EP2032137A2 - Zusammensetzungen mit nanoteilchen-naproxen und kontrolliert freigesetztes hydrocodon - Google Patents

Zusammensetzungen mit nanoteilchen-naproxen und kontrolliert freigesetztes hydrocodon

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Publication number
EP2032137A2
EP2032137A2 EP07799011A EP07799011A EP2032137A2 EP 2032137 A2 EP2032137 A2 EP 2032137A2 EP 07799011 A EP07799011 A EP 07799011A EP 07799011 A EP07799011 A EP 07799011A EP 2032137 A2 EP2032137 A2 EP 2032137A2
Authority
EP
European Patent Office
Prior art keywords
hydrocodone
composition
naproxen
release
modified release
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP07799011A
Other languages
English (en)
French (fr)
Inventor
Paul Stark
John Devane
Niall Fanning
Gary Liversidge
Scott Jenkins
Gurvinder Singh-Rekhi
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Elan Pharma International Ltd
Original Assignee
Elan Pharma International Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Elan Pharma International Ltd filed Critical Elan Pharma International Ltd
Publication of EP2032137A2 publication Critical patent/EP2032137A2/de
Withdrawn legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/485—Morphinan derivatives, e.g. morphine, codeine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
    • A61K9/2081—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets with microcapsules or coated microparticles according to A61K9/50
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5073—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings
    • A61K9/5078—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings with drug-free core
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/14—Antitussive agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to compositions comprising nanoparticulate naproxen, or a salt or derivative thereof, in combination with a multiparticulate modified release composition comprising hydrocodone, or a salt or derivative thereof.
  • the present invention relates to compositions comprising nanoparticulate naproxen, or a salt or derivative thereof, in combination with a multiparticulate modified release composition that in operation delivers hydrocodone, or a salt or derivative thereof, in a bimodal or multimodal manner.
  • the present invention further relates to solid oral dosage forms comprising such multiparticulate controlled release compositions as well as methods for delivering such compositions to a patient in need thereof.
  • the effectiveness of pharmaceutical compounds in the prevention and treatment of disease states depends on a variety of factors including the rate and duration of delivery of the compound from the dosage form to the patient.
  • the combination of delivery rate and duration exhibited by a given dosage form in a patient can be described as its in vivo release profile and, depending on the pharmaceutical compound administered, will be associated with a concentration and duration of the pharmaceutical compound in the blood plasma, referred to as a plasma profile.
  • a plasma profile concentration and duration of the pharmaceutical compound in the blood plasma
  • the release profiles of dosage forms may exhibit different rates and durations of release and may be continuous or pulsatile.
  • Continuous release profiles include release profiles in which one or more pharmaceutical compounds are released continuously, either at a constant or variable rate
  • pulsatile release profiles include release profiles in which at least two discrete quantities of one or more pharmaceutical compounds are released at different rates and/or over different time frames.
  • the release profile for a given dosage form gives rise to an associated plasma profile in a patient.
  • the associated plasma profile in a patient may exhibit constant or variable blood plasma concentration levels of the pharmaceutical compounds in the dosage form over the duration of action and may be continuous or pulsatile.
  • Continuous plasma profiles include plasma profiles of all rates and duration which exhibit a single plasma concentration maximum.
  • Pulsatile plasma profiles include plasma profiles in which at least two higher blood plasma concentration levels of pharmaceutical compound are separated by a lower blood plasma concentration level. Pulsatile plasma profiles exhibiting two peaks may be described as "bimodal."
  • the release profile of the dosage form as a whole is a combination of the individual release profiles.
  • the release profile of a two-component dosage form in which each component has a different release profile may described as "bimodal.”
  • the resultant release profile of the dosage form may be described as "multimodal.”
  • a bimodal or multimodal release profile may result in either a continuous or a pulsatile plasma profile in a patient.
  • modified release compositions or formulations which substantially mimic the release of frequent IR dosage regimes, while reducing the need for frequent dosing, is desirable.
  • modified release compositions or formulations which combine the benefits of at least two different release profiles to achieve a resultant plasma profile exhibiting phatinacokinetic values within therapeutically effective parameters is also desirable.
  • Giunchedi et al. Int. J. Pharm (1991) 77:177-181 discloses the use of a hydrophilic matrix multiple-unit formulation for the pulsed release of ketoprofen.
  • Giunchedi et al. teach that ketoprofen is rapidly eliminated from the blood after dosing (plasma half- life 1-3 hours) and consecutive pulses of drug may be more beneficial than constant release for some treatments.
  • the multiple-unit formulation disclosed comprises four identical hydrophilic matrix tablets placed in a gelatin capsule. Although the in vivo studies show two peaks in the plasma profile there is no well defined wash out period and the variation between the peak and trough plasma levels is small. Conte et al., Drug Dev. Ind.
  • the three layer tablet is made up of a first layer containing the active ingredient, a barrier layer (the second layer) of semi-permeable material which is interposed between the first layer and a third layer containing an additional amount of active ingredient.
  • the barrier layer and the third layer are housed in an impermeable casing.
  • the first layer dissolves upon contact with a dissolving fluid while the third layer is only available after dissolution or rupture of the barrier layer. In such a tablet the first portion of active ingredient must be released instantly.
  • This approach also requires the provision of a semi-permeable layer between the first and third layers in order to control the relative rates of delivery of the two portions of active ingredient. Additionally, rupture of the semi-permeable layer leads to uncontrolled dumping of the second portion of the active ingredient which may not be desirable.
  • U.S. Pat. No. 5,158,777 discloses a formulation comprising captopril within an enteric or delayed release coated pH stable core combined with additional captopril which is available for immediate release following administration.
  • chelating agents such as disodium edetate or surfactants such as polysorbate 80 are used either alone or in combination with a buffering agent.
  • the compositions have an amount of captopril available for immediate release following oral administration and an additional amount of pH stabilized captopril available for release in the colon.
  • U.S. Pat. Nos. 4,728,512, 4,794,001 and 4,904,476 relate to preparations providing three distinct releases.
  • the preparation contains three groups of spheroids containing an active medicinal substance: the first group of spheroids is uncoated and rapidly disintegrates upon ingestion to release an initial dose of medicinal substance; the second group of spheroids is coated with a pH sensitive coat to provide a second dose; and the third group of spheroids is coated with a pH independent coat to provide to third dose.
  • the preparation is designed to provide repeated release of medicinal substances which are extensively metabolized presystemically or have relatively short elimination half-lives.
  • U.S. Pat. No. 5,837,284 discloses a methylphenidate dosage form having immediate release and delayed release particles.
  • the delayed release is provided by the use of ammonio methacrylate pH independent polymers combined with certain fillers.
  • hydrocodone A typical example of a drug which may produce tolerance in patients is hydrocodone.
  • Hydrocodone or dihydrocodeinone (marketed as Vicodin®, Anexsia®, Dicodid®, Hycodan®, Hycomine®, Lorcet®, Lortab®, Norco®, Hydroco®, Tussionex®, and Vicoprofen®), also known as 4,5a-Epoxy-3-methoxy-17-methylmorphinan-6-one tartrate (1:1) hydrate (2:5), is an opiod derived from either of the naturally occurring opiates codeine or thebaine.
  • the compound has the following structure:
  • Hydrocodone has the chemical formula C 18 H 21 No 3 , a molecular weight of 299.368, and a half life of 4-8 hours. Hydrocodone is an orally active narcotic analgesic and antitussive. Sales and production of this drug have increased significantly in recent years, as have diversion and illicit use. Hydrocodone is commonly available in tablet, capsule and syrup form.
  • hydrocodone relieves pain by binding to opioid receptors in the brain and spinal cord. It may be taken with or without food. When taken with alcohol, it can intensify drowsiness. It may interact with monoamine oxidase inhibitors, as well as other drugs that cause drowsiness. Common side effects include dizziness, lightheadedness, nausea, drowsiness, euphoria, vomiting, and constipation. Some less common side effects are allergic reaction, blood disorders, changes in mood, mental fogginess, anxiety, lethargy, difficulty urinating, spasm of the ureter, irregular or depressed respiration and rash.
  • Hydrocodone can be habit-forming , and can lead to physical and psychological addiction. In the U.S., pure hydrocodone and forms containing more than 15 mg per dosage unit are considered Schedule II drugs. Those containing less than or equal to 15 mg per dosage unit in combination with acetaminophen or another non-controlled drug are called Hydrocodone Compounds and are considered Schedule III drugs. Hydrocodone can be found in combination with other drugs such as paracetamol (acetaminophen), aspirin, ibuprofen and homatropine methylbromide.
  • other drugs such as paracetamol (acetaminophen), aspirin, ibuprofen and homatropine methylbromide.
  • acetaminophen in hydrocodone-containing products deters many drug users from taking excessive amounts. However, some users will get around this by extracting a portion of the acetaminophen using hot/cold water, taking advantage of the water-soluble element of the drug. It is not uncommon for addicts to have liver problems from consuming excessive amounts of acetaminophen over a long period of time; taking 10,000 to 15,000 miligrams of acetaminophen in a period of 24 hours typically results in severe hepatoxicity, and doses in the range of 15,000-20,0000 miligrams a day have been reported as fatal. It is this factor that leads many addicts to use only single entity opiates such as Oxycontin.
  • hydrocodone overdosage Some specially compounded products are routinely given to chronic pain patients in doses of up to 180 mg of hydrocodone per day. Tolerance to this drug can increase very rapidly if abused. Because of this, addicts often overdose from taking handfiills of pills, in pursuit of the high they experienced very early on in their hydrocodone use. Symptoms of hydrocodone overdosage include respiratory depression, extreme somnolence, coma, stupor, cold and/or clammy skin, sometimes bradycardia, and hypotension. A severe overdose may involve circulatory collapse, cardiac arrest and/or death.
  • Naproxen which is highly water insoluble, i.e., less than 10 mg/ml, has the following chemical structure:
  • Naproxen is a non-steroidal anti-inflammatory drug (NSAID) often used to relieve the inflammation, swelling, stiffness, and joint pain associated with rheumatoid arthritis, osteoarthritis (the most common form of arthritis), juvenile arthritis, ankylosing spondylitis (spinal arthritis), tendinitis, bursitis, and acute gout. In addition, it is used to treat pain associated with menstrual periods, migraine headaches, and other types of mild to moderate pain.
  • NSAID non-steroidal anti-inflammatory drug
  • Naproxen acts by suppressing the production of prostaglandins, which are hormone-like substances that act on local tissues to produce pain and inflammation.
  • Its pharmaceutical forms of delivery include tablets, capsules, and liquids. Delivery characteristics and forms are disclosed in, for example, U.S. Patent Nos. 3,904,682; 4,009,197; 4,780,320; 4,888,178; 4,919,939; 4,940,588; 4,952,402; 5,200,193; 5,354,556; 5,462,747; and 5,480,650, all of which are specifically incorporated by reference.
  • the synthesis of naproxen is described in U.S. Patent Nos. 3,904,682 and 4,009,197.
  • Naproxen is a more potent pain reliever than aspirin, especially for menstrual cramps, toothaches, minor arthritis, and injuries accompanied by inflammation, such as tendinitis.
  • the naproxen sodium salt is specifically indicated in the treatment of various types of acute and very high intensity pain because it induces a rapid and sustained remission.
  • naproxen Because of naproxen's low solubility, it is generally formulated for oral administration. However, oral administration of naproxen frequently results in gastrointestinal irritation. All NSAIDs produce gastrointestinal symptoms to some degree upon oral administration. Such symptoms most commonly are constipation, gastric burns, diarrhea, stomatitis, dyspepsia, nausea, vomiting, upper abdominal pain, and heartburn. Oral administration may also lead to an ulcer or bleeding from the stomach or duodenum.
  • Gastrointestinal irritation resulting from oral administration of an NSAID can be significant.
  • Numerous literature articles detail the severity of gastric irritation caused by NSAID compositions. For example, one report states that between 10,000 and 20,000 people in Canada each year are hospitalized with major gastro-intestinal bleeding caused by oral ingestion of NSAIDs, with effects resulting in death for at least 1,000 of these patients. See Marketplace, October 24, 1996. Yet another reference states that gastrointestinal complications of NSAID use may be responsible for over 10,000 deaths each year. See American Family Physician, March 1997. D. Background Regarding Nanoparticulate Active Agent Compositions
  • Nanoparticulate active agent compositions are particles consisting of a poorly soluble therapeutic or diagnostic agent having adsorbed onto or associated with the surface thereof a non-crosslinked surface stabilizer. Methods of making nanoparticulate active agent compositions are described in, for example, U.S. Patent Nos. 5,518,187 and 5,862,999, both for "Method of Grinding
  • Nanoparticulate active agent compositions are also described, for example, in U.S. Patent Nos. 5,298,262 for "Use of Ionic Cloud Point Modifiers to Prevent Particle Aggregation During Sterilization;" 5,302,401 for “Method to Reduce Particle Size Growth During Lyophilization;” 5,318,767 for “X-Ray Contrast Compositions Useful in Medical Imaging;” 5,326,552 for “Novel Formulation For Nanoparticulate X-Ray Blood Pool Contrast Agents Using High Molecular Weight Non-ionic Surfactants;” 5,328,404 for “Method of X-Ray Imaging Using Iodinated Aromatic Propanedioates;” 5,336,507 for “Use of Charged Phospholipids to Reduce Nanoparticle Aggregation;” 5,340,564 for “Formulations Comprising Olin 10-G to Prevent Particle Aggregation and Increase Stability;” 5,346,702 for "Use of Non-Ionic Cloud
  • Patent Publication No. 20040156895 for "Solid dosage forms comprising pullulan;" U.S. Patent Publication No. U.S. Patent Publication No. U.S. Patent Publication No. 20040156872 for "Novel nimesulide compositions;” U.S. Patent Publication No. 20040141925 for "Novel triamcinolone compositions;” U.S. Patent Publication No. 20040115134 for "Novel nifedipine compositions;” U.S. Patent Publication No. 20040105889 for "Low viscosity liquid dosage forms;” U.S. Patent Publication No. 20040105778 for "Gamma irradiation of solid nanoparticulate active agents;” U.S.
  • Patent Publication No. 20040101566 for "Novel benzoyl peroxide compositions;” U.S. Patent Publication No. 20040057905 for “Nanoparticulate beclomethasone dipropionate compositions;” U.S. Patent Publication No. 20040033267 for "Nanoparticulate compositions of angiogenesis inhibitors;” U.S. Patent Publication No. 20040033202 for “Nanoparticulate sterol formulations and novel sterol combinations;” U.S. Patent Publication No. 20040018242 for "Nanoparticulate nystatin formulations;” U.S. Patent Publication No. 20040015134 for "Drug delivery systems and methods;” U.S. Patent Publication No.
  • Another object of the invention is to provide a composition comprising nanoparticulate naproxen, or a salt or derivative thereof, in combination with a controlled release hydrocodone composition in which a first portion of the composition, i.e., a hydrocodone or a salt or derivative thereof, is released immediately upon administration and a second portion of the hydrocodone, or a salt or derivative thereof, is released rapidly after an initial delay period in a bimodal manner.
  • a first portion of the composition i.e., a hydrocodone or a salt or derivative thereof
  • Conventional frequent dosage regimes in which an immediate release (IR) dosage form is administered at periodic intervals typically gives rise to a pulsatile plasma profile.
  • the present invention further relates to a composition comprising nanoparticulate naproxen, or a salt or derivative thereof, in combination with a controlled release composition comprising hydrocodone, or a salt or derivative thereof, which in operation produced a hydrocodone plasma profile that eliminates the "peaks" and “troughs” produced by the administration of two or more IR dosage forms given sequentially if such a profile is beneficial.
  • This type of profile can be obtained using a controlled release mechanism that allows for "zero- order" delivery.
  • compositions comprising nanoparticulate naproxen, or a salt or derivative thereof, in combination with a controlled release hydrocodone composition which in operation delivers hydrocodone, or a salt or derivative thereof, in a pulsatile manner or a zero-order manner.
  • Multiparticulate modified controlled release compositions similar to those disclosed herein are disclosed and claimed in the United States Patent Nos. 6,228,398 and 6,730,325 to Devane et al; both of which are incorporated by reference herein. All of the relevant prior art in this field may also be found therein.
  • Another object of the invention is to provide a composition comprising nanoparticulate naproxen, or a salt or derivative thereof, in combination with a controlled release composition which substantially reduces or eliminates the development of patient tolerance to hydrocodone, or a salt or derivative thereof.
  • Another object of the invention is to formulate the dosage in the form of erodable formulations, diffusion controlled formulations, or osmotic controlled formulations.
  • Another object of the invention is to provide a controlled release composition capable of releasing a hydrocodone or a nanoparticulate naproxen in a bimodal or multi-modal manner in which a first portion of the active is released either immediately or after a delay time to provide a pulse of drug release and one or more additional portions of the hydrocodone or a nanoparticulate naproxen is released, after a respective lag time, to provide additional pulses of drug release during a period of up to twenty- four hours.
  • compositions comprising nanoparticulate naproxen, or a salt or derivative thereof, in combination with a multiparticulate modified release composition comprising at least two populations of hydrocodone-comprising particles in which the amount of the one or more active ingredients in the first population of particles is a minor portion of the amount of the one or more active ingredients in the composition, and the amount of the one or more active ingredients in the one or more additional population of particles is a major portion of the amount of the one or more active ingredients in the composition.
  • a solid dosage form comprising the composition comprising nanoparticulate naproxen, or a salt or derivative thereof, in combination with the multiparticulate modified release composition of the present invention.
  • a preferred dosage form of the invention is a solid oral dosage form, although any pharmaceutically acceptable dosage form can be utilized.
  • compositions comprising a composition according to the invention and a pharmaceutically acceptable carrier, as well as any one or more of a number of desired excipients.
  • One embodiment of the invention encompasses a composition comprising nanoparticulate naproxen, or a salt or derivative thereof, in combination with a multiparticulate modified release composition comprising at least two populations of hydrocodone-comprising particles, wherein the pharmacokinetic profile of the nanoparticulate naproxen, or a salt or derivative thereof, is not affected by the fed or fasted state of a subject ingesting the naproxen composition.
  • the invention encompasses a composition comprising nanoparticulate naproxen, or a salt or derivative thereof, in combination with a multiparticulate modified release composition comprising at least two populations of hydrocodone-comprising particles, wherein administration of the nanoparticulate naproxen to a subject in a fasted state is bioequivalent to administration of the nanoparticulate naproxen to a subject in a fed state.
  • the nanoparticulate naproxen particles have an effective average particle size of less than about 2000 nm, and preferable also comprise at least one surface stabilizer adsorbed on or are associated with the surface of the naproxen particles.
  • This invention further discloses a method of making the nanoparticulate naproxen compositions.
  • Such a method comprises contacting the naproxen particles with at least one surface stabilizer for a time and under conditions to reduce the effective average particle size of the naproxen particles to less than about 2000 nm.
  • the present invention is also directed to methods of treatment including but not limited to, the treatment of pain, comprising administering a dosage form comprising a therapeutically effective amount of the composition of the invention to provide bimodal or multimodal release of the hydrocodone comprised therein.
  • a once daily dosage form of a hydrocodone and a nanoparticulate naproxen which, in operation, produces a plasma profile substantially similar to the plasma profile produced by the administration of two immediate release hydrocodone dosage forms given sequentially and a method for prevention and treatment of pain conditions based on the administration of such a dosage form.
  • compositions comprising a nanoparticulate naproxen, or a salt or derivative thereof, in combination with a controlled release composition having a first component comprising a first population of hydrocodone particles, and a second component or formulation comprising a second population of hydrocodone particles.
  • the hydrocodone- comprising particles of the second component further comprise a modified release constituent comprising a release coating or release matrix material, or both.
  • the composition in operation delivers a hydrocodone in a pulsatile or zero order manner.
  • the compositions of the invention delivers a hydrocodone in a pulsatile or zero order manner during a period of up to twenty- four hours.
  • the present invention utilizes controlled release delivery of hydrocodone, or a salt or derivative thereof, from a solid oral dosage formulation to allow dosage less frequently than before, and preferably once-a-day administration, increasing patient convenience and compliance.
  • the mechanism of controlled release would preferably utilize, but not be limited to, erodable formulations, diffusion controlled formulations and osmotic controlled formulations. A portion of the total dose may be released immediately to allow for rapid onset of effect.
  • the invention would be useful in improving compliance and, therefore, therapeutic outcome for all treatments requiring a hydrocodone, including but not limited to, the treatment of pain conditions.
  • Preferred controlled release formulations are erodable formulations, diffusion controlled formulations and osmotic controlled formulations.
  • a portion of the total dose may be released immediately to allow for rapid onset of effect, with the remaining portion of the total dose released over an extended time period.
  • the invention would be useful in improving compliance and, therefore, therapeutic outcome for all treatments requiring a hydrocodone.
  • FIG. 1 shows single dose simulations of 10 mg hydrocodone formulations in which 20% of the hydrocodone is contained in the IR component.
  • FIG. 2 shows single dose simulations of 10 mg hydrocodone formulations in which 20% of the hydrocodone is contained in the IR component.
  • FIG. 3 shows steady state simulations of 10 mg hydrocodone formulations in which 20% of the hydrocodone is contained in the IR component.
  • FIG. 4 shows steady state simulations of 10 mg hydrocodone formulations in which 20% of the hydrocodone is contained in the IR component.
  • FIG. 5 shows single dose simulations of 10 mg hydrocodone formulations in which 50% of the hydrocodone is contained in the IR component.
  • FIG. 6 shows single dose simulations of 10 mg hydrocodone formulations in which 50% of the hydrocodone is contained in the IR component.
  • FIG. 7 shows steady state simulations of 10 mg hydrocodone formulations in which 50% of the hydrocodone is contained in the IR component.
  • FIG. 8 shows steady state simulations of 10 mg hydrocodone formulations in which 50% of the hydrocodone is contained in the IR component.
  • FIG. 9 shows single dose simulations of 20-160 mg/day hydrocodone formulations (Option 1) in which 20% of the hydrocodone is contained in the IR component.
  • FIG. 10 shows steady state simulations of 20-160 mg/day hydrocodone formulations (Option 1) in which 20% of the hydrocodone is contained in the IR component.
  • FIG. 11 shows single dose simulations of 20-80 mg BID hydrocodone formulations (Option 3) in which 20% of the hydrocodone is contained in the IR component.
  • FIG. 12 shows steady state simulations of 20-80 mg BID hydrocodone formulations (Option 3) in which 20% of the hydrocodone is contained in the IR component.
  • FIG. 13 shows single dose simulations of 20-160 mg/day hydrocodone formulations (Option 1) in which 50% of the hydrocodone is contained in the IR component.
  • FIG. 14 shows steady state simulations of 20-160 mg/day hydrocodone formulations (Option 1) in which 50% of the hydrocodone is contained in the IR component.
  • FIG. 15 shows single dose simulations of 20-160 mg/day hydrocodone formulations
  • FIG. 16 shows steady state simulations of 20-160 mg/day hydrocodone formulations (Option 3) in which 50% of the hydrocodone is contained in the IR component.
  • compositions of the invention comprise (a) a composition comprising a nanoparticulate naproxen, or a salt or derivative thereof, and at least one surface stabilizer; and (b) an oral controlled release composition of a hydrocodone, or a salt or derivative thereof.
  • non-controlled release nanoparticulate naproxen compositoin in combination with the controlled release hydrocodone is at least twofold: (1) to provide increased analgesia via drug synergy; and (2) to limit the intake of hydrocodone by causing unpleasant and often unsafe side effects at higher than prescribed doses.
  • the present invention provides a method of treating a patient needing pain relief utilizing a composition according to the invention.
  • the method comprises administering a therapeutically effective amount of a dosage form, such as a solid oral dosage form, comprising a nanoparticulate naproxen composition in combination with a controlled release hydrocodone composition, to provide a pulsed or bimodal or zero order delivery of the hydrocodone.
  • Advantages of the present invention include reducing the dosing frequency required by conventional multiple IR dosage regimes while still maintaining the benefits derived from a pulsatile plasma profile or eliminating or minimizing the "peak" to "trough” ratio. This reduced dosing frequency is advantageous in terms of patient compliance to have a formulation which may be administered at reduced frequency.
  • the reduction in dosage frequency made possible by utilizing the present invention would contribute to reducing health care costs by reducing the amount of time spent by health care workers on the administration of drugs.
  • the nanoparticulate naproxen composition in accordance with standard pharmacokinetic practice, has a bioavailability that is about 100% greater, about 90% greater, about 80% greater, about 70% greater, about 60% greater, about 50% greater, about 40% greater, about 30% greater, about 20% greater, or about 10% greater than a conventional non-nanoparticulate naproxen dosage form.
  • compositions of the invention can be administered to a subject via any conventional means including, but not limited to, orally, rectally, ocularly, parenterally (e.g., intravenous, intramuscular, or subcutaneous), intracisternally, pulmonary, intravaginally, intraperitoneally, locally (e.g., powders, ointments or drops), or as a buccal or nasal spray.
  • parenterally e.g., intravenous, intramuscular, or subcutaneous
  • intracisternally e.g., intravenous, intramuscular, or subcutaneous
  • pulmonary e.g., intravaginally
  • intraperitoneally e.g., powders, ointments or drops
  • buccal or nasal spray e.g., a buccal or nasal spray.
  • subject is used to mean an animal, preferably a mammal, including a human or non-human.
  • patient and subject may be used interchangeably.
  • compositions suitable for parenteral injection may comprise physiologically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions.
  • suitable aqueous and nonaqueous carriers, diluents, solvents, or vehicles including water, ethanol, polyols (propyleneglycol, polyethylene-glycol, glycerol, and the like), suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate.
  • Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
  • compositions may also contain adjuvants such as preserving, wetting, emulsifying, and dispensing agents. Prevention of the growth of microorganisms can be ensured by various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like. Prolonged absorption of the injectable pharmaceutical form can be brought about by the use of agents delaying absorption, such as aluminum monostearate and gelatin.
  • Solid dosage forms for oral administration include, but are not limited to, capsules, tablets, pills, powders, and granules.
  • the active agents are admixed with at least one of the following: (a) one or more inert excipients (or carriers), such as sodium citrate or dicalcium phosphate; (b) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and silicic acid; (c) binders, such as carboxymethylcellulose, alignates, gelatin, polyvinylpyrrolidone, sucrose, and acacia; (d) humectants, such as glycerol; (e) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (f) solution retarders, such as paraffin; (g) absorption accelerators, such as quaternary ammonium compounds; (
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs.
  • the liquid dosage forms may comprise inert diluents commonly used in the art, such as water or other solvents, solubilizing agents, and emulsifiers.
  • Exemplary emulsifiers are ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butyleneglycol, dimethylformamide, oils, such as cottonseed oil, groundnut oil, corn germ oil, olive oil, castor oil, and sesame oil, glycerol, tetrahydrofurfuryl alcohol, polyethyleneglycols, fatty acid esters of sorbitan, or mixtures of these substances, and the like.
  • oils such as cottonseed oil, groundnut oil, corn germ oil, olive oil, castor oil, and sesame oil
  • glycerol tetrahydrofurfuryl alcohol
  • polyethyleneglycols fatty acid esters of sorbitan, or mixtures of these substances, and the like.
  • the composition can also include adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • naproxen and hydrocodone dosages are, in particular instances, measured as oral dosages, or with reference to drug levels as measured in blood.
  • effective amounts of a naproxen and a hydrocodone can be determined empirically and can be employed in pure form or, where such forms exist, in pharmaceutically acceptable salt, ester, or prodrug form.
  • Actual dosage levels of a naproxen and a hydrocodone in the compositions of the invention may be varied to obtain an amount of a naproxen and a hydrocodone that is effective to obtain a desired therapeutic response for a particular composition and method of administration.
  • the selected dosage lever therefore depends upon the desired therapeutic effect, the route of administration, the potency of the administered naproxen, the desired duration of treatment, and other factors.
  • Dosage unit compositions may contain such amounts of such submultiples thereof as may be used to make up the daily dose. It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors: the type and degree of the cellular or physiological response to be achieved; activity of the specific agent or composition employed; the specific agents or composition employed; the age, body weight, general health, sex, and diet of the patient; the time of administration, route of administration, and rate of excretion of the agent; the duration of the treatment; drugs used in combination or coincidental with the specific agent; and like factors well known in the medical arts.
  • Enhancers refers to a compound which is capable of enhancing the absorption and/or bioavailability of an active ingredient by promoting net transport across the gastrointestinal tract (GIT) in an animal, such as a human.
  • Enhancers include but are not limited to medium chain fatty acids and salts, esters, ethers and derivatives thereof, including glycerides and triglycerides; non-ionic surfactants such as those that can be prepared by reacting ethylene oxide with a fatty acid, a fatty alcohol, an alkylphenol or a sorbitan or glycerol fatty acid ester; cytochrome P450 inhibitors, P-glycoprotein inhibitors and the like; and mixtures thereof.
  • pill refers to a state of matter which is characterized by the presence of discrete particles, pellets, beads or granules irrespective of their size, shape or morphology.
  • multiparticulate as used herein means a plurality of discrete or aggregated particles, pellets, beads, granules or mixture thereof, irrespective of their size, shape or morphology.
  • modified release as used herein with respect to the coating or coating material or used in any other context, means release which is not immediate release and is taken to encompass controlled release, sustained release and delayed release.
  • time delay refers to the duration of time between administration of the composition and the release of the hydrocodone from a particular component.
  • lag time refers to the time between delivery of the hydrocodone from one component and the subsequent delivery hydrocodone from another component.
  • electrode refers to formulations which may be worn away, diminished, or deteriorated by the action of substances within the body.
  • diffusion controlled refers to formulations which may spread as the result of their spontaneous movement, for example, from a region of higher to one of lower concentration.
  • osmotic controlled refers to formulations which may spread as the result of their movement through a semipermeable membrane into a solution of higher concentration that tends to equalize the concentrations of the formulation on the two sides of the membrane.
  • composition according to the invention comprises at least two populations of hydrocodone, or a salt or derivative thereof, comprising particles which have different in vitro dissolution profiles.
  • the multiparticulate modified release composition and dosage forms made therefrom comprise at least two hydrocodone-comprising components.
  • the release of the hydrocodone, or a salt or derivative thereof, from the second and subsequent components, if any, is modified such that there is a lag time between the release of hydrocodone, or a salt or derivative thereof, from the first component and each subsequent component.
  • the number of pulses in the release profile arising from such a composition in operation will depend on the number of hydrocodone-comprising components in the composition.
  • a composition comprising two hydrocodone-comprising components will give rise to two pulses in the release profile, and a composition comprising three hydrocodone-comprising components will give rise to up to three pulses in the release profile.
  • the release of the active ingredients from subsequent components is modified such that the release of hydrocodone from the first component and each subsequent component begins substantially upon administration but over different periods of time and/or at different rates.
  • a controlled release composition can have a first component comprising a first population of a hydrocodone, or a salt or derivative thereof, and a second component comprising a second population of a hydrocodone, or a salt or derivative thereof.
  • the hydrocodone-comprising particles of the second component are coated with a modified release coating.
  • the second population of hydrocodone-comprising particles further comprises a modified release matrix material.
  • the composition in operation delivers the hydrocodone, or a salt or derivative thereof, in a pulsatile or zero order manner.
  • the controlled release composition comprising hydrocodone, or a salt or derivative thereof, in operation delivers the hydrocodone in a bimodal or pulsatile or zero order manner.
  • a composition in operation produces a plasma profile which substantially mimics that obtained by the sequential administration of two IR hydrocodone doses.
  • the present invention further relates to a controlled release composition
  • a controlled release composition comprising a hydrocodone, or a salt or derivative thereof, which in operation produced a plasma profile that eliminates or minimizes the "peaks" and “troughs” produced by the administration of two or more IR dosage forms given sequentially if such a profile is beneficial.
  • This type of profile can be obtained using a controlled release mechanism that allows for "zero-order" delivery.
  • the invention provides solid oral dosage forms comprising a composition according to the invention.
  • the time release characteristics for the delivery of the hydrocodone, or a salt or derivative thereof, from each of the components may be varied by modifying the composition of each component, including modifying any of the excipients or coatings which may be present.
  • the release of the hydrocodone, or a salt or derivative thereof may be controlled by changing the composition and/or the amount of the modified release coating on the particles, if such a coating is present. If more than one modified release component is present, the modified release coating for each of these components may be the same or different. Similarly, when modified release is facilitated by the inclusion of a modified release matrix material, release of the hydrocodone, or a salt or derivative thereof, may be controlled by the choice and amount of modified release matrix material utilized.
  • the modified release coating may be present, in each component, in any amount that is sufficient to yield the desired delay time for each particular component.
  • the modified release coating may be preset, in each component, in any amount that is sufficient to yield the desired time lag between components.
  • the lag time or delay time for the release of the hydrocodone, or a salt or derivative thereof, from each component may also be varied by modifying the composition of each of the components, including modifying any excipients and coatings which may be present.
  • the first component may be an immediate release component wherein the hydrocodone, or a salt or derivative thereof, is released immediately upon administration.
  • the first component may be, for example, a time-delayed immediate release component in which the hydrocodone, or a salt or derivative thereof, is released substantially in its entirety immediately after a time delay.
  • the second component may be, for example, a time-delayed immediate release component as just described or, alternatively, a time-delayed sustained release or extended release component in which the hydrocodone, or a salt or derivative thereof, is released in a controlled fashion over an extended period of time.
  • suitable hydrocodones also include all pharmaceutically acceptable salts, acids, esters, complexes or other derivatives of hydrocodone, and may be present either in the form of one enantiomer or as a mixture, racemic or otherwise, of enantiomers.
  • the hydrocodone in each component may be the same or different.
  • the first component comprises a first hydrocodone, or a salt or derivative thereof
  • the second component comprises a second hydrocodone, or a salt or derivative thereof.
  • two or more hydrocodones may be incorporated into one or more components.
  • a hydrocodone present in one component of the composition may be accompanied by, for example, an enhancer compound or a sensitizer compound in another component of the composition, to modify the bioavailability or therapeutic effect of the hydrocodone.
  • the amount of the hydrocodone comprised in the composition and in dosage forms made threfrom may be allocated evenly or unevenly across the different particle populations comprising the components of the composition and comprised in the dosage forms made therefrom.
  • the hydrocodone, or a salt or derivative thereof, comprised in the particles of the first component comprises a minor portion of the total amount of hydrocodone, or a salt or derivative thereof, in the composition or dosage form, and the amount of the hydrocodone, or a salt or derivative thereof, in the other components comprises a major portion of the total amount of hydrocodone, or a salt or derivative thereof, in the composition or dosage form.
  • about 20% of the total amount of the hydrocodone, or a salt or derivative thereof, is comprised in the particles of the first component, and about 80% of the total amount of the hydrocodone, or a salt or derivative thereof, is comprised in the particles of the second component.
  • the hydrocodone, or a salt or derivative thereof is preferably present in the composition and in dosage forms made therefrom in an amount of from about 0.1 to about 1000 mg, from about 1 to about 160 mg, or from about 5 to about 80 mg.
  • the hydrocodone, or a salt or derivative thereof is present in an amount of from about 5 to about 80 mg, about 5 to about 60 mg, about 5 to about 40 mg, about 5 to about 20 mg, about 5 to about 10 mg, about 10 to about 80 mg, about 10 to about 60 mg, about 10 to about 40 mg, about 10 to about 20 mg, about 20 to about 80 mg, about 20 to about 60 mg, about 20 to about 40 mg, about 40 to about 80 mg, about 40 to about 60 mg, or about 60 to about 80 mg.
  • the active ingredient is hydrocodone, it is preferably present in the composition and in dosage forms made therefrom in an amount of from about 5 to about 160 mg; more preferably the active ingredient is present in the first component in an amount of from about 10 to about 80 mg.
  • the profile for the release of the hydrocodone, or a salt or derivative thereof, from each component of the composition may be varied by modifying the composition of each component, including modifying any of the excipients or coatings which may be present.
  • the release of the hydrocodone, or a salt or derivative thereof may be controlled by the choice and amount of the modified release coating applied to the particles where such a coating is present. If more than one modified release component is present, the modified release coating for each of these components may be the same or different.
  • release of the hydrocodone, or a salt or derivative thereof may be controlled by the choice and amount of modified release matrix material utilized.
  • the modified release coating applied to the second population of a hydrocodone, or a salt or derivative thereof causes a lag time between the release of active from the first population of active hydrocodone-comprising particles and the release of active from the second population of hydrocodone-comprising particles.
  • the presence of a modified release matrix material in the second population of hydrocodone-comprising particles causes a lag time between the release of hydrocodone from the first population of hydrocodonecomprising particles and the release of hydrocodone, or a salt or derivative thereof, from the second population of hydrocodone-comprising particles.
  • the duration of the lag time may be varied by altering the composition and/or the amount of the modified release coating and/or altering the composition and/or amount of modified release matrix material utilized.
  • the duration of the lag time can be designed to mimic a desired plasma profile.
  • the first component may be an immediate release component wherein the hydrocodone, or a salt or derivative thereof, comprised therein is released substantially immediately upon administration.
  • the first component may be a delayed release component in which the hydrocodone, or a salt or derivative thereof, is released substantially immediately after a time delay.
  • the second component may be a modified release component in which the hydrocodone, or a salt or derivative thereof, is released over a period of time or substantially immediately after a time delay.
  • the controlled release composition comprise an immediate release component and at least one modified release component, the immediate release component comprising a first population of hydrocodone-comprising particles and the modified release components comprising second and subsequent populations of hydrocodone-comprising particles.
  • the second and subsequent modified release components may comprise a controlled release coating. Additionally or alternatively, the second and subsequent modified release components may comprise a modified release matrix material.
  • administration of such a multiparticulate modified release composition having, for example, a single modified release component results in characteristic pulsatile plasma concentration levels of the hydrocodone in which the immediate release component of the composition gives rise to a first peak in the plasma profile and the modified release component gives rise to a second peak in the plasma profile.
  • Embodiments of the invention comprising more than one modified release component give rise to further peaks in the plasma profile.
  • the exact nature of the plasma profile will be influenced by the combination of all of the factors described above.
  • numerous plasma profiles may result therefrom upon administration to a patient.
  • the plasma profile resulting therefrom may be bimodal or multimodal, and may define well separated and clearly defined peaks associated with each component (e.g., when the lag time between immediate release and delayed release components is long) or superimposed peaks associated with each component (e.g., in when the lag time is short).
  • administration of a multiparticulate modified release composition having an immediate release component and a single modified release component can result in a plasma profile in which the immediate release component of the composition gives rise to a first peak in the plasma profile and the modified release component gives rise to a second peak in the plasma profile.
  • Embodiments of the invention comprising more than one modified release component may give rise to further peaks in the plasma profile.
  • administration of a multiparticulate modified release composition having an immediate release component and one or more modified release components can result in a bimodal or multimodal release profile but a plasma profile having a single peak or peaks fewer in number than the number of components contained in the composition.
  • the plasma profile produced from the administration of a single dosage unit of the present invention is advantageous when it is desirable to deliver two or more portions of hydrocodone, or a salt or derivative thereof, without the need for administration of two or more dosage units. Additionally, in the case of some disorders it is particularly useful to have such a bimodal plasma profile.
  • the compositions and dosage forms of the present invention may provide continuous analgesia for up to 24 hours by providing minimum peak to trough fluctuations in plasma levels and reduce or eliminate side effects associated with such drug compounds. Any coating material which modifies the release of the hydrocodone, or a salt or derivative thereof, in the desired manner may be used in the practice of the present invention.
  • coating materials suitable for use in the practice of the invention include but are not limited to polymer coating materials, such as cellulose acetate phthalate, cellulose acetate trimaletate, hydroxy propyl methylcellulose phthalate, polyvinyl acetate phthalate, ammonio methacrylate copolymers such as those sold under the Trade Mark Eudragit ® RS and RL, poly acrylic acid and poly acrylate and methacrylate copolymers such as those sold under the trademark Eudragit ® S and L, polyvinyl acetaldiethylamino acetate, hydroxypropyl methylcellulose acetate succinate, shellac; hydrogels and gel-forming materials, such as carboxyvinyl polymers, sodium alginate, sodium carmellose, calcium carmellose, sodium carboxymethyl starch, poly vinyl alcohol, hydroxyethyl cellulose, methyl cellulose, gelatin, starch, and cellulose based cross-linked polymers in which the degree of crosslinking is low so as to
  • polyvinylpyrrolidone m. wt. ⁇ 10k-360k
  • anionic and cationic hydrogels polyvinyl alcohol having a low acetate residual, a swellable mixture of agar and carboxymethyl cellulose, copolymers of maleic anhydride and styrene, ethylene, propylene or isobutylene, pectin (m. wt. -30k-300k), polysaccharides such as agar, acacia, karaya, tragacanth, algins and guar, polyacrylamides, Polyox ® polyethylene oxides (m. wt.
  • AquaKeep ® acrylate polymers diesters of polyglucan, crosslinked polyvinyl alcohol and poly N-vinyl-2-pyrrolidone, sodium starch glycolate (e.g., Explotab ® ; Edward Mandell C. Ltd.); hydrophilic polymers such as polysaccharides, methyl cellulose, sodium or calcium carboxymethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, nitro cellulose, carboxymethyl cellulose, cellulose ethers, polyethylene oxides (e.g.
  • Polyox ® Union Carbide
  • plasticisers include for example acetylated monoglycerides; butyl phthalyl butyl glycolate; dibutyl tartrate; diethyl phthalate; dimethyl phthalate; ethyl phthalyl ethyl glycolate; glycerin; propylene glycol; triacetin; citrate; tripropioin; diacetin; dibutyl phthalate; acetyl monoglyceride; polyethylene glycols; castor oil; triethyl citrate; polyhydric alcohols, glycerol, acetate esters, gylcerol triacetate, acetyl triethyl citrate, dibenzyl phthalate, dihexyl phthalate, butyl octyl phthalate, diisononyl phthalate, butyl octy
  • modified release component comprises a modified release matrix material
  • any suitable modified release matrix material or suitable combination of modified release matrix materials may be used. Such materials are known to those skilled in the art.
  • modified release matrix material includes hydrophilic polymers, hydrophobic polymers and mixtures thereof which are capable of modifying the release of a hydrocodone, or a salt or derivative thereof, dispersed therein in vitro or in vivo.
  • Modified release matrix materials suitable for the practice of the present invention include but are not limited to microcrystalline cellulose, sodium carboxymethylcellulose, hydroxyalkylcelluloses such as hydroxypropylmethyl-cellulose and hydroxypropylcellulose, polyethylene oxide, alkylcelluloses such as methylcellulose and ethylcellulose, polyethylene glycol, polyvinylpyrrolidone, cellulose acetate, cellulose acetate butyrate, cellulose acetate phthalate, cellulose acetate trimellitate, polyvinylacetate phthalate, polyalkylmethacrylates, polyvinyl acetate and mixture thereof.
  • a multiparticulate modified release composition according to the present invention may be incorporated into any suitable dosage form which facilitates release of the hydrocodone, or a salt or derivative thereof, in a bimodal or multimodal manner.
  • the dosage form may be a blend of the different populations of a hydrocodone, or a salt or derivative thereof, comprising particles which make up the immediate release and the modified release components, the blend being filled into suitable capsules, such as hard or soft gelatin capsules.
  • suitable capsules such as hard or soft gelatin capsules.
  • the different individual populations of a hydrocodone, or a salt or derivative thereof, comprising particles may be compressed (optionally with additional excipients) into mini-tablets which may be subsequently filled into capsules in the appropriate proportions.
  • Another suitable dosage form is that of a multilayer tablet.
  • the first component of the multiparticulate modified release composition may be compressed into one layer with the second component being subsequently added as a second layer of the multilayer tablet.
  • the populations of hydrocodone, or a salt or derivative thereof, comprising particles comprising the composition of the invention may further be included in rapidly dissolving dosage forms such as an effervescent dosage form or a fast-melt dosage form.
  • the composition of the invention and the dosage forms made therefrom release the hydrocodone, or a salt or derivative thereof, such that substantially all hydrocodone, or a salt or derivative thereof, comprised in the first component is released prior to release of a hydrocodone, or a salt or derivative thereof, from the second component.
  • the first component comprises an IR component
  • release of the hydrocodone, or a salt or derivative thereof, from the second component may be delayed until substantially all the hydrocodone, or a salt or derivative thereof, in the IR component has been released.
  • Release of the hydrocodone, or a salt or derivative thereof, from the second component may be delayed as detailed above by the use of a modified release coating and/or a modified release matrix material.
  • the controlled release composition of the present invention is particularly useful for administering a hydrocodone, or a salt or derivative thereof, for which patient tolerance may be problematical.
  • This controlled release composition is therefore advantageous for reducing or minimizing the development of patient tolerance to the hydrocodone, or a salt or derivative thereof, in the composition.
  • release of the hydrocodone, or a salt or derivative thereof, from the second component is delayed until substantially all of the hydrocodone, or a salt or derivative thereof, comprised in the first component has been released, and further delayed until at least a portion of the hydrocodone, or a salt or derivative thereof, released from the first component has been cleared from the patient's system.
  • release of the hydrocodone, or a salt or derivative thereof, from the second component of the composition is substantially, if not completely, delayed for a period of at least about two hours after administration of the composition.
  • composition of the invention and the dosage forms made therefrom release the hydrocodone, or a salt or derivative thereof, such that the hydrocodone, or a salt or derivative thereof, comprised in the first component is released during the release of hydrocodone, or a salt or derivative thereof, from the second component.
  • release of the hydrocodone, or a salt or derivative thereof, from the second component of the composition occurs during and beyond the release of the hydrocodone, or a salt or derivative thereof, from the first component.
  • the invention includes various types of controlled release systems by which the hydrocodone, or a salt or derivative thereof, may be delivered in a pulsatile or zero order manner.
  • These systems include, but are not limited to: films with the hydrocodone, or a salt or derivative thereof, in a polymer matrix (monolithic devices); the hydrocodone, or a salt or derivative thereof, contained by the polymer (reservoir devices); polymeric colloidal particles or microencapsulates (microparticles, microspheres or nanoparticles) in the form of reservoir and matrix devices; hydrocodone, or a salt or derivative thereof, contained by a polymer containing a hydrophilic and/or leachable additive e.g., a second polymer, surfactant or plasticiser, etc.
  • a hydrophilic and/or leachable additive e.g., a second polymer, surfactant or plasticiser, etc.
  • a porous device or a device in which the hydrocodone, or a salt or derivative thereof, release may be osmotically 'controlled' (both reservoir and matrix devices); enteric coatings (ionise and dissolve at a suitable pH); (soluble) polymers with (covalently) attached 'pendant' hydrocodone, or a salt or derivative thereof, molecules; devices where release rate is controlled dynamically: e.g., the osmotic pump.
  • the delivery mechanism of the invention will control the rate of release of the drug. While some mechanisms will release the hydrocodone, or a salt or derivative thereof, at a constant rate (zero order), others will vary as a function of time depending on factors such as changing concentration gradients or additive leaching leading to porosity, etc. Polymers used in sustained release coatings are necessarily biocompatible, and ideally biodegradable.
  • a typical approach to controlled release is to encapsulate or contain the hydrocodone, or a salt or derivative thereof, entirely (e.g., as a core), within a polymer film or coat (i.e., microcapsules or spray/pan coated cores).
  • the rate of release decreases exponentially with time as the concentration (activity) of the agent (i.e., the driving force for release) within the device decreases (i.e., first order release). If, however, the hydrocodone, or a salt or derivative thereof, is in a saturated suspension, then the driving force for release is kept constant (zero order) until the device is no longer saturated.
  • the release-rate kinetics may be desorption controlled, and a function of the square root of time.
  • Transport properties of coated tablets may be enhanced compared to free -polymer films, due to the enclosed nature of the tablet core (permeant) which may enable the internal build-up of an osmotic pressure which will then act to force the permeant out of the tablet.
  • KCl transport through films containing just 10% PEG was negligible, despite extensive swelling observed in similar free films, indicating that porosity was necessary for the release of the KCl which then occurred by 'trans-pore diffusion.
  • Coated salt tablets, shaped as disks were found to swell in deionised water and change shape to an oblate spheroid as a result of the build-up of internal hydrostatic pressure: the change in shape providing a means to measure the 'force' generated.
  • the osmotic force decreased with increasing levels of PEG content.
  • the lower PEG levels allowed water to be imbibed through the hydrated polymer; whilst the porosity resulting from the coating dissolving at higher levels of PEG content (20 to 40%) allowed the pressure to be relieved by the flow of KCl.
  • Monolithic (matrix) devices are possibly the most common of the devices for controlling the release of drugs. This is possibly because they are relatively easy to fabricate, compared to reservoir devices, and there is not the danger of an accidental high dosage that could result from the rupture of the membrane of a reservoir device.
  • the hydrocodone, or a salt or derivative thereof is present as a dispersion within the polymer matrix, and they are typically formed by the compression of a polymer/drug mixture or by dissolution or melting.
  • the dosage release properties of monolithic devices may be dependent upon the solubility of the hydrocodone, or a salt or derivative thereof, in the polymer matrix or, in the case of porous matrices, the solubility in the sink solution within the particle's pore network, and also the tortuosity of the network (to a greater extent than the permeability of the film), dependent on whether the hydrocodone, or a salt or derivative thereof, is dispersed in the polymer or dissolved in the polymer.
  • the hydrocodone, or a salt or derivative thereof will be released by a solution-diffusion mechanism (in the absence of pores).
  • the release mechanism will be complicated by the presence of cavities formed near the surface of the device as the hydrocodone, or a salt or derivative thereof, is lost: such cavities fill with fluid from the environment increasing the rate of release of the drug.
  • a plasticiser e.g., a poly(ethylene glycol)
  • surfactant e.g., an ingredient which increases effectiveness
  • adjuvant i.e., an ingredient which increases effectiveness
  • surfactant may increase the hydrocodone, or a salt or derivative thereof, release rate by three possible mechanisms: (i) increased solubilisation, (ii) improved 'wettability' to the dissolution media, and (iii) pore formation as a result of surfactant leaching.
  • Composite devices consisting of a polymer/drug matrix coated in a polymer containing no drug also exist. Such a device was constructed from aqueous Eudragit ® latices, and was found to give zero order release by diffusion of the drug from the core through the shell. Similarly, a polymer core containing the drug has been produced, but coated this with a shell that was eroded by the gastric fluid. The rate of release of the drug was found to be relatively linear (a function of the rate limiting diffusion process through the shell) and inversely proportional to the shell thickness, whereas the release from the core alone was found to decrease with time.
  • microspheres Methods for the preparation of hollow microspheres ('microballoons') with the drug dispersed in the sphere's shell, and also highly porous matrix-type microspheres ('microsponges') have been described.
  • the microsponges were prepared by dissolving the drug and polymer in ethanol. On addition to water, the ethanol diffused from the emulsion droplets to leave a highly porous particle.
  • the hollow microspheres were formed by preparing a solution of ethanol/dichloro-methane containing the drug and polymer.
  • a means of attaching a range of drugs such as analgesics and antidepressants, etc., by means of an ester linkage to poly(acrylate) ester latex particles prepared by aqueous emulsion polymerization has been developed. These latices when passed through an ion exchange resin such that the polymer end groups were converted to their strong acid form could 'self-catalyse' the release of the drug by hydrolysis of the ester link.
  • Drugs have been attached to polymers, and also monomers have been synthesized with a pendent drug attached.
  • the research group have also prepared their own dosage forms in which the drug is bound to a biocompatible polymer by a labile chemical bond e.g., polyanhydrides prepared from a substituted anhydride (itself prepared by reacting an acid chloride with the drug: methacryloyl chloride and the sodium salt of methoxy benzoic acid) were used to form a matrix with a second polymer (Eudragit ® RL) which released the drug on hydrolysis in gastric fluid.
  • polymeric Schiff bases suitable for use as carriers of pharmaceutical amines has also been described.
  • Enteric films consist of pH sensitive polymers. Typically the polymers are carboxylated and interact (swell) very little with water at low pH, whilst at high pH the polymers ionise causing swelling, or dissolving of the polymer. Coatings can therefore be designed to remain intact in the acidic environment of the stomach (protecting either the drug from this environment or the stomach from the drug), but to dissolve in the more alkaline environment of the intestine. 6. Osmotically controlled devices
  • the osmotic pump is similar to a reservoir device but contains an osmotic agent (e.g., the active agent in salt form) which acts to imbibe water from the surrounding medium via a semipermeable membrane.
  • an osmotic agent e.g., the active agent in salt form
  • Pressure is generated within the device which forces the active agent out of the device via an orifice (of a size designed to minimise solute diffusion, whilst preventing the build-up of a hydrostatic pressure head which has the effect of decreasing the osmotic pressure and changing the dimensions ⁇ volume ⁇ of the device). Whilst the internal volume of the device remains constant, and there is an excess of solid (saturated solution) in the device, then the release rate remains constant delivering a volume equal to the volume of solvent uptake. 7. Electrically stimulated release devices
  • Monolithic devices have been prepared using polyelectrolyte gels which swelled when, for example, an external electrical stimulus was applied, causing a change in pH. The release could be modulated, by the current, giving a pulsatile release profile.
  • Hydrogels find a use in a number of biomedical applications, in addition to their use in drug matrices (e.g., soft contact lenses, and various 'soft' implants, etc.).
  • compositions of the invention comprise a nanoparticulate naproxen composition.
  • the nanoparticulate naproxen composition comprises particles of naproxen having an effective average particle size of less than about 2000 nm and preferably at least one surface stabilizer adsorbed on or associated with the surface of the drug.
  • nanoparticulate naproxen compositions of the invention as compared to conventional, non-nanop articulate or solubilized dosage forms of naproxen include, but are not limited to: (1) smaller tablet or other solid dosage form size; (2) smaller doses of drug required to obtain the same pharmacological effect; (3) increased bioavailability; (4) substantially similar pharmacokinetic profiles of the naproxen compositions when administered in the fed versus the fasted state; (5) bioequivalency of the naproxen compositions when administered in the fed versus the fasted state; (6) an increased rate of dissolution for the naproxen compositions; and (7) the naproxen compositions can be used in conjunction with other active agents useful in the prevention and treatment of infective conditions.
  • the present invention also includes nanoparticulate naproxen compositions together with one or more non-toxic physiologically acceptable carriers, adjuvants, or vehicles, collectively referred to as carriers.
  • the compositions can be formulated for parental injection (e.g., intravenous, intramuscular, or subcutaneous), oral administration in solid, liquid, or aerosol form, vaginal, nasal, rectal, ocular, local (powders, ointments, or drops), buccal, intracisternal, intraperitoneal, or topical administrations, and the like.
  • a preferred dosage form of the invention is a solid dosage form, although any pharmaceutically acceptable dosage form can be utilized.
  • Exemplary solid dosage forms include, but are not limited to, tablets, capsules, sachets, lozenges, powders, pills, or granules, and the solid dosage form can be, for example, a fast melt dosage form, controlled release dosage form, lyophilized dosage form, delayed release dosage form, extended release dosage form, pulsatile release dosage form, mixed immediate release and controlled release dosage form, or a combination thereof.
  • a solid dose tablet formulation is preferred.
  • effective average particle size means that at least about 50% of the nanoparticulate naproxen particles have a size of less than about 2000 nm, by weight or by other suitable measurement technique (e.g., such as by volume, number, etc.), when measured by, for example, sedimentation flow fractionation, photon correlation spectroscopy, light scattering, disk centrifugation, and other techniques known to those of skill in the art.
  • stable means that the particles do not appreciably flocculate or agglomerate due to interparticle attractive forces or otherwise increase in particle size.
  • Stable connotes, but is not limited to one or more of the following parameters: (1) the particles do not appreciably flocculate or agglomerate due to interparticle attractive forces or otherwise significantly increase in particle size over time; (2) the physical structure of the particles is not altered over time, such as by conversion from an amorphous phase to a crystalline phase; (3) the particles are chemically stable; and/or (4) where the naproxen or a salt or derivative thereof has not been subject to a heating step at or above the melting point of the naproxen particles in the preparation of the nanoparticles of the present invention.
  • non-nanoparticulate active agent shall mean an active agent which is solubilized or which has an effective average particle size of greater than about 2000 nm. Nanoparticulate active agents as defined herein have an effective average particle size of less than about 2000 nm.
  • pooledly water soluble drugs 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.
  • therapeutically effective amount shall mean that drug dosage that provides the specific pharmacological response for which the drug is administered in a significant number of subjects in need of such treatment. It is emphasized that a therapeutically effective amount of a drug that is administered to a particular subject in a particular instance will not always be effective in treating the conditions/diseases described herein, even though such dosage is deemed to be a therapeutically effective amount by those of skill in the art.
  • nanoparticulate naproxen formulations of the invention exhibit increased bioavailability, and require smaller doses as compared to prior conventional, non-nanoparticulate naproxen formulations.
  • the invention also provides nanoparticulate naproxen, or a salt or derivative thereof, compositions having a desirable pharmacokinetic profile when administered to mammalian subjects.
  • the desirable pharmacokinetic profile of the compositions comprising naproxen includes but is not limited to: (1) a C max for naproxen, when assayed in the plasma of a mammalian subject following administration, that is preferably greater than the C max for a non-nanoparticulate formulation of the same naproxen, administered at the same dosage; and/or (2) an AUC for naproxen, when assayed in the plasma of a mammalian subject following administration, that is preferably greater than the AUC for a non-nanoparticulate formulation of the same naproxen, administered at the same dosage; and/or (3) a T max for naproxen, when assayed in the plasma of a mammalian subject following administration, that is preferably less than the T max for a non-nanoparticulate formulation of the same naproxen, administered
  • a composition comprising a nanoparticulate naproxen exhibits in comparative pharmacokinetic testing with a non-nanoparticulate formulation of the same naproxen, administered at the same dosage, a T max not greater than about 90%, not greater than about 80%, not greater than about 70%, not greater than about 60%, not greater than about 50%, not greater than about 40%, not greater than about 30%, not greater than about 25%, not greater than about 20%, not greater than about 15%, not greater than about 10%, or not greater than about 5% of the T max exhibited by the non-nanoparticulate naproxen formulation.
  • the composition comprising a nanoparticulate naproxen exhibits in comparative pharmacokinetic testing with a non-nanoparticulate formulation of the same naproxen, administered at the same dosage, a C max 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%, at least about 900%, at least about 1000%, at least about 1100%, at least about 1200%, at least about 1300%, at least about 1400%, at least about 1500%, at least about 1600%, at least about 1700%, at least about 1800%, or at least about 1900% greater than the C max exhibited by the non-nanoparticulate naproxen formulation.
  • composition comprising a nanoparticulate naproxen exhibits in comparative pharmacokinetic testing with a non-nanoparticulate formulation of the same naproxen, administered at the same dosage, an AUC which 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
  • the T max of naproxen when assayed in the plasma of the mammalian subject, is less than about 6 to about 8 hours. In other embodiments of the invention, the T max of naproxen 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 than about 30 minutes after administration.
  • the desirable pharmacokinetic profile is the pharmacokinetic profile measured after the initial dose of naproxen or a salt or derivative thereof.
  • the compositions can be formulated in any way as described herein and as known to those of skill in the art.
  • the invention encompasses naproxen compositions wherein the pharmacokinetic profile of naproxen is not substantially affected by the fed or fasted state of a subject ingesting the composition. This means that there is no substantial difference in the quantity of drug absorbed or the rate of drug absorption when the nanoparticulate naproxen compositions are administered in the fed versus the fasted state.
  • Benefits of a dosage form which substantially eliminates the effect of food, include an increase in subject convenience, thereby increasing subject compliance, as the subject does not need to ensure that they are taking a dose either with or without food. This is significant, as with poor subject compliance an increase in the medical condition for which the drug is being prescribed may be observed.
  • the invention also encompasses provides a nanoparticulate naproxen composition in which administration of the composition to a subject in a fasted state is bioequivalent to administration of the composition to a subject in a fed state.
  • the difference in absorption (AUC) or C max of the nanoparticulate naproxen compositions of the invention, when administered in the fed versus the fasted state preferably is 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%.
  • the invention encompasses compositions comprising a nanoparticulate naproxen, wherein administration of the composition to a subject in a fasted state is bioequivalent to administration of the composition to a subject in a fed state, in particular as defined by C max and AUC guidelines given by the U.S. Food and Drug Administration and the corresponding European regulatory agency (EMEA). Under U.S. FDA guidelines, two products or methods are bioequivalent if the 90% Confidence Intervals (CI) for AUC and C max are between 0.80 to 1.25 (T max measurements are not relevant to bioequivalence for regulatory purposes).
  • CI 90% Confidence Intervals
  • nanoparticulate naproxen compositions of the invention are proposed to have unexpectedly dramatic dissolution profiles. Rapid dissolution of an administered active agent is preferable, as faster dissolution generally leads to faster onset of action and greater bioavailability. To improve the dissolution profile and bioavailability of the naproxen, it would be useful to increase the drug's dissolution so that it could attain a level close to 100%.
  • the naproxen compositions of the invention preferably have a dissolution profile in which within about 5 minutes at least about 20% of the composition is dissolved. In other embodiments of the invention, at least about 30% or at least about 40% of naproxen composition is dissolved within about 5 minutes. In yet other embodiments of the invention, preferably at least about 40%, at least about 50%, at least about 60%, at least about 70%, or at least about 80% of the naproxen composition is dissolved within about 10 minutes. Finally, in another embodiment of the invention, preferably at least about 70%, at least about 80%, at least about 90%, or at least about 100% of the naproxen composition is dissolved within about 20 minutes. Dissolution is preferably measured in a medium which is discriminating.
  • Such a dissolution medium will produce two very different dissolution curves for two products having very different dissolution profiles in gastric juices; i.e., the dissolution medium is predictive of in vivo dissolution of a composition.
  • An exemplary dissolution medium is an aqueous medium containing the surfactant sodium lauryl sulfate at 0.025 M. Determination of the amount dissolved can be carried out by spectrophotometry. The rotating blade method (European Pharmacopoeia) can be used to measure dissolution.
  • compositions of the invention redisperse such that the effective average particle size of the redispersed naproxen particles is less than about 2 microns. This is significant, as if upon administration the naproxen compositions of the invention did not redisperse to a substantially nanoparticulate particle size, then the dosage form may lose the benefits afforded by formulating the naproxen into a nanoparticulate particle size.
  • nanoparticulate active agent compositions benefit from the small particle size of the active agent; if the active agent does not redisperse into the small particle sizes upon administration, then "clumps" or agglomerated active agent particles are formed, owing to the extremely high surface free energy of the nanoparticulate system and the thermodynamic driving force to achieve an overall reduction in free energy. With the formation of such agglomerated particles, the bioavailability of the dosage form may fall well below that observed with the liquid dispersion form of the nanoparticulate active agent.
  • the nanoparticulate naproxen or a salt or derivative thereof compositions of the invention exhibit dramatic redispersion of the nanoparticulate naproxen particles upon administration to a mammal, such as a human or animal, as demonstrated by reconstitution/redispersion in a biorelevant aqueous media such that the effective average particle size of the redispersed naproxen particles is less than about 2 microns.
  • a biorelevant aqueous media can be any aqueous media that exhibit the desired ionic strength and pH, which form the basis for the biorelevance of the media.
  • the desired pH and ionic strength are those that are representative of physiological conditions found in the human body.
  • Such biorelevant aqueous media can be, for example, aqueous electrolyte solutions or aqueous solutions of any salt, acid, or base, or a combination thereof, which exhibit the desired pH and ionic strength.
  • Biorelevant pH is well known in the art.
  • the pH ranges from slightly less than 2 (but typically greater than 1) up to 4 or 5.
  • the pH can range from 4 to 6, and in the colon it can range from 6 to 8.
  • Biorelevant ionic strength is also well known in the art. Fasted state gastric fluid has an ionic strength of about 0.1M while fasted state intestinal fluid has an ionic strength of about 0.14. See e.g., Lindahl et al., "Characterization of Fluids from the Stomach and Proximal Jejunum in Men and Women," Pharm. Res., 14 (4): 497-502 (1997).
  • pH and ionic strength of the test solution is more critical than the specific chemical content. Accordingly, appropriate pH and ionic strength values can be obtained through numerous combinations of strong acids, strong bases, salts, single or multiple conjugate acid-base pairs (i.e., weak acids and corresponding salts of that acid), monoprotic and polyprotic electrolytes, etc.
  • electrolyte solutions can be, but are not limited to, HCl solutions, ranging in concentration from about 0.001 to about 0.1 M, and NaCl solutions, ranging in concentration from about 0.001 to about 0.1 M, and mixtures thereof.
  • electrolyte solutions can be, but are not limited to, about 0.1 M HCl or less, about 0.01 M HCl or less, about 0.001 M HCl or less, about 0.1 M NaCl or less, about 0.01 M NaCl or less, about 0.001 M NaCl or less, and mixtures thereof.
  • 0.01 M HCl and/or 0.1 M NaCl are most representative of fasted human physiological conditions, owing to the pH and ionic strength conditions of the proximal gastrointestinal tract.
  • Electrolyte concentrations of 0.001 M HCl, 0.01 M HCl, and 0.1 M HCl correspond to pH 3, pH 2, and pH 1, respectively.
  • a 0.01 M HCl solution simulates typical acidic conditions found in the stomach.
  • a solution of 0.1 M NaCl provides a reasonable approximation of the ionic strength conditions found throughout the body, including the gastrointestinal fluids, although concentrations higher than 0.1 M may be employed to simulate fed conditions within the human GI tract.
  • Exemplary solutions of salts, acids, bases or combinations thereof, which exhibit the desired pH and ionic strength include but are not limited to phosphoric acid/phosphate salts + sodium, potassium and calcium salts of chloride, acetic acid/acetate salts + sodium, potassium and calcium salts of chloride, carbonic acid/bicarbonate salts + sodium, potassium and calcium salts of chloride, and citric acid/citrate salts + sodium, potassium and calcium salts of chloride.
  • the redispersed naproxen particles of the invention include but are not limited to phosphoric acid/phosphate salts + sodium, potassium and calcium salts of chloride, acetic acid/acetate salts + sodium, potassium and calcium salts of chloride, carbonic acid/bicarbonate salts + sodium, potassium and calcium salts of chloride, and citric acid/citrate salts + sodium, potassium and calcium salts of chloride.
  • the redispersed naproxen particles of the invention include but are not limited to phosphoric acid/phosphate salts + sodium,
  • redispersed in an aqueous, biorelevant, or any other suitable media have an effective average particle size of less than about less than about 1900 nm, less than about 1800 nm, less than about 1700 nm, less than about 1600 nm, less than about 1500 nm, less than about 1400 nm, less than about 1300 nm, less than about 1200 nm, less than about 1100 nm, less than about 1000 nm, less than about 900 nm, less than about 800 nm, less than about 700 nm, less than about 600 nm, less than about 500 nm, less than about 400 nm, less than about 300 nm, less than about 250 nm, less than about 200 nm, less than about 150 nm, less than about 100 nm, less than about 75 nm, or less than about 50 nm, as measured by light-scattering methods, microscopy, or other appropriate methods.
  • compositions comprising naproxen particles and at least one surface stabilizer.
  • the surface stabilizers preferably are adsorbed on, or associated with, the surface of the naproxen particles.
  • Surface stabilizers especially useful herein preferably physically adhere on, or associate with, the surface of the nanoparticulate naproxen particles, but do not chemically react with the naproxen particles or itself.
  • Individually adsorbed molecules of the surface stabilizer are essentially free of intermolecular cross-linkages.
  • the invention also includes naproxen compositions together with one or more non-toxic physiologically acceptable carriers, adjuvants, or vehicles, collectively referred to as carriers.
  • the compositions can be formulated for parenteral injection (e.g., intravenous, intramuscular, or subcutaneous), oral administration in solid, liquid, or aerosol form, vaginal, nasal, rectal, ocular, local (powders, ointments or drops), buccal, intracisternal, intraperitoneal, or topical administration, and the like.
  • compositions of the invention comprise particles of naproxen or a salt or derivative thereof.
  • the particles can be in a crystalline phase, semi-crystalline phase, amorphous phase, semi- amorphous phase, or a combination thereof.
  • surface stabilizers include hydroxypropyl methylcellulose (now known as hypromellose), hydroxypropylcellulose, polyvinylpyrrolidone, sodium lauryl sulfate, dioctylsulfosuccinate, gelatin, casein, lecithin (phosphatides), dextran, gum acacia, cholesterol, tragacanth, stearic acid, benzalkonium chloride, calcium stearate, glycerol monostearate, cetostearyl alcohol, cetomacrogol emulsifying wax, sorbitan esters, polyoxyethylene alkyl ethers (e.g., macrogol ethers such as cetomacrogol 1000), polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters (e.g., the commercially available Tweens ® such as e.g., Tween 20 ® and Tween 80 ® (ICI Speciality Chemicals)); polyethylene glycol glyco
  • polyoxyethylene stearates polyoxyethylene stearates, colloidal silicon dioxide, phosphates, carboxymethylcellulose calcium, carboxymethylcellulose sodium, methylcellulose, hydroxyethylcellulose, hypromellose phthalate, noncrystalline cellulose, magnesium aluminium silicate, triethanolamine, polyvinyl alcohol (PVA), 4-(l,l,3,3-tetramethylbutyl)-phenol polymer with ethylene oxide and formaldehyde (also known as tyloxapol, superione, and triton), poloxamers (e.g., Pluronics F68 ® and F108 ® , which are block copolymers of ethylene oxide and propylene oxide); poloxamines (e.g., Tetronic 908 ® , also known as Poloxamine 908 ® , which is a tetrafunctional block copolymer derived from sequential addition of propylene oxide and ethylene oxide to ethylenediamine (BASF Wyand
  • cationic surface stabilizers include, but are not limited to, polymers, biopolymers, polysaccharides, cellulosics, alginates, phospholipids, and nonpolymeric compounds, such as zwitterionic stabilizers, poly-n-methylpyridinium, anthryul pyridinium chloride, cationic phospholipids, chitosan, polylysine, polyvinylimidazole, polybrene, polymethylmethacrylate trimethylammoniumbromide bromide (PMMTMABr), hexyldesyltrimethylammonium bromide (HDMAB), and polyvinylpyrrolidone-2-dimethylaminoethyl methacrylate dimethyl sulfate.
  • cationic stabilizers include, but are not limited to, cationic lipids, sulfonium, phosphonium, and quarternary ammonium compounds, such as stearyltrimethylammonium chloride, benzyl-di(2-chloroethyl)ethylammonium bromide, coconut trimethyl ammonium chloride or bromide, coconut methyl dihydroxyethyl ammonium chloride or bromide, decyl triethyl ammonium chloride, decyl dimethyl hydroxyethyl ammonium chloride or bromide, C ⁇ -isdimethyl hydroxyethyl ammonium chloride or bromide, coconut dimethyl hydroxyethyl ammonium chloride or bromide, myristyl trimethyl ammonium methyl sulphate, lauryl dimethyl benzyl ammonium chloride or bromide, lauryl dimethyl (ethenoxy) 4 ammonium chloride or bromide,
  • Such exemplary cationic surface stabilizers and other useful cationic surface stabilizers are described in J. Cross and E. Singer, Cationic Surfactants: Analytical and Biological Evaluation (Marcel Dekker, 1994); P. and D. Rubingh (Editor), Cationic Surfactants: Physical Chemistry (Marcel Dekker, 1991); and J. Richmond, Cationic Surfactants: Organic Chemistry, (Marcel Dekker, 1990).
  • Nonpolymeric surface stabilizers are any nonpolymeric compound, such benzalkonium chloride, a carbonium compound, a phosphonium compound, an oxonium compound, a halonium compound, a cationic organometallic compound, a quarternary phosphorous compound, a pyridinium compound, an anilinium compound, an ammonium compound, a hydroxylammonium compound, a primary ammonium compound, a secondary ammonium compound, a tertiary ammonium compound, and quarternary ammonium compounds of the formula NR 1 R 2 R 3 R 4 ⁇ .
  • R 1 -R 4 are CH 3 ;
  • two of R 1 -R 4 are CH 3 , one of R 1 -R 4 is C O H S CH 2 , and one of R 1 -R 4 is an alkyl chain of seven carbon atoms or less;
  • R 1 -R 4 are CH 3 , one of R 1 -R 4 is C O H S CH 2 , and one of R 1 -R 4 is an alkyl chain of nineteen carbon atoms or more;
  • R 1 -R 4 two of R 1 -R 4 are CH 3 , one of R 1 -R 4 is C O H S CH 2 , and one of R 1 -R 4 comprises at least one heteroatom;
  • R 1 -R 4 two of R 1 -R 4 are CH 3 , one of R 1 -R 4 is C O H S CH 2 , and one of R 1 -R 4 comprises at least one halogen;
  • (x) two of R 1 -R 4 are CH 3 , one of R 1 -R 4 is C O H S CH 2 , and one of R 1 -R 4 comprises at least one cyclic fragment; (xi) two of R 1 -R 4 are CH 3 and one of R 1 -R 4 is a phenyl ring; or (xii) two of R 1 -R 4 are CH 3 and two of R 1 -R 4 are purely aliphatic fragments.
  • Such compounds include, but are not limited to, behenalkonium chloride, benzethonium chloride, cetylpyridinium chloride, behentrimonium chloride, lauralkonium chloride, cetalkonium chloride, cetrimonium bromide, cetrimonium chloride, cethylamine hydrofluoride, chlorallylmethenamine chloride (Quaternium-15), distearyldimonium chloride (Quaternium-5), dodecyl dimethyl ethylbenzyl ammonium chloride(Quaternium-14), Quaternium-22, Quaternium- 26, Quaternium-18 hectorite, dimethylaminoethylchloride hydrochloride, cysteine hydrochloride, diethanolammonium POE (10) oletyl ether phosphate, diethanolammonium POE (3)oleyl ether phosphate, tallow alkonium chloride, dimethyl dioctadecylammoniumbentonite
  • the 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 the Handbook of Pharmaceutical Excipients, published jointly by the American Pharmaceutical Association and The Pharmaceutical Society of Great Britain (The Pharmaceutical Press, 2000), specifically incorporated by reference.
  • compositions according to the invention may also comprise one or more binding agents, filling agents, lubricating agents, suspending agents, sweeteners, flavoring agents, preservatives, buffers, wetting agents, disintegrants, effervescent agents, and other excipients.
  • excipients are known in the art.
  • filling agents are lactose monohydrate, lactose anhydrous, and various starches
  • binding agents are various celluloses and cross-linked polyvinylpyrrolidone, microcrystalline cellulose, such as Avicel ® PHlOl and Avicel ® PH 102, microcrystalline cellulose, and silicified microcrystalline cellulose (ProSolv SMCCTM)
  • Suitable lubricants including agents that act on the flowability of the powder to be compressed, are colloidal silicon dioxide, such as Aerosil ® 200, talc, stearic acid, magnesium stearate, calcium stearate, and silica gel.
  • sweeteners are any natural or artificial sweetener, such as sucrose, xylitol, sodium saccharin, cyclamate, aspartame, and acsulfame.
  • sweeteners are any natural or artificial sweetener, such as sucrose, xylitol, sodium saccharin, cyclamate, aspartame, and acsulfame.
  • flavoring agents are Magnasweet ® (trademark of MAFCO), bubble gum flavor, and fruit flavors, and the like.
  • preservatives examples include potassium sorbate, methylparaben, propylparaben, benzoic acid and its salts, other esters of parahydroxybenzoic acid such as butylparaben, alcohols such as ethyl or benzyl alcohol, phenolic compounds such as phenol, or quarternary compounds such as benzalkonium chloride.
  • Suitable diluents include pharmaceutically acceptable inert fillers, such as microcrystalline cellulose, lactose, dibasic calcium phosphate, saccharides, and/or mixtures of any of the foregoing.
  • examples of diluents include microcrystalline cellulose, such as Avicel ® PHlOl and Avicel ® PH102; lactose such as lactose monohydrate, lactose anhydrous, and Pharmatose ® DCL21; dibasic calcium phosphate such as Emcompress ® ; mannitol; starch; sorbitol; sucrose; and glucose.
  • Suitable disintegrants include lightly crosslinked polyvinyl pyrrolidone, corn starch, potato starch, maize starch, and modified starches, croscarmellose sodium, cross-povidone, sodium starch glycolate, and mixtures thereof.
  • effervescent agents are effervescent couples such as an organic acid and a carbonate or bicarbonate.
  • Suitable organic acids include, for example, citric, tartaric, malic, fumaric, adipic, succinic, and alginic acids and anhydrides and acid salts.
  • Suitable carbonates and bicarbonates include, for example, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, magnesium carbonate, sodium glycine carbonate, L-lysine carbonate, and arginine carbonate.
  • sodium bicarbonate component of the effervescent couple may be present.
  • compositions of the invention comprise naproxen particles which have an effective average 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, less than about 75 nm, or less than about 50 nm, as measured by light-scattering methods, microscopy, or other appropriate methods.
  • an effective average particle size of less than about 2000 nm it is meant that at least 50% of the naproxen particles have a particle size of less than the effective average, by weight or by another suitable measurement technique (e.g., volume, number, etc.), i.e., less than about 2000 nm, 1900 nm, 1800 nm, etc., when measured by the above-noted techniques.
  • at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, or at least about 99% of the naproxen particles have a particle size of less than the effective average, i.e., less than about 2000 nm, 1900 nm, 1800 nm, 1700 nm, etc.
  • the value for D50 of a nanoparticulate naproxen composition is the particle size below which 50% of the naproxen particles fall, by weight.
  • D90 is the particle size below which 90% of the naproxen particles fall, by weight.
  • the relative amounts of naproxen and one or more surface stabilizers can vary widely.
  • the optimal amount of the individual components can depend, for example, upon the particular naproxen selected, the hydrophilic lipophilic balance (HLB), melting point, and the surface tension of water solutions of the stabilizer, etc.
  • HLB hydrophilic lipophilic balance
  • the concentration of naproxen can vary from about 99.5% to about 0.001%, from about 95% to about 0.1%, or from about 90% to about 0.5%, by weight, based on the total combined dry weight of naproxen and at least one surface stabilizer, not including other excipients.
  • the concentration of the at least one surface stabilizer can vary from about 0.5% to about
  • Nanoparticulate Naproxen Compositions can be made using, for example, milling, homogenization, precipitation, freezing, or template emulsion techniques. Exemplary methods of making nanoparticulate compositions are described in the V 684 patent. Methods of making nanoparticulate compositions are also described in U.S. Patent No. 5,518,187 for "Method of Grinding Pharmaceutical Substances;” U.S. Patent No. 5,718,388 for "Continuous Method of Grinding Pharmaceutical Substances;” U.S. Patent No. 5,862,999 for "Method of Grinding Pharmaceutical Substances;” U.S. Patent No.
  • the resultant nanop articulate naproxen compositions or dispersions can be utilized 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, extended release formulations, pulsatile release formulations, mixed immediate release and controlled release formulations, etc.
  • Milling a naproxen to obtain a nanoparticulate dispersion comprises dispersing the naproxen particles in a liquid dispersion medium in which the naproxen is poorly soluble, followed by applying mechanical means in the presence of grinding media to reduce the particle size of the naproxen 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 naproxen particles can be reduced in size in the presence of at least one surface stabilizer. Alternatively, naproxen particles can be contacted with one or more surface stabilizers after attrition.
  • Another method of forming the desired nanoparticulate naproxen composition is by microprecipitation.
  • This is a method of preparing stable dispersions of poorly soluble active agents in the presence of one or more surface stabilizers and one or more colloid stability enhancing surface active agents free of any trace toxic solvents or solubilized heavy metal impurities.
  • Such a method comprises, for example: (1) dissolving the naproxen in a suitable solvent; (2) adding the formulation from step (1) to a solution comprising at least one surface stabilizer; and (3) precipitating the formulation from step (2) using an appropriate non- solvent.
  • the method can be followed by removal of any formed salt, if present, by dialysis or diafiltration and concentration of the dispersion by conventional means. 3. Homogenization to Obtain Nanoparticulate Naproxen Compositions
  • Such a method comprises dispersing particles of a naproxen in a liquid dispersion medium, followed by subjecting the dispersion to homogenization to reduce the particle size of a naproxen to the desired effective average particle size.
  • the naproxen particles can be reduced in size in the presence of at least one surface stabilizer.
  • the naproxen particles can be contacted with one or more surface stabilizers either before or after attrition.
  • Other compounds, such as a diluent can be added to the naproxen/surface stabilizer composition, either before, during, or after the size reduction process.
  • Dispersions can be manufactured continuously or in a batch mode.
  • Another method of forming the desired nanoparticulate naproxen composition is by spray freezing into liquid (SFL).
  • SFL liquid
  • This technology comprises an organic or organoaqueous solution of naproxen with stabilizers, which is injected into a cryogenic liquid, such as liquid nitrogen.
  • the droplets of the naproxen solution freeze at a rate sufficient to minimize crystallization and particle growth, thus formulating nano structured naproxen particles.
  • the nanoparticulate naproxen particles can have varying particle morphology.
  • the nitrogen and solvent are removed under conditions that avoid agglomeration or ripening of the naproxen particles.
  • ultra rapid freezing may also be used to created equivalent nanostructured naproxen particles with greatly enhanced surface area.
  • URF comprises an organic or organoaqueous solution of naproxen with stabilizers onto a cryogenic substrate.
  • Template emulsion creates nanostructured naproxen particles with controlled particle size distribution and rapid dissolution performance.
  • the method comprises an oil-in-water emulsion that is prepared, then swelled with a non-aqueous solution comprising the naproxen and stabilizers.
  • the particle size distribution of the naproxen particles is a direct result of the size of the emulsion droplets prior to loading with the naproxen a property which can be controlled and optimized in this process.
  • emulsion stability is achieved with no or suppressed Ostwald ripening.
  • the solvent and water are removed, and the stabilized nanostructured naproxen particles are recovered.
  • Various naproxen particles morphologies can be achieved by appropriate control of processing conditions.
  • purified water refers to water that has been purified by passing it through a water filtration system. It is to be understood that the examples are for illustrative purposes only, and should not be interpreted as restricting the spirit and scope of the invention, as defined by the scope of the claims that follow. All references identified herein, including U.S. patents, are hereby expressly incorporated by reference.
  • the purpose of this example is to describe preparation of a multiparticulate modified release composition comprising a hydrocodone that can be used in the combination compositions of the invention.
  • Multiparticulate modified release hydrocodone compositions according to the present invention having an immediate release component and a modified release component having a modified release coating are prepared according to the formulations shown in Tables 1 and 2.
  • HPMC 2910 1.0 2.0 2.0 - - 1.5
  • Triethyl Citrate 1.5 1.6 - 1.1 - - 1.5
  • Silicon Dioxide 1.0 1.0 1.0 - 2.0 1.0 -
  • the sugar spheres (30/35 mesh) are provided as inert cores that act as a carrier for the active ingredient and other excipients present in the formulation.
  • the quality and size selected reflect the requirement to produce multiparticulates with a mean diameter in the size range 0.5-0.6 mm to facilitate the subsequent coating and encapsulation process.
  • Hydroxypropylmethylcellulose 2910) (Methocal E6 Premium LV) is used to prepare the immediate-release coating solution that is coated onto the sugar spheres to produce the IR beads and acts as a binding agent.
  • Silicon Dioxide (Syloid 244FP) is an anti-adherent that is used in the preparation of the IR coating solution (Table 1) and the modified release coating suspension (Table
  • Ammonio methyacrylate copolymer Type B (Eudragit RS 100) is a rate-controlling polymer that imparts the controlled release properties to the formulation and exhibits pH independent release properties.
  • Talc Altaic 200
  • Acetone and isopropyl alcohol are the two solvents in which the rate-controlling polymer is dissolved to produce the coating suspension that is applied to the IR beads to form the modified release beads.
  • the resultant coating suspension is applied to the IR beads to form the modified release beads.
  • Modified release beads are dried in an oven for 10-20 hours at 40-500C / 30-60% RH to remove residual solvents and to obtain a moisture content of about 3 -6 %. Suitable processing procedures are further detailed in U.S. Patent No. 6,066,339 which is incorporated herein by reference in its entirety.
  • Table 3 shows the dissolution profiles for two multiparticulate modified release formulations prepared in accordance with Tables 1 and 2. These results indicate that about 20% of the hydrocodone was released in the first hour and about 80% of the hydrocodone was released over a period of about 11 hours.
  • a randomized, single-dose, parallel-group, placebo-controlled, active-comparator study was performed to evaluate the safety, efficacy, and PK of hydrocodone formulations in subjects immediately following bunionectomy study.
  • the study treatments were 10, 20, 30, 40 mg of hydrocodone bitartarate, matching active comparator (10 mg hydrocodone/ AP AP) or matching placebo.
  • blood was collected at baseline and at up to 17 additional time points, from 115 subjects (approx. 17 to 21 subjects per group), to determine the concentrations in plasma of hydrocodone.
  • the following PK parameters were calculated and are presented in Tables 4-6.
  • hydrocodone formulations of the present invention were conducted to simulate the profiles associated with twice-daily administration hydrocodone for both single dose and steady state.
  • the target doses were 10, 20, 40 and 80 mg, and the targeted minimum concentration was 5- 10 ng/ml.
  • the formulations of the study were two-component dosage forms comprising an immediate release component and a modified release component in which the hydrocodone was allocated evenly (50/50) or unevenly (20/80) across the two components.
  • Non-compartmental parameters were used to find estimates of the unit input response and a one-compartment model was assumed for all simulations.
  • Non-compartmental parameters following a 10 mg oral dose of hydrocodone administered to five adult males are reported as shown in Table 7 below.
  • KlO and V/f were estimated to be 0.18 and 334.29L respectively.
  • absorption rate constant k ⁇ l
  • several profiles were simulated using different estimates of k ⁇ l. The secondary parameters estimates were compared to identify an appropriate ka as set forth in Table 8 below.
  • the purpose of this example is to describe preparation of a naproxen composition that can be used in the combination compositions of the invention.
  • hydroxypropylcellulose Kermel Type EF; Aqualon
  • 300 g of naproxen was dispersed into the HPC solution until a homogeneous suspension was obtained.
  • a laboratory scale media mill filled with polymeric grinding media was used in a continuous fashion until the mean particle size was approximately 200 nm as measured by laser light scattering technique, ex. Microtrak UPA.
  • the purpose of this example is to describe preparation of a naproxen composition that can be used in the combination compositions of the invention.
  • EXAMPLE 4 The purpose of this example is to describe preparation of a naproxen composition that can be used in the combination compositions of the invention.
  • a nanoparticulate naproxen dispersion was prepared in a roller mill as follows.
  • a 250 ml glass jar was charged with 120 ml of 1.0 mm pre-cleaned Zirconium oxide beads (Zirbeads XR, available from Zircoa Inc., having a nominal diameter of 1.0 mm), 60 g of an aqueous slurry containing 3 g naproxen (5% by weight), purchased from Sigma, St. Louis, Mo., particle size 20-30 microns, and 1.8 g (3% by weight) Pluronic F-68, purchased from BASF Fine Chemicals, Inc., as the surface stabilizer.
  • Zirconium oxide beads Zirbeads XR, available from Zircoa Inc., having a nominal diameter of 1.0 mm
  • 60 g of an aqueous slurry containing 3 g naproxen (5% by weight) purchased from Sigma, St. Louis, Mo., particle size 20-30 microns
  • Pluronic F-68
  • the beads were pre-cleaned by rinsing in IN H 2 SO 4 overnight followed by several rinses with deionized water. The batch was rolled at 92 RPM for a total of 120 hours. The dispersion was stable when a portion was added to 0.1N HCI. The average particle size measured by photon correlation spectroscopy was 240-300 nm.

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US20090311335A1 (en) * 2008-06-12 2009-12-17 Scott Jenkins Combination of a triptan and an nsaid
WO2010089132A1 (en) 2009-02-06 2010-08-12 Egalet A/S Immediate release composition resistant to abuse by intake of alcohol
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