WO2009014534A1 - Formulations d'analgésiques non opioïdes et d'analgésiques opioïdes captifs - Google Patents

Formulations d'analgésiques non opioïdes et d'analgésiques opioïdes captifs Download PDF

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Publication number
WO2009014534A1
WO2009014534A1 PCT/US2007/073957 US2007073957W WO2009014534A1 WO 2009014534 A1 WO2009014534 A1 WO 2009014534A1 US 2007073957 W US2007073957 W US 2007073957W WO 2009014534 A1 WO2009014534 A1 WO 2009014534A1
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WIPO (PCT)
Prior art keywords
hours
composition
acetaminophen
hydrocodone
released
Prior art date
Application number
PCT/US2007/073957
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English (en)
Inventor
Joerg Rosenberg
Gerd Woehrle
Thomas Y. Kessler
Joerg Breitenbach
Salih Durak
Friedrich W. Richter
Wei Liu
Sandeep Dutta
Original Assignee
Abbott Gmbh & Co. Kg
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Filing date
Publication date
Priority to NZ581767A priority Critical patent/NZ581767A/en
Priority to KR1020107003775A priority patent/KR20100055431A/ko
Priority to AU2007356880A priority patent/AU2007356880A1/en
Priority to BRPI0721940-7A priority patent/BRPI0721940A2/pt
Application filed by Abbott Gmbh & Co. Kg filed Critical Abbott Gmbh & Co. Kg
Priority to MX2010000803A priority patent/MX2010000803A/es
Priority to EP07813144A priority patent/EP2182928A1/fr
Priority to PCT/US2007/073957 priority patent/WO2009014534A1/fr
Priority to RU2010106202/15A priority patent/RU2477995C2/ru
Priority to JP2010516964A priority patent/JP2010534204A/ja
Priority to CA2690829A priority patent/CA2690829A1/fr
Priority to CN200780053839XA priority patent/CN101917977B/zh
Priority to TW097105831A priority patent/TW200904431A/zh
Publication of WO2009014534A1 publication Critical patent/WO2009014534A1/fr
Priority to IL202680A priority patent/IL202680A0/en
Priority to ZA2009/08900A priority patent/ZA200908900B/en

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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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/284—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
    • 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
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/2853—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers, poly(lactide-co-glycolide)
    • 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
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
    • A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/36—Opioid-abuse

Definitions

  • the present invention relates to compositions for oral administration.
  • the invention teaches at least one abuse-resistant composition for delivering a drug having an abuse potential, related methods of preparing these dosage forms, and methods of treating a patient in need thereof comprising administering the inventive compositions to the patient.
  • these compositions include at least one non-opioid analgesic and at least one confined opioid analgesic.
  • Opioids are one common class of drugs that is subject to abuse. Opioids are the major class of analgesics used in the management of moderate to severe pain in the United States of America because of their effectiveness, ease of titration, and favorable risk-to-benefit ratio.
  • opioid administration is the ability of such drugs in some individuals to alter mood and feeling in a manner so as to provide a desirable sense of "well-being" dissociated from therapeutic ameliorative effects. Repeated illicit abuse further results in certain users being addicted to opioids. Similar to the opioids, many other classes of drugs are also subject to abuse, although the patterns and effects of the abuse vary.
  • compositions, formulations and methodologies exist to address abuse of drugs, all compositions, formulations and methods have limitations to a greater or lesser extent. Accordingly, there is a need for providing new and/or improved formulations, compositions and methods of preventing abuse of drugs having abuse potential. More specifically, there is a need to develop oral formulations that would meet the biphasic drug dissolution profile and also have attributes that include drug deterrence and desirable appearance to meet the criteria for a marketable tablet.
  • This background information is provided for the purpose of making known some information believed by the applicant to be of possible relevance to the present invention. No admission is intended, nor should be construed, that any of the preceding information constitutes prior art to the present invention.
  • Certain preferred embodiments of the present invention provide dosage forms and methods for the delivery of drugs, particularly drugs of abuse, characterized by resistance to solvent extraction; tampering, crushing or grinding, and providing an initial burst of release of drug followed by a prolonged period of controllable drug release.
  • the dosage form includes at least one non-opioid analgesic and at least one confined opioid analgesic.
  • the present invention provides a pharmaceutical composition having a core and a non-core layer, comprising: (a) hydrocodone, a pharmaceutically acceptable salt or a hydrate thereof, and (b) acetaminophen or ibuprofen.
  • the core at least 75% all of the hydrocodone, pharmaceutically acceptable salt or hydrate thereof is in the core, and the acetaminophen or the ibuprofen is the non-core layer.
  • this composition is adapted so as to be useful for oral administration to a human 3, 2, or 1 times daily.
  • greater than 90% of the hydrocodone, pharmaceutically acceptable salt or hydrate thereof is in the core.
  • substantially all of the hydrocodone, pharmaceutically acceptable salt or hydrate thereof is in the core.
  • the core further comprises acetaminophen or ibuprofen. More preferably, the core further comprises acetaminophen.
  • the following pharmacokinetic profile is preferably exhibited when the single dose comprises about 15 mg of hydrocodone bitartrate pentahemihydrate and about 500 mg of acetaminophen, administered to the patient, when fasting.
  • the pharmaceutical composition when administered to a human patient the pharmaceutical composition produces a plasma profile characterized by a Cmax for hydrocodone from about 0.6 ng/mL/mg to about 1.4 ng/mL/mg and a Cmax for acetaminophen from about 2.8 ng/mL/mg and 7.9 ng/mL/mg after a single dose.
  • the pharmaceutical composition produces a plasma profile characterized by a Cmax for hydrocodone of about 0.4 ng/mL/mg to about 1.9 ng/mL/mg and a Cmax for acetaminophen of about 2.0 ng/mL/mg to about 10.4 ng/mL/mg after a single dose.
  • the pharmaceutical composition produces a plasma profile characterized by a Cmax for hydrocodone of from about 0.6 ng/mL/mg to about 1.0 ng/mL/mg and a Cmax for acetaminophen of from about 3.0 ng/mL/mg to about 5.2 ng/mL/mg after a single dose.
  • dosage form examples include about 5-20 mg of hydrocodone bitartrate pentahemihydrate and about 400-600 mg of acetaminophen. Yet another embodiment of the dosage form includes 10-15 mg of hydrocodone bitartrate pentahemihydrate and about 500-600 mg of acetaminophen.
  • the following pharmacokinetic profile is preferably exhibited when the single dose comprises about 15 mg of hydrocodone bitartrate pentahemihydrate and about 500 mg of acetaminophen, administered to the patient, when fasting.
  • the dosage form produces an AUC for hydrocodone of about 9.1 ng*hr/mL/mg to about 19.9 ng*hr/mL/mg and an AUC for acetaminophen of about 28.6 ng*hr/mL/mg to about 59.1 ng*hr/mL/mg.
  • the dosage form produces an AUC for hydrocodone of about 7.0 ng*hr/mL/mg to about 26.2 ng*hr/mL/mg and an AUC for acetaminophen of about 18.4 ng*hr/mL/mg to about 79.9 ng*hr/mL/mg.
  • the dosage form produces an AUC for hydrocodone of about 11.3 ng*hr/mL/mg to about 18.7 ng*hr/mL/mg and an AUC for acetaminophen of about 28.7 ng*hr/mL/mg to about 53.5 ng*hr/mL/mg.
  • the in vitro rate of release of the pharmaceutical composition has a biphasic release profile, and wherein for each phase of the in vitro rate of release is zero order or first order for acetaminophen and zero order or first order for hydrocodone bitartrate pentahemihydrate.
  • the following pharmacokinetic profile is preferably exhibited when the single dose comprises about 15 mg of hydrocodone bitartrate pentahemihydrate and about 500 mg of acetaminophen, administered to the patient, when fasting.
  • the dosage form produces a plasma concentration at 1 hour (Cl) for hydrocodone of about 0.18 ng/niL/mg to about 1.51 ng/mL/mg, and a plasma concentration at 1 hour Cl for acetaminophen of about 2.34 ng/mL/mg to about 7.24 ng/mL/mg.
  • the dosage form produces a Cl for hydrocodone of about 0.32 ng/mL/mg to about 1.51 ng/mL/mg and a Cl for acetaminophen of about 2.34 ng/mL/mg to about 5.50 ng/mL/mg.
  • the following pharmacokinetic profile is preferably exhibited when the single dose comprises about 15 mg of hydrocodone bitartrate pentahemihydrate and about 500 mg of acetaminophen, administered to the patient, when fasting.
  • the dosage form produces a plasma concentration at 1 hour (Cl) for hydrocodone from about 0.30 ng/mL/mg to about 1.06 ng/mL/mg, and a Cl for acetaminophen from about 2.75 ng/mL/mg to about 5.57 ng/mL/mg.
  • the dosage from produces a Cl for hydrocodone from about 0.45 ng/mL/mg to about 1.06 ng/mL/mg and a Cl for acetaminophen from about 2.75 ng/mL/mg to about 4.43 ng/mL/mg.
  • the dosage form produces a combined C 1 for hydrocodone and acetaminophen from about 1.18 ⁇ g/mL to about 3.63 ⁇ g/mL, after a single dose of 15 mg hydrocodone bitartrate pentahemihydrate and 500 mg of acetaminophen, on fasting.
  • the dosage from produces a combined Cl for hydrocodone and acetaminophen from about 1.18 ⁇ g/mL to about 2.76 ⁇ g/mL, after a single dose of 15 mg hydrocodone bitartrate pentahemihydrate and 500 mg of acetaminophen.
  • the dosage form produces a combined Cl for hydrocodone and acetaminophen from about 1.38 ⁇ g/mL to about 2.79 ⁇ g/mL, after a single dose of 15 mg hydrocone bitartrate pentahemihydrate and 500 mg of acetaminophen.
  • the dosage from produces a combined Cl for hydrocodone and acetaminophen from about 1.38 ⁇ g/mL to about 2.23 ⁇ g/mL, after a single dose of 15 mg hydrocodone bitartrate pentahemihydrate and 500 mg of acetaminophen.
  • the dosage form produces a combined Cl for hydrocodone and acetaminophen of 1.80 ⁇ 0.42 ⁇ g/mL with the 95% confidence interval for the mean value falling between about 1.61 ⁇ g/mL to about 2.00 ⁇ g/mL, after a single dose of 15 mg hydrocodone bitartrate pentahemihydrate and 500 mg of acetaminophen.
  • the 95% confidence interval of combined Cl for hydrocodone and acetaminophen for the preferred embodiments and the Control overlapped.
  • the 95% confidence interval for the mean value of combined Cl for hydrocodone and acetaminophen for the Control ranged from about 1.46 to 1.96 ⁇ g/mL, after administered as a single dose of 15 mg hydrocodone and 500 mg of acetaminophen to the human patient.
  • the Control provides sufficient plasma levels of opioid and nonopioid analgesic to provide a reduction in pain intensity within about 1 hour after administration.
  • At least 90% of the hydrocodone is released from the pharmaceutical composition in about 8 hours to about 12 hours and at least 60% to about 99% of the acetaminophen is released in vitro from the pharmaceutical compositions in about 6 hours to about 8.5 hours.
  • at least 90% of the hydrocodone is released from the pharmaceutical composition in about 8 hours to about 11 hours and at least 90% of the acetaminophen is released in vitro from the pharmaceutical compositions in about 8 hours to about 11 hours.
  • at least 95% of the hydrocodone is released from the pharmaceutical composition in about 9 hours to about 12 hours and at least 95% of the acetaminophen is released in vitro from the pharmaceutical compositions in about 9 hours to about 12 hours.
  • At least 95% is of the hydrocodone is released from the pharmaceutical composition in about 10 hours to about 12 hours and at least 95% of the acetaminophen is released in vitro from the pharmaceutical compositions in about 10 hours to about 12 hours.
  • at least 99% of the hydrocodone is released from the pharmaceutical composition in about 11 hours to about 12 hours and at least 99% of the acetaminophen is released in vitro from the pharmaceutical compositions in about 11 hours to about 12 hours.
  • at least 99% of the hydrocodone is released from the pharmaceutical composition in less than about 13 hours and at least 99% of the acetaminophen is released in vitro from the pharmaceutical compositions in less than about 13 hours.
  • the a slow-release version of the formulation is adapted to be suitable for, or intended for administration to a human, twice daily, as needed, then at least 90% of the hydrocodone is released from the pharmaceutical composition in about 18 hours to about 23 hours and at least 90% of the acetaminophen is released in vitro from the pharmaceutical compositions in about 18 hours to about 23 hours.
  • at least 95% of the hydrocodone is released from the pharmaceutical composition in about 20 hours to about 25 hours and at least 95% of the acetaminophen is released in vitro from the pharmaceutical compositions in about 20 hours to about 25 hours.
  • At least 95% is of the hydrocodone is released from the pharmaceutical composition in about 21 hours to about 22 hours and at least 95% of the acetaminophen is released in vitro from the pharmaceutical compositions in about 21 hours to about 22 hours.
  • at least 99% of the hydrocodone is released from the pharmaceutical composition in about 22 hours to about 26 hours and at least 99% of the acetaminophen is released in vitro from the pharmaceutical compositions in about 22 hours to about 26 hours.
  • the present invention provides a composition where the core layer comprises an excipient or a mixture of excipients capable of controlling the drug release and the non-core layer comprises an excipient capable of instantly releasing the drug.
  • the core layer is manufactured by melt-extrusion followed by direct shaping of the drug-containing melt and the non-core layer is spray coated over the core layer.
  • the composition comprises about 500mg of acetaminophen and about 15 mg of hydrocodone bitartrate pentahemihydrate.
  • the present invention provides a pharmaceutical composition having a core and a non-core layer, comprising: (a) an abuse-relevant drug, a pharmaceutically acceptable salt or a hydrate thereof and a non-abuse-relevant drug or a pharmaceutically acceptable salt thereof in the core layer, and (b) a non-abuse-relevant drug, a pharmaceutically acceptable salt or a hydrate thereof in the non-core layer.
  • this composition is characterized by at least one of the following features: i) the amount of abuse-relevant drug that is extracted from the composition by 40% aqueous ethanol within one hour at 37 °C in vitro is less than or equal 1.5 times the amount of the abuse- relevant drug that is extracted by 0.01 N hydrochloric acid in vitro within one hour at 37 °C, ii) the composition does not break under a force of 150 newtons, preferably 300 newtons, more preferably 450 newtons, yet more preferably 500 newtons as measured by "Pharma Test PTB 501" hardness tester, iii) the composition releases at least 20% of the abuse-relevant drug and not more than 45% of the abuse-relevant drug during the first hour of in vitro dissolution testing and preferably also during the first hour of in vivo testing, iv) the composition releases a therapeutically effective dose of the non-abuse relevant drug within 1 to 2 hours after a single dose, v) the composition releases a therapeutically effective dose of the non-abuse
  • the amount of the abuse-relevant drug that is extracted from the formulation by 40% aqueous ethanol within one hour at 37 °C is about 70% to about 130% of the amount of the drug that is extracted by 0.01 N hydrochloric acid within one hour at 37 °C. In another embodiment, the amount of the abuse-relevant drug that is extracted from the formulation by 40% aqueous ethanol within one hour at 37 °C is about 70% to about 90% of the amount of the drug that is extracted by 0.01 N hydrochloric acid within one hour at 37 °C.
  • the abuse-relevant drug that is extracted from the formulation by 40% aqueous ethanol within one hour at 37 °C is about 75% to about 90% of the amount of the drug that is extracted by 0.01 N hydrochloric acid within one hour at 37 °C.
  • a pharmaceutical composition having a core layer and a non-core layer.
  • the core layer comprises a mixture of: (a) at least one opioid; and (b) at least one rate altering pharmaceutically acceptable polymer, copolymer, or a combination thereof.
  • the non-core layer comprises at least one non-opioid analgesic.
  • these compositions are adapted so as to be useful for oral administration to a human 3, 2, or 1 times daily.
  • the core layer further comprises at least one non-opioid analgesic.
  • the composition is characterized by at least one of the following features: i) the amount of abuse-relevant drug that is extracted from the composition by 40% aqueous ethanol within one hour at 37 °C in vitro is less than or equal 1.5 times the amount of the abuse- relevant drug that is extracted by 0.01 N hydrochloric acid in vitro within one hour at 37 °C, ii) the composition does not break under a force of 150 newtons, preferably 300 newtons, more preferably 450 newtons, yet more preferably 500 newtons as measured by "Pharma Test PTB 501" hardness tester, iii) the composition releases at least 20% of the abuse-relevant drug and not more than 45% of the abuse-relevant drug during the first hour of in vitro dissolution testing and preferably also during the first hour of in vivo testing, iv) the composition releases a therapeutically effective dose of the non-abuse relevant drug within 1 to 2 hours
  • the opioid is selected from the group consisting of alfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine, bezitramide, buprenorphine, butorphanol, clonitazene, codeine, cyclazocine, desomorphine, dextromoramide, dezocine, diampromide, dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene, fentanyl, heroin, hydrocodone, hydromorphone, hydroxypethidine, isomethadone, ketobemidone, levallorphan, levophenacylmorphan, levorphanol, l
  • the non-opioid analgesic is selected from the group consisting of acetaminophen, aspirin, fentaynl, ibuprofen, indomethacin, ketorolac, naproxen, phenacetin, piroxicam, sufentanyl, sunlindac, interferon alpha, and salts, hydrates and mixtures thereof.
  • the opioid is hydrocodone and the non-opioid analgesic is acetaminophen or ibuprofen. More preferably, the opioid is hydrocodone and the non-opioid analgesic is acetaminophen.
  • the following pharmacokinetic profile is preferably exhibited when the single dose comprises about 15 mg of hydrocodone bitartrate pentahemihydrate and about 500 mg of acetaminophen, administered to the patient, when fasting.
  • the pharmaceutical composition when administered to a human patient the pharmaceutical composition produces a plasma profile characterized by a Cmax for hydrocodone from about 0.6 ng/mL/mg to about 1.4 ng/mL/mg and a Cmax for acetaminophen from about 2.8 ng/mL/mg and 7.9 ng/mL/mg after a single dose.
  • the pharmaceutical composition produces a plasma profile characterized by a Cmax for hydrocodone of about 0.4 ng/mL/mg to about 1.9 ng/mL/mg and a Cmax for acetaminophen of about 2.0 ng/mL/mg to about 10.4 ng/mL/mg after a single dose.
  • the pharmaceutical composition produces a plasma profile characterized by a Cmax for hydrocodone of from about 0.6 ng/mL/mg to about 1.0 ng/mL/mg and a Cmax for acetaminophen of from about 3.0 ng/mL/mg to about 5.2 ng/mL/mg after a single dose.
  • the following pharmacokinetic profile is preferably exhibited when the single dose comprises about 15 mg of hydrocodone bitartrate pentahemihydrate and about 500 mg of acetaminophen, administered to the patient, when fasting.
  • the dosage form produces an AUC for hydrocodone of about 9.1 ng*hr/mL/mg to about 19.9 ng*hr/mL/mg and an AUC for acetaminophen of about 28.6 ng*hr/mL/mg to about 59.1 ng*hr/mL/mg.
  • the dosage form produces an AUC for hydrocodone of about 7.0 ng*hr/mL/mg to about 26.2 ng*hr/mL/mg and an AUC for acetaminophen of about 18.4 ng*hr/mL/mg to about 79.9 ng*hr/mL/mg.
  • the dosage form produces an AUC for hydrocodone of about 11.3 ng*hr/mL/mg to about 18.7 ng*hr/mL/mg and an AUC for acetaminophen of about 28.7 ng*hr/mL/mg to about 53.5 ng*hr/mL/mg.
  • the in vitro rate of release of the pharmaceutical composition has a biphasic release profile, and wherein for each phase of the in vitro rate of release is zero order or first order for acetaminophen and zero order or first order for hydrocodone bitartrate pentahemihydrate.
  • the following pharmacokinetic profile is preferably exhibited when the single dose comprises about 15 mg of hydrocodone bitartrate pentahemihydrate and about 500 mg of acetaminophen, administered to the patient, when fasting.
  • the pharmaceutical composition produces a plasma concentration at 1 hour (Cl) for hydrocodone of about 0.18 ng/mL/mg to about 1.51 ng/mL/mg, and a plasma concentration at 1 hour Cl for acetaminophen of about 2.34 ng/mL/mg to about 7.24 ng/mL/mg.
  • the dosage form produces a Cl for hydrocodone of about 0.32 ng/mL/mg to about 1.51 ng/mL/mg and a Cl for acetaminophen of about 2.34 ng/mL/mg to about 5.50 ng/mL/mg.
  • the following pharmacokinetic profile is preferably exhibited when the single dose comprises about 15 mg of hydrocodone bitartrate pentahemihydrate and about 500 mg of acetaminophen, administered to the patient, when fasting.
  • the pharmaceutical composition when administered to a human patient the pharmaceutical composition produces a plasma concentration at 1 hour (Cl) for hydrocodone from about 0.30 ng/mL/mg to about 1.06 ng/mL/mg, and a Cl for acetaminophen from about 2.75 ng/mL/mg to about 5.57 ng/mL/mg.
  • the dosage from produces a Cl for hydrocodone from about 0.45 ng/mL/mg to about 1.06 ng/mL/mg and a Cl for acetaminophen from about 2.75 ng/mL/mg to about 4.43 ng/mL/mg.
  • the dosage form produces a combined Cl for hydrocodone and acetaminophen from about 1.18 ⁇ g/mL to about 3.63 ⁇ g/mL, after a single dose of 15 mg hydrocodone bitartrate pentahemihydrate and 500 mg of acetaminophen.
  • the dosage from produces a combined Cl for hydrocodone and acetaminophen from about 1.18 ⁇ g/mL to about 2.76 ⁇ g/mL, after a single dose of 15 mg hydrocodone bitartrate pentahemihydrate and 500 mg of acetaminophen.
  • the dosage form produces a combined Cl for hydrocodone and acetaminophen from about 1.38 ⁇ g/mL to about 2.79 ⁇ g/mL, after a single dose of 15 mg hydrocodone bitartrate pentahemihydrate and 500 mg of acetaminophen.
  • the dosage from produces a combined Cl for hydrocodone and acetaminophen from about 1.38 ⁇ g/mL to about 2.23 ⁇ g/mL, after a single dose of 15 mg hydrocodone bitartrate pentahemihydrate and 500 mg of acetaminophen.
  • the dosage form produces a combined Cl for hydrocodone and acetaminophen of 1.80 ⁇ 0.42 ⁇ g/mL with the 95% confidence interval for the mean value falling between about 1.61 ⁇ g/mL to about 2.00 ⁇ g/mL, after a single dose of 15 mg hydrocodone bitartrate pentahemihydrate and 500 mg of acetaminophen.
  • the 95% confidence interval of combined Cl for hydrocodone and acetaminophen for the preferred embodiments and the Control overlapped.
  • the 95% confidence interval for the mean value of combined Cl for hydrocodone and acetaminophen for the Control ranged from about 1.46 to 1.96 ⁇ g/mL, after administered as a single dose of 15 mg hydrocodone bitartrate pentahemihydrate and 500 mg of acetaminophen to the human patient.
  • the Control provides sufficient plasma levels of opioid and nonopioid analgesic to provide a reduction in pain intensity within about 1 hour after administration.
  • At least 90% of the hydrocodone is released from the pharmaceutical composition in about 8 hours to about 12 hours and at least 60% to about 99% of the acetaminophen is released in vitro from the pharmaceutical compositions in about 6 hours to about 8.5 hours.
  • at least 90% of the hydrocodone is released from the pharmaceutical composition in about 8 hours to about 11 hours and at least 90% of the acetaminophen is released in vitro from the pharmaceutical compositions in about 8 hours to about 11 hours.
  • at least 95% of the hydrocodone is released from the pharmaceutical composition in about 9 hours to about 12 hours and at least 95% of the acetaminophen is released in vitro from the pharmaceutical compositions in about 9 hours to about 12 hours.
  • At least 95% is of the hydrocodone is released from the pharmaceutical composition in about 10 hours to about 12 hours and at least 95% of the acetaminophen is released in vitro from the pharmaceutical compositions in about 10 hours to about 12 hours.
  • at least 99% of the hydrocodone is released from the pharmaceutical composition in about 11 hours to about 12 hours and at least 99% of the acetaminophen is released in vitro from the pharmaceutical compositions in about 11 hours to about 12 hours.
  • at least 99% of the hydrocodone is released from the pharmaceutical composition in less than about 13 hours and at least 99% of the acetaminophen is released in vitro from the pharmaceutical compositions in less than about 13 hours.
  • the a slow-release version of the formulation is adapted to be suitable for, or intended for administration to a human, twice daily, as needed, then at least 90% of the hydrocodone is released from the pharmaceutical composition in about 18 hours to about 23 hours and at least 90% of the acetaminophen is released in vitro from the pharmaceutical compositions in about 18 hours to about 23 hours.
  • at least 95% of the hydrocodone is released from the pharmaceutical composition in about 20 hours to about 25 hours and at least 95% of the acetaminophen is released in vitro from the pharmaceutical compositions in about 20 hours to about 25 hours.
  • At least 95% is of the hydrocodone is released from the pharmaceutical composition in about 21 hours to about 22 hours and at least 95% of the acetaminophen is released in vitro from the pharmaceutical compositions in about 21 hours to about 22 hours.
  • at least 99% of the hydrocodone is released from the pharmaceutical composition in about 22 hours to about 26 hours and at least 99% of the acetaminophen is released in vitro from the pharmaceutical compositions in about 22 hours to about 26 hours.
  • at least 99% of the hydrocodone is released from the pharmaceutical composition in less than about 27 hours and at least 99% of the acetaminophen is released in vitro from the pharmaceutical compositions in less than about 27 hours.
  • the present invention provides a composition where the core layer comprises an excipient capable of controlling the drug release and the non-core layer comprises an excipient capable of instantly releasing the drug.
  • the core layer is manufactured by melt-extrusion followed by direct shaping of the drug-containing melt and the non-core layer is spray coated over the core layer.
  • the composition comprises about 500mg of acetaminophen and about 15 mg of hydrocodone bitartrate pentahemihydrate.
  • the present invention provides a pharmaceutical composition having a core layer and a non-core layer.
  • the core layer comprises a mixture of (a) at least one opioid and at least one first non-opioid analgesic; (b) at least one rate altering pharmaceutically acceptable polymer, copolymer, or a combination thereof.
  • the non-core layer comprises at least one second non-opioid analgesic.
  • the composition is adapted so as to be useful for oral administration to a human 3, 2, or 1 times daily.
  • the opioid comprises hydrocodone and the first and the second non-opioid analgesic comprises acetaminophen or ibuprofen.
  • the opioid comprises hydrocodone and the first and the second non-opioid analgesic comprises acetaminophen.
  • the non-core layer comprises: (a) acetaminophen; and (b) at least one rate altering pharmaceutically acceptable polymer, copolymer, or a combination thereof.
  • the polymer or copolymer is selected from the group consisting of: hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose; polymethacrylate, polyvinyl alcohol, polyethylene oxide, and combinations thereof.
  • the polymer or copolymer is selected from the group consisting of: hydroxypropyl methylcellulose, and polyvinyl alcohol, or combinations thereof. Yet more preferably, the polymer or copolymer is selected from the group consisting of: polyvinyl alcohol and polyethylene oxide graft copolymers. Further, in this embodiment, the ratio of acetaminophen to the rate controlling polymer or copolymer or combination thereof is about 1 : 1 to about 10:1. More preferably, the ratio of acetaminophen to the rate controlling polymer or copolymer or combination thereof is about 3 : 1 to about 5:1. As provided in the present invention, in one preferred embodiment, the non-core layer has at least one of the following characteristics:
  • the following pharmacokinetic profile is preferably exhibited when the single dose comprises about 15 mg of hydrocodone bitartrate pentahemihydrate and about 500 mg of acetaminophen, administered to the patient, when fasting.
  • the pharmaceutical composition when administered to a human patient the pharmaceutical composition produces a plasma profile characterized by a Cmax for hydrocodone from about 0.6 ng/mL/mg to about 1.4 ng/mL/mg and a Cmax for acetaminophen from about 2.8 ng/mL/mg and 7.9 ng/mL/mg after a single dose.
  • the pharmaceutical composition produces a plasma profile characterized by a Cmax for hydrocodone of about 0.4 ng/mL/mg to about 1.9 ng/mL/mg and a Cmax for acetaminophen of about 2.0 ng/mL/mg to about 10.4 ng/mL/mg after a single dose.
  • the pharmaceutical composition produces a plasma profile characterized by a Cmax for hydrocodone of from about 0.6 ng/mL/mg to about 1.0 ng/mL/mg and a Cmax for acetaminophen of from about 3.0 ng/mL/mg to about 5.2 ng/mL/mg after a single dose.
  • the following pharmacokinetic profile is preferably exhibited when the single dose comprises about 15 mg of hydrocodone bitartrate pentahemihydrate and about 500 mg of acetaminophen, administered to the patient, when fasting.
  • the dosage form produces an AUC for hydrocodone of about 9.1 ng*hr/mL/mg to about 19.9 ng*hr/mL/mg and an AUC for acetaminophen of about 28.6 ng*hr/mL/mg to about 59.1 ng*hr/mL/mg.
  • the dosage form produces an AUC for hydrocodone of about 7.0 ng*hr/mL/mg to about 26.2 ng*hr/mL/mg and an AUC for acetaminophen of about 18.4 ng*hr/mL/mg to about 79.9 ng*hr/mL/mg.
  • the dosage form produces an AUC for hydrocodone of about 11.3 ng*hr/mL/mg to about 18.7 ng*hr/mL/mg and an AUC for acetaminophen of about 28.7 ng*hr/mL/mg to about 53.5 ng*hr/mL/mg.
  • the in vitro rate of release of the pharmaceutical composition has a biphasic release profile, and wherein for each phase of the in vitro rate of release is zero order or first order for acetaminophen and zero order or first order for hydrocodone bitartrate pentahemihydrate.
  • the following pharmacokinetic profile is preferably exhibited when the single dose comprises about 15 mg of hydrocodone bitartrate pentahemihydrate and about 500 mg of acetaminophen, administered to the patient, when fasting.
  • the pharmaceutical composition when administered to a human patient the pharmaceutical composition produces a plasma concentration at 1 hour (Cl) for hydrocodone of about 0.18 ng/mL/mg to about 1.51 ng/mL/mg, and a plasma concentration at 1 hour Cl for acetaminophen of about 2.34 ng/mL/mg to about 7.24 ng/mL/mg.
  • the dosage form produces a Cl for hydrocodone of about 0.32 ng/mL/mg to about 1.51 ng/mL/mg and a Cl for acetaminophen of about 2.34 ng/mL/mg to about 5.50 ng/mL/mg.
  • the following pharmacokinetic profile is preferably exhibited when the single dose comprises about 15 mg of hydrocodone bitartrate pentahemihydrate and about 500 mg of acetaminophen, administered to the patient, when fasting.
  • the pharmaceutical composition produces a plasma concentration at 1 hour (Cl) for hydrocodone from about 0.30 ng/mL/mg to about 1.06 ng/mL/mg, and a Cl for acetaminophen from about 2.75 ng/mL/mg to about 5.57 ng/mL/mg.
  • the dosage from produces a Cl for hydrocodone from about 0.45 ng/mL/mg to about 1.06 ng/mL/mg and a Cl for acetaminophen from about 2.75 ng/mL/mg to about 4.43 ng/mL/mg.
  • the dosage form produces a combined Cl for hydrocodone and acetaminophen from about 1.18 ⁇ g/mL to about 3.63 ⁇ g/mL, after a single dose of 15 mg hydrocodone bitartrate pentahemihydrate and 500 mg of acetaminophen.
  • the dosage from produces a combined Cl for hydrocodone and acetaminophen from about 1.18 ⁇ g/mL to about 2.76 ⁇ g/mL, after a single dose of 15 mg hydrocodone bitartrate pentahemihydrate and 500 mg of acetaminophen.
  • the dosage form produces a combined Cl for hydrocodone and acetaminophen from about 1.38 ⁇ g/mL to about 2.79 ⁇ g/mL, after a single dose of 15 mg hydrocodone bitartrate pentahemihydrate and 500 mg of acetaminophen.
  • the dosage from produces a combined Cl for hydrocodone and acetaminophen from about 1.38 ⁇ g/mL to about 2.23 ⁇ g/mL, after a single dose of 15 mg hydrocodone bitartrate pentahemihydrate and 500 mg of acetaminophen.
  • the dosage form produces a combined Cl for hydrocodone and acetaminophen of 1.80 ⁇ 0.42 ⁇ g/mL with the 95% confidence interval for the mean value falling between about 1.61 ⁇ g/mL to about 2.00 ⁇ g/mL, after a single dose of 15 mg hydrocodone bitartrate pentahemihydrate and 500 mg of acetaminophen.
  • the 95% confidence interval of combined Cl for hydrocodone and acetaminophen for the preferred embodiments and the Control overlapped.
  • the 95% confidence interval for the mean value of combined Cl for hydrocodone and acetaminophen for the Control ranged from about 1.46 to 1.96 ⁇ g/mL, after administered as a single dose of 15 mg hydrocodone and 500 mg of acetaminophen to the human patient.
  • the Control provides sufficient plasma levels of opioid and nonopioid analgesic to provide a reduction in pain intensity within about 1 hour after administration.
  • At least 90% of the hydrocodone is released from the pharmaceutical composition in about 8 hours to about 12 hours and at least 60% to about 99% of the acetaminophen is released in vitro from the pharmaceutical compositions in about 6 hours to about 8.5 hours.
  • at least 90% of the hydrocodone is released from the pharmaceutical composition in about 8 hours to about 11 hours and at least 90% of the acetaminophen is released in vitro from the pharmaceutical compositions in about 8 hours to about 11 hours.
  • at least 95% of the hydrocodone is released from the pharmaceutical composition in about 9 hours to about 12 hours and at least 95% of the acetaminophen is released in vitro from the pharmaceutical compositions in about 9 hours to about 12 hours.
  • At least 95% is of the hydrocodone is released from the pharmaceutical composition in about 10 hours to about 12 hours and at least 95% of the acetaminophen is released in vitro from the pharmaceutical compositions in about 10 hours to about 12 hours.
  • at least 99% of the hydrocodone is released from the pharmaceutical composition in about 11 hours to about 12 hours and at least 99% of the acetaminophen is released in vitro from the pharmaceutical compositions in about 11 hours to about 12 hours.
  • at least 99% of the hydrocodone is released from the pharmaceutical composition in less than about 13 hours and at least 99% of the acetaminophen is released in vitro from the pharmaceutical compositions in less than about 13 hours.
  • the a slow-release version of the formulation is adapted to be suitable for, or intended for administration to a human, twice daily, as needed, then at least 90% of the hydrocodone is released from the pharmaceutical composition in about 18 hours to about 23 hours and at least 90% of the acetaminophen is released in vitro from the pharmaceutical compositions in about 18 hours to about 23 hours.
  • at least 95% of the hydrocodone is released from the pharmaceutical composition in about 20 hours to about 25 hours and at least 95% of the acetaminophen is released in vitro from the pharmaceutical compositions in about 20 hours to about 25 hours.
  • At least 95% is of the hydrocodone is released from the pharmaceutical composition in about 21 hours to about 22 hours and at least 95% of the acetaminophen is released in vitro from the pharmaceutical compositions in about 21 hours to about 22 hours.
  • at least 99% of the hydrocodone is released from the pharmaceutical composition in about 22 hours to about 26 hours and at least 99% of the acetaminophen is released in vitro from the pharmaceutical compositions in about 22 hours to about 26 hours.
  • at least 99% of the hydrocodone is released from the pharmaceutical composition in less than about 27 hours and at least 99% of the acetaminophen is released in vitro from the pharmaceutical compositions in less than about 27 hours.
  • the present invention provides a composition where the core layer comprises an excipient capable of controlling the drug release and the non-core layer comprises an excipient capable of instantly releasing the drug.
  • the core layer is manufactured by melt-extrusion followed by direct shaping of the drug-containing melt and the non-core layer is spray coated over the core layer.
  • the composition comprises about 500mg of acetaminophen and about 15 mg of hydrocodone bitartrate pentahemihydrate.
  • Figure 1 depicts that coating the extrudated tablets resulted in significant smoothing of the tablet surface.
  • Figure 2 depicts schematics for calculation of Surface Roughness using Centre Line Average
  • FIG. 3 depicts Centre Line Average (CLA) for an uncoated formulation.
  • CLA Centre Line Average
  • Figure 4 depicts Centre Line Average (CLA) for an uncoated formulation.
  • CLA 10.4
  • N 69
  • Figure 5 depicts preliminary mean hydrocodone concentration-time profiles for Formulations 15, and 16 and Control 1 for (a) 48 hours and (b) 12 hours.
  • Figure 6 depicts preliminary mean acetaminphen concentration-time profiles for Formulations 15, and 16 and Control 1 for (a) 48 hours and (b) 12 hours.
  • Figure 7 depicts in vitro drug release profiles for hydrocodone and acetaminphen for Formulations 17, and 18, Control 2 and uncoated Formulation VM-I for 480 minutes.
  • EUDRAGIT® Polymers derived from esters of acrylic and methacrylic acid; METHOCEL®: Methyl or methoxyl Cellulose
  • KOLLICOAT IR® Polyvinyl alcohol-polyethylene gly col-graft copolymers
  • PLASDONE® Polyvinylpyrrolidone polymer or -copolymer
  • L AUROGL YCOL® Propylene glycol laurate ester SPAN®: Sorbitan fatty acid esters
  • POLOXAMER® Polyoxy ethylene polyoxypropylene block copolymers or polyoxy ethylene polypropyleneglycol
  • T WEEN® Polyethoxylated Sorbitan esters
  • KLUCEL® Hydroxypropylcellulose
  • KOLLIDON® Polyvinlypyrrolidone homo- or copolymers
  • ISOMAL T® An equimolar composition of 6-0- ⁇ -D-glucopyranosido-D-sorbitol (1,6-GPS) and
  • POLY OX® Water-Soluble Resins based on polyethyleneoxide
  • PLUROL OLEIQUE® Oleic esters of polyglycerol
  • LUTROL® Polyoxy ethylene polyoxypropylene block copolymers or polyoxy ethylene polypropyleneglycol ETHOCEL®: Ethylcellulose
  • PRIMO JEL® Sodium starch glycolate
  • the present invention provides an improved solid or solid solution, oral dosage formulation that provides for the in vivo sustained-release of pharmaceutically active compounds ("drugs") that have properties that make them likely to be abused or have been shown to be frequently abused, as well as salts, esters, prodrugs and other pharmaceutically-acceptable equivalents thereof.
  • drug pharmaceutically active compounds
  • AUC refers to the area under the concentration time curve, calculated using the trapezoidal rule and Clast/k, where Clast is the last observed concentration and k is the calculated elimination rate constant.
  • AUCt refers to the area under the concentration time curve to last observed concentration calculated using the trapezoidal rule.
  • Cmax refers to the plasma concentration of the referent abuse relevant drug at Tmax, expressed as ng/mL and ⁇ g/mL, respectively, produced by the oral ingestion of a composition of the invention. Unless specifically indicated, Cmax refers to the overall maximum observed concentration.
  • Cmin refers to the minimum observed concentration within the intended dosing interval, e.g., a twelve hour dosing interval for a formulation labelled as suitable for dosing every 12 hours or as needed, of a dosage form of the invention administered for 5 doses contiguous dosing intervals.
  • ng*hr/mL/mg refers to the amount of the substance measured in nanograms times the number of hours per milliliter of blood divided by the milligrams of the abuse relevant drug administered to the animal or human.
  • the phrase "ascending release rate” refers to a dissolution rate that generally increases over time, such that the drug dissolves in the fluid at the environment of use at a rate that generally increases with time, rather than remaining constant or decreasing, until the dosage form is depleted of about 80% of the drug.
  • a therapeutically effective dose of one of the compounds of the present invention can be employed in pure form or, where such forms exist, in pharmaceutically acceptable salt, ester or prodrug form.
  • therapeutically effective dose of the compound includes of the invention means a sufficient amount of the compound to treat disorders, at a reasonable benefit/risk ratio applicable to any medical treatment. It will be understood, however, that the total daily usage of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment.
  • the specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed; and like factors well known in the medical arts.
  • the invention provides dosage forms that inhibit the extraction of the drug by common solvents, e.g., without limitation, distilled aqueous ethanol, from the formulation.
  • the formulation dissuades abuse by limiting the ability of persons to extract the opioid from the formulation (either intentionally or unintentionally), such that the opioid cannot easily be concentrated for parenteral administration. Also these abuse resistant formulations may not be easily broken down into smaller particulates or powder-form that are easily abused by nasal snorting. Such an abuse-resistant formulation does not require incorporation of an opioid antagonist (albeit, an opioid antagonist may be added to the preparation to further dissuade abuse). While not desiring to be bound by any particular theory, it is believed that incorporation of alkylcelluloses, such as (without limitation) hydroxymethylcelluloses, and preferably hydroxypropylmethylcelluloses contribute to the formulation's resistance to extraction in alcohol, particularly in 20% or 40% aqueous ethanol.
  • the alkylcellulose preferably has at least 12% substitution with an alkylsubstituent, more preferably at least 16% substitution with an alkyl substituent, and most preferably at least 19% substitution with an alkyl substituent.
  • the alkyl substituent is preferably C 1 -C 6 , more preferably C 1 , C 2 or C 4 , and most preferably C 3 , and can be straight-chained or branched when the alkyl substituent contains 3 or more carbon atoms.
  • the dosage forms optionally resists cutting, grinding, pulverization and the like.
  • a convenient measure for this aspect of the invention is "breaking strength," as measured by "Pharma Test PTB 501" hardness tester.
  • the inventive formulation preferably has a breaking strength of at least 150 newtons (150 N). More preferably, the inventive formulation has breaking strength of at least 300 N, yet more preferably of at least 450 N, and yet more preferably of at least 500 N.
  • Breaking strength according to the present invention can be determined with a tablet 10 mm in diameter and 5 mm in width according to the method for determining the breaking strength of tablets published in the European Pharmacopoeia 1997, page 143, 144, method no. 2.9.8.
  • the apparatus can optionally be obtained from Zwick GmbH & Co. KG, UIm, Germany.
  • the formulation is preferably melt-processed, and more preferably melt-extruded, and then in either case directly shaped without milling or grinding the formulation.
  • the directly shaped tablets of the formulation can be optionally coated with a swallowing aid, such as without limitation, a gelatin coat. While not desiring to be bound by any particular theory, it is believed that direct shaping to prevent undesirable sharp features from forming on the formulation without an intermediate grinding step contributes to the superior breaking strength of the formulation. Additionally, embodiments of the inventive formulation optionally gain additional breaking strength by employing at least two melt-processed polymers. While not ascribing to any particular theory, it is believed that the second melt-processed polymer preferentially interacts with the first melt- processed polymer so as to advantageously adjust the transition glass temperature of the composition as a whole during the formation of the tablet.
  • the formulation may use a polymer, or a copolymer, or a combination thereof to create the melt-processed, and more preferably melt-extruded, directly shaped formulation.
  • Polymers that are pharmacologically inactive and provide enteric coatings or sustained release profile for the formulation can also be used.
  • suitable polymers/copolymers include poly(meth)acrylate like e.g. Eudragit L- or S-type, which are pharmacologically inactive.
  • EUDRAGIT® is a tradename for some preferred polymers that are suitable for use in the invention and are derived from esters of acrylic and methacrylic acid.
  • the properties of the EUDRAGIT polymers are principally determined by functional groups incorporated into the monomers of the EUDRAGIT polymers.
  • the individual EUDRAGIT® grades differ in their proportion of neutral, alkaline or acid groups and thus in terms of physicochemical properties.
  • Ammonioalklyl methacrylate copolymers or methacrylate copolymers may be used having the following formula:
  • EUDRAGIT® (L) will be resistant to gastric fluid and will release the active agent in the colon.
  • the functional group is a trimethylammonioethyl methacrylate moiety
  • the EUDRAGIT® (RL or RS) polymers are insoluble, permeable, dispersible and pH-independent. These EUDRAGIT® (RL or RS) polymers may therefore be used for delayed drug release for sustained release formulations.
  • EUDRAGIT® is sold in various forms such as in solid form (EUDRAGIT® LlOO/ SlOO/ L-100-55, EUDRAGIT® E PO, EUDRAGIT® RL PO, Eudragit RS PO), granules (EUDRAGIT® ElOO, EUDRAGIT®RL 100/RS 100), dispersions (L 30 D-55/FS 3OD 30%, EUDRAGIT® NE 30 D/40 D 30%/40% polymer content, EUDRAGIT®RL 30 D RS 30 D 30%) and organic solutions (EUDRAGIT® L 12.5, EUDRAGIT® E12.5, EUDRAGIT® RL 12.5/RS 12.5 - 12.5% organic solution).
  • solid form EUDRAGIT® LlOO/ SlOO/ L-100-55
  • EUDRAGIT® E PO EUDRAGIT® RL PO, Eudragit RS PO
  • granules EUDRAGIT® ElOO, EUDRAGIT®RL 100/RS 100
  • dispersions L 30 D-55/
  • melt-processed polymers one is preferably a cellulose derivative, more preferably a hydroxyalkylcellulose derivative, and optionally hydroxypropylmethylcellulose, and independently, the other polymer is preferably a cellulose derivative, more preferably a hydroxyalkylcellulose derivative, and optionally hydroxypropylmethylcellulose, and independently, the other polymer is preferably a cellulose derivative, more preferably a hydroxyalkylcellulose derivative, and optionally hydroxypropylmethylcellulose, and independently, the other polymer is preferably a cellulose derivative, more preferably a hydroxyalkylcellulose derivative, and optionally hydroxypropylmethylcellulose, and independently, the other polymer is preferably a cellulose derivative, more preferably a hydroxyalkylcellulose derivative, and optionally hydroxypropylmethylcellulose, and independently, the other polymer is preferably a cellulose derivative, more preferably a hydroxyalkylcellulose derivative, and optionally hydroxypropylmethylcellulose, and independently, the other polymer is preferably a
  • (meth)acrylate polymer such as, any suitable Eudragit polymer.
  • the (meth)acrylate polymer polymers preferred in the context of the invention are Eudragit L and Eudragit RS.
  • One more preferred polymer in the context of the invention is Eudragit RL.
  • the Eudragit polymers can be used in combinations, with mixtures of Eudragit RS and RL being preferred. Persons that (albeit inadvisedly) drink substantial quantities of alcoholic beverages when taking physician prescribed medications can substantially alter the composition of the gastric juices contained in the stomach, and in extreme cases these gastric juices can comprise up to 40% alcohol.
  • embodiments of the inventive abuse-deterrent formulation optionally comprises a melt-processed mixture of at least one abuse-relevant drug, at least one cellulose ether or cellulose ester, and at least one (meth)acrylic polymer, wherein the amount of the drug that is extracted from the formulation by 20% aqueous ethanol, or 40% aqueous ethanol, or both, within one hour at 37 °C is less than or equal 1.5 times the amount of the drug that is extracted by 0.01 N hydrochloric acid within one hour at 37 °C, or at 25 °C or both.
  • the resistance to extraction by 40% ethanol is advantageous in those situations in which an individual purposefully attempts to extract an abuse relevant drug from a medicine containing an abuse relevant drug.
  • the amounts of the drug that is extracted from the formulation by 20% or 40% aqueous ethanol is less than or equal 1.5 times the amount of the drug that is extracted by 0.01 N hydrochloric acid within one hour. In a yet more preferred embodiments, the amount of the drug that is extracted from the formulation by 20% or 40% aqueous ethanol is less than or equal the amount of the drug that is extracted by 0.01 N hydrochloric acid within one hour.
  • the amount of the drug that is extracted from the formulation by 20% or 40% aqueous ethanol is less than or equal 0.9 times the amount of the drug that is extracted by 0.01 N hydrochloric acid within one hour.
  • the present invention also provides a sustained release formulation of at least one abuse relevant drug that hampers the extraction of the drug from the formulation when extraction is by solvent extraction with commonly available household extraction solvents such as isopropyl alcohol, distilled alcohols exemplified by vodka, white vinegar, water and aqueous ethanol (e.g., 20% ethanol). Whereas the formulation is largely resistant to solvent-extraction, it still provides adequate drug release in aqueous solutions such as gastric fluids.
  • the amount of the abuse relevant drug released from the time of placing in 3 oz. of one, or two, or three, or more than three, of the household solvents listed above (i.e., 0 hours) to 1 hour is expected to be not more than 15% greater than the amount released over the same time as when swallowed by an ordinary human, or the more than 1 hour to about 4 hours is not more than 15% greater than the amount released over the same time as when swallowed by an ordinary human, or both.
  • Exemplary preferred compositions of the invention comprise cellulose ethers and cellulose esters, which can be used alone or in combination in the invention have a preferable molecular weight in the range of 50,000 to 1,250,000 daltons.
  • Cellulose ethers are preferably selected from alkylcelluloses, hydroxalkylcelluloses, hydroxyalkyl alkylcelluloses or mixtures therefrom, such as ethylcellulose, methylcellulose, hydroxypropyl cellulose (NF), hydroxyethyl cellulose (NF), and hydroxpropyl methylcellulose (USP), or combinations thereof.
  • Useful cellulose esters are, without limitation, cellulose acetate (NF), cellulose acetate butyrate, cellulose acetate propionate, hydroxypropylmethyl cellulose phthalate, hydroxypropylmethyl cellulose acetate phthalate, and mixtures thereof. Most preferably, non-ionic polymers, such as hydroxypropylmethyl cellulose may be used.
  • the amount of substituent groups on the anhydroglucose units of cellulose can be designated by the average number of substituent groups attached to the ring, a concept known to cellulose chemists as "degree of substitution" (D. S.). If all three available positions on each unit are substituted, the D. S. is designated as 3, if an average of two on each ring are reacted, the D. S. is designated as 2, etc.
  • the cellulose ether has an alkyl degree of substitution of 1.3 to 2.0 and hydroxyalkyl molar substitution of up to 0.85.
  • the alkyl substitution is methyl.
  • the preferred hydroxyalkyl substitution is hydroxpropyl.
  • a particularly preferred cellulose ether is hydroxpropyl methylcellulose.
  • Hydroxpropyl methylcellulose is available under the brand name METHOCEL E (methyl D. S. about 1.9, hydroxypropyl molar substitution about 0.23), METHOCEL F (methyl D. S. about 1.8, hydroxypropyl molar substitution about 0.13), and METHOCEL K (methyl D. S. about 1.4, hydroxypropyl molar substitution about 0.21).
  • METHOCEL F and METHOCEL K are preferred hydroxpropyl methylcelluloses for use in the present invention.
  • the acrylic polymer suitably includes homopolymers and copolymers (which term includes polymers having more than two different repeat units) comprising monomers of acrylic acid and/or alkacrylic acid and/or an alkyl (alk)acrylate.
  • alkyl (alk)acrylate refers to either the corresponding acrylate or alkacrylate ester, which are usually formed from the corresponding acrylic or alkacrylic acids, respectively.
  • alkyl (alk)acrylate refers to either an alkyl alkacrylate or an alkyl acrylate.
  • the alkyl (alk)acrylate is a (C 1 -C 22 )alkyl ((C 1 -C 10 )alk)acrylate.
  • C 1 -C 22 alkyl groups of the alkyl (alk)acrylates include methyl, ethyl, n-propyl, n-butyl, iso-butyl, tert- butyl, iso-propyl, pentyl, hexyl, cyclohexyl, 2-ethyl hexyl, heptyl, octyl, nonyl, decyl, isodecyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, eicosyl, behenyl, and iso
  • the alkyl group may be straight or branched chain.
  • the (C 1 -C 2 2)alkyl group represents a (C 1 -C 6 )alkyl group as defined above, more preferably a (C 1 -C 4 )alkyl group as defined above.
  • C 1-10 alk groups of the alkyl (alk)acrylate examples include methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, pentyl, hexyl, cyclohexyl, 2-ethyl hexyl, heptyl, octyl, nonyl, decyl and isomers thereof.
  • the alk groups may be straight or branched chain.
  • the (C 1 -C 10 )alk group represents a (C 1 -C 6 )alk group as defined above, more preferably a (C 1 -C 4 ) alk group as defined above.
  • the alkyl (alk)acrylate is a (C 1 -C 4 )alkyl ((C 1 -C 4 ) alk)acrylate, most preferably a (C 1 - C 4 )alkyl (meth)acrylate.
  • (C 1 -C 4 )alkyl (meth)acrylate refers to either (C 1 -C 4 )alkyl acrylate or (C 1 -C 4 )alkyl methacrylate.
  • Examples of (C 1 -C 4 )alkyl (meth)acrylate include methyl methacrylate (MMA), ethyl methacrylate (EMA), n-propyl methacrylate (PMA), isopropyl methacrylate (IPMA), n-butyl methacrylate (BMA), isobutyl methacrylate (IBMA), tert-butyl methacrylate (TBMA): methyl acrylate (MA), ethyl acrylate (EA), n-propyl acrylate (PA), n-butyl acrylate (BA), isopropyl acrylate (IPA), isobutyl acrylate (IBA), and combinations thereof.
  • MMA methacrylate
  • EMA ethyl methacrylate
  • PMA n-propyl methacrylate
  • IPMA isopropyl methacrylate
  • BMA isobutyl methacrylate
  • IBMA isobuty
  • the alkacrylic acid monomer is a (C 1 -C 10 )alkacrylic acid.
  • (C 1 - C 10 )alkacrylic acids include methacrylic acid, ethacrylic acid, n-propacrylic acid, iso-propacrylic acid, n-butacrylic acid, iso-butacrylic acid, tert-butacrylic acid, pentacrylic acid, hexacrylic acid, heptacrylic acid and isomers thereof.
  • the (C 1 -C 10 )alkacrylic acid is a (C 1 -C 4 )alkacrylic acid, most preferably methacrylic acid.
  • the alkyl groups may be substituted by aryl groups.
  • alkyl refers to a straight chain, branched or cyclic, saturated or unsaturated aliphatic hydrocarbons.
  • the alkyl group has 1-16 carbons, and may be unsubstituted or substituted by one or more groups selected from halogen, hydroxy, alkoxy carbonyl, amido, alkylamido, dialkylamido, nitro, amino, alkylamino, dialkylamino, carboxyl, thio and thioalkyl.
  • a "hydroxy” group refers to an OH group.
  • An "alkoxy” group refers to an --O-alkyl group wherein alkyl is as defined above.
  • a "thio" group refers to an --SH group.
  • a “thioalkyl” group refers to an --SR group wherein R is alkyl as defined above.
  • An “amino” group refers to an -NH 2 group.
  • An “alkylamino” group refers to an --NHR group wherein R is alkyl is as defined above.
  • a “dialkylamino” group refers to an --NRR' group wherein R and R' are all as defined above.
  • An “amido” group refers to an -CONH 2 .
  • An “alkylamido” group refers to an --C0NHR group wherein R is alkyl is as defined above.
  • a “dialkylamido” group refers to an --C0NRR group wherein R and R are alkyl as defined above.
  • a "nitro” group refers to an NO 2 group.
  • a “carboxyl” group refers to a COOH group.
  • the alkyl groups may be substituted by aryl groups.
  • aryl includes both carbocyclic and heterocyclic aromatic rings, both monocyclic and fused polycyclic, where the aromatic rings can be 5- or 6-membered rings.
  • Representative monocyclic aryl groups include, but are not limited to, phenyl, furanyl, pyrrolyl, thienyl, pyridinyl, pyrimidinyl, oxazolyl, isoxazolyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl and the like.
  • Fused poly cyclic aryl groups are those aromatic groups that include a 5- or 6-membered aromatic or heteroaromatic ring as one or more rings in a fused ring system.
  • Representative fused polycyclic aryl groups include naphthalene, anthracene, indolizine, indole, isoindole, benzofuran, benzothiophene, indazole, benzimidazole, benzthiazole, purine, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, quinoxaline, 1,8-naphthyridine, pteridine, carbazole, acridine, phenazine, phenothiazine, phenoxazine, and azulene.
  • aryl group also includes an arylalkyl group.
  • arylalkyl refers to moieties, such as benzyl, wherein an aromatic is linked to an alkyl group.
  • the acrylic polymer is an acrylic copolymer.
  • the acrylic copolymer comprises monomers derived from alkyl (alk)acrylate, and/or acrylic acid and/or alkacrylic acid as defined hereinbefore.
  • the acrylic copolymer comprises monomers derived from alkyl (alk)acrylate, i.e. copolymerisable alkyl acrylate and alkyl alkacrylate monomers as defined hereinbefore.
  • acrylic copolymers include a (C 1 -C 4 )alkyl acrylate monomer and a copolymerisable (C 1 -C 4 )alkyl (C 1 -C 4 )alkacrylate comonomer, particularly copolymers formed from methyl methacrylate and a copolymerisable comonomer of methyl acrylate and/or ethyl acrylate and/or n-butyl acrylate.
  • the (meth)acrylic polymer is a ionic (meth)acrylic polymer, in particular a cationic (meth)acrylic polymer.
  • Ionic (meth)acrylic polymer are manufactured by copolymerising (meth)acrylic monomers carrying ionic groups with neutral (meth)acrylic monomers.
  • the ionic groups preferably are quaternary ammonium groups.
  • the (meth)acrylic polymers are generally water-insoluble, but are swellable and permeable in aqueous solutions and digestive fluids.
  • the molar ratio of cationic groups to the neutral (meth)acrylic esters allows for are control of the water-permeabilty of the formulation.
  • the (meth)acrylic polymer is a copolymer or mixture of copolymers wherein the molar ratio of cationic groups to the neutral (meth)acrylic esters is in the range of about 1 :20 to 1 :35 on average.
  • the ratio can by adjusted by selecting an appropriate commercially available cationic (meth)acrylic polymer or by blending a cationic (meth)acrylic polymer with a suitable amount of a neutral (meth)acrylic polymer.
  • Suitable (meth)acrylic polymers are commercially available from Rohm Pharma under the
  • Eudragit preferably Eudragit RL and Eudragit RS.
  • Eudragit RL and Eudragit RS are copolymers of acrylic and methacrylic esters with a low content of quaternary ammonium groups, the molar ratio of ammonium groups to the remaining neutral (meth)acrylic esters being 1 :20 in Eudragit RL and 1 :40 in Eudragit RS.
  • the mean molecular weight is about 150,000.
  • further pharmaceutically acceptable polymers may be incorporated in the inventive formulations in order to adjust the properties of the formulation and/or improve the ease of manufacture thereof.
  • polymers may be selected from the group comprising: homopolymers of N-vinyl lactams, especially polyvinylpyrrolidone (PVP), copolymers of a N-vinyl lactam and and one or more comonomers copolymerizable therewith, the comonomers being selected from nitrogen-containing monomers and oxygen-containing monomers; especially a copolymer of N-vinyl pyrrolidone and a vinyl carboxylate, preferred examples being a copolymer of N-vinyl pyrrolidone and vinyl acetate or a copolymer of N-vinyl pyrrolidone and vinyl propionate; polyvinyl alcohol-polyethylene glycol-graft copolymers (available as, e.g., Kollicoat® IR from BASF AG, Ludwigshafen, Germany); high molecular polyalkylene oxides such as polyethylene oxide and polypropylene oxide and copolymers of ethylene oxide and propylene oxide;
  • PVP generates hydrocodone N-oxide during extrusion, therefore use of PVP -polymers and -copolymers is not always preferred. However, when a small amount (0.2 - 0.6 % w/w of the total formulation) of antioxidant is used, then PVP may be used preferably.
  • “Abuse-relevant drug” is intended to mean any biologically effective ingredient the distribution of which is subject to regulatory restrictions.
  • Drugs of abuse that can be usefully formulated in the context of the invention include without limitation pseudoephedrine, anti-depressants, strong stimulants, diet drugs, steroids, and non-steroidal anti-inflammatory agents.
  • strong stimulants methamphetamine is one drug that has recently received popular attention as a drug of abuse.
  • atropine hyoscyamine
  • phenobarbital scopolamine
  • Another major class of abuse- relevant drugs are analgesics, especially the opioids.
  • opioid it is meant a substance, whether agonist, antagonist, or mixed agonist- antagonist, which reacts with one or more receptor sites bound by endogenous opioid peptides such as the enkephalins, endorphins and the dynorphins.
  • Opioids include, without limitation, alfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine, bezitramide, buprenorphine, butorphanol, clonitazene, codeine, cyclazocine, desomorphine, dextromoramide, dezocine, diampromide, dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene, fentanyl, heroin, hydrocodone, hydromorphone, hydroxypethidine, isomethadone, ketobemidone, levallorphan, levophenacylmorphan, levorphanol, lofentanil,
  • the inventive formulation includes at least one additional therapeutic drug.
  • the additional therapeutic dug can be, without limitation, selected from the group consisting of non-steroidal, non-opioidal analgesics, and is optionally further selected from the group consisting of acetaminophen, aspirin, fentaynl, ibuprofen, indomethacin, ketorolac, naproxen, phenacetin, piroxicam, sufentanyl, sunlindac, and interferon alpha.
  • Particularly preferred are those combinations of drug currently sold as fixed dose combinations to the public under the authority of a suitable national or regional regulatory agency, such as (by way of example) the U.S. Food and Drug Administration.
  • Such drugs include without limitation a (fixed dose) combination of hydrocodone and acetaminophen, or a (fixed dose) combination of hydrocodone and ibuprofen.
  • the abuse-relevant drug(s) are preferably dispersed evenly throughout a matrix that is preferably formed by a cellulose ether or cellulose ester, and one acrylic or methacrylic polymer as well as other optional ingredients of the formulation.
  • This description is intended to also encompass systems having small particles, typically of less than 1 ⁇ m in diameter, of drug in the matrix phase. These systems preferably do not contain significant amounts of active opioid ingredients in their crystalline or microcrystalline state, as evidenced by thermal analysis (DSC) or X-ray diffraction analysis (WAXS).
  • At least 98% (by weight) of the total amount of drug is preferably present in an amorphous state.
  • additional non-abuse relevant drug actives like e.g. acetaminophen are additionally present in a formulation according to the present invention, this additional drug active(s) may be in a crystalline state embedded in the formulation.
  • a dispersion of the components is such that the system is chemically and physically uniform or substantially homogenous throughout or consists of one thermodynamic phase, such a dispersion is called a "solid solution”. Solid solutions of abuse-relevant actives are preferred.
  • the formulation can also comprise one or more additives selected from sugar alcohols or derivatives thereof, maltodextrines; pharmaceutically acceptable surfactants, flow regulators, disintegrants, bulking agents and lubricants.
  • useful sugar alcohols are exemplified by mannitol, sorbitol, xylitol; useful sugar alcohol derivatives include without limitation isomalt, hydrogenated condensed palatinose and others that are both similar and dissimilar.
  • Pharmaceutically acceptable surfactants are preferably pharmaceutically acceptable non-ionic surfactant. Incorporation of surfactants is especially preferred for matrices containing poorly water-soluble active ingredients and/or to improve the wettability of the formulation.
  • the surfactant can effectuate an instantaneous emulsification of the active ingredient released from the dosage form and prevent precipitation of the active ingredient in the aqueous fluids of the gastrointestinal tract.
  • Some additives include polyoxyethylene alkyl ethers, e.g. polyoxyethylene (3) lauryl ether, polyoxyethylene (5) cetyl ether, polyoxyethylene (2) stearyl ether, polyoxyethylene (5) stearyl ether; polyoxyethylene alkylaryl ethers, e.g. polyoxyethylene (2) nonylphenyl ether, polyoxyethylene (3) nonylphenyl ether, polyoxyethylene (4) nonylphenyl ether or polyoxyethylene (3) octylphenyl ether; polyethylene glycol fatty acid esters, e.g.
  • polyoxyethyleneglycerol triricinoleate or polyoxyl 35 castor oil (Cremophor® EL; BASF Corp.) or polyoxyethyleneglycerol oxystearate such as polyethylenglycol 40 hydrogenated castor oil (Cremophor® RH 40) or polyethylenglycol 60 hydrogenated castor oil (Cremophor® RH 60); or block copolymers of ethylene oxide and propylene oxide, also known as polyoxyethylene polyoxypropylene block copolymers or polyoxyethylene polypropyleneglycol such as Pluronic® F68, Pluronic® F127, Poloxamer® 124, Poloxamer® 188, Poloxamer® 237, Poloxamer® 388, or Poloxamer® 407 (BASF Wyandotte Corp.); or mono fatty acid esters of polyoxyethylene (20) sorbitan, e.g.
  • polyoxyethylene (20) sorbitan monooleate Tween® 80
  • polyoxyethylene (20) sorbitan monostearate Tween® 60
  • polyoxyethylene (20) sorbitan monopalmitate Tween® 40
  • polyoxyethylene (20) sorbitan monolaurate Tween® 20
  • flow regulators such as colloidal silica
  • lubricants, fillers, disintegrants, plasticizers, stabilizers such as antioxidants, light stabilizers, radical scavengers or stabilizers against microbial attack.
  • the acetaminophen-containing overcoat layer has a bitter taste derived from acetaminophen itself, sweeteners and/or flavors etc. may be used as additives to reduce this bitter taste.
  • One preferred way to reduce the bitter taste is a thin additional non-acetaminophen-containing overcoat.
  • the formulations of the invention can be obtained through any suitable melt process such as by the use of a heated press, and are preferably prepared by melt extrusion. In order to obtain a homogeneous distribution and a sufficient degree of dispersion of the drug, the drug-containing melt can be kept in the heated barrel of a melt extruder during a sufficient residence time.
  • Melting occurs at the transition into a liquid or rubbery state in which it is possible for one component to be homogeneously embedded in the other. Melting usually involves heating above the softening point of meltable excipients of the formulation, e.g. a cellulose ether/ester, sugar alcohol and/or (meth)acrylic polymer.
  • the preparation of the melt can take place in a variety of ways. Usually, the melt temperature is in the range of 70 to 250 °C, preferably 80 to 180 °C, most preferably 100 to 140 °C.
  • the melting and/or mixing can take place in an apparatus customarily used for this purpose.
  • extruders or kneaders are particularly suitable.
  • Suitable extruders include single screw extruders, intermeshing screw extruders, and multiscrew extruders, preferably twin screw extruders, which can be co-rotating or counterrotating and are optionally equipped with kneading disks.
  • the working temperatures will also be determined by the kind of extruder or the kind of configuration within the extruder that is used. Part of the energy needed to melt, mix and dissolve the components in the extruder can be provided by heating elements.
  • the friction and shearing of the material in the extruder may also provide the mixture with a substantial amount of energy and aid in the formation of a homogeneous melt of the components.
  • the invention provides an oral, sustained release dosage form characterized in that it has at least two of the following features (a) the abuse relevant drug that is extracted from the formulation by ethanolic solvent, e.g.
  • the dosage form is resistant to tampering and does not break under a force of 150 newtons, preferably 300 newtons, more preferably 450 newtons, yet more preferably 500 newtons as measured by "Pharma Test PTB 501" hardness tester, and (c) the dosage form releases at least 15%, more preferably 18%, and optionally 24% of the drug, but not more than 45%, more preferably 38% and optionally 34% of the drug during the 30 minutes, first hour, or first two hours in in vitro dissolution testing and optionally also in vivo (i.e., in the digestive tract of an animal or human).
  • acetaminophen is accomplished by providing a high drug load in the formulation, especially in the non-core region.
  • Drug loading for a single active ingredient, such as acetaminophen in some embodiments of the inventive formulation can be greater than about 60%, 70%, 75%, 80%, 85%, by weight.
  • the drug loading of acetaminophen can be limited to 80%.
  • a preferred embodiment of this dosage form is a monolithic form or a solid solution.
  • the term "monolithic” is derived from roots meaning “single” and "stone".
  • a monolithic form or a solid preferably has at least one dimension that is more than 5mm.
  • the abuse relevant drug is preferably contained in a single solid, or a single solid solution, element.
  • the monolithic solid or solid solution can optionally be overcoated or combined with other materials. These other materials preferably do not contain a substantial amount of the abuse relevant drug and these materials preferably do not substantially affect the rate of dissolution or dispersion of the abuse relevant drug in vivo or in vitro.
  • the in vitro and/or in vivo release rates of the abuse relevant drug or abuse relevant drugs after about the first hour are preferably substantially constant for at least about 6, 8, 10, 12, or 16 hours.
  • embodiments of the invention provides a single phase drug formulation that can be adapted to provide a burst of the abuse relevant drug(s) to allow therapeutic levels of the drug to be quickly obtained in the blood of a patient or animal, and to be maintained to provide therapeutic quantities for at least about 8, 12, or 24 hours.
  • the drug formulation is preferably suitable for repeated administration to a human or animal once, twice or three times a day.
  • preferred embodiments of the inventive dosage form release substantially the entire quantity of the abuse relevant drug incorporated into the dosage form.
  • the inventive dosage form can be adapted to deliver greater than 90%, and preferably 95%, of the drug in in vitro dissolution testing within about 16, and optionally 12 or 9 hours.
  • the cumulative blood concentration, or AUC cannot be directly known from the time at which 90% of the drug is released from the formulation, however, in general higher AUCs per mg of the abuse relevant drug can be achieved when the drug formulation releases substantially all, or all, of the abuse relevant drug in portions of the digestive tract capable of absorbing the drug into the patient's (or animals) blood system.
  • the invention provides a process for the manufacture of an abuse-resistant drug dosage formulation comprising melt extruding a formulation comprising at least one therapeutic drug further comprising directly shaping the extrudate into a dosage form without (an intermediate) milling step.
  • the melt-extrudate preferably comprises a cellulose derivative, and preferably also comprises a Eudragit polymer.
  • Preferred Eudragit polymers include Eudragit L or Eudragit RS or both, and particularly preferred is Eudragit RL or a combination of Eudragit RL and Eudragit RS.
  • the melt can range from pasty to viscous.
  • the melt Before allowing the melt to solidify, the melt optionally can be shaped into virtually any desired shape. Conveniently, shaping of the extrudate optionally can be carried out by a calender, preferably with two counter-rotating rollers with mutually matching depressions on their surface. A broad range of tablet forms can be obtained by using rollers with different forms of depressions.
  • the extrudate can be cut into pieces, either before (“hot-cut") or after solidification (“cold-cut”) or used in a die injection process. Melt processes involving heated presses optionally can also be calendered.
  • the formed melt can be optionally overcoated with materials that do not contain substantial amount of the drug with abuse potential.
  • the monolithic dosage form containing the drug of abuse can be overcoated with a color coat, a swallowing aid, or another layer of pharmaceutically acceptable materials.
  • the materials layered over the monolithic form preferably do not materially alter the rate of release of the active ingredient from the dosage form.
  • the dosage form In order to facilitate the intake of such a dosage form by a mammal, it is advantageous to give the dosage form an appropriate shape. Large tablets that can be swallowed comfortably are therefore preferably elongated rather than round in shape.
  • a film coat on the dosage form further contributes to the ease with which it can be swallowed.
  • a film coat also improves taste and provides an elegant appearance.
  • the film coat may be an enteric coat.
  • the film coat usually includes a polymeric film- forming material such as hydroxypropyl methylcellulose, hydroxypropylcellulose, and acrylate or methacrylate copolymers.
  • the film-coat may further comprise a plasticizer, e.g. polyethylene glycol, a surfactant, e.g. a Tween® type, and optionally a pigment, e.g., titanium dioxide, iron oxides and/or sweeteners or flavors.
  • the film-coating may also comprise talc as an anti-adhesive.
  • the film coat usually accounts for less than about 5% by weight of the dosage form.
  • Certain exemplary embodiments of the present invention provide monolithic dosage formulations having biphasic release profile for readily water-soluble drugs having a polymer- containing tablet produced by extrusion and calendering.
  • the formulations preferably have combination of immediate release and controlled release formulations of hydrocodone and acetaminophen compositions.
  • These monolithic dosage formulation, especially having narcotic drugs may have abuse deterrent profiles such that the drug dissolution of the dosage forms has reduced/minimal dose dumping in 40% aqueous ethanol solution. Yet more preferably, these formulations may provide reproducible manufacturing processes offering options for rapid transfer to production scale.
  • the desired biphasic drug dissolution of acetaminophen can be achieved while retaining a monolithic dosage form by embedding the active ingredient (acetaminophen) in two formulations with differing release rates which are then combined to produce a two-layer or multi-layer tablet.
  • Processes suitable for this purpose include coextrusion methods for the production of multilayer tablets as described in EP 0857062 specifically for extrudate dosage forms.
  • One disadvantage of this technique is that two extruders have to be operated simultaneously and their mass and volume flows have to be coordinated with great exactness.
  • the two melts have to be combined with each other in a ratio that is maintained very exactly to ensure compliance with the assay and content uniformity requirements of the tablets as specified in the pharmacopoeias (e.g. USP, Ph. Eur.). This requires a high level of effort.
  • the drug content of the film-coating formulation must be very high so that the layers do not become too thick.
  • the drug-containing solution or dispersion used for film coating must have a high concentration to avoid long process times which would otherwise make the process uneconomical.
  • the film coating layer should also offer sufficient mechanical stability even with a large layer thickness, must not be tacky etc. and must be flexible enough that no cracking occurs even with thick layers. Good adhesion on the surface of the extruded cores must also be guaranteed.
  • the drug dissolution from the film-coating layer should also be rapid when using thick layers (about a maximum of 1 h in a preferred embodiment).
  • the organoleptic properties of the film-coating layer must also be largely unchanged with large layer thicknesses and during storage for extended periods of time at elevated temperature, high or very low relative humidity or a combination of such (i.e. no cracking, adhesion, chipping of the coating etc.).
  • finely ground acetaminophen is used for the film coating layers, together with relatively small amounts of a suitable water soluble or water- swellable polymer.
  • the film coating formulations according to the invention were capable of very effectively smoothing the rough surfaces of the extruded tablets, i.e. the film coating sealed the indentations on the surface of the tablets very effectively. This was surprising considering that almost all commercially available film coatings and the polymers used to produce them actually do not possess and are not intended to possess this very property.
  • Known polymers and film-coating formulations are designed to reproduce in detail the embossed elements (logos, etc.) and break lines in detail.
  • Suitable polymers for the manufacture of the film-coating formulations are water soluble and water-swellable pharmaceutically accepted polymers which have already been used to date for the preparation of film coatings.
  • the total solids content of the solution or dispersion must also have an active ingredient content of at least 50% (preferably 60%, particularly preferably 70% or higher).
  • Non-aqueous solutions or suspensions are also possible if non-toxic, pharmaceutically accepted solvents such as ethanol are used. Mixtures of these organic solvents with water are also possible.
  • purely aqueous solutions or suspensions are preferred.
  • Particularly preferred are polymers which form comparatively low viscosity solutions in aqueous solution even at high concentrations in order to maintain the viscosity of the spray solution within the range in which an acceptable spray behavior of the solution or the suspension is still assured even when using the high total solids contents mentioned above.
  • Suitable polymers include: non-ionic cellulose polymers such as hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose; cationic polymethacrylates such as Eudragit® E,
  • suitable polymers are selected from hydroxypropyl methylcellulose, Eudragit® NE30D and polyvinyl alcohol, or combinations thereof. More preferably, suitable polymers are polyvinyl alcohol/polyethylene oxide graft copolymers (e.g.Kollicoat® IR, BASF).
  • the active ingredient (preferred: acetaminophen) must either be soluble in the aforementioned high concentrations in the aqueous or aqueous / organic or purely organic solvents. If (as with acetaminophen) the aqueous solubility is not sufficient, preferably drug suspensions or dispersions can also be used. In this case, however, the decisive factor is that the particle size distribution of the active ingredient should be sufficiently fine since otherwise undesired, i.e. too rapid sedimentation of the suspended active ingredient in the spray solution occurs and/or the spray nozzles of the film coater become blocked.
  • Preferred particle sizes are: not more than 10% of the particles above 0.25 mm (particularly preferred: not more than 5%), not more than 20% (particularly preferred not more than 10%) of the particles above 0.1 mm, and not more than 35% (particularly preferred not more than 20%) of the particles above 0.063 mm.
  • the drugs may be comminuted in grinding processes (dry and wet grinding are suitable).
  • the film coating layers according to the invention not only adhere extremely well to the tablets but also do not become brittle or tacky and show no cracking even during storage at elevated temperatures of up to 60 °C. There was also no detachment of the coating layer from the tablet core.
  • Example 1 Manufacture of the tablets for film coating
  • a homogeneous powder mixture consisting of 61.8% by weight acetaminophen, 12.6% by weight Eudragit® RL, 12.6% by weight xylitol, 6% by weight hydroxypropyl methylcellulose (Methocel® KlOO), 6% by weight hydroxypropyl methylcellulose (Methocel® KlOOM) and 1.0% by weight Aerosil® 200 was metered at a rate of 20 kg/h into a co-rotating twin screw extruder (ZSK-40) and extruded at a temperature of about 140 °C to produce a homogeneous, white melt ribbon.
  • ZSK-40 co-rotating twin screw extruder
  • this melt ribbon was introduced into the roll slit of a counter-rotating forming roller calender, the rollers of which had recesses on their surface from which tablets could be formed directly from the melt ribbon.
  • the resulting tablets had a mean weight of 720 mg after cooling and deburring. The surface of the tablets was rough and uneven in places.
  • Acetaminophen with a particle size of 1% greater than 0.25 mm, 5% greater than 0.1 mm and 16% greater than 0.063 mm was suspended in water by stirring.
  • the active ingredient showed a decreased tendency to settle after switching off the stirrer compared to the material which was used in example 2.
  • the drug dissolution of the tablets according to Example 1 was determined in an apparatus as per US Pharmacopoeia (USP Dissolution Apparatus II (Paddle), USP XXV; 37 °C, 0.01 M HCl, 50 rpm).
  • the amount of active ingredient released from the tablets into the aqueous HCl medium was determined by HPLC at different intervals.
  • the drug dissolution of the tablets according to Example 2 was determined in an apparatus as per US Pharmacopoeia (USP Dissolution Apparatus II (Paddle), USP XXV; 37 °C, 0.01 M HCl, 50 rpm).
  • US Pharmacopoeia USP Dissolution Apparatus II (Paddle)
  • USP XXV USP XXV
  • 37 °C 0.01 M HCl, 50 rpm
  • the amount of active ingredient released from the tablets into the aqueous HCl medium was determined by HPLC at different intervals.
  • Film-coated tablet with 90 mg acetaminophen in the film coat Drug dissolution measured after 30 minutes: 16% Drug dissolution measured after 60 minutes: 20% Drug dissolution measured after 120 minutes: 27% Drug dissolution measured after 240 minutes: 36%
  • the drug dissolution rates increased by about 10% at each test interval due to the initially rapid release of the active ingredient present in the film coat.
  • the drug dissolution of the tablets according to Example 3 was determined in an apparatus as per US Pharmacopoeia apparatus (paddle method, USP XXV; 37 °C, 0.01 M HCl, 50 rpm).
  • the amount of active ingredient released from the tablets into the aqueous HCl medium was determined by HPLC at different intervals.
  • Film-coated tablet with 120 mg acetaminophen in the film coat Drug dissolution measured after 30 minutes: 28% Drug dissolution measured after 60 minutes: 35% Drug dissolution measured after 120 minutes: 43% Drug dissolution measured after 240 minutes: 53% Drug dissolution measured after 360 minutes: 62% Drug dissolution measured after 480 minutes: 69%
  • the drug dissolution rates increased by about 25% at each test interval due to the rapid initial release of the active ingredient present in the film coat.
  • Example 8 The test was performed as for Example 3, but instead of Kollicoat® IR a solid trituration based on hydroxypropyl methylcellulose was used which contained a small portion of iron oxide color pigments. Because of the markedly higher viscosity of the aqueous suspension the total solid concentration could only be adjusted to 20% by weight, as a result of which the spraying times increased while the other process parameters remained unchanged. Very good adhesion of the coating on the tablets was observed. The surface of the reddish/brownish film-coated tablets was smooth and uniform.
  • Example 8 Example 8:
  • Example 3 The test was performed as for Example 3, but instead of Kollicoat® IR a solid trituration based on polyvinyl alcohol was used which contained a small portion of titanium dioxide pigments. Because of the slightly higher viscosity of the aqueous suspension the total solid concentration could only be adjusted to 25% by weight, as a result of which the spraying times increased while the other process parameters remained unchanged. Very good adhesion of the coating on the tablets was observed. The surface of the pure white film-coated tablets was smooth and uniform.
  • Example 9 Film tablets manufactured in accordance with Examples 3, 7 and 8 were stored in closed glass bottles at temperatures of 40 °C and 60 °C. After 1 month no cracks were visible on the tablets and no tackiness was observed. Drug dissolution measured by the method described for Example 4 revealed no changes compared to the values recorded at the beginning of storage.
  • a film-coated tablet manufactured in accordance with Example 3 (90 mg acetaminophen in the film coating layer) was sampled and a thin section was taken in the transverse direction of the tablet with the aid of a microtome and examined under a microscope.
  • the film coating layer was easily distinguishable from the tablet core in the images.
  • the film coating layer was determined as being about 300 micrometers in the images.
  • the smoothing effect of the coating suspension on the rough tablet surfaces was particularly evident, as also seen in Figures 1, 3 and 4.
  • Example 11 Dissolution in HCl and Aqueous Ethanol
  • Sample preparation used as is Analytical finish: UV detection, wavelength 280 nm
  • Table XIV depicts dissolution data for hydrocodone (XIV (a)) and acetaminophen (XIV (b)).
  • Table XVI depicts dissolution data for hydrocodone (XVI(a)) and acetaminophen (XVI(b)).
  • Fraction 1 particle size > 355 ⁇ m ( ⁇ 20 % of the total amount of powder)
  • Fraction 2 particle size > 63 ⁇ m and ⁇ 355 ⁇ m ( ⁇ 66 % of the total amount of powder)
  • Coating of the extrudated tablets resulted in significant smoothing of the tablet surface as can be seen in Figure 1 :
  • To determine the change in surface roughness coated and uncoated tablets were cut in half along the minor axis. The surface of this cross section was milled to obtain a plain and smooth surface.
  • Optical micrographs of the cross section were used to determine the average surface roughness.
  • Centre Line Average approach (CLA) was used as depicted in Figure 2, in which the average height per unit length off the centre line is determined. The centre line was put in the micrograph such that the area above and below the line are approximately equal.
  • the CLA is calculated by using samples at evenly spaced positions according to the following equation:
  • the total length 1 was 4.69 mm, the distance between the increments was 68 ⁇ m.
  • Example 12 Compare Bioavailability of Test Formulations against Control
  • the objective of the study was to compare the bioavailability of two test formulations 15 and 16 with that of the reference Control table.
  • the study design included single-dose, fasting, open- label, three-period, crossover study in 21 subjects.
  • Regimen A included one tablet of Formulation 15;
  • Regimen B included one tablet of Formulation 16;
  • Regimen C included one tablet of Control 1.
  • Blood samples were collected at 0, 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36 and 48 hours after the dose on Study Day 1.
  • Table XXVIII illustrates compositions of test Formulations 15, 16 and Control 1. See also Figures 5 and 6 for mean hydrocodone and acetaminophen concentrations for Formulations 15, 16 and Control 1.
  • Formulations 5, 7 and 15 are substantially identical to each other, however they have been numbered differently based on the different numbering of the tests and experiments.
  • formulations and 6, 8 and 16 are substantially identical to each other, however they have been numbered differently based on the different numbering of the tests and experiments.
  • Controls 1 and 2 are substantially identical to each other, however they have been numbered differently based on the different numbering of the tests and experiments.
  • a preferred dosage form is Formulation 15 since Formulation 15 provides better blending properties than Formulation 16, both for blending of hydrocodone bitartrate pentahemihydrate and HPMC and blending of all components. Further, Formulation 15 blend provides for better flow properties than Formulation 16 into the extruder. Also Formulation 15 provides better direct shaping property than Formulation 16 since
  • Formulation 15 is less sticky than Formulation 16. Moreover, Formulation 15 is expected to have better abuse deterrence than Formulation 16.
  • test Formulations 15 and 16 are bioequivalent to Control 1 with respect to both C max and AUC 00 .
  • the initial rate of hydrocodone absorption is slightly slower for test formulations 15 and 16 compared to Control 1.
  • Example 14 Manufacturing of tablets by melt extrusion, deburring and film-coating: For each of the examples according to Table XXXII a homogeneous powder blend was prepared containing all ingredients. In the case of examples 14A to 16A a two-step blending was performed in order to ensure a homogeneous distribution of the low-dose API component (hydrocodon bitartrate 2.5 hydrate) in the final blend. Blending process is described in Table XXXIII. In the case of examples 14A - 16A a total number of 5 powder samples from each final powder blend prior to extrusion were analyzed with respect to content uniformity of hydrocodone bitartrate 2.5. hydrate.
  • Table XXXII depicts composition of powder blends before extrusion and final extrudate tablet (after melt extrusion and direct shaping). All Ingredients were tested and released as specified according to US Pharmacopoeia (USP, NF) and/or European Pharmacopoeia (Ph. Eur.). Table XXXII:
  • Tablets according to examples 14C, 15C and 17C were transferred into a Driam 600 f ⁇ lm-coater.
  • a first step the tablets were tumbled in the coater at maximum rotation speed in order to polish the tablets and to remove the seems surrounding the tablets which derive from the calendering shaping process. This material which was removed from the tablets was removed from the coating drum together with the exhausting air.
  • film-coating of the tablets was directly started in the same coater.
  • examples 16C tablets were placed in closed stainless steel container and tumbled for 10 minutes once removal of edges and seems was complete. Tablets were then dedusted on a sieve and transferred to the same Driam f ⁇ lm- coater as in the case of the other examples.
  • Composition of film-coating layer and process parameter settings of deburring step and of subsequent film-coating are listed in Table XXXV.
  • Table XXXV depicts deburring of tablets after calendering
  • Manufacturing of the film-coating suspension for examples 14E - 16E was generally prepared by the following steps: First, acetaminophen was dispersed in water at room temperature during stirring. To this suspension the polymer (Kollicoat® IR) was added and stirring was continued until a homogeneous suspension was formed. This suspension was directly used for film-coating Stirring was continued during the whole film-coating process. For examples 14E - 17E a ready to use acetaminophen powder was used (Rhodia, acetaminophen "fine powder"). No additional sieving or micronizing was performed. Composition of film-coating suspensions are summarized in Table XXXVI.
  • Table XXXVI depicts composition of film-coating suspension Table XXXVI:
  • certain preferred embodiments of the present invention provide dosage forms and methods for the delivery of drugs, particularly drugs of abuse, characterized by resistance to solvent extraction; tampering, crushing or grinding, and providing an initial burst of release of drug followed by a prolonged period of controllable drug release.
  • the present invention provides a pharmaceutical composition having a core and a non-core layer, comprising: (a) hydrocodone, a pharmaceutically acceptable salt or a hydrate thereof, and (b) acetaminophen or ibuprofen.
  • a pharmaceutical composition having a core and a non-core layer, comprising: (a) hydrocodone, a pharmaceutically acceptable salt or a hydrate thereof, and (b) acetaminophen or ibuprofen.
  • this composition is adapted so as to be useful for oral administration to a human 3, 2, or 1 times daily.
  • greater than 90% of the hydrocodone, pharmaceutically acceptable salt or hydrate thereof is in the core.
  • the core further comprises acetaminophen or ibuprofen. More preferably, the core further comprises acetaminophen. Table XXXVIII
  • the following pharmacokinetic profile is preferably exhibited when the single dose comprises about 15 mg of hydrocodone bitartrate pentahemihydrate and about 500 mg of acetaminophen, administered to the patient, when fasting.
  • the pharmaceutical composition when administered to a human patient the pharmaceutical composition produces a plasma profile characterized by a Cmax for hydrocodone from about 0.6 ng/mL/mg to about 1.4 ng/mL/mg and a Cmax for acetaminophen from about 2.8 ng/mL/mg and 7.9 ng/mL/mg after a single dose.
  • the pharmaceutical composition produces a plasma profile characterized by a Cmax for hydrocodone of about 0.4 ng/mL/mg to about 1.9 ng/mL/mg and a Cmax for acetaminophen of about 2.0 ng/mL/mg to about 10.4 ng/mL/mg after a single dose.
  • the pharmaceutical composition produces a plasma profile characterized by a Cmax for hydrocodone of from about 0.6 ng/mL/mg to about 1.0 ng/mL/mg and a Cmax for acetaminophen of from about 3.0 ng/mL/mg to about 5.2 ng/mL/mg after a single dose.
  • dosage form examples include about 5-20 mg of hydrocodone bitartrate pentahemihydrate and about 400-600 mg of acetaminophen. Yet another embodiment of the dosage form includes 10-15 mg of hydrocodone bitartrate pentahemihydrate and about 500-600 mg of acetaminophen.
  • the following pharmacokinetic profile is preferably exhibited when the single dose comprises about 15 mg of hydrocodone bitartrate pentahemihydrate and about 500 mg of acetaminophen, administered to the patient, when fasting.
  • the dosage form produces an AUC for hydrocodone of about 9.1 ng*hr/mL/mg to about 19.9 ng*hr/mL/mg and an AUC for acetaminophen of about 28.6 ng*hr/mL/mg to about 59.1 ng*hr/mL/mg.
  • the dosage form produces an AUC for hydrocodone of about 7.0 ng*hr/mL/mg to about 26.2 ng*hr/mL/mg and an AUC for acetaminophen of about 18.4 ng*hr/mL/mg to about 79.9 ng*hr/mL/mg.
  • the dosage form produces an AUC for hydrocodone of about 11.3 ng*hr/mL/mg to about 18.7 ng*hr/mL/mg and an AUC for acetaminophen of about 28.7 ng*hr/mL/mg to about 53.5 ng*hr/mL/mg.
  • the in vitro rate of release of the pharmaceutical composition has a biphasic release profile, and wherein for each phase of the in vitro rate of release is zero order or first order for acetaminophen and zero order or first order for hydrocodone bitartrate pentahemihydrate.
  • the following pharmacokinetic profile is preferably exhibited when the single dose comprises about 15 mg of hydrocodone bitartrate pentahemihydrate and about 500 mg of acetaminophen, administered to the patient, when fasting.
  • the pharmaceutical composition when administered to a human patient the pharmaceutical composition produces a plasma concentration at 1 hour (Cl) for hydrocodone of about 0.18 ng/mL/mg to about 1.51 ng/niL/mg, and a plasma concentration at 1 hour Cl for acetaminophen of about 2.34 ng/mL/mg to about 7.24 ng/mL/mg.
  • the dosage form produces a Cl for hydrocodone of about 0.32 ng/mL/mg to about 1.51 ng/mL/mg and a Cl for acetaminophen of about 2.34 ng/mL/mg to about 5.50 ng/mL/mg.
  • the following pharmacokinetic profile is preferably exhibited when the single dose comprises about 15 mg of hydrocodone bitartrate pentahemihydrate and about 500 mg of acetaminophen, administered to the patient, when fasting.
  • the pharmaceutical composition produces a plasma concentration at 1 hour (Cl) for hydrocodone from about 0.30 ng/mL/mg to about 1.06 ng/mL/mg, and a Cl for acetaminophen from about 2.75 ng/mL/mg to about 5.57 ng/mL/mg.
  • the dosage from produces a Cl for hydrocodone from about 0.45 ng/mL/mg to about 1.06 ng/mL/mg and a Cl for acetaminophen from about 2.75 ng/mL/mg to about 4.43 ng/mL/mg.
  • the dosage form produces a combined Cl for hydrocodone and acetaminophen from about 1.18 ⁇ g/mL to about 3.63 ⁇ g/mL, after a single dose of 15 mg hydrocodone bitartrate pentahemihydrate and 500 mg of acetaminophen.
  • the dosage from produces a combined Cl for hydrocodone and acetaminophen from about 1.18 ⁇ g/mL to about 2.76 ⁇ g/mL, after a single dose of 15 mg hydrocodone bitartrate pentahemihydrate and 500 mg of acetaminophen.
  • the dosage form produces a combined Cl for hydrocodone and acetaminophen from about 1.38 ⁇ g/mL to about 2.79 ⁇ g/mL, after a single dose of 15 mg hydrocodone bitartrate pentahemihydrate and 500 mg of acetaminophen.
  • the dosage from produces a combined Cl for hydrocodone and acetaminophen from about 1.38 ⁇ g/mL to about 2.23 ⁇ g/mL, after a single dose of 15 mg hydrocodone bitartrate pentahemihydrate and 500 mg of acetaminophen.
  • the dosage form produces a combined Cl for hydrocodone and acetaminophen of 1.80 ⁇ 0.42 ⁇ g/mL with the 95% confidence interval for the mean value falling between about 1.61 ⁇ g/mL to about 2.00 ⁇ g/mL, after a single dose of 15 mg hydrocodone bitartrate pentahemihydrate and 500 mg of acetaminophen.
  • the 95% confidence interval for the mean value of combined Cl for hydrocodone and acetaminophen for the Control ranged from about 1.46 to 1.96 ⁇ g/mL, after administered as a single dose of 15 mg hydrocodone bitartrate pentahemihydrate and 500 mg of acetaminophen to the human patient.
  • the Control provides sufficient plasma levels of opioid and nonopioid analgesic to provide a reduction in pain intensity within about 1 hour after administration.
  • At least 90% of the hydrocodone is released from the pharmaceutical composition in about 8 hours to about 12 hours and at least 60% to about 99% of the acetaminophen is released in vitro from the pharmaceutical compositions in about 6 hours to about 8.5 hours.
  • at least 90% of the hydrocodone is released from the pharmaceutical composition in about 8 hours to about 11 hours and at least 90% of the acetaminophen is released in vitro from the pharmaceutical compositions in about 8 hours to about 11 hours.
  • at least 95% of the hydrocodone is released from the pharmaceutical composition in about 9 hours to about 12 hours and at least 95% of the acetaminophen is released in vitro from the pharmaceutical compositions in about 9 hours to about 12 hours.
  • At least 95% is of the hydrocodone is released from the pharmaceutical composition in about 10 hours to about 12 hours and at least 95% of the acetaminophen is released in vitro from the pharmaceutical compositions in about 10 hours to about 12 hours.
  • at least 99% of the hydrocodone is released from the pharmaceutical composition in about 11 hours to about 12 hours and at least 99% of the acetaminophen is released in vitro from the pharmaceutical compositions in about 11 hours to about 12 hours.
  • at least 99% of the hydrocodone is released from the pharmaceutical composition in less than about 13 hours and at least 99% of the acetaminophen is released in vitro from the pharmaceutical compositions in less than about 13 hours.
  • the a slow-release version of the formulation is adapted to be suitable for, or intended for administration to a human, twice daily, as needed, then at least 90% of the hydrocodone is released from the pharmaceutical composition in about 18 hours to about 23 hours and at least 90% of the acetaminophen is released in vitro from the pharmaceutical compositions in about 18 hours to about 23 hours.
  • at least 95% of the hydrocodone is released from the pharmaceutical composition in about 20 hours to about 25 hours and at least 95% of the acetaminophen is released in vitro from the pharmaceutical compositions in about 20 hours to about 25 hours.
  • At least 95% is of the hydrocodone is released from the pharmaceutical composition in about 21 hours to about 22 hours and at least 95% of the acetaminophen is released in vitro from the pharmaceutical compositions in about 21 hours to about 22 hours.
  • at least 99% of the hydrocodone is released from the pharmaceutical composition in about 22 hours to about 26 hours and at least 99% of the acetaminophen is released in vitro from the pharmaceutical compositions in about 22 hours to about 26 hours.
  • at least 99% of the hydrocodone is released from the pharmaceutical composition in less than about 27 hours and at least 99% of the acetaminophen is released in vitro from the pharmaceutical compositions in less than about 27 hours.
  • the present invention provides a composition where the core layer comprises an excipient or a mixture of excipients capable of controlling the drug release and the non-core layer comprises an excipient capable of instantly releasing the drug.
  • the core layer is manufactured by melt-extrusion followed by direct shaping of the drug-containing melt and the non-core layer is spray coated over the core layer.
  • the composition comprises about 500mg of acetaminophen and about 15 mg of hydrocodone bitartrate pentahemihydrate.
  • the non-core layer, or the tablet layering may be prepared by another methodology. In this methodology the film-coating layer is separately manufactured by extrusion and the extrudate is shaped into a foil. This foil is introduced into the calendar during manufacturing of the cores. This method is especially suitable for thick layers (saving long spray-coating time) and is a solvent-free process. This technology is also known as the Xellex technology.
  • the present invention provides a pharmaceutical composition having a core and a non-core layer, comprising: (a) an abuse-relevant drug, a pharmaceutically acceptable salt or a hydrate thereof and a non-abuse-relevant drug or a pharmaceutically acceptable salt thereof in the core layer, and (b) a non-abuse-relevant drug, a pharmaceutically acceptable salt or a hydrate thereof in the non-core layer.
  • this composition is characterized by at least one of the following features: i) the amount of abuse-relevant drug that is extracted from the composition by 40% aqueous ethanol within one hour at 37 °C in vitro is less than or equal 1.5 times the amount of the abuse- relevant drug that is extracted by 0.01 N hydrochloric acid in vitro within one hour at 37 °C, ii) the composition does not break under a force of 150 newtons, preferably 300 newtons, more preferably 450 newtons, yet more preferably 500 newtons as measured by "Pharma Test PTB 501" hardness tester, iii) the composition releases at least 20% of the abuse-relevant drug and not more than 45% of the abuse-relevant drug during the first hour of in vitro dissolution testing and preferably also during the first hour of in vivo testing, iv) the composition releases a therapeutically effective dose of the non-abuse relevant drug within 1 to 2 hours after a single dose, v) the composition releases a therapeutically effective dose of the non-abuse
  • the amount of the abuse-relevant drug that is extracted from the formulation by 40% aqueous ethanol within one hour at 37 °C is about 70% to about 130% of the amount of the drug that is extracted by 0.01 N hydrochloric acid within one hour at 37 °C. In another embodiment, the amount of the abuse-relevant drug that is extracted from the formulation by 40% aqueous ethanol within one hour at 37 °C is about 70% to about 90% of the amount of the drug that is extracted by 0.01 N hydrochloric acid within one hour at 37 °C.
  • the abuse-relevant drug that is extracted from the formulation by 40% aqueous ethanol within one hour at 37 °C is about 75% to about 90% of the amount of the drug that is extracted by 0.01 N hydrochloric acid within one hour at 37 °C.
  • a pharmaceutical composition having a core layer and a non-core layer.
  • the core layer comprises a mixture of: (a) at least one opioid; and (b) at least one rate altering pharmaceutically acceptable polymer, copolymer, or a combination thereof.
  • the non-core layer comprises at least one non-opioid analgesic.
  • these compositions are adapted so as to be useful for oral administration to a human 3, 2, or 1 times daily.
  • the core layer further comprises at least one non-opioid analgesic.
  • the composition is characterized by at least one of the following features: i) the amount of abuse-relevant drug that is extracted from the composition by 40% aqueous ethanol within one hour at 37 °C in vitro is less than or equal 1.5 times the amount of the abuse- relevant drug that is extracted by 0.01 N hydrochloric acid in vitro within one hour at 37 °C, ii) the composition does not break under a force of 150 newtons, preferably 300 newtons, more preferably 450 newtons, yet more preferably 500 newtons as measured by "Pharma Test PTB 501" hardness tester, iii) the composition releases at least 20% of the abuse-relevant drug and not more than 45% of the abuse-relevant drug during the first hour of in vitro dissolution testing and preferably also during the first hour of in vivo testing, iv) the composition releases a therapeutically effective dose of the non-abuse relevant drug within 1 to 2 hours
  • the opioid is selected from the group consisting of alfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine, bezitramide, buprenorphine, butorphanol, clonitazene, codeine, cyclazocine, desomorphine, dextromoramide, dezocine, diampromide, dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene, fentanyl, heroin, hydrocodone, hydromorphone, hydroxypethidine, isomethadone, ketobemidone, levallorphan, levophenacylmorphan, levorphanol, l
  • the non-opioid analgesic is selected from the group consisting of acetaminophen, aspirin, fentaynl, ibuprofen, indomethacin, ketorolac, naproxen, phenacetin, piroxicam, sufentanyl, sunlindac, interferon alpha, and salts, hydrates and mixtures thereof.
  • the opioid is hydrocodone and the non-opioid analgesic is acetaminophen or ibuprofen. More preferably, the opioid is hydrocodone and the non-opioid analgesic is acetaminophen.
  • the following pharmacokinetic profile is preferably exhibited when the single dose comprises about 15 mg of hydrocodone bitartrate pentahemihydrate and about 500 mg of acetaminophen, administered to the patient, when fasting.
  • the pharmaceutical composition produces a plasma concentration at 1 hour (Cl) for hydrocodone of about 0.18 ng/mL/mg to about 1.51 ng/niL/mg, and a plasma concentration at 1 hour Cl for acetaminophen of about 2.34 ng/mL/mg to about 7.24 ng/mL/mg.
  • the dosage form produces a Cl for hydrocodone of about 0.32 ng/mL/mg to about 1.51 ng/mL/mg and a Cl for acetaminophen of about 2.34 ng/mL/mg to about 5.50 ng/mL/mg.
  • the following pharmacokinetic profile is preferably exhibited when the single dose comprises about 15 mg of hydrocodone bitartrate pentahemihydrate and about 500 mg of acetaminophen, administered to the patient, when fasting.
  • the pharmaceutical composition when administered to a human patient the pharmaceutical composition produces a plasma concentration at 1 hour (Cl) for hydrocodone from about 0.30 ng/mL/mg to about 1.06 ng/mL/mg, and a Cl for acetaminophen from about 2.75 ng/mL/mg to about 5.57 ng/mL/mg.
  • the dosage from produces a Cl for hydrocodone from about 0.45 ng/mL/mg to about 1.06 ng/mL/mg and a Cl for acetaminophen from about 2.75 ng/mL/mg to about 4.43 ng/mL/mg.
  • the dosage form produces a combined Cl for hydrocodone and acetaminophen from about 1.18 ⁇ g/mL to about 3.63 ⁇ g/mL, after a single dose of 15 mg hydrocodone bitartrate pentahemihydrate and 500 mg of acetaminophen.
  • the dosage from produces a combined Cl for hydrocodone and acetaminophen from about 1.18 ⁇ g/mL to about 2.76 ⁇ g/mL, after a single dose of 15 mg hydrocodone bitartrate pentahemihydrate and 500 mg of acetaminophen.
  • the dosage form produces a combined Cl for hydrocodone and acetaminophen from about 1.38 ⁇ g/mL to about 2.79 ⁇ g/mL, after a single dose of 15 mg hydrocodone bitartrate pentahemihydrate and 500 mg of acetaminophen.
  • the dosage from produces a combined Cl for hydrocodone and acetaminophen from about 1.38 ⁇ g/mL to about 2.23 ⁇ g/mL, after a single dose of 15 mg hydrocodone bitartrate pentahemihydrate and 500 mg of acetaminophen.
  • the dosage form produces a combined Cl for hydrocodone and acetaminophen of 1.80 ⁇ 0.42 ⁇ g/mL with the 95% confidence interval for the mean value falling between about 1.61 ⁇ g/mL to about 2.00 ⁇ g/mL, after a single dose of 15 mg hydrocodone bitartrate pentahemihydrate and 500 mg of acetaminophen.
  • the 95% confidence interval of combined Cl for hydrocodone and acetaminophen for the preferred embodiments and the Control overlapped.
  • the 95% confidence interval for the mean value of combined Cl for hydrocodone and acetaminophen for the Control ranged from about 1.46 to 1.96 ⁇ g/mL, after administered as a single dose of 15 mg hydrocodone bitartrate pentahemihydrate and 500 mg of acetaminophen to the human patient.
  • the Control provides sufficient plasma levels of opioid and nonopioid analgesic to provide a reduction in pain intensity within about 1 hour after administration.
  • the following pharmacokinetic profile is preferably exhibited when the single dose comprises about 15 mg of hydrocodone bitartrate pentahemihydrate and about 500 mg of acetaminophen, administered to the patient, when fasting.
  • the pharmaceutical composition when administered to a human patient the pharmaceutical composition produces a plasma profile characterized by a Cmax for hydrocodone from about 0.6 ng/mL/mg to about 1.4 ng/mL/mg and a Cmax for acetaminophen from about 2.8 ng/mL/mg and 7.9 ng/mL/mg after a single dose.
  • the pharmaceutical composition produces a plasma profile characterized by a Cmax for hydrocodone of about 0.4 ng/mL/mg to about 1.9 ng/mL/mg and a Cmax for acetaminophen of about 2.0 ng/mL/mg to about 10.4 ng/mL/mg after a single dose.
  • the pharmaceutical composition produces a plasma profile characterized by a Cmax for hydrocodone of from about 0.6 ng/mL/mg to about 1.0 ng/mL/mg and a Cmax for acetaminophen of from about 3.0 ng/mL/mg to about 5.2 ng/mL/mg after a single dose.
  • the following pharmacokinetic profile is preferably exhibited when the single dose comprises about 15 mg of hydrocodone bitartrate pentahemihydrate and about 500 mg of acetaminophen, administered to the patient, when fasting.
  • the dosage form produces an AUC for hydrocodone of about 9.1 ng*hr/mL/mg to about 19.9 ng*hr/mL/mg and an AUC for acetaminophen of about 28.6 ng*hr/mL/mg to about 59.1 ng*hr/mL/mg.
  • the dosage form produces an AUC for hydrocodone of about 7.0 ng*hr/mL/mg to about 26.2 ng*hr/mL/mg and an AUC for acetaminophen of about 18.4 ng*hr/mL/mg to about 79.9 ng*hr/mL/mg.
  • the dosage form produces an AUC for hydrocodone of about 11.3 ng*hr/mL/mg to about 18.7 ng*hr/mL/mg and an AUC for acetaminophen of about 28.7 ng*hr/mL/mg to about 53.5 ng*hr/mL/mg.
  • the in vitro rate of release of the pharmaceutical composition has a biphasic release profile, and wherein for each phase of the in vitro rate of release is zero order or first order for acetaminophen and zero order or first order for hydrocodone.
  • At least 90% of the hydrocodone is released from the pharmaceutical composition in about 8 hours to about 12 hours and at least 60% to about 99% of the acetaminophen is released in vitro from the pharmaceutical compositions in about 6 hours to about 8.5 hours.
  • at least 90% of the hydrocodone is released from the pharmaceutical composition in about 8 hours to about 11 hours and at least 90% of the acetaminophen is released in vitro from the pharmaceutical compositions in about 8 hours to about 11 hours.
  • at least 95% of the hydrocodone is released from the pharmaceutical composition in about 9 hours to about 12 hours and at least 95% of the acetaminophen is released in vitro from the pharmaceutical compositions in about 9 hours to about 12 hours.
  • At least 95% is of the hydrocodone is released from the pharmaceutical composition in about 10 hours to about 12 hours and at least 95% of the acetaminophen is released in vitro from the pharmaceutical compositions in about 10 hours to about 12 hours.
  • at least 99% of the hydrocodone is released from the pharmaceutical composition in about 11 hours to about 12 hours and at least 99% of the acetaminophen is released in vitro from the pharmaceutical compositions in about 11 hours to about 12 hours.
  • at least 99% of the hydrocodone is released from the pharmaceutical composition in less than about 13 hours and at least 99% of the acetaminophen is released in vitro from the pharmaceutical compositions in less than about 13 hours.
  • the a slow-release version of the formulation is adapted to be suitable for, or intended for administration to a human, twice daily, as needed, then at least 90% of the hydrocodone is released from the pharmaceutical composition in about 18 hours to about 23 hours and at least 90% of the acetaminophen is released in vitro from the pharmaceutical compositions in about 18 hours to about 23 hours.
  • at least 95% of the hydrocodone is released from the pharmaceutical composition in about 20 hours to about 25 hours and at least 95% of the acetaminophen is released in vitro from the pharmaceutical compositions in about 20 hours to about 25 hours.
  • At least 95% is of the hydrocodone is released from the pharmaceutical composition in about 21 hours to about 22 hours and at least 95% of the acetaminophen is released in vitro from the pharmaceutical compositions in about 21 hours to about 22 hours.
  • at least 99% of the hydrocodone is released from the pharmaceutical composition in about 22 hours to about 26 hours and at least 99% of the acetaminophen is released in vitro from the pharmaceutical compositions in about 22 hours to about 26 hours.
  • at least 99% of the hydrocodone is released from the pharmaceutical composition in less than about 27 hours and at least 99% of the acetaminophen is released in vitro from the pharmaceutical compositions in less than about 27 hours.
  • the present invention provides a composition where the core layer comprises an excipient capable of controlling the drug release and the non-core layer comprises an excipient capable of instantly releasing the drug.
  • the core layer is manufactured by melt-extrusion followed by direct shaping of the drug-containing melt and the non-core layer is spray coated over the core layer.
  • the composition comprises about 500mg of acetaminophen and about 15 mg of hydrocodone bitartrate pentahemihydrate.
  • the present invention provides a pharmaceutical composition having a core layer and a non-core layer.
  • the core layer comprises a mixture of (a) at least one opioid and at least one first non-opioid analgesic; (b) at least one rate altering pharmaceutically acceptable polymer, copolymer, or a combination thereof.
  • the non-core layer comprises at least one second non-opioid analgesic.
  • the composition is adapted so as to be useful for oral administration to a human 3, 2, or 1 times daily.
  • the opioid comprises hydrocodone and the first and the second non-opioid analgesic comprises acetaminophen or ibuprofen.
  • the opioid comprises hydrocodone and the first and the second non-opioid analgesic comprises acetaminophen.
  • the non-core layer comprises: (a) acetaminophen; and (b) at least one rate altering pharmaceutically acceptable polymer, copolymer, or a combination thereof.
  • the polymer or copolymer is selected from the group consisting of: hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose; polymethacrylate, polyvinyl alcohol, polyethylene oxide, and combinations thereof.
  • the polymer or copolymer is selected from the group consisting of: hydroxypropyl methylcellulose, and polyvinyl alcohol, or combinations thereof. Yet more preferably, the polymer or copolymer is selected from the group consisting of: polyvinyl alcohol and polyethylene oxide graft copolymers. Further, in this embodiment, the ratio of acetaminophen to the rate controlling polymer or copolymer or combination thereof is about 1 : 1 to about 10:1. More preferably, the ratio of acetaminophen to the rate controlling polymer or copolymer or combination thereof is about 3 : 1 to about 5:1. As provided in the present invention, in one preferred embodiment, the non-core layer has at least one of the following characteristics:
  • the following pharmacokinetic profile is preferably exhibited when the single dose comprises about 15 mg of hydrocodone bitartrate pentahemihydrate and about 500 mg of acetaminophen, administered to the patient, when fasting.
  • the pharmaceutical composition produces a plasma concentration at 1 hour (Cl) for hydrocodone of about 0.18 ng/mL/mg to about 1.51 ng/niL/mg, and a plasma concentration at 1 hour Cl for acetaminophen of about 2.34 ng/mL/mg to about 7.24 ng/mL/mg.
  • the dosage form produces a Cl for hydrocodone of about 0.32 ng/mL/mg to about 1.51 ng/mL/mg and a Cl for acetaminophen of about 2.34 ng/mL/mg to about 5.50 ng/mL/mg.
  • the following pharmacokinetic profile is preferably exhibited when the single dose comprises about 15 mg of hydrocodone bitartrate pentahemihydrate and about 500 mg of acetaminophen, administered to the patient, when fasting.
  • the pharmaceutical composition produces a plasma concentration at 1 hour (Cl) for hydrocodone from about 0.30 ng/mL/mg to about 1.06 ng/mL/mg, and a Cl for acetaminophen from about 2.75 ng/mL/mg to about 5.57 ng/mL/mg.
  • the dosage from produces a Cl for hydrocodone from about 0.45 ng/mL/mg to about 1.06 ng/mL/mg and a Cl for acetaminophen from about 2.75 ng/mL/mg to about 4.43 ng/mL/mg.
  • the dosage form produces a combined Cl for hydrocodone and acetaminophen from about 1.18 ⁇ g/mL to about 3.63 ⁇ g/mL, after a single dose of 15 mg hydrocodone bitartrate pentahemihydrate and 500 mg of acetaminophen.
  • the dosage from produces a combined Cl for hydrocodone and acetaminophen from about 1.18 ⁇ g/mL to about 2.76 ⁇ g/mL, after a single dose of 15 mg hydrocodone bitartrate pentahemihydrate and 500 mg of acetaminophen.
  • the dosage form produces a combined Cl for hydrocodone and acetaminophen from about 1.38 ⁇ g/mL to about 2.79 ⁇ g/mL, after a single dose of 15 mg hydrocodone bitartrate pentahemihydrate and 500 mg of acetaminophen.
  • the dosage from produces a combined Cl for hydrocodone and acetaminophen from about 1.38 ⁇ g/mL to about 2.23 ⁇ g/mL, after a single dose of 15 mg hydrocodone bitartrate pentahemihydrate and 500 mg of acetaminophen.
  • the dosage form produces a combined Cl for hydrocodone and acetaminophen of 1.80 ⁇ 0.42 ⁇ g/mL with the 95% confidence interval for the mean value falling between about 1.61 ⁇ g/mL to about 2.00 ⁇ g/mL, after a single dose of 15 mg hydrocodone bitartrate pentahemihydrate and 500 mg of acetaminophen.
  • the 95% confidence interval of combined Cl for hydrocodone and acetaminophen for the preferred embodiments and the Control overlapped.
  • the 95% confidence interval for the mean value of combined Cl for hydrocodone and acetaminophen for the Control ranged from about 1.46 to 1.96 ⁇ g/mL, after administered as a single dose of 15 mg hydrocodone bitartrate pentahemihydrate and 500 mg of acetaminophen to the human patient.
  • the Control provides sufficient plasma levels of opioid and nonopioid analgesic to provide a reduction in pain intensity within about 1 hour after administration.
  • the following pharmacokinetic profile is preferably exhibited when the single dose comprises about 15 mg of hydrocodone bitartrate pentahemihydrate and about 500 mg of acetaminophen, administered to the patient, when fasting.
  • the pharmaceutical composition when administered to a human patient the pharmaceutical composition produces a plasma profile characterized by a Cmax for hydrocodone from about 0.6 ng/mL/mg to about 1.4 ng/mL/mg and a Cmax for acetaminophen from about 2.8 ng/mL/mg and 7.9 ng/mL/mg after a single dose.
  • the pharmaceutical composition produces a plasma profile characterized by a Cmax for hydrocodone of about 0.4 ng/mL/mg to about 1.9 ng/mL/mg and a Cmax for acetaminophen of about 2.0 ng/mL/mg to about 10.4 ng/mL/mg after a single dose.
  • the pharmaceutical composition produces a plasma profile characterized by a Cmax for hydrocodone of from about 0.6 ng/mL/mg to about 1.0 ng/mL/mg and a Cmax for acetaminophen of from about 3.0 ng/mL/mg to about 5.2 ng/mL/mg after a single dose.
  • the following pharmacokinetic profile is preferably exhibited when the single dose comprises about 15 mg of hydrocodone bitartrate pentahemihydrate and about 500 mg of acetaminophen, administered to the patient, when fasting.
  • the dosage form When administered to the human patient, the dosage form produces an AUC for hydrocodone of about 9.1 ng*hr/mL/mg to about 19.9 ng*hr/mL/mg and an AUC for acetaminophen of about 28.6 ng*hr/mL/mg to about 59.1 ng*hr/mL/mg.
  • the dosage form produces an AUC for hydrocodone of about 7.0 ng*hr/mL/mg to about 26.2 ng*hr/mL/mg and an AUC for acetaminophen of about 18.4 ng*hr/mL/mg to about 79.9 ng*hr/mL/mg.
  • the dosage form produces an AUC for hydrocodone of about 11.3 ng*hr/mL/mg to about 18.7 ng*hr/mL/mg and an AUC for acetaminophen of about 28.7 ng*hr/mL/mg to about 53.5 ng*hr/mL/mg.
  • the in vitro rate of release of the pharmaceutical composition has a biphasic release profile, and wherein for each phase of the in vitro rate of release is zero order or first order for acetaminophen and zero order or first order for hydrocodone.
  • At least 90% of the hydrocodone is released from the pharmaceutical composition in about 8 hours to about 12 hours and at least 60% to about 99% of the acetaminophen is released in vitro from the pharmaceutical compositions in about 6 hours to about 8.5 hours.
  • at least 90% of the hydrocodone is released from the pharmaceutical composition in about 8 hours to about 11 hours and at least 90% of the acetaminophen is released in vitro from the pharmaceutical compositions in about 8 hours to about 11 hours.
  • at least 95% of the hydrocodone is released from the pharmaceutical composition in about 9 hours to about 12 hours and at least 95% of the acetaminophen is released in vitro from the pharmaceutical compositions in about 9 hours to about 12 hours.
  • At least 95% is of the hydrocodone is released from the pharmaceutical composition in about 10 hours to about 12 hours and at least 95% of the acetaminophen is released in vitro from the pharmaceutical compositions in about 10 hours to about 12 hours.
  • at least 99% of the hydrocodone is released from the pharmaceutical composition in about 11 hours to about 12 hours and at least 99% of the acetaminophen is released in vitro from the pharmaceutical compositions in about 11 hours to about 12 hours.
  • at least 99% of the hydrocodone is released from the pharmaceutical composition in less than about 13 hours and at least 99% of the acetaminophen is released in vitro from the pharmaceutical compositions in less than about 13 hours.
  • the a slow-release version of the formulation is adapted to be suitable for, or intended for administration to a human, twice daily, as needed, then at least 90% of the hydrocodone is released from the pharmaceutical composition in about 18 hours to about 23 hours and at least 90% of the acetaminophen is released in vitro from the pharmaceutical compositions in about 18 hours to about 23 hours.
  • at least 95% of the hydrocodone is released from the pharmaceutical composition in about 20 hours to about 25 hours and at least 95% of the acetaminophen is released in vitro from the pharmaceutical compositions in about 20 hours to about 25 hours.
  • At least 95% is of the hydrocodone is released from the pharmaceutical composition in about 21 hours to about 22 hours and at least 95% of the acetaminophen is released in vitro from the pharmaceutical compositions in about 21 hours to about 22 hours.
  • at least 99% of the hydrocodone is released from the pharmaceutical composition in about 22 hours to about 26 hours and at least 99% of the acetaminophen is released in vitro from the pharmaceutical compositions in about 22 hours to about 26 hours.
  • at least 99% of the hydrocodone is released from the pharmaceutical composition in less than about 27 hours and at least 99% of the acetaminophen is released in vitro from the pharmaceutical compositions in less than about 27 hours.
  • the present invention provides a composition where the core layer comprises an excipient capable of controlling the drug release and the non-core layer comprises an excipient capable of instantly releasing the drug.
  • the core layer is manufactured by melt-extrusion followed by direct shaping of the drug-containing melt and the non-core layer is spray coated over the core layer.
  • the composition comprises about 500mg of acetaminophen and about 15 mg of hydrocodone bitartrate pentahemihydrate.
  • the composition is characterized by at least one of the following features: i) the amount of abuse-relevant drug that is extracted from the composition by 40% aqueous ethanol within one hour at 37 °C in vitro is less than or equal 1.5 times the amount of the hydrocodone that is extracted by 0.01 N hydrochloric acid in vitro within one hour at 37 °C, ii) the composition does not break under a force of 150 newtons, preferably 300 newtons, more preferably 450 newtons, yet more preferably 500 newtons as measured by "Pharma Test PTB 501" hardness tester, iii) the composition releases at least 20% of the hydrocodone and not more than 45% of the hydrocodone during the first hour of in vitro dissolution testing and preferably also during the first hour of in vivo testing, iv) the composition releases a therapeutically effective dose of the acetaminophen within 1 to 2 hours after a single dose, v) the composition releases a therapeutically effective dose of the acet

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Abstract

Les modes de réalisation préférés de la présente application fournissent des formulations et des procédés destinés à administrer des médicaments, en particulier des produits toxicologiques dans lesquels on trouve une substance toxique essentiellement confinée dans le noyau et une substance non toxique dans la région secondaire. Ces formulations ont une toxicité réduite. Dans la formulation, la substance toxique est de préférence un opioïde, et la substance non toxique est de l'acétaminophène ou de l'ibuprofène. De préférence, l'opioïde est de l'hydrocodone et l'analgésique non toxique est de l'acétaminophène. Dans certaines modes préférés de réalisation, les formes posologiques sont caractérisées par une résistance à l'extraction par solvant, à l'altération, à la trituration et au broyage. Certains modes de réalisation des inventions fournissent des formes posologiques qui donnent un pic initial de libération du médicament suivi d'une période prolongée de libération contrôlée du médicament.
PCT/US2007/073957 2007-07-20 2007-07-20 Formulations d'analgésiques non opioïdes et d'analgésiques opioïdes captifs WO2009014534A1 (fr)

Priority Applications (14)

Application Number Priority Date Filing Date Title
EP07813144A EP2182928A1 (fr) 2007-07-20 2007-07-20 Formulations d'analgésiques non opioïdes et d'analgésiques opioïdes captifs
AU2007356880A AU2007356880A1 (en) 2007-07-20 2007-07-20 Formulations of nonopioid and confined opioid analgesics
BRPI0721940-7A BRPI0721940A2 (pt) 2007-07-20 2007-07-20 Formulações de analgésicos opióides confinados e não-opióides
RU2010106202/15A RU2477995C2 (ru) 2007-07-20 2007-07-20 Составы неопиоидных и ограниченных опиоидных аналгетиков
MX2010000803A MX2010000803A (es) 2007-07-20 2007-07-20 Formulaciones de analgesicos no opioides y opioides confinados.
KR1020107003775A KR20100055431A (ko) 2007-07-20 2007-07-20 비오피오이드 및 한정된 오피오이드 진통제의 제형
PCT/US2007/073957 WO2009014534A1 (fr) 2007-07-20 2007-07-20 Formulations d'analgésiques non opioïdes et d'analgésiques opioïdes captifs
NZ581767A NZ581767A (en) 2007-07-20 2007-07-20 Formulations of nonopioid and confined opioid analgesics
JP2010516964A JP2010534204A (ja) 2007-07-20 2007-07-20 非オピオイド鎮痛薬と閉じ込められたオピオイド鎮痛薬の製剤
CA2690829A CA2690829A1 (fr) 2007-07-20 2007-07-20 Formulations d'analgesiques non opioides et d'analgesiques opioides captifs
CN200780053839XA CN101917977B (zh) 2007-07-20 2007-07-20 非阿片样物质和限制的阿片样物质止痛药的制剂
TW097105831A TW200904431A (en) 2007-07-20 2008-02-19 Formulations of nonopioid and confined opioid analgesics
IL202680A IL202680A0 (en) 2007-07-20 2009-12-10 Formulations of nonopioid and confined opioid analgesics
ZA2009/08900A ZA200908900B (en) 2007-07-20 2009-12-14 Formulations of nonopioid and confined opioid analgesics

Applications Claiming Priority (1)

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PCT/US2007/073957 WO2009014534A1 (fr) 2007-07-20 2007-07-20 Formulations d'analgésiques non opioïdes et d'analgésiques opioïdes captifs

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EP (1) EP2182928A1 (fr)
JP (1) JP2010534204A (fr)
KR (1) KR20100055431A (fr)
CN (1) CN101917977B (fr)
AU (1) AU2007356880A1 (fr)
BR (1) BRPI0721940A2 (fr)
CA (1) CA2690829A1 (fr)
IL (1) IL202680A0 (fr)
MX (1) MX2010000803A (fr)
NZ (1) NZ581767A (fr)
RU (1) RU2477995C2 (fr)
TW (1) TW200904431A (fr)
WO (1) WO2009014534A1 (fr)
ZA (1) ZA200908900B (fr)

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US8722086B2 (en) 2007-03-07 2014-05-13 Gruenenthal Gmbh Dosage form with impeded abuse
WO2014191396A1 (fr) * 2013-05-29 2014-12-04 Grünenthal GmbH Forme dosifiée inviolable à profil de libération bimodale
US9161917B2 (en) 2008-05-09 2015-10-20 Grünenthal GmbH Process for the preparation of a solid dosage form, in particular a tablet, for pharmaceutical use and process for the preparation of a precursor for a solid dosage form, in particular a tablet
US9492444B2 (en) 2013-12-17 2016-11-15 Pharmaceutical Manufacturing Research Services, Inc. Extruded extended release abuse deterrent pill
US9629807B2 (en) 2003-08-06 2017-04-25 Grünenthal GmbH Abuse-proofed dosage form
US9636303B2 (en) 2010-09-02 2017-05-02 Gruenenthal Gmbh Tamper resistant dosage form comprising an anionic polymer
US9655853B2 (en) 2012-02-28 2017-05-23 Grünenthal GmbH Tamper-resistant dosage form comprising pharmacologically active compound and anionic polymer
US9675610B2 (en) 2002-06-17 2017-06-13 Grünenthal GmbH Abuse-proofed dosage form
US9707184B2 (en) 2014-07-17 2017-07-18 Pharmaceutical Manufacturing Research Services, Inc. Immediate release abuse deterrent liquid fill dosage form
US9750701B2 (en) 2008-01-25 2017-09-05 Grünenthal GmbH Pharmaceutical dosage form
US9855263B2 (en) 2015-04-24 2018-01-02 Grünenthal GmbH Tamper-resistant dosage form with immediate release and resistance against solvent extraction
US9872835B2 (en) 2014-05-26 2018-01-23 Grünenthal GmbH Multiparticles safeguarded against ethanolic dose-dumping
US9913814B2 (en) 2014-05-12 2018-03-13 Grünenthal GmbH Tamper resistant immediate release capsule formulation comprising tapentadol
US9925146B2 (en) 2009-07-22 2018-03-27 Grünenthal GmbH Oxidation-stabilized tamper-resistant dosage form
US10058548B2 (en) 2003-08-06 2018-08-28 Grünenthal GmbH Abuse-proofed dosage form
US10064945B2 (en) 2012-05-11 2018-09-04 Gruenenthal Gmbh Thermoformed, tamper-resistant pharmaceutical dosage form containing zinc
US10080721B2 (en) 2009-07-22 2018-09-25 Gruenenthal Gmbh Hot-melt extruded pharmaceutical dosage form
US10130591B2 (en) 2003-08-06 2018-11-20 Grünenthal GmbH Abuse-proofed dosage form
US10154966B2 (en) 2013-05-29 2018-12-18 Grünenthal GmbH Tamper-resistant dosage form containing one or more particles
US10172797B2 (en) 2013-12-17 2019-01-08 Pharmaceutical Manufacturing Research Services, Inc. Extruded extended release abuse deterrent pill
US10195153B2 (en) 2013-08-12 2019-02-05 Pharmaceutical Manufacturing Research Services, Inc. Extruded immediate release abuse deterrent pill
US10201502B2 (en) 2011-07-29 2019-02-12 Gruenenthal Gmbh Tamper-resistant tablet providing immediate drug release
US10300141B2 (en) 2010-09-02 2019-05-28 Grünenthal GmbH Tamper resistant dosage form comprising inorganic salt
US10335373B2 (en) 2012-04-18 2019-07-02 Grunenthal Gmbh Tamper resistant and dose-dumping resistant pharmaceutical dosage form
US10449547B2 (en) 2013-11-26 2019-10-22 Grünenthal GmbH Preparation of a powdery pharmaceutical composition by means of cryo-milling
DE102019002444A1 (de) 2018-04-20 2019-10-24 Scania Cv Ab Verfahren zum Steuern eines Antriebsstrangs, Steueranordnung, Fahrzeug, Computerprogramm und computerlesbares Medium
US10624862B2 (en) 2013-07-12 2020-04-21 Grünenthal GmbH Tamper-resistant dosage form containing ethylene-vinyl acetate polymer
US10695297B2 (en) 2011-07-29 2020-06-30 Grünenthal GmbH Tamper-resistant tablet providing immediate drug release
US10729658B2 (en) 2005-02-04 2020-08-04 Grünenthal GmbH Process for the production of an abuse-proofed dosage form
US10842750B2 (en) 2015-09-10 2020-11-24 Grünenthal GmbH Protecting oral overdose with abuse deterrent immediate release formulations
US10959958B2 (en) 2014-10-20 2021-03-30 Pharmaceutical Manufacturing Research Services, Inc. Extended release abuse deterrent liquid fill dosage form
US11224576B2 (en) 2003-12-24 2022-01-18 Grünenthal GmbH Process for the production of an abuse-proofed dosage form
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JP2018520165A (ja) * 2015-07-10 2018-07-26 サン、ファーマ、アドバンスト、リサーチ、カンパニー、リミテッドＳｕｎ Ｐｈａｒｍａ Ａｄｖａｎｃｅｄ Ｒｅｓｅａｒｃｈ Ｃｏｍｐａｎｙ Ｌｉｍｉｔｅｄ ヒドロコドンの多数錠剤乱用抵抗性即時放出型固体投薬形態物
JP6858729B2 (ja) * 2018-05-25 2021-04-14 ▲財▼▲団▼法人国防教育研究基金会Ｎａｔｉｏｎａｌ Ｄｅｆｅｎｓｅ Ｅｄｕｃａｔｉｏｎ Ａｎｄ Ｒｅｓｅａｒｃｈ Ｆｏｕｎｄａｔｉｏｎ 肝臓に対する副作用がない、新しいアセトアミノフェン複合組成
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US9675610B2 (en) 2002-06-17 2017-06-13 Grünenthal GmbH Abuse-proofed dosage form
US10369109B2 (en) 2002-06-17 2019-08-06 Grünenthal GmbH Abuse-proofed dosage form
US10058548B2 (en) 2003-08-06 2018-08-28 Grünenthal GmbH Abuse-proofed dosage form
US10130591B2 (en) 2003-08-06 2018-11-20 Grünenthal GmbH Abuse-proofed dosage form
US9629807B2 (en) 2003-08-06 2017-04-25 Grünenthal GmbH Abuse-proofed dosage form
US11224576B2 (en) 2003-12-24 2022-01-18 Grünenthal GmbH Process for the production of an abuse-proofed dosage form
US11844865B2 (en) 2004-07-01 2023-12-19 Grünenthal GmbH Abuse-proofed oral dosage form
US10675278B2 (en) 2005-02-04 2020-06-09 Grünenthal GmbH Crush resistant delayed-release dosage forms
US10729658B2 (en) 2005-02-04 2020-08-04 Grünenthal GmbH Process for the production of an abuse-proofed dosage form
US8722086B2 (en) 2007-03-07 2014-05-13 Gruenenthal Gmbh Dosage form with impeded abuse
US9750701B2 (en) 2008-01-25 2017-09-05 Grünenthal GmbH Pharmaceutical dosage form
US9161917B2 (en) 2008-05-09 2015-10-20 Grünenthal GmbH Process for the preparation of a solid dosage form, in particular a tablet, for pharmaceutical use and process for the preparation of a precursor for a solid dosage form, in particular a tablet
US10080721B2 (en) 2009-07-22 2018-09-25 Gruenenthal Gmbh Hot-melt extruded pharmaceutical dosage form
US10493033B2 (en) 2009-07-22 2019-12-03 Grünenthal GmbH Oxidation-stabilized tamper-resistant dosage form
US9925146B2 (en) 2009-07-22 2018-03-27 Grünenthal GmbH Oxidation-stabilized tamper-resistant dosage form
US9636303B2 (en) 2010-09-02 2017-05-02 Gruenenthal Gmbh Tamper resistant dosage form comprising an anionic polymer
US10300141B2 (en) 2010-09-02 2019-05-28 Grünenthal GmbH Tamper resistant dosage form comprising inorganic salt
US10695297B2 (en) 2011-07-29 2020-06-30 Grünenthal GmbH Tamper-resistant tablet providing immediate drug release
US10201502B2 (en) 2011-07-29 2019-02-12 Gruenenthal Gmbh Tamper-resistant tablet providing immediate drug release
US10864164B2 (en) 2011-07-29 2020-12-15 Grünenthal GmbH Tamper-resistant tablet providing immediate drug release
FR2979242A1 (fr) * 2011-08-29 2013-03-01 Sanofi Sa Comprime contre l'usage abusif, a base de paracetamol et d'oxycodone
WO2013030177A1 (fr) * 2011-08-29 2013-03-07 Sanofi Comprimé résistant à l'abus comprenant de l'oxycodone et du paracétamol
US9655853B2 (en) 2012-02-28 2017-05-23 Grünenthal GmbH Tamper-resistant dosage form comprising pharmacologically active compound and anionic polymer
US10335373B2 (en) 2012-04-18 2019-07-02 Grunenthal Gmbh Tamper resistant and dose-dumping resistant pharmaceutical dosage form
US10064945B2 (en) 2012-05-11 2018-09-04 Gruenenthal Gmbh Thermoformed, tamper-resistant pharmaceutical dosage form containing zinc
WO2014191396A1 (fr) * 2013-05-29 2014-12-04 Grünenthal GmbH Forme dosifiée inviolable à profil de libération bimodale
AU2014273226B2 (en) * 2013-05-29 2019-06-27 Grunenthal Gmbh Tamper resistant dosage form with bimodal release profile
US10154966B2 (en) 2013-05-29 2018-12-18 Grünenthal GmbH Tamper-resistant dosage form containing one or more particles
US9737490B2 (en) 2013-05-29 2017-08-22 Grünenthal GmbH Tamper resistant dosage form with bimodal release profile
US10624862B2 (en) 2013-07-12 2020-04-21 Grünenthal GmbH Tamper-resistant dosage form containing ethylene-vinyl acetate polymer
US10639281B2 (en) 2013-08-12 2020-05-05 Pharmaceutical Manufacturing Research Services, Inc. Extruded immediate release abuse deterrent pill
US10195153B2 (en) 2013-08-12 2019-02-05 Pharmaceutical Manufacturing Research Services, Inc. Extruded immediate release abuse deterrent pill
US10449547B2 (en) 2013-11-26 2019-10-22 Grünenthal GmbH Preparation of a powdery pharmaceutical composition by means of cryo-milling
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
US10792254B2 (en) 2013-12-17 2020-10-06 Pharmaceutical Manufacturing Research Services, Inc. Extruded extended release abuse deterrent pill
US9913814B2 (en) 2014-05-12 2018-03-13 Grünenthal GmbH Tamper resistant immediate release capsule formulation comprising tapentadol
US9872835B2 (en) 2014-05-26 2018-01-23 Grünenthal GmbH Multiparticles safeguarded against ethanolic dose-dumping
US9707184B2 (en) 2014-07-17 2017-07-18 Pharmaceutical Manufacturing Research Services, Inc. Immediate release abuse deterrent liquid fill dosage form
US10959958B2 (en) 2014-10-20 2021-03-30 Pharmaceutical Manufacturing Research Services, Inc. Extended release abuse deterrent liquid fill dosage form
US9855263B2 (en) 2015-04-24 2018-01-02 Grünenthal GmbH Tamper-resistant dosage form with immediate release and resistance against solvent extraction
US10842750B2 (en) 2015-09-10 2020-11-24 Grünenthal GmbH Protecting oral overdose with abuse deterrent immediate release formulations
DE102019002444A1 (de) 2018-04-20 2019-10-24 Scania Cv Ab Verfahren zum Steuern eines Antriebsstrangs, Steueranordnung, Fahrzeug, Computerprogramm und computerlesbares Medium

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ZA200908900B (en) 2014-05-28
IL202680A0 (en) 2010-06-30
TW200904431A (en) 2009-02-01
KR20100055431A (ko) 2010-05-26
CN101917977B (zh) 2013-05-29
NZ581767A (en) 2012-05-25
CA2690829A1 (fr) 2009-01-29
RU2010106202A (ru) 2011-08-27
EP2182928A1 (fr) 2010-05-12
BRPI0721940A2 (pt) 2014-03-18
MX2010000803A (es) 2010-06-23
AU2007356880A1 (en) 2009-01-29
RU2477995C2 (ru) 2013-03-27
JP2010534204A (ja) 2010-11-04

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