US20120225122A1 - Abuse-Resistant Formulations - Google Patents

Abuse-Resistant Formulations Download PDF

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Publication number
US20120225122A1
US20120225122A1 US13/470,963 US201213470963A US2012225122A1 US 20120225122 A1 US20120225122 A1 US 20120225122A1 US 201213470963 A US201213470963 A US 201213470963A US 2012225122 A1 US2012225122 A1 US 2012225122A1
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Prior art keywords
hydromorphone
granules
ethylcellulose
hydroxypropylmethylcellulose
coated
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Abandoned
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US13/470,963
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English (en)
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Ehab Hamed
Manuel A. Vega Zepeda
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Cima Labs Inc
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Cima Labs Inc
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Priority to US13/470,963 priority Critical patent/US20120225122A1/en
Publication of US20120225122A1 publication Critical patent/US20120225122A1/en
Priority to US14/296,572 priority patent/US9474721B2/en
Abandoned legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • 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
    • 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
    • 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
    • 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
    • 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
    • A61K9/5005—Wall or coating material
    • A61K9/5015—Organic compounds, e.g. fats, sugars
    • 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
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
    • A61K9/5042—Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose
    • A61K9/5047—Cellulose ethers containing no ester groups, e.g. hydroxypropyl methylcellulose

Definitions

  • This invention relates to a sustained-release oral dosage form of hydromorphone for once-a-day administration.
  • Hydromorphone is administered to patients to reduce pain. Successful pain management in many of these patients requires maintenance of certain blood levels of hydromorphone throughout the day.
  • One way of obtaining acceptable blood levels used commonly in the pharmaceutical industry, is providing a dose which contains far more drug than is necessary to obtain the desired blood level.
  • Blood levels shortly after the tablet is ingested reach a maximum or C max in a relatively short time, often within hours of ingestion (T max ) and thereafter, as the body uses, processes and excretes drug from the blood system, the blood level drops. If the C max attained is sufficiently high, and the body's clearance of the drug is sufficiently slow, the blood levels may not fall to sub-therapeutic levels for 4-12 hours or even longer. With drugs like hydromorphone, however, this is an impractical and inefficient dosing system. In addition, there is a risk to the patient in that such high initial API levels can cause significant side effects.
  • An extended release can be achieved in many different ways and there are many different release profiles that can be attained. Not only could this strategy reduce the number of doses that need to be taken in a day, it also may prevent one from being exposed to the side effects which can come from unnecessarily high initial blood levels.
  • the ethanol or water may act as a solvent, dissolving or eroding the dosage form and circumventing the intended controlled release.
  • the resulting material can then be administered generally, orally, or in a syringe by a drug abuser.
  • Such abuse can have rather far ranging consequences.
  • cancer patients, patients with post-operative or pre-operative pain, and patients with chronic pains from arthritis or back injuries need to have useful drugs (e.g., hydromorphone) available to them.
  • useful drugs e.g., hydromorphone
  • the potential for abuse is a constant concern to regulators and law enforcement as these prescription drugs may be more freely obtainable than truly illegal illicit substances.
  • There are also the societal problems relating to drug use which includes the cost of their health care, the cost of their rehabilitation, the increase in crime which may come from supporting their drug habit, and the like.
  • Sustained-release oral dosage forms for once-a-day administration of hydromorphone are provided.
  • dosages that are extended release, such as once-a-day typically contain a larger concentration of pharmaceutically active ingredients.
  • Such larger concentrations of pharmaceutically active ingredients make the dosage forms more dangerous, especially if the dosage forms are susceptible to dumping the pharmaceutically active ingredients (releasing an undesirable high concentration of the active ingredient in a short amount of time) when they are crushed, taken with alcohol, and/or are taken with food. Therefore, dosage forms that are resistant to one or more causes of dose dumping are desirable.
  • the dosage forms described herein can include a matrix having a viscosity modifier and coated granules comprising hydromorphone or a salt form thereof (e.g., hydromorphone HCl).
  • a dosage form, as described herein has a release profile such that after 16 hours in 500 mL of 0.1N HCl, less than about 85 percent of the hydromorphone is released.
  • a dosage form may have alcohol, crush resistance, and/or be resistant to food effect.
  • a dosage form, as described herein has a release profile which is not significantly affected by varying pH conditions, e.g. between low, acidic, pH and neutral pH.
  • Dosage forms can be also resistant to food effect, meaning that the Cmax of the dosage form will not change more than 50%, 45%, 40%, or 35% when it is consumed with food vs. without food.
  • formulations that are resistant to food effect are generally safer, because their safety is not as reliant upon patient compliance.
  • a sustained-release oral dosage form for once-a-day administration comprising: a matrix, wherein the matrix comprises a viscosity modifier in an amount from about 20 to about 60 percent by weight of the dosage form; and coated granules comprising hydromorphone or a salt form thereof, such as hydromorphone hydrochloride.
  • the release of hydromorphone from the dosage form after 16 hours is less than about 85 percent. In some embodiments, the release of the hydromorphone from the dosage form after 20 hours is less than about 90 percent.
  • the percent of hydromorphone released after 2 hours in a solution of 0.1N HCl and 40% alcohol is no more than 10 percentage points greater than the percent of hydromorphone released in a solution of 0.1N HCl in the absence of alcohol.
  • the release of hydromorphone from the dosage form 30 minutes after simulated oral tampering is less than about 50 percent.
  • the mean blood levels of hydromorphone in the humans are at least about 50 percent of the mean C max , and the mean hydromorphone blood levels are maintained above at least about 50 percent of the mean C max for 24 hours following administration.
  • the ratio of the mean C max to the mean plasma hydromorphone level is from about 1.0 to about 3.0, and at 24 hours the ratio of the mean C max to the mean plasma hydromorphone level is from about 1.0 to about 3.0.
  • the ratios at 2 hours and 24 hours can independently be from about 1.0 to less than about 2.0.
  • the median T max measured in the humans is from about 5 to about 15 hours, including from about 8 to about 15 hours.
  • the ratio of the mean C max after co-ingestion with alcohol to the mean C max without alcohol is from about 0.5 to about 1.8.
  • the alcohol can be administered in amount of 4, 20 or 40 percent v/v alcohol in water.
  • a viscosity modifier can be selected from the group consisting of: sodium alginate, hydroxypropylmethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, polyvinylpyrrolidone, crosslinked polyacrylic acid, gelatin, pectins, gums, polyethylene oxides, Konjac flour, carrageenan, xanthan gum, or mixtures thereof.
  • a viscosity modifier can be a gelling polymer, such as natural and synthetic starches, natural and synthetic celluloses, acrylates, and polyalkylene oxides.
  • the gelling polymer is selected from the group consisting of: hydroxypropylmethylcellulose, hydroxypropylcellulose, methylcellulose, hydroxyethylcellulose, and carboxymethylcellulose.
  • a gelling polymer can be hydroxypropylmethylcellulose.
  • the viscosity modifier is present in an amount from about 25 to about 45 percent by weight of the dosage form.
  • the viscosity modifier can be present in an amount from about 30 to about 40 percent by weight of the dosage form.
  • the viscosity modifier is present in an amount from about 33 to about 37 percent by weight of the dosage form.
  • the viscosity modifier is present in an amount of about 35 percent by weight of the dosage form.
  • a coated granule can comprise a granule comprising hydromorphone or a salt form thereof in an amount from about 0.1 to about 90 percent by weight of the granule, a first strong film former in an amount from about 1 to about 90 percent by weight of the granule, a second viscosity modifier in an amount from about 1 to about 90 percent by weight of the granule, and a first fat/wax in an amount from about 0 to about 40 percent by weight of the granule; and a coating on the granule, wherein the coating is present in an amount from about 20 to about 80 percent by weight of the coated granule, and wherein the coating comprises a second strong film former in an amount from about 10 to about 50 percent by weight of the coated granule, and a second fat/wax in an amount from about 10 to about 30 percent by weight of the coated granule.
  • the first and second strong film formers can be independently selected from the group consisting of: natural and synthetic starches, natural and synthetic celluloses, acrylics, vinylics, resins, methacrylate or shellac.
  • the first and second strong film formers can be independently selected from the group consisting of: ethylcellulose; Ammonio Methacrylate Copolymer, Type B; Ammonio Methacrylate Copolymer, Type A; Amino Methacrylate Copolymer; Ethyl Acrylate and Methyl Methacrylate Copolymer Dispersion; Methacrylic Acid Copolymer, Type A; Methacrylic Acid Copolymer, Type B; and shellac.
  • the first and second strong film formers are ethylcellulose.
  • the first strong film former and the second strong film former are the same.
  • the first strong film former is present in an amount from about 10 to about 60 percent by weight of the granule.
  • the first strong film former can be present in an amount from about 15 to about 30 percent by weight of the granule.
  • the second viscosity modifier can be selected from the same group as defined above for the first viscosity modifier.
  • the second viscosity modifier can be selected from the group consisting of: sodium alginate, hydroxypropylmethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, polyvinylpyrrolidone, crosslinked polyacrylic acid, gelatin, pectins, gums, polyethylene oxides, Konjac flour, carrageenan, xanthan gum, or mixtures thereof.
  • the second viscosity modifier is selected from the group consisting of: hydroxypropylmethylcellulose, hydroxypropylcellulose, methylcellulose, hydroxyethylcellulose, and carboxymethylcellulose.
  • the second viscosity modifier can be hydroxypropylmethylcellulose.
  • the second viscosity modifier is present in an amount from about 10 to about 70 percent by weight of the granule.
  • the second viscosity modifier can be present in an amount from about 25 to about 60 percent by weight of the granule.
  • the first and second fat/wax can be independently selected from the group consisting of: glycerol fatty esters, fatty glyceride derivatives, waxes, or fatty alcohols.
  • the first and second fat/wax can be independently selected from the group consisting of: glycerol behenate, glycerol palmitostearate, stearoyl macroglycerides, carnauba wax, bees wax, microcrystalline wax, and cetyl alcohol.
  • the first and second fat/wax are glycerol behenate.
  • the first fat/wax and the second fat/wax are the same.
  • the second fat/wax is present in an amount from about 10 to about 25 percent by weight of the coated granule. In some embodiments, the granule does not contain a first fat/wax and the second fat/wax is present in an amount from about 10 to about 25 percent by weight of the coated granule.
  • the hydromorphone salt is hydromorphone hydrochloride. In some embodiments, the hydromorphone or salt form thereof is present in an amount from about 1 to about 60 percent by weight of the granule. For example, the hydromorphone or salt form thereof is present in an amount from about 15 to about 40 percent by weight of the granule.
  • the granule can also comprise an antioxidant.
  • antioxidants include butylated hydroxyanisole, ascorbic acid, glutathione, lipoic acid, uric acid, carotenes, ⁇ -tocopherol, selenium, resveratrol, tumeric, curcumin, ubiquinol, ascorbyl palmitate, butylated hydroxyl toluene, propyl gallate, citric acid, fumaric acid, malic acid, propionic acid, phosphoric acid, sodium sulfite, sodium thiosulfate, sodium bisulfite, sodium metabisulfite, potassium metabisulfite, methionine, erythorbic acid, ethyl oleate, sodium ascorbate, and mixtures thereof.
  • the granules are coated and in some embodiments, the coating is present in an amount from about 30 to about 70 percent by weight of the coated granule.
  • the coating can be present in an amount from about 40 to about 55 percent by weight of the coated granule.
  • the coated granule comprises less than about 5 percent water per weight of the coated granule.
  • the coated granule comprises less than about 3 percent water per weight of the coated granule.
  • sustained-release oral dosage form for once-a-day administration comprising: a matrix, wherein the matrix comprises a viscosity modifier in an amount from about 20 to about 60 percent by weight of the dosage form; and coated granules, wherein the coated granules comprise: a granule comprising hydromorphone or a salt form thereof in an amount from about 0.1 to about 90 percent by weight of the granule, a first strong film former in an amount from about 1 to about 90 percent by weight of the granule, a second viscosity modifier in an amount from about 1 to about 90 percent by weight of the granule, and a first fat/wax in an amount from about 0 to about 40 percent by weight of the granule; and a coating on the granule, wherein the coating is present in an amount from about 20 to about 80 percent by weight of the coated granule, and wherein the coating comprises a second strong film former in an amount from about 10 to about 50 percent by weight of the coated
  • the dosage form can comprise a matrix, wherein the matrix comprises hydroxypropylmethylcellulose in an amount from about 25 to about 45 percent by weight of the dosage form; and coated granules, wherein the coated granules comprise: a granule comprising hydromorphone in an amount from about 10 to about 60 percent by weight of the granule, ethylcellulose in an amount from about 10 to about 60 percent by weight of the granule, hydroxypropylmethylcellulose in an amount from about 10 to about 70 percent by weight of the granule, and glycerol behenate in an amount from about 0 to about 20 percent by weight of the granule; and a coating on the granule, wherein the coating is present in an amount from about 30 to about 70 percent by weight of the coated granule, and wherein the coating comprises ethylcellulose in an amount from about 20 to about 50 percent by weight of the coated granule, and glycerol behenate in an amount from about 10
  • a dosage form comprising: a matrix, wherein the matrix comprises hydroxypropylmethylcellulose in an amount of about 35 percent by weight of the dosage form; and coated granules, wherein the coated granules comprise: a granule comprising hydromorphone in an amount of about 27 percent by weight of the granule, ethylcellulose in an amount from about 19 to about 21 percent by weight of the granule, and hydroxypropylmethylcellulose in an amount from about 51 to about 53 percent by weight of the granule; and a coating on the granule, wherein the coating is present in an amount of about 45 percent by weight of the coated granule, and wherein the coating comprises ethylcellulose in an amount from about 28 to about 32 percent by weight of the coated granule, and glycerol behenate in an amount from about 14 to about 16 percent by weight of the coated granule.
  • the release of hydromorphone from a dosage form after 16 hours is less than about 85 percent. In some embodiments, the percent of hydromorphone released after 2 hours in a solution of 0.1N HCl and 40% alcohol is no more than 10 percentage points greater than the percent of hydromorphone released in a solution of 0.1N HCl in the absence of alcohol.
  • FIG. 1 is a line drawing of the plasma hydromorphone concentration as a function of time following administration of three sustained-release hydromorphone formulations to fasted healthy human subjects.
  • FIG. 2 is a line drawing of the plasma hydromorphone concentration as a function of time following administration of a sustained-release hydromorphone formulation in both fasted and fed healthy human subjects.
  • FIG. 3 is a line drawing of the plasma hydromorphone concentration as a function of time following administration of a sustained-release hydromorphone formulation co-administered with alcohol in fasted healthy human subjects.
  • FIG. 4 is a line drawing comparing the plasma hydromorphone concentration as a function of time following administration of a sustained-release hydromorphone formulation co-administered with 4% ethanol in fasted healthy human subjects.
  • FIG. 5 is a line drawing comparing the plasma hydromorphone concentration as a function of time following administration of a sustained-release hydromorphone formulation co-administered with 20% ethanol in fasted healthy human subjects.
  • FIG. 6 is a line drawing comparing the plasma hydromorphone concentration as a function of time following administration of a sustained-release hydromorphone formulation co-administered with 40% ethanol in fasted healthy human subjects.
  • FIG. 7 is a line drawing comparing the % release of hydromorphone from a 32 mg hydromorphone formulation of the invention as a function of time in dissolution media at varying pH.
  • FIG. 8 is a line drawing comparing the % release of hydromorphone from a 12 mg hydromorphone formulation of the invention as a function of time in dissolution media at varying pH.
  • a dosage form can include a matrix having a viscosity modifier and coated granules comprising hydromorphone or a salt form thereof (e.g., hydromorphone HCl).
  • a dosage form, as described herein has a release profile such that after 16 hours in 500 mL of 0.1N HCl, less than about 85 percent of the hydromorphone is released.
  • a dosage form may have alcohol and/or crush resistance.
  • a dosage form, as described herein has a release profile which is not significantly affected by varying pH conditions, e.g. between low, acidic, pH and neutral pH.
  • matrix refers to a monolithic system comprising active substance-containing particles (e.g., coated granules) dispersed and entrapped in a continuum of excipients, i.e., the “matrix forming” substances; see, for example, Colombo, P., Santi, P., Siepmann, J., Colombo, G., Sonvico, F., Rossi, A., Luca Strusi, O., 2008. Swellable and Rigid Matrices Controlled Relelase Matrices with Cellulose Ethers. In: Pharmaceutical Dosage Forms Tablets, Volume 2: Rational Design and Formulation. Third Edition, Augsburger, L. and Hoag, S. (eds.). Informa Healthcare, New York, London. As set forth further herein, coated granules comprising hydromorphone are dispersed within a described matrix.
  • a sustained-release oral dosage form including a matrix, comprising a viscosity modifier in an amount from about 20 to about 60 percent (e.g., about 25 to about 60 percent, about 30 to about 60 percent, about 20 to about 55 percent, about 20 to about 50 percent, about 20 to about 45 percent, about 20 to about 40 percent, about 25 to about 45 percent, about 30 to about 40 percent, and about 33 to about 37 percent) by weight of the dosage form, and coated granules comprising hydromorphone or a salt form thereof.
  • the viscosity modifier is present in an amount from about 30 to about 60 percent by weight of the dosage form. In some embodiments, the viscosity modifier is present in an amount of about 35 percent by weight of the dosage form.
  • the dosage forms described herein can have a release profile such that the release of hydromorphone from the dosage form after 16 hours is less than about 85 percent. In some embodiments, the release of hydromorphone from the dosage form after 20 hours is less than about 90 percent. Release of hydromorphone is measured using the USP dissolution apparatus number 2 and 500 mL of a 0.1 N HCl solution as the dissolution medium. See Example 38.
  • hydromorphone in 500 mL of a 0.1 HCl solution (pH about 1.2) as the dissolution medium is not significantly different from the release of hydromorphone in sodium acetate trihydrate buffer, adjusted to appropriate pH with glacial acetic acid (pH about 4.5) or in potassium phosphate monobasic buffer, adjusted to appropriate pH with 1 N sodium hydroxide (pH about 6.8). See FIGS. 7 and 8 and Example 41.
  • the consistent release profiles at varying pH levels of formulations of the present invention is advantageous since it alleviates the effect of inter- and intra-patient variability in stomach and intestinal pH on the kinetics of drug release from the dosage form.
  • the release of hydromorphone from the dosage form after administration to humans can also exhibit a fast rise and steady level of hydromorphone in the blood over a 24 hour period.
  • the mean blood levels of hydromorphone can reach at least about 50% of the mean C max within 2 hours of administration of the dosage form and the mean hydromorphone blood levels can be maintained above at least about 50% of the mean C max for 24 hours following administration.
  • the ratio of the mean C max to the mean plasma hydromorphone level is from about 1.0 to about 3.0.
  • the ratio can be from about 1.0 to less than about 2.0.
  • the ratio of the mean C max to the mean plasma hydromorphone level is from about 1.0 to about 3.0.
  • the ratio can be from about 1.0 to less than about 2.0.
  • the median T max is from about 5 to about 15 hours, including from about 8 to about 15 hours (e.g., about 8 to about 14 hours, about 8 to about 12 hours, about 8 to about 10 hours, about 9 to about 15 hours, about 10 to about 15 hours, about 12 to about 15 hours, about 13 to about 15 hours, and about 9 to about 12 hours).
  • concentrations of hydromorphone in human plasma samples can be measured using a validated high-performance liquid chromatography method with tandem mass spectrometric detection (LC-MS/MS).
  • the dosage form may be alcohol resistant. Resistance to alcohol is measured using the USP dissolution apparatus number 2 (paddles) at 37° C. and 500 mL of a 0.1 N HCl solution (normal dissolution) or a 0.1N HCl and 40% ethanolic solution (dose dumping dissolution) as the dissolution medium.
  • a 0.1 N HCl solution normal dissolution
  • a 0.1N HCl and 40% ethanolic solution dose dumping dissolution
  • an alcohol resistant dosage form as described herein, will not release any more than 30% of the hydromorphone in the solution having 0.1N HCl and 40% ethanol. See Example 38.
  • the ratio of the mean C max after co-ingestion of alcohol to mean C max in the absence of alcohol is about 0.5 to about 1.8 (e.g., about 1.0 to about 1.8).
  • concentrations of hydromorphone in human plasma samples can be measured using a validated high-performance liquid chromatography method with tandem mass spectrometric detection (LC-MS/MS).
  • a dosage form as described herein, can be crush resistant.
  • Crush resistance is measured using techniques designed to simulate oral tampering. Such methods involve placing a tablet of the dosage form in a ceramic mortar (13 cm outer diameter). A pestle is then used to apply force vertically downward onto the tablet until it breaks. The broken tablet is further crushed using a 360° circular motion with downward force applied throughout. The circular crushing motion is repeated eleven times (twelve strokes total). The resulting powder is transferred to a dissolution vessel to measure in vitro drug release. The in vitro release profile of the crushed tablet samples is obtained in 500 mL of 0.1N HCl dissolution medium. The samples are agitated at 50 rpm using USP apparatus 2 (paddles) at 37° C. After 30 minutes in the dissolution medium, a crush resistant dosage form exhibits a release of hydromorphone from the dosage form of less than about 50 percent. See Example 38.
  • the dosage form may be resistant to food effect. Resistance to food effect is measured using the methodology described in Example 41, provided herein. Generally, resistance to food effect is identified by comparing pharmacokinetic parameters from subjects that are fasted to those that have consumed a standard diet prior to administration. In some situations a standard diet can be high fat (i.e., about 50% of the calories are from fat), high carbohydrate or any other standard diet. A dosage form that is resistant to food effect (i.e., a % change in pharmacokinetic parameters comparing fasted and fed states) will show a smaller % change in pharmacokinetic parameters, such as C max , T max , or AUC at various time points when compared to other dosage forms.
  • Example 41 For example, the formulation described and tested in Example 41, below, showed a 0% change in T max between the fed and fasted data and the formulation tested in Example 40, below, showed an approximately 60% change in T max between the fed and fasted data.
  • the formulation shown in Example 41 is more resistant to food effect.
  • the percent change in T max will be less than 50%, 45%, 40%, 35%, 30%, 20%, 15% depending upon the formulation and its resistance to food effect.
  • the % change of the mean C max when tested in a group of at least five fasted healthy humans and compared to a group of at least 5 fed healthy humans, as described herein, the % change of the mean C max will be less than about 50%, 45%, 40%, 30%, 25%, 20%, or 15%.
  • the percent change in AUC at a specific time point can show less than a 50%, 45%, 40%, 35%, 30%, 20%, or 15% change when the fed and fasted data is compared.
  • the concentration of hydromorphone human plasma samples can be measured using a validated high-performance liquid chromatography method with tandem mass spectrometric detection (LC-MS/MS).
  • the dosage forms described herein exhibit one or more of the above pharmokinetic and tamper-resistant characteristics.
  • a viscosity modifier is a material, which upon dissolution or dispersion in an aqueous solution or dispersion (e.g., water) at a concentration of 2% w/w (based on the dry material), creates a solution/dispersion with a viscosity of from about 100 to about 200,000 mPa s (e.g., 4,000 to 175,000 mPa ⁇ s, and 75,000 to 140,000 mPa ⁇ s) as measured at 20° C. ( ⁇ 0.2° C.) using the analysis method described in the USP 33 monograph for hypromellose (incorporated herein by reference).
  • an aqueous solution or dispersion e.g., water
  • a concentration of 2% w/w based on the dry material
  • viscosity modifiers examples include sodium alginate, hydroxypropylmethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone, crosslinked polyacrylic acid (e.g., carbomers), gelatin, pectins, gums (e.g., gum arabic, gum tragacanth, xanthan gums, and guar gums), polyethylene oxides, Konjac flour, carrageenan, or mixtures thereof.
  • the viscosity modifier is a natural or synthetic cellulose such as hydroxypropylmethylcellulose.
  • the viscosity modifier is a gelling polymer.
  • Gelling polymers can include natural and synthetic starches, natural and synthetic celluloses, acrylates, and polyalkylene oxides. Examples include hydroxypropylmethylcellulose, hydroxypropylcellulose, methylcellulose, hydroxyethylcellulose, and carboxymethylcellulose. In some embodiments, the gelling polymer is hydroxypropylmethylcellulose (HPMC).
  • HPMC hydroxypropylmethylcellulose
  • One or more viscosity modifiers can be used in the granules, coat on the granules, and in the matrix.
  • the matrix contains at least one viscosity modifier and less than 5%, 4%, 3%, 2%, or 1% of fat/wax. Such matrixes can show resistance to food effect.
  • the HPMC can have different methyl to hydroxypropyl substitution percent ratios ranging from 30:0 in the A-type, 29:8.5 for the E-type, 28:5 in the F-type, 22:8 for the K-type all available from DOW Chemical Company, Midland, Mich. or any other HPMC polymers available from other suppliers such as Aqualon.
  • Coated granules of the dosage forms described herein include a granule comprising hydromorphone or a salt form thereof and a coating on the granule.
  • a coated granule can include a granule comprising hydromorphone or a salt form thereof in an amount from about 0.1 to about 90 percent by weight of the granule, a first strong film former in an amount from about 1 to about 90 percent by weight of the granule, a second viscosity modifier in an amount from about 1 to about 90 percent by weight of the granule, and a first fat/wax in an amount from about 0 to about 40 percent by weight of the granule; and a coating on the granule, wherein the coating is present in an amount from about 20 to about 80 percent by weight of the coated granule, and wherein the coating comprises a second strong film former in an amount from about 10 to about 50 percent by weight of the coated granule, and a second fat/wax in an
  • Hydromorphone can be present in the dosage form as a neutral compound or as a salt form (e.g., hydromorphone hydrochloride).
  • references to hydromorphone include hydromorphone and salts thereof, especially hydromorphone hydrochloride.
  • a person skilled in the art will know how to prepare and select suitable salt forms for example, as described in Handbook of Pharmaceutical Salts: Properties, Selection, and Use By P. H. Stahl and C. G. Wermuth (Wiley-VCH 2002 ).
  • the hydromorphone or a salt form thereof is present in an amount from about 1 to about 60 percent by weight of the granule.
  • the hydromorphone or a salt form thereof is present in an amount from about 20 to about 50 percent by weight of the granule. In some embodiments, the hydromorphone or a salt form thereof is present in an amount from about 20 to about 35 percent by weight of the granule.
  • a strong film former is a polymer, which is at least slightly soluble, preferably, soluble in alcohol and at most slightly soluble in water and forms a dry 3-mil film with tensile strength not less than 1000 lb/in 2 when measured by the appropriate tensile strength measuring equipment such as the texture analyzer manufactured by Texture Technologies, Brookfield, Lloyd Instruments, and the like.
  • a strong film former can be selected from natural and synthetic starches, natural and synthetic celluloses, acrylics, vinylics and resins.
  • a strong film former is selected from ethylcellulose; polyvinyl acetate; (meth)acrylate copolymers such as Ammonio Methacrylate Copolymer, Type B (Eudragit RS); Ammonio Methacrylate Copolymer, Type A (Eudragit RL); Amino Methacrylate Copolymer (Eudragit E); Ethyl Acrylate and Methyl Methacrylate Copolymer Dispersion (Eudragit NE); Methacrylic Acid Copolymer, Type A (Eudragit L); Methacrylic Acid Copolymer, Type B (Eudragit S); and shellac.
  • the first and second strong film formers are the same.
  • a strong film former is a natural or synthetic cellulose such as ethylcellulose (EC).
  • Ethylcellulose is an inert, hydrophobic polymer and is essentially tasteless, odorless, colorless, non-caloric, and physiologically inert.
  • EC ethylcellulose
  • the ethylcellulose used can have different ethoxy content such as 48.0-49.5% described as N-type; 49.6-51.5% described as T-type; 50.5-52.5% described as X-type; all available from Aqualon, Hercules Research Center, Wilmington, Del.
  • the ethylcellulose used can have different molecular weights such as including EC polymers of the N-type that form 5% w/w solution in toluene:ethanol (80:20) that have viscosity ranges of 5.6-8.0 centipoise (cps) described as N7; 8.0-11 cps described as N10; 12-16 cps described as N14; 18-24 cps described as N22; 40-52 cps described as N50; 80-105 cps described as N100.
  • the ethylcellulose used can also include different degrees of substitution of ethoxy groups per anhydroglucose unit, such as 2.65-2.81 for the X-type.
  • N-type has values of 2.46-2.58.
  • the first strong film former is present in an amount from about 10 to about 60 percent by weight of the granule.
  • the first strong film former can be present in an amount from about 15 to about 30 percent by weight of the granule.
  • the second strong film former is present in an amount from about 20 to about 50 percent by weight of the coated granule.
  • the second strong film former can be present in an amount from about 25 to about 40 percent by weight of the coated granule.
  • a second viscosity modifier is the same as the viscosity modifier used in the matrix of the dosage form.
  • the second viscosity modifier is hydroxypropylmethylcellulose.
  • the second viscosity modifier is present in an amount from about 10 to about 70 percent by weight of the granule. In some embodiments, the second viscosity modifier is present in an amount from about 25 to about 60 percent by weight of the granule.
  • a fat/wax is generally hydrophobic and a solid at room temperature (25° C.).
  • Fats are fatty acid based compounds generally having a hydrophilic/lipophilic balance (HLB) of about 6 or less (e.g., 4 or less; 2 or less), and also have a melting point of at least 30° C. (e.g., at least 40° C.; at least 50° C.).
  • HLB hydrophilic/lipophilic balance
  • the fat has an HLB of about 6 or less and a melting point of at least about 30° C.
  • it has an HLB of about 4 or less and a melting point of at least about 40° C.
  • the fat has an HLB of about 2 or less and a melting point of at least 50° C.
  • Fats including fatty acids and fatty esters, may be substituted or unsubstituted, saturated or unsaturated. In some cases, they have a chain length of at least about 14.
  • Fatty esters may include fatty acid groups bound to alcohols, glycols, or glycerol. With regard to glyercols, the glycerols may be mono-, di-, and tri-fatty substituted glycerols, or mixtures thereof. Thixotropic fats/waxes can also be used.
  • Suitable fat ingredients include, without limitation, glycerol fatty esters, fatty glyceride derivatives, waxes and fatty alcohols such as, for example, glycerol behenate (COMPRITOL®), glycerol palmitostearate (PRECIROL®), stearoyl macroglycerides (GELUCIRE® 50/13).
  • the fat/wax is glycerol behenate.
  • Waxes are very complex and difficult to classify. See Kirk-Othmer, Encyclopedia of Chemical Technology (4th ed. 1998) Vol. 25 pp. 614-26, the text of which is incorporated by reference. They often meet the criteria described previously for fats (e.g., HLB of about 6 or less and melting point of at least about 30° C., HLB of about 4 or less and a melting point of at least about 40° C., HLB of about 2 or less and a melting point of at least 50° C.), but waxes that do not meet these criteria may also be used. Waxes include, without limitation, insect and animal waxes, vegetable waxes, mineral waxes, petroleum waxes, and synthetic waxes.
  • the fat/wax is a fatty acid ester of glycerol.
  • the fatty acid ester of glycerol can be glycerol behenate.
  • Fat/waxes used in accordance with the present invention may be used in a molten form. It has been discovered, however, that even when used as a generally solid, non-molten form such as relatively small particles at room temperature, they can provide some, if not all of the advantages as molten materials. Any usable particle size which allows for proper formation of the granules or coating and which provides the desired properties may be used.
  • the first and second fat/wax are the same. In some cases, the first fat/wax may be present in an amount from about 0 to about 20 percent by weight of the granule. In some embodiments, the second fat/wax is present in an amount from about 5 to about 30 percent by weight of the coated granule.
  • the second fat/wax can be present from about 10 to about 25 percent by weight of the coated granule.
  • the fat/wax may be present in the coating of the granule but not in the core of the granule.
  • the granule further includes a stabilizing agent such as an antioxidant.
  • a stabilizing agent such as an antioxidant.
  • An antioxidant can be selected from butylated hydroxyanisole, ascorbic acid, glutathione, lipoic acid, uric acid, carotenes, ⁇ -tocopherol, selenium, resveratrol, tumeric, curcumin, ubiquinol, ascorbyl palmitate, butylated hydroxyl toluene, propyl gallate, citric acid, fumaric acid, malic acid, propionic acid, phosphoric acid, sodium sulfite, sodium thiosulfate, sodium bisulfite, sodium metabisulfite, potassium metabisulfite, methionine, erythorbic acid, ethyl oleate, sodium ascorbate, and mixtures thereof.
  • the antioxidant is present in an amount from about 0.001 to about 1% by weight of the granule (e.g. about 0.005 to about 0.2 percent; about 0.01 to about 0.2 percent). In some embodiments, the antioxidant is present in an amount of about 0.05 percent by weight of the granule.
  • an antioxidant can contribute to the stability of the dosage form.
  • the antioxidant can protect the dosage form from degradation due to oxidation.
  • use of an antioxidant in the dosage form is accompanied with removal of water from the manufacturing process.
  • the coated granule comprises less than about 5 percent water per weight of the coated granule.
  • the coated granule can have less than about 3 percent water per weight of the coated granule.
  • organic solvents may replace the water in the processing of the granules. For example, alcohol, such as ethanol, or acetone may be used.
  • coating is meant to encompass a material which substantially surrounds the granules and provides some additional function, such as, without limitation, taste masking, storage stability, reduced reactivity, controlled release, and/or abuse resistance.
  • the coating is present in an amount from about 30 to about 70 percent by weight of the coated granule.
  • the coating can be present in an amount of about 40 to about 60 percent by weight of the coated granule, including about 45 percent.
  • the sustained-release oral dosage form for once-a-day administration described herein comprises a matrix, wherein the matrix comprises hydroxypropylmethylcellulose in an amount from about 20 to about 60 percent by weight of the dosage form, for example, from about 30 to about 60 percent by weight, including about 35 percent by weight, of the dosage form; and coated granules, wherein the coated granules comprise a granule comprising hydromorphone or a salt form thereof in an amount from about 10 to about 60 percent by weight of the granule, ethylcellulose in an amount from about 10 to about 60 percent by weight of the granule, hydroxypropylmethylcellulose in an amount from about 10 to about 70 percent by weight of the granule, and glycerol behenate in an amount from about 0 to about 20 percent by weight of the granule; and a coating on the granule, wherein the coating is present in an amount from about 30 to about 70 percent by weight of the coated granule, and wherein
  • a sustained-oral dosage form comprises a matrix, wherein the matrix comprises hydroxypropylmethylcellulose in an amount of about 35 percent by weight of the dosage form; and coated granules, wherein the coated granules comprise a granule comprising hydromorphone hydrochloride in an amount of about 27 percent by weight of the granule, ethylcellulose in an amount from about 19 to about 21 percent by weight of the granule, and hydroxypropylmethylcellulose in an amount from about 51 to about 53 percent by weight of the granule; and a coating on the granule, wherein the coating is present in an amount of about 40, 45, 50, or 60 percent by weight of the coated granule, and wherein the coating comprises ethylcellulose in an amount from about 28 to about 32 percent by weight of the coated granule, and glycerol behenate in an amount from about 10 to about 20 percent by weight of the coated granule, including about 14 to about 16 percent by weight
  • coated granules and dosage forms as described herein can be prepared using methods known to those in the art, see, for example, U.S. Publication No. 2008/0311205, incorporated herein by reference.
  • hydromorphone or a salt form thereof is formulated into polymer-rich granules onto which a polymeric coat is applied.
  • the coated granules are subsequently mixed with a viscosity modifier.
  • the dosage form may also include at least one other ingredient or excipient in addition to the coated particle and viscosity modifier in the matrix.
  • the other ingredient or excipient may include, but is not limited to, taste masking agents, binders, fillers, sugars, artificial sweeteners, polymers, flavoring agents, coloring agents, lubricants, glidants, bio- or muco-adhesives, surfactants, buffers, and disintegrants.
  • the amount of any one or more of these ingredients will vary with the amount of coating, granule size, shape of the dosage form, form of the dosage form, number of ingredients used, the particular mixture of ingredients used, the number of dosage forms that will formulate a dose, the amount of hydromorphone per dose and the like. Any combination or amounts are contemplated sufficient to produce a dosage form having the described release profile and/or tamper-resistance provided.
  • Taste masking agent(s) include anything known to be used as a taste masking agents in this art. Examples include Eudragit E-100, ethylcellulose, hydroxypropylmethylcellulose, hydroxypropyl cellulose, methylcellulose, Hydroxyethylcellulose, carboxymethylcellulose, shellac, zein, carbomers, fats, waxes, glycerol mono-, di-, tri-glycerides, compritol, precirol, gelucires, poloxamers, modified chitosans, carrageenans, cellulose acetate trimellitate, hydroxypropyl methylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, methacrylic acid copolymers including Eudragit L 100, S100, L30D-55, polyvinylacetate phthalate (PVAP).
  • PVAP polyvinylacetate phthalate
  • Taste masking agents can be used in conventional amounts, for example, in an amount of about 0 to about 50 percent by weight of the total dosage form (e.g., about 5 to about 40 percent by weight of the total dosage form; about 10 to about 30 percent by weight of the total dosage form).
  • Binders can be used to add cohesiveness to powders and provide the necessary bonding to form granules that can be compressed into hard tablets that have acceptable mechanical strength to withstand subsequent processing or shipping and handling.
  • binders include acacia, tragacanth, gelatin, starch (both modified or unmodified), cellulose materials such as methylcellulose, ethylcellulose, hydroxypropylmethylcellulose, hydroxypropyl cellulose, hydroxyethylcellulose and sodium carboxy methylcellulose, alginic acids and salts thereof, magnesium aluminum silicate, polyethylene glycol, guar gum, polysaccharide acids, bentonites, sugars, invert sugars, and the like, fats, waxes, polyvinylpyrrolidone, polymethacrylate and other acrylic and vinyl-based polymers. Binders can be used in conventional amounts, for example, in an amount of about 0 to about 50 percent by weight of the total dosage form (e.g., about 2 to about 10 percent by weight of the total dosage
  • Fillers can include mannitol, dextrose, sorbitol, lactose, sucrose, and calcium carbonate. Fillers can be used in conventional amounts, for example, in an amount of about 0 to about 90 percent by weight of the total dosage form (e.g., from about 10 to about 50 percent by weight of the total dosage form).
  • a filler can be a sugar.
  • sugar sugar alcohols, ketoses, saccharides, polysaccharides, oligosaccharides and the like, as well as celluloses and modified celluloses.
  • Sugars may also include direct compression and/or non-direct compression sugars.
  • Non-direct compression sugars include, without limitation, dextrose, mannitol, sorbitol, trehalose, lactose and sucrose. These sugars generally exist as either a direct compression sugar, i.e., a sugar which has been modified to increase its compressibility and/or flow, or a non-direct compression sugar which does not have sufficient flowability and/or compressibility to allow it to be used in high speed processing and multi-tablet presses without some sort of augmentation such as, without limitation, a glidant to increase flow, granulation to increase flow and/or compressibility and the like. While not definitive, sometimes a non-direct compression sugar will have at least about 90% of its particles smaller than about 200 microns, and more preferably 80% smaller than about 150 microns.
  • the amount of total sugar can range from about 0 to about 90 (e.g., about 5 to about 75; about 10 and 50) by weight of the total dosage form.
  • Other non-carbohydrate diluents and fillers which may be used include, for example, dihydrated or anhydrous dibasic calcium phosphate, tricalcium phosphate, calcium carbonate, anhydrous or hydrated calcium sulphate, and calcium lactate trihydrate.
  • Non-carbohydrate diluents and fillers may be used in an amount of from about 0 to about 90 percent (e.g., from about 5 to about 75 percent; from about 10 to about 50 percent) by weight of the total dosage form.
  • Artificial sweeteners can include saccharin, aspartame, sucralose, neotame, and acesulfame potassium. Artificial sweeteners may be used in conventional amounts, for example, in an amount ranging from about 0.1 to about 2 percent by weight of the total dosage form.
  • Flavoring agents can include synthetic flavor oils and flavoring aromatics and/or natural oils, extracts from plants, leaves, flowers, fruits and so forth and combinations thereof.
  • flavoring agents are also useful as flavoring agents, citrus oil, including lemon, orange, banana, grape, lime and grapefruit, and fruit essences, including apple, pear, peach, strawberry, raspberry, cherry, plum, pineapple, apricot and so forth.
  • Flavoring agents may be used in conventional amounts, for example, in an amount ranging from about 0.01 to about 3 percent by weight of the dosage form (e.g., from about 0.1 to about 2.5 percent by weight of the dosage form; from about 0.25 to about 2 percent by weight of the dosage form).
  • Coloring agents can include titanium dioxide, iron oxides such as red or yellow iron oxide, and dyes suitable for food such as those known as FD&C dyes and natural coloring agents such as grape skin extract, beet red powder, beta-carotene, annatto, carmine, turmeric, and paprika. Coloring agents may be used in conventional amounts, for example, in an amount ranging from about 0.001 to about 1% by weight of the total dosage form.
  • Lubricants can include intrinsic or extrinsic lubricants.
  • Intrinsic lubricants may include magnesium, calcium, zinc salts of stearic acid, hydrogenated and partially hydrogenated vegetable oils, animal fats, polyethylene glycol, polyoxyethylene monostearate, talc, light mineral oils, magnesium oxide and the like.
  • Lubricants may be used in conventional amounts, for example, in an amount from about 0.1 to about 5 percent by weight of the dosage form (e.g., from about 0.25 to about 2.5 percent; from about 0.5 to about 2 percent).
  • Surfactants can include, without limitation, various grades of the following commercial products: Arlacel®, Tween®, Capmul®, Centrophase®, Cremophor®, Labrafac®, Labrafil®, Labrasol®, Myverol®, Tagat®, and any non-toxic short and medium chain alcohols.
  • Surfactants can be used in conventional amounts, for example, in an amount of about 0.01 to about 5 percent by weight of the dosage form (e.g., in an amount of about 0.1 to about 2 percent).
  • Buffers can include any weak acid or weak base or, preferably, any buffer system that is not harmful to the gastrointestinal mucosa. These include, but are not limited to, sodium carbonate, potassium carbonate, potassium carbonate, disodium hydrogen phosphate, sodium dihydrogen phosphate, and the equivalent potassium salts. Buffers can be used in conventional amounts, for example, in an amount of about 0.1 to about 10 percent by weight of the dosage form (e.g., from about 1 to about 5 percent).
  • the dosage form may also contain minor amounts of nontoxic substances such as wetting or emulsifying agents, pH buffering agents and the like, for example, sodium acetate, sorbitan monolaurate, triethanolamine, sodium acetate, triethanolamine oleate, sodium lauryl sulfate, dioctyl sodium sulfosuccinate, polyoxyethylene sorbitan fatty acid esters.
  • nontoxic substances such as wetting or emulsifying agents, pH buffering agents and the like, for example, sodium acetate, sorbitan monolaurate, triethanolamine, sodium acetate, triethanolamine oleate, sodium lauryl sulfate, dioctyl sodium sulfosuccinate, polyoxyethylene sorbitan fatty acid esters.
  • a “dosage form”, as used herein, is a tablet, capsule, caplet, sachet, powder or other solid known for the administration of medicines orally. It is generally made from a mixture as defined herein and is generally formed (as in a tablet) into a form for use by a doctor or patient for administration.
  • Dosage forms may be provided in a range of shapes and sizes.
  • the dosage form is in a size capable of oral administration and provides a therapeutic amount of hydromorphone.
  • dosage forms will be less than 1.5 inches in any one direction, more preferably less than 1 inch and most preferably less than 0.75 inch.
  • Shapes include but not limited to round with both flat or convex face, capsule shape (caplets), diamond shape, triangular, rectangular, hexagonal, pentagonal, heart-shaped, animal shaped tablets like rabbits, elephants etc.
  • Dosage forms can be any size and shape, but preferable of a size and shape to avoid crushing or abuse.
  • Dosage forms are formulated for once-a-day administration.
  • the amount of hydromorphone present in the dosage form can vary from about 2 mg to about 70 mg (e.g. 2 mg, 4 mg, 8 mg, 12 mg, 16 mg, 24 mg, 32 mg, and 64 mg).
  • the dosage form may be used to manage persistent, moderate-to-severe pain in patients requiring continuous, around-the-clock pain relief for an extended period of time.
  • the tablet can have a hardness from about 20-300 Newtons.
  • Tablets can either be manufactured by direct compression, wet granulation, dry granulation followed by coating and tablet compression or any other tablet manufacturing technique. See, e.g., U.S. Pat. Nos. 5,178,878, 5,223,264 and 6,024,981 which are incorporated by reference herein.
  • Granules were manufactured in a high shear granulator where hydromorphone HCl, hydroxypropylmethylcellulose, compritol, and a portion of the ethylcellulose were dry mixed for 2 minutes. Then, a 10% hydro-ethanolic (30:70) solution of the remaining ethylcellulose was slowly added while maintaining the granulator impeller and chopper speeds at pre-selected values to provide enough shear for granule formation and growth. Solution addition was continued until the aforementioned percentage of ethylcellulose was realized. The granules were then milled in a granumill and finally dried.
  • the uncoated granules were then coated in a bottom spray fluid bed using a 15% alcoholic suspension of a 2:1 ethylcellulose/compritol mixture to provide a coat of 50% by weight of the coated granules.
  • Coated granules were mixed with lactose and hydroxypropylmethylcellulose in a V-blender for a period of about 30 minutes. Magnesium stearate was added and the mixture blended for an additional 5 minutes. The amount of coated granules charged into the tablet is based on the actual coated granule content of hydromorphone, it is not based on the theoretical content.
  • the blended mixture was then compressed in a rotary tablet press to form tablets.
  • the 3 ⁇ 8 inch round tablets weighed 400 mg and had an average hardness of 82 N.
  • Granules were manufactured in a high shear granulator where hydromorphone HCl, hydroxypropylmethylcellulose, compritol, and a portion of the ethylcellulose were dry mixed for 2 minutes. Then, a 10% hydro-ethanolic (30:70) solution of the remaining ethylcellulose was slowly added while maintaining the granulator impeller and chopper speeds at pre-selected values to provide enough shear for granule formation and growth. Solution addition was continued until the aforementioned percentage of ethylcellulose was realized. The granules were then milled in a granumill and finally dried.
  • the uncoated granules were then coated in a bottom spray fluid bed using a 15% alcoholic suspension of a 2:1 ethylcellulose/compritol mixture to provide a coat of 50% by weight of the coated granules.
  • Coated granules were mixed with lactose and hydroxypropylmethylcellulose in a V-blender for a period of about 30 minutes. Magnesium stearate was added and the mixture blended for an additional 5 minutes. The amount of coated granules charged into the tablet is based on the actual coated granule content of hydromorphone, it is not based on the theoretical content.
  • the blended mixture was then compressed in a rotary tablet press to form tablets.
  • the 3 ⁇ 8 inch round tablets weighed 400 mg and had an average hardness of 88 N.
  • Granules were manufactured in a high shear granulator where hydromorphone HCl, hydroxypropylmethylcellulose, compritol, and a portion of the ethylcellulose were dry mixed for 2 minutes. Then, a 10% hydro-ethanolic (30:70) solution of the remaining ethylcellulose was slowly added while maintaining the granulator impeller and chopper speeds at pre-selected values to provide enough shear for granule formation and growth. Solution addition was continued until the aforementioned percentage of ethylcellulose was realized. The granules were then milled in a granumill and finally dried.
  • the uncoated granules were then coated in a bottom spray fluid bed using a 15% alcoholic suspension of a 2:1 ethylcellulose/compritol mixture to provide a coat of 50% by weight of the coated granules.
  • Coated granules were mixed with lactose and hydroxypropylmethylcellulose in a V-blender for a period of about 30 minutes. Magnesium stearate was added and the mixture blended for an additional 5 minutes. The amount of coated granules charged into the tablet is based on the actual coated granule content of hydromorphone, it is not based on the theoretical content.
  • the blended mixture was then compressed in a rotary tablet press to form tablets.
  • the 3 ⁇ 8 inch round tablets weighed 400 mg and had an average hardness of 66 N.
  • Granules were manufactured in a high shear granulator where hydromorphone HCl, hydroxypropylmethylcellulose, compritol, and a portion of the ethylcellulose were dry mixed for 2 minutes. Then, a 10% hydro-ethanolic (30:70) solution of the remaining ethylcellulose was slowly added while maintaining the granulator impeller and chopper speeds at pre-selected values to provide enough shear for granule formation and growth. Solution addition was continued until the aforementioned percentage of ethylcellulose was realized. The granules were then milled in a granumill and finally dried.
  • the uncoated granules were then coated in a bottom spray fluid bed using a 15% alcoholic suspension of a 2:1 ethylcellulose/magnesium stearate mixture to provide a coat of 50% by weight of the coated granules.
  • Coated granules were mixed with lactose and hydroxypropylmethylcellulose in a V-blender for a period of about 30 minutes. Magnesium stearate was added and the mixture blended for an additional 5 minutes. The amount of coated granules charged into the tablet is based on the actual coated granule content of hydromorphone, it is not based on the theoretical content.
  • the blended mixture was then compressed in a rotary tablet press to form tablets.
  • the 3 ⁇ 8 inch round tablets weighed 400 mg and had an average hardness of 36 N.
  • Granules were manufactured in a high shear granulator where hydromorphone HCl, hydroxypropylmethylcellulose and a portion of the ethylcellulose and were dry mixed for 2 minutes. Then, an ethanolic solution of the remaining ethylcellulose and ⁇ -tocopherol was slowly added while maintaining the granulator impeller and chopper speeds at pre-selected values to provide enough shear for granule formation and growth. Solution addition was continued until the aforementioned percentage of ethylcellulose was realized. The granules were then milled in a granumill and finally dried.
  • the uncoated granules were then coated in a bottom spray fluid bed using a 15% alcoholic suspension of a 2:1 ethylcellulose/compritol mixture to provide a coat of 50% by weight of the coated granules.
  • Coated granules were mixed with lactose and hydroxypropylmethylcellulose in a V-blender for a period of about 30 minutes. Magnesium stearate was added and the mixture blended for an additional 5 minutes. The amount of coated granules charged into the tablet is based on the actual coated granule content of hydromorphone, it is not based on the theoretical content.
  • the blended mixture was then compressed in a rotary tablet press to form tablets.
  • the 3 ⁇ 8 inch round tablets weighed 400 mg and had an average hardness of 58 N.
  • Granules were manufactured in a high shear granulator where hydromorphone HCl, hydroxypropylmethylcellulose and a portion of the ethylcellulose and were dry mixed for 2 minutes. Then, an ethanolic solution of the remaining ethylcellulose and butylated hydroxyanisole was slowly added while maintaining the granulator impeller and chopper speeds at pre-selected values to provide enough shear for granule formation and growth. Solution addition was continued until the aforementioned percentage of ethylcellulose was realized. The granules were then milled in a granumill and finally dried.
  • the uncoated granules were then coated in a bottom spray fluid bed using a 15% alcoholic suspension of a 2:1 ethylcellulose/compritol mixture to provide a coat of 50% by weight of the coated granules.
  • Coated granules were mixed with lactose and hydroxypropylmethylcellulose in a V-blender for a period of about 30 minutes. Magnesium stearate was added and the mixture blended for an additional 5 minutes. The amount of coated granules charged into the tablet is based on the actual coated granule content of hydromorphone, it is not based on the theoretical content.
  • the blended mixture was then compressed in a rotary tablet press to form tablets.
  • the 3 ⁇ 8 inch round tablets weighed 400 mg and had an average hardness of 62 N.
  • Granules were manufactured in a high shear granulator where hydromorphone HCl, hydroxypropylmethylcellulose and a portion of the ethylcellulose and were dry mixed for 2 minutes. Then, an ethanolic solution of the remaining ethylcellulose and butylated hydroxyanisole was slowly added while maintaining the granulator impeller and chopper speeds at pre-selected values to provide enough shear for granule formation and growth. Solution addition was continued until the aforementioned percentage of ethylcellulose was realized. The granules were then milled in a granumill and finally dried.
  • the uncoated granules were then coated in a bottom spray fluid bed using a 15% alcoholic suspension of a 2:1 ethylcellulose/compritol mixture to provide a coat of 50% by weight of the coated granules.
  • Coated granules were mixed with lactose and hydroxypropylmethylcellulose in a V-blender for a period of about 30 minutes. Magnesium stearate was added and the mixture blended for an additional 5 minutes. The amount of coated granules charged into the tablet is based on the actual coated granule content of hydromorphone, it is not based on the theoretical content.
  • the blended mixture was then compressed in a rotary tablet press to form tablets.
  • the 3 ⁇ 8 inch round tablets weighed 400 mg and had an average hardness of 152 N.
  • Granules were manufactured in a high shear granulator where hydromorphone HCl, hydroxypropylmethylcellulose and a portion of the ethylcellulose and were dry mixed for 2 minutes. Then, an ethanolic solution of the remaining ethylcellulose and butylated hydroxyanisole was slowly added while maintaining the granulator impeller and chopper speeds at pre-selected values to provide enough shear for granule formation and growth. Solution addition was continued until the aforementioned percentage of ethylcellulose was realized. The granules were then milled in a granumill and finally dried.
  • the uncoated granules were then coated in a bottom spray fluid bed using a 15% alcoholic suspension of a 2:1 ethylcellulose/compritol mixture to provide a coat of 50% by weight of the coated granules.
  • Coated granules were mixed with lactose and hydroxypropylmethylcellulose in a V-blender for a period of about 30 minutes. Magnesium stearate was added and the mixture blended for an additional 5 minutes. The amount of coated granules charged into the tablet is based on the actual coated granule content of hydromorphone, it is not based on the theoretical content.
  • the blended mixture was then compressed in a rotary tablet press to form tablets.
  • the 1 ⁇ 2 inch round tablets weighed 600 mg and had an average hardness of 97 N.
  • Granules were manufactured in a high shear granulator where hydromorphone HCl, hydroxypropylmethylcellulose and a portion of the ethylcellulose and were dry mixed for 2 minutes. Then, an ethanolic solution of the remaining ethylcellulose and butylated hydroxyanisole was slowly added while maintaining the granulator impeller and chopper speeds at pre-selected values to provide enough shear for granule formation and growth. Solution addition was continued until the aforementioned percentage of ethylcellulose was realized. The granules were then milled in a granumill and finally dried.
  • the uncoated granules were then coated in a bottom spray fluid bed using a 15% alcoholic suspension of a 2:1 ethylcellulose/compritol mixture to provide a coat of 55% by weight of the coated granules.
  • Coated granules were mixed with lactose and hydroxypropylmethylcellulose in a V-blender for a period of about 30 minutes. Magnesium stearate was added and the mixture blended for an additional 5 minutes. The amount of coated granules charged into the tablet is based on the actual coated granule content of hydromorphone, it is not based on the theoretical content.
  • the blended mixture was then compressed in a rotary tablet press to form tablets.
  • the capsule-shaped tablets (0.625 ⁇ 0.275 in) weighed 600 mg and had an average hardness of 138 N.
  • Granules were manufactured in a high shear granulator where hydromorphone HCl, hydroxypropylmethylcellulose, compritol, and a portion of the ethylcellulose were dry mixed for 2 minutes. Then, an ethanolic solution of the remaining ethylcellulose and butylated hydroxyanisole was slowly added while maintaining the granulator impeller and chopper speeds at pre-selected values to provide enough shear for granule formation and growth. Solution addition was continued until the aforementioned percentage of ethylcellulose was realized. The granules were then milled in a granumill and finally dried.
  • the uncoated granules were then coated in a bottom spray fluid bed using a 15% alcoholic suspension of a 2:1 ethylcellulose/compritol mixture to provide a coat of 55% by weight of the coated granules.
  • Coated granules were mixed with lactose and hydroxypropylmethylcellulose in a V-blender for a period of about 30 minutes. Magnesium stearate was added and the mixture blended for an additional 5 minutes. The amount of coated granules charged into the tablet is based on the actual coated granule content of hydromorphone, it is not based on the theoretical content.
  • the blended mixture was then compressed in a rotary tablet press to form tablets.
  • the capsule-shaped tablets (0.625 ⁇ 0.275 in) weighed 500 mg and had an average hardness of 56 N.
  • Granules were manufactured in a high shear granulator where hydromorphone HCl, hydroxypropylmethylcellulose, compritol, and a portion of the ethylcellulose were dry mixed for 2 minutes. Then, an ethanolic solution of the remaining ethylcellulose and butylated hydroxyanisole was slowly added while maintaining the granulator impeller and chopper speeds at pre-selected values to provide enough shear for granule formation and growth. Solution addition was continued until the aforementioned percentage of ethylcellulose was realized. The granules were then milled in a granumill and finally dried.
  • the uncoated granules were then coated in a bottom spray fluid bed using a 15% alcoholic suspension of a 2:1 ethylcellulose/compritol mixture to provide a coat of 55% by weight of the coated granules.
  • Coated granules were mixed with lactose and hydroxypropylmethylcellulose in a V-blender for a period of about 30 minutes. Magnesium stearate was added and the mixture blended for an additional 5 minutes. The amount of coated granules charged into the tablet is based on the actual coated granule content of hydromorphone, it is not based on the theoretical content.
  • the blended mixture was then compressed in a rotary tablet press to form tablets.
  • the 5/16 inch round tablets weighed 187.5 mg and had an average hardness of 23 N.
  • Granules were manufactured in a high shear granulator where hydromorphone HCl, hydroxypropylmethylcellulose and a portion of the ethylcellulose were dry mixed for 2 minutes. Then, an ethanolic solution of the remaining ethylcellulose and butylated hydroxyanisole was slowly added while maintaining the granulator impeller and chopper speeds at pre-selected values to provide enough shear for granule formation and growth. Solution addition was continued until the aforementioned percentage of ethylcellulose was realized. The granules were then milled in a granumill and finally dried.
  • the uncoated granules were then coated in a bottom spray fluid bed using a 15% alcoholic suspension of a 2:1 ethylcellulose/compritol mixture to provide a coat of 50% by weight of the coated granules.
  • Coated granules were mixed with lactose and hydroxypropylmethylcellulose in a V-blender for a period of about 30 minutes. Magnesium stearate was added and the mixture blended for an additional 5 minutes. The amount of coated granules charged into the tablet is based on the actual coated granule content of hydromorphone, it is not based on the theoretical content.
  • the blended mixture was then compressed in a rotary tablet press to form tablets.
  • the blended mixture was then compressed in a rotary tablet press to form tablets.
  • the capsule-shaped tablets (0.625 ⁇ 0.275 in) weighed 600 mg and had an average hardness of 241 N.
  • Granules were manufactured in a high shear granulator where hydromorphone HCl, hydroxypropylmethylcellulose and a portion of the ethylcellulose were dry mixed for 2 minutes. Then, an ethanolic solution of the remaining ethylcellulose and butylated hydroxyanisole was slowly added while maintaining the granulator impeller and chopper speeds at pre-selected values to provide enough shear for granule formation and growth. Solution addition was continued until the aforementioned percentage of ethylcellulose was realized. The granules were then milled in a granumill and finally dried.
  • the uncoated granules were then coated in a bottom spray fluid bed using a 15% alcoholic suspension of a 2:1 ethylcellulose/compritol mixture to provide a coat of 50% by weight of the coated granules.
  • Coated granules were mixed with lactose and hydroxypropylmethylcellulose in a V-blender for a period of about 30 minutes. Magnesium stearate was added and the mixture blended for an additional 5 minutes. The amount of coated granules charged into the tablet is based on the actual coated granule content of hydromorphone, it is not based on the theoretical content.
  • the blended mixture was then compressed in a rotary tablet press to form tablets.
  • the blended mixture was then compressed in a rotary tablet press to form tablets.
  • the capsule-shaped tablets (0.625 ⁇ 0.275 in) weighed 600 mg and had an average hardness of 239 N.
  • Granules were manufactured in a high shear granulator where hydromorphone HCl, hydroxypropylmethylcellulose and a portion of the ethylcellulose were dry mixed for 2 minutes. Then, an ethanolic solution of the remaining ethylcellulose and butylated hydroxyanisole was slowly added while maintaining the granulator impeller and chopper speeds at pre-selected values to provide enough shear for granule formation and growth. Solution addition was continued until the aforementioned percentage of ethylcellulose was realized. The granules were then milled in a granumill and finally dried.
  • the uncoated granules were then coated in a bottom spray fluid bed using a 15% alcoholic suspension of a 2:1 ethylcellulose/compritol mixture to provide a coat of 50% by weight of the coated granules.
  • Coated granules were mixed with lactose, hydroxypropylmethylcellulose, and Celpheres CP-203 in a V-blender for a period of about 30 minutes. Magnesium stearate was added and the mixture blended for an additional 5 minutes. The amount of coated granules charged into the tablet is based on the actual coated granule content of hydromorphone, it is not based on the theoretical content.
  • the blended mixture was then compressed in a rotary tablet press to form tablets.
  • the blended mixture was then compressed in a rotary tablet press to form tablets.
  • the capsule-shaped tablets (0.625 ⁇ 0.275 in) weighed 600 mg and had an average hardness of 156 N.
  • Granules were manufactured in a high shear granulator where hydromorphone HCl, hydroxypropylmethylcellulose and a portion of the ethylcellulose were dry mixed for 2 minutes. Then, an ethanolic solution of the remaining ethylcellulose and butylated hydroxyanisole was slowly added while maintaining the granulator impeller and chopper speeds at pre-selected values to provide enough shear for granule formation and growth. Solution addition was continued until the aforementioned percentage of ethylcellulose was realized. The granules were then milled in a granumill and finally dried.
  • the uncoated granules were then coated in a bottom spray fluid bed using a 15% alcoholic suspension of a 2:1 ethylcellulose/compritol mixture to provide a coat of 50% by weight of the coated granules.
  • Coated granules were mixed with lactose and hydroxypropylmethylcellulose in a V-blender for a period of about 30 minutes. Magnesium stearate was added and the mixture blended for an additional 5 minutes. The amount of coated granules charged into the tablet is based on the actual coated granule content of hydromorphone, it is not based on the theoretical content.
  • the blended mixture was then compressed in a rotary tablet press to form tablets.
  • the blended mixture was then compressed in a rotary tablet press to form tablets.
  • the capsule-shaped tablets (0.625 ⁇ 0.275 in) weighed 600 mg and had an average hardness of 48 N.
  • Granules were manufactured in a high shear granulator where hydromorphone HCl, hydroxypropylmethylcellulose and a portion of the ethylcellulose were dry mixed for 2 minutes Then, an ethanolic solution of the remaining ethylcellulose and butylated hydroxyanisole was slowly added while maintaining the granulator impeller and chopper speeds at pre-selected values to provide enough shear for granule formation and growth. Solution addition was continued until the aforementioned percentage of ethylcellulose was realized. The granules were then milled in a granumill and finally dried.
  • the uncoated granules were then coated in a bottom spray fluid bed using a 15% alcoholic suspension of a 2:1 ethylcellulose/compritol mixture to provide a coat of 50% by weight of the coated granules.
  • the color and Avicel PH 113 were blended in a V-blender for 15 minutes and milled. The milled blend was blended with coated granules, lactose and hydroxypropylmethylcellulose for 30 minutes. Magnesium stearate was added and the mixture blended for an additional 5 minutes. The amount of coated granules charged into the tablet is based on the actual coated granule content of hydromorphone, it is not based on the theoretical content.
  • the blended mixture was then compressed in a rotary tablet press to form tablets.
  • the blended mixture was then compressed in a rotary tablet press to form tablets.
  • the capsule-shaped tablets (0.625 ⁇ 0.275 in) weighed 600 mg and had an average hardness of 154 N.
  • Granules were manufactured in a high shear granulator where hydromorphone HCl, hydroxypropylmethylcellulose and a portion of the ethylcellulose were dry mixed for 2 minutes. Then, an ethanolic solution of the remaining ethylcellulose and butylated hydroxyanisole was slowly added while maintaining the granulator impeller and chopper speeds at pre-selected values to provide enough shear for granule formation and growth. Solution addition was continued until the aforementioned percentage of ethylcellulose was realized. The granules were then milled in a granumill and finally dried.
  • the uncoated granules were then coated in a bottom spray fluid bed using a 15% alcoholic suspension of a 2:1 ethylcellulose/compritol mixture to provide a coat of 45% by weight of the coated granules.
  • Coated granules were mixed with lactose and hydroxypropylmethylcellulose in a V-blender for a period of about 30 minutes. Magnesium stearate was added and the mixture blended for an additional 5 minutes. The amount of coated granules charged into the tablet is based on the actual coated granule content of hydromorphone, it is not based on the theoretical content.
  • the blended mixture was then compressed in a rotary tablet press to form tablets.
  • the capsule-shaped tablets (0.5000 ⁇ 0.3125 in) weighed 600 mg and had an average hardness of 61 N.
  • Granules were manufactured in a high shear granulator where hydromorphone HCl, hydroxypropylmethylcellulose and a portion of the ethylcellulose were dry mixed for 2 minutes. Then, an ethanolic solution of the remaining ethylcellulose and butylated hydroxyanisole was slowly added while maintaining the granulator impeller and chopper speeds at pre-selected values to provide enough shear for granule formation and growth. Solution addition was continued until the aforementioned percentage of ethylcellulose was realized. The granules were then milled in a granumill and finally dried.
  • the uncoated granules were then coated in a bottom spray fluid bed using a 15% alcoholic suspension of a 2:1 ethylcellulose/compritol mixture to provide a coat of 50% by weight of the coated granules.
  • Coated granules were mixed with lactose and hydroxypropylmethylcellulose in a V-blender for a period of about 30 minutes. Magnesium stearate was added and the mixture blended for an additional 5 minutes. The amount of coated granules charged into the tablet is based on the actual coated granule content of hydromorphone, it is not based on the theoretical content.
  • the blended mixture was then compressed in a rotary tablet press to form tablets.
  • the blended mixture was then compressed in a rotary tablet press to form tablets.
  • the 3 ⁇ 8 inch round tablets weighed 400 mg and had an average hardness of 128 N.
  • Granules were manufactured in a high shear granulator where hydromorphone HCl, hydroxypropylmethylcellulose and a portion of the ethylcellulose were dry mixed for 2 minutes. Then, an ethanolic solution of the remaining ethylcellulose and butylated hydroxyanisole was slowly added while maintaining the granulator impeller and chopper speeds at pre-selected values to provide enough shear for granule formation and growth. Solution addition was continued until the aforementioned percentage of ethylcellulose was realized. The granules were then milled in a granumill and finally dried.
  • the uncoated granules were then coated in a bottom spray fluid bed using a 15% alcoholic suspension of a 2:1 ethylcellulose/compritol mixture to provide a coat of 50% by weight of the coated granules.
  • Coated granules were mixed with lactose and hydroxypropylmethylcellulose in a V-blender for a period of about 30 minutes. Magnesium stearate was added and the mixture blended for an additional 5 minutes. The amount of coated granules charged into the tablet is based on the actual coated granule content of hydromorphone, it is not based on the theoretical content.
  • the blended mixture was then compressed in a rotary tablet press to form tablets.
  • the blended mixture was then compressed in a rotary tablet press to form tablets.
  • the 3 ⁇ 8 inch round tablets weighed 400 mg and had an average hardness of 143 N.
  • Granules were manufactured in a high shear granulator where hydromorphone HCl, hydroxypropylmethylcellulose and a portion of the ethylcellulose were dry mixed for 2 minutes. Then, an ethanolic solution of the remaining ethylcellulose and butylated hydroxyanisole was slowly added while maintaining the granulator impeller and chopper speeds at pre-selected values to provide enough shear for granule formation and growth. Solution addition was continued until the aforementioned percentage of ethylcellulose was realized. The granules were then milled in a granumill and finally dried.
  • the uncoated granules were then coated in a bottom spray fluid bed using a 15% alcoholic suspension of a 2:1 ethylcellulose/compritol mixture to provide a coat of 50% by weight of the coated granules.
  • Coated granules were mixed with lactose and hydroxypropylmethylcellulose in a V-blender for a period of about 30 minutes. Magnesium stearate was added and the mixture blended for an additional 5 minutes. The amount of coated granules charged into the tablet is based on the actual coated granule content of hydromorphone, it is not based on the theoretical content.
  • the blended mixture was then compressed in a rotary tablet press to form tablets.
  • the blended mixture was then compressed in a rotary tablet press to form tablets.
  • the 3 ⁇ 8 inch round tablets weighed 400 mg and had an average hardness of 89 N.
  • Granules were manufactured in a high shear granulator where hydromorphone HCl, hydroxypropylmethylcellulose and a portion of the ethylcellulose were dry mixed for 2 minutes. Then, an ethanolic solution of the remaining ethylcellulose and butylated hydroxyanisole was slowly added while maintaining the granulator impeller and chopper speeds at pre-selected values to provide enough shear for granule formation and growth. Solution addition was continued until the aforementioned percentage of ethylcellulose was realized. The granules were then milled in a granumill and finally dried.
  • the uncoated granules were then coated in a bottom spray fluid bed using a 15% alcoholic suspension of a 2:1 ethylcellulose/compritol mixture to provide a coat of 50% by weight of the coated granules.
  • Coated granules were mixed with lactose and hydroxypropylmethylcellulose in a V-blender for a period of about 30 minutes. Magnesium stearate was added and the mixture blended for an additional 5 minutes. The amount of coated granules charged into the tablet is based on the actual coated granule content of hydromorphone, it is not based on the theoretical content.
  • the blended mixture was then compressed in a rotary tablet press to form tablets.
  • the blended mixture was then compressed in a rotary tablet press to form tablets.
  • the 1 ⁇ 2 inch round tablets weighed 600 mg and had an average hardness of 80 N.
  • Granules were manufactured in a high shear granulator where hydromorphone HCl, hydroxypropylmethylcellulose and a portion of the ethylcellulose were dry mixed for 2 minutes. Then, an ethanolic solution of the remaining ethylcellulose and butylated hydroxyanisole was slowly added while maintaining the granulator impeller and chopper speeds at pre-selected values to provide enough shear for granule formation and growth. Solution addition was continued until the aforementioned percentage of ethylcellulose was realized. The granules were then milled in a granumill and finally dried.
  • the uncoated granules were then coated in a bottom spray fluid bed using a 15% alcoholic suspension of a 2:1 ethylcellulose/compritol mixture to provide a coat of 50% by weight of the coated granules.
  • Coated granules were mixed with lactose and hydroxypropylmethylcellulose in a V-blender for a period of about 30 minutes. Magnesium stearate was added and the mixture blended for an additional 5 minutes. The amount of coated granules charged into the tablet is based on the actual coated granule content of hydromorphone, it is not based on the theoretical content.
  • the blended mixture was then compressed in a rotary tablet press to form tablets.
  • the blended mixture was then compressed in a rotary tablet press to form tablets.
  • the 1 ⁇ 2 inch round tablets weighed 600 mg and had an average hardness of 92 N.
  • Granules were manufactured in a high shear granulator where hydromorphone HCl, hydroxypropylmethylcellulose and a portion of the ethylcellulose were dry mixed for 2 minutes. Then, an ethanolic solution of the remaining ethylcellulose and butylated hydroxyanisole was slowly added while maintaining the granulator impeller and chopper speeds at pre-selected values to provide enough shear for granule formation and growth. Solution addition was continued until the aforementioned percentage of ethylcellulose was realized. The granules were then milled in a granumill and finally dried.
  • the uncoated granules were then coated in a bottom spray fluid bed using a 15% alcoholic suspension of a 2:1 ethylcellulose/compritol mixture to provide a coat of 50% by weight of the coated granules.
  • Coated granules were mixed with lactose and hydroxypropylmethylcellulose in a V-blender for a period of about 30 minutes. Magnesium stearate was added and the mixture blended for an additional 5 minutes. The amount of coated granules charged into the tablet is based on the actual coated granule content of hydromorphone, it is not based on the theoretical content.
  • the blended mixture was then compressed in a rotary tablet press to form tablets.
  • the blended mixture was then compressed in a rotary tablet press to form tablets.
  • the capsule-shaped tablets (0.625 ⁇ 0.275 in) weighed 600 mg and had an average hardness of 161 N.
  • Granules were manufactured in a high shear granulator where hydromorphone HCl, hydroxypropylmethylcellulose and a portion of the ethylcellulose were dry mixed for 2 minutes. Then, an ethanolic solution of the remaining ethylcellulose and butylated hydroxyanisole was slowly added while maintaining the granulator impeller and chopper speeds at pre-selected values to provide enough shear for granule formation and growth. Solution addition was continued until the aforementioned percentage of ethylcellulose was realized. The granules were then milled in a granumill and finally dried.
  • the uncoated granules were then coated in a bottom spray fluid bed using a 15% alcoholic suspension of a 2:1 ethylcellulose/compritol mixture to provide a coat of 60% by weight of the coated granules.
  • Coated granules were mixed with lactose and hydroxypropylmethylcellulose in a V-blender for a period of about 30 minutes. Magnesium stearate was added and the mixture blended for an additional 5 minutes. The amount of coated granules charged into the tablet is based on the actual coated granule content of hydromorphone, it is not based on the theoretical content.
  • the blended mixture was then compressed in a rotary tablet press to form tablets.
  • the blended mixture was then compressed in a rotary tablet press to form tablets.
  • the capsule-shaped tablets (0.625 ⁇ 0.275 in) weighed 600 mg and had an average hardness of 135 N.
  • Granules were manufactured in a high shear granulator where hydromorphone HCl, hydroxypropylmethylcellulose and a portion of the ethylcellulose were dry mixed for 2 minutes. Then, an ethanolic solution of the remaining ethylcellulose and butylated hydroxyanisole was slowly added while maintaining the granulator impeller and chopper speeds at pre-selected values to provide enough shear for granule formation and growth. Solution addition was continued until the aforementioned percentage of ethylcellulose was realized. The granules were then milled in a granumill and finally dried.
  • the uncoated granules were then coated in a bottom spray fluid bed using a 15% alcoholic suspension of a 2:1 ethylcellulose/compritol mixture to provide a coat of 40% by weight of the coated granules.
  • Coated granules were mixed with lactose and hydroxypropylmethylcellulose in a V-blender for a period of about 30 minutes. Magnesium stearate was added and the mixture blended for an additional 5 minutes. The amount of coated granules charged into the tablet is based on the actual coated granule content of hydromorphone, it is not based on the theoretical content.
  • the blended mixture was then compressed in a rotary tablet press to form tablets.
  • the capsule-shaped tablets (0.625 ⁇ 0.275 in) weighed 500 mg and had an average hardness of 85 N.
  • Granules were manufactured in a high shear granulator where hydromorphone HCl, hydroxypropylmethylcellulose and a portion of the ethylcellulose were dry mixed for 2 minutes. Then, an ethanolic solution of the remaining ethylcellulose and butylated hydroxyanisole was slowly added while maintaining the granulator impeller and chopper speeds at pre-selected values to provide enough shear for granule formation and growth. Solution addition was continued until the aforementioned percentage of ethylcellulose was realized. The granules were then milled in a granumill and finally dried.
  • the uncoated granules were then coated in a bottom spray fluid bed using a 15% alcoholic suspension of a 2:1 ethylcellulose/compritol mixture to provide a coat of 50% by weight of the coated granules.
  • Coated granules were mixed with lactose and hydroxypropylmethylcellulose in a V-blender for a period of about 30 minutes. Magnesium stearate was added and the mixture blended for an additional 5 minutes. The amount of coated granules charged into the tablet is based on the actual coated granule content of hydromorphone, it is not based on the theoretical content.
  • the blended mixture was then compressed in a rotary tablet press to form tablets.
  • the capsule-shaped tablets (0.625 ⁇ 0.275 in) weighed 600 mg and had an average hardness of 210 N.
  • Granules were manufactured in a high shear granulator where hydromorphone HCl, hydroxypropylmethylcellulose and a portion of the ethylcellulose were dry mixed for 2 minutes. Then, an ethanolic solution of the remaining ethylcellulose and butylated hydroxyanisole was slowly added while maintaining the granulator impeller and chopper speeds at pre-selected values to provide enough shear for granule formation and growth. Solution addition was continued until the aforementioned percentage of ethylcellulose was realized. The granules were then milled in a granumill and finally dried.
  • the uncoated granules were then coated in a bottom spray fluid bed using a 15% alcoholic suspension of a 2:1 ethylcellulose/compritol mixture to provide a coat of 50% by weight of the coated granules.
  • Coated granules were mixed with lactose, hydroxypropylmethylcellulose, and Avicel PH-102 in a V-blender for a period of about 30 minutes. Magnesium stearate was added and the mixture blended for an additional 5 minutes. The amount of coated granules charged into the tablet is based on the actual coated granule content of hydromorphone, it is not based on the theoretical content.
  • the blended mixture was then compressed in a rotary tablet press to form tablets.
  • the capsule-shaped tablets (0.625 ⁇ 0.275 in) weighed 600 mg and had an average hardness of 260 N.
  • Granules were manufactured in a high shear granulator where hydromorphone HCl, hydroxypropylmethylcellulose and a portion of the ethylcellulose were dry mixed for 2 minutes. Then, an ethanolic solution of the remaining ethylcellulose and butylated hydroxyanisole was slowly added while maintaining the granulator impeller and chopper speeds at pre-selected values to provide enough shear for granule formation and growth. Solution addition was continued until the aforementioned percentage of ethylcellulose was realized. The granules were then milled in a granumill and finally dried.
  • the uncoated granules were then coated in a bottom spray fluid bed using a 15% alcoholic suspension of a 2:1 ethylcellulose/compritol mixture to provide a coat of 50% by weight of the coated granules.
  • Coated granules were mixed with lactose and hydroxypropylmethylcellulose in a V-blender for a period of about 30 minutes. Magnesium stearate was added and the mixture blended for an additional 5 minutes. The amount of coated granules charged into the tablet is based on the actual coated granule content of hydromorphone, it is not based on the theoretical content.
  • the blended mixture was then compressed in a rotary tablet press to form tablets.
  • the capsule-shaped tablets (0.625 ⁇ 0.275 in) weighed 600 mg and had an average hardness of 256 N.
  • Granules were manufactured in a high shear granulator where hydromorphone HCl, hydroxypropylmethylcellulose and a portion of the ethylcellulose were dry mixed for 2 minutes. Then, an ethanolic solution of the remaining ethylcellulose and butylated hydroxyanisole was slowly added while maintaining the granulator impeller and chopper speeds at pre-selected values to provide enough shear for granule formation and growth. Solution addition was continued until the aforementioned percentage of ethylcellulose was realized. The granules were then milled in a granumill and finally dried.
  • the uncoated granules were then coated in a bottom spray fluid bed using a 15% alcoholic suspension of a 2:1 ethylcellulose/compritol mixture to provide a coat of 60% by weight of the coated granules.
  • Coated granules were mixed with lactose and hydroxypropylmethylcellulose in a V-blender for a period of about 30 minutes. Magnesium stearate was added and the mixture blended for an additional 5 minutes. The amount of coated granules charged into the tablet is based on the actual coated granule content of hydromorphone, it is not based on the theoretical content.
  • the blended mixture was then compressed in a rotary tablet press to form tablets.
  • the capsule-shaped tablets (0.625 ⁇ 0.275 in) weighed 600 mg and had an average hardness of 106 N.
  • Granules were manufactured in a high shear granulator where hydromorphone HCl, hydroxypropylmethylcellulose and a portion of the ethylcellulose were dry mixed for 2 minutes. Then, an ethanolic solution of the remaining ethylcellulose and butylated hydroxyanisole was slowly added while maintaining the granulator impeller and chopper speeds at pre-selected values to provide enough shear for granule formation and growth. Solution addition was continued until the aforementioned percentage of ethylcellulose was realized. The granules were then milled in a granumill and finally dried.
  • the uncoated granules were then coated in a bottom spray fluid bed using a 15% alcoholic suspension of a 2:1 ethylcellulose/compritol mixture to provide a coat of 50% by weight of the coated granules.
  • Coated granules were mixed with lactose and hydroxypropylmethylcellulose in a V-blender for a period of about 30 minutes. Magnesium stearate was added and the mixture blended for an additional 5 minutes. The amount of coated granules charged into the tablet is based on the actual coated granule content of hydromorphone, it is not based on the theoretical content.
  • the blended mixture was then compressed in a rotary tablet press to form tablets.
  • the capsule-shaped tablets (0.625 ⁇ 0.275 in) weighed 600 mg and had an average hardness of 138 N.
  • Granules were manufactured in a high shear granulator where hydromorphone HCl, hydroxypropylmethylcellulose and a portion of the ethylcellulose were dry mixed for 2 minutes. Then, an ethanolic solution of the remaining ethylcellulose and butylated hydroxyanisole was slowly added while maintaining the granulator impeller and chopper speeds at pre-selected values to provide enough shear for granule formation and growth. Solution addition was continued until the aforementioned percentage of ethylcellulose was realized. The granules were then milled in a granumill and finally dried.
  • the uncoated granules were then coated in a bottom spray fluid bed using a 15% alcoholic suspension of a 2:1 ethylcellulose/compritol mixture to provide a coat of 40% by weight of the coated granules.
  • Coated granules were mixed with lactose and hydroxypropylmethylcellulose in a V-blender for a period of about 30 minutes. Magnesium stearate was added and the mixture blended for an additional 5 minutes. The amount of coated granules charged into the tablet is based on the actual coated granule content of hydromorphone, it is not based on the theoretical content.
  • the blended mixture was then compressed in a rotary tablet press to form tablets.
  • the capsule-shaped tablets (0.625 ⁇ 0.275 in) weighed 600 mg and had an average hardness of 130 N.
  • Granules were manufactured in a high shear granulator where hydromorphone HCl, hydroxypropylmethylcellulose and a portion of the ethylcellulose were dry mixed for 2 minutes. Then, an ethanolic solution of the remaining ethylcellulose and butylated hydroxyanisole was slowly added while maintaining the granulator impeller and chopper speeds at pre-selected values to provide enough shear for granule formation and growth. Solution addition was continued until the aforementioned percentage of ethylcellulose was realized. The granules were then milled in a granumill and finally dried.
  • the uncoated granules were then coated in a bottom spray fluid bed using a 15% alcoholic suspension of a 2:1 ethylcellulose/compritol mixture to provide a coat of 50% by weight of the coated granules.
  • Coated granules were mixed with lactose and hydroxypropylmethylcellulose in a V-blender for a period of about 30 minutes. Magnesium stearate was added and the mixture blended for an additional 5 minutes. The amount of coated granules charged into the tablet is based on the actual coated granule content of hydromorphone, it is not based on the theoretical content.
  • the blended mixture was then compressed in a rotary tablet press to form tablets.
  • the capsule-shaped tablets (0.625 ⁇ 0.275 in) weighed 600 mg and had an average hardness of 293 N.
  • Granules were manufactured in a high shear granulator where hydromorphone HCl, hydroxypropylmethylcellulose and a portion of the ethylcellulose were dry mixed for 2 minutes. Then, an ethanolic solution of the remaining ethylcellulose and butylated hydroxyanisole was slowly added while maintaining the granulator impeller and chopper speeds at pre-selected values to provide enough shear for granule formation and growth. Solution addition was continued until the aforementioned percentage of ethylcellulose was realized. The granules were then milled in a granumill and finally dried.
  • the uncoated granules were then coated in a bottom spray fluid bed using a 15% alcoholic suspension of a 2:1 ethylcellulose/Compritol mixture to provide a coat of 45% by weight of the coated granules.
  • the color and Avicel PH 113 were blended in a V-blender for 15 minutes and milled. The milled blend was blended with coated granules, lactose and hydroxypropylmethylcellulose for 30 minutes. Magnesium stearate was added and the mixture blended for an additional 5 minutes. The amount of coated granules charged into the tablet is based on the actual coated granule content of hydromorphone, it is not based on the theoretical content.
  • the blended mixture was then compressed in a rotary tablet press to form tablets.
  • the capsule-shaped tablets (0.5000 ⁇ 0.3125 in) weighed 600 mg and had an average hardness of 249 N.
  • Granules were manufactured in a high shear granulator where hydromorphone HCl, hydroxypropylmethylcellulose and a portion of the ethylcellulose were dry mixed for 2 minutes. Then, an ethanolic solution of the remaining ethylcellulose and butylated hydroxyanisole was slowly added while maintaining the granulator impeller and chopper speeds at pre-selected values to provide enough shear for granule formation and growth. Solution addition was continued until the aforementioned percentage of ethylcellulose was realized. The granules were then milled in a granumill and finally dried.
  • the uncoated granules were then coated in a bottom spray fluid bed using a 15% alcoholic suspension of a 2:1 ethylcellulose/Compritol mixture to provide a coat of 45% by weight of the coated granules.
  • the color and Avicel PH 113 were blended in a V-blender for 15 minutes and milled. The milled blend was blended with coated granules, lactose and hydroxypropylmethylcellulose for 30 minutes. Magnesium stearate was added and the mixture blended for an additional 5 minutes. The amount of coated granules charged into the tablet is based on the actual coated granule content of hydromorphone, it is not based on the theoretical content.
  • the blended mixture was then compressed in a rotary tablet press to form tablets.
  • the capsule-shaped tablets (0.5000 ⁇ 0.3125 in) weighed 600 mg and had an average hardness of 206 N.
  • Granules were manufactured in a high shear granulator where hydromorphone HCl, hydroxypropylmethylcellulose and a portion of the ethylcellulose were dry mixed for 2 minutes. Then, an ethanolic solution of the remaining ethylcellulose and butylated hydroxyanisole was slowly added while maintaining the granulator impeller and chopper speeds at pre-selected values to provide enough shear for granule formation and growth. Solution addition was continued until the aforementioned percentage of ethylcellulose was realized. The granules were then milled in a granumill and finally dried.
  • the uncoated granules were then coated in a bottom spray fluid bed using a 15% alcoholic suspension of a 2:1 ethylcellulose/Compritol mixture to provide a coat of 45% by weight of the coated granules.
  • the color and Avicel PH 113 were blended in a V-blender for 15 minutes and milled. The milled blend was blended with coated granules, lactose and hydroxypropylmethylcellulose for 30 minutes. Magnesium stearate was added and the mixture blended for an additional 5 minutes. The amount of coated granules charged into the tablet is based on the actual coated granule content of hydromorphone, it is not based on the theoretical content.
  • the blended mixture was then compressed in a rotary tablet press to form tablets.
  • the capsule-shaped tablets (0.5000 ⁇ 0.3125 in) weighed 600 mg and had an average hardness of 171 N.
  • Granules were manufactured in a high shear granulator where hydromorphone HCl, hydroxypropylmethylcellulose and a portion of the ethylcellulose were dry mixed for 2 minutes. Then, an ethanolic solution of the remaining ethylcellulose and butylated hydroxyanisole was slowly added while maintaining the granulator impeller and chopper speeds at pre-selected values to provide enough shear for granule formation and growth. Solution addition was continued until the aforementioned percentage of ethylcellulose was realized. The granules were then milled in a granumill and finally dried.
  • the uncoated granules were then coated in a bottom spray fluid bed using a 15% alcoholic suspension of a 2:1 ethylcellulose/compritol mixture to provide a coat of 50% by weight of the coated granules.
  • the red iron oxide and Avicel PH 113 were blended in a V-blender for 15 minutes and milled. The milled blend was blended with coated granules, lactose and hydroxypropylmethylcellulose for 30 minutes. Magnesium stearate was added and the mixture blended for an additional 5 minutes. The amount of coated granules charged into the tablet is based on the actual coated granule content of hydromorphone, it is not based on the theoretical content.
  • the blended mixture was then compressed in a rotary tablet press to form tablets.
  • the capsule-shaped tablets (0.625 ⁇ 0.275 in) weighed 600 mg and had an average hardness of nearly 150 N.
  • Granules were manufactured in a high shear granulator where hydromorphone HCl, hydroxypropylmethylcellulose and a portion of the ethylcellulose were dry mixed for 2 minutes. Then, an ethanolic solution of the remaining ethylcellulose and butylated hydroxyanisole was slowly added while maintaining the granulator impeller and chopper speeds at pre-selected values to provide enough shear for granule formation and growth. Solution addition was continued until the aforementioned percentage of ethylcellulose was realized. The granules were then milled in a granumill and finally dried.
  • the uncoated granules were then coated in a bottom spray fluid bed using a 15% alcoholic suspension of a 2:1 ethylcellulose/compritol mixture to provide a coat of 50% by weight of the coated granules.
  • Coated granules were mixed with lactose and hydroxypropylmethylcellulose in a V-blender for a period of about 30 minutes. Magnesium stearate was added and the mixture blended for an additional 5 minutes. The amount of coated granules charged into the tablet is based on the actual coated granule content of hydromorphone, it is not based on the theoretical content.
  • the blended mixture was then compressed in a rotary tablet press to form tablets.
  • the capsule-shaped tablets (0.625 ⁇ 0.275 in) weighed 600 mg and had an average hardness of nearly 45 N.
  • Dissolution in 0.1N HCl, 0.1N HCl and 40% v/v alcohol, and simulated oral tampering of various formulations disclosed herein were tested.
  • tablets were tested using the USP dissolution apparatus number 2 using 500 mL of 0.1 N HCl (normal dissolution) or 40% ethanolic solution (dose dumping dissolution) as the dissolution medium.
  • aliquots were removed after 60, 120, 240, 480, 720, 960, 1200, and 1440 minutes of stiffing in the normal dissolution test and after 15, 30, 45, 60, 120, 180, 240, and 360 minutes for the dose dumping dissolution.
  • Samples were analyzed for hydromorphone using HPLC.
  • Simulated oral tampering testing was conducted by crushing the tablets using ceramic mortars and pestles.
  • a tablet is placed in a ceramic mortar (13 cm outer diameter).
  • a pestle is used to apply force vertically downward onto the tablet until it breaks.
  • the broken tablet is further crushed using a 360° circular motion with downward force applied throughout.
  • the circular crushing motion is repeated eleven times (twelve strokes total).
  • the resulting powder is transferred to a dissolution vessel for in vitro drug release.
  • the in vitro release profile of the crushed tablet samples is obtained in 500 mL of 0.1 N HCl dissolution medium.
  • the samples are agitated at 50 rpm with USP apparatus 2 (paddles) at 37° C. These are the same in vitro conditions as those employed in the in vitro dissolution test described above. Unless otherwise specified, aliquots are removed after 15, 30, 45, 60, and 120 minutes of stiffing and are analyzed for hydromorphone using HPLC.
  • Treatments A (40% coat), B (50% coat), and C (60% coat), and one commercially available immediate-release hydromorphone HCl formulation (Treatment D; 4 ⁇ 8 mg doses) were utilized in this study.
  • the four doses of the immediate-release product were separated by approximately 6 hours.
  • Hydromorphone was administered to the subjects under fasting conditions. Subjects were to receive each treatment during the study, with a minimum 5-day washout between dosing periods. Subjects also received one 50-mg tablet of naltrexone for blockade of opioid effects every 12 hours starting approximately 15 hours before and continuing until approximately 33 hours after each hydromorphone administration. During each treatment period, venous blood samples ( ⁇ 3 mL each) were collected from each subject by venipuncture or indwelling catheter for determination of plasma concentrations of hydromorphone.
  • Samples were collected immediately before and 15, 30, and 45 minutes, and 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 18, 24, 30, 36, 48, 60, and 72 hours after administration of Treatments A, B, and C.
  • Treatment D samples were collected immediately before and 15, 30, and 45 minutes, and 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 3, 3.5, 4, 5, 6, 12, 18, 18.25, 18.5, 18.75, 19, 19.25, 19.5, 19.75, 20, 20.25, 20.5, 21, 21.5, 22, 23, 24, 30, 36, 48, 60, and 72 hours after the initial drug administration.
  • Subjects were randomly assigned to 1 of 2 treatment sequences: ABC or BAC, whereby A was a single dose of the 80-mg oxycodone hydrochloride extended release tablet administered with the subject in a fasted state, B was a single dose of the 80-mg oxycodone hydrochloride extended release tablet administered with the subject in a fed state, and C was one 80-mg oxycodone hydrochloride extended release administered twice daily (bid) for 4.5 days (data from treatment group C not shown).
  • the study consisted of a screening visit (visit 1) within 21 days before the 1st dose of study drug, followed by 2 open-label single-dose administration periods (periods 1 and 2, visits 2 and 3); 1 open-label, 4.5-day, multiple-dose administration period (period 3, included in visit 3); and a follow-up visit (visit 4). There was a minimum 5-day washout between administration of study drug in periods 1 and 2. Administration period 3 began immediately after collection of the 48-hour pharmacokinetic sample in administration period 2.
  • Subjects were required to fast (no food or beverages) overnight beginning at approximately 2100 hours on the evening prior to study drug administration in periods 1 and 2. Subjects randomly assigned to Treatment A continued to fast for a minimum of 4 hours after study drug administration. Subjects randomly assigned to Treatment B fasted until approximately 30 minutes prior to study drug administration, at which time they were provided a standard high-fat breakfast, which must have been consumed in its entirety prior to dosing. Subjects receiving Treatment B were then required to remain fasting until a minimum of 4 hours after study drug administration. All subjects (irrespective of randomized treatment) were permitted to have nonmineral water up to 1 hour before and starting 1 hour after each study drug administration.
  • blood samples (3 mL) were collected by venipuncture or indwelling catheter. Samples were collected immediately (within approximately 5 minutes) before each study drug administration and 15, 30, and 45 minutes and 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 10, 12, 16, 24, 36, and 48 hours after each study drug administration.
  • Oxycodone ER (Fasted) Oxycodone ER (Fed) Cmax (ng/mL) 81.9 ⁇ 22.23 135.1 ⁇ 20.47 tmax (hr)a 8.0 (3.0-12.0) 5.0 (4.0-10.0) AUC0-12 637.8 ⁇ 150.29 870.8 ⁇ 136.17 (ng ⁇ hr/mL) AUC0-t 1140.6 ⁇ 233.66 1215.6 ⁇ 253.02 (ng ⁇ hr/mL) AUC0- ⁇ 1145.8 ⁇ 234.70 1218.8 ⁇ 253.97 (ng ⁇ hr/mL) t1 ⁇ 2 (hr)b 5.4 ⁇ 0.58 5.3 ⁇ 0.90 ⁇ z (hr ⁇ 1) 0.13 ⁇ 0.013 0.13 ⁇
  • Subjects were randomly assigned to 1 of the following 5 treatment sequences: ABCDE, BCDEA, CDEAB, DEABC, or EABCD, whereby A was the tablet administered under fasted conditions with 240 mL water, B was the tablet administered under fed conditions with 240 mL water, and C, D, and E included administration of the tablet under fasted conditions with 240 mL of 4%, 20%, or 40% ethanol, respectively.
  • venous blood samples ⁇ 3 mL each
  • Samples were collected immediately before each hydromorphone administration and 15, 30, and 45 minutes and 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 18, 24, 30, 36, 48, 60, and 72 hours after each administration.
  • Another embodiment of the invention provides a method of treating pain comprising administering to a patient who has not eaten for at least about 8 hours (e.g. at least about 10 hours) an effective amount of formulation of the invention, or administering to a patient who has eaten within 10, 8, 6, 4, or 2 hours, an effective amount of formulation.
  • Dissolution in 0.1N HCl, in dissolution medium at pH 4.5 and in dissolution medium at pH 6.8 of formulations described in Examples 36 and 37 were tested. Tablets were tested using the USP dissolution apparatus number 2 using 500 mL of 0.1 N HCl (normal dissolution), 22 mM sodium acetate trihydrate buffer, adjusted to pH 4.5 with glacial acetic acid, and 50 mM potassium phosphate monobasic buffer, adjusted to pH 6.8 with 1 N sodium hydroxide as the dissolution media. Aliquots were removed after 60, 120, 240, 480, 720, 960, 1200, and 1440 minutes of stirring. Samples were analyzed for hydromorphone using HPLC. Results are shown in FIGS. 7 and 8 .
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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9005660B2 (en) 2009-02-06 2015-04-14 Egalet Ltd. Immediate release composition resistant to abuse by intake of alcohol
US9023394B2 (en) 2009-06-24 2015-05-05 Egalet Ltd. Formulations and methods for the controlled release of active drug substances
US9132096B1 (en) 2014-09-12 2015-09-15 Alkermes Pharma Ireland Limited Abuse resistant pharmaceutical compositions
US20160106680A1 (en) * 2013-05-31 2016-04-21 Pharmascience Inc. Abuse Deterrent Immediate Release Formulation
US9642809B2 (en) 2007-06-04 2017-05-09 Egalet Ltd. Controlled release pharmaceutical compositions for prolonged effect
US10335405B1 (en) 2016-05-04 2019-07-02 Patheon Softgels, Inc. Non-burst releasing pharmaceutical composition

Families Citing this family (44)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8784336B2 (en) 2005-08-24 2014-07-22 C. R. Bard, Inc. Stylet apparatuses and methods of manufacture
US8388546B2 (en) 2006-10-23 2013-03-05 Bard Access Systems, Inc. Method of locating the tip of a central venous catheter
US7794407B2 (en) 2006-10-23 2010-09-14 Bard Access Systems, Inc. Method of locating the tip of a central venous catheter
US10449330B2 (en) 2007-11-26 2019-10-22 C. R. Bard, Inc. Magnetic element-equipped needle assemblies
US8781555B2 (en) 2007-11-26 2014-07-15 C. R. Bard, Inc. System for placement of a catheter including a signal-generating stylet
US9521961B2 (en) 2007-11-26 2016-12-20 C. R. Bard, Inc. Systems and methods for guiding a medical instrument
US8849382B2 (en) 2007-11-26 2014-09-30 C. R. Bard, Inc. Apparatus and display methods relating to intravascular placement of a catheter
ES2465915T3 (es) 2007-11-26 2014-06-09 C.R. Bard, Inc. Sistema integrado para la colocación intravascular de un catéter
US9649048B2 (en) 2007-11-26 2017-05-16 C. R. Bard, Inc. Systems and methods for breaching a sterile field for intravascular placement of a catheter
US10524691B2 (en) 2007-11-26 2020-01-07 C. R. Bard, Inc. Needle assembly including an aligned magnetic element
US10751509B2 (en) 2007-11-26 2020-08-25 C. R. Bard, Inc. Iconic representations for guidance of an indwelling medical device
US8478382B2 (en) 2008-02-11 2013-07-02 C. R. Bard, Inc. Systems and methods for positioning a catheter
WO2010022370A1 (fr) 2008-08-22 2010-02-25 C.R. Bard, Inc. Ensemble cathéter comprenant un capteur d'électrocardiogramme et ensembles magnétiques
US8437833B2 (en) 2008-10-07 2013-05-07 Bard Access Systems, Inc. Percutaneous magnetic gastrostomy
US9445734B2 (en) 2009-06-12 2016-09-20 Bard Access Systems, Inc. Devices and methods for endovascular electrography
US9532724B2 (en) 2009-06-12 2017-01-03 Bard Access Systems, Inc. Apparatus and method for catheter navigation using endovascular energy mapping
BRPI1010773B1 (pt) 2009-06-12 2021-06-01 Bard Access Systems, Inc Adaptador para eletrocardiografia endovascular referência cruzada para pedidos relacionados
EP2517622A3 (fr) 2009-09-29 2013-04-24 C. R. Bard, Inc. Stylets destinés à être utilisés avec un appareil de placement intravasculaire d'un cathéter
WO2011044421A1 (fr) 2009-10-08 2011-04-14 C. R. Bard, Inc. Entretoises utilisées avec une sonde ultrasonore
JP2013518676A (ja) 2010-02-02 2013-05-23 シー・アール・バード・インコーポレーテッド カテーテルナビゲーションおよびチップの位置を特定するための装置および方法
ES2924130T3 (es) 2010-05-28 2022-10-04 Bard Inc C R Aparato para su uso con sistema de guiado de inserción de aguja
EP2912999B1 (fr) 2010-05-28 2022-06-29 C. R. Bard, Inc. Appareil destiné à être utilisé avec un système de guidage d'insertion d'aiguille
JP2013535301A (ja) 2010-08-09 2013-09-12 シー・アール・バード・インコーポレーテッド 超音波プローブヘッド用支持・カバー構造
EP2605699A4 (fr) 2010-08-20 2015-01-07 Bard Inc C R Reconfirmation de positionnement de bout de cathéter assistée par ecg
US8801693B2 (en) 2010-10-29 2014-08-12 C. R. Bard, Inc. Bioimpedance-assisted placement of a medical device
WO2013006817A1 (fr) 2011-07-06 2013-01-10 C.R. Bard, Inc. Détermination et étalonnage de longueur d'aiguille pour un système de guidage d'introduction
USD699359S1 (en) 2011-08-09 2014-02-11 C. R. Bard, Inc. Ultrasound probe head
US9211107B2 (en) 2011-11-07 2015-12-15 C. R. Bard, Inc. Ruggedized ultrasound hydrogel insert
US20150086626A1 (en) * 2012-04-17 2015-03-26 Mylan, Inc Stable dosage forms of skeletal muscle relaxants with extended release coating
EP2861153A4 (fr) 2012-06-15 2016-10-19 Bard Inc C R Appareil et procédés permettant la détection d'un capuchon amovible sur une sonde à ultrasons
WO2014034929A1 (fr) * 2012-09-03 2014-03-06 第一三共株式会社 Composition pharmaceutique à libération prolongée administrée par voie orale contenant du chlorhydrate d'hydromorphone
CA3042642A1 (fr) 2013-08-12 2015-02-19 Pharmaceutical Manufacturing Research Services, Inc. Comprime extrude anti-abus a liberation immediate
US9492444B2 (en) 2013-12-17 2016-11-15 Pharmaceutical Manufacturing Research Services, Inc. Extruded extended release abuse deterrent pill
US10172797B2 (en) 2013-12-17 2019-01-08 Pharmaceutical Manufacturing Research Services, Inc. Extruded extended release abuse deterrent pill
WO2015120256A2 (fr) 2014-02-06 2015-08-13 C.R. Bard, Inc. Systèmes et procédés pour le guidage et le placement d'un dispositif intravasculaire
CA2955229C (fr) 2014-07-17 2020-03-10 Pharmaceutical Manufacturing Research Services, Inc. Forme posologique remplie de liquide anti-abus a liberation immediate
WO2016064873A1 (fr) 2014-10-20 2016-04-28 Pharmaceutical Manufacturing Research Services, Inc. Forme galénique anti-abus de remplissage de liquide à libération prolongée
US10973584B2 (en) 2015-01-19 2021-04-13 Bard Access Systems, Inc. Device and method for vascular access
WO2016210325A1 (fr) 2015-06-26 2016-12-29 C.R. Bard, Inc. Interface de raccord pour système de positionnement de cathéter basé sur ecg
US9943513B1 (en) 2015-10-07 2018-04-17 Banner Life Sciences Llc Opioid abuse deterrent dosage forms
US11000207B2 (en) 2016-01-29 2021-05-11 C. R. Bard, Inc. Multiple coil system for tracking a medical device
US10335375B2 (en) 2017-05-30 2019-07-02 Patheon Softgels, Inc. Anti-overingestion abuse deterrent compositions
US10992079B2 (en) 2018-10-16 2021-04-27 Bard Access Systems, Inc. Safety-equipped connection systems and methods thereof for establishing electrical connections
WO2021100728A1 (fr) 2019-11-20 2021-05-27 塩野義製薬株式会社 Formulation solide contenant un dérivé de morphinane 6,7-insaturé du 7-carbamoyl

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4990341A (en) * 1986-10-31 1991-02-05 Euroceltique, S.A. Controlled release hydromorphone composition
WO2008033523A1 (fr) * 2006-09-15 2008-03-20 Cima Labs Inc. Préparation médicamenteuse empêchant l'utilisation abusive

Family Cites Families (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5178878A (en) 1989-10-02 1993-01-12 Cima Labs, Inc. Effervescent dosage form with microparticles
US5223264A (en) 1989-10-02 1993-06-29 Cima Labs, Inc. Pediatric effervescent dosage form
IL110014A (en) * 1993-07-01 1999-11-30 Euro Celtique Sa Solid controlled-release oral dosage forms of opioid analgesics
US6024981A (en) 1997-04-16 2000-02-15 Cima Labs Inc. Rapidly dissolving robust dosage form
PE20001396A1 (es) * 1999-01-18 2000-12-23 Gruenenthal Chemie Formulaciones medicamentosas retardadas que contienen una combinacion de un opioide o una sal fisiologicamente tolerables del mismo, un o-agonista
US20030068375A1 (en) * 2001-08-06 2003-04-10 Curtis Wright Pharmaceutical formulation containing gelling agent
PL1765303T5 (pl) * 2004-07-01 2023-05-22 Grünenthal GmbH Tabletka doustna zabezpieczona przed nadużywaniem
US8445018B2 (en) 2006-09-15 2013-05-21 Cima Labs Inc. Abuse resistant drug formulation
EP2200593B1 (fr) * 2007-09-13 2016-08-24 Cima Labs Inc. Formulation médicamenteuse contre l'abus
PL2057984T3 (pl) * 2007-11-09 2010-05-31 Acino Pharma Ag Tabletki z hydromorfonem o przedłużonym uwalnianiu
CA2798702A1 (fr) * 2010-05-11 2011-11-17 Cima Labs Inc. Formes dosifiees orales a liberation prolongee contenant du metoprolol resistantes aux alcools

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4990341A (en) * 1986-10-31 1991-02-05 Euroceltique, S.A. Controlled release hydromorphone composition
WO2008033523A1 (fr) * 2006-09-15 2008-03-20 Cima Labs Inc. Préparation médicamenteuse empêchant l'utilisation abusive

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9642809B2 (en) 2007-06-04 2017-05-09 Egalet Ltd. Controlled release pharmaceutical compositions for prolonged effect
US9005660B2 (en) 2009-02-06 2015-04-14 Egalet Ltd. Immediate release composition resistant to abuse by intake of alcohol
US9358295B2 (en) 2009-02-06 2016-06-07 Egalet Ltd. Immediate release composition resistant to abuse by intake of alcohol
US9023394B2 (en) 2009-06-24 2015-05-05 Egalet Ltd. Formulations and methods for the controlled release of active drug substances
US20160106680A1 (en) * 2013-05-31 2016-04-21 Pharmascience Inc. Abuse Deterrent Immediate Release Formulation
US9132096B1 (en) 2014-09-12 2015-09-15 Alkermes Pharma Ireland Limited Abuse resistant pharmaceutical compositions
US9452163B2 (en) 2014-09-12 2016-09-27 Recro Gainesville Llc Abuse resistant pharmaceutical compositions
US9486451B2 (en) 2014-09-12 2016-11-08 Recro Gainesville Llc Abuse resistant pharmaceutical compositions
US9713611B2 (en) 2014-09-12 2017-07-25 Recro Gainesville, LLC Abuse resistant pharmaceutical compositions
US10092559B2 (en) 2014-09-12 2018-10-09 Recro Gainesville Llc Abuse resistant pharmaceutical compositions
US10960000B2 (en) 2014-09-12 2021-03-30 Recro Gainesville Llc Abuse resistant pharmaceutical compositions
US10335405B1 (en) 2016-05-04 2019-07-02 Patheon Softgels, Inc. Non-burst releasing pharmaceutical composition

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