. U.S. patent No. 5,470,583 describes nanoparticle active agent compositions having a nonionic surface stabilizer and a charged phospholipid as a cloud point modifier.

The prior art also describes methods of limiting crystal growth in nanoparticulate active agent compositions by the addition of crystal growth regulators (see U.S. patent nos. 5,662,883 and 5,665,331). Furthermore, U.S. patent No. 5,302,401 describes nanoparticle active agent compositions having polyvinylpyrrolidone (PVP) as a surface stabilizer and sucrose as a cryoprotectant (allowing for lyophilization of the nanoparticles). The composition exhibited minimal particle aggregation after lyophilization.

Another method known prior to the present invention to limit particle aggregation or crystal growth of nanoparticulate active agent compositions upon sterilization is the use of purified surface stabilizers. U.S. patent No. 5,352,459 describes a nanoparticulate active agent composition having a purified surface stabilizer (less than 15% impurities) and a cloud point modifier. Purification of surface stabilizers can be expensive and time consuming, thereby significantly increasing the cost of manufacturing compositions requiring such stabilizers to produce stable nanoparticulate active agent compositions.

2. Sterile filtration

When the filter membrane pore size is less than or equal to about 0.2 microns (200nm), filtration is an effective method for uniform solution sterilization because a 0.2 micron filter is sufficient to remove substantially all bacteria. Sterile filtration is not generally used to sterilize conventional suspensions of micron-sized drug particles because the drug particles are too large to pass through the membrane pores. In principle, 0.2 μm filtration can be used to sterilize the nanoparticulate active agent composition. However, because the nanoparticulate active agent composition has a range of sizes, many particles of a typical nanoparticulate active agent composition having an average particle size of 200nm may have a size greater than 200 nm. Such larger particles tend to clog sterilization filters. Thus, only nanoparticulate active agent compositions having a very small average particle size can be filter sterilized.

3. Ethylene oxide process

The ethylene oxide process has been widely used in sterilization processes for suspension/dispersion products where neither the product nor the components are heat-labile. Most products currently on the market utilize this technique, wherein the components are sterilized and then aseptically processed or assembled together. However, this technique requires elimination of residual ethylene oxide from the product, a process that is time consuming and difficult because residual ethylene oxide can contaminate the final drug product.

4. Gamma irradiation

US 2004105778A 1 to Lee et al, "Gamma Irradiation of Solid nanoparticles Active Agents", relates to a method of terminally sterilizing a Solid form of a nanoparticle Active agent composition by Gamma Irradiation. The nanoparticulate active agent has an average particle size of less than about 2 micrometers prior to being blended into a solid form for sterilization. The resulting sterile composition exhibits excellent redispersibility, homogeneity and uniformity. Also included are compositions made by the methods and methods of treating animals and humans with such compositions.

WO 2004/105809 to Bosch et al, "Sterilization of Dispersions of nanoparticulate Active Agents with gamma irradiation" relates to a method of sterilizing a dispersion of one or more nanoparticulate Active Agents by gamma irradiation and to the pharmaceutical compositions obtainable thereby.

There remains a need in the art for sterile, stable glucocorticoid compositions having increased pharmaceutical efficacy. The present invention satisfies this need.

Summary of The Invention

The present invention relates to the unexpected discovery that glucocorticoids can be readily sterilized thermally, without significant changes in particle size or chemical purity, in the presence of one or more nonionic surface stabilizers, provided that amphiphilic lipids are incorporated into the composition prior to the sterilization processing step.

The present invention relates to a pharmaceutical composition comprising an aqueous dispersion or suspension of a heat-sterilized glucocorticoid. Such pharmaceutical compositions are known to be effective in maintenance therapy of asthma, as a prophylactic treatment of nasal symptoms of seasonal and perennial allergic and non-allergic rhinitis in adult and pediatric patients, and to alleviate signs and symptoms of seasonal allergic conjunctivitis. The dispersion is formulated as a sterile pharmaceutical composition with the glucocorticoid particles suspended in an aqueous carrier comprising at least one non-ionic surface stabilizer and at least one amphiphilic lipid. The glucocorticoid particles have an effective average particle size of less than about 2000 nm. Thus, in one embodiment of the invention, the composition comprises a sterile composition comprising: (a) particles of at least one glucocorticoid, wherein the particles have an effective average particle size of less than about 2000 nm; (b) at least one nonionic surface stabilizer; and (c) at least one amphiphilic lipid.

In one embodiment of the invention, the composition may be sterilized by moist heat sterilization. Exemplary sterilization temperatures are from about 110 ℃ to about 135 ℃.

The compositions of the invention comprise an aqueous suspension of a glucocorticoid (such as budesonide, fluticasone propionate and beclomethasone dipropionate) and at least one non-ionic surface stabilizer (such as polysorbate 80, tyloxapol or Lutrol F127 NF) and an amphiphilic lipophilic lipid (such as soy or egg yolk lecithin (egg lecithin) phospholipid which, in addition to the essential component phosphatidylcholine, must also comprise a negatively charged phospholipid, such as phosphatidylinositol, phosphatidylserine, phosphatidic acid, phosphatidylglycerol and the corresponding lysophospholipids). Preferably, the amphiphilic lipid is a phospholipid preferentially enriched in negatively charged phospholipids, such as phosphatidylglycerol, phosphatidic acid, phosphatidylserine, phosphatidylinositol and the corresponding lysophospholipids. However, amphiphilic lipids rich in positively charged phospholipids may also be used in the present invention. The compositions may optionally contain one or more excipients suitable for the manufacture of sterile pharmaceutical formulations for parenteral, inhalation or topical administration (e.g. buffers, isotonicity adjusting agents, chelating agents and antioxidants).

Examples of glucocorticoids include, but are not limited to, budesonide, triamcinolone acetonide, triamcinolone, mometasone furoate, flunisolide, fluticasone propionate, fluticasone, beclomethasone dipropionate, dexamethasone, triamcinolone, beclomethasone, fluocinolone acetonide, flunisolide hemihydrate, mometasone furoate monohydrate, clobetasol, and combinations thereof.

In one embodiment of the invention, the chemical purity of the glucocorticoid may be greater than about 99%. In another embodiment, the chemical purity of the glucocorticoid can be greater than about 99.5%.

Exemplary amounts of glucocorticoids (in concentrated form or diluted in a pharmaceutically acceptable carrier) that may be present in the compositions of the present invention include, but are not limited to, about 0.01% to about 20% by weight.

Examples of nonionic surface stabilizers include, but are not limited to, sorbitol esters, polyoxyethylene sorbitan esters, poloxamers, polysorbates, spans, sorbitan oleates, sorbitan palmitates, sorbitan stearates, polyoxyethylene sorbitan monolaurates, polyoxyethylene sorbitan monooleates, glycerol monolaurates, surfactants containing polyoxyethylene chains, polysorbate 80, polysorbate 60, poloxamer 407, and mixtures thereof, F68、F108、F127, hydroxypropyl methylcellulose, hydroxypropyl celluloseVitamins, polyvinylpyrrolidone, random copolymers of vinylpyrrolidone and vinyl acetate, dextran, cholesterol, polyoxyethylene alkyl ethers, polyglycol ethers, cetostearyl alcohol 1000, polyoxyethylene castor oil derivatives, polyethylene glycols, CarbowaxCarbowax Polyoxyethylene stearate, methylcellulose, hydroxyethyl cellulose, amorphous cellulose, polyvinyl alcohol, tyloxapol, poloxamer, para-isononylphenoxypoly (glycidol), C₁₈H₃₇CH₂C(O)N(CH₃)-CH₂(CHOH)₄(CH₂OH)₂(ii) a 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 derivatives, PEG-vitamin A, PEG-vitamin E and mixtures thereof.

In one embodiment of the invention, the concentration of the non-ionic surface stabilizer in the composition is from about 0.01% to about 90%, from about 0.1% to about 50%, or from about 1% to about 10% by weight based on the total combined dry weight of the glucocorticoid and the surface stabilizer.

In another embodiment of the invention, the non-ionic surface stabilizer may be poloxamer 407, polysorbate 80, polysorbate 60, tyloxapol, or a block copolymer of ethylene oxide and propylene oxide. For example, the nonionic surface stabilizer can be F68、F108 or F127。

In one embodiment of the invention, the amphiphilic lipid may be a phospholipid comprising at least one negatively charged phospholipid. Examples of such phospholipids include, but are not limited to, anionic phospholipids, lecithin NF, synthetic phospholipids, partially purified hydrogenated lecithin, partially purified lecithin, anionic phospholipid-containing soybean lecithin phospholipid, anionic phospholipid-containing yolk lecithin, anionic phospholipid-containing hydrogenated soybean lecithin, anionic phospholipid-containing hydrogenated yolk lecithin, anionic phospholipid-containing lecithin, synthetic phosphatidylglycerol, synthetic phosphatidic acid, synthetic phosphatidylinositol, synthetic phosphatidylserine, phosphatidylinositol, phosphatidylserine, phosphatidic acid, phosphatidylglycerol, lysophosphatidylinositol, lysophosphatidylserine, lysophosphatidic acid, lysophosphatidylglycerol, distearoylphosphatidylinositol, distearoylphosphatidylserine, distearoylphosphatidic acid, etc, Distearoyl lysophosphatidylglycerol, distearoyl lysophosphatidylinositol, distearoyl lysophosphatidylserine, distearoyl lysophosphatidic acid, dipalmitoyl phosphatidylinositol, dipalmitoyl phosphatidylserine, dipalmitoyl phosphatidic acid, dipalmitoyl phosphatidylglycerol, dipalmitoyl lysophosphatidylinositol, dipalmitoyl lysophosphatidylserine, dipalmitoyl lysophosphatidic acid, dipalmitoyl lysophosphatidylglycerol, or mixtures thereof. In one embodiment, the phospholipid is lecithin, which comprises less than 90% phosphatidylcholine. In another embodiment, the phospholipid is a lecithin, which is composed essentially of hydrogenated phosphatidylcholine, with the remainder consisting essentially of hydrogenated anionic phospholipids.

In one embodiment, the compositions of the present invention may further comprise sodium salts of ethylenediaminetetraacetic acid, calcium salts of ethylenediaminetetraacetic acid, or combinations thereof. For example, the sodium and/or calcium salts of ethylenediaminetetraacetic acid may be present in the compositions of the present invention in an amount of from about 0.0001% to about 5%, from about 0.001% to about 1%, or from about 0.01% to about 0.1%.

The compositions of the present invention may also comprise one or more pharmaceutically acceptable excipients. Furthermore, the compositions of the invention may be: (a) formulated for inhalation, injection, otic, oral, rectal, pulmonary, ocular, colonic, parenteral, intracisternal, intravaginal, intraperitoneal, topical, buccal, nasal, or topical administration; (b) formulated as a powder, lyophilized powder, spray-dried powder, spray-granulated powder, solid lozenge, capsule, tablet, pill, granule, liquid dispersion, gel, aerosol, ointment, or cream; (c) formulated into a dosage form selected from the group consisting of controlled release formulations, solid dose fast melt formulations, lyophilized formulations, delayed release formulations, extended release formulations, pulsatile release formulations, and mixed immediate release and controlled release formulations; or (d) formulated into any combination thereof. In one embodiment of the invention, the composition is formulated as a nasal spray. In another embodiment, the composition is formulated as a pulmonary aerosol.

The compositions of the present invention may be formulated as an inhaled, nasal or ophthalmic formulation, in which case a sterile formulation is preferred or required by regulatory agencies. Formulations for inhalation take the form of sterile dispersions or suspensions, wherein the composition of the invention is a liquid for delivery of aqueous droplets containing the glucocorticoid to the pulmonary system (e.g., bronchial system and lungs) by nebulizer. For inhalation, it is also contemplated that sterile dispersions or suspensions of the compositions of the present invention may be used in combination with other liquids and excipients and optionally a propellant for delivery to the pulmonary system by a Metered Dose Inhaler (MDI). For inhalation, it is also contemplated that sterile dispersions or suspensions of the compositions of the present invention may be used in combination with other liquids or excipients, converted into dry powders alone, and delivered to the pulmonary system by a Dry Powder Inhaler (DPI) (see, e.g., US 20020102294 a1, "Aerosols complexing NanoparticleDrugs (Aerosols) to Bosch et al). Sterile nasal formulations may take the form of a solution of the composition of the invention in a suitable liquid phase, with excipients and surface stabilizers, if desired. Ophthalmic formulations may take the form of a solution of the composition of the invention in a suitable liquid phase, with excipients and surface stabilizers added if desired.

Yet another aspect of the invention relates to a pharmaceutical glucocorticoid nanoparticle composition comprising an aqueous suspension for inhalation and/or nasal spray. Pharmaceutical nanoparticulate compositions comprise a therapeutically effective amount of a nanoparticulate glucocorticoid (e.g., budesonide, fluticasone propionate, beclomethasone dipropionate) composition in combination with one or more surface stabilizers and an amphiphilic lipid.

In one embodiment of the invention, the compositions of the invention are formulated as an aqueous aerosol comprising from about 0.015mg/mL up to about 600mg/mL of a glucocorticoid. In another embodiment, the composition is formulated as an aqueous aerosol with a glucocorticoid concentration of about 10mg/mL or more, about 100mg/mL or more, about 200mg/mL or more, about 400mg/mL or more, or about 600 mg/mL.

The invention also includes compositions of the invention formulated as aqueous aerosols wherein the aerosol droplets have a mass median aerodynamic diameter of less than or equal to about 100 microns, from about 0.1 to about 10 microns, from about 2 to about 6 microns, less than about 2 microns, from about 5 to about 100 microns, or from about 30 to about 60 microns.

The invention also includes compositions of the invention formulated as aerosols, further comprising one or more solvents and/or propellants dissolved in a non-aqueous solution, for simultaneous administration from a multidose inhaler.

In another embodiment of the present invention, the composition of the invention further comprises at least one non-glucocorticoid active agent. Such non-glucocorticoid active agents may be active agents that are helpful in the treatment of asthma, allergic conjunctivitis, seasonal allergic rhinitis, or other inflammatory or allergic diseases that are routinely treated with glucocorticoids. Examples of such non-glucocorticoid active agents include, but are not limited to, long-acting beta-agonists, leukotriene modulators, theophylline, nedocromil, cromolyn sodium, short-acting beta-agonists, ipratropium bromide, prednisone, prednisolone, methylprednisolone, salmeterol, formoterol, montelukast, zafirlukast, zileuton, salbutamol, levalbuterol, bitolterol, pirbuterol, and terbutaline.

In yet another embodiment, the compositions of the present invention may be formulated as an aqueous aerosol, wherein: (a) substantially each droplet of the aqueous aerosol formulation comprises at least one nanoparticulate glucocorticoid particle; (b) the aerosol droplets have a Mass Median Aerodynamic Diameter (MMAD) of less than or equal to about 100 microns; (c) the glucocorticoid is selected from the group consisting of fluticasone, budesonide, triamcinolone acetonide, triamcinolone, mometasone furoate, fluticasone propionate, beclomethasone dipropionate, dexamethasone, triamcinolone, beclomethasone, fluocinolone acetonide, flunisolide hemihydrate, flunisolide, mometasone furoate monohydrate, clobetasol, and combinations thereof; (d) the concentration of glucocorticoid is from about 0.015mg/mL up to about 600 mg/mL; (e) the nonionic stabilizer is polyoxyethylene sorbitan fatty acid ester; and (f) the amphiphilic lipid is a phospholipid.

Yet another aspect of the present invention relates to a method of treating a mammal for an indication of a glucocorticoid (e.g., budesonide, fluticasone propionate, beclomethasone dipropionate) comprising administering to the mammal a therapeutically effective amount of a nanoparticulate glucocorticoid composition of the present invention.

The invention also discloses a preparation method of the sterilized nanoparticle glucocorticoid composition. Such methods comprise contacting the glucocorticoid with at least one non-ionic surface stabilizer for a time and under conditions sufficient to provide a nanoparticulate glucocorticoid composition. The one or more non-ionic surface stabilizers may be contacted with the glucocorticoid before, simultaneously with, or after the size of the glucocorticoid is reduced. At least one amphiphilic lipid is added to the composition prior to sterilization. The composition is then sterilized. The amphipathic lipid may be added before, simultaneously with, or after the size reduction of the glucocorticoid. In addition, the dispersion may be formulated as a dry powder prior to sterilization.

For example, one embodiment of the present invention includes a method of making a sterile composition comprising: (a) particles of at least one glucocorticoid, wherein the particles have an effective average particle size of less than about 2000 nm; (b) at least one nonionic surface stabilizer; and (c) at least one amphiphilic lipid, wherein the process comprises: (i) contacting glucocorticoid particles with at least one non-ionic surface stabilizer for a time and under conditions to reduce the effective average particle size of the particles to less than about 2000 nm; (ii) adding at least one amphipathic lipid to the glucocorticoid composition prior to, simultaneously with, or after particle size reduction; and (iii) steam heating the composition to a temperature of from about 115 ℃ to about 135 ℃.

The invention also relates to methods of treatment using the sterilized nanoparticulate glucocorticoid compositions of the invention. In one embodiment, the invention includes a method of treating a patient in need thereof comprising administering to the patient a therapeutically effective amount of a sterile composition comprising: (a) particles of at least one glucocorticoid, wherein the particles have an effective average particle size of less than about 2000 nm; (b) at least one nonionic surface stabilizer; and (c) at least one amphiphilic lipid.

Such treatments are useful for inflammatory diseases. In another embodiment, asthma, cystic fibrosis, chronic obstructive pulmonary disease, emphysema, respiratory distress syndrome, chronic bronchitis, respiratory diseases associated with acquired immunodeficiency syndrome, and ocular inflammatory diseases, skin inflammatory diseases, ear inflammatory diseases, ocular allergic diseases, skin allergic diseases, allergic conjunctivitis, or seasonal allergic rhinitis may be treated.

In yet another embodiment, the delivery time for a patient administered an aerosol of the composition of the present invention may be from about 15 seconds up to about 15 minutes.

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 become readily apparent to those skilled in the art from the following detailed description of the invention.

Detailed Description

The present invention relates to the surprising and unexpected discovery that nanoparticulate glucocorticoid compositions comprising at least one nonionic surface stabilizer can be successfully moist heat sterilized when the composition to be sterilized additionally comprises at least one amphiphilic lipid. The glucocorticoid particles have an effective average particle size of less than about 2000 nm. As shown in the following examples, it is surprising that the present invention is applicable to glucocorticoids of different chemical structures (e.g., budesonide, beclomethasone dipropionate and fluticasone propionate), nonionic surface stabilizers of different structures and low and high molecular weights (e.g., polysorbate-80, tyloxapol and Lutrol F127 NF), and amphiphilic lipids of different structures (e.g., lecithin NF, partially purified hydrogenated lecithin (LIOID S75-3), partially purified lecithin (LIOID S45), distearoyl phosphatidyl glycerol (LIOID PG18:0/18:0) and dipalmitoyl phosphatide (LILIPD PA 16:0/16: 0)). It was shown that various drugs, non-ionic surface stabilizers and amphiphilic lipids all successfully prepared nanoparticulate glucocorticoid compositions that could be sterilized with moist heat without significant increase in glucocorticoid particle size.

The sterilized dispersion of nanoparticulate glucocorticoid can then be formulated into any suitable dosage form, such as solid, semi-solid, or liquid dosage forms, including dosage forms for oral, pulmonary, nasal, parenteral, rectal, topical, buccal, or topical administration. The invention is particularly useful for aqueous dosage forms which are contamination-conducting, such as injections, aerosols or ophthalmic dosage forms, or liquid dosage forms for otic administration. The sterile dispersion may be formulated as a dry powder, such as a nanoparticle active agent dispersion lyophilized powder, a spray dried powder, or a spray granulated powder. The dosage form can also be a controlled release formulation, a solid dose fast-melt formulation, an aerosol formulation, a lyophilized formulation, a tablet, a solid lozenge, a capsule, a powder, an ophthalmic formulation, an otic formulation, or an injection.

The heat sterilization process significantly destroys all microbial and viral contamination in the dispersion, such as microorganisms, mycoplasma, yeast, viruses and molds. The microbial contamination to be destroyed is typically bacterial, mycoplasma, yeast and mold contamination. Moist heat sterilization step: (1) the particle size of the stored glucocorticoid is minimally increased (if any), (2) the chemical integrity of the nanoparticulate glucocorticoid is maintained, and (3) the concentration of impurities that shows the glucocorticoid composition to be widely accepted after thermal sterilization. The moist heat sterilization process does not significantly degrade glucocorticoids or reduce the efficacy of glucocorticoids. The invention enables the product to meet the cGMP requirements of sterile products without damaging the active agent.

Surprisingly, the nanoparticulate glucocorticoid dispersion or dispersions exhibit unexpected overall stability after sterilization, maintaining the physical and chemical properties prior to sterilization, while meeting the cGMP requirements for sterilization. It is particularly surprising that moist heat sterilization of a dispersion of one or more nanoparticulate glucocorticoids does not significantly alter the particle size of the one or more glucocorticoids. This is important because if the sterilized product forms aggregates or large crystals, the dispersion will lose the advantages provided by formulating into a nanoparticulate glucocorticoid composition.

The sterile compositions (both aqueous and dry powders) of the invention are particularly useful in the treatment of respiratory-related diseases such as asthma, emphysema, respiratory distress syndrome, chronic bronchitis, cystic fibrosis, chronic obstructive pulmonary disease, respiratory diseases associated with acquired immunodeficiency syndrome, and inflammatory and allergic diseases of the dermis (skin) (e.g., psoriasis), the eye and ear. The formulations and methods improve the surface coverage of the administered compositions of the invention at the site of application (e.g., lung, nose, eye, ear, etc.).

Sterile dosage forms are particularly suitable for patients at risk of infection, such as neonates, children, the elderly, and patients with immunodeficiency, and are particularly suitable for dosage forms to be administered to areas at risk of infection (e.g., the eye, ear, mouth, lung, nasal cavity). The need for sterile dosage forms is also evidenced by the guidelines recently issued by the U.S. food and drug administration that require that the inhaled product be sterile. The sterility requirements of nanoparticulate drug formulations are problematic because thermal sterilization can result in dissolution and subsequent recrystallization of the component drug particles. Moreover, drugs that become soluble in aqueous media may also be more susceptible to chemical degradation. This process results in an increase in the size distribution of the drug particles. In addition, some nanoparticle formulations also exhibit particle aggregation after exposure to elevated temperatures for thermal sterilization.

Crystal growth and particle aggregation in nanoparticle formulations is highly undesirable for several reasons. The presence of large crystals in the nanoparticle composition can lead to undesirable side effects, particularly when the formulation is an injection. As does particle agglomeration. Larger particles formed by particle aggregation and recrystallization can interfere with blood flow, leading to pulmonary embolism and death.

In addition, the presence of large crystals, and thus altered particle size and/or particle aggregation, can alter the pharmacokinetic profile of a given drug. For oral formulations, the presence of large crystals or aggregates results in variable bioavailability because smaller particles dissolve faster than larger aggregates or larger crystal particles. The faster the dissolution rate, the greater the bioavailability, and the slower the dissolution rate, the lower the bioavailability. This is because bioavailability is proportional to the surface area of the administered drug and, therefore, increases as the particle size of the dispersant decreases (see U.S. patent No. 5,662,833). For compositions with a wide variety of particle sizes, bioavailability becomes very variable and unstable, making it difficult to determine the dose. Moreover, the quality of the nanoparticle composition is not stable because such crystal growth and particle aggregation are uncontrollable and unpredictable. For intravenously injected microparticle formulations, the presence of large crystals or aggregates, in addition to the embolization effect described above, can induce immune system responses that result in macrophages transporting larger particles to the liver or spleen and metabolism.

At temperatures above the cloud point of the surface stabilizer, aggregation of the nanoparticle composition upon heating is directly related to precipitation of the surface stabilizer. At this point, the bound surface stabilizer molecules may dissociate and precipitate from the nanoparticles leaving them unprotected. The unprotected nanoparticles then aggregate into clusters. It has been unexpectedly found that glucocorticoids, in combination with at least one nonionic surface stabilizer and at least one amphiphilic lipid, can be successfully sterilized thermally to give sterile compositions having an effective average particle size of less than about 2000nm with minimal or no degradation of the glucocorticoids. Such particle size growth results in a loss of the pharmaceutical advantages provided by formulating the active agent into a nanoparticulate dosage form, such as faster onset of action (particularly critical for the treatment of asthma and allergic diseases), reduced toxicity and lower active agent doses.

A. Definition of

The invention is described herein with several definitions, as described below and throughout the application.

As used herein, "effective average particle size" means that at least 50% (i.e., "D50") of the glucocorticoid particles have a particle size, by weight, volume, number, or other suitable measure, that is less than the effective average (e.g., less than about 2000nm, 1900nm, 1800nm, etc.) when measured by, for example, sedimentation field flow fractionation, photon correlation spectroscopy, light scattering, disk centrifugation, and other methods known to those skilled in the art.

As used herein, the definition of "about" will be understood by those skilled in the art to vary somewhat depending on the context in which it is used. If the term is used, it will be unclear to one of ordinary skill in the art even in light of the context in which the term is used, and the term "about" will mean up to plus or minus 10% of a particular value.

As used herein, reference to stable glucocorticoid particles denotes, but is not limited to, one or more of the following parameters: (1) the glucocorticoid particles do not significantly flocculate or agglomerate due to interparticle attractive forces nor do they significantly increase in particle size over time; (2) the glucocorticoid particles do not dissolve significantly upon addition of stabilizers or amphiphilic lipids or upon subsequent moist heat treatment; (3) the physical structure of the glucocorticoid particles does not change over time, such as from an amorphous phase to a crystalline phase; (4) glucocorticoid particles are chemically stable; and/or (5) the glucocorticoid is not subjected to a heating step at or above the melting point of the glucocorticoid in the preparation of the nanoparticles of the present invention.

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

The phrase "poorly water soluble drug" refers to a drug having a solubility in water of less than about 30mg/ml, preferably less than about 20mg/ml, preferably less than about 10mg/ml, or preferably less than about 1 mg/ml.

As used herein, the phrase "therapeutically effective amount" shall refer to the dosage of a drug that provides the particular pharmacological response desired to be produced by administration of the drug in a large number of patients in need of such treatment. It should be emphasized that a therapeutically effective amount of a drug administered to a particular patient in a particular instance is not necessarily effective in treating the conditions/diseases described herein, even though such a dose is considered by those skilled in the art to be a therapeutically effective amount.

B. Composition comprising a metal oxide and a metal oxide

Any poorly water soluble glucocorticoid that does not readily undergo chemical changes upon moist heat treatment of the process can be used in the composition of the present invention. Glucocorticoids have been shown to possess a broad inhibitory activity against a variety of cell types (such as mast cells, eosinophils, neutrophils, macrophages and lymphocytes) and mediators (such as histamine, eicosanoids, leukotrienes and cytokines) associated with allergic and non-allergic/irritant-mediated inflammation. The effect of corticosteroids on the delayed (6 hours) response elicited by allergens is greater than the histamine-related immediate response (20 minutes).

Exemplary glucocorticoids include, but are not limited to, budesonide, triamcinolone acetonide, mometasone furoate, flunisolide, fluticasone propionate, beclomethasone dipropionate, dexamethasone, fluocinolone acetonide, flunisolide hemihydrate, mometasone furoate monohydrate, clobetasol, and combinations thereof. Preferred glucocorticoids are budesonide, fluticasone, triamcinolone, mometasone, beclomethasone, and combinations thereof. Although the amount of glucocorticoid (either concentrated or diluted in a pharmaceutically acceptable carrier) is typically from about 0.01% to about 20% by weight, other glucocorticoid concentrations are encompassed by the present invention.

In one embodiment of the invention, the glucocorticoid has a chemical purity of more than 99%. In another embodiment of the invention, the glucocorticoid has a chemical purity of more than 99.5%.

The sterilized glucocorticoid formulation of the present invention further comprises at least one non-crosslinked, low or high molecular weight non-ionic surface stabilizer. The nonionic surface stabilizers used herein physically adhere to the nanoparticulate glucocorticoid surface, but do not chemically interact with the glucocorticoid particles or themselves. The individual molecules of the surface stabilizer are preferably substantially free of intermolecular crosslinks. As used herein, a "nonionic" surface stabilizer is a stabilizer in which the polar groups of the compound are uncharged. Generally, surface stabilizers have a hydrocarbon tail and a polar head, the oxygen atom of which attracts water molecules to make the head soluble in water, but the surface stabilizer does not carry an ionic charge.

Exemplary nonionic surface stabilizers include, but are not limited to, sorbitol esters, polyoxyethylene sorbitan esters, i.e., polysorbate 80, polysorbate 60; poloxamers (e.g., poloxamers 407 and 407)F68, F108 and F127, which are block copolymers of ethylene oxide and propylene oxide), polysorbates, spans and other sorbitol esters, sorbitan oleates, sorbitan palmitates, sorbitan stearates, polyoxyethylene sorbitan monolaurates, polyoxyethylene sorbitan monooleates, glycerol monooleates and glycerol monolaurates, and other surfactants which are polymers or copolymers in nature (such as surfactants containing polyethylene oxide chains) and mixtures thereof, hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinylpyrrolidone (PVP), random copolymers of vinylpyrrolidone and vinyl acetateDextran, cholesterol, polyoxyethylene alkyl ethers (e.g. polyethylene glycol ethers such as cetomacrol 1000), polyoxyethylene castor oil derivatives, polyethylene glycols (e.g. Carbowax)And(Unioncarbide)), polyoxyethylene stearate, methyl cellulose, hydroxyethyl cellulose, amorphous cellulose, polyvinyl alcohol (PVA), 4- (1, 1,3, 3-tetramethylbutyl) -phenol polymers with ethylene oxide and formaldehyde (also known as tyloxapol, superone and triton), poloxamers (such as Pluronics)Andis a block copolymer of ethylene oxide and propylene oxide), also known asPara-isononylphenoxy poly (glycidol) (Olin Chemicals, Stamford, CT); and SA9OHCO, is C₁₈H₃₇CH₂C(O)N(CH₃)-CH₂(CHOH)₄(CH₂OH)₂(Eastman Kodak Co.); decanoyl-N-methylglucamide; n-decyl β -D-glucopyranoside; n-decyl β -D-maltopyranoside; n-dodecyl β -D-glucopyranoside; n-dodecyl β -D-maltoside; heptanoyl-N-methylglucamide; n-heptyl- β -D-glucopyranoside; n-heptyl β -D-thioglucoside; n-hexyl β -D-glucopyranoside; nonanoyl-N-methylglucamide; n-noyl β -D-glucopyranoside; octanoyl-N-methylglucamide; n-octyl- β -D-glucopyranoside; octyl β -D-thioglucopyranoside; PEG-phospholipid, PEG-cholesterol derivatives, PEG-vitamin A, PEG-vitamin E, etc. Useful nonionic surface stabilizers include polyoxyethylene sorbitan esters, particularly polysorbate 80, which is commercially available as Tween 80.

The amphiphilic lipids incorporated into the sterilized glucocorticoid formulation of the present invention may be selected from a variety of phospholipids, provided that the composition comprises some negatively charged phospholipids. Exemplary phospholipids include, but are not limited to, lecithin NF grade or synthetic phospholipids, including lecithin NF, purified lecithin (LIOID S45), hydrogenated lecithin (LIOID S75-3), soybean or egg yolk lecithin phospholipids (containing anionic phospholipids such as phosphatidylinositol, phosphatidylserine, phosphatidic acid, phosphatidylglycerol, mixtures of the corresponding lysophospholipids), synthetic phosphatidylglycerol (LIOID PG18:0/18:0), synthetic phosphatidic acids, and mixtures thereof. Other phospholipids that may be used in the present invention include anionic phospholipids, lecithin NF, synthetic phospholipids, partially purified hydrogenated lecithin, partially purified lecithin, soybean lecithin phospholipid-containing phospholipid, yolk lecithin phospholipid-containing phospholipid, hydrogenated soybean lecithin-containing anionic phospholipid, hydrogenated yolk lecithin-containing anionic phospholipid, synthetic phosphatidylglycerol, synthetic phosphatidic acid, synthetic phosphatidylinositol, synthetic phosphatidylserine, phosphatidylinositol, phosphatidylserine, phosphatidic acid, phosphatidylglycerol, lysophosphatidylinositol, lysophosphatidylserine, lysophosphatidic acid, lysophosphatidylglycerol, distearoylphosphatidylinositol, distearoylphosphatidylserine, distearoylphosphatidic acid, distearoylphosphatidylglycerol, etc, Distearoyl lysophosphatidylinositol, distearoyl lysophosphatidylserine, distearoyl lysophosphatidic acid, dipalmitoyl phosphatidylinositol, dipalmitoyl phosphatidylserine, dipalmitoyl phosphatidic acid, dipalmitoyl phosphatidylglycerol, dipalmitoyl lysophosphatidylinositol, dipalmitoyl lysophosphatidylserine, dipalmitoyl lysophosphatidic acid, dipalmitoyl lysophosphatidylglycerol, and mixtures thereof.

In one embodiment of the invention, the amphiphilic lipid is lecithin, which lecithin comprises less than 90% phosphatidylcholine. In another embodiment of the invention, the amphiphilic lipid is lecithin, which mainly comprises hydrogenated phosphatidylcholine, the remaining components mainly consisting of hydrogenated anionic phospholipids.

The sterilized glucocorticoid formulation of the present invention may additionally comprise a chelating agent, such as ethylenediaminetetraacetic acid (EDTA) or ethylene glycol-bis (β -aminoethyl ether) -N, N' -tetraacetic acid (EGTA), added to the formulation immediately prior to sterilization. Preferably, the amount of EDTA or EGTA added to the glucocorticoid formulation depends on the amount of amphiphilic lipid added as a surface stabilizer. The larger the amount of amphiphilic lipid added, the larger the amount of EDTA or EGTA added, and vice versa-the less amphiphilic lipid added, the less EDTA or EGTA added. Thus, in one embodiment of the invention, the composition may comprise sodium or calcium salts of EDTA or EGTA and combinations thereof. In another embodiment of the invention, the sodium and/or calcium salt of EDTA or EGTA may be from about 0.0001% to about 5%, from about 0.001% to about 1%, from about 0.01% to about 0.1%.

The compositions of the present invention may be formulated into any suitable dosage form. For example, the compositions of the present invention may be formulated for injection, otic, oral, rectal, pulmonary, ocular, colonic, parenteral, intracisternal, intravaginal, intraperitoneal, topical, buccal, nasal, or topical administration; the compositions of the present invention may be formulated as powders, lyophilized powders, spray dried powders, spray granulated powders, solid lozenges, capsules, tablets, pills, granules, liquid dispersions, gels, aerosols, ointments or creams; the compositions of the present invention may be formulated into dosage forms such as controlled release formulations, solid dose fast melt formulations, controlled release formulations, fast melt formulations, lyophilized formulations, delayed release formulations, extended release formulations, pulsatile release formulations, and mixed immediate release and controlled release formulations; or any combination thereof. Preferred sterile dosage forms include, but are not limited to, aerosols for nasal or pulmonary delivery, injections, and ophthalmic dosage forms.

1. Aqueous aerosol

One embodiment of a nanoparticulate glucocorticoid dispersion for nasal, pulmonary (upper lung), pulmonary (deep lung), oral, ocular, or otic delivery is an aerosol (e.g., nasal aerosol, lingual (oral) aerosol, or inhalation aerosol). The aqueous formulation of the present invention consists of a colloidal dispersion of a poorly water soluble nanoparticulate glucocorticoid composition in an aqueous carrier, atomized with an air jet atomizer or ultrasonic atomizer. The advantages of using such aqueous aerosols are best understood by comparing the size of the nanoparticulate and conventional micronized glucocorticoid compositions of the present invention with the liquid droplet size produced with conventional nebulizers. Conventional micropowder materials typically have diameters of about 2 to about 5 microns or more, and are about the same size as liquid droplets produced by medical nebulizers. In contrast, nanoparticulate glucocorticoid compositions having a size of 2 microns or less are of equal size or smaller than the droplets in such aerosols. Thus, aerosols containing the nanoparticulate glucocorticoid composition of the present invention improve drug delivery efficacy. Such aerosols may also comprise a larger amount of nanoparticles per unit dose, such that each atomized glucocorticoid droplet contains an active composition of the present invention.

Thus, aerosol formulations containing nanoparticulate glucocorticoid compositions cover a larger surface area of bronchopulmonary or nasopharyngeal tissue after administration of the same dose of the composition of the invention.

Another advantage of using these aqueous aerosols is that they allow the poorly water soluble compositions of the invention to be delivered to the deep lung with an aqueous formulation. Conventional micronized medications are too large to reach the peripheral lungs regardless of the size of the droplets produced by the nebulizer. An aqueous aerosol formulation comprising the composition of the present invention allows a nebulizer that produces very small (about 0.5 to about 2 microns) water droplets to deliver the water-insoluble composition of the present invention in the form of nanoparticles to the alveoli. One example of such a device is a Circular device^TMAerosol (Westmed Corp., Tucson, Ariz.).

Yet another advantage of aqueous glucocorticoid aerosols is that poorly water soluble compositions of the present invention can be delivered to the lungs using an ultrasonic nebulizer. Unlike conventional micropowder compositions of the present invention, the compositions of the present invention in nanoparticulate form are readily atomized and exhibit good in vitro deposition characteristics. A particular advantage of these aqueous glucocorticoid aerosols is that they allow for the atomization of poorly water soluble glucocorticoid compositions with an ultrasonic atomizer which requires that the nanoparticles containing the composition of the present invention pass through very fine pores to control the size of the atomized droplets. It is expected that conventional drug materials will block the pores, while such nanoparticles are much smaller and can pass through the pores without difficulty.

For aqueous aerosol formulations, the nanoparticulate glucocorticoid compositions of the present invention are present in concentrations ranging from about 0.001mg/mL up to about 600 mg/mL. In other embodiments of the invention, the concentration of the glucocorticoid may be about 0.015mg/mL to up to about 3mg/mL, about 10mg/mL or more, about 100mg/mL or more, about 200mg/mL or more, about 400mg/mL or more, or about 600 mg/mL. The invention also includes dry powder aerosols of the glucocorticoid composition of the invention. For dry powder aerosol formulations, the concentration of the compositions of the present invention is from about 0.001mg/g up to about 990mg/g, depending on the desired dosage. The invention specifically includes concentrated nanoparticulate aerosols, defined as formulations containing the compositions of the invention at a concentration of from about 0.015mg/mL up to about 3mg/mL or from about 10mg/mL up to about 600mg/mL for aqueous glucocorticoid aerosol formulations, and from about 0.015mg/g up to about 3mg/g or from about 10mg/g up to about 990mg/g for dry powder aerosol formulations. Such formulations can be effectively delivered to the appropriate region of the mouth, lungs or nasal cavity within a short administration time (i.e., less than about 15 seconds, as compared to 4-20 minutes for conventional pulmonary nebulizer therapies). In other embodiments of the invention, the aerosol may be administered for a period of time from about 10 seconds to about 30 minutes long, from about 10 seconds to about 25 minutes long, from about 10 seconds to about 20 minutes long, from about 10 seconds to about 15 minutes long, from about 10 seconds to about 10 minutes long, from about 10 seconds to about 9 minutes long, from about 10 seconds to about 8 minutes long, from about 10 seconds to about 7 minutes long, from about 10 seconds to about 6 minutes long, from about 10 seconds to about 5 minutes long, from about 10 seconds to about 4 minutes long, from about 10 seconds to about 3 minutes long, from about 10 seconds to about 2 minutes long, from about 10 seconds to about 1 minute long. In other embodiments of the invention, the aerosol of the invention may be administered for a period of time of about 10 seconds or more, about 15 seconds or more, about 20 seconds or more, about 25 seconds or more, about 30 seconds or more, about 35 seconds or more, about 40 seconds or more, about 45 seconds or more, about 50 seconds or more, or about 55 seconds or more, or any combination thereof, such as from about 20 seconds to about 8 minutes.

In one embodiment of the invention, the aerosol droplets have a Mass Median Aerodynamic Diameter (MMAD) of less than or equal to about 100 microns. In other embodiments of the invention, the aerosol droplets have a Mass Median Aerodynamic Diameter (MMAD) of (1) from about 0.1 to about 10 microns; (2) about 2 to about 6 microns; (3) less than about 2 microns; (4) about 5 to about 100 microns; or (5) from about 30 to about 60 microns. In another embodiment of the invention, substantially each droplet of the aqueous aerosol formulation comprises at least one nanoparticulate glucocorticoid particle.

2. Dry powder aerosol formulation

Dry powder inhalation formulations may be prepared by spray drying aqueous nanoparticulate glucocorticoid dispersions of the compositions of the present invention. Alternatively, dry powders comprising the nanoparticle compositions of the present invention can be prepared by freeze-drying nanoparticle dispersions. A combination of spray-dried and freeze-dried nanoparticulate powders can be used for DPI and pMDI. For dry powder aerosol formulations, the nanoparticle compositions of the present invention may be present in a concentration of from about 0.015mg/g up to about 990 mg/g.

Dry Powder Inhalers (DPIs) that involve deaggregation of the dry powder and aerosol formulation typically rely on a sudden burst of inhaled air from the device to deliver a dose of medicament. Such devices are described, for example, in U.S. patent No. 4,807,814, the entire contents of which are incorporated herein by reference, which relates to a pulmonary powder injector having a suction phase and an injection phase; SU 628930 (abstract) describes a hand-held powder disperser with an axial gas flow tube; fox et al, Powder and bulk engineering, pages 33-36 (March 1988), describe a venturi injector having an axial inlet tube in the upstream region of a venturi restriction; EP 347779 describes a hand-held powder dispenser with a collapsible expansion chamber, and U.S. patent No. 5,785,049 relating to a dry drug powder delivery device, the entire contents of which are incorporated herein by reference.

Dry powder inhalation formulations can also be delivered by aerosol formulations. The powder may consist of respirable aggregates of the nanoparticle composition of the invention, or respirable particles comprising at least one embedded diluent of the composition of the invention. Powders containing the nanoparticle compositions of the present invention can be prepared from aqueous dispersions of the nanoparticles by removing the water by spray drying or lyophilization (freeze drying). Spray drying is less time consuming and less expensive than freeze drying and therefore more cost effective.

Dry powder aerosol delivery devices must be capable of accurately, precisely and reproducibly delivering the desired amount of the composition of the present invention. Moreover, such devices must be capable of completely dispersing the dry powder into individual particles of respirable size. Conventional micronized drug particles 2-3 microns in diameter are often difficult to meter and disperse into small quantities due to the electrostatic agglomeration forces inherent in such powders. These difficulties can lead to drug depletion by the delivery device and incomplete dispersion and poor delivery of the powder to the lungs. Many pharmaceutical compounds are intended for deep pulmonary delivery and systemic absorption. Because the average particle size of conventionally prepared dry powders is typically in the 2-3 micron range, the fraction of material that actually reaches the alveolar region may be small. Thus, delivery of dry powders to the lungs, particularly the alveolar region, is generally less effective because of the nature of the powder itself.

Dry powder aerosols comprising the nanoparticle compositions of the invention can be prepared to be smaller than comparable micronized drugs and thus suitable for efficient delivery to the deep lung. Furthermore, the aggregates of the nanoparticle compositions of the present invention are geometrically spherical and have good flow characteristics, thereby facilitating dosing and deposition of the administered composition into the lungs or nasal cavity.

The dried nanoparticle compositions are useful in DPI and pMDI. (in the context of the present invention, "dry" refers to a composition having less than about 5% water.) nanoparticle aerosol formulations are described in U.S. Pat. No. 6,811,767 to Bosch et al, which is specifically incorporated herein by reference.

Nasal formulations may take the form of a solution of the composition of the invention in a suitable solvent, or a dispersion or suspension of the composition of the invention in a liquid phase and a stabiliser, or a dry powder. The solution consists of the composition of the invention and a suitable solvent and optionally one or more co-solvents. Water is a typical solvent. However, the compositions of the present invention may not be soluble in water alone, in which case it may be necessary to use one or more co-solvents to form the solution. Suitable co-solvents include, but are not limited to, short chain alcohols, particularly ethanol.

Nasal formulations may also take the form of dispersions or suspensions. In these types of formulations, the compositions of the present invention may take the form of nanoparticulates of glucocorticoids dispersed or suspended in water (with or without one or more suspending agents). Inhalation therapies (i.e. dose inhalers) comprising the nanoparticulate glucocorticoid composition of the invention and a pMDI (pressurized metered dose inhaler) may comprise discrete nanoparticles and surface stabilizers, nanoparticles and surface stabilizer aggregates, or mobile diluent particles (mobile diluent particles) containing embedded nanoparticles or solutions of drugs or combinations in solvents and/or propellants. pMDI can be used to target the nasal cavity, conducting airways or alveoli of the lung. The present invention increases delivery to the deep lung region compared to conventional formulations, since inhaled nanoparticles are smaller than conventional micropowder materials (<2 microns) and can be distributed over a larger mucosal or alveolar surface area compared to micropowder drugs.

a. Spray-dried powder containing glucocorticoid nanoparticles

Powders comprising the nanoparticulate glucocorticoid composition of the present invention may be prepared by spray drying an aqueous dispersion of the nanoparticulate composition and a surface stabilizer to form a dry powder comprised of the aggregated nanoparticulate composition of the present invention. The aggregates may have a size of about 1 to about 2 microns suitable for deep lung drug delivery. The aggregate particle size can be increased to target a selected delivery site, such as the upper airway area or nasal mucosa, by increasing the concentration of the composition of the invention in the spray-dried dispersion or increasing the droplet size produced by the spray dryer.

Alternatively, aqueous dispersions of the nanoparticulate glucocorticoid composition and the surface stabilizer of the present invention may comprise a dissolved diluent, such as lactose or mannitol, which when spray dried form inhalable diluent particles, each comprising at least one embedded nanoparticulate glucocorticoid of the present invention, a nonionic surface stabilizer, and an amphiphilic lipid. The diluent particles comprising embedded glucocorticoid nanoparticles may have a particle size of about 1 to about 2 microns, suitable for deep lung delivery. In addition, the diluent particle size can be increased by increasing the concentration of the dissolved diluent in the aqueous dispersion prior to spray drying or increasing the droplet size produced by the spray dryer, thereby increasing the diluent particle size to target a selected delivery site, such as the upper airway area or nasal mucosa.

Spray-dried powders can be used in DPI or pMDI, alone or in combination with freeze-dried nanoparticle powders. In addition, spray-dried powders containing the nanoparticle compositions of the present invention can be reconstituted and used in a spray or ultrasonic atomizer to produce an aqueous dispersion having a respirable droplet size, wherein each droplet contains at least one nanoparticle composition of the present invention. Concentrated nanoparticle dispersions may also be used in these aspects of the invention.

b. Freeze-dried powders containing the nanoparticle compositions of the present invention

Nanoparticulate glucocorticoid compositions of the invention in the form of nanoparticulate glucocorticoid dispersions can also be freeze-dried to obtain powders suitable for nasal or pulmonary delivery. Such powders may comprise an aggregated nanoparticulate glucocorticoid composition of the present invention having at least one nonionic surface stabilizer and at least one amphiphilic lipid. Such aggregates may have a size in the respirable range, i.e., about 2 to about 5 microns. Larger aggregate particle sizes may be obtained to target selected sites of drug delivery, such as the nasal mucosa.

Lyophilized powders of suitable particle size may also be prepared by freeze-drying an aqueous dispersion of the composition of the invention, which also contains a dissolved diluent such as lactose or mannitol. In these cases, the freeze-dried powder consists of respirable diluent particles, each of which contains at least one embedded nanoparticle composition of the invention.

The freeze-dried powder can be used in DPI or pMDI, alone or in combination with spray-dried nanoparticle powders. In addition, a lyophilized powder containing the nanoparticle compositions of the present invention can be reconstituted and used in a spray or ultrasonic nebulizer to produce an aqueous dispersion having the size of respirable droplets, wherein each droplet contains at least one nanoparticle composition of the present invention. Concentrated nanoparticle dispersions may also be used in these aspects of the invention.

3. Particle size

The compositions of the present invention comprise nanoparticulate glucocorticoid particles having an effective average particle size of less than about 2000nm (i.e., 2 microns). In other embodiments of the invention, the glucocorticoid particles have an effective average particle size of less than about 1900nm, less than about 1800nm, less than about 1700nm, less than about 1600nm, less than about 1500nm, less than about 1400nm, less than about 1300nm, less than about 1200nm, less than about 1100nm, less than about 1000nm, less than about 990nm, less than about 980nm, less than about 970nm, less than about 960nm, less than about 950nm, less than about 940nm, less than about 930nm, less than about 920nm, less than about 910nm, less than about 900nm, less than about 890nm, less than about 880nm, less than about 870nm, less than about 860nm, less than about 850nm, less than about 840nm, less than about 830nm, less than about 820nm, less than about 810nm, less than about 800nm, less than about 790nm, less than about 780nm, less than about 770nm, less than about 760nm, less than about 750nm, less than about 740nm, less than about 730nm, less than about 720nm, Less than about 710nm, less than about 700nm, less than about 690nm, less than about 680nm, less than about 670nm, less than about 660nm, less than about 650nm, less than about 640nm, less than about 630nm, less than about 620nm, less than about 610nm, less than about 600nm, less than about 590nm, less than about 580nm, less than about 570nm, less than about 560nm, less than about 550nm, less than about 540nm, less than about 530nm, less than about 520nm, less than about 510nm, less than about 500nm, less than about 490nm, less than about 480nm, less than about 470nm, less than about 460nm, less than about 450nm, less than about 440nm, less than about 430nm, less than about 420nm, less than about 410nm, less than about 400nm, less than about 390nm, less than about 380nm, less than about 370nm, less than about 360nm, less than about 350nm, less than about 340nm, less than about 330nm, less than about 320nm, less than about 310nm, less than about 300nm, less than about 290nm, Less than about 280nm, less than about 270nm, less than about 260nm, less than about 250nm, less than about 240nm, less than about 230nm, less than about 220nm, less than about 210nm, less than about 200nm, less than about 190nm, less than about 180nm, less than about 170nm, less than about 160nm, less than about 150nm, less than about 140nm, less than about 130nm, less than about 120nm, less than about 110nm, less than about 100nm, less than about 75nm, or less than about 50nm, as measured by light scattering, microscopy, or other suitable methods.

By "effective average particle size of less than about 2000 nm" is meant that at least 50% (i.e., "D50") of the glucocorticoid particles have a particle size, by weight, volume, number, or other suitable measure, that is less than the effective average (in this case, 2 microns) when measured by the technique indicated above. In other embodiments of the invention, the "effective average particle size" of the glucocorticoid particles of the inventive compositions is defined as wherein at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, or at least about 99% of the glucocorticoid particles have a particle size that is less than the effective average particle size described above, i.e., less than about 2000nm, 1900nm, 1800nm, 1700nm,.. less than about 1000nm, less than about 990nm, less than about 980nm, less than about 970nm, etc. (also referred to as D60, D70, D80, D90, D95, and D99 particle sizes). In another embodiment of the present invention, the "effective average particle size" described above is the average particle size of the composition (i.e., the present invention includes compositions having an average particle size of less than about 2000nm,.. times.less than about 1000nm, less than about 990nm, less than about 980nm, less than about 970nm, etc.).

In the present invention, the D50 value of a nanoparticulate glucocorticoid composition refers to the particle size below which 50% of the glucocorticoid particles are below, by weight, by volume, by number, or any other suitable measure. Similarly, D90 refers to the particle size below which 90% of the glucocorticoid particles are below, by weight, by volume, by number, or any other suitable measure.

4. Concentration of glucocorticoid, nonionic surface stabilizer and amphiphilic lipid

The relative amounts of glucocorticoid, one or more nonionic surface stabilizers, and at least one amphiphilic lipid can vary widely. The optimum amount of each component may depend, for example, on the particular glucocorticoid selected, the particular nonionic surface stabilizer selected, the particular amphipathic lipid selected, the Hydrophilic Lipophilic Balance (HLB), the melting point, and the surface tension of the aqueous solution of the nonionic surface stabilizer, among others.

In one embodiment, the glucocorticoid concentration may be from about 99.5% to about 0.001%, from about 95% to about 0.1%, or from about 90% to about 0.5%, based on the total combined weight of the glucocorticoid, the at least one nonionic surface stabilizer, and the at least one amphiphilic lipid (excluding other excipients).

In another embodiment, the concentration of the at least one nonionic surface stabilizer may be from about 0.01% to about 99%, from about 0.1% to about 50%, or from about 1% to about 10% by weight, based on the total combined weight of the glucocorticoid, the at least one nonionic surface stabilizer, and the at least one amphiphilic lipid (excluding other excipients).

In another embodiment, the concentration of the at least one amphipathic lipid may be from about 0.01% to about 99%, from about 0.1% to about 50%, and from about 1% to about 10% by weight, based on the total combined weight of the glucocorticoid, the at least one nonionic surface stabilizer, and the at least one amphipathic lipid (excluding other excipients).

In an exemplary embodiment of the invention, the nanoparticulate glucocorticoid composition comprises a glucocorticoid at a concentration of about 10-30% w/w in contact with a non-ionic surface stabilizer at a concentration of about 5-10% of the total glucocorticoid concentration.

5. Composite composition

The dispersion to be sterilized may comprise a plurality of glucocorticoids, one or more glucocorticoid compositions having a plurality of particle sizes, or a combination thereof. For example, the dispersion may comprise: (1) nanoparticulate glucocorticoid a and nanoparticulate glucocorticoid B; (2) nanoparticulate glucocorticoid a and microparticulate glucocorticoid a; (3) nanoparticulate glucocorticoid a and microparticulate glucocorticoid B; (3) nanoparticulate glucocorticoid A having an effective average particle size of 250nm and nanoparticulate glucocorticoid A having an effective average particle size of 800nm, or a combination thereof.

a. Compositions comprising microparticulate active agents

The sterilized micronised glucocorticoid particles may be combined with a sterile dispersion of one or more nanoparticulate glucocorticoid particles, either before or after sterilization, to give a sustained or controlled release composition. Such sterilized micronised particulate glucocorticoid particles may also be combined with sterile dispersions that have been processed into powders or other dry dosage forms.

The combination of very small glucocorticoid particles, i.e. nanoparticulate glucocorticoid particles, combined with larger active agent particles, i.e. micronized glucocorticoid particles, allows for both a fast release (IR) and a Controlled Release (CR) of the different glucocorticoid components. The micronized glucocorticoid particles and nanoparticulate glucocorticoid particles may be the same glucocorticoid or different glucocorticoids.

As used herein, "nanoparticulate" active agents have an effective average particle size of less than about 2 microns and the micropowder active agents have an effective average particle size of greater than about 2 microns. The micronized active agent particles and nanoparticulate active agent particles can be sterilized simultaneously with a suitable sterilization process, or in a separate process.

Nanoparticulate glucocorticoid particles, representing the IR component, provide rapid in vivo dissolution due to their small and concomitantly large specific surface area. Micronized glucocorticoid particles, which represent the CR component, provide slower in vivo dissolution due to the relatively large particle size and concomitant small specific surface area.

The IR and CR components, which represent various in vivo dissolution rates (and thus absorption in vivo infusion rates), can be adjusted by precisely controlling the particle size of the glucocorticoid. Thus, the composition may comprise a mixture of nanoparticulate glucocorticoid particles, wherein each particle has a defined size associated with a precise release rate, and the composition may comprise a mixture of microparticulate glucocorticoid particles, wherein each particle has a defined size associated with a precise release rate;

b. compositions comprising multiple nanoparticle sizes

In yet another embodiment of the present invention, a first nanoparticulate glucocorticoid dispersion providing the desired pharmacokinetic profile is combined with at least one other nanoparticulate glucocorticoid dispersion yielding a different desired pharmacokinetic profile. More than two nanoparticulate glucocorticoid dispersions may be combined. The first glucocorticoid dispersion has a nanoparticulate particle size, while the other glucocorticoid or glucocorticoids may be nanoparticulate, solubilized, or have a conventional microparticle size.

The second, third, fourth, etc. glucocorticoid dispersions may be different from the first and may differ from each other, e.g., (1) the effective average particle size of the glucocorticoids may differ; or (2) the dosage of the glucocorticoid may be varied.

Preferably, when it is desired to administer both a "fast acting" formulation and a "long acting" formulation simultaneously, the two formulations are combined in a single composition, such as a dual release composition.

6. Glucocorticoid compositions in combination with other active agents

The glucocorticoid compositions of the present invention may additionally comprise one or more compounds useful in the treatment of asthma, allergic conjunctival and seasonal allergic rhinitis, as well as other inflammatory and allergic diseases conventionally treated with glucocorticoids. The compositions of the present invention may be co-formulated with such other active agents, or the compositions of the present invention may be administered in combination with such active agents or sequentially.

For the treatment of asthma or allergic diseases and can be used in combination with the composition of the present inventionExemplary agents include, but are not limited to, long-acting beta-agonists, such as salmeterolAnd formoterolLeukotriene modulators, e.g. montelukastZafirlukastHe Qi TongTheophyllineAndnedocromilCromolyn sodium saltShort-acting beta-agonists (also known as "bronchodilators"), such as salbutamolAndl-salbutamolBitolterolPibuterolAnd terbutalineIpratropium bromidePrednisoneAndprednisoloneAndand methylprednisolone

7. Additional surface stabilizers

In one embodiment of the invention, the composition may also include one or more ionic (including cationic and anionic), anionic or zwitterionic surface stabilizers of low or high molecular weight, polymeric or copolymeric nature. If such surface stabilizers are used in the compositions of the present invention, they are preferably added after the composition has been moist heat sterilized. Exemplary useful ionic, anionic, cationic, nonionic, or zwitterionic surface stabilizers include, but are not limited to, known organic and inorganic pharmaceutically acceptable excipients. Such excipients include various polymers, copolymers, low molecular weight oligomers, natural products, and surfactants. The present invention may use a combination of more than one surface stabilizer.

Representative examples of ionic, cationic, anionic or zwitterionic surface stabilizers include, but are not limited to, albumin, including, but not limited to, human serum albumin and bovine albumin, sodium lauryl sulfate, dioctyl sulfosuccinate, gelatin, casein, gum arabic, tragacanth, stearic acid, benzalkonium chloride, calcium stearate, glyceryl monostearate, cetostearyl alcohol, cetomacrogol emulsifying wax, colloidal silica, phosphate esters, carboxymethylcellulose calcium, carboxymethylcellulose sodium, hydroxypropylmethylcellulose phthalate, magnesium aluminum silicate, triethanolamine, poloxamers (e.g., TetronicAlso known as PoloxamineIs a tetrafunctional block copolymer produced by the sequential addition of propylene oxide and ethylene oxide to ethylenediamine (BASF wyandotte corporation, Parsippany, n.j.); tetronic(T-1508)(BASFWyandotte Corporation)、Tritons (is alkylaryl polyether sulfonate (Dow)); crodestas(is a mixture of sucrose stearate and sucrose distearate (Croda Inc.)); crodestas(Croda, Inc.); random copolymers of lysozyme, PVP and PVA (e.g.S630), and so on.

Examples of useful cationic surface stabilizers include, but are not limited to, polymers, biopolymers, polysaccharides, cellulose, alginates, phospholipids and non-polymeric compounds, such as zwitterionic stabilizers, poly-n-methylpyridinium, anthracycll pyridinium chloride, cationic phospholipids, chitosan, polylysine, polyvinylimidazole, polybrene, polymethyl methacrylate trimethylammonium bromide (PMMTMABr), hexyldiphenyl ketotrimethyl ammonium bromide (HDMAB) and polyvinylpyrrolidone-2-dimethylaminoethyl methacrylate dimethylsulfate. Other useful cationic stabilizers include, but are not limited to, cationic lipids, sulfonium, onium, and quaternary ammonium compounds, such as stearyl trimethylammonium chloride, benzyl-bis (2-chloroethyl) ethylammonium bromide, coco trimethylammonium chloride or bromide, coco methyldiethyl ammonium chloride or bromide, decyl triethylammonium chloride, decyl dimethylhydroxyethyl ammonium chloride or bromideAmmonium, C_12-15Dimethyl hydroxyethyl ammonium chloride or bromide, coconut dimethyl hydroxyethyl ammonium chloride or bromide, myristyl trimethyl ammonium methyl sulfate, lauryl dimethyl benzyl ammonium chloride or bromide, lauryl dimethyl (ethyleneoxy)₄Ammonium chloride or bromide, N-alkyl (C)_12-18) Dimethyl benzyl ammonium chloride, N-alkyl (C)_14-18) Dimethyl-benzyl ammonium chloride, N-tetradecyldimethylbenzylammonium chloride monohydrate, dimethyldidecyl ammonium chloride, N-alkyl and (C)_12-14) Dimethyl-1-naphthylmethylammonium chloride, trimethylammonium halides, alkyl-trimethylammonium and dialkyl-dimethylammonium salts, lauryltrimethylammonium chloride, ethoxylated alkylamidoalkyldialkylammonium salts and/or ethoxylated trialkylammonium salts, dialkylbenzenedialkylammonium chloride, N-didecyldimethylammonium chloride, N-tetradecyldimethylbenzylammonium chloride monohydrate, N-alkyl (C)_12-14) Dimethyl 1-naphthylmethylammonium chloride, dodecyldimethylbenzylammonium chloride, dialkylphenylalkylammonium chloride, lauryltrimethylammonium chloride, alkylbenzylmethylammonium chloride, alkylbenzyldimethylammonium bromide, C₁₂、C₁₅、C₁₇Trimethyl ammonium bromide, dodecylbenzyltriethyl ammonium chloride, polydiallyldimethyl ammonium chloride (DADMAC), dimethyl ammonium chloride, alkyldimethyl ammonium halides, tricetylmethyl ammonium chloride, decyltrimethylammonium bromide, dodecyltriethylammonium bromide, tetradecyltrimethylammonium bromide, methyltrioctylammonium chloride (ALIQUAT 336)^TM)、POLYQUAT 10^TMTetrabutylammonium bromide, benzyltrimethylammonium bromide, choline esters (e.g. of fatty acids), benzalkonium chloride, stearylalkylammonium chloride compounds (e.g. stearyltrimethylammonium chloride and Di-stearyldimethylammonium chloride), cetylpyridinium bromide or chloride, halide salts of quaternized polyoxyethylalkylamines, MIRAPOL^TMAnd ALKAQUAT^TM(Alkaril Chemical Company), alkylpyridinium salts; amines, e.g. alkylamines, dialkylamines, alkanolamines, polyethylenepolyamines, N-dialkylaminoalkylacrylates, ethylenesAlkenyl pyridines, amine salts such as lauryl amine acetate, stearyl amine acetate, alkyl pyridinium salts, and alkyl imidazolium salts, and amine oxides; azomethine (imide azolinium) salts; protonated quaternary acrylamides; methylated quaternary polymers, e.g. poly [ diallyldimethylammonium chloride]And poly- [ N-methylvinylpyridinium chloride](ii) a And cationic guar gum.

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 (cationic surfactant: Analytical and biological Evaluation) (MarcelDekker, 1994); p. and d.rubinggh (editors), Cationic Surfactants: physical chemistry (cationic surfactant: physicochemical) (Marcel Dekker, 1991); and j.richmond, Cationic Surfactants: organic Chemistry (cationic surfactants: Organic Chemistry), (Marcel Dekker, 1990).

Particularly preferred non-polymeric primary stabilizers (primary stabilizers) are any non-polymeric compounds, such as benzalkonium chloride, carbonium compounds, phosphonium compounds, oxonium compounds, halonium compounds, cationic organometallic compounds, quaternary phosphorus compounds, pyridinium compounds, anilinium compounds, ammonium compounds, hydroxylammonium compounds, primary ammonium compounds, secondary ammonium compounds, tertiary ammonium compounds and compounds of the formula NR₁R₂R₃R₄ ⁽⁺⁾The quaternary ammonium compound of (1). For formula NR₁R₂R₃R₄ ⁽⁺⁾The compound of (1):

(i)R₁-R₄none of which is CH₃；

(ii)R₁-R₄One of which is CH₃；

(iii)R₁-R₄Three of which are CH₃；

(iv)R₁-R₄Are all CH₃；

(v)R₁-R₄Two of which are CH₃，R₁-R₄One of them being C₆H₅CH₂，R₁-R₄One of which is an alkyl chain of 7 or less carbon atoms;

(vi)R₁-R₄two of which are CH₃，R₁-R₄One of them being C₆H₅CH₂，R₁-R₄One of which is an alkyl chain of 19 or more than 19 carbon atoms;

(vii)R₁-R₄two of which are CH₃，R₁-R₄One of which is a group C₆H₅(CH₂)_nWherein n is>1；

(viii)R₁-R₄Two of which are CH₃，R₁-R₄One of which is a group C₆H₅CH₂，R₁-R₄One of which contains at least one heteroatom;

(ix)R₁-R₄two of which are CH₃，R₁-R₄One of which is a group C₆H₅CH₂，R₁-R₄One of which contains at least one halogen;

(x)R₁-R₄two of which are CH₃，R₁-R₄One of which is a group C₆H₅CH₂，R₁-R₄One of which comprises at least one cyclic fragment;

(xi)R₁-R₄two of which are CH₃，R₁-R₄One of them is a benzene ring; or

(xii)R₁-R₄Two of which are CH₃，R₁-R₄Two of which are purely aliphatic segments.

Such compounds include, but are not limited to, behenylbenzyldimethylammonium chloride, benzethonium chloride, cetylpyridinium chloride, behenyltrimethylammonium chloride, lorammonium chloride, cetrimide hydrofluoride, chloroallylhexamethylenetetramine (Quaternium-15), distearyldimethylammonium chloride (Quaternium-5), dodecyldimethylethylbenzylammonium chloride (Quaternium-14), Quaternium-22, Quaternium-26, Quaternium-18 hectorite, dimethylaminoethyl chloride hydrochloride, cysteine hydrochloride, diethanolammonium POE (10) oleyl ether phosphate (diethanolammonium POE (10) olylether phosphate), diethanolammonium POE (3) oleyl ether phosphate, denylalkyl ammonium chloride (tallonitium chloride), dimethyldioctadecylammonium chloride, bentonite, benzalkonium chloride (benzalkonium chloride), benzalkonium chloride (dimethyl dioctadecyl chloride), cetylammonium chloride (bentonite), benzalkonium chloride (tallow ammonium chloride), benzalkonium chloride (cetonium chloride (dimethyl chloride), Myristylbenzyldimethylammonium chloride, lauryl trimethyl ammonium chloride, ethylenediamine dihydrochloride, guanidine hydrochloride, pyridoxine hydrochloride, iodofinamide hydrochloride, meglumine hydrochloride, methylbenzyl ammonium chloride, myristyl trimethyl ammonium bromide, oleyl trimethyl ammonium chloride, polyquaternium-1, procaine hydrochloride, cocobetaine, selelammonium chloride bentonite, selelammonium chloride hectorite, stearyl trishydroxyethyl propylenediamine dihydrofluoride, tallow trimethyl ammonium chloride and cetyl trimethyl ammonium bromide.

Most of these surface stabilizers are known Pharmaceutical Excipients, described in detail in The Handbook of Pharmaceutical Excipients (The Pharmaceutical Press, 2000), commonly published by The American Pharmaceutical Association and The Pharmaceutical Society of great Excipients, specifically incorporated by reference. Surface stabilizers are commercially available and/or can be prepared using techniques known in the art.

8. Other pharmaceutical excipients

The pharmaceutical compositions of the present invention may also contain one or more binders, fillers, lubricants, suspending agents, sweetening agents, flavoring agents, preservatives, buffering agents, wetting agents, disintegrating agents, foaming agents and other excipients. Such excipients are known in the art.

Filling inExamples of the agent are lactose monohydrate, anhydrous lactose and various starches; examples of binders are various celluloses and crosslinked polyvinylpyrrolidones, microcrystalline celluloses, e.g. cellulose acetate, cellulose acetatePH101 andPH102, microcrystalline cellulose, and silicified microcrystalline cellulose (SMCC).

Suitable lubricants, including substances which influence the flowability of the powder to be compacted, are colloidal silicas, e.g. silica200 of a carrier; talc, stearic acid, magnesium stearate, calcium stearate and silica gel.

Examples of sweeteners are any natural or artificial sweetener such as sucrose, xylitol, saccharin sodium, cyclamate, aspartame and acesulfame. An example of a flavoring agent is(trade mark of MAFCO), bubble gum flavoring, fruit flavoring, and the like.

Examples of preservatives are potassium sorbate, methyl paraben, propyl paraben, benzoic acid and its salts, other esters of p-hydroxybenzoic acid such as butyl paraben, alcohols such as ethanol or benzyl alcohol, phenolic compounds such as phenol, or quaternary ammonium compounds such as benzalkonium chloride.

Suitable diluents include pharmaceutically acceptable inert fillers such as microcrystalline cellulose, lactose, dibasic calcium phosphate, sugars and/or mixtures of any of the above. Examples of diluents include microcrystalline cellulose, such asPH101 andPH 102; lactose such as lactose monohydrate, anhydrous lactose andDCL 21; dibasic calcium phosphates such asMannitol; starch; sorbitol; sucrose; and glucose.

Suitable disintegrants include lightly cross-linked polyvinylpyrrolidone, corn starch, potato starch, maize starch and modified starches, croscarmellose sodium, crospovidone, sodium starch glycolate, and mixtures thereof.

Examples of blowing agents are twin blowing agents such as organic acids and carbonates or bicarbonates. 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 acid component of the paired blowing agent may be present.

Compositions suitable for parenteral injection may comprise physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions and sterile powders for reconstitution into sterile injectable solutions or dispersions. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, sodium chloride, ringer's solution, ringer's lactate, stabilizer solutions, tonicity enhancing agents (sucrose, dextrose, mannitol, and the like), polyols (propylene glycol, polyethylene glycol, glycerol, and the like), suitable mixtures thereof, vegetable oils (e.g., olive oil), and injectable organic esters such as ethyl oleate. Suitable fluids are described in Remington's pharmaceutical Sciences published by Mack Publishing Co., 17 th edition, p 1543.

D. Process for the preparation of the composition of the invention

In another aspect of the invention, there is provided a process for the preparation of a nanoparticulate glucocorticoid formulation according to the invention. The method comprises one of the following methods: milling or grinding (including but not limited to wet milling), homogenization, precipitation, freezing, template emulsion methods, supercritical fluid methods, nanoelectrospray methods, or any combination thereof. An exemplary method of preparing a nanoparticle composition is described in U.S. Pat. No. 5,145,684. Methods for Preparing nanoparticle Compositions are also described in U.S. Pat. No. 5,518,187 "Method of growing Pharmaceutical Substances", U.S. Pat. No. 5,718,388 "Continuous Method of growing Pharmaceutical Substances", U.S. Pat. No. 5,862,999 "Method of growing Pharmaceutical Substances", U.S. Pat. No. 5,665,331 "Co-precipitation of Nanoparticles of Pharmaceutical Agents with Growth modulators" (Co-precipitation of Nanoparticles of Pharmaceutical Agents with Crystal Growth regulators) ", U.S. Pat. No. 5,662,883" Co-precipitation of Nanoparticles of Pharmaceutical Agents with Growth modulators "(Co-precipitation of Nanoparticles of Pharmaceutical Agents)", U.S. Pat. No. 2 "Method of Preparing Nanoparticles of Pharmaceutical Compositions (Co-precipitation of Nanoparticles of Pharmaceutical Agents)", and U.S. Pat. No. 5,518,187 "Method of growing Pharmaceutical Subst" (Method of Grinding Pharmaceutical Agents) ", U.S. Pat. No. 5,518,187" Continuous Method of growing Nanoparticles of Pharmaceutical Compositions (Co-precipitation of Nanoparticles of Pharmaceutical Agents) ", U.S. Pat. No. 5,518,36" Method of Preparing Nanoparticles of Pharmaceutical Compositions (Co-preparation of Nanoparticles of Pharmaceutical Agents of Pharmaceutical Compositions of Growth modulators of Nanoparticles of Pharmaceutical Compositions of Pharmaceutical Agents of Nanoparticles of Pharmaceutical Agents of Nanoparticles of Pharmaceutical Compositions of Nanoparticles of Pharmaceutical Compositions of Nanoparticles of Pharmaceutical Compositions of, U.S. Pat. No. 5,534,270 "Method of Preparing Nanoparticles of a preparation Stable Drug", U.S. Pat. No. 5,510,118 "Process of Preparing Therapeutic compositions containing Nanoparticles" and U.S. Pat. No. 5,470,583 "Method of Preparing Nanoparticles compositions containing Charged Phospholipids to Reduce Aggregation", are hereby specifically incorporated herein by reference in their entirety.

After milling, homogenization, precipitation, etc., the resulting nanoparticulate glucocorticoid composition may be sterilized and then used in a dosage form suitable for administration.

The preferred dispersion medium for the particle size reduction process is an aqueous medium. However, any medium in which the glucocorticoid is rendered poorly soluble and dispersible can be used as the dispersion medium. Examples of non-aqueous dispersion media include, but are not limited to, aqueous salt solutions, safflower oil and solvents such as ethanol, t-butanol, hexane and glycols.

Effective methods for providing mechanical force for reducing the particle size of glucocorticoids include ball milling, media milling and homogenization, e.g. with(Microfluidics Corp.). Ball milling is a low energy milling process that uses milling media, drugs, stabilizers, and liquids. The material is placed in a grinder rotating at an optimal speed so that the medium gradually reduces the drug particle size by impact. The media used must have a high density because the energy to reduce the particles is provided by gravity and the mass of the grinding media.

1. Grinding glucocorticoids to reduce particle size

Upon milling, the particles of the composition of the invention are dispersed in a liquid dispersion medium in which the particles are poorly soluble, and the particle size of the composition of the invention is reduced to the desired effective average particle size using mechanical means in the presence of milling media. The size of the particles may be reduced in the presence of one or more nonionic surface stabilizers. Alternatively, the particles may be contacted with one or more nonionic surface stabilizers after milling. Other compounds such as diluents may be added to the composition during particle size reduction. The dispersion can be prepared in a continuous or batch manner.

Media milling is a high energy milling process. The drug, stabilizer and liquid are placed in a container and recirculated in a chamber containing the medium and a rotating shaft/impeller. The rotating shaft agitates the media, subjecting the drug to impact and shear forces, thereby reducing the drug particle size.

Upon milling, the compositions of the present invention may be added to a liquid medium in which the composition is substantially insoluble to form a premix. The concentration of the composition of the present invention in the liquid medium may be from about 5 to about 60%, from about 15 to about 50% (w/v), and from about 20 to about 40%. The nonionic surface stabilizer may be present in the premix or may be added to the drug dispersion after particle size reduction. The concentration of the nonionic surface stabilizer can be from about 0.1 to about 50%, from about 0.5 to about 20%, and from about 1 to about 10% by weight.

The premix can be used directly to apply a mechanical tool to the premix to reduce the average particle size of the composition of the invention in the dispersion to less than about 2000 nm. When milling is performed by ball milling, the premix is preferably used directly. Alternatively, the composition of the invention and the surface stabilizer may be dispersed in the liquid medium with suitable agitation, such as a Cowles-type mixer, until a homogeneous dispersion is seen in which large aggregates are not visible to the naked eye. When milling with a recirculating media mill, it is preferred to subject the premix to such a pre-mill dispersion step.

The mechanical means for reducing the particle size of the composition of the invention conveniently takes the form of a dispersion mill. Suitable dispersion mills include ball mills, agitator mills, vibratory mills, and media mills such as sand mills and bead mills. Media milling is preferred because a relatively shorter milling time is required to reduce to the desired particle size. The apparent viscosity of the premix is preferably from about 100 to about 1,000 centipoise during media milling, and from about 1 to about 100 centipoise for ball milling. Such a range tends to achieve an optimal balance between effective particle size reduction and media erosion.

Milling times can vary widely, depending primarily on the particular machine tool and processing conditions selected. For ball milling, processing times of up to 5 days or more may be required. Alternatively, when a high shear media mill is used, a processing time of less than 1 day (residence time of 1 minute to several hours) may be required.

2. Non-aqueous non-pressurized grinding system

The nanoparticle compositions of the present invention are prepared in a non-aqueous non-pressurized milling system using a non-aqueous liquid as the wet milling medium, the non-aqueous liquid having a vapor pressure at room temperature of about 1atm or less than 1atm in which the compositions of the present invention are substantially insoluble. In such processes, a slurry comprising the composition of the present invention is milled in a non-aqueous medium to obtain the nanoparticle composition of the present invention, which is then moist heat sterilized. Examples of suitable non-aqueous media include ethanol, trichloromonofluoromethane (CFC-11), and dichlorotetrafluoroethane (CFC-114). The advantage of using CFC-11 is that it can be handled at approximately cool room temperature, whereas CFC-114 requires more controlled conditions to avoid evaporation. After milling is complete, the composition can be sterilized and the liquid medium removed and recovered under vacuum or heat to provide a dry nanoparticle composition comprising the composition of the present invention. Alternatively, the dried composition may be sterilized after removal of the liquid medium. The dry composition can then be filled into a suitable container and the final propellant added. Exemplary end product propellants, preferably not containing chlorinated hydrocarbons, include HFA-134a (tetrafluoroethane) and HFA-227 (heptafluoropropane). Chlorinated propellants may also be used in this aspect of the invention, although non-chlorinated propellants may be preferred for environmental reasons.

In a non-aqueous pressure milling system, a non-aqueous liquid medium having a vapor pressure at room temperature significantly greater than 1atm is used in the milling process to produce compositions comprised of the nanoparticle components of the present invention. The composition is then sterilized. If the grinding medium is a suitable halogenated hydrocarbon propellant, the resulting dispersion can be filled directly into a suitable pMDI container. Alternatively, the grinding media can be removed and recovered under vacuum or heat to provide a dry composition comprised of the nanoparticulate composition of the present invention. The composition may then be sterilized, filled into suitable containers, and filled with a suitable propellant for use in a pMDI.

3. Grinding media

The grinding media may comprise particles, preferably substantially spherical, such as particles consisting essentially of a polymer or copolymer resin. Alternatively, the grinding media may comprise a core to which is attached a coating of a polymer or copolymer resin.

Generally, suitable polymer or copolymer resins are chemically and physically inactive, substantially free of metals, solvents, and monomers, sufficiently hard and brittleAnd (3) properties that enable it to avoid chopping or crushing during grinding. Suitable polymer or copolymer resins include crosslinked polystyrene, such as polystyrene crosslinked with divinylbenzene; a styrene copolymer; a polycarbonate; polyacetals, e.g. Delrin^TM(e.i. du Pont de Nemours and Co.); vinyl chloride polymers and copolymers; a polyurethane; a polyamide; poly (tetrafluoroethylene) s, e.g.(e.i. du Pont de Nemours and Co.) and other fluoropolymers; high density polyethylene; polypropylene; cellulose ethers and esters such as cellulose acetate; polyhydroxymethacrylate; polyhydroxyethyl acrylate; and silicone-containing polymers such as polysiloxanes and the like. The polymer may be biodegradable. Exemplary biodegradable polymers or copolymers include poly (lactide) s of lactide and glycolide, poly (glycolide) copolymers, polyanhydrides, poly (hydroxyethyl methacrylate), poly (iminocarbonate), poly (N-acyl hydroxyproline) esters, poly (N-palmitoyl hydroxyproline) esters, ethylene-vinyl acetate copolymers, poly (orthoesters), poly (caprolactone), and poly (phosphazene). For biodegradable polymers or copolymers, the contamination from the medium itself is preferably metabolized in vivo into a biologically acceptable product that can be cleared from the body.

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

The polymer or copolymer resin may have about 0.8 to about 3.0g/cm³The density of (c).

In a preferred milling process, the particles are prepared continuously. Such methods comprise continuously feeding a composition of the present invention into a milling chamber, contacting the composition of the present invention with a milling media in the chamber to reduce the particle size of the composition of the present invention, and continuously withdrawing a nanoparticulate composition of nanoparticles of the present invention from the milling chamber.

In a second step the grinding media is separated from the milled nanoparticulate composition of the invention using conventional separation techniques, such as simple filtration, sieving through a sieve or sieve, etc. Other separation techniques such as centrifugation may also be used.

4. Homogenization of glucocorticoids to effect particle size reduction

Homogenization is a technique that does not use grinding media. The drug, nonionic surface stabilizer and liquid (or drug and liquid, added after particle size reduction) constitute a treatment stream that is propelled into a treatment zone in which the drug is presentReferred to as an Interaction Chamber. The product to be treated is introduced into the pump and then forcibly discharged.The trigger valve(s) purge air out of the pump. Once the product fills the pump, the trigger valve is closed and product is forced through the interaction chamber. The geometry of the interaction chamber creates strong shear forces, impact forces and cavitation responsible for particle size reduction. In particular, within the interaction chamber, the pressurized product splits into two streams, accelerating to very high velocities. The resulting jets are then aligned with each other and collide at the interaction zone. The resulting product has a very fine and uniform particle or droplet size and is suitable for sterilization.A heat exchanger is also provided, allowing the product to be cooled. U.S. Pat. No. 5,510,118, specifically incorporated by reference herein, teachesA process for producing nanoparticle particles.

5. Precipitation to obtain the nanoparticle composition of the present invention

Another method of forming the desired nanoparticulate glucocorticoid dispersion is microprecipitation. This is a method of preparing a stable dispersion of nanoparticulate particles of the composition of the present invention in the presence of one or more nonionic surface stabilizers and one or more colloidal stability-enhancing surfactants that are free of any trace toxic solvent or dissolved heavy metal impurities. Such methods include, for example, (1) dissolving the present compositions in a suitable solvent with mixing; (2) adding the formulation of step (1) to a solution containing at least one non-ionic surface stabilizer with mixing to form a clear solution; and (3) precipitating the formulation of step (2) with a suitable non-solvent, with mixing. The process may be followed by conventional methods to remove any salts formed (if present) by dialysis or diafiltration and concentration of the dispersion. The resulting nanoparticle composition of the nanoparticle dispersion of the present invention can be sterilized and then used in, for example, a liquid atomizer, or processed to form a dry powder for DPI or pMDI.

6. Supercritical fluid process for preparing nanoparticles

The nanoparticle compositions can also be prepared by supercritical fluid methods. In such methods, the glucocorticoid is dissolved in a solution or carrier (which may also comprise at least one nonionic surface stabilizer). The solution and supercritical fluid are then introduced simultaneously into the particle former. If the nonionic surface stabilizer is not pre-added to the carrier, it can be added to the particle former. The temperature and pressure are controlled so that the dispersion and extraction of the carrier is substantially simultaneous by the action of the supercritical fluid. The chemical agents that can be used as supercritical fluids include carbon dioxide, nitrous oxide, sulfur hexafluoride, xenon, ethylene, chlorotrifluoromethane, ethane, and trifluoromethane.

Examples of known supercritical processes for preparing nanoparticles include international patent application No. WO 97/144407, published 24/4/1997 to Pace et al, which mentions the preparation of water-insoluble particles of biologically active compounds having an average size of 100nm to 300nm by dissolving the compound in a solution in the presence of a suitable surface stabilizer and then spraying the solution into a compressed gas, liquid or supercritical fluid. For the purposes of the present invention, the surface stabilizers used are nonionic surface stabilizers.

Similarly, U.S. patent No. 6,406,718 to Cooper et al describes a method of forming a particulate fluticasone propionate product comprising simultaneously introducing into a particle former a supercritical fluid and a vehicle comprising at least fluticasone propionate in solution or suspension, the temperature and pressure therein being controlled so that the vehicle is substantially simultaneously dispersed and extracted by the action of the supercritical fluid. The chemical agents that can be used as supercritical fluids include carbon dioxide, nitrous oxide, sulfur hexafluoride, xenon, ethylene, chlorotrifluoromethane, ethane, and trifluoromethane. The supercritical fluid may optionally comprise one or more modifiers, such as methanol, ethanol, ethyl acetate, acetone, acetonitrile, or any mixture thereof. A supercritical fluid modifier (or co-solvent) is a chemical agent that, when added to a supercritical fluid, changes the intrinsic properties of the supercritical fluid at or around the critical point. According to Cooper et al, the fluticasone propionate particles prepared with supercritical fluid have a particle size range of 1-10 microns, preferably 1-5 microns.

7. Low temperature process for obtaining nanoparticulate glucocorticoid compositions

Another method of forming the desired nanoparticulate glucocorticoid composition is spray freezing to a liquid ("SFL"). The method comprises injecting an organic or organic aqueous solution of a glucocorticoid containing a stabilizing agent into a cryogenic liquid, such as liquid nitrogen. The droplets of glucocorticoid solution are frozen at a rate sufficient to minimize crystallization and particle growth, thereby formulating into nanostructured glucocorticoid particles. The nanoparticulate glucocorticoid particles can have a variety of particle morphologies depending on the solvent system and processing conditions selected. In the separation step, the nitrogen and solvent are removed under conditions that avoid aggregation or maturation of the glucocorticoid particles.

As a complementary technique to SFL, ultrafreeze ("URF") can also be used to produce equivalent nanostructured glucocorticoid particles with significantly increased surface area. URF involves placing an organic or organic aqueous solution of a stabilizer-containing glucocorticoid onto a low temperature substrate.

8. Emulsion method for obtaining nanoparticulate glucocorticoid compositions

Another method of forming the desired nanoparticulate glucocorticoid composition is the templated emulsion method. The template emulsion produces nanostructured glucocorticoid particles with controlled particle size distribution and fast dissolution properties. The process involves preparing an oil-in-water emulsion and then swelling (swell) with a non-aqueous solution containing a glucocorticoid and a stabilizer. The particle size distribution of the glucocorticoid particles is a direct result of the emulsion droplet size prior to loading with glucocorticoid, and this property can be controlled and optimized in the process. Moreover, by selective use of solvents and stabilizers, Ostwald ripening can be eliminated or inhibited and emulsion stability achieved. Subsequently, the solvent and water are removed and the stabilized nanostructured glucocorticoid particles are recovered. Various glucocorticoid particle forms are obtained by appropriate control of the processing conditions.

9. Nano-electrospray technique for obtaining nanoparticulate glucocorticoid compositions

In electrospray ionization, a liquid is pushed through a very small, charged (usually metallic) capillary tube. The liquid contains the desired substance, such as a glucocorticoid (or "analyte"), dissolved in a large volume of solvent, which is typically much more volatile than the analyte. A volatile acid, base or buffer is then usually added to the solution as well. The analyte is present in solution as ions, either in protonated form or in anionic form. Like charge repulsion, the liquid pushes itself out of the capillary, forming a mist or aerosol of droplets of about 10 μm. Such a projected aerosol droplet is produced at least in part by the process of forming a Taylor cone and projecting from the tip of the cone. A neutral carrier gas, such as nitrogen, is sometimes used to aid in the atomization of the liquid and to aid in the evaporation of the neutral solvent from the droplets. As the droplets evaporate, they become suspended in the air, forcing the charged analyte molecules closer together. As similarly charged molecules come closer together, the droplet becomes unstable and the droplet breaks up again. This is called coulombic fission because it is the repulsive coulomb force between charged analyte molecules that drives the fission. The process repeats itself until the analyte is solvent free and is a lone ion.

In nanotechnology, single particles such as glucocorticoid particles can be deposited on a surface by electrospray. This is done by spraying the gum and ensuring that on average no more than one particle per drop is present. The surrounding solvent is finally dried to obtain an aerosol stream of the desired type of single particles. Here, the ionization characteristics of the method are not important for the application, but can be used for electrostatic precipitation of particles.

10. Exemplary Process for preparing glucocorticoid compositions

In an exemplary method, a nanoparticulate composition comprising a glucocorticoid and a nonionic surface stabilizer is diluted with water to about 5-20% (w/w) glucocorticoid and about 0.25% to about 2.0% (w/w) nonionic surface stabilizer. Lecithin phospholipids, including some anionic phospholipids, are added to the diluted nanoparticulate glucocorticoid composition at a concentration that is less than about 1% to less than about 5% (w/w) of the glucocorticoid concentration. Thus from about 0.05% to about 1% (w/w) of the lecithin phospholipid produces glucocorticoid nanoparticles.

Other excipients or components (e.g. EDTA, antioxidants, nitrogen) that help to chemically protect the glucocorticoid during thermal sterilization may also be added to the nanoparticulate glucocorticoid composition.

The nanoparticulate glucocorticoid composition is then steam autoclaved at a temperature of about 116 ℃ to about 130 ℃, preferably at a temperature of 121 ℃ for a suitable period of time to achieve a sterilization cycle against potential bacterial, yeast and mold contamination.

The sterilized nanoparticulate glucocorticoid composition is diluted and re-compounded under sterile conditions to obtain an acceptable sterile pharmaceutical composition suitable for the treatment of inflammatory and allergic diseases, such as inflammatory and allergic diseases of the pulmonary, nasal, ocular and otic systems. Other ingredients may include excipients such as buffers and tonicity agents.

An exemplary final pharmaceutical composition may be comprised of a glucocorticoid at a concentration of about 0.00125% to about 0.05%, a non-ionic surface stabilizer at a concentration of about 0.000625% to about 0.005%, and an amphoteric lipid at a concentration of about 0.0000125% to about 0.0025%. The final pharmaceutical composition after steam autoclave sterilization demonstrated an effective average particle size of the glucocorticoid nanoparticles of less than about 2000nm and glucocorticoid chemodegradants of less than 1% of the total glucocorticoid level.

11. Process for preparing aerosol formulation

The nanoparticle compositions of the present invention for aerosol administration can be prepared, for example, (1) by atomizing an aqueous dispersion of the nanoparticle composition of the present invention; (2) aerosolizing a dry powder of an agglomerate of the nanoparticle composition of the present invention (the aerosolized composition may additionally comprise a diluent); or (3) aerosolizing a suspension of nanoparticulate aggregates of the composition of the invention in a non-aqueous propellant. The nanoparticulate composition aggregates of the present invention, which may additionally comprise a diluent, may be prepared in a non-pressurized or pressurized non-aqueous system. Concentrated aerosol formulations can also be prepared by such methods.

a. Spray-dried powder aerosol formulations

Spray drying is a process used to obtain a powder containing nanoparticulate drug particles after reducing the particle size of a composition comprised of the nanoparticulate composition of the present invention in a liquid medium. Typically, spray drying is used when the liquid medium has a vapor pressure of less than about 1atm at room temperature. Spray dryers are devices that allow evaporation of the liquid and collection of the powder. A liquid sample of the solution or suspension is added to the nozzle. The nozzle produces sample droplets having diameters in the range of about 20 to about 100 μm ("microns") and then transports them with a carrier gas into the drying chamber. The carrier gas temperature is typically from about 80 to about 200 degrees celsius. The droplets are subjected to rapid liquid evaporation leaving dry particles which are collected in a dedicated vessel below the cyclone.

If the liquid sample consists of an aqueous dispersion of nanoparticles of the composition of the invention, the collected product will consist of spherical aggregates of nanoparticles of the composition of the invention. If the liquid sample consists of an aqueous dispersion of nanoparticles in which an inert diluent material (e.g., lactose or mannitol) is dissolved, the collected product will consist of particles of diluent (e.g., lactose or mannitol) containing the embedded nanoparticle composition of the present invention. The final size of the collected product can be controlled depending on the concentration of the nanoparticle composition and/or diluent of the present invention in the liquid sample, and the droplet size produced by the spray dryer nozzle. For deep lung delivery, the collected product size is preferably less than about 2 microns in diameter, for conducting airway delivery, the collected product size is preferably from about 2 to about 6 microns in diameter, and for nasal delivery, the collected product size is preferably from about 5 to about 100 μm. Compositions for ocular, otic or topical delivery may vary in glucocorticoid particle size. The collected product can then be used in conventional DPIs for pulmonary or nasal delivery, dispersed in a propellant for pMDI, or the particles can be reconstituted in water for nebulization.

In some cases, it may be preferred to add an inert carrier to the spray-dried material to improve the metering characteristics of the final product. This is particularly true when the spray dry powder agent is very small (less than about 5 microns) or when the intended dose is extremely small, making it difficult to meter the dose. Typically, such carrier particles (also known as bulking agents) are too large to be delivered to the lung, simply impacting the mouth and throat and being swallowed. Such carriers are usually composed of sugars such as lactose, mannitol or trehalose. Other inert materials including polysaccharides and cellulose may also be used as carriers.

Spray-dried powders comprising the nanoparticle compositions of the present invention may be used in conventional DPIs, dispersed in a propellant for pMDI, or reconstituted in a liquid medium for use in an atomizer.

b. Freeze-dried nanoparticle compositions

Sublimation (also known as freeze-drying or lyophilization) can also be used to obtain dry powder nanoparticle compositions. Sublimation may also increase the storage stability of the compositions of the invention, particularly biologicals. The freeze-dried particles may also be reconstituted for use in an atomizer. The freeze-dried nanoparticulate aggregates of the compositions of the present invention may be mixed with dry powder intermediates or used alone in DPI and pMDI for nasal or pulmonary delivery.

Sublimation involves freezing the product and subjecting the sample to strong vacuum conditions. This allows the ice formed to be converted directly from the solid state to the gaseous state. Such a process is very efficient and therefore gives a greater yield than spray drying. The resulting freeze-dried product comprises the composition of the present invention. The compositions of the invention are typically in an aggregated state and may be used for inhalation alone (lung or nose), in combination with diluent materials (lactose, mannitol, etc.), in DPI or pMDI, or reconstituted for use in a nebulizer.

E. Methods of use of nanoparticulate glucocorticoid compositions

The present invention provides a method of treatment of a mammal, including a human, in need of administration of a sterile dosage form of a glucocorticoid. The method comprises administering to the patient an effective amount of a sterile composition of the invention.

The sterile compositions of the present invention may be administered to a patient by any conventional route, including, but not limited to, inhalation, oral, rectal, ocular, parenteral (e.g., intravenous, intramuscular, or subcutaneous), otic, intracisternal, pulmonary, intravaginal, intraperitoneal, topical (e.g., powders, ointments, or drops), or as an oral or nasal spray. As used herein, the term "patient" is used to refer to an animal, preferably a mammal, including a human or a non-human. The terms patient and subject are used interchangeably.

The sterile compositions (aqueous and dry powder) of the present invention are particularly useful in the treatment of respiratory related diseases such as asthma, emphysema, respiratory distress syndrome, chronic bronchitis, cystic fibrosis, chronic obstructive pulmonary disease, respiratory diseases associated with acquired immunodeficiency syndrome, and inflammatory and allergic diseases of the dermis (skin), eye and ear. The formulations and methods improve the surface coverage of a given composition of the invention at the site of administration (e.g., mouth, lung, nose, eye, ear, etc.).

Administration by inhalation of glucocorticoids reduces the risk of systemic side effects compared to oral administration. Since glucocorticoids are locally highly active but only weakly systemically active, this mode of administration reduces the risk of side effects and thus minimizes the effects on the pituitary-adrenal axis, skin and eye. The side effects associated with inhalation therapy are mainly oropharyngeal candidiasis and dysphonia (due to atrophy of the laryngeal muscles). Oral administration of glucocorticoids results in atrophy of the dermis with thin skin, streaks and ecchymosis, but inhaled glucocorticoids do not cause similar changes in the respiratory tract.

Other advantages of inhaled administration over oral administration include the direct deposition of steroids in the airways, generally providing more predictable administration. The oral dosage required for adequate control varies considerably, whereas inhaled glucocorticoids are generally effective in a more narrow range. However, there are many factors that affect the availability of inhaled glucocorticoids: the extent of airway inflammation, the extent of lung metabolism, the amount of drug swallowed and metabolized in the GI tract, the patient's ability to coordinate with the release and inhalation of the drug, the glucocorticoid type, and the delivery system.

Compositions suitable for parenteral injection may comprise physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, sodium chloride, ringer's solution, ringer's lactate, stabilizer solutions, tonicity enhancing agents (sucrose, dextrose, mannitol, and the like), polyols (propylene glycol, polyethylene glycol, glycerol, and the like), suitable mixtures thereof, vegetable oils (e.g., olive oil), and injectable organic esters such as ethyl oleate.

The nanoparticulate active agent composition may also comprise adjuvants such as preservatives, wetting agents, emulsifying agents, and dispersing agents. Various antibacterial and antifungal agents such as parabens, chlorobutanol, phenol, sorbic acid, and the like can ensure prevention of microbial growth. Isotonic agents, such as sugars, sodium chloride and the like may also preferably be included. Prolonged absorption of the injectable pharmaceutical form can be brought about by the use of agents delaying absorption, for example, aluminum monostearate and gelatin.

Solid dosage forms for oral administration include, but are not limited to, capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active agent is mixed with at least one of the following ingredients: (a) one or more inert excipients (or carriers), such as sodium citrate or dicalcium phosphate; (b) fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol, and silicic acid; (c) binders such as carboxymethyl cellulose, alginate, gelatin, polyvinyl pyrrolidone, 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 retarding agents, such as paraffin; (g) absorption accelerators, such as quaternary ammonium compounds; (h) wetting agents, such as cetyl alcohol and glyceryl monostearate; (i) adsorbents such as kaolin and bentonite; and (j) a lubricant, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof. For capsules, tablets and pills, the dosage forms may also comprise buffering agents.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs. In addition to the active agent, the liquid dosage form may contain inert diluents commonly used in the art (such as water or other solvents), solubilizing agents, and emulsifiers. Exemplary emulsifiers are ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1, 3-butylene glycol, dimethylformamide, oils (such as cottonseed, groundnut, corn germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols, fatty acid esters of sorbitan, or mixtures of these substances, and the like.

In addition to such inert diluents, the compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

One skilled in the art will appreciate that effective amounts of the active agent can be determined empirically, and either pure or pharmaceutically acceptable salt, ester or prodrug forms (when such forms are present) can be used. The actual dosage level of the active agent in the nanoparticle compositions of the present invention can be varied to obtain an amount of the active agent effective to achieve the desired therapeutic effect for the particular composition and method of administration. The selected dosage level will therefore depend on the desired therapeutic effect, the route of administration, the efficacy of the active agent administered, the desired course of treatment, and other factors.

The dosage unit composition may contain multiple sub-doses, for constituting a daily dose. However, it will be understood that the specific dose level for any particular patient will depend upon a variety of factors: the type and extent of the cellular or physiological effect to be obtained; the activity of the particular agent or composition employed; the particular agent or composition used; the age, weight, general health, sex, and diet of the patient; time of administration, route of administration, and rate of excretion of the drug; the duration of treatment; drugs used in combination or concomitantly with specific agents; and similar factors well known in the pharmaceutical arts.

The foregoing general and detailed description are exemplary and explanatory and the following examples are intended to further illustrate the invention as claimed. Other objects, advantages and novel features will be readily apparent to those skilled in the art from the following examples, which are provided to more particularly set forth how the glucocorticoid formulations of the present invention are made and used. It must be noted, however, that they are presented for illustrative purposes only and should not be construed to limit the subject matter and scope of the present invention as defined by the claims.

Example 1

The purpose of this example was to evaluate the particle size of budesonide nanoparticle dispersions having polysorbate 80 as a nonionic surface stabilizer in the presence and absence of the amphiphilic lipid lecithin.

Budesonide has the formula:

budesonide is chemically known as the acetal of (RS) -11, 16, 17, 21-tetrahydroxy-pregna-1, 4-diene-3, 20-dione cyclic 16, 17-diol and butyraldehyde. Budesonide is provided as a mixture of two epimers (22R and 22S). The empirical formula of budesonide is C₂₅H₃₄O₆Its molecular weight is 430.5.

Budesonide is a white to off-white odorless powder, is hardly soluble in water and heptane, is slightly soluble in ethanol, and is readily soluble in chloroform.

An aqueous colloidal dispersion (NCD) containing 30% (w/w) budesonide and 1.5% (w/w) polysorbate-80 was prepared by adding 10g polysorbate-80 to 456.7g sterile water for injection (Abbott Labs) and 200g budesonide (Farmabios). The slurry was then mixed with 593g of PolyMill^TM-500(Dow Inc.) Polymer grinding media were combined and charged1215mL chamber of the grinding system. The slurry was milled at 1000rpm for 45 minutes. After the milling was completed, the resulting milled budesonide/polysorbate-80 dispersion was collected with a stainless steel screen. The particle size of the budesonide/polysorbate-80 dispersion was analyzed using a Horiba LA-910 particle size analyzer (Irvine, CA) and showed an average particle size of 205nm, D50 of 192nm and D90 of 291 nm. A portion of the 30% budesonide, 1.5% polysorbate-80 dispersion was then re-diluted with sterile water for injection to give 20% (w/w), 10% (w/w) and 5% (w/w) budesonide containing 1% (w/w), 0.5% (w/w) and 0.25% (w/w) polysorbate-80, respectively.

For table I, a separate portion of 30% budesonide, 1.5% polysorbate-80 dispersion was further compounded and diluted for preparation:

(#1) 20% (w/w) budesonide, 0.33% (w/w) lecithin NF (LIPOID), 1% (w/w) polysorbate-80,

(#2) 10% (w/w) budesonide, 0.05% (w/w) lecithin NF, 0.5% (w/w) polysorbate-80 or

(#3) 5% (w/w) budesonide, 0.25% (w/w) lecithin NF, 0.25% (w/w) polysorbate 80.

Lecithin NF is derived from soybean and is composed of various components, phosphatidylcholine, phosphatidylinositol, phosphatidylserine and other lipid components. All the resulting budesonide dispersions were placed in glass bottles, sealed with aluminum crimp rubber stoppers and then steam heated in a Fedagari autoclave at 116 ℃ aluminum crimp temperature for 48.5 minutes.

After autoclaving, the samples were examined for budesonide particle size using a Horiba LA-910 particle size analyzer and the results are shown in Table I.

Table I: particle size of budesonide dispersion after autoclaving: results for polysorbate-80 alone or polysorbate-80 plus lecithin-NF

Final budesonide formulation	Average number (nm)	D50(nm)	D90(nm)
Final budesonide formulation	Average number (nm)	D50(nm)	D90(nm)	20% budesonide, 1% polysorbate-80	668	421	1492
10% budesonide, 0.5% polysorbate-80	776	425	1854	20% budesonide, 1% polysorbate-80	668	421	1492
10% budesonide, 0.5% polysorbate-80	776	425	1854	5% budesonide, 0.25% polysorbate-80	879	431	2213
20% budesonide, 1% polysorbate-80, 0.33% lecithin NF	352	337	504	5% budesonide, 0.25% polysorbate-80	879	431	2213
20% budesonide, 1% polysorbate-80, 0.33% lecithin NF	352	337	504	10% budesonide, 0.5% polysorbate-80, 0.5% lecithin NF	346	331	500
5% budesonide, 0.25% polysorbate-80, 0.25% lecithin NF	343	328	493	10% budesonide, 0.5% polysorbate-80, 0.5% lecithin NF	346	331	500

The results demonstrate that the presence of amphiphilic lipids can reduce budesonide size growth that occurs after autoclaving. The average particle size of the budesonide formulation containing the amphipathic lipid is about half or less than about half of the budesonide formulation lacking the amphipathic lipid. Furthermore, with the D90 particle size measurement, more significant results were obtained confirming that the presence of amphiphilic lipids effectively eliminated any budesonide macrocrystal growth after heat treatment.

Example 2

The purpose of this example was to determine the effect of varying amounts of nonionic surface stabilizer and amphiphilic lipid on the particle size of nanoparticulate budesonide dispersions after autoclaving.

Separate portions of the 30% budesonide, 1.5% polysorbate-80 milled dispersion described in example 1 were further diluted and compounded with the addition of different levels of sterile water for injection (SWFI), lecithin NF, and polysorbate-80 to examine the effect of different percentages of polysorbate-80 and lecithin NF on budesonide particle size after autoclaving. The effect of different high pressure exposure temperatures is also listed in table II ("API" is active pharmaceutical ingredient or budesonide). All in table II are weight percentages.

Table II: particle size of budesonide dispersion after autoclaving: effect of different percentages of polysorbate-80 and lecithin NF

The data show that a higher percentage of polysorbate-80 results in larger particle size growth when exposed to autoclaving than a lower percentage of polysorbate-80. A higher percentage of lecithin NF appears to be advantageous for making smaller post-high pressure particle sizes.

Example 3

The purpose of this example is to determine the effect of phospholipid type on budesonide particle size after autoclaving.

An aqueous dispersion of 30% (w/w) budesonide and 1.5% (w/w) polysorbate-80 was prepared by adding 12g polysorbate-80 to 548g sterile water for injection (Abbott Labs) and 240g budesonide (Farmabios). The slurry was then mixed with 474.3g PolyMill^TM-500(Dow Inc) polymer grinding media are combined and added1215mL chamber of the grinding system. The slurry was milled at 1200rpm for 95 minutes. After the milling was completed, the resulting nanoparticulate budesonide/polysorbate 80 dispersion was collected with a stainless steel screen. The particle size of the budesonide/polysorbate-80 dispersion was analyzed using a Horiba LA-910 particle size analyzer (Irvine, CA) and showed an average particle size of 197nm, D50 of 185nm, and D90 of 277 nm.

The resulting budesonide/polysorbate-80 dispersion was then diluted with sterile water for injection and re-compounded with disodium EDTA and one of various phospholipids. Next, 10g of the sample was placed in a 20cc glass bottle, sealed with an aluminum crimp rubber stopper, and steam-heated at 121 ℃ for 15 minutes in a Fedagari autoclave. The various phospholipids tested during formulation represent lecithin NF and examples of Lipoid available from the company Lipoid, including partially purified lecithin (LIOIDS 45), partially purified hydrogenated lecithin (LIOID S75-3), purified lecithin (LIOIDS 100-3), distearoylphosphatidylethanolamine (PE 18:0/18:0), distearoylphosphatidylglycerol (PG 18:0/18:0) and dipalmitoylphosphatidic acid (PA 16:0/16: 0).

After steam autoclave cycling, particle size measurements were performed using Horiba LA-910, and the results are shown in Table III.

Table III: particle size of budesonide dispersion after autoclaving: effect of phospholipid type

The results show that only impure phospholipid mixtures (i.e., lecithin NF, Lipoid S45, or Lipoid S75-3) and negatively charged phospholipids in these aqueous solutions (i.e., Lipoid PG18:0/18:0 and Lipoid PA 16:0/16:0) effectively maintained small particle size and prevented particle size growth after exposure to high temperatures during high pressure cycling. In contrast, those phospholipids that are not negatively charged in aqueous solution, such as phosphatidylcholine (Lipoid S100-3) combined with polysorbate-80 or Lipoid PE16:0/16:0, resulted in significant particle size growth after exposure to autoclaving.

Example 4

The purpose of this example was to determine the resistance of nanoparticulate budesonide dispersions to thermally induced budesonide chemical degradation, determining whether EDTA could provide additional protection against such degradation.

The NCD described in example 3 was further compounded with lecithin NF with and without EDTA to study the chemical stability of budesonide dispersions after hot autoclaving. 50 grams of the sample were autoclaved at 121 ℃ for 15, 25 and 35 minutes and the resulting particle size and total level of budesonide related degradants were determined. Table IV summarizes the total budesonide degradants levels determined by HPLC for three autoclaving times.

Table IV: resistance of budesonide dispersions to thermally induced chemical degradation: additional protection in the Presence of EDTA

Preparation containing budesonide 10% and polysorbate 0.5%80, 0.5% lecithin NF	Non-autoclaving treatment	Total degradants% at 121 ℃ for 15 min	Total degradants% at 121 ℃ for 25 min	Total degradants% at 121 ℃ for 35 min
	Non-autoclaving treatment	Total degradants% at 121 ℃ for 15 min	Total degradants% at 121 ℃ for 25 min	Total degradants% at 121 ℃ for 35 min	Autoclaving, without EDTA		0.17％	0.17％	0.13％
Autoclaving in the presence of 0.0020% EDTA		0.12％	0.12％	0.12％	Autoclaving, without EDTA		0.17％	0.17％	0.13％
Autoclaving in the presence of 0.0020% EDTA		0.12％	0.12％	0.12％	No autoclaving, no EDTA	0.12％

The results demonstrate the resistance of the various formulations (with or without EDTA) to chemical degradation of budesonide. However, the presence of EDTA provided a slight advantage, with a reduction in the total level of budesonide degradants observed. The unsterilized control had a total degradant level of 0.12%.

Example 5

The purpose of this example was to determine whether dilution and further compounding of the glucocorticoid dispersion to a concentration level suitable for use as an inhalation formulation for treatment had an effect on the particle size of the glucocorticoid.

An aqueous nanoparticulate budesonide dispersion (NCD) containing 30% (w/w) budesonide and 1.5% (w/w) polysorbate-80 was prepared by adding 12g polysorbate-80 to 548g sterile water for injection (Abbott Labs) and 240g budesonide (Farmabios). The slurry was then mixed with 474.3g PolyMill^TM-500(Dow Inc) polymer grinding media are combined and charged1215mL chamber of the grinding system. The slurry was milled at 1200rpm for 95 minutes. Go toAfter grinding, the resulting NCD was collected with a stainless steel screen. The particle size of the budesonide/polysorbate-80 dispersion was analyzed using a Horiba LA-910 particle size analyzer (Irvine, CA) and showed an average particle size of 197nm, D50 of 185nm, and D90 of 277 nm.

The resulting NCD was then diluted with sterile water for injection, lecithin NF, and disodium EDTA to prepare a formulation containing 10% (w/w) budesonide, 0.5% (w/w) polysorbate-80, 0.5% (w/w) lecithin NF, and 0.002% (w/w) EDTA. A10 gram aliquot of the formulation was placed in a 20cc glass vial, sealed with an aluminum crimp rubber stopper, and steam heated in a Fedagari autoclave at 121 ℃ for 15 minutes. After autoclaving, 10% (w/w) each budesonide dispersion was diluted with water, citric acid, sodium citrate and additional polysorbate-80 and disodium EDTA to prepare dispersions containing 0.1% budesonide or 0.0125% budesonide and various levels of polysorbate-80 and lecithin NF.

The diluted and compounded samples were stored at room temperature for 7 days and then the particle size was determined using a Horiba LA-910 particle size analyzer. The results are shown in table V below.

Table V: budesonide NCD was diluted and compounded to levels useful as an inhalation preparation for treatment: retention of Small Dispersion particle size

Preparation	Average number (nm)	D50(nm)	D90(nm)
Preparation	Average number (nm)	D50(nm)	D90(nm)	0.0125% API, 0.000625% polysorbate-80, 0.000625% lecithin NF, 0.02% citric acid, 0.03% sodium citrate and 0.002% EDTA	357	343	508
0.0125% API, 0.002500% polysorbate-80, 0.000625% lecithin NF, 0.02% citric acid, 0.03% sodium citrate and 0.002％EDTA	356	342	508		357	343	508
	356	342	508	0.1% API, 0.005% polysorbate-80, 0.005% lecithin NF, 0.02% citric acid, 0.03% sodium citrate and 0.002% EDTA	356	341	507
0.1% API, 0.020% polysorbate-80, 0.005% lecithin NF, 0.02% citric acid, 0.03% sodium citrate and 0.002% EDTA	353	339	504		356	341	507

The results demonstrate that the nanoparticulate budesonide dispersion can be diluted and compounded to the desired level for use as an inhalation article for treatment without significantly altering the particle size of the dispersion.

Example 6

The purpose of this example was to evaluate the sterility of the nanoparticulate budesonide dispersion after autoclaving.

The Sterility of selected NCD formulations exposed to cycles of autoclaving in Fedagari Model FOB2-3 or Getinge GEV-6613 at 121 ℃ for various periods of time was evaluated using 6454 USP/EP Sterility by Direct Transfer with Transfer. The results of the sterility test are set forth in Table VI, and meet the requirements set forth in the current USP <71> sterility test and the current EPw.6.1 sterility. After the completion of the incubation period, no microbial growth was shown. The NCD autoclave formulation consists of:

(1) r & D formulation # 1: 5% (w/w) budesonide, 0.25% (w/w) polysorbate-80, 0.25% (w/w) LIPOID S75-3, 0.001% (w/w) EDTA, 94.5% (w/w) water.

(2) R & D formulation # 3: 10% (w/w) budesonide, 0.5% (w/w) polysorbate-80, 0.5% (w/w) LIPOID S75-3, 0.001% (w/w) EDTA, 89% (w/w) water.

(3) R & D formulation # 4: 5% (w/w) budesonide, 0.25% (w/w) polysorbate-80, 0.25% (w/w) Lipoid S75-3, 0.001% EDTA, 94.5% (w/w) water.

(4) GMP formulation # 5: 5% (w/w) budesonide, 0.25% (w/w) polysorbate-80, 0.25% (w/w) Lipoid S75-3, 0.001% (w/w) EDTA, 94.5% (w/w) sterile water for injection.

Table VI: sterility of budesonide dispersions after thermal autoclaving

Preparation	Sterility results at 121 ℃ for 10 min	Sterility results at 121 ℃ for 15 min	Sterility results at 121 ℃ for 20min
Preparation	Sterility results at 121 ℃ for 10 min	Sterility results at 121 ℃ for 15 min	Sterility results at 121 ℃ for 20min	Formulation #1		No growth was observed	No growth was observed
Formulation #2			No growth was observed	Formulation #1		No growth was observed	No growth was observed
Formulation #2			No growth was observed	Formulation #3	No growth was observed
Formulation #4		No growth was observed		Formulation #3	No growth was observed

Example 7

The purpose of this example was to evaluate the particle size of a beclometasone dipropionate nanoparticle dispersion with polysorbate-80 as a nonionic surface stabilizer in the presence and absence of the amphiphilic lipid, LIPOID 45 or LIPOID S75-3.

Beclomethasone dipropionate has the following structural formula:

it is a white powder with a molecular weight of 521.25, very slightly soluble in water.

By being atIn-system use of PolyMill^TM-500(Dow Inc) Polymer grinding media milling for 40 minutes to prepare an aqueous nanoparticle dispersion (NCD) comprising 10% (w/w) beclometasone dipropionate and 0.5% polysorbate-80 (w/w). The particle size of the beclomethasone dipropionate/polysorbate-80 dispersion was analyzed using a Horiba LA-910 particle size Analyzer (Irvine, CA) and showed coagulation with an average particle size of 30503 nm. Additional polysorbate-80 was added to the formulation to give 10% (w/w) beclometasone dipropionate and 1.0% polysorbate-80 (w/w). Regrind for 5 minutes and then re-analyze the particle size to show an average particle size of 272nm, D50 of 254nm and D90 of 386 nm.

The resulting nanoparticulate beclomethasone dipropionate/polysorbate-80 dispersion was then diluted to prepare three separate formulations, namely:

(1) 5% (w/w) beclometasone dipropionate, 0.5% (w/w) polysorbate-80 and 0.5% (w/w) LIPOID S45;

(2) 5% (w/w) beclometasone dipropionate, 0.5% (w/w) polysorbate-80 and 0.25% (w/w) LIPOID S75-3; and

(3) 5% (w/w) beclometasone dipropionate, 0.5% (w/w) polysorbate-80 and 0.5% (w/w) LIPOID S75-3.

All the resulting NCD samples were placed in glass bottles, crimped with rubber stoppers and aluminum, and then autoclaved for 10 minutes at 121.1 ℃ in a Fedagari autoclave. After autoclaving, the samples were examined for particle size using a Horiba LA-910 particle size analyzer, the results of which are shown in Table VII.

Table VII: particle size of beclomethasone dipropionate dispersion after autoclaving: effect of Polysorbate-80 alone and Polysorbate-80 plus Lipoid S75-3

Preparation	Average number (nm)	D50(nm)	D90(nm)
Preparation	Average number (nm)	D50(nm)	D90(nm)	10% of beclomethasone dipropionate and 1% of polysorbate-80	5336	5002	10260
5% beclomethasone dipropionate, 0.5% polysorbate-80, 0.5% LIPOID S45	2539	2082	5056	10% of beclomethasone dipropionate and 1% of polysorbate-80	5336	5002	10260
	2539	2082	5056	5% beclomethasone dipropionate, 0.5% polysorbate-80, 0.25% LIPOIDS75-3	2432	2065	4736
5% beclomethasone dipropionate, 0.5% polysorbate-80, 0.5% LIPOIDS75-3	2404	2037	4670		2432	2065	4736

Example 8

The purpose of this example was to determine the effect of tyloxapol alone, a non-ionic surface stabilizer, on the particle size of beclomethasone dipropionate after autoclaving, compared to tyloxapol in combination with amphoteric lipids.

By being atIn-system use of PolyMill^TM-500(Dow Inc) Polymer grinding media milling for 30 minutes to prepare a slurry having 10% (w/w) beclomethasone dipropionate and 1.0% (w/w) tyloxapolBeclomethasone dipropionate aqueous nanoparticle dispersion (NCD). The particle size of the beclomethasone dipropionate/tyloxapol dispersion was analysed with a horiba LA-910 particle size analyser (Irvine, CA) and showed an average particle size of 146nm, D50 of 141nm and D90 of 201 nm.

The resulting NCD was then diluted to make four separate formulations, namely:

(1) 5% (w/w) beclometasone dipropionate and 0.5% (w/w) tyloxapol;

(2) 5% (w/w) beclometasone dipropionate, 0.5% (w/w) tyloxapol and 0.5% (w/w) lecithin NF;

(3) 5% (w/w) beclometasone dipropionate, 0.5% (w/w) tyloxapol and 0.25% (w/w) lecithin NF; and

(4) 5% (w/w) beclometasone dipropionate, 0.5% (w/w) tyloxapol and 0.25% (w/w) LIOID S75-3.

All samples were placed in rubber stoppered vials with crimped caps and steam sterilized at 121.1 ℃ for 10 minutes. The particle size after sterilization is shown in table VIII below.

Table VIII: particle size of beclomethasone dipropionate dispersion after autoclaving: action of tyloxapol alone or tyloxapol plus phospholipid

Preparation	Average number (nm)	D50(nm)	D90(nm)
Preparation	Average number (nm)	D50(nm)	D90(nm)	5% of beclomethasone dipropionate and 0.5% of tyloxapol	3251	2832	6757
5% of beclomethasone dipropionate, 0.5% of tyloxapol and 0.5% of lecithin NF	785	746	1255	5% of beclomethasone dipropionate and 0.5% of tyloxapol	3251	2832	6757
	785	746	1255	5% of beclomethasone dipropionate, 0.5% of tyloxapol and 0.25% of lecithin NF	795	752	1274
5% of beclomethasone dipropionate, 0.5% of tyloxapol and 0.25% of LIPOID S75-3	779	725	1268		795	752	1274

Example 9

The purpose of this example was to determine the effect of non-ionic surface stabilizers in combination with amphiphilic lipids on the particle size of the glucocorticoid fluticasone propionate after autoclaving.

Fluticasone propionate has the chemical name S- (fluoromethyl) 6a, 9-difluoro-11 b, 17-dihydroxy-16 a-methyl-3-oxoandrosta-1, 4-diene-17 b-thiocarboxylate, 17-propionate and the following chemical structure:

the fluticasone propionate is white to off-white powder with molecular weight of 500.6 and empirical formula C₂₅H₃₁F₃O₅And S. Is practically insoluble in water.

By being atIn-system use of PolyMill^TM-500(Dow Inc) Polymer grinding media milling for 25 minutes to prepare a fluticasone propionate aqueous nanoparticle dispersion (NCD) with 10% (w/w) fluticasone propionate and 0.5% (w/w) polysorbate-80 (w/w). The particle size of the fluticasone propionate/polysorbate-80 dispersion was analyzed with a Horiba LA-910 particle size analyzer (Irvine, CA) and showed coacervation with an average particle size of 23145 nm.

Incorporation of additional polysorbate-80Within the formulation, 10% (w/w) fluticasone propionate and 1.0% (w/w) polysorbate-80 (w/w) were obtained. Grinding was continued for 5 minutes and then re-analyzed to continue to show large particle size (D)_{Mean number}20675 nm).

Lecithin NF was incorporated into the formulation to give 10% (w/w) fluticasone propionate, 1.0% (w/w) polysorbate-80 and 0.5% (w/w) lecithin NF. Milling was continued for 10 minutes. The final average particle size was 171nm, D50 164nm and D90 232 nm.

The resulting NCD was then diluted to 5% (w/w) fluticasone propionate, 0.5% (w/w) polysorbate-80 and 0.5% (w/w) lecithin NF. Both samples were placed in aluminum crimp capped rubber stopper bottles and steam heated in a Fedagari autoclave at 121.1 ℃ for 10 minutes. Particle size after sterilization is shown in table IX below.

Table IX: particle size of fluticasone propionate dispersion after autoclaving: action of polysorbate-80 plus lecithin NF

Preparation	Average number (nm)	D50(nm)	D90(nm)
Preparation	Average number (nm)	D50(nm)	D90(nm)	10% fluticasone propionate, 1.0% polysorbate-80, 0.5% lecithin NF	306	294	431
5% fluticasone propionate, 0.5% polysorbate-80, 0.5% lecithin NF	312	300	439		306	294	431

Example 10

The purpose of this example was to determine the effect of the non-ionic surface stabilizer Lutrol F127NF on the budesonide particle size after autoclaving as compared to Lutrol F127NF in combination with the amphiphilic lipid lecithin NF or LIOID S75-3.

By being atIn-system use of PolyMill^TM-500(Dow Inc) Polymer grinding media milling for 40 minutes to prepare a budesonide aqueous nanoparticle dispersion (NCD) having 10% (w/w) budesonide and 1.0% (w/w) Lutrol F127 NF. The particle size of the budesonide/Lutrol F127NF dispersion was analyzed by a Horiba LA-910 particle size Analyzer (Irvine, Calif.) and showed average particle sizes of 221nm, 202nm for D50 and 324nm for D90. The resulting NCD was then diluted to make three separate formulations, namely:

(1) 5% (w/w) budesonide, 0.5% (w/w) Lutrol F127NF and 0.5% (w/w) lecithin NF;

(2) 5% (w/w) budesonide, 0.5% (w/w) Lutrol F127NF, and 0.25% (w/w) lecithin NF; and

(3) 5% (w/w) budesonide, 0.5% (w/w) Lutrol F127NF, and 0.25% (w/w) LIOID S75-3.

All samples were placed in aluminum crimp-topped rubber stopper bottles and steam heated at 121.1 ℃ for 10 minutes using a Fedagari autoclave. The particle size after sterilization is shown in table X below.

Table X: particle size of budesonide dispersion after autoclaving: lutrol F127NF and Lutrol F127NF plus lecithin NF action

Preparation	Average number (nm)	D50(nm)	D90(nm)
Preparation	Average number (nm)	D50(nm)	D90(nm)	10% budesonide, 1% Lutrol F127NF	1141	717	2582
5% budesonide, 0.5% Lutrol F127NF, 0.5% lecithin NF	838	611	1748	10% budesonide, 1% Lutrol F127NF	1141	717	2582
5% budesonide, 0.5% Lutrol F127NF, 0.5% lecithin NF	838	611	1748	5% budesonide, 0.5% Lutrol F127NF, 0.25% lecithin NF	863	641	1788
5% budesonide, 0.5% Lutrol F127NF, 0.25% LIPOIDS75-3	936	6814	1967	5% budesonide, 0.5% Lutrol F127NF, 0.25% lecithin NF	863	641	1788

The results suggest that the presence of amphiphilic lipids significantly reduces the particle size of the budesonide dispersion upon autoclaving.

Example 11

The purpose of this example is to determine the effect of tyloxapol on the granularity of budesonide after autoclaving compared to tyloxapol in combination with lecithin NF.

By being atIn-system use of PolyMill^TM-500(Dow Inc) polymer grinding media milling for 30 minutes to prepare budesonide aqueous nanoparticle dispersion (NCD) with 10% (w/w) budesonide and 1.0% (w/w) tyloxapol. The particle size of the budesonide/tyloxapol dispersion was analyzed with a Horiba LA-910 particle size analyzer (Irvine, CA) and showed an average particle size of 159nm, D50 of 152nm and D90 of 221 nm. The resulting NCD was then diluted to make four separate formulations, namely:

(1) 5% (w/w) budesonide and 0.5% (w/w) tyloxapol;

(2) 5% (w/w) budesonide, 0.5% (w/w) tyloxapol and 1.0% (w/w) lecithin NF;

(3) 5% (w/w) budesonide, 0.5% (w/w) tyloxapol and 0.5% (w/w) lecithin NF; and

(4) 5% (w/w) budesonide, 0.5% (w/w) tyloxapol and 0.25% (w/w) lecithin NF.

All samples were placed in aluminum crimp-topped rubber stopper bottles and steam heated at 121.1 ℃ for 10 minutes using a Fedagari autoclave. The particle size after autoclaving is shown in Table XI below.

Table XI: particle size of budesonide dispersion after autoclaving: effects of tyloxapol and tyloxapol plus lecithin NF

Preparation	Average number (nm)	D50(nm)	D90(nm)
Preparation	Average number (nm)	D50(nm)	D90(nm)	5% budesonide, 0.5% tyloxapol	4806	432	5777
5% budesonide, 0.5% tyloxapol, 1.0% lecithin NF	406	344	697	5% budesonide, 0.5% tyloxapol	4806	432	5777
5% budesonide, 0.5% tyloxapol, 1.0% lecithin NF	406	344	697	5% budesonide, 0.5% tyloxapol, 0.5% lecithin NF	401	341	689
5% budesonide, 0.5% tyloxapol, 0.25% lecithin NF	410	344	712	5% budesonide, 0.5% tyloxapol, 0.5% lecithin NF	401	341	689

The results demonstrate that the particle size of heat sterilized glucocorticoids can be significantly reduced in combination with a non-ionic surface stabilizer in the presence of amphiphilic lipids.

* * * *

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 subject 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

1. A sterile composition, said composition comprising:

(a) particles of at least one glucocorticoid, wherein the particles have an effective average particle size of less than about 2000 nm;

(b) at least one nonionic surface stabilizer; and

(c) at least one amphiphilic lipid.

2. The composition of claim 1, wherein the composition is sterilized by moist heat sterilization.

3. The composition of claim 2, wherein the sterilization temperature is from about 110 ℃ to about 135 ℃.

4. The composition of any one of claims 1-3, wherein the glucocorticoid is selected from the group consisting of budesonide, triamcinolone acetonide, triamcinolone, mometasone furoate, flunisolide, fluticasone propionate, fluticasone, beclomethasone dipropionate, dexamethasone, triamcinolone, beclomethasone, fluocinolone acetonide, flunisolide hemihydrate, mometasone furoate monohydrate, clobetasol, and combinations thereof.

5. The composition of any of claims 1-4, wherein the non-ionic surface stabilizer is selected from the group consisting of sorbitol esters, polyoxyethylene sorbitan esters, poloxamers, polysorbates, spans, sorbitan oleates, sorbitan palmitates, sorbitan stearates, polyoxyethylene sorbitan monolaurates, polyoxyethylene sorbitan monooleates, glycerol monolaurate, surfactants containing polyoxyethylene chains, polysorbate 80, polysorbate 60, poloxamer 407, and mixtures thereof, F68、 F108、F127, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, a random copolymer of vinylpyrrolidone and vinyl acetate, dextran, cholesterol, polyoxyethylene alkyl ether, polyglycol ether, cetostearyl alcohol 1000, polyoxyethylene castor oil derivative, polyethylene glycol, CarbowaxCarbowax Polyoxyethylene stearate, methylcellulose, hydroxyethyl cellulose, amorphous cellulose, polyvinyl alcohol, tyloxapol, poloxamer, p-isononylphenoxypoly- (glycidol), C₁₈H₃₇CH₂C(O)N(CH₃)-CH₂(CHOH)₄(CH₂OH)₂(ii) a 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 derivatives, PEG-vitamin A, PEG-vitamin E and mixtures thereof.

6. The composition of claim 5, wherein the nonionic surface stabilizer is selected from the group consisting of poloxamer 407, polysorbate 80, polysorbate 60, tyloxapol, and block copolymers of ethylene oxide and propylene oxide.

7. The composition of claim 6 wherein the nonionic surface stabilizer is selected from the group consisting ofF68、F108 and F127。

8. the composition of any one of claims 1-7, wherein the amphiphilic lipid is a phospholipid comprising at least one negatively charged phospholipid.

9. The composition of claim 8, wherein the phospholipid is selected from the group consisting of anionic phospholipids, lecithin NF, synthetic phospholipids, partially purified hydrogenated lecithin, partially purified lecithin, anionic phospholipid-containing soybean lecithin phospholipid, anionic phospholipid-containing egg yolk lecithin, anionic phospholipid-containing hydrogenated soybean lecithin, anionic phospholipid-containing hydrogenated egg yolk lecithin, anionic phospholipid-containing lecithin, synthetic phosphatidylglycerol, synthetic phosphatidic acid, synthetic phosphatidylinositol, synthetic phosphatidylserine, phosphatidylinositol, phosphatidylserine, phosphatidic acid, phosphatidylglycerol, lysophosphatidylinositol, lysophosphatidylserine, lysophosphatidic acid, lysophosphatidylglycerol, distearoylphosphatidylinositol, distearoylphosphatidylserine, distearoylphosphatidic acid, distearoylphosphatidylglycerol, etc, Distearoyl lysophosphatidylglycerol, distearoyl lysophosphatidylinositol, distearoyl lysophosphatidylserine, distearoyl lysophosphatidic acid, dipalmitoyl phosphatidylinositol, dipalmitoyl phosphatidylserine, dipalmitoyl phosphatidic acid, dipalmitoyl phosphatidylglycerol, dipalmitoyl lysophosphatidylinositol, dipalmitoyl lysophosphatidylserine, dipalmitoyl lysophosphatidic acid, dipalmitoyl lysophosphatidylglycerol, and mixtures thereof.

10. The composition of claim 9, wherein the phospholipid is lecithin, which lecithin comprises less than 90% phosphatidylcholine.

11. The composition of claim 10, wherein the lecithin consists essentially of hydrogenated phosphatidylcholine, and the remaining ingredients consist essentially of hydrogenated anionic phospholipids.

12. The composition of any one of claims 1 to 11, wherein the chemical purity of the glucocorticoid is greater than 99%.

13. The composition of any one of claims 1 to 13, wherein the chemical purity of the glucocorticoid is greater than 99.5%.

14. The composition of any one of claims 1 to 13, wherein the amount of glucocorticoid in concentrated form or diluted in a pharmaceutically acceptable carrier is about 0.01% to about 20% by weight.

15. The composition of any of claims 1-14, further comprising a sodium salt of ethylenediaminetetraacetic acid, a calcium salt of ethylenediaminetetraacetic acid, or a combination thereof.

16. The composition of claim 15 wherein the amount of ethylenediaminetetraacetic acid sodium and/or calcium salt ranges from about 0.0001% to about 5%, from about 0.001 to about 1%, and from about 0.01% to about 0.1%.

17. The composition of any one of claims 1 to 16, wherein the concentration of the non-ionic surface stabilizer is selected from the group consisting of about 0.01% to about 90%, about 0.1% to about 50%, and about 1% to about 10% by weight, based on the total combined dry weight of the glucocorticoid and the surface stabilizer.

18. The composition of any one of claims 1 to 17, wherein the effective average particle size of the glucocorticoid particles is selected from the group consisting of less than about 1900nm, less than about 1800nm, less than about 1700nm, less than about 1600nm, less than about 1500nm, less than about 1400nm, less than about 1300nm, less than about 1200nm, less than about 1100nm, less than about 1000nm, less than about 900nm, less than about 800nm, less than about 700nm, less than about 600nm, less than about 500nm, less than about 400nm, less than about 300nm, less than about 250nm, less than about 200nm, less than about 150nm, less than about 100nm, less than about 75nm, and less than about 50 nm.

19. The composition of any one of claims 1 to 18, wherein at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, or at least about 99% of the glucocorticoid particles have a particle size that is less than the effective average particle size.

20. The composition of any one of claims 1-19, further comprising one or more pharmaceutically acceptable excipients.

21. The composition of any one of claims 1 to 20 in the form of:

(a) formulated for inhalation, injection, otic, oral, rectal, pulmonary, ocular, colonic, parenteral, intracisternal, intravaginal, intraperitoneal, topical, buccal, nasal, or topical administration;

(b) formulated as a powder, lyophilized powder, spray-dried powder, spray-granulated powder, solid lozenge, capsule, tablet, pill, granule, liquid dispersion, gel, aerosol, ointment, or cream;

(c) formulated into a dosage form selected from the group consisting of controlled release formulations, solid dose fast melt formulations, controlled release formulations, fast melt formulations, lyophilized formulations, delayed release formulations, extended release formulations, pulsatile release formulations, and mixed immediate release and controlled release formulations; or

(d) Any combination thereof.

22. The composition of any one of claims 1-21, formulated as a nasal spray.

23. The composition of any one of claims 1-21, formulated as a pulmonary aerosol.

24. The composition of any one of claims 1-23, formulated as an aqueous aerosol comprising from about 0.015mg/mL up to about 600mg/mL of the glucocorticoid.

25. The aerosol composition of claim 24, wherein the glucocorticoid concentration is selected from the group consisting of about 10mg/mL or more, about 100mg/mL or more, about 200mg/mL or more, about 400mg/mL or more, and about 600 mg/mL.

26. The composition of any one of claims 1 to 25 formulated as an aqueous aerosol, wherein the aerosol droplets have a mass median aerodynamic diameter selected from the group consisting of less than or equal to about 100 microns, about 0.1 to about 10 microns, about 2 to about 6 microns, less than about 2 microns, about 5 to about 100 microns, and about 30 to about 60 microns.

27. The composition of any one of claims 1 to 26, formulated as an aerosol, further comprising one or more solvents and/or propellants dissolved in a non-aqueous solution, for co-administration by a multi-dose inhaler.

28. The composition of any one of claims 1-27, further comprising at least one non-glucocorticoid active agent.

29. The composition of claim 28, wherein the at least one non-glucocorticoid active agent is useful for treating asthma, allergic conjunctivitis, seasonal allergic rhinitis, or other inflammatory or allergic diseases conventionally treated with glucocorticoids.

30. The composition of claim 28, wherein the non-glucocorticoid active agent is selected from the group consisting of long acting beta-agonists, leukotriene modulators, theophylline, nedocromil, cromolyn sodium, short acting beta-agonists, ipratropium bromide, prednisone, prednisolone, methylprednisolone, salmeterol, formoterol, montelukast, zafirlukast, zileuton, salbutamol, levalbuterol, bitolterol, pirbuterol, and terbutaline.

31. The composition of any one of claims 1-30, formulated as an aqueous aerosol, wherein

(a) Substantially each droplet of the aqueous aerosol formulation comprises at least one nanoparticulate glucocorticoid particle;

(b) droplets of the aerosol have a Mass Median Aerodynamic Diameter (MMAD) of less than or equal to about 100 microns;

(c) the glucocorticoid is selected from the group consisting of fluticasone, budesonide, triamcinolone acetonide, triamcinolone, mometasone furoate, fluticasone propionate, beclomethasone dipropionate, dexamethasone, triamcinolone, beclomethasone, fluocinolone acetonide, flunisolide hemihydrate, flunisolide, mometasone furoate monohydrate, clobetasol, and combinations thereof;

(d) the glucocorticoid is at a concentration of about 0.015mg/mL to at most about 600 mg/mL;

(e) the nonionic stabilizer is polyoxyethylene sorbitan fatty acid ester; and is

(f) The amphiphilic lipid is a phospholipid.

32. A method of making a sterile composition, the composition comprising:

(b) at least one nonionic surface stabilizer; and

(c) at least one amphiphilic lipid, wherein the amphiphilic lipid is selected from the group consisting of,

wherein the method comprises:

(i) contacting glucocorticoid particles with at least one non-ionic surface stabilizer for a time and under conditions to reduce the effective average particle size of the particles to less than about 2000 nm;

(ii) adding at least one amphipathic lipid to the glucocorticoid composition prior to, simultaneously with, or after particle size reduction; and

(iii) the composition is steam heated to a temperature of from about 115 ℃ to about 135 ℃.

33. A method of treating a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a sterile composition comprising:

(b) at least one nonionic surface stabilizer; and

(c) at least one amphiphilic lipid.

34. The method of claim 33, wherein the composition comprises at least one pharmaceutically acceptable excipient or carrier.

35. The method of claim 33 or claim 34, wherein the treatment is for an inflammatory disease.

36. The method of any one of claims 33-35, wherein the treatment is for asthma, cystic fibrosis, chronic obstructive pulmonary disease, emphysema, respiratory distress syndrome, chronic bronchitis, respiratory diseases associated with acquired immunodeficiency syndrome, and ocular inflammatory diseases, skin inflammatory diseases, otic inflammatory diseases, ocular allergic diseases, skin allergic diseases, allergic conjunctivitis, and seasonal allergic rhinitis.

37. The method of any one of claims 33-36, wherein the composition is administered via a nasal or pulmonary aerosol.

38. The method of claim 37, wherein for aerosol administration, the patient delivery time is from about 15 seconds up to about 15 minutes.