MX2007015304A - Nanoparticulate acetaminophen formulations - Google Patents

Abstract

The invention is directed to compositions comprising a nanoparticulate acetaminophen composition, or a salt or derivative thereof, having improved bioavailability. The nanoparticulate acetaminophen particles of the composition have an effective average particle size of less than about 2000 nm and are useful in the treatment of aches and pain, and in the reduction of fever and related conditions.

Description

PE ACETAMINOFEN FORMULATIONS IN NANOPARTICLES CROSS REFERENCE TO RELATED REQUESTS This application claims the benefit under 35 U.S.C. § 119 (e) for the provisional application of E.U.A. No. 60 / 687,114, filed June 3, 2005, the entire contents of which are incorporated herein by reference.

FIELD OF THE INVENTION The present invention relates generally to compounds and compositions useful in the treatment of persistent painful sensations and pain, and reduction of fever and related conditions. More specifically, the invention relates to acetaminophen compositions in nanoparticles. The acetaminophen compositions in nanoparticles have an effective average particle size of less than about 2000 nm.

BACKGROUND OF THE INVENTION A. Background concerning acetaminophen Acetaminophen, chemically known as 4'-hydroxyacetanilide, has an empirical formula of C8H9NO2 and a molecular weight of 151.16. Acetaminophen has the chemical structure shown below: Acetaminophen, a crystalline powder, slightly bitter, white, odorless, is an analgesic and antipyretic that is neither opiate nor salicylate. It is commercially available from multiple sources, such as under the brand name TYLENOL® Tablet, from McNeil Consumer, and is available in various strengths, such as 325 mg, 500 mg and 650 mg. Representative inactive ingredients include cellulose, corn starch, magnesium stearate, sodium starch glycolate. Acetaminophen produces analgesia by raising the threshold of pain and antipyresis through action on the hypothalamic heat-regulating center. It is useful for temporary relief of persistent painful sensations and small pains due to headaches, persistent painful muscular sensations, persistent painful sensations of back, arthritis, colds, persistent painful sensations of molars, menstrual cramps and fever reduction.

Acetaminophen compounds have been described, for example, in U.S. Patent No. 4,439,453 to Vogel entitled "Directly Compressible Acetaminophen Granulation", U.S. Patent No. 4,661, 521 to Salpekar et al. entitled "Direct Tableting Acetaminophen Compositions", U.S. Patent No. 4,771, 077 of Reuter et al. entitled "Spray Dried Acetaminophen", United States Patent Nos. 4,820,522; 4,968,509; and 5,004,613 to Radebaugh et al. entitled "Oral Sustained Relase Acetaminophen Formulation and Process", United States Patent No. 4,943,565 to Tencza et al. entitled "Analgesic Tablet or Aspirin and Caffeine Containing Low-Substituted Hydroxypropyl Cellulose," U.S. Patent No. 5,336,691 to Raffa et al. entitled "Composition Comprising to Tramadol Material and Acetaminophen and Its Use", U.S. Patent No. 5,972,916 to Armellino et al. entitled "Compositions Containing the Nonprescription Combination of Acetaminophen, Aspirin and Caffeine to Alleviate the Pain and Symptoms of Migraine", United States Patent No. 6,126,967 to Clemente et al. entitled "Extended Relase Acetaminophen Particles", United States Patent No. 6,254,891 to Anaebonam et al. entitled "Extended Relase Acetaminophen Particles", and United States Patent No. 6,391, 337 to Hunter et al. entitled "Directly Compressible High Load Acetaminophen Formulations". All of these patents are incorporated herein by reference. Acetaminophen has a high therapeutic value in the treatment of persistent painful sensations and pain, and reduction of fever and related conditions. However, since acetaminophen is practically insoluble in water, the dissolution of conventional acetaminophen tablets is reduced in the fasted state compared to the fed state. The low dissolution rate results in a slow absorption rate. Due to the slow absorption rate, maximum concentrations of acetaminophen in the plasma do not appear until approximately 0.4 to 1 hour after the administration of a dose. The improvement in the rate of dissolution would increase the absorption rate of acetaminophen allowing the maximum concentration in the plasma could be achieved much more quickly and therefore the therapeutic efficacy would be much sooner. further, the food delays the time to a maximum concentration of acetaminophen in the serum. Therefore, acetaminophen has limited bioavailability in the fasted state compared to the fed state that limits the therapeutic outcome for all treatments that require acetaminophen. In the art there is a need for acetaminophen formulations that overcome this and other problems associated with the use of acetaminophen in the treatment of persistent painful sensations and pain, and the reduction of fever and related conditions. The present invention satisfies this need.

B. Background relating to active agent compositions in nanoparticles The active agent compositions in nanoparticles, first described in the patent of E.U.A. No. 5,145,684 ("the '684 patent"), are particles comprising a poorly soluble therapeutic or diagnostic agent that has adsorbed onto or associated with the surface thereof a non-interlaced surface solubilizer. The 684 patent does not disclose acetaminophen compositions in nanoparticles. Methods for making active agent compositions in nanoparticles are described in, for example, U.S. Patents. Nos. 5,518,187 and 5,862,999, both entitled "Method of Grinding Pharmaceutical Substances"; patent of E.U.A. No. 5,718,388, entitled "Continuous Method of Grinding Pharmaceutical Substances"; and patent of E.U.A. No. 5,510,118 entitled "Process of Preparing Therapeutic Compositions Containing Nanoparticles." The compositions in nanoparticles are also described, for example, in the patents of E.U.A. Nos. 5,298,262 entitled "Use of Lonic Cloud Point Modifiers to Prevent Partial Aggregation During Sterilization"; 5,302,401 entitled "Method to Reduce Particle Size Growth During Lyophilization"; 5,318,767 entitled "X-Ray Contrast Compositions Useful in Medical Imaging"; 5,326,552 entitled "Novel Formulation for Nanoparticulate X-Ray Blood Pool Contrast Agents Using High Molecular Weight Non-ionic Surfactants"; 5,328,404 entitled "Method of X-Ray Imaging Using Lodinated Aromatic Propanedioates"; 5,336,507 entitled "Use of Charged Phospholipids to Reduce Nanoparticle Aggregation"; 5,340,564 entitled "Formulations Comprising Olin 10-G to Prevent Particle Aggregation and Increase Stability"; 5,346,702 entitled "Use of Non-lonic Cloud Point Modifiers to Minimize Nanoparticulate Aggregation During Sterilization"; 5,349,957 entitled "Preparation and Magnetic Properties of Very Small Magnetic-Dextran Particles"; 5,352,459 entitled "Use of Purified Surface Modifiers to Prevent Particle Aggregation During Sterilization"; 5,399,363 and 5,494,683, both entitled "Surface Modified Anticancer Nanoparticles"; 5,401, 492 entitled "Water Insoluble Non-Magnetic Manganese Particles as Magnetic Resonance Enhancement Agents"; 5,429,824 entitled "Use of Tyloxapol as a Nanoparticulate Stabilizer"; 5,447,710 entitled "Method for Making Nanoparticulate X-Ray Blood Pool Contrast Agents Using High Molecular Weight Non-ionic Surfactants"; 5,451, 393 entitled "X-Ray Contrast Compositions Useful in Medical Imaging"; 5,466,440 entitled "Formulations of Oral Gastrointestinal Diagnostic X-Ray Contrast Agents in Combination with Pharmaceutically Acceptable Clays"; 5,470,583 entitled "Method of Preparing Nanoparticle Compositions Containing Charged Phospholipids to Reduce Aggregation"; 5,472,683 entitled "Nanoparticulate Diagnostic Mixed Carbamic Anhydrides as X-Ray Contrast Agents for Blood Pool and Lymphatic System Imaging"; 5,500,204 entitled "Nanoparticulate Diagnostic Dimers as X-Ray Contrast Agents for Blood Pool and Lymphatic System Imaging"; 5,518,738 entitled "Nanoparticulate NSAID Formulations"; 5,521, 218 entitled "Nanoparticulate lododipamide Derivatives for Use as X-Ray Contrast Agents"; 5,525,328 entitled "Nanoparticulate Diagnostic Diatrizoxy Ester X-Ray Contrast Agents for Blood Pool and Lymphatic System Imaging"; 5,543,133 entitled "Process of Preparing X-Ray Contrast Compositions Containing Nanoparticles"; 5,552,160 entitled "Surface Modified NSAID Nanoparticles"; 5,560,931 entitled "Formulations of Compounds as Nanoparticulate Dispersions in Digestible Oils or Fatty Acids"; 5,565,188 entitled "Polyalkylene Block Copolymers as Surface Modifiers for Nanoparticles"; 5,569,448 entitled "Sulfated Non-ionic Block Copolymer Surfactant as Stabilizer Coatings for Nanoparticle Compositions"; 5,571, 536 entitled "Formulations of Compounds as Nanoparticulate Dispersions in Digestible Oils or Fatty Acids"; 5,573,749 entitled "Nanoparticulate Diagnostic Mixed Carboxylic Anydrides as X-Ray Contrast Agents for Blood Pool and Lymphatic System Imaging"; 5,573,750 entitled "Diagnostic Imaging X-Ray Contrast Agents"; 5,573,783 entitled "Redispersible Nanoparticulate Film Matrices With Protective Overcoats"; 5,580,579 entitled "Site-specific Adhesion Within the Gl Tract Using Nanoparticles Stabilized by High Molecular Weight, Linear Poly (Ethylene Oxide) Polymers"; 5,585,108 entitled "Formulations of Oral Gastrointestinal Therapeutic Agents in Combination with Pharmaceutically Acceptable Clays"; 5,587,143 entitled "Butylene Oxide-Ethylene Oxide Block Copolymers Surfactants as Stabilizer Coatings for Nanoparticulate Compositions"; 5,591, 456 entitled "Milled Naproxen with Hydroxypropyl Cellulose as Dispersion Stabilizer"; 5,593,657 entitled "Novel Barium Salt Formulations Stabilized by Non-ionic and Anionic Stabilizers"; 5,622,938 entitled "Sugar Based Surfactant for Nanocrystals"; 5,628,981 entitled "Improved Formulations of Oral Gastrointestinal Diagnostic X-Ray Contrast Agents and Oral Gastrointestinal Therapeutic Agents"; 5,643,552 entitled "Nanoparticulate Diagnostic Mixed Carbonic Anhydrides as X-Ray Contrast Agents for Blood Pool and Lymphatic System Imaging"; 5,718,388 entitled "Continuous Method of Grinding Pharmaceutical Substances"; 5,718,919 entitled "Nanoparticles Containing the R (-) Enantiomer of Ibuprofen"; 5,747,001 entitled "Aerosols Containing Beclomethasone Nanoparticle Dispersions"; 5,834,025 entitled "Reduction of Intravenously Administered Nanoparticulate Formulation Induced Adverse Physiological Reactions"; 6,045,829"Nanocrystalline Formulations of Human Immunodeficiency Virus (HIV) Protease Inhibitors Using Cellulosic Surface Stabilizers"; 6,068,858 entitled "Methods of Making Nanocrystalline Formulations of Human Immunodeficiency Virus (HIV) Protease Inhibitors Using Cellulosic Surface Stabilizers"; 6,153,225 entitled "Injectable Formulations of Nanoparticulate Naproxen"; 6,165,506 entitled "New Solid Dose Form of Nanoparticulate Naproxen"; 6,221, 400 entitled "Methods of Treating Mammals Using Nanocrystalline Formulations of Human Immunodeficiency Virus (HIV) Protease Inhibitors"; 6,264,922 entitled "Nebulized Aerosols Containing Nanoparticle Dispersions"; 6,267,989 entitled "Methods for Preventing Crystal Growth and Particle Aggregation in Nanoparticle Compositions"; 6,270,806 entitled "Use of PEG-Derivatized Lipids as Surface Stabilizers for Nanoparticulate Compositions"; 6,316,029 entitled "Rapidly Disintegrating Solid Oral Dosage Form," 6,375,986 entitled "Solid Dose Nanoparticulate Compositions Comprising a Synergistic Combination of a Polymeric Surface Stabilizer and Dioctyl Sodium Sulfosuccinate"; 6,428,814 entitled "Bioadhesive Nanoparticulate Compositions Having Cationic Surface Stabilizers"; 6,431, 478 entitled "Small Scale Mili"; 6,432,381 entitled "Methods for Targeting Drug Delivery to the Upper and Lower Gastrointestinal Tract," 6,592,903 entitled "Nanoparticulate Dispersions Comprising a Synergistic Combination of a Polymeric Surface Stabilizer and Dioctyl Sodium Sulfosuccinate," 6,582,285 entitled "Apparatus for sanitary wet milling"; 6,656,504 entitled "Nanoparticulate Compositions Comprising Amorphous Cyclosporine"; 6,742,734 titled "System and Method for Milling Materials"; 6,745,962 entitled "Small Scale Mili and Method Thereof"; 6,811, 767 entitled "Liquid droplet aerosols of nanoparticulate drugs"; 6,908,626 entitled "Compositions having a combination of immediate release and controlled reléase characteristics"; 6,969,529 entitled "Nanoparticulate compositions comprising copolymers of vinyl pyrrolidone and vinyl acetate as surface stabilizers"; and 6,976,647 entitled "System and Method for Milling Materials," all of which are specifically incorporated by reference. In addition, the patent publication of E.U.A. No. 20020012675 A1, entitled "Controlled Relay Nanoparticulate Compositions"; patent publication of E.U.A. No. 20050276974 entitled "Nanoparticulate Fibrate Formulations"; patent publication of E.U.A. No. 20050238725 entitled "Nanoparticulate compositions having a peptide as a surface stabilizer"; patent publication of E.U.A. No. 20050233001 entitled "Nanoparticulate megestrol formulations"; patent publication of E.U.A. No. 20050147664 entitled "Compositions comprising antibodies and methods of using the same for targeting nanoparticulate active agent delivery"; patent publication of E.U.A. No. 20050063913 entitled "Novel metaxalone compositions"; patent publication of E.U.A. No. 20050042177 entitled "Novel compositions of sildenafil free base"; patent publication of E.U.A. No. 20050031691 entitled "Gel stabilized nanoparticulate active agent compositions"; patent publication of E.U.A. No. 20050019412 entitled "Novel glipizide compositions"; patent publication of E.U.A. No. 20050004049 entitled "Novel griseofulvin compositions"; patent publication of E.U.A. No. 20040258758 entitled "Nanoparticulate topiramate formulations"; patent publication of E.U.A. No. 20040258757 entitled "Liquid dosage compositions of stable nanoparticulate active agents"; patent publication of E.U.A. No. 20040229038 entitled "Nanoparticulate meloxicam formulations"; patent publication of E.U.A. No. 20040208833 entitled "Novel fluticasone formulations"; patent publication of E.U.A. No. 20040195413 entitled "Compositions and method for milling materials"; patent publication of E.U.A. No. 20040156895 entitled "Solid dosage forms comprising pullulan"; patent publication of E.U.A. No. 20040156872 entitled "Novel nimesulide compositions"; patent publication of E.U.A. No. 20040141925 entitled "Novel triamcinolone compositions"; patent publication of E.U.A. No. 20040115134 entitled "Novel nifedipine compositions"; patent publication of E.U.A. No. 20040105889 entitled "Low viscosity liquid dosage forms"; patent publication of E.U.A. No. 20040105778 entitled "Gamma irradiation of solid nanoparticulate active agents"; patent publication of E.U.A. No. 20040101566 entitled "Novel benzoyl peroxide compositions"; patent publication of E.U.A. No. 20040057905 entitled "Nanoparticulate beclomethasone dipropionate compositions"; patent publication of E.U.A. No. 20040033267 entitled "Nanoparticulate compositions of angiogenesis inhibitors"; patent publication of E.U.A. No. 20040033202 entitled "Nanoparticulate sterol formulations and novel sterol combinations"; patent publication of E.U.A. No. 20040018242 entitled "Nanoparticulate nystatin formulations"; patent publication of E.U.A. No. 20040015134 entitled "Drug delivery systems and methods"; patent publication of E.U.A. No. 20030232796 entitled "Nanoparticulate polycosanol formulations &novel polycosanol combinations"; patent publication of E.U.A. No. 20030215502 entitled "Fast dissolving dosage forms having reduced friability"; patent publication of E.U.A. No. 20030185869 entitled "Nanoparticulate compositions having lysozyme as a surface stabilizer"; patent publication of E.U.A. No. 20030181411 entitled "Nanoparticulate compositions of mitogen-activated protein (MAP) kinase inhibitors"; patent publication of E.U.A. No. 20030137067 entitled "Compositions having a combination of immediate release and controlled reléase characteristics"; patent publication of E.U.A. No. 20030108616 entitled "Nanoparticulate compositions comprising copolymers of vinyl pyrrolidone and vinyl acetate as surface stabilizers"; patent publication of E.U.A. No. 20030095928 entitled "Nanoparticulate insulin"; patent publication of E.U.A. No. 20030087308 entitled "Method for high throughput screening using a small scale milli or microfluidics"; patent publication of E.U.A. No. 20030023203 entitled "Drug delivery systems & methods"; patent publication of E.U.A. No. 20020179758 entitled "System and method for milling materials, and U.S. Patent Publication No. 20010053664 entitled" Apparatus for sanitary wet milling, "describe active agent compositions in nanoparticles and are specifically incorporated by reference., the patent of E.U.A. No. 5,518,738, entitled "Nanoparticulate NSAID Compositions," and U.S. Patent No. 5,552,160 entitled "Surface Modified NSAID Nanoparticles," describe NSAID compositions in nanoparticles The '738 patent discloses compositions comprising a crystalline NACED in combination with polyvinylpyrrolidone, Hydroscopic Sugar and Sodium Lauryl Sulfate The '60 patent describes crystalline NSADDs having a surface modifier adsorbed on the surface thereof in an amount sufficient to maintain an effective average particle size of less than about 400 nm. specifically acetaminophen in nanoparticles Amorphous small particle compositions are described, for example, in US Patent Nos. 4,783,484 entitled "Particulate Composition and Use Thereof as Antimicrobial Agent"; 4,826,689 entitled "Method for Making Uniformly Sized Particles from Water-lnsoluble Organic Compounds"; 4,997,454 entitled "Method for Making Uniformly-Sized Particles From Insoluble Compounds"; 5,741, 522 entitled "Ultrasmall, Non-aggregated Porous Particles of Uniform Size for Entrapping Gas Bubbles Within and Methods"; and 5,776,496, entitled "Ultrasmall Porous Particles for Enhancing Ultrasound Back Scatter." Again, all the aforementioned patents are incorporated herein by reference. There is a need in the art to provide dosage forms of acetaminophen. The present invention. satisfies that need.

BRIEF DESCRIPTION OF THE INVENTION The present invention relates to acetaminophen compositions comprising acetaminophen, or a salt or derivative thereof. The compositions comprise acetaminophen particles in nanoparticles and at least one surface stabilizer. The surface stabilizer can be adsorbed onto or associated with the surface of the acetaminophen particles. The acetaminophen particles in nanoparticles have an effective average particle size of less than about 2,000 nm. A preferred dosage form of the invention is a solid dosage form, although any pharmaceutically acceptable dosage form can be used. Another aspect of the invention is directed to pharmaceutical compositions comprising an acetaminophen in nanoparticles, or a salt or derivative thereof, particles and at least one surface stabilizer, and a pharmaceutically acceptable carrier, as well as any desired excipients. One embodiment of the invention encompasses an acetaminophen composition in nanoparticles, wherein the pharmacokinetic profile of acetaminophen in nanoparticles is not significantly affected by the fed or fasted state of a subject who ingests the composition. In still another embodiment, the invention encompasses an acetaminophen composition in nanoparticles, wherein the administration of the composition to a subject in a fasted state is bioequivalent to the administration of the composition to a subject in a fed state. Another embodiment of the invention is directed to acetaminophen nanoparticle compositions comprising one or more additional useful compounds in the treatment of persistent painful sensations and pain, and / or reduction of fever and related conditions. This invention further discloses a method for making the acetaminophen compositions in nanoparticles of the invention. Said method comprises contacting acetaminophen, or a salt or derivative thereof, with at least one surface stabilizer for a time and under conditions sufficient to provide a stabilized nanoparticle acetaminophen composition having an effective average particle size of less of approximately 2000 nm. The present invention is also directed to methods of treatment including but not limited to the treatment of persistent painful sensations and pain, and / or reduction of fever and related conditions, using the acetaminophen compositions in novel nanoparticles described herein. Such methods comprise administering to a subject a therapeutically effective amount of an acetaminophen composition in nanoparticles, or a salt or derivative thereof. Other methods of treatment using the acetaminophen compositions in nanoparticles of the invention are known to those skilled in the art. Both the brief description of the previous invention and the following brief description of the drawings and detailed description of the invention are illustrative and explanatory and are intended to provide additional details of the invention as claimed. Other objects, advantages and novel features will be apparent to those skilled in the art from the following detailed description of the invention.

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1: Shows a 100x phase objective using immersion oil of a nanoparticle formulation of 10% (w / w) acetaminophen, 2.5% (w / w) hydroxypropylcellulose SL (HPC-SL), and 0.1% ( p / p) of docusate sodium; and Figure 2: Shows a 100x phase objective using immersion oil of a nanoparticle formulation of 10% (w / w) acetaminophen, 2.5% (w / w) Plasdone K29 / 32, and 0.1% (p / p) p) of sodium lauryl sulphate.

DETAILED DESCRIPTION OF THE INVENTION I. Acetaminophen Compositions in Nanoparticles The present invention is directed to acetaminophen compositions comprising acetaminophen, or a salt or derivative thereof. The compositions comprise acetaminophen, or a salt or derivative thereof, and preferably at least one surface stabilizer adsorbed on or associated with the surface of the drug. The acetaminophen particles, or a salt or derivative thereof, have an effective average particle size of less than about 2000 nm. As taught in the '684 patent, and as illustrated in the following examples, not every combination of surface stabilizer and active agent will result in a stable nanoparticle composition. It was surprisingly discovered that acetaminophen stable formulations can be made in nanoparticles, or a salt or derivative thereof. The advantages of the acetaminophen formulations in nanoparticles of the invention compared to acetaminophen compositions not in nanoparticles or microcrystallines above include, but are not limited to: (1) smaller tablets or other size of solid dosage form; (2) smaller doses of drug required to obtain the same pharmacological effect; (3) increased bioavailability; (4) substantially similar pharmacokinetic profiles of the acetaminophen compositions when administered in the fed versus the fasted state; (5) bioequivalence of the acetaminophen compositions when administered in the fed state versus the fasting state; (6) improved pK profiles; (7) an increased dissolution rate; and (8) the acetaminophen compositions can be used in conjunction with other active agents useful in the treatment of persistent painful sensations and pain, and reduction of fever and related conditions. The present invention also includes acetaminophen in nanoparticles, or a salt or derivative thereof, compositions together with one or more non-toxic pharmaceutically acceptable carriers, adjuvants or carriers, collectively referred to as carriers. The compositions can be formulated for parenteral (e.g., intravenous, intramuscular, or subcutaneous) injection, oral administration in solid, liquid or aerosol form, vaginal, nasal, rectal, ocular, local administrations (powders, ointments or drops), buccal, intracisternal, intraperitoneal or topical, and the like. A preferred dosage form of the invention is a solid dosage form, although any pharmaceutically acceptable dosage form can be used. Exemplary solid dosage forms include, but are not limited to, tablets, capsules, pouches, pills, powders, pills or granules, and the solid dose form can be, for example, a fast molded dose form, dosage form of controlled release, freeze-dried dosage form, delayed-release dosage form, sustained-release dosage form, pulsatile-release dosage form, immediate-release and controlled-release mixed dose form, or a combination thereof. A solid dose tablet formulation is preferred. The present invention is described herein using various definitions, as discussed below and throughout the application. The term "effective average particle size," as used herein, means that at least about 50% of the acetaminophen particles in nanoparticles have a size of less than about 2000 nm, by weight or in another suitable measurement technique ( e.g., such as in volume, number, etc.), when measured, for example, by fractionation of sedimentation flow, photon correlation spectroscopy, light scattering, disk centrifugation, and other techniques known to the experts in the art. As used herein, "approximately" will be understood by those skilled in the art and will vary to some degree depending on the context in which it is used. If there are uses of the term that are clear to those skilled in the art given the context in which it is used, "approximately" will mean up to plus or minus 10% of the particular term. As used herein with reference to stable acetaminophen particles, "stable" means that the particles do not flocculate or agglomerate appreciably due to attraction forces between particles or otherwise increase in particle size. "Stable" has the connotation of, but is not limited to, one or more of the following parameters: (1) the particles do not flocculate or agglomerate appreciably due to attractive forces between particles or otherwise increase in size. particle with time; (2) the physical structure of the particles is not altered over time, such as by conversion from an amorphous phase to a crystalline phase; (3) the particles are chemically stable; and / or (4) wherein the acetaminophen or a salt or derivative thereof has not been subjected to a heating step at or above the melting point of the acetaminophen particles in the preparation of the nanoparticles of the present invention. The term "conventional" or "non-nanoparticle active agent" shall mean an active agent that is solubilized or has an effective average particle size greater than about 2000 nm. Active agents of nanoparticles, as defined herein, have an effective average particle size of less than about 2000 nm. The phrase "drugs poorly soluble in water", as used herein, refers to drugs having a solubility in water of less than about 30 mg / ml, less than about 20 mg / ml, less than about 10 mg / ml, or less than about 1 mg / ml. As used herein, the phrase "therapeutically effective amount" will mean that dose of drug that provides the specific pharmacological response for which the drug is administered in a significant number of subjects in need of such treatment. It is emphasized that a therapeutically effective amount of a drug that is administered to a particular subject in a particular case will not always be effective to treat the conditions / diseases described herein, even if said dose is considered to be a therapeutically effective amount by the patients. experts in the art.

A. Preferred characteristics of acetaminophen compositions in nanoparticles of the invention 1. Increased bioavailability It is proposed that acetaminophen in nanoparticles, or a salt or derivative thereof, formulations of the invention exhibit increased bioavailability, and require smaller doses compared to conventional acetaminophen formulations above. 2. Improved pharmacokinetic profiles The invention also provides acetaminophen compositions in nanoparticles, or a salt or derivative thereof, which have a desirable pharmacokinetic profile when administered to mammalian subjects. The desirable pharmacokinetic profile of the compositions comprising acetaminophen includes but is not limited to: (1) a CmaX for an acetaminophen, when tested in the plasma of a mammalian subject after administration, ie preferably greater than Cm.x. for a non-nanoparticulate formulation of the same acetaminophen, administered at the same dose; and / or (2) an AUC for acetaminophen, when tested in the plasma of a mammalian subject after administration, ie preferably greater than AUC for a non-nanoparticulate formulation of the same acetaminophen, administered at the same dose; and / or (3) a Tmax for acetaminophen, when tested in the plasma of a mammalian subject after administration, ie preferably less than Tmax for a non-nanoparticulate formulation of the same acetaminophen, administered at the same dose. The desirable pharmacokinetic profile, as used herein, is the pharmacokinetic profile measured after the initial dose of acetaminophen or a salt or derivative thereof. In one embodiment, a composition comprising acetaminophen in nanoparticles presents in a comparative pharmacokinetic test with a non-nanoparticulate formulation of the same acetaminophen, administered at the same dose, a Tmax not greater than about 90%, not greater than about 80%, no greater than about 70%, no greater than about 60%, no greater than about 50%, no greater than about 30%, no greater than about 25%, no greater than about 20%, no greater than about 15%, no greater than about 10%, or not more than about 5% of the Tmax presented by the non-nanoparticulate acetaminophen formulation. In another embodiment, the composition comprising acetaminophen in nanoparticles presents in a comparative pharmacokinetic test with a non-nanoparticulate formulation of the same acetaminophen, administered at the same dose, a CmaX which is at least about 50%, at least about 100%, at least about 200%, at least about 300%, at least about 400%, at least about 500%, at least about 600%, at least about 700%, at least about 800%, by at least about 900%, at least about 1000%, at least about 1100%, at least about 1200%, at least about 1300%, at least about 1400%, at least about 1500%, so less about 1600%, at least about 1700%, at least about 1800%, or at least about 1900% greater than the Cmax presented by the formula non-nanoparticulate acetaminophen. In yet another embodiment, the composition comprising an acetaminophen in nanoparticles presents in a comparative pharmacokinetic test with a non-nanoparticulate formulation of the same acetaminophen, administered at the same dose, an AUC that is at least about 25%, at least about 50 %, at least about 75%, at least about 100%, at least about 125%, at least about 150%, at least about 175%, at least about 200%, at least about 225% , at least about 250%, at least about 275%, at least about 300%, at least about 350%, at least about 400%, at least about 450%, at least about 500%, at least about 550%, at least about 600%, at least about 750%, at least about 700%, at least about 750%, at least about 800%, at least about 850%, at least about 900%, at least about 950%, by at least about 1000%, at least about 1050%, at least about 1100%, at least about 1150%, or at least about 1200% greater than the AUC presented by the non-nanoparticulate acetaminophen formulation. In one embodiment of the invention, the Tmax of acetaminophen, when tested in the plasma of the animal subject, is less than about 6 to about 8 hours. In other embodiments of the invention, the Tmax of acetaminophen is less than about 6 hours, less than about 5 hours, less than about 4 hours, less than about 3 hours, less than about 2 hours, less than about 1 hour, or less approximately 30 minutes after administration. The desirable pharmacokinetic profile, as used herein, is the pharmacokinetic profile measured after the initial dose of acetaminophen or a salt or derivative thereof. The compositions can be formulated in any form as described herein and as is known to those skilled in the art. 3. The pharmacokinetic profiles of the acetaminophen compositions of the invention are not affected by the fed or fasting state of the subject ingesting the compositions. The invention encompasses acetaminophen composition wherein the pharmacokinetic profile of acetaminophen is not substantially affected by the fed or fasting of the subject who ingests the composition. This means that there is no substantial difference in the amount of drug absorbed or the rate of drug absorption when the acetaminophen compositions in nanoparticles are administered in the fed versus the fasted state. For conventional acetaminophen formulations, ie TYLENOL®, the absorption of acetaminophen is increased when administered with food. This difference in absorption observed with conventional acetaminophen formulations is undesirable. The acetaminophen formulations of the invention overcome this problem, since the acetaminophen formulations reduce or preferably significantly eliminate significantly different levels of absorption when administered under food compared to fasting conditions. The benefits of a dosage form that substantially eliminates the effect of food includes an increase in the suitability of the subject, thus increasing the subject's compliance, since the subject does not need to make sure that he is taking a dose with or without food. This is significant, since with an adherence of the deficient subject an increase in the medical condition for which the drug is being prescribed may be observed, that is, increased pain or fever for compliance of the deficient subject with acetaminophen. 4. Bioequivalence of acetaminophen compositions of the invention when administered in the fed versus the fasted state The invention also encompasses providing an acetaminophen nanoparticle composition in which the administration of the composition to a subject in a fasted state is bioequivalent to the administration of the composition in a subject in the fed state. The difference in absorption (AUC) or Cmax of the acetaminophen compositions in nanoparticles of the invention, when administered in the fed state versus the fasting state, is preferably less than about 60%, less than about 55%, less than about 50%, less than about 45%, less than about 40%, less than about 35%, less than about 30%, less than about 25%, less than about 20%, less than about 15%, less than about 10% , less than about 5%, or less than about 3%. In one embodiment of the invention, the invention encompasses compositions comprising acetaminophen in nanoparticles, wherein the administration of the composition to a subject in a fasted state is bioequivalent to the administration of the composition to a subject in a fed state, in particular as defined by Cmax and the AUC guidelines given by the US Food and Drug Administration (Food and Drug Administration of the US) and the corresponding European regulatory agency (EMEA). Under the guidelines of the U.S. FDA, two products or methods are bioequivalent if 90% confidence intervals (Cl) for AUC and Cmax are between 0.80 to 1.25 (Tmax measurements are not relevant to bioequivalence for regulatory purposes). To show bioequivalence between two compounds or administration conditions according to the European EMEA guidelines, 90% of Cl for AUC should be between 0.80 and 1.25 and 90% of Cl for Cmax should be between 0.70 and 1.43.

. Dissolution profiles of the acetaminophen compositions of the invention It is proposed that the acetaminophen nanoparticle compositions, or a salt or derivative thereof, of the invention have unexpectedly drastic dissolution profiles. The rapid dissolution of an active agent administered is preferable, since the faster dissolution generally leads to a faster onset of action and greater bioavailability. To improve the dissolution profile and the bioavailability of acetaminophen, it would be useful to increase the dissolution of the drug so that it could achieve a level close to 100%.

The acetaminophen compositions of the invention preferably have a dissolution profile in which at least about 20% of the composition dissolves within about 5 minutes. In other embodiments of the invention, at least about 30% or about 40% of the acetaminophen composition dissolves within about 5 minutes. In other embodiments of the invention, preferably at least about 40%, at least about 50%, at least about 60%, at least about 70%, or at least about 80% of the acetaminophen composition is dissolved in about 10 minutes. Finally, in another embodiment of the invention, preferably at least about 70%, at least about 80%, at least about 90%, or at least about 100% of the acetaminophen composition dissolves within 20 minutes. The dissolution is preferably measured in a medium that is discriminatory. Said dissolution medium will produce two very different dissolution curves for two products having very different dissolution profiles in gastric juices; that is, the dissolution medium is predictive of dissolution of a composition in vivo. An illustrative dissolution medium is an aqueous medium containing the surfactant sodium lauryl sulfate at 0.025 M. The determination of the dissolved amount can be carried out by spectrophotometry. The rotary knife method (European Pharmacopoeia) can be used to measure the dissolution. 6. Redispersion Capability of the Acetaminophen Compositions of the Invention A further feature of the acetaminophen compositions, or a salt or derivative thereof, of the invention is that the compositions are redispersed in such a way that the effective average particle size of the particles of redisperse acetaminophen is less than about 2 microns. This is significant, since if under administration the acetaminophen compositions of the invention did not redisperse to a nanoparticle size substantially, then the dosage form may lose the benefits given when formulating the acetaminophen in a nanoparticle size. This is because the active agent compositions in nanoparticles benefit from the small particle size of the active agent; if the active agent is not dispersed in small particle sizes when administered, "clots" or agglomerates of active agent particles are formed, due to the extremely high surface free energy of the nanoparticle system and the thermodynamic driving force achieves a global reduction in free energy. With the formulation of said agglomerated particles, the bioavailability of the dosage form can fall well below that observed with the liquid dispersion form of the active agent in nanoparticulas.

In other embodiments of the invention, the acetaminophen particles, or a salt or derivative thereof, of the invention have an effective average particle size of less than about 1900 nm, less than about 1800 nm, less than about 1700 nm, less of about 1600 nm, less than about 1500 nm, less than about 1400 nm, less than about 1300 nm, less than about 1200 nm, less than about 1100 nm, less than about 1000 nm, less than about 900 nm, less than about 800 nm, less than about 700 nm, less than about 600 nm, less than about 500 nm, less than about 400 nm, less than about 300 nm, less than about 250 nm, less than about 200 nm, less than about 150 nm , less than about 100 nm, less than about 75 nm, or less than about 50 nm, as measured by light scattering methods, microscopy opiate, or foals appropriate methods. Moreover, compositions of acetaminophen in nanoparticles or a salt or derivative thereof of the invention exhibit drastic redispersion of the acetaminophen particles in nanoparticles under administration to a mammal, such as a human or animal, as demonstrated by reconstitution / redispersion in a biorelevant aqueous medium such that the effective average particle size of the redispersed acetaminophen particles is less than about 2 microns.

Said biorelevant aqueous medium can be any aqueous medium having the desired ionic concentration and pH, which form the basis for the biorelevance of the medium. The desired pH and ionic concentration are those that are representative of physiological conditions found in the human body. Said biorelevant aqueous medium can be, for example, solutions of aqueous electrolytes or aqueous solutions of any salt, acid or base, or a combination thereof, which has the desired pH and ionic concentration. Biorelevant pH is well known in the art. For example, in the stomach, the pH ranges are slightly less than 2 (but typically greater than 1) to 4 or 5. In the small intestine, the pH can vary from 4 to 6, and in the colon it can vary from 6 to 6. to 8. The biorelevant ionic concentration is also well known in the art. The fasting gastric fluid has an ionic concentration of approximately 0.1 M whereas the intestinal fluid in the fasted state has an ionic concentration of approximately 0.14. See e.g., Lindahl et al., "Characterization of Fluids from the Stomach and Proximal Jejunum in Men and Women," Pharm. Res., 14 (4): 497-502 (1997). It is believed that the pH and ionic strength of the test solution is more critical than the specific chemical content. Accordingly, appropriate values of pH and ionic concentration can be obtained through numerous combinations of strong acids, strong bases, salts, single or multiple conjugated acid-base pairs (ie, weak acids and corresponding salts of that acid) , monoprotic and polyprotic electrolytes, etc. Representative electrolyte solutions may be, but are not limited to, HCI solutions, ranging in concentration from about 0.001 to about 0.1 M, and NaCl solutions, ranging in concentration from about 0.001 to about 0.1 M, and mixtures thereof. same. For example, electrolyte solutions can be, but are not limited to, about 0.1 M HCl or less, about 0.01 M HCl or less, about 0.001 M HCl or less, about 0.1 M NaCl or less, about 0.01 M of NaCl or less, about 0.001 M NaCl or less, and mixtures thereof. Of these electrolyte solutions, 0.01 M HCl and / or 0.1 M NaCl, are the most representative of the human physiological conditions fasting, due to the pH and ionic concentration conditions of the proximal gastrointestinal tract. Electrolyte concentrations of 0.001 M HCl, 0.01 M HCl and 0.1 M HCI correspond to pH 3, pH 2 and pH 1, respectively. Therefore, a 0.01 M solution of HCI stimulates the typical acidic conditions found in the stomach. A 0.1 M solution of NaCl provides a reasonable approximation of ionic concentration conditions found throughout the body, including gastrointestinal fluids, although concentrations greater than 0.1 M can be used to stimulate feeding conditions within the human Gl tract.

Illustrative solutions of salts, acids, bases or combinations thereof, having the desired pH and ionic concentration, include but are not limited to phosphoric acid / phosphate salts + sodium chloride, potassium and calcium salts, acetic acid / salts of acetate + sodium chloride, potassium and calcium salts, carbonic acid / bicarbonate salts + sodium chloride, potassium and calcium salts, and citric acid / citrate salts + sodium chloride, potassium and calcium salts. In other embodiments of the invention, the acetaminophen particles, or a salt or derivative thereof, redisperses of the invention (redispersed in an aqueous, biorelevant medium, or any other suitable medium) have an effective average particle size of less than about less than about 1900 nm, less than about 1800 nm, less than about 1700 nm, less than about 1600 nm, less than about 1500 nm, less than about 1400 nm, less than about 300 nm, less than about 1200 nm, less than about 1100 nm, less than about 1000 nm, less than about 900 nm, less of about 800 nm, less than about 700 nm, less than about 650 nm, less than about 600 nm, less than about 550 nm, less than about 500 nm, less than about 450 nm, less than about 400 nm, less than about 350 nm, less than about 300 nm, less than about 250 nm, less than about 200 nm, less than about 150 nm, less than about 100 nm, less than about 75 nm, or less than about 50 nm, as measured by light scattering methods, microscopy, or other appropriate methods. Such methods suitable for measuring the effective average particle size are known to one skilled in the art. The redispersion capability can be tested using any suitable means known in the art. See e.g., the exemplary sections of the U.S. patent. No. 6,375,986 entitled "Solid Dose Nanoparticulate Compositions Comprising to Synergistic Combination of a Polymeric Surface Stabilizer and Dioctyl Sodium Sulfosuccinate." 7. Acetaminophen compositions used in conjunction with other active agents The acetaminophen compositions, or a salt or derivative thereof, of the invention may further comprise one or more compounds useful in the treatment of persistent painful sensations and pain, and reduction of fever and related conditions. , or the acetaminophen compositions can be administered together with said compound. Such compounds include, but are not limited to, narcotic analgesics, such as, but not limited to, morphine, codeine, hydrocodone, and oxycodone.

B. Acetaminophen Compositions in Nanopaiticles The invention provides compositions comprising acetaminophen particles, or a salt or derivative thereof, and at least one surface stabilizer. The surface stabilizers are preferably adsorbed on, or associated with, the surface of the acetaminophen particles. Especially useful surface stabilizers herein are preferably physically adhered to, or associated with, the surface of the acetaminophen particles in nanoparticles, but do not react chemically with the acetaminophen particles or with themselves. Molecules of the individually adsorbed surface stabilizer are essentially free of intermolecular interlacing. The present invention also includes acetaminophen, or a salt or a derivative thereof, compositions together with one or more non-toxic pharmaceutically acceptable carriers, adjuvants or vehicles, collectively referred to as carriers. The compositions can be formulated for parenteral (e.g., intravenous, intramuscular, or subcutaneous) injection, oral administration in solid, liquid, or aerosol form, vaginal, nasal, rectal, ocular, local administration (powders, ointments or drops). , buccal, intracisternal, intraperitoneal or topical, and the like. 1. Acetaminophen particles The compositions of the invention comprise acetaminophen particles or a salt or derivative thereof. The particles may be in a crystalline phase, semi-crystalline phase, amorphous phase, semi-amorphous phase, or a combination thereof. 2, Surface Stabilizers Combinations of more than one surface stabilizer can be used in the invention. Useful surface stabilizers that can be used in the invention include, but are not limited to, known organic and inorganic pharmaceutical excipients. Such excipients include various polymers, low molecular weight oligomers, natural products, and surfactants. Illustrative surface stabilizers include nonionic, ionic, anionic, cationic and zwitterionic surfactants. Representative examples of surface stabilizers include hydroxypropylmethylcellulose (now known as hypromellose), hydroxypropylcellulose, polyvinylpyrrolidone, sodium lauryl sulfate, dioctyl sulfosuccinate, gelatin, casein, lecithin (phosphatides), dextran, acacia gum, cholesterol, tragacanth, stearic acid, benzalkonium chloride , calcium stearate, glycerol monostearate, cetostearyl alcohol, cetomacrogol emulsifying wax, sorbitan esters, polyoxyethylene alkyl ethers (e.g., macrogol ethers such as cetomacrogol 1000), polyoxyethylene castor oil derivatives, esters of polyoxyethylene sorbitan fatty acid (e.g., commercially available Tweens® such as eg, Tween 20® and Tween 80® (ICI Specialty Chemicals)); polyethylene glycols (e.g., Carbowaxs 3550® and 934® (Union Carbide)), polyoxyethylene stearates, colloidal silicon dioxide, phosphates, calcium carboxymethylcellulose, sodium carboxymethylcellulose, methylcellulose, hydroxyethylcellulose, hypromellose phthalate, non-crystalline cellulose, magnesium aluminum silicate, triethanolamine, polyvinyl alcohol (PVA), polymer of 4- (1,1,3,3-tetramethylbutyl) -phenol with ethylene oxide and formaldehyde (also known as tyloxapol, superione and triton), poloxamers ( v.gr., Pluronics F68® and Fl 08®, which are block copolymers of ethylene oxide and propylene oxide); poloxamines (e.g., Tetronic 908®, also known as Poloxamine 908®, which is a tetrafunctional block copolymer derived from the sequential addition of propylene oxide and ethylene oxide to ethylenediamine (BASF Wyandotte Corporation, Parsippany, NJ.) ); Tetronic 1508® (T-1508) (BASF Wyandotte Corporation), Tritons X-200®, which is an alkylaryl polyethersulfonate (Rohm and Haas); Crodestas F-110®, which is a mixture of sucrose stearate and sucrose distearate (Croda Inc.); p-isononylphenoxypoli- (glycidol), also known as Olin-IOG® or surfactant 10-G® (Olin Chemicals, Stamford, CT); Crodestas SL-40® (Croda, Inc.); and SA90HCO, which is C18H37CH2 (CON (CH3) -CH2 (CHOH) 4 (CH20H) 2 (Eastman Kodak Co.); decanoyl-N-methylglucamide; n-decyl-pD-glucopyranoside; n-decol- -D-maltopyranoside n-dodecyl-pD-glucopyranoside, n-dodecyl-pD-maltoside, heptanoyl-N-methylglucamide, n-heptyl-D-glucopyranoside, n-heptyl-pD-thioglucoside, n-hexyl ^ -D-glucopyranoside, nonanoyl -N-methylglucamide;? - ??? - ß-D-glucopyranoside, octanoyl-N-methylglucamide, n-octyl-pD-glucopyranoside, octyl-pD-thioglucopyranoside, PEG-phospholipid, PEG-cholesterol, PEG-cholesterol derivative , PEG-vitamin A, PEG-vitamin E, lysozyme, random copolymers of vinylpyrrolidone and vinyl acetate, and the like Examples of useful cationic surface stabilizers include, but are not limited to, polymers, biopolymers, polysaccharides, cellulosics, alginates, phospholipids, and non-polymeric compounds, such as zwitterionic stabilizers, poly-n-methylpyridinium, antriulpyridinium chloride, cationic phospholipids, chitoses polyvinyl, polyvinylimidazole, polybrene, polymethyl-trimethylammonium methacrylate bromide (PMMTMABr), hexyldesyltrimethylammonium bromide (HDMAB), and polyovinylpyrrolidone-2-dimethylaminoethyl methacrylate dimethyl sulfate. Other useful cationic stabilizers include, but are not limited to, cationic lipids, sulfonium, phosphonium, and quaternary ammonium compounds, such as stearyltrimethylammonium chloride compounds, benzyl-di (2-chloroethyl) ethylammonium bromide, cocotrimethylammonium chloride or bromide. , chloride or bromide cocometildihidroxietilamonio, decyl triethyl ammonium chloride or bromide decildimetilhidroxietilamonio, dimethyl hydroxyethyl ammonium chloride or bromide C-12-15, chloride or bromide cocodimetilhidroxietilamonio methylsulfate, myristyl, lauryldimethylbenzylammonium chloride or bromide, lauryl dimethyl ammonium chloride or bromide chloride (ethenoxy) 4-ammonium, N-alkyl- (Ci2-i8) dimethylbenzyl ammonium chloride, N-alkyl (Ci4-i8) dimethyl-benzylammonium chloride, N-tetradecylmethylbenzylammonium chloride monohydrate, dimethyldidecylammonium chloride, chloride of N-alkyl and (Ci2-i4) dimethyl-1-naphthlmethylammonium, trimethylammonium halide, alkyl trimethylammonium salts and salts of dialkyl-dimethylammonium, lauryltrimethylammonium chloride, ethoxylated alkylamidoalkyldialkylammonium salt and / or an ethoxylated trialkylammonium salt, dialkylbenzenedialkylammonium chloride, N-didecyldimethylammonium chloride, N-tetradecyldimethylbenzylammonium chloride monohydrate, N-alkyl chloride (C 2 -4) -dimethyl-1-naphthylmethylammonium and dodecyldimethylbenzylammonium chloride, dialkylbenzenealkylammonium, lauryltrimethylammonium chloride, alkylbenzylmethylammonium chloride, alkylbenzyldimethylammonium bromide, trimethyl ammonium bromide of C12, Ci5lC17, dodecylbenzyltriethylammonium chloride, poly-diallyldimethylammonium chloride (DADMAC), dimethyl ammonium chlorides, alkyldimethylammonium halides, tricetylmethylammonium chloride, decyltrimethylammonium bromide, dodecyltriethylammonium bromide, tetradecyltrimethylammonium bromide, methyltrioctylammonium chloride (ALIQUAT 336 ™), POLYQUAT 10 ™, tetrabutylammonium bromide, benzyltrimethylammonium bromide, choline esters ( as fatty acid choline esters), benzalkonium chloride, stearalkonium chloride (such as stearyltrimonium chloride and di-stearyldimonium chloride), cetylpyridinium bromide or chloride, quaternized polyoxyethylalkylamino halide salts, MIRAPOL ™ and ALKAQUAT ™ (Alkaril Chemical Company), alkyl pyridinium salts; amines, such as alkylamines, dialkylamines, alkanolamines, polyethylenepolyamines,?,? - dialkylaminoacylacrylate acrylates, and vinylpyridine, amine salts, such as laurylamine acetate, stearylamine acetate, alkyl pyridinium salt, and alkylimidazolium salt, and oxides of amine; imidazolinium salts; protonated quaternary acrylamides; methylated quaternary polymers, such as poly [diallylmethylammonium chloride] and poly- [N-methylvinylpyridinium] chloride; and cationic guar. Such illustrative cationic surface stabilizers and other useful cationic surface stabilizers are described in J. Cross and E. Singer, Cationic Surfactants: Analytical and Biological Evaluation (Marcel Dekker, 1994); P. and D. Rubingh (Editor), Cationic Surfactants: Physical Chemistry (Marcel Dekker, 1991); and J. Richmond, Cationic Surfactants: Organic Chemistry, (Marcel Dekker, 1990). Non-polymeric surface stabilizers are any non-polymeric compound, such as benzalkonium chloride, a carbonate compound, a phosphonium compound, an oxonium compound, a halonium compound, a cationic organometallic compound, a quaternary phosphorus compound, a compound of pyridinium, an anilinium compound, an ammonium compound, a hydroxylammonium compound, a primary ammonium compound, a secondary ammonium compound, a tertiary ammonium compound, and quaternary ammonium compounds of the formula NR R2R3R4 (+). For compounds of the formula NR ^ R ^^: (i) none of R1-4 are CH3; (i) one of R R4 is CH3; (iii) three of R1-R4 are CH3; (iv) all of R1-R4 are CH3; (v) two of R1-R4 are CH3, one of Ri-R4 is C6H5CH2, and one of R1-R4 is an alkyl chain of seven carbon atoms or less; (vi) two of R1-R4 are CH3, one of RrR4 is C6H5CH2, and one of R4 is an alkyl chain of nineteen carbon atoms or more; (vii) two of R R4 are CH3 and one of RrR4 is the group C6H5 (CH2) n, where n > 1; (viii) two of R1-R4 are CH3, one of R1-R4 is C6H5CH2, and one of Ri-R4 comprises at least one heteroatom; (ix) two of Ri-R4 are CH3) one of R1 -R4 is C6H5CH2) and one of Ri -R4 comprises at least one halogen; (x) two of R1-R4 are CH3, one of RrR4 is C6H5CH2, and one of R-i-R4 comprises at least one cyclic fragment; (x) two of R1-R4 are CH3 and one of R1-R4 is a phenyl ring; or (xii) two of R1 -R4 are CH3 and two of R1-R4 are purely aliphatic fragments. Such compounds include, but are not limited to, behenalconium chloride, benzethonium chloride, cetylpyridinium chloride, behentrimonium chloride, lauralconium chloride, cetalconium chloride, cetrimonium chloride, cetrimonium chloride, cetylamine hydrofluoride, chlorallylmetenamine chloride ( Quaternium-15), distearyldimonium chloride (Quaternium-5), dodecyldimethylbenzylammonium chloride (Quaternium-14), Quaternium-22, Quatemium-26, Quaterniurn-18 hectorite, dimethylaminoethyl chloride hydrochloride, cysteine hydrochloride, oleyl ether phosphate of diethanolammonium POE (10), diethanolammonium oleyl ether phosphate POE (3), ceboalkonium chloride, dimethyldioctadecylammonium bentonite, stearalkyl chloride, domifen bromide, denatonium benzoate, miristalkonium chloride, laurythrimonium chloride, ethylenediamine dihydrochloride, hydrochloride guanidine, pyridoxine HCI, isophetamine hydrochloride, meglumine hydrochloride, methylbenzethonium chloride, bromide d erythrimonium, oleyltrimonium chloride, polyquaternium-1, procaine hydrochloride, cocobetaine, stearalkoniumbentonite, stearalkoniohectonite, stearyltrihydroxyethylpropylenediamine difluorohydrate, cebotrimony chloride, and hexadecyltrimethylammonium bromide. Surface stabilizers are commercially available and / or can be prepared by techniques known in the art. Most of these surface stabilizers are known pharmaceutical excipients and are described in detail in Handbook of Pharmaceutical Excipients, published jointly by the American Pharmaceutical Association and The Pharmaceutical Society of Great Britain (The Pharmaceutical Press, 2000), specifically incorporated herein by reference. 3. Other pharmaceutical excipients The pharmaceutical compositions according to the invention may also comprise one or more binding agents, fillers, lubricants, suspending agents, sweeteners, flavoring agents, preservatives, pH regulators, wetting agents, disintegrators, effervescent agents and others. excipients Such excipients are known in the art. Examples of fillers are lactose monohydrate, anhydrous lactose, and various starches; examples of binding agents are various celluloses and entangled polyvinylpyrrolidone, microcrystalline cellulose, such as Avicel® PHIOI and Avicel® PH102, microcrystalline cellulose, and silicified microcrystalline cellulose (ProSolv SMCC ™). Stable lubricants, including agents that act on the flowability of the powder to be compressed, are colloidal silicon dioxide, such as Aerosil® 200, talc, stearic acid, magnesium stearate, calcium stearate, and silica gel. Examples of sweeteners are any natural or artificial sweetener, such as sucrose, xylitol, sodium saccharin, cyclamate, aspartame, and acesulfame. Examples of flavoring agents are Magnasweet® (trademark of MAFCO), chewing gum flavor, and fruit flavors, and the like. Examples of preservatives are potassium sorbate, methylparaben, propylparaben, benzoic acid and its salts, other esters of parahydroxybenzoic acid such as butylparaben, alcohols such as ethyl or benzyl alcohol, phenolic compounds such as phenol, or quaternary compounds such as benzalkonium chloride. Suitable diluents include pharmaceutically acceptable inert fillers, such as microcrystalline cellulose, lactose, dibasic calcium phosphate, saccharides, and / or mixtures of any of the foregoing. Examples of diluents include microcrystalline cellulose, such as Avicel® PHIOI and Avicel® PH102; lactose such as lactose monohydrate, anhydrous lactose, and Pharmatose® DCL21; dibasic calcium phosphate such as Emcompress®; mannitol; starch; sorbitol; sucrose and glucose. Suitable disintegrants include slightly interlaced polyvinylpyrrolidone, corn starch, potato starch, corn starch, and modified starches, croscarmellose sodium, crospovidone, sodium starch glycolate, and mixtures thereof. Examples of effervescent agents are effervescent couples such as an organic acid and a carbonate or bicarbonate. Suitable organic acids include, for example, citric, tartaric, malic, fumaric, adipic, succinic, and alginic acids and anhydrides and acid salts. Suitable carbonates and bicarbonates include, for example, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, magnesium carbonate, glycine-sodium carbonate, L-lysine carbonate, and arginine carbonate. Alternatively, only the sodium bicarbonate component of the effervescent couple can be present. 4. Acetaminophen particle size in nanoparticles The compositions of the invention comprise acetaminophen in nanoparticles, or a salt or derivative thereof, particles having an average effective particle size of less than about 2000 nm (i.e., 2 microns), less than about 1900 nm, less than about 1800 nm, less than about 1700 nm, less than about 1600 nm, less than about 1500 nm, less than about 1400 nm, less than about 1300 nm, less than about 1200 nm, less than about 1100 nm, less than about 1000 nm, less than about 900 nm, less than about 800 nm, less than about 700 nm, less than about 600 nm, less than about 500 nm, less than about 400 nm, less than about 300 nm, less than about 250 nm, less than about 200 nm, less than about 150 nm, less than about 100 nm, about 75 nm, or less than about 50 nm, as measured by light scattering methods, microscopy, or other appropriate methods. By "an effective average particle size of less than about 2000 nm" it is understood that at least 50% of the acetaminophen particles have a particle size of less than the effective average, by weight (or by another suitable measurement technique, such as in volume, number, etc.), that is, less than approximately 2000 nm, 1900 nm, 1800 nm, etc., when measured by the above-indicated techniques. In other embodiments of the invention, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, or at least about 99% the acetaminophen particles have a particle size of less than the effective average, that is, less than about 2000 nm, 1900 nm, 1800 nm, 1700 nm, etc. In the present invention, the value for D50 of an acetaminophen composition in nanoparticles is the particle size below which 50% by weight of the particles of acetaminophen particles fall. Similarly, D90 is the particle size below which 90% by weight of the acetaminophen particles fall.

. Concentration of Acetaminophen and Surface Stabilizers The relative amounts of acetaminophen, or a salt or derivative thereof, and one or more surface stabilizers can vary widely. The optimum amount of the individual components may depend, for example, on the particular acetaminophen and / or surface stabilizer selected, the hydrophilic-lipophilic balance (HLB), melting point, and the surface tension of water solutions of the surface stabilizer, etc. The concentration of acetaminophen can vary from about 99.5% to about 0.001%, from about 95% to about 0.1%, or from about 90% to about 0.5%, by weight, based on the total combined weight of acetaminophen and at least one surface stabilizer, not including other excipients. The concentration of at least one surface stabilizer can vary from about 0.5% to about 99.999%, from about 5.0% to about 99.9%, or from about 10% to about 99.5%, by weight, based on the total combined dry weight of acetaminophen and at least one surface stabilizer, not including other excipients. 6. Acetaminophen tablet formulations in illustrative nanoparticles Various acetaminophen tablet formulations in illustrative nanoparticles are given below. These examples are not intended to limit the claims in any way, but rather to provide illustrative tablet formulations of acetaminophen that can be used in the methods of the invention. Said illustrative tablets may also comprise a coating agent.

TABLE 1 Formulation of acetaminophen tablet in nanoparticles illustrative # 1 TABLE 2 Formulation of acetaminophen tablet in nanoparticles illustrative # 2 TABLE 3 Formulation of Acetaminophen Tablet in Illustrative Nanoparticles # 3 TABLE 4 Formulation of Acetaminophen Tablet in Illustrative Nanoparticles # 4 C. Methods for making acetaminophen compositions in nanoparticles Acetaminophen compositions in nanoparticles, or a salt or derivative thereof, can be made using, for example, milling, homogenization, precipitation, freezing, or mold emulsion techniques. Illustrative methods for making active agent compositions in nanoparticles are described in the '684 patent. Methods for making acetaminophen compositions are also described in the U.S.A. No. 5,518,187 for "Method of Grinding Pharmaceutical Substances;" the patent of E.U.A. No. 5,718,388 for "Continuous Method of Grinding Pharmaceutical Substances;" the patent of E.U.A. No. 5,862,999 for "Method of Grinding Pharmaceutical Substances;" the patent of E.U.A. No. 5,665,331 for "Co-Microprecipitation of Nanoparticulate Pharmaceutical Agents with Crystal Growth Modifiers;" the patent of E.U.A. No. 5,662,883 for "Co-Microprecipitation of Nanoparticulate Pharmaceutical Agents with Crystal Growth Modifiers;" the patent of E.U.A. No. 5,560,932 for "Microprecipitation of Nanoparticulate Pharmaceutical Agents;" the patent of E.U.A. No. 5,543,133 for "Process of Preparing X-Ray Contrast Compositions Containing Nanoparticles;" the patent of E.U.A. No. 5,534,270 for "Method of Preparing Stable Drug Nanoparticles;" the patent of E.U.A. No. 5,510,118 for "Process of Preparing Therapeutic Compositions Containing Nanoparticles;" and the patent of E.U.A. No. 5,470,583 for "Method of Preparing Nanoparticle Compositions Containing Charged Phospholipids to Reduce Aggregation," all of which are incorporated specifically by reference. Acetaminophen compositions or dispersions in resulting nanoparticles can be used in solid or liquid dosage formulations, such as liquid dispersions, gels, aerosols, ointments, creams, controlled release formulations, fast melt formulations, lyophilized formulations, tablets, capsules, delayed release formulations, sustained release formulations, pulsatile release formulations, and mixed immediate and controlled release formulations, etc. 1. Grinding to obtain particulate acetaminophen dispersions Grinding an acetaminophen dispersion, or a salt or derivative thereof, to obtain a nanoparticle dispersion comprises dispersing the acetaminophen particles in a liquid dispersion medium in which acetaminophen is poorly soluble , followed by the application of mechanical means in the presence of grinding media to reduce the particle size of acetaminophen to the desired effective average particle size. The dispersion medium can be, for example, water, safflower oil, ethanol, t-butanol, glycerin, polyethylene glycol (PEG), hexane or glycol. A preferred dispersion medium is water. The acetaminophen particles can be reduced in size in the presence of at least one surface stabilizer. Alternatively, the acetaminophen particles can be contacted with one or more surface stabilizers after rubbing. Other compounds, such as a diluent, can be added to the acetaminophen / surface stabilizer composition during the size reduction process. The dispersions can be manufactured continuously or in an intermittent mode. 2. Precipitation to obtain acetaminophen compositions in nanoparticles Another method for forming the desired nanoparticle acetaminophen composition, or a salt or derivative thereof, is by microprecipitation. This is a method for preparing stable dispersions of poorly soluble active agents in the presence of one or more surface stabilizers and one or more colloidal stability surface active agents free of any trace toxic solvents or solubilized heavy metal impurities. Said method comprises, for example: (1) dissolving acetaminophen in a suitable solvent; (2) adding the formulation of step (1) to a solution comprising at least one surface stabilizer; and (3) precipitating the formulation of step (2) using an appropriate non-solvent. The method can be followed by removal of any salt formed, if present, by dialysis or diafiltration and concentration of the dispersion by conventional means. 3. Homogenization to obtain acetaminophen compositions in nanoparticles Illustrative homogenization methods for preparing active agent nanoparticle compositions are described in the U.S.A. No. 5,510,118, entitled "Process of Preparing Therapeutic Compositions Containing Nanoparticles." Said method comprises dispersing particles of an acetaminophen, or a salt or derivative thereof, in a liquid dispersion medium, followed by subjecting the dispersion to homogenization to reduce the particle size of an acetaminophen to the desired effective average particle size. The acetaminophen particles can be reduced in size in the presence of at least one surface stabilizer. Alternatively, the acetaminophen particles can be contacted with one or more surface stabilizers either before or after rubbing. Other compounds, such as a diluent, can be added to the acetaminophen / surface stabilizer composition either before, during or after the size reduction process. The dispersions can be manufactured continuously or in an intermittent mode. 4. Cryogenic methodologies for obtaining acetaminophen compositions in nanoparticles Another method for forming the desired acetaminophen nanoparticle composition, or a salt or derivative thereof, is by liquid spray freezing (SFL). This technology comprises an organic or organocose solution of acetaminophen with stabilizers, which are injected into a cryogenic liquid, such as liquid nitrogen. The drops of the acetaminophen solution are frozen at a sufficient rate to minimize crystallization and particle growth, thus formulating nanostructured acetaminophen particles. Depending on the choice of solvent system and processing conditions, acetaminophen particles in nanoparticles may have variable particle morphology. In the isolation step, the nitrogen and solvent are removed under conditions that prevent agglomeration or maturation of the acetaminophen particles. As a complementary technology to SFL, ultrafast freezing (URF) can also be used to create equivalent nanostructured acetaminophen particles with greatly increased surface area. URF comprises an organic or organocose solution of acetaminophen with stabilizers in a cryogenic substrate.

. Emulsion methodologies for obtaining acetaminophen compositions in nanoparticles Another method for forming the composition of acetaminophen in nanoparticles, or a desired salt or derivative thereof, is by in-mold emulsion. The in-mold emulsion creates nanostructured acetaminophen particles with controlled particle size distribution and fast dissolution performance. The method comprises an oil-in-water emulsion which is prepared, then swelled with a non-aqueous solution comprising acetaminophen and stabilizers. The particle size distribution of acetaminophen particles is a direct result of the size of the emulsion droplets before loading with acetaminophen a property that can be controlled and optimized in this procedure. In addition, through the selected use of solvents and stabilizers, the stability of the emulsion is achieved without Ostwald maturation or suppressed. Subsequently, the solvent and water are removed, and the stabilized nanostructured acetaminophen particles are recovered. Several particles of acetaminophen morphologies can be achieved by appropriate control of processing conditions.

D. Methods for using acetaminophen compositions in nanoparticles of the invention The invention provides a method for increasing the bioavailability of an acetaminophen, or a salt or derivative thereof, in a subject. Said method comprises administering orally to a subject an effective amount of a composition comprising an acetaminophen. In an embodiment of the invention, acetaminophen compositions, in accordance with standard pharmacokinetic practice, have a bioavailability that is approximately 50% greater than a conventional dosage form, approximately 40% higher, approximately 30% higher, approximately 20% or approximately 10% higher. The compositions of the invention are useful in the treatment of persistent painful sensations and pain, and reduction of fever and related conditions. The acetaminophen compounds, or a salt or derivative thereof, of the invention can be administered to a subject by any conventional means including, but not limited to, oral, rectal, ocular, otic, parenteral (e.g., intravenous, intramuscular, or subcutaneous), intracisternal, pulmonary, intravaginal, intraperitoneal, local (e.g., powders, ointments or drops), or as a buccal or nasal spray. As used herein, the term "subject" is used to mean an animal, preferably a mammal, including a human or non-human. The terms patient and subject can be used interchangeably. Compositions suitable for parenteral injection may comprise physiologically acceptable aqueous or non-aqueous solutions, dispersions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Examples of suitable vehicles, diluents, solvents or aqueous and non-aqueous carriers including water, ethanol, polyols (propylene glycol, polyethylene glycol, glycerol and the like), suitable mixtures thereof, vegetable oils (such as olive oil) and organic ethers injectables such as ethyl oleate. The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants. The acetaminophen nanoparticle compositions, or a salt or derivative thereof, may also comprise adjuvants such as preservatives, humectants, emulsifiers and dispersants. The prevention of the growth of microorganisms can be ensured by various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride and the like. Prolonged absorption of the injectable pharmaceutical form can occur approximately through the use of agents that retard absorption, such as aluminum monostearate and gelatin. Solid dosage forms for oral administration include, but are not limited to, capsules, tablets, pills, powders, and granules. In those solid dose forms, the active agent is mixed with at least one of the following: (a) one or more inert excipients (or carriers), such as sodium citrate or dicalcium phosphate; (b) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol and silicic acid; (c) binders, such as carboxymethyl cellulose, alignates, 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 retarders, such as paraffin; (g) absorption accelerators, such as quaternary ammonium compounds; (h) wetting agents, such as cetyl alcohol and glycerol monostearate; (i) adsorbents, such as caolin and bentonite; and (j) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium laurisulfate, or mixtures thereof. For capsules, tablets and pills, the dosage forms can also comprise pH regulating agents. Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs. In addition to an acetaminophen, the liquid dosage forms may comprise inert diluents commonly used in the art, such as water or other solvents, solubilizing agents and emulsifiers. Illustrative emulsifiers are ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils, such as cottonseed oil, walnut oil, oil. of corn germ, olive oil, castor oil, and sesame oil, glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols, sorbitan fatty acid esters or mixtures of these substances, and the like. In addition to said inert diluents, the composition may also include adjuvants, such as wetting, emulsifying and suspending, sweetening, flavoring and perfume agents. "Therapeutically effective amount" as used herein with respect to an acetaminophen, will mean that dose which provides the specific pharmacological response for which an acetaminophen is administered in a significant number of subjects in need of such treatment. Emphasis is made that 'therapeutically effective amount' administered to a particular subject in a particular case will not always be effective in the treatment of the diseases described herein, even though said dose is considered a 'therapeutically effective amount' by the experts in the art. technique. It is understood that acetaminophen doses are, in particular cases, measured as oral doses, or with reference to drug levels as measured in the blood. One skilled in the art will appreciate that effective amounts of an acetaminophen can be determined empirically and can be used in pure form or, where such forms exist, in the form of a pharmaceutically acceptable salt, ester or prodrug. The actual dose levels of an acetaminophen in the acetaminophen compositions of the invention can be varied to obtain an amount of an acetaminophen that is effective to obtain a desired therapeutic response for a particular composition and method of administration. The selected dose level therefore depends on the desired therapeutic effect, the route of administration, the potency of the acetaminophen administered, the desired duration of treatment, and other factors. The dosage unit compositions may contain the amounts of said submultiples thereof as may be used to constitute the daily dose. However, it will be understood that the specific dose level for any particular patient will depend on a variety of factors: the type and degree of the cellular or physiological response to be achieved; activity of the specific agent or composition used; the specific agents or composition used; age, body weight, general health, sex, and diet of the patient; the time of administration, route of administration, and rate of excretion of the agent; the duration of the treatment; drugs used in combination or coincident with the specific agent; and similar factors well known in the medical arts. The following examples are given to illustrate the present invention. However, it is understood that the spirit and scope of the invention is not limited to the specific conditions or details described in the examples but should only be limited by the scope of the claims that follow. All references identified herein, including US patents, are expressly incorporated herein by reference.

EXAMPLE 1 The purpose of this example was to prepare acetaminophen compositions in nanoparticles using various combinations of surface stabilizers. An aqueous dispersion of acetaminophen combined with one or more surface stabilizers, in the concentrations shown in Table 5, below, was milled in a 10 ml or 50 ml chamber of a NanoMill® 0.01 (NanoMill Systems, King of Prussia, PA, see e.g., U.S. Patent No. 6,431, 478), together with 500 micras of PolyMill® Rubbing Media (Dow Chemical) (89% media loading). The milling time and milling speed used for the preparation of each formulation is also shown in table 5.

TABLE 5 Acetaminophen formulations The milled compositions were harvested and analyzed by microscopy. Microscopy was done using a Lecia DM5000B and Lecia CTR 5000 light source (Laboratory Instruments and Supplies Ltd., Ashbourne Co., Meath, Ireland). The microscopy observations for each formulation are shown later in Table 6.

TABLE 6 fifteen TABLE 7 Particle sizes that vary significantly after sonication are undesirable, since it is indicative of the presence of acetaminophen aggregates. Said aggregates result in compositions having highly variable particle sizes. Such highly variable particle sizes can result in variable absorption between doses of a drug, and therefore are undesirable. The data demonstrate the successful preparation of acetaminophen in nanoparticle formulations using various surface stabilizers, including various combinations of surface stabilizers. It will be apparent to those skilled in the art that various modifications and variations may be made in the methods and compositions of the present inventions without departing from the spirit and scope of the invention. Therefore, it is intended that the present invention cover the modification and variations of the invention as long as they fall within the scope of the appended claims and their equivalents.

Claims (25)

NOVELTY OF THE INVENTION CLAIMS

1. - A stable nanoparticle acetaminophen composition comprising: (a) acetaminophen particles or a salt or derivative thereof having an effective average particle size of less than about 2000 nm; and (b) at least one surface stabilizer.

2. - The composition according to claim 1, further characterized in that the acetaminophen particles or a salt or derivative thereof are selected from the group consisting of a crystalline phase, an amorphous phase, a semi-crystalline phase, a semi-phase -amorfa and mixtures thereof.

3. The composition according to claim 1 or claim 2, further characterized in that the effective average particle size of acetaminophen or a salt or derivative thereof is selected from the group consisting of less than about 1900 nm, less than about 1800 nm, less than about 1700 nm, less than about 1600 nm, less than about 1500 nm, less than about 1400 nm, less than about 1300 nm, less than about 1200 nm, less than about 1100 nm, less than about 1000 nm , less than about 900 nm, less than about 800 nm, less than about 700 nm, less than about 600 nm, less than about 500 nm, less than about 400 nm, less than about 300 nm, less than about 250 nm, less of about 200 nm, less than about 100 nm, less than about 75 nm, and less than about 50 nm.

4. The composition according to any of claims 1 to 3, further characterized in that the composition is formulated: (a) for administration selected from the group consisting of parenteral injection, oral administration in solid, liquid or aerosol form, administration vaginal, nasal, rectal, otic, ocular, local, buccal, intracisternal, intraperitoneal and topical; (b) in a dosage form selected from the group consisting of liquid dispersions, gels, bags, solutions, aerosols, ointments, tablets, capsules, creams and mixtures thereof; (c) in a dosage form selected from the group consisting of controlled release formulations, fast melt formulations, lyophilized formulations, delayed release formulations, sustained release formulations, pulse release formulations, and immediate release and release formulations controlled mixed; or (d) any combination thereof.

5. The composition according to any of claims 1 to 4, further characterized in that the composition further comprises one or more excipients, pharmaceutically acceptable carriers or a combination thereof.

6. - The composition according to any of claims 1 to 5, further characterized in that: (a) the acetaminophen is present in an amount consisting of from about 99.5% to about 0.001%, from about 95% to about 0.1%, and about 90% to about 0.5%, by weight, based on the total combined weight of acetaminophen and at least one surface stabilizer, not including other excipients; (b) at least one surface stabilizer is present in an amount from about 0.5% to about 99.999% by weight, from about 5.0% to about 99.9% by weight, and from about 10% to about 99.5% by weight, based on in the total combined dry weight of acetaminophen and at least one surface stabilizer, not including other excipients; or (c) a combination thereof.

7. - The composition according to any of claims 1 to 6, further characterized in that the surface stabilizer is selected from the group consisting of a nonionic surface stabilizer, an anionic surface stabilizer, a cationic surface stabilizer., a zwitterionic surface stabilizer, and an ion surface stabilizer.

8. The composition according to any of claims 1 to 7, further characterized in that the surface stabilizer is selected from the group consisting of cetylpyridinium chloride, gelatin, casein, phosphatides, dextran, glycerol, gum acacia, cholesterol, tragacanth , stearic acid, benzalkonium chloride, calcium stearate, glycerol monostearate, cetostearyl alcohol, cetomacrogol emulsifying wax, sorbitan esters, polyoxyethylene alkyl ethers, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, polyethylene glycols, dodecyltrimethylammonium bromide, polyoxyethylene stearates, colloidal silicon dioxide, phosphates, sodium dodecylisulfate, calcium carboxymethylcellulose, hydroxypropylcelluloses, hiromelose sodium carboxymethylcellulose, methylcellulose, hydroxyethylcellulose, hypromellose phthalate, non-crystalline cellulose, magnesium aluminum silicate, triethanolamine, alcohol polyvinyl, polyvinylpyrrolidone, polymer of 4- (1,1,1,3-tetramethylbutyl) -phenol with ethylene oxide and formaldehyde, poloxamers; poloxamines, a charged phospholipid, dioctylsulfosuccinate, dialkyl esters of sodium sulfosuccinic acid, sodium lauryl sulfate, alkylaryl polyethersulfonates, mixtures of sucrose stearate and sucrose distearate, p-isononylphenoxypoly- (glycidol), decanoyl-N-methylglucamide; n-decyl-β-D-glucopyranoside; n-decol-p-D-maltopyranoside; n-dodecyl ^ -D-glucopyranoside; n-dodecyl- -D-maltoside; heptanoyl-N-methylglucamide; n-heptyl-D-glucopyranoside; n-heptyl-D-thioglucoside; n-hexyl-β -? - glucopyranoside; nonanoyl-N-methylglucamide; ? - ??? - ß-D-glucopyranoside; octanoyl-N-methylglucamide; n-octyl- -D-glucopyranoside; octyl-β-α-thioglucopyranoside; lysozyme, PEG-phospholipid, PEG-cholesterol, PEG-cholesterol derivative, PEG-vitamin A, PEG-vitamin E, lysozyme, random copolymers of vinyl acetate and vinylpyrrolidone, a cationic polymer, a cationic biopolymer, a cationic polysaccharide, a cationic cellulose, a cationic agglutinate, a non-polymeric cationic compound, a cationic phospholipid, cationic lipids, trimethyl ammonium bromide of polymethyl methacrylate, sulfonium compounds, dimethylispyrrolidone dimethylisulfate-2-dimethylaminoethyl methacrylate, hexadecyltrimethylammonium bromide, phosphonium compounds, quaternary ammonium, benzyl-di (2-chloroethyl) ethylammonium bromide, cocotrimethylammonium chloride, cocotrimethylammonium bromide, cocomethyldihydroxyethylammonium chloride, cocomethyldihydroxyethylammonium bromide, decyltriethylammonium chloride, decyldimethylhydroxyethylammonium chloride, decyldimethylhydroxyethylammonium bromide, dimethylhydroxyethylammonium chloride of C12-15 , br dimethylhydroxyethylammonium chloride of C12-15, cocodimethylhydroxyethylammonium chloride, cocodimethylhydroxyethylammonium bromide, myristyltrimethylammonium methylsulfate, lauryldimethylbenzylammonium chloride, lauryldimethylbenzylammonium bromide, lauryldimethyl (ethenoxy) 4-ammonium chloride, lauryldimethyl (ethenoxy) 4-ammonium bromide, N-alkyl- (C12-i8) dimethylbenzylammonium chloride, N-alkyl (Ci4-18) dimethyl-benzylammonium chloride, N-tetradecylmethylbenzylammonium chloride monohydrate, dimethyldidecylammonium chloride, N-alkyl and (C12-i) dimethyl chloride -1-naphthylmethasone, trimethylammonium halide, alkyl trimethylammonium salts, dialkyl-dimethylammonium salts, lauryltrimethylammonium chloride, ethoxylated alkylamidoalkyldialkylammonium salt, an ethoxylated trialkylammonium salt, dialkylbenzenedialkylammonium chloride, N-didecyldimethylammonium chloride, N-tetradecyldimethylbenzylammonium monohydrate, N-alkyl (Ci2-i4) dimethyl-1-naphthylmethylammonium chloride, dodecyldimethylbenzylammonium, dialkylbenzealkylammonium, lauryltrimethylammonium chloride, alkylbenzylmethylammonium chloride, alkylbenzyldimethylammonium bromide, trimethyl ammonium bromides of Ci2) trimethyl ammonium bromide of Ci5, trimethyl ammonium bromides of C17, dodecylbenzyltriethylammonium chloride, poly-diallyldimethylammonium chloride (DADMAC) , dimethylammonium chlorides, alkyldimethylammonium halides, tricetylmethylammonium chloride, decyltrimethylammonium bromide, dodecyltriethylammonium bromide, tetradecyltrimethylammonium bromide, methyltrioctylammonium chloride, POLYQUAT 10 ™, tetrabutylammonium bromide, benzyltrimethylammonium bromide, choline esters, benzalkonium chloride, compounds of stearalkonium chloride, cetylpyridinium bromide, cetylpyridinium chloride, quaternized polyoxyethylalkylamine halide salts, MIRAPOL ™ and ALKAQUAT ™, alkylpyridinium salts; amines, amine salts, amine oxides, imidazolinium salts; protonated quaternary acrylamides; methylated quaternary polymers, and cationic guar.

9. - The composition according to any of claims 1 to 8, further characterized in that it additionally comprises one or more active agents useful for the treatment of persistent painful sensations and pain, and the reduction of fever and related conditions.

10. The composition according to claim 9, further characterized in that one or more active agents are selected from the group consisting of an analgesic selected from the group consisting of morphine, codeine, hydrocodone, oxycodone and combinations thereof.

11. The composition according to claim 10, further characterized in that one or more active agents comprise hydrocodone.

12. The composition according to any of claims 1 to 11, further characterized in that (a) under administration to a mammal the acetaminophen particles or a salt or derivative thereof are redispersed in such a way that the particles have a effective average particle size selected from the group consisting of less than about 2 microns, less than about 1900 nm, less than about 1800 nm, less than about 1700 nm, less than about 1600 nm, less than about 1500 nm, less than about 1400 nm, less than about 1300 nm, less than about 1200 nm, less than about 1100 nm, less than about 1000 nm, less than about 900 nm, less than about 800 nm, less than about 700 nm, less than about 600 nm , less than about 500 nm, less than about 400 nm, less than about 300 nm, less than about 250 nm, less than about 200 nm, less than about 150 nm, less than about 100 nm, less than about 75 nm, and less than about 50 nm; (b) the acetaminophen particles or a salt or derivative thereof are redispersed in a biorelevant medium such that the particles have an effective average particle size selected from the group consisting of less than about 2 microns, less than about 1900 nm , less than about 1800 nm, less than about 1700 nm, less than about 1600 nm, less than about 1500 nm, less than about 1400 nm, less than about 1300 nm, less than about 1200 nm, less than about 1100 nm, less of about 1000 nm, less than about 900 nm, less than about 800 nm, less than about 700 nm, less than about 600 nm, less than about 500 nm, less than about 400 nm, less than about 300 nm, less than about 250 nm, less than about 200 nm, less than about 150 nm, less than about 100 nm, less than about 75 n m, and less than about 50 nm; or (c) a combination of (a) and (b).

13. - The composition according to claim 12, further characterized in that the biorelevant medium is selected from the group consisting of water, aqueous electrolyte solutions, aqueous solutions of a salt, aqueous solutions of an acid, aqueous solutions of a base, and combinations thereof.

14. The composition according to any of claims 1 to 13, further characterized in that: (a) the Tmax of acetaminophen or a salt or derivative thereof, when tested in the plasma of a mammalian subject after administration, is less than Tmax for a non-nanoparticulate composition of the same acetaminophen, administrable at the same dose; (b) the Cmax of acetaminophen or a salt or derivative thereof, when tested in the plasma of a mammalian subject after administration, is greater than C max for a non-nanoparticulate composition of the same acetaminophen, administrable at the same dose; (c) the AUC of acetaminophen or a salt or derivative thereof, when tested in the plasma of a mammalian subject after administration, is greater than the AUC for a non-nanoparticulate composition of the same acetaminophen, administrable at the same dose; or (d) any combination thereof.

15. The composition according to claim 14, further characterized in that: (a) the Tmax is selected from the group consisting of no greater than about 90%, no greater than about 80%, no greater than about 70%, no greater than about 60%, no greater than about 50%, no greater than about 30%, no more than about 25%, no more than about 20%, no more than about 15%, no more than about 10%, and no greater than about 5% of the Tmax presented by a non-nanoparticulate composition of the same acetaminophen, administrable at the same dose; (b) C max is selected from the group consisting of at least about 50%, at least about 100%, at least about 200%, at least about 300%, at least about 400%, at least about 500%, at least about 600%, at least about 700%, at least about 800%, at least about 900%, at least about 1000%, at least about 1100%, at least about 1200%, at least about 1300%, at least about 1400%, at least about 1500%, at least about 1600%, at least about 1700%, at least about 1800%, or at least about 1900% greater than the Cmax presented by a non-nanoparticulate composition of the same acetaminophen, administrable at the same dose; (c) the AUC is selected from the group consisting of at least about 25%, at least about 50%, at least about 75%, at least about 100%, at least about 125%, at least about 150%, at least about 175%, at least about 200%, at least about 225%, at least about 250%, at least about 275%, at least about 300%, at least about 350%, at least about 400%, at least about 450%, at least about 500%, at least about 550%, at least about 600%, by at least about 750%, at least about 700%, at least about 750%, at least about 800%, at least about 850%, at least about 900%, at least about 950%, so less than about 1000%, at least about 1050%, at least about 1 100%, at least about 150%, or at least about 1200% greater than the AUC presented by the non-nanoparticulate formulation of the same etaminophen, administrable at the same dose; or (d) any combination thereof.

16. - The composition according to any of claims 1 to 15, further characterized in that the composition does not produce significantly different absorption levels when it is administrable under fed conditions compared to fasting conditions.

17. - The composition according to claim 16, further characterized in that the difference in absorption of acetaminophen, when it is administrable in the fed state versus the fasted state, is selected from the group consisting of less than about 100%, less than about 90%, less than about 80%, less than about 70%, less than about 60%, less than about 50%, less than about 40%, less than about 30%, less than about 25%, less than about 20 %, less than about 15%, less than about 10%, less than about 5%, and less than about 3%.

18. The composition according to any of claims 1 to 17, further characterized in that the pharmacokinetic profile of the composition is not significantly affected by the fed or fasted state of a subject ingesting the composition.

19. - The composition according to any of claims 1 to 18, further characterized in that the administration of the composition to a human in a fasted state is bioequivalent to the administration of the composition to a subject in a fed state.

20. The composition according to claim 19, further characterized in that "bioequivalence" is established by: (a) a 90% confidence interval of between 0.80 and 1.25 for both Cm¾x and AUC; or (b) a 90% confidence interval between 0.80 and 1.25 for AUC and a 90% confidence interval between 0.70 to 1.43 for C max.

21. The use of a composition of any of claims 1 to 20 for the manufacture of a medicament useful for the treatment of persistent painful sensations and pain and for the reduction of fever and related conditions.

22. The use as claimed in claim 21, wherein the medicament further comprises one or more active agents selected from the group consisting of a narcotic analgesic selected from the group consisting of morphine, codeine, hydrocodone, oxycodone and combinations thereof. same.

23. - A method for preparing a composition comprising acetaminophen in nanoparticles or a salt or derivative thereof, comprising contacting acetaminophen particles or a salt or derivative thereof with at least one surface stabilizer for a while and under conditions sufficient to provide an acetaminophen composition having an effective average particle size of less than about 2000 nm.

24. The method according to claim 23, further characterized in that the contact comprises grinding, wet grinding, homogenization, mold emulsion, precipitation, freezing or a combination thereof.

25. The method according to claim 23 or claim 24, further characterized in that the effective average particle size of the acetaminophen particles is selected from the group consisting of less than about 1900 nm, less than about 1800 nm, less of about 1700 nm, less than about 1600 nm, less than about 1500 nm, less than about 1000 nm, less than about 1400 nm, less than about 1300 nm, less than about 1200 nm, less than about 1100 nm, less than about 900 nm, less than about 800 nm, less than about 700 nm, less than about 600 nm, less than about 500 nm, less than about 400 nm, less than about 300 nm, less than about 250 nm, less than about 200 nm , less than about 100 nm, less than about 75 nm, and less than about 50 nm.