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WO2012040651A2 - Formulations d'opioïdes à libération contrôlée - Google Patents

Formulations d'opioïdes à libération contrôlée Download PDF

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Publication number
WO2012040651A2
WO2012040651A2 PCT/US2011/053132 US2011053132W WO2012040651A2 WO 2012040651 A2 WO2012040651 A2 WO 2012040651A2 US 2011053132 W US2011053132 W US 2011053132W WO 2012040651 A2 WO2012040651 A2 WO 2012040651A2
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WO
WIPO (PCT)
Prior art keywords
oxycodone
salt
opioid
pharmaceutical formulation
formulation
Prior art date
Application number
PCT/US2011/053132
Other languages
English (en)
Other versions
WO2012040651A3 (fr
Inventor
Edward M. Rudnic
Michael Vachon
Gary W. Pace
Joseph Berry
Felix De La Iglesia
Original Assignee
QRxPharma Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from US13/024,319 external-priority patent/US20110195989A1/en
Application filed by QRxPharma Ltd. filed Critical QRxPharma Ltd.
Priority to CN2011800562785A priority Critical patent/CN103476403A/zh
Priority to JP2013530379A priority patent/JP2013537915A/ja
Priority to AU2011305161A priority patent/AU2011305161A1/en
Priority to CA2812570A priority patent/CA2812570A1/fr
Priority to EP11764653.9A priority patent/EP2618820A2/fr
Publication of WO2012040651A2 publication Critical patent/WO2012040651A2/fr
Publication of WO2012040651A3 publication Critical patent/WO2012040651A3/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/485—Morphinan derivatives, e.g. morphine, codeine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
    • A61K9/209—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5026—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5073—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings
    • 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

Definitions

  • the invention is directed to pharmaceutical formulations comprising opioid components that each has a release profile.
  • the components may provide immediate or controlled release of the opioid.
  • the invention is also directed to methods of controlling release of one or more opioid compounds and methods of treating pain.
  • Opioids are a class of pain-relieving prescription medications frequently used in the treatment of a variety of acute and chronic, moderate to severe, pain.
  • opioids can be rapidly absorbed and systemically excreted by the body through metabolic inactivation.
  • administration of opioids often requires careful dosing at frequent intervals to maintain effective steady state blood levels of the opioid, and thereby provide consistent analgesia. Otherwise, blood levels of the opioid can oscillate, resulting in poor and inconsistent pain relief.
  • the invention relates to pharmaceutical formulations for treating pain that comprise components containing opioid compounds and having different release profiles.
  • the invention also relates to methods of controlling release of one or more opioid compounds and methods of treating pain.
  • the pharmaceutical formulations of the invention may comprise one or more components having one or more release profiles, in which at least one of the components comprise a compound having opioid receptor agonist activity.
  • the components may have the same release profile, or the components may have different release profiles.
  • the compounds having opioid receptor agonist activity may have agonist activity toward the mu (" ⁇ > " morphine receptor), sigma (" ⁇ ,” the phencyclidine receptor), kappa (" ⁇ ,” the ketocyclazocine receptor) or delta (" ⁇ ,” the endorphinlenkephalin receptor) opioid receptors.
  • Such compounds may include, among others, morphine, codeine, hydromorphone, hydrocodone, oxycodone, dihydrocodeine, dihydromorphine, oxymorphone, mixtures thereof, or salts thereof.
  • a component may comprise two opioid compounds in varying ratios.
  • a component may comprise morphine and oxycodone, or salts thereof, in about a 3:2 ratio by weight.
  • the components may have an immediate release profile or a controlled release profile.
  • the formulation may comprise one or more additional components, such as at least two, at least three, at least four, or at least five components.
  • the one or more additional components may comprise one or more active agents.
  • the one or more active agents may be compounds having opioid receptor agonist activity.
  • the one or more active agents may be one or more non-opioid analgesic compound(s), or a mixture of one or more non-opioid analgesic compound(s) and one or more compound(s) with opioid receptor agonist activity, or pharmaceutically acceptable salts, esters or prodrugs thereof.
  • the one or more active agents may be one or more hybrid opioid compound(s), or a mixture of one or more hybrid opioid compound(s) and one or more compound(s) with opioid receptor agonist activity, or pharmaceutically acceptable salts, esters or prodrugs thereof.
  • the pharmaceutical formulation may comprise one or more opioid components, wherein at least one of the opioid components is a controlled release opioid component that comprises an opioid.
  • the opioid is selected from the group consisting of morphine, codeine, hydromorphone, hydrocodone, oxycodone, dihydrocodeine, dihydromorphine, oxymorphone, mixtures thereof, and salts thereof.
  • the opioid is oxycodone or a salt thereof.
  • the pharmaceutical formulation provides a time to maximum opioid plasma concentration (T max ) of about 4.5 to about 8 hours after repeated administration.
  • T max is about 5 to about 6 hours, or about 6 hours, after repeated administration.
  • the controlled release component provides a time to minimum oxycodone plasma concentration (T m i n ) of about 13 to about 16 hours after repeated administration. In particular embodiments, T m i n is about 14 hours after repeated
  • the repeated administration is through steady-state conditions.
  • dissolution of the pharmaceutical formulation releases about 0 to about 20 % of the opioid after two hours, or releases about 15 to about 60 % of the opioid after four hours, or releases about 25 to about 80 % of the opioid after six hours, or releases about 35 to about 85 % of the opioid after eight hours, or releases about 45 to about 95 % of the opioid after ten hours, or releases about 60 to about 100 % of the opioid after twelve hours, as measured in a USP type I apparatus at 37° C in water at 50 rpm.
  • the pharmaceutical formulation when the pharmaceutical formulation comprises about 2 mg of opioid, the pharmaceutical formulation may provide a mean maximum plasma
  • the repeated administration may be through steady- state conditions.
  • the area-under-the-curve for between about 0 and about 24 hours (AUC 24 ) may be about 14.7 ng-hr/mL to about 23.0 ng-hr/mL, or about 15.8 ng-hr/mL to about 21.0 ng-hr/mL, or about 17.1 ng-hr/mL to about 19.7 ng-hr/mL, after single administration.
  • the pharmaceutical formulation when the pharmaceutical formulation comprises about 5 mg of opioid, the pharmaceutical formulation may provide a mean C max of about 3 to about 7 ng/mL, or about 5 ng/mL, after repeated administration.
  • the repeated administration may be through steady-state conditions.
  • the AUC 24 may be about 40.2 ng-hr/mL to about 62.8 ng-hr/mL, or about 43.2 ng-hr/mL to about 57.2 ng-hr/mL, or about 46.7 ng-hr/mL to about 53.7 ng-hr/mL, after single administration.
  • the pharmaceutical formulation when the pharmaceutical formulation comprises about 10 mg of opioid, the pharmaceutical formulation may provide a mean C max of about 5 to about 15 ng/mL, or about 10 ng/mL, after repeated administration.
  • the repeated administration may be through steady-state conditions.
  • the AUC 24 may be about 80.5 ng-hr/mL to about 125.9 ng-hr/mL, or about 86.6 ng-hr/mL to about 1 14.8 ng-hr/mL, or about 93.7 ng-hr/mL to about 107.7 ng-hr/mL, after single administration.
  • the pharmaceutical formulation when the pharmaceutical formulation comprises about 20 mg of opioid, the pharmaceutical formulation may provide a mean C max of about 10 to about 30 ng/mL, or about 20 ng/mL, after repeated administration.
  • the repeated administration may be through steady-state conditions.
  • the AUC24 may be about 166.0 ng-hr/mL to about 259.3 ng-hr/mL, or about 178.5 ng-hr/mL to about 236.6 ng-hr/mL, or about 193.0 ng-hr/mL to about 222.0 ng-hr/mL, after single
  • the pharmaceutical formulation when the pharmaceutical formulation comprises about 40 mg of opioid, the pharmaceutical formulation may provide a mean C max of about 25 to about 55 ng/mL, or about 40 ng/mL, after repeated administration.
  • the repeated administration may be through steady-state conditions.
  • the AUC 24 may be about 338.5 ng-hr/mL to about 528.9 ng-hr/mL, or about 363.9 ng-hr/mL to about 482.3 ng-hr/mL, or about 393.5 ng-hr/mL to about 452.7 ng-hr/mL, after single
  • the pharmaceutical formulation when the pharmaceutical formulation comprises about 80 mg of opioid, the pharmaceutical formulation may provide a mean C max of about 50 to about 1 10 ng/mL, or about 80 ng/mL, after repeated administration.
  • the repeated administration may be through steady-state conditions.
  • the AUC24 may be about 868.4 ng-hr/mL to about 1356.9 ng-hr/mL, or about 933.5 ng-hr/mL to about 1237.5 ng-hr/mL, or about 1009.5 ng-hr/mL to about 1 161.5 ng-hr/mL, after single administration.
  • the pharmaceutical formulation provides a mean minimum oxycodone plasma concentration (C m i n ) of about 0.5 to about 40 ng/mL, or about 4 to about 15 ng/mL, after repeated administration.
  • the repeated administration is through steady-state conditions.
  • the pharmaceutical formulation comprises a second controlled release opioid component.
  • the second controlled release opioid component comprises an opioid selected from the group consisting of morphine, codeine, hydromorphone, hydrocodone, oxycodone, dihydrocodeine, dihydromorphine, oxymorphone, mixtures thereof, and salts thereof.
  • the pharmaceutical formulation comprises an immediate- release opioid component.
  • the immediate-release opioid component comprises an opioid selected from the group consisting of morphine, codeine, hydromorphone, hydrocodone, oxycodone, dihydrocodeine, dihydromorphine, oxymorphone, mixtures thereof, and salts thereof.
  • the opioid in the immediate- release opioid component is morphine or a salt thereof.
  • the total morphine, or salt thereof, and the total oxycodone, or salt thereof, in the formulation are in a ratio of about 3 :2, morphine or salt thereof to oxycodone or salt thereof, by weight.
  • the pharmaceutical formulation comprises a second opioid component and a third opioid component, wherein: (a) the second opioid component is an immediate-release opioid component and comprises an opioid having ⁇ agonist activity; and (b) the third opioid component is a controlled release opioid component and comprises an opioid having mu agonist activity.
  • the opioid having ⁇ agonist activity is oxycodone or a salt thereof, and the opioid having ⁇ agonist activity is morphine or a salt thereof.
  • the controlled release opioid component comprises morphine or a salt thereof. In some embodiments, the controlled release opioid component comprises morphine or salt thereof and oxycodone or salt thereof in an amount of about 3 :2 by weight.
  • the pharmaceutical formulation may comprise one or more opioid components for humans in need thereof, such that the one or more opioid components comprise one or more release profiles, and at least one of the opioid components is a controlled release opioid component comprising oxycodone or a salt thereof;
  • compositions when containing a total dose of oxycodone, or a salt thereof, of about 2 mg, provides a T max of about 4.5 to about 7.5 hours, or about 5 to about 6 hours, or about 6 hours, after repeated administration, and an AUC 24 of about 14.7 ng-hr/mL to about 23.0 ng-hr/mL, or about 15.8 ng-hr/mL to about 21.0 ng-hr/mL, or about 17.1 ng-hr/mL to about 19.7 ng-hr/mL, after single administration.
  • the repeated administration may be through steady-state conditions.
  • the pharmaceutical formulation is formulated for a total dose of oxycodone, or a salt thereof, that is different from about 2 mg of oxycodone, or a salt thereof, and has an AUC 24 that is proportional to the 2 mg AUC 24 .
  • the total dose AUC 24 is linearly proportional to the 2 mg AUC 24 .
  • the pharmaceutical formulation when containing a total dose of oxycodone, or a salt thereof, of about 2 mg, provides a C max of about 1 to about 3 ng/mL, or about 2 mg, after repeated administration.
  • the repeated administration when containing a total dose of oxycodone, or a salt thereof, of about 2 mg, provides a C max of about 1 to about 3 ng/mL, or about 2 mg, after repeated administration.
  • the repeated administration when containing a total dose of oxycodone, or a salt thereof, of about 2 mg, provides a C max of about 1 to about 3 ng/mL, or about 2 mg, after repeated administration.
  • the repeated administration when containing a total dose of oxycodone, or a salt thereof, of about 2 mg, provides a C max of about 1 to about 3 ng/mL, or about 2 mg, after repeated administration.
  • the repeated administration when containing a total dose of oxycodone, or a salt thereof, of about 2 mg, provides
  • the pharmaceutical formulation is formulated for a total dose of oxycodone, or a salt thereof, that is different from about 2 mg of oxycodone, or a salt thereof, and has a C max that is proportional to the 2 mg C max .
  • the total dose C max is linearly proportional to the 2 mg C max .
  • the pharmaceutical formulation when containing a total dose of about 2 mg, provides a T m in of about 13 to about 16 hours after repeated administration.
  • the repeated administration is through steady-state conditions.
  • the pharmaceutical formulation may comprise one or more opioid components for humans in need thereof, such that the one or more opioid components comprise one or more release profiles, and at least one of the opioid components is a controlled release opioid component comprising oxycodone or a salt thereof; the pharmaceutical formulation, when containing a total dose of oxycodone, or a salt thereof, of about 5 mg, provides a T max of about 4.5 to about 7.5 hours, or about 5 to about 6 hours, or about 6 hours, after repeated administration, and an AUC 24 of about 40.2 ng-hr/mL to about 62.8 ng-hr/mL, or about 43.2 ng-hr/mL to about 57.2 ng-hr/mL, or about 46.7 ng-hr/mL to about 53.7 ng-hr/mL, after single administration.
  • the repeated administration may be through steady-state conditions.
  • the pharmaceutical formulation is formulated for a total dose of oxycodone, or a salt thereof, that is different from about 5 mg of oxycodone, or a salt thereof, and has an AUC24 that is proportional to the 5 mg AUC24.
  • the total dose AUC 24 is linearly proportional to the 5 mg AUC 24 .
  • the pharmaceutical formulation when containing a total dose of oxycodone, or a salt thereof, of about 5 mg, provides a C max of about 3 to about 7 ng/mL, or about 5 ng/mL, after repeated administration.
  • the repeated administration is through steady-state conditions.
  • the pharmaceutical formulation is formulated for a total dose of oxycodone, or a salt thereof, that is different from about 5 mg of oxycodone, or a salt thereof, and has a C max that is proportional to the 5 mg C max .
  • the total dose C max is linearly proportional to the 5 mg C max .
  • the pharmaceutical formulation when containing a total dose of oxycodone, or a salt thereof, of about 5 mg, provides a T m i n of about 13 to about 16 hours after repeated administration.
  • the repeated administration is through steady-state conditions.
  • the pharmaceutical formulation may comprise one or more opioid components for humans in need thereof, such that the one or more opioid components comprise one or more release profiles, and at least one of the opioid components is a controlled release opioid component comprising oxycodone or a salt thereof; the pharmaceutical formulation, when containing a total dose of oxycodone, or a salt thereof, of about 10 mg, provides a T max of about 4.5 to about 7.5 hours, or about 5 to about 6 hours, or about 6 hours, after repeated administration, and an AUC 24 of about 80.5 ng-hr/mL to about 125.9 ng-hr/mL, or about 86.6 ng-hr/mL to about 114.8 ng-hr/mL, or about 93.7 ng-hr/mL to about 107.7 ng-hr/mL, after single administration.
  • the repeated administration may be through steady-state conditions.
  • the pharmaceutical formulation is formulated for a total dose of oxycodone, or a salt thereof, that is different from about 10 mg of oxycodone, or a salt thereof, and has an AUC 24 that is proportional to the 10 mg AUC 24 .
  • the total dose AUC24 is linearly proportional to the 10 mg AUC24.
  • the pharmaceutical formulation when containing a total dose of oxycodone, or a salt thereof, of about 10 mg, provides a C max of about 5 to about 15 ng/mL, or about 10 ng/mL, after repeated administration. In some embodiments, the repeated administration is through steady-state conditions. In some embodiments, the pharmaceutical formulation is formulated for a total dose of oxycodone, or a salt thereof, that is different from about 10 mg of oxycodone, or a salt thereof, and has a C max that is proportional to the 10 mg Cmax- In some embodiments, the total dose C ma x is linearly proportional to the 10 mg C
  • the pharmaceutical formulation when containing a total dose of oxycodone, or a salt thereof, of about 10 mg, provides a T m i n of about 13 to about 16 hours after repeated administration.
  • the repeated administration is through steady-state conditions.
  • the pharmaceutical formulation may comprise one or more opioid components for humans in need thereof, such that the one or more opioid components comprise one or more release profiles, and at least one of the opioid components is a controlled release opioid component comprising oxycodone or a salt thereof; the pharmaceutical formulation, when containing a total dose of oxycodone, or a salt thereof, of about 20 mg, provides a T max of about 4.5 to about 7.5 hours, or about 5 to about 6 hours, or about 6 hours, after repeated administration, and an AUC 24 of about 166.0 ng-hr/mL to about 259.3 ng-hr/mL, or about 178.5 ng-hr/mL to about 236.6 ng-hr/mL, or about 193.0 ng-hr/mL to about 222.0 ng-hr/mL, after single administration.
  • the repeated administration may be through steady-state conditions.
  • the pharmaceutical formulation is formulated for a total dose of oxycodone, or a salt thereof, that is different from about 20 mg of oxycodone, or a salt thereof, and has an AUC 24 that is proportional to the 20 mg AUC 24 .
  • the total dose AUC 24 is linearly proportional to the 20 mg AUC 24 .
  • the pharmaceutical formulation when containing a total dose of oxycodone, or a salt thereof, of about 20 mg, provides a C max of about 10 to about 30 ng/mL, or about 20 ng/mL, after repeated administration. In some embodiments, the repeated administration is through steady-state conditions. In some embodiments, the pharmaceutical formulation is formulated for a total dose of oxycodone, or a salt thereof, that is different from about 20 mg of oxycodone, or a salt thereof, and has a C max that is proportional to the 20 mg C max .
  • the total dose C max is linearly proportional to the 20 mg C ⁇ max-
  • the pharmaceutical formulation when containing a total dose of oxycodone, or a salt thereof, of about 20 mg, provides a T m iuza of about 8 hours after repeated administration. In some embodiments, the repeated administration is through steady-state conditions.
  • the pharmaceutical formulation is formulated for a total dose different from about 20 mg of oxycodone, or a salt thereof, and having a C m i n proportional to the 20 mg C m i n .
  • the total dose C m i n is linearly proportional to the 20 mg C m i n .
  • the pharmaceutical formulation may comprise one or more opioid components for humans in need thereof, such that the one or more opioid components comprise one or more release profiles, and at least one of the opioid components is a controlled release opioid component comprising oxycodone or a salt thereof; the pharmaceutical formulation,, when containing a total dose of oxycodone, or a salt thereof, of about 40 mg, provides a T max of about 4.5 to about 7.5 hours, or about 5 to about 6 hours, or about 6 hours, after repeated administration, and an AUC 24 of about 338.5 ng-hr/mL to about 528.9 ng-hr/mL, or about 363.9 ng-hr/mL to about 482.3 ng-hr/mL, or about 393.5 ng-hr/mL to about 452.7 ng-hr/mL, after single administration.
  • the repeated administration may be through steady-state conditions.
  • the pharmaceutical formulation is formulated for a total dose of oxycodone, or a salt thereof, that is different from about 40 mg of oxycodone, or a salt thereof, and has an AUC 24 that is proportional to the 40 mg AUC 24 .
  • the total dose AUC 24 is linearly proportional to the 40 mg AUC 24 .
  • the pharmaceutical formulation when containing a total dose of oxycodone, or a salt thereof, of about 40 mg, provides a C ma x of about 25 to about 55 ng/mL, or about 40 ng/mL, after repeated administration. In some embodiments, the repeated administration is through steady-state conditions. In some embodiments, the pharmaceutical formulation is formulated for a total dose of oxycodone, or a salt thereof, that is different from about 40 mg of oxycodone, or a salt thereof, and has a C max that is proportional to the 40 mg C max . In some embodiments, the total dose C max is linearly proportional to the 40 mg C ⁇ max-
  • the pharmaceutical formulation when containing a total dose of oxycodone, or a salt thereof, of about 40 mg, provides a T m irade of about 13 to about 16 hours after repeated administration.
  • the repeated administration is through steady-state conditions.
  • the pharmaceutical formulation may comprise one or more opioid components for humans in need thereof, such that the one or more opioid components comprise one or more release profiles, and at least one of the opioid components is a controlled release opioid component comprising oxycodone or a salt thereof; the pharmaceutical formulation, when containing a total dose of oxycodone, or a salt thereof, of about 80 mg, provides a T max of about 4.5 to about 7.5 hours, or about 5 to about 6 hours, or about 6 hours, after repeated administration, and an AUC 24 of about 868.4 ng-hr/mL to about 1356.9 ng-hr/mL, or about 933.5 ng-hr/mL to about 1237.5 ng-hr/mL, or about 1009.5 ng-hr/mL to about 1161.5 ng-hr/mL, after single administration.
  • the repeated administration may be through steady-state conditions.
  • the pharmaceutical formulation is formulated for a total dose of oxycodone, or a salt thereof, that is different from about 80 mg of oxycodone, or a salt thereof, and has an AUC 24 that is proportional to the 80 mg AUC 24 .
  • the total dose AUC 24 is linearly proportional to the 80 mg AUC 24 .
  • the pharmaceutical formulation when containing a total dose of oxycodone, or a salt thereof, of about 80 mg, provides a C max of about 50 to about 1 10 ng/mL, or about 80 ng/mL, after repeated administration. In some embodiments, the repeated administration is through steady-state conditions. In some embodiments, the pharmaceutical formulation is formulated for a total dose of oxycodone, or a salt thereof, that is different from about 80 mg of oxycodone, or a salt thereof, and has a C max that is proportional to the 80 mg C max . In some embodiments, the total dose C max is linearly proportional to the 80 mg C
  • the pharmaceutical formulation when containing a total dose of oxycodone, or a salt thereof, of about 80 mg, provides a T m irade of about 13 to about 16 hours after repeated administration.
  • the repeated administration is through steady-state conditions.
  • the method for controlling release of one or more compounds having opioid receptor agonist activity for absorption in a human comprises administering a pharmaceutical formulation comprising one or more components, such that the one or more opioid components comprise one or more release profiles, and at least one of the opioid components is a controlled release opioid component comprising an opioid.
  • the pharmaceutical formulation administered to the human is in accordance to the pharmaceutical formulations of the invention.
  • the method of treating pain in a human comprises administering a pharmaceutical formulation comprising one or more components, such that the one or more opioid components comprise one or more release profiles, and at least one of the opioid components is a controlled release opioid component comprising an opioid.
  • the pharmaceutical formulation administered to the human is in accordance to the pharmaceutical formulations of the invention.
  • FIG. la and lb provide schematic images of two embodiments of opioid formulations of the present invention.
  • FIG. 2 provides a target release profile for oxycodone coated pellets used in the opioid formulations of the present invention.
  • FIG. 3 provides a target release profile for morphine coated pellets used in the opioid formulations of the present invention.
  • FIG. 4 provides a target release profile for oxycodone granulation coated with Eudragit L30D-55 used in the opioid formulations of the present invention.
  • FIG. 5 provides a target release profile for total oxycodone release in the opioid formulations of the present invention.
  • FIG. 6 provides a target release profile for total oxycodone and morphine release used in the dual-opioid coated tablets of the present invention.
  • FIG. 7 provides a schematic demonstrating the methods used in producing the oxycodone granules used in the present invention.
  • FIG. 8 provides a schematic demonstrating the methods used in producing the oxycodone core pellets used in the present invention.
  • FIG. 9 provides a schematic demonstrating the methods used in producing the morphine core pellets used in the present invention.
  • FIG. 10 provides a schematic demonstrating the methods used in coating the either morphine or oxycodone core pellets used in the present invention.
  • FIG. 11 provides a schematic demonstrating the methods used in producing the dual opioid coated tablets used in the present invention.
  • FIG. 12 provides a flow diagram for preparing extended release intermediate oxycodone pellets used in the clinical study (Example 2).
  • FIG. 13 provides an oxycodone plasma concentration profile of two opioid formulations of the present invention (Formulation A and Formulation B) and a Reference Formulation (MS Contin ® 30 mg (morphine CR) co-administered with OxyContin ® 20 mg (oxycodone CR)) through 72 hours after treatment.
  • FIG. 14 provides an oxycodone plasma concentration profile of two opioid formulations of the present invention (Formulation A and Formulation B) and a Reference Formulation (MS Contin ® 30 mg (morphine CR) co-administered with OxyContin ® 20 mg (oxycodone CR)) through 24 hours after treatment.
  • FIG. 15 provides a projected oxycodone plasma profile from administration of multiple doses at 12 hour intervals of an opioid formulation of the present invention.
  • FIG. 16 provides a projected oxycodone plasma profile from administration of multiple doses of an opioid formulation of the present invention having different dosing strengths.
  • FIG. 17 provides a projected oxycodone plasma profile from administration of multiple doses at 12 hour intervals of an opioid composite formulation (immediate release + controlled release) of the present invention.
  • FIG. 18 provides a projected oxycodone plasma profile from administration of multiple doses of an opioid composite formulation (immediate release + controlled release) of the present invention having different dosing strengths.
  • RS Ammonio Methacrylate Copolymer
  • RL Type A
  • RS Ammonio Methacrylate Copolymer
  • RL Type A
  • FIG. 21 provides a release profile of morphine sulfate in enteric coated tablets (using 50 % coated beadlets of Ammonio Methacrylate Copolymer Type B (RS) and Type A (RL) in a ratio of 90/10) at various % enteric coating levels.
  • RS Ammonio Methacrylate Copolymer Type B
  • RL Type A
  • FIG. 22 provides a release profile of oxycodone hydrochloride in enteric coated tablets (using 50 % coated beadlets of Ammonio Methacrylate Copolymer Type B (RS) and Type A (RL) in a ratio of 90/10) at various % enteric coating levels.
  • FIG. 23 provides a release profile for morphine sulfate in enteric coated tablets (10 % and 15 % coating level) at low, mid or high hardness levels.
  • FIG. 24 provides a release profile for oxycodone hydrochloride in enteric coated tablets (10 % and 15 % coating level) at low, mid or high hardness levels.
  • RS Ammonio Methacrylate Copolymer Type B
  • RL Type A
  • RS Ammonio Methacrylate Copolymer Type B
  • RL Type A
  • RS/RL Ammonio Methacrylate Copolymer Type B
  • RL Type A
  • the invention relates to pharmaceutical formulations and methods for the alleviation of acute or chronic pain by controlling the release of compounds having opioid agonist activity for absorption in humans.
  • the pharmaceutical formulations and methods of the invention may provide effective analgesia to a patient while reducing or eliminating undesired side effects typically experienced with the administration of opioid analgesic compounds. Due to the controlled release of the compound (s), it is possible to obtain a substantially constant rate of release of the compound(s) over a specific period of time, corresponding to the dosage necessary for the treatment in question, so that adherence to a strict dosage regimen, e.g. requiring administration of a drug at set intervals up to several times a day, may be dispensed with.
  • formulations and methods described herein are used to treat different types of pain, including neuropathic pain and nociceptive pain, somatic pain and visceral pain.
  • formulations and methods described herein are used to treat diabetic neuropathy, trigeminal neuralgia, postherpetic zoster pain, and thalamic pain syndrome (a central pain).
  • Neuropathic pain frequently coexists with nociceptive pain, and the inventive compounds and salts may be used to treat mixed pain states, i.e. a combination of neuropathic and nociceptive pain.
  • trauma that damages tissue and nerves, burns (that burn skin as well as nerve endings), and external nerve compression may cause both neuropathic and nociceptive pain.
  • Examples of external nerve compression include tumor nerve compression and sciatica from herniated discs pressing on nerves.
  • the formulations and methods are used to treat low back pain, cancer pain, osteoarthritis pain, fibromyalgia pain and postoperative pain.
  • the formulations and methods are used to treat pain associated with inflammation, bone pain, and joint disease.
  • the formulations and methods of the invention may be used to treat pain caused by a variety of conditions, including, but not limited to, pain after surgery or trauma, pain associated with a medical illness and the like.
  • the present invention encompasses formulations that can be administered to provide two opioids.
  • An objective of the present invention is to activate certain opioid receptors in the brain by one opioid, and stage the arrival of a second opioid at some timepoint after that receptor is occupied by the first opioid.
  • a dual-opioid extended-release tablet is designed to accomplish this.
  • formulations that contain oxycodone and morphine there is a need to delay the release of morphine until the oxycodone is at the receptor by at least one- half hour, and preferably more than one hour.
  • the components of the pharmaceutical formulations may comprise a compound having opioid receptor agonist activity.
  • Such compounds may have agonist activity toward the ⁇ -, K-, ⁇ -, or ⁇ -opioid receptors, including other classified receptor subtypes.
  • the compounds having opioid receptor agonist activity may be naturally occurring, semisynthetic or fully synthetic opiate compounds, derivatives or analogs thereof, or
  • Naturally occurring opiates are alkaloid compounds that are found in the resin of the opium poppy, and include morphine, codeine and thebaine.
  • Semi-synthetic or fully synthetic opiates include, but are not limited to, dihydromorphine, heterocodeine, dihydrocodeine, dihydrornorphinone, dihydrocodeinone, 3,6-diacetyl morphine, morphinone, 6-desoxymorphine, heroin, oxymorphone, oxycodone, 6- methylene-dihydromorphine, hydrocodone, etorphine, bupemorphine, naloxone or naltrexone.
  • Compounds having ⁇ -opioid receptor agonist activity may include, but are not limited to, morphine (and structurally related analogs and derivatives), alvimopan, buprenorphine, codeine, 6-desomorphine, dihydromorphine, dihydrornorphinone, dihydrocodeine, dihydrocodeinone, 3,6-diacetylmorphine, 6-methylene-dihydromorphine, diphenoxylate, drotebanol, eseroline, etorphine, fentanyl, hydrocodone, levophenacylmorphan, methadone, oxymorphone, nicomorphine, pethidine, picenadol, tapentadole, thebaine, and trimebutane.
  • morphine and structurally related analogs and derivatives
  • alvimopan buprenorphine
  • codeine codeine
  • 6-desomorphine dihydromorphine
  • dihydrornorphinone dihydro
  • Compounds having ⁇ -opioid receptor agonist activity may include, but are not limited to, asimadoline, butorphanol, bremazocine, cyclazocine, dextromethorphan, dynorphin, enadoline, ketazocine, nalbuphine, nalfurafine, norbuprenorphine, oxycodone, pentazocine, salvinorin A, 2-methoxymethyl salvinorin B and its ethoxymethyl and fluoroethoxymethyl homologues, spiradoline, and tifluadom.
  • Compounds having ⁇ -opioid receptor agonist activity may include, but are not limited to, deltorphin, ethoxymetopon, leu-enkephalin, met-enkephalin, mitragyna speciosa (kratom), mitragynine, mitragynine-pseudoindoxyl, N-phenethyl-14- norbuprenorphine, norclozapine, and 7-spiroindanyloxymorphone.
  • the compound is selected from morphine, codeine, hydromorphone, hydrocodone, oxycodone, dihydrocodeine, dihydromorphine, oxymorphone, mixtures thereof, and pharmaceutically acceptable salts thereof.
  • Salts include, but are not limited to, hydrochloride, sulfate, bisulfate, tartrate, nitrate, citrate, bitratrate, phosphate, malate, maleate, hydrobromide, hydroiodide, fumarate, succinate and the like.
  • the components of the pharmaceutical formulations may contain more than one compound, such that the more than one compound is present in a ratio by weight.
  • the components may comprise two compounds, such that the compounds are present in a 2: 1, 2:2, 2:3, 2:5, 3 : 1, or 3 :4 weight ratio.
  • the compounds are morphine and oxycodone, or pharmaceutical salts thereof, in ratio of about 3:2 by weight.
  • Pharmaceutical formulations comprising compounds that contain morphine and oxycodone, or pharmaceutical salts thereof, in ratio of about 3 :2 by weight can administer up to a total amount of 18 mg morphine and 12 mg oxycodone per dosage.
  • pharmaceutical salts thereof in ratio of about 3:2 by weight, can administer up to an amount of about 600 mg morphine, or pharmaceutical salts thereof, and about 400 mg oxycodone, or pharmaceutical salts thereof, per day.
  • At least one of the components in the pharmaceutical formulations comprises a compound having opioid receptor agonist activity and has a controlled release profile.
  • the formulations may comprise additional components, wherein the additional components may have an immediate release profile or a controlled release profile for the compound.
  • immediate release refers to a release profile in which there is substantially no delay in the release of the compound for absorption.
  • controlled release refers to a release profile in which there is a modification in the release of the compound as compared to an immediate release profile.
  • Types of controlled release profiles include delayed release, extended release, and pulsatile release profiles.
  • delayed release refers to a release profile in which there is a delay in the release of the compound for absorption.
  • extended release refers to a release profile in which the active compound is released at such a rate that blood levels are maintained within the therapeutic range, but below toxic levels, over a period of time of about 8 hours, or about 10 hours, or about 12 hours, or about 15 hours, or about 20 hours, or about 24 hours or about 30 hours, or about 35 hours, or even longer.
  • extended release differentiates release profile in accordance with the invention from “immediate release” and “delayed release” release profiles.
  • delayed-extended release refers to release profiles in which release of the active compound is delayed, but is still extended greater than
  • pulsatile release refers to a release profile in which the compound is released at intervals for absorption.
  • the immediate release component may provide about 1 % to about 50 % of the total dosage of the compound(s) to be delivered by the pharmaceutical formulation.
  • the immediate release component may provide at least about 5 %, or about 10 % to about 30 %, or about 45 % to about 50 % of the total dosage of the compound(s) to be delivered by the formulation.
  • the immediate release component provides about 2,
  • the immediate release component may be a mixture of ingredients that breaks down quickly after administration to release the opioid compound. This can take the form of, for example, granules, particles, powders, liquids and pellets.
  • the controlled release component may provide about 30-95 % of the total dosage of the compound(s) to be delivered by the pharmaceutical formulation.
  • the immediate release component may provide about 70-90 %, or about 80 % of the total dosage of the compound(s) to be delivered by the pharmaceutical formulation.
  • the controlled release component provides about 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90 or 95 % of the total dosage of the compound(s) to be delivered by the formulation.
  • a controlled release component may have a T max of about 1 to about 25 hours following repeated or single administration, or about 20, 17, 15, 12, 11, 8, 6, 5, 4, 3, 2 or 1 hours following administration.
  • a controlled release component may have a T max of about 4.5 to about 8 hours after repeated administration, or about 5 to about 6 hours after repeated administration, or about 6 hours after repeated administration.
  • a controlled release component may have may have a T m in about 10 to about 25 hours after repeated administration, or about 12, 13, 14, 15, 16, 17, 18, 19 or 20 hours following administration.
  • a controlled release component may have a T m i n of about 13 to about 16 hours after repeated administration, or about 14 hours after repeated
  • Dissolution of a controlled release component release about 0 to about 20 % of the compound or salt thereof after two hours, or releases about 15 to about 60 % of the compound or salt thereof after four hours, or releases about 25 to about 80 % of the compound or salt thereof after six hours, or releases about 35 to about 85 % of the compound or salt thereof after eight hours, or releases about 45 to about 95 % of the compound or salt thereof after ten hours, or releases about 60 to about 100 % of the compound or salt thereof after twelve hours, as measured in a USP type I apparatus at 37° C in water at 50 rpm.
  • a controlled release component may comprise about 2 mg to about 80 mg of the compound. When controlled release component comprises about 2 mg, the controlled release component may provide a mean C max of about 1 to about 3 ng/mL, or about 2 ng/mL, after repeated administration.
  • the AUC 24 may be about 14.7 ng-hr/mL to about 23.0 ng-hr/mL, or about 15.8 ng-hr/mL to about 21.0 ng-hr/mL, or about 17.1 ng-hr/mL to about 19.7 ng-hr/mL, after single administration.
  • the controlled release component may provide a mean C max of about 3 to about 7 ng/mL, or about 5 ng/mL, after repeated administration.
  • the AUC 24 may be about 40.2 ng-hr/mL to about 62.8 ng-hr/mL, or about 43.2 ng-hr/mL to about 57.2 ng-hr/mL, or about 46.7 ng-hr/mL to about 53.7 ng-hr/mL, after single administration.
  • the controlled release component may provide a mean C max of about 5 to about 15 ng/mL, or about 10 ng/mL, after repeated administration.
  • the AUC 24 may be about 80.5 ng-hr/mL to about 125.9 ng-hr/mL, or about 86.6 ng-hr/mL to about 114.8 ng-hr/mL, or about 93.7 ng-hr/mL to about 107.7 ng-hr/mL, after single administration.
  • the controlled release component may provide a mean C max of about 10 to about 30 ng/mL, or about 20 ng/mL, after repeated administration.
  • the AUC24 may be about 166.0 ng-hr/mL to about 259.3 ng-hr/mL, or about 178.5 ng-hr/mL to about 236.6 ng-hr/mL, or about 193.0 ng-hr/mL to about 222.0 ng-hr/mL, after single administration.
  • the controlled release component may provide a mean C max of about 25 to about 55 ng/mL, or about 40 ng/mL, after repeated administration.
  • the AUC 24 may be about 338.5 ng-hr/mL to about 528.9 ng-hr/mL, or about 363.9 ng-hr/mL to about 482.3 ng-hr/mL, or about 393.5 ng-hr/mL to about 452.7 ng-hr/mL, after single administration.
  • the controlled release component may provide a mean C max of about 50 to about 1 10 ng/mL, or about 80 ng/mL, after repeated administration.
  • the AUC 24 may be about 868.4 ng-hr/mL to about 1356.9 ng-hr/mL, or about 933.5 ng-hr/mL to about 1237.5 ng-hr/mL, or about 1009.5 ng-hr/mL to about 1 161.5 ng-hr/mL, after single administration.
  • a controlled release component provides a mean C m i n of about 0.5 to about 40 ng/mL, or about 4 to about 15 ng/mL, after repeated administration.
  • T max , T m i n , mean C max , and C m i n may be determined after repeated administrations through steady state conditions.
  • steady state means that a plasma level for a given drug has been achieved and which is maintained with subsequent doses of the drug at a level which is at or above the minimum effective therapeutic level and is below the minimum toxic plasma level for compound.
  • opioid analgesics such as oxycodone
  • the minimum effective therapeutic level will be partially determined by the amount of pain relief achieved in a given patient. It will be well understood by those skilled in the medical art that pain measurement is highly subjective and great individual variations may occur among patients. It is clear that after the administration of each dose the concentration passes through a maximum and then again drops to a minimum.
  • the one or more additional components may comprise one or more active agents.
  • the active agents may be any of the compounds having opioid receptor agonist activity as discussed herein.
  • the active agents may also comprise one or more non-opioid analgesic compound(s), or a mixture of one or more non-opioid analgesic compound(s) and one or more compound(s) with opioid receptor agonist activity, or pharmaceutically acceptable salts, esters or prodrugs thereof.
  • Non-opioid analgesic compounds may act to alleviate pain by other mechanisms not associated with binding to an opioid receptor.
  • the non-opioid analgesic compound may be a non-steroidal anti-inflammatory compound (NSAID), examples of which can include, but are not limited to, piroxicam, lomoxicam, tenoxicam, salicylic acid (aspirin) and other salicylates such as diflunisal; 2-arylpropionic acids such as ibuprofen, carprofen, fenbufen, fenoprofen, flubiprofen, ketoprofen, ketorolac, loxoprofen, naproxen, oxaprozin, tiaprofenic acid and suprofen; n-arylanthranilic acids such as metenamic acid and meclofenamic acid; arylalkanoic acids such as diclofenac, aceclofenac, acemetacin, etodolac, idomethacin, sulindac and tolmetin and the like; or mixtures thereof
  • the non-opioid analgesic compound may also be a COX-1 or COX-2 inhibitor compound including, but not limited to, celecoxib (Celebrex ® ), etoricoxib, lumiracoxib, parecoxib, rofecoxib, valdecoxib, or mixtures thereof.
  • the non-opioid analgesic may also be a calcium channel binding agent such as gabapentin or pregabalin, or a derivative, analog or prodrug thereof, or mixtures thereof.
  • the non-analgesic compound is gabapentin enacarbil (SolziraTM), which is a prodrug of gabapentin with the chemical name l-[[[[[l-(2-Methyl-l- oxopropoxy)ethoxy]carbonyl]amino]methyl]cyclohexaneacetic acid.
  • gabapentin enacarbil SolziraTM
  • the structures of gabapentin, pregabalin and gabapentin enacarbil are shown below:
  • the active agents may further be one or more hybrid opioid compound(s), or a mixture of one or more hybrid opioid compound(s) and one or more compound(s) with opioid receptor agonist activity, or pharmaceutically acceptable salts, esters or prodrugs thereof.
  • Hybrid opioid compounds are compounds formed by covalently binding together two or more opioid compounds with a linker component. The linker component may be stable or may hydrolyze under physiological conditions to provide the parent opioid compounds.
  • Hybrid opioid compounds are described in U.S. Provisional Application Serial No. 61/153,537 to Holaday et al, filed February 18, 2009.
  • Hybrid opioid compounds are also described in International Patent Application Publication No. WO 2006/073396 to Portoghese et al.
  • the hybrid opioid compound may comprise two or more compounds having opioid receptor agonist activity, linked by a covalent linker component.
  • the hybrid opioid compound may also comprise a compound having opioid receptor agonist activity linked to a non-opioid active agent including, but not limited to, a non-opioid analgesic compound as described above.
  • the non-opioid active agent is gabapentin, pregabalin, or gabapentin enacarbil.
  • the hybrid opioid compound may comprise two or more opiate compounds bonded together by a covalent linker.
  • the opiate compounds may include, but are not limited to, the opiate compounds described above.
  • the active compounds may be bonded to the linker components by various chemical bonds, preferably at a position on the active agent that does not impair the biological activity of the active agent.
  • the active agents may be bonded to the linker by a reactive group on the active compound or at a position that may be activated to react with a linker component.
  • excipients used in the pharmaceutical compositions described herein are commercially-available, and listed in either the USP or NF. Excipients are selected that will contribute to the function and purpose of each of the active intermediate components and also to the final component. One of ordinary skill will appreciate that the concentrations of these excipients used may be increased or decreased as desired to increase or decrease specific properties in a final opioid formulation. Coating materials used herein are also commercially-available and listed in the USP or NF which are incorporated herein by reference.
  • the technology used to produce a compound-opioid extended-release tablet described herein is a combination of known pharmaceutical manufacturing processes.
  • the unit processes for the manufacture of each active intermediate have been used in several commercially-available products, and therefore are scalable.
  • Two important aspects in producing the compound-opioid extended-release tablet are in the manufacture and performance of the different types of delayed, modified-release pellets.
  • the manufacture and performance of the delayed, modified-release oxycodone pellets and the delayed, modified-release morphine pellets is similarly important. These pellets should perform the same as free-flowing, untableted pellets as after tablet compaction. This important feature is best accomplished by adequately plasticizing the coating network to avoid cracking and brittle fracture of the coatings when under compression during tablet compaction.
  • the materials to be added to the compound(s) for the immediate release component can be, but are not limited to, microcrystalline cellulose, com starch, pregelatinized starch, potato starch, rice starch, sodium carboxymethyl starch, hydroxypropylcellulose,
  • hydroxychitosan hydroxymethylated chitosan, cross-linked chitosan, cross-linked hydroxymethyl chitosan, maltodextrin, mannitol, sorbitol, dextrose, maltose, fructose, glucose, levulose, sucrose, polyvinylpyrrolidone (PVP), acrylic acid derivatives (Carbopol, Eudragit, etc.), polyethylene glycols, such a low molecular weight PEGs (PEG2000- 10000) and high molecular weight PEGs (Polyox) with molecular weights above 20,000 daltons. It may be useful to have these materials present in the range of 1.0 to 60% (W/W).
  • ingredients in this system may be useful to have other ingredients in this system to aid in the dissolution of the drug, or the breakdown of the component after ingestion or administration.
  • These ingredients can be surfactants, such as sodium lauryl sulfate, sodium monoglycerate, sorbitan monooleate, sorbitan monooleate, polyoxyethylene sorbitan monooleate, glyceryl monostearate, glyceryl monooleate, glyceryl monobutyrate, one of the non-ionic surfactants such as the Pluronic line of surfactants, or any other material with surface active properties, or any combination of the above. These materials may be present in the rate of 0.05-15% (W/W).
  • the materials in controlled release components are the same as the materials in the immediate release component, but with additional polymers integrated into the component, or as coatings over the pellet or granule.
  • the kind of materials useful for this purpose can be, but are not limited to, ethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, carboxymethylcellulose, methylcellulose, nitrocellulose, Eudragit R, and Eudragit RL, Carbopol, or polyethylene glycols with molecular weights in excess of 8,000 daltons. These materials can be present in concentrations from 4-20% (W/W).
  • components may have pH-sensitive delayed release profiles or non-pH sensitive delayed release profiles.
  • Materials in the pH-sensitive delayed release components may be the same as the materials in the immediate release component, but with additional polymers integrated into the component, or as coatings over the pellet or granule.
  • the kind of materials useful for this purpose can be, but are not limited to, cellulose acetate pthalate, Eudragit L, and other pthalate salts of cellulose derivatives. These materials can be present in concentrations from 4-20% (W/W).
  • Materials in the pH-sensitive delayed release components may be the same as the materials in the immediate release component, but with additional polymers integrated into the component, or as coatings over the pellet or granule.
  • the kind of materials useful for this purpose can be, but are not limited to, polyethylene glycol (PEG) with molecular weight above 4,000 daltons (Carbowax, Polyox), waxes such as white wax or bees wax, paraffin, acrylic acid derivatives (Eudragit), propylene glycol, and ethylcellulose. Typically these materials can be present in the range of 0.5-25% (W/W) of this component.
  • the pharmaceutical formulations may comprise one or more components having one or more release profiles.
  • Each of the components may comprise the same compound(s), may comprise different compound(s), or a mixture thereof (e.g., some components have the same compounds, other components have different compounds, within the same formulation).
  • components may comprise active agents as described herein.
  • the formulations may comprise at least one component, such that the one component has a controlled release profile.
  • the formulations may also comprise at least two components (a first and second component), such that each components has a different release profile.
  • the second of the at least two components initiates release of the compound(s) contained therein at least one hour after the first component, with the initiation of the release therefrom generally occurring no more than six hours after initiation of release of compound(s) from the first component.
  • the formulations may also comprise at least three components (a first, second, and third component).
  • the first component may be an immediate release component whereby initiation of release of the compound(s) therefrom is not substantially delayed after administration of the formulation.
  • the second and third components are controlled release components, whereby the release of the compound(s) may be delayed.
  • the controlled release components may be a pH sensitive or a non-pH sensitive delayed component, depending on the type of formulation.
  • the compound(s) released from the delayed release components may be delayed until after initiation of release of the compound(s) from the immediate release component.
  • the compound(s) release from the second component may achieve a C max at a time after the compound(s) released from the immediate release component may achieve a C max in the serum.
  • the compound(s) released from the third component may achieve a C max in the serum after the C max of the compound(s) released from the second component.
  • the immediate release component may produce a C max for the compound(s) released therefrom within from about 0.5 to about 2 hours, with the second component producing a C ma x for the compound(s) released therefrom in no more than about four hours.
  • the C max for such a second component may be achieved no earlier than two hours after administration of the formulation; however, it is possible to achieve C max in a shorter period of time by adjusting the concentration of excipients and/or coatings described herein to achieve a formulation with a desired pharmacokinetic profile.
  • release of compound(s) from the third component may be started after initiation of release of compound(s) from both the first and second components.
  • C max for compound(s) released from the third component may be achieved within eight hours.
  • the formulations may also comprise at least four components (a first, second, third, and fourth component), with each of the at least four components having different release profiles.
  • the compound(s) released from each of the at least four different components may achieve a C max at a different time.
  • the formulations may also comprise at least five components (a first, second, third, fourth, and fifth component).
  • the first component may be an immediate release component of a first compound or a first set of compounds, while the second and third components may be controlled release components of the first compound or a first set of compounds.
  • the fourth and fifth components may be controlled release components of a second compound or a second set of compounds.
  • the first compound may be oxycodone and the second compound may be morphine.
  • the formulation may be in the form of a capsule, comprising components that are in the form of separate tablets or pellets.
  • an immediate release component may be in the form of a tablet or pellet
  • controlled release components may be in the form of other tablets or pellets, each of which provides for a delayed release of the compound(s) contained therein, whereby the C max of the compound(s) released from each of the pellets, or tablets containing the pellets, is reached at different times, with the C ma x of the formulation being achieved in less than twelve hours.
  • the pharmaceutical formulation itself will comprise a controlled release profile.
  • C max for all of the compound(s) released from the formulation may be achieved in about 20, 17, 15, 12, 1 1, 8, 6, 5, 4, 3, 2 or 1 hours following administration of the formulation. In some embodiments, C max may be achieved in less than 2, 1 or 0.5 hours following administration of the formulations. In other embodiments, C max may be achieved in greater than 4.5, 5, 6, 7, 8, 9, or 10 hours following administration of the component.
  • the formulation may have a T max of about 1 to about 25 hours following repeated or single administration, or about 20, 17, 15, 12, 1 1, 8, 6, 5, 4, 3, 2 or 1 hours following administration.
  • T max may be about 4.5 to about 8 hours, or about 5 to about 6 hours, or about 6 hours, after repeated administration. In some embodiments, the repeated administration is under steady state conditions.
  • the formulation may comprise about 1 mg to about 100 mg of the compounds(s), or may comprise about 2 mg to about 80 mg of the compound(s).
  • the controlled release component may provide a mean C max of about 1 to about 3 ng/mL, or about 2 ng/mL, after repeated administration.
  • the AUC 24 may be about 14.7 ng-hr/mL to about 23.0 ng-hr/mL, or about 15.8 ng-hr/mL to about 21.0 ng-hr/mL, or about 17.1 ng-hr/mL to about 19.7 ng-hr/mL, after single administration.
  • the controlled release component may provide a mean C max of about 3 to about 7 ng/mL, or about 5 ng/mL, after repeated administration.
  • the AUC 24 may be about 40.2 ng-hr/mL to about 62.8 ng-hr/mL, or about 43.2 ng-hr/mL to about 57.2 ng-hr/mL, or about 46.7 ng-hr/mL to about 53.7 ng-hr/mL, after single administration.
  • the controlled release component may provide a mean C max of about 5 to about 15 ng/mL, or about 10 ng/mL, after repeated administration.
  • the AUC 24 may be about 80.5 ng-hr/mL to about 125.9 ng-hr/mL, or about 86.6 ng-hr/mL to about 1 14.8 ng-hr/mL, or about 93.7 ng-hr/mL to about 107.7 ng-hr/mL, after single administration.
  • the controlled release component may provide a mean C max of about 10 to about 30 ng/mL, or about 20 ng/mL, after repeated administration.
  • the AUC 24 may be about 166.0 ng-hr/mL to about 259.3 ng-hr/mL, or about 178.5 ng-hr/mL to about 236.6 ng-hr/mL, or about 193.0 ng-hr/mL to about 222.0 ng-hr/mL, after single administration.
  • the controlled release component may provide a mean C max of about 25 to about 55 ng/mL, or about 40 ng/mL, after repeated administration.
  • the AUC 24 may be about 338.5 ng-hr/mL to about 528.9 ng-hr/mL, or about 363.9 ng-hr/mL to about 482.3 ng-hr/mL, or about 393.5 ng-hr/mL to about 452.7 ng-hr/mL, after single administration.
  • the controlled release component may provide a mean C max of about 50 to about 110 ng/mL, or about 80 ng/mL, after repeated administration.
  • the AUC 24 may be about 868.4 ng-hr/mL to about 1356.9 ng-hr/mL, or about 933.5 ng-hr/mL to about 1237.5 ng-hr/mL, or about 1009.5 ng-hr/mL to about 1161.5 ng-hr/mL, after single administration.
  • C m i n may occur within about 12 to about 18 hours following administration of the component during steady-state conditions. In some embodiments, C m i n may occur at about 12, 13, 14, 15, 16, 17, 18, 19 or 20 hours following administration of the formulation. In some embodiments, C m i n may occur less than about 10, 9, 8, 7, 6, 5, or 4 hours following administration of the formulation. In some embodiments, C m in may occur at greater than about 14, 15, 16, 17, 18, 19, or 20 hours following administration of the formulation. In particular embodiments, the C m i n that occurs more than about 12 hours after administration, may occur up to about 1, 2, 3, or 4 hours after the administration of a formulation that has not yet been absorbed into the bloodstream.
  • the formulation may have a T m in about 10 to about 25 hours after repeated administration, or about 12, 13, 14, 15, 16, 17, 18, 19 or 20 hours following administration.
  • the formulation may have a T m i n of about 13 to about 16 hours after repeated administration, or about 14 hours after repeated administration.
  • the formulation may provide a mean C m i n of about 0.5 to about 40 ng/mL, or about 4 to about 15 ng/mL, after repeated administration. Dissolution of the formulation releases about 0 to about 20 % of the compound(s) or salt thereof after two hours, or releases about 15 to about 60 % of the compound(s) or salt thereof after four hours, or releases about 25 to about 80 % of the compound(s) or salt thereof after six hours, or releases about 35 to about 85 % of the compound(s) or salt thereof after eight hours, or releases about 45 to about 95 % of the compound(s) or salt thereof after ten hours, or releases about 60 to about 100 % of the compound(s) or salt thereof after twelve hours, as measured in a USP type I apparatus at 37° C in water at 50 rpm.
  • the pharmaceutical formulation may comprise one or more components that contain two opioid compounds in a 2: 1, 2:2, 2:3, 2:5, 3 : 1, or 3:4 weight ratio.
  • the components may comprise morphine and oxycodone in about a 3 :2 weight ratio.
  • the pharmaceutical formulation may comprise a controlled release component comprising a mixture of morphine and oxycodone, and an immediate release component comprising oxycodone.
  • the T max of oxycodone in the immediate release component may be from about 10 minutes to about one hour after ingestion. In other embodiments, the T max will be from about 10 minutes to about 30 minutes or 45 minutes.
  • the controlled release component may be released at a slower rate and over a longer period of time.
  • the controlled release component may release effective amounts of the mixture of morphine and oxycodone over 12 hours.
  • the controlled release component may release effective amounts of morphine and oxycodone over 4 hours or over 8 hours.
  • the controlled release component t may release effective amounts of morphine and oxycodone over 15, 18, 24 or 30 hours.
  • the later released active agents may be released from the pharmaceutical formulation in pulses so that pulses of the compounds are released at intervals after ingestion of the formulation.
  • controlled release component may release a first pulse of the later released active agents about 0.5 - 1 hour after ingestion, followed by a second pulse after about of 4 hours after ingestion and a third pulse of drug after about 8 hours after ingestion.
  • the pharmaceutical compositions are tablets and capsules for oral administration. These tablets or capsules may contain conventional excipients such as binding agents, fillers, lubricants, disintegrants, or wetting agents. In one aspect the tablets or capsules are coated according to methods well known in the art.
  • the tablet is less than about 500 mg, about 450 mg, about 400 mg, about 350 mg, about 300 mg, about 250mg, about 200 mg, about 150 mg, about 100 mg, about 50 mg, about 25 mg, or about 10 mg weight, and the drug load is about 20%, about 15% , about 10% , about 5% (w/w) or less of the formulation.
  • the goal would be to have as efficient a tablet size as possible, while affording good uniformity and integrity of the pellets in the tablet.
  • the disintegrant used in the tablet of the present invention is not particularly limited, as far as it is a disintegrant used for pharmaceutical preparations.
  • examples can include crospovidone, crystalline cellulose, hydroxypropylcellulose with a low degree of substitution, croscarmellose sodium, carmellose calcium, carboxystarch sodium, carboxymethyl starch sodium, potato starch, wheat starch, com starch, rice starch, partly pregelatinized starch, and hydroxypropyl starch.
  • Crospovidone is particularly preferable.
  • the sort of disintegrant used for coating granules according to the present invention may be identical to or different from that used inside the granules.
  • Examples of pharmaceutically acceptable additives used in the tablet of the present invention can include excipients, lubricants, pH adjusters, taste-masking agents, sweeteners, acidifiers, refrigerants, foaming agents, preservatives, fluidizers, antioxidants, colorants, stabilizers, surfactants, buffering agents, flavors, binders and drug solubilizers.
  • excipients lubricants, pH adjusters, taste-masking agents, sweeteners, acidifiers, refrigerants, foaming agents, preservatives, fluidizers, antioxidants, colorants, stabilizers, surfactants, buffering agents, flavors, binders and drug solubilizers.
  • a person skilled in the art may immediately list specific examples of these additives.
  • These additives can be appropriately formulated in the inside of a granule, in the outside of a granule coated with a disintegrant, in the coating of a disintegrant and in all these, as far as they do not damage the advantages of the
  • any lubricant used for pharmaceutical preparation can be used without limitation.
  • the lubricant used in the tablet of the present invention can include light anhydrous silicic acid, magnesium stearate, stearic acid, calcium stearate, aluminum stearate, aluminum monostearate, sucrose fatty acid esters, polyethylene glycol, sodium stearyl fumarate, stearyl alcohol, talc, titanium oxide, hydrous silicon dioxide, magnesium silicate, synthetic aluminum silicate, calcium hydrogen phosphate, hardened castor oil, hardened rapeseed oil, Carnauba Wax, bees wax, microcrystalline wax and sodium lauryl sulfate.
  • One or two or more kinds of these lubricants can be used.
  • silicic anhydride contained in the inside of a granule and magnesium stearate contained in the outside of the granule is preferable.
  • the shape of the tablet is not particularly limited, as far as it can be produced without difficulty using an ordinary manufacturing apparatus or a manufacturing apparatus with some modifications.
  • a disc shape that is a general concept for tablets can be mentioned as a typical example.
  • the whole size is not particularly limited.
  • the shorter diameter (diameter for a disc tablet) is appropriately in the range of 6 to 20 mm, preferably 8 to 12 mm.
  • the thickness is neither particularly limited, but appropriately 1 to 10 mm, preferably 2 to 8 mm.
  • This coating may be white, or colored or clear or opaque if desired.
  • An identifying NDC code (in the United States) or similar identifying code may also be printed on the tablet if desired.
  • the compound used in the tablet of the present invention may be coated with a filmcoating agent, an excipient, a binder, a lubricant, or the like depending on its properties and a plasticizer may be added.
  • a filmcoating agent an excipient, a binder, a lubricant, or the like depending on its properties and a plasticizer may be added.
  • compositions described herein possess properties that are useful in deterring their use to create compositions that are likely to be used for nonmedical purposes, or as a drug of abuse.
  • Intentional or inadvertent tampering from extended release formulations will rapidly deliver a massive dose (as a result of converting the sustained release product into an immediate release form) and produce profound a variety of serious and life threatening side effects, including respiratory depression and failure, sedation, cardiovascular collapse, coma and death.
  • One mode of abuse involves the extraction of the opioid from the component by first mixing the table or capsule with a suitable solvent (e.g., water or alcohol), and then filtering and/or extracting the opioid component from the mixture for intravenous injection.
  • a suitable solvent e.g., water or alcohol
  • Another mode of abuse of extended release opioids involves dissolving the drug in water, alcohol or another "recreational solvent" to hasten its release and to ingest the contents orally, in order to provide high peak concentrations and maximum euphoriant effects.
  • tampering means any manipulation by mechanical, thermal and/or chemical means which changes the physical properties of the component, e.g., to liberate the opioid for immediate release if it is in sustained release form, or to make the opioid agonist available for inappropriate use such as administration by an alternate route, e.g., parenterally.
  • the tampering can be, e.g., by means of crushing, shearing, grinding, mechanical extraction, solvent extraction, solvent immersion, combustion, heating or any combination thereof.
  • opioid agonist abuse or “opioid abuse” in the context of the present invention, when it refers to the effects of opioid agonists in causing such, includes intermittent use, recreational use and chronic use of opioid agonists alone or in conjunction with other drugs: (i) in quantities or by methods and routes of administration that do not conform to standard medical practice; (ii) outside the scope of specific instructions for use provided by a qualified medical professional; (iii) outside the supervision of a qualified medical professional; (iv) outside the approved instructions on proper use provided by the drug's legal manufacturer; (v) which is not in specifically approved components for medical use as pharmaceutical agents; (vi) where there is an intense desire for and efforts to procure same; (vii) with evidence of compulsive use; (viii) through acquisition by manipulation of the medical system, including falsification of medical history, symptom intensity, disease severity, patient identity, doctor shopping, prescription forgeries; (ix) where there is impaired control over use; (x) despite harm; (xi) by
  • compositions and methods that (i) resist, deter, discourage, diminish, delay and/or frustrate the intentional, unintentional or accidental physical manipulation or tampering of the component (e.g., crushing, shearing, grinding, chewing, dissolving, melting, needle aspiration, inhalation, insufflation, extraction by mechanical, thermal and chemical means, and/or filtration); (ii) resist, deter, discourage, diminish, delay and/or frustrate the intentional, unintentional or accidental use or misuse of the component outside the scope of specific instructions for use provided by a qualified medical professional, outside the supervision of a qualified medical professional and outside the approved instructions on proper use provided by the drug's legal manufacturer (e.g., intravenous use, intranasal use, inhalational use and oral ingestion to provide high peak concentrations); (iii) resist, deter, discourage, diminish, delay and/or frustrate the intentional, unintentional or accidental conversion of an extended release component of the invention into
  • pharmaceutical formulation reduces the amount of opioid agonist released in immediate release form, which in turn reduces the euphoric, pleasurable, reinforcing, rewarding, mood altering and toxic effects of the opioid agonist of the component.
  • the use of certain excipients such as Povidone (Kollidon 30) or Polyoxyl 35 Castor Oil (Cremophor ELTM) or Sodium Lauryl Sulfate create an unusable gelatinous mass if tampered with.
  • the addition of aqueous or hydroalcoholic solvents would render the pulverized excipient and drug mixture to a gelatinous mass that would be problematic for easy extraction of the opioid.
  • the Cremophor, in admixture with the methacrylic acid polymers and cellulosic polymers are examples of prime ingredients that cause this feature of the invention.
  • An aspect of the present invention is a method for treating pain comprising administering a formulation as described herein.
  • the formulations may be administered, for example, by any of the following routes of administration: sublingual, buccal, transmucosal, transdermal, parenteral, oral etc.
  • the formulations may be prepared in a manner suitable for oral administration.
  • each of the components may be used as a pellet, granule, powder, liquid or a particle, which are then formed into a unitary pharmaceutical product, for example, in a capsule, or embedded in a tablet, or suspended in a liquid for oral administration.
  • formulation as used herein also refers to a unitary pharmaceutical product containing at least one component.
  • the formulations are for oral administration and may be in the form of a tablet or a capsule or in the form of a multiple unit component.
  • the formulations may be adapted for oral administration 1-6 times a day, normally 1-4 times daily such as 1-3 times, twice daily, or once daily.
  • once daily is intended to mean that it is only necessary to administer the pharmaceutical composition once a day in order to obtain an effective therapeutic amount of the compound to provide a suitable therapeutic response.
  • the final dose of the compound(s) provided by administration of the formulation may be about, by weight, 100 mg, about 95 mg, about 90 mg, about 85 mg, about 80 mg, about 75 mg, about 70 mg, about 65 mg, about 60 mg, about 55 mg, about 50 mg, about 45 mg, about 40 mg, about 35 mg, about 30 mg, about 25 mg, about 20 mg, about 15 mg, about 12 mg, about 10 mg, about 8 mg, about 5 mg, about 4, mg, about 3 mg, about 2 mg, or about 1 mg.
  • the dosage of the opioid compound depends on the particular substance, the age, weight condition, etc., of the human or animal that will be treated with the composition, etc. All such factors are well known to a person skilled in the art.
  • Target Component 1 (morphine):
  • Target Component 2 (morphine):
  • Target Component 3 (morphine):
  • Target Component 4 (morphine):
  • An oxycodone formulation is provided that has the following pharmacokinetic profile.
  • the pharmacokinetic profile is achieved by adjusting the concentration of excipients using the methods described in the charts shown in FIGS. 7-11.
  • This 8mg oxycodone formulation has a C max of 8 hours and a C m in of 14 hours.
  • An oxycodone formulation is provided that has the following pharmacokinetic profile.
  • the pharmacokinetic profile is achieved by adjusting the concentration of opioid compound and excipients using the methods described in the charts shown in FIGS. 7-1 1.
  • This 8mg oxycodone formulation has a C max of 6 hours and a C m in of 16 hours.
  • a dual opioid oxycodone/morphine formulation is provided that has the following pharmacokinetic profile.
  • the pharmacokinetic profile is achieved by adjusting the concentration of opioid compound and excipients using the methods described in the charts shown in FIGS. 7-11.
  • This 8mg oxycodone/4 mg morphine formulation has a C max of 6-20 hours for both opioids, and a C m i n of 15-26 hours for both opioids.
  • a dual opioid oxycodone/morphine formulation is provided that has the following pharmacokinetic profile.
  • the pharmacokinetic profile is achieved by adjusting the concentration of opioid compound and excipients using the methods described in the charts shown in FIGS. 7-11.
  • This 18mg morphine/12 mg oxycodone formulation has a C max of 6 hours, and a C m i n of 16 hours.
  • Extended release intermediate pellet formulations A and B were prepared having the compositions as shown in Tables 9 and 10.
  • the manufacturing process of mixing the formulations is illustrated in the flow diagram of FIG. 12.
  • oxycodone hydrochloride, microcrystalline cellulose, and Povidone Karl Fischer screened through a # 20 mesh screen into a collecting container.
  • the screened mix was transferred to a granulation bowl of a high shear granulator and dry mixed for three minutes.
  • a granulating solution comprising purified water mixed with Polyoxyl 35 Castor Oil was sprayed at a constant rate into the granulation bowl, mixing at low-speed- impeller or low-speed-chopper setting. The resulting granulation mixture was visually assessed continuously, and additional purified water was sprayed onto the mass as required.
  • the granulation mixture then underwent an extrusion-spheronization process using an extruder and plate spheronizer.
  • the wet mass was uniformly extruded through a 0.8 mm screen into the marmurizing bowl where the extrudate was formed into appropriate sized pellets.
  • the pellets were dried using a Fluid Bed Dryer Granulator to a Loss on Drying (LOD) test target of ⁇ 3%. To obtain the preferred fraction, the dried pellets were sieved through a # 20 and # 40 mesh size stainless steel screen into a double polyethylene-lined fiber drum for storage pending pellet spray coating.
  • LOD Loss on Drying
  • the pellets then underwent spray coating using a Fluid Bed Dryer.
  • the coating components were mixed into an isopropyl alcohol/water solution using a pneumatic propeller mixer for at least one hour until a clear solution resulted.
  • the enteric coating solution was prepared by mixing the enteric coating components with a pneumatic mixer for at least one hour until a clear solution resulted. .
  • the polymer coating solutions were sprayed onto the pellets while continuously monitoring the spray conditions.
  • the completed pellets were discharged into a double polyethylene- lined fiber drum for work-in-process storage pending lubrication.
  • the lubricated pellets were sieved through a # 18 and # 40 mesh size stainless steel screen to obtain the preferred fraction, and discharged into a double polyethylene-lined fiber drum for storage pending tablet blending.
  • each subject participated in a series of three periods, wherein each period was comprised of (i) pre-administration screening and check- in, (ii) administration of the formulation, and (iii) post-administration sample collection and follow-up.
  • the subjects received a different formulation in each period, and were divided randomly to determine in which order the formulations were administered.
  • the pre-administration screening and check-in involved a physical examination and recordation of the subject's vital signs.
  • Naltrexone 50 mg
  • an opioid antagonist was administered 0.5 hours prior to administration.
  • Blood samples were collected at 10 minutes and after 0.5, 1, 2, 3, 4, 5, 5.5, 6, 6.5, 7, 8, 10, 12, 14, 18, 21, 24, 48, and 72 hours post-dose of the formulation.
  • Morphine and oxycodone in the plasma of the blood samples were measured by liquid chromatography with tandem mass spectrometry (LC/MS/MS) methods that were validated across the following ranges:
  • the mean plasma concentration of oxycodone at the sample collection timepoints is shown in FIG. 13 (through 72 hours) and FIG. 14 (the first 24 hours). As compared to the
  • Formulation A resulted in higher plasma levels of oxycodone between 5 and 16 hours after treatment, although the plasma levels were generally lower thereafter.
  • Formulation B produced about the same or greater plasma levels of oxycodone as compared to the Reference Formulation at 6 hours after treatment and continuing through 48 hours. During this period, the plasma levels of oxycodone provided by
  • Formulation B were, on average, 30 % greater than the plasma levels provided by the
  • FIG. 15 presents the oxycodone plasma profile through administration of 4 doses of Formulation B and indicates that, under this dosing regimen, oxycodone plasma levels can be maintained between about 7 and about 20 ng/mL.
  • FIG. 16 shows the oxycodone plasma profile that may result from different dosing strengths, and focuses on a single dose with the multiple dose regimen after the plasma levels achieve a steady-state; steady state is characterized by consistent peaks and troughs in the multiple dose plasma profile.
  • FIG. 16 indicates that, at steady state, C max will reflect the strength of the administered dose.
  • FIGS. 17 and 18 present projections of the oxycodone plasma profile for multiple doses of a formulation comprising a composite of an immediate release formulation (10 %) and Formulation B (90%).
  • FIG. 17 demonstrates the oxycodone plasma profile through administration of 4 doses of the composite formulation and indicates that, under this dosing regimen, oxycodone plasma levels can be maintained between about 10 and about 19 ng/mL.
  • FIG. 18 shows the oxycodone plasma profile that may result following administration of the composite formulation at different dosing strengths.
  • FIG. 18 focuses on a single dose with the multiple dose regimen after the plasma levels achieve a steady-state, which is characterized by consistent peaks and troughs in the multiple dose plasma profile. The projection indicates that, at steady state, C ma x will be less than the administered dose.
  • An oral solid oral component tablet comprising a core of 5.0 mg oxycodone hydrochloride and 5.0 mg morphine sulfate as active ingredients together with ammonio methacrylate copolymer, hypromellose, lactose, magnesium stereate, polyethylene glycol 400, povidone, sodium hydroxide, sorbic acid, stearyl alcohol, talc, titanium dioxide and triacetin, is prepared according to standard methods known in the art for preparation of tablets.
  • the outside of the tablet is coated with a controlled release formulation comprising 10 mg of oxycodone hydrochloride and gelatin, hypromellose, maize starch, polyethylene glycol, polysorbate 80, red iron oxide, silicon dioxide, dodium laurel sulfate, sucrose, titanium dioxide and yellow iron oxide.
  • a controlled release formulation comprising 10 mg of oxycodone hydrochloride and gelatin, hypromellose, maize starch, polyethylene glycol, polysorbate 80, red iron oxide, silicon dioxide, dodium laurel sulfate, sucrose, titanium dioxide and yellow iron oxide.
  • Example 6 General Procedure for Preparation of Controlled Release Formulations The following manufacturing description is provided by way of example for the preparation of an controlled release, compressed tablet containing morphine sulfate and oxycodone hydrochloride.
  • the active drug substances (morphine sulfate and oxycodone hydrochloride), microcrystalline cellulose, USP and Povidone K30, NF were individually manually screened through a # 20 mesh screen into a collecting container. The screened mix was transferred to the granulation bowl of a high shear granulator such as the PMA-25 or PMA-65 and dry mixed for 3 minutes.
  • a granulating solution consisting of a previously mixed solution of Purified Water, USP and Polyoxyl 35 Castor Oil, NF was sprayed at a constant rate into the granulation bowl and mixed at low speed impeller/low speed chopper setting. Granulation outcome was visually assessed on a continuous basis and additional Purified Water, USP was sprayed onto the mass if required. At the end of the granulation period, a sample was removed for an in- process test for water content.
  • the granulation was discharged to the extrusion- spheronization process using a Luwa extruder and plate spheronizer or equivalent.
  • the wet mass was uniformly extruded through a 0.8 mm screen into the marmurizing bowl where the extrudate was formed into appropriate sized pellets.
  • Fluid bed drying of the pellets was conducted using suitable process parameters with a GPCG-3, GPCG-5 or equivalent to a Loss on Drying (LOD) test target of ⁇ 5%.
  • the dried pellets were sieved to obtain the preferred fraction through a # 20 and # 40 mesh size stainless steel screen into a double PE-lined fiber drum for work-in-process storage pending pellet spray coating.
  • ammonio methacrylate copolymers and triethyl citrate were mixed using a pneumatic propeller mixer into an isopropyl alcohol/water solution contained in a stainless steel vessel for at least one hour until a clear solution was obtained. Talc was then added to the vessel with continuous stirring. Fluid bed spray coating of the core pellets was conducted using suitable process parameters with a GPCG-5 Wurster fitted with a 1.0 mm spray nozzle.
  • the enteric coating solution was prepared by mixing methacrylic acid copolymer and triethyl citrate with a pneumatic mixer in a stainless steel vessel for at least one hour. Talc was then added to the vessel with continuous stirring. The polymer coating solutions were successively sprayed at a constant rate to completion onto the beadlets while the spray conditions were continuously monitored. The enteric coated beadlets were discharged into a double polyethylene-lined fiber drum for work-in-process storage pending lubrication.
  • the dissolution test method was designed to be used with an automated dissolution sampling station (e.g., Varian VK 8000). If such an instrument is not available, appropriate adjustments can be made in order to pull samples manually.
  • an automated dissolution sampling station e.g., Varian VK 8000. If such an instrument is not available, appropriate adjustments can be made in order to pull samples manually.
  • Apparatus USP ⁇ 71 1> Apparatus 2 (Paddles)
  • Vessel Size/Type About 1000 mL / clear glass, round-bottom vessel
  • Stage 2 (Buffer Stage) from 2-11 hours: 1000 mL at 37.0 ⁇ 0.5 °C, created by adding 250 mL of Dissolution Medium B and 20 mL Dissolution Medium A to the remnants of the media in the vessel from Stage 1.
  • the Stage 2 media should have a pH of about 6.8
  • Sinker Basket Sinker (0.46" x 0.80") 40 Mesh, 316-SS wire cloth Pull Volume: About 10 mL
  • Filter Type/Size In-line 10- ⁇ polyethylene full flow filter
  • FIGS. 19(a) and 20(a) provide representative dissolution profiles for morphine sulfate and oxycodone hydrochloride, respectively.
  • Table 14 Tablet Formulations Using Morphine / Oxycodone Enteric Coated / Modified Release Beadlets.
  • FIGS. 21 and 22 provide representative dissolution profiles for morphine sulfate and oxycodone hydrochloride, respectively.
  • Example 9 Dissolution Testing of Various % Modified Release Coating Levels and Enteric Coating Levels.
  • coated pellets obtained from Lot 1 were subjected to enteric coating at different % coating levels (10%, 15 %, 25 %, 30 % and 40 %) to produce enteric coated tablets and dissolution testing was performed (FIGS. 21 and 22).
  • Enteric coated tablet lots (using 10 % and 15 % enteric coat) were also analyzed for dissolution as a function of tablet hardness (low, medium or high) to determine the resistance of the tablets to various compression levels (FIGS. 23 and 24).
  • FIGS. 19 and 20 show the versatility of modified release core beadlets at various % g levels in obtaining the dissolution profile of interest.
  • a full spectrum of dissolution profiles allows for the targeting of specific in vivo pharmacokinetic plasma levels and the determination of in vitro to in vivo correlations.
  • FIGS. 21 and 22 also show the versatility of enteric coated, modified release core beadlets at various % enteric coating levels in obtaining the dissolution profile of interest. Once again, a full spectrum of dissolution profiles allows for the targeting of specific in vivo pharmacokinetic plasma levels and the determination of in vitro to in vivo correlations.
  • FIGS. 23 and 24 show the effect of compression forces on tablets that contain enteric coated beadlets comprising a modified release coated pellet of morphine sulfate and oxycodone hydrochloride. It is generally known that a high compression force can significantly reduce the dissolution of tablets, especially when coating polymers are employed that are known to be brittle, such as with ammonio methacrylate copolymer Type A and B. FIGS. 23 and 24 demonstrate that a low or high compression force does not affect the dissolution of tablets. This result is unexpected and demonstrates the resilience of the formulation / coatings to compression forces.
  • Table 16 Tablet Formulations of Modified Release Beadlets (RS/RL) with/without
  • FIGS. 25-27 provide representative dissolution profiles for morphine sulfate and oxycodone hydrochloride, respectively, for the formulations provided in Table 16. These figures show the versatility of modified release core beadlets at various % coating levels in obtaining the dissolution profile of interest. Enteric coated beadlet formulations are also provided that allow for a full spectrum of dissolution profiles to be achieved.

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Abstract

La présente invention concerne des formulations pharmaceutiques contenant des composants opioïdes qui possèdent chacun un profil de libération. Ces composants peuvent procurer une libération immédiate ou contrôlée de l'opioïde. L'invention a également trait à des procédés de régulation de la libération d'un ou de plusieurs composés opioïdes et à des méthodes de traitement de la douleur.
PCT/US2011/053132 2010-09-24 2011-09-23 Formulations d'opioïdes à libération contrôlée WO2012040651A2 (fr)

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JP2013530379A JP2013537915A (ja) 2010-09-24 2011-09-23 オピオイドの制御放出製剤
AU2011305161A AU2011305161A1 (en) 2010-09-24 2011-09-23 Controlled release formulations of opioids
CA2812570A CA2812570A1 (fr) 2010-09-24 2011-09-23 Formulations d'opioides a liberation controlee
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JP2013537915A (ja) 2013-10-07
EP2618820A2 (fr) 2013-07-31
WO2012040651A3 (fr) 2012-05-18
AU2011305161A1 (en) 2013-05-09
CN103476403A (zh) 2013-12-25

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