WO2007120864A3 - Compositions and methods for enhancing analgesic potency of covalently bound compounds, attenuating its adverse side effects, and preventing their abuse - Google Patents

Compositions and methods for enhancing analgesic potency of covalently bound compounds, attenuating its adverse side effects, and preventing their abuse Download PDF

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Publication number
WO2007120864A3
WO2007120864A3 PCT/US2007/009220 US2007009220W WO2007120864A3 WO 2007120864 A3 WO2007120864 A3 WO 2007120864A3 US 2007009220 W US2007009220 W US 2007009220W WO 2007120864 A3 WO2007120864 A3 WO 2007120864A3
Authority
WO
WIPO (PCT)
Prior art keywords
covalently bound
compositions
methods
covalently
analgesic
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/US2007/009220
Other languages
French (fr)
Other versions
WO2007120864A2 (en
Inventor
Randal J Kirk
Suma Krishnan
James Scott Moncrief
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Shire LLC
Original Assignee
Shire LLC
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Shire LLC filed Critical Shire LLC
Priority to CA002648659A priority Critical patent/CA2648659A1/en
Priority to AU2007238625A priority patent/AU2007238625A1/en
Priority to JP2009505510A priority patent/JP2009533459A/en
Priority to US12/296,715 priority patent/US20100144645A1/en
Priority to EP07755474A priority patent/EP2007389A2/en
Publication of WO2007120864A2 publication Critical patent/WO2007120864A2/en
Publication of WO2007120864A3 publication Critical patent/WO2007120864A3/en
Priority to IL194651A priority patent/IL194651A0/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

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
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
    • A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0043—Nose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/36—Opioid-abuse

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Neurosurgery (AREA)
  • Otolaryngology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Neurology (AREA)
  • Biomedical Technology (AREA)
  • Organic Chemistry (AREA)
  • Dermatology (AREA)
  • Emergency Medicine (AREA)
  • Molecular Biology (AREA)
  • Addiction (AREA)
  • Psychiatry (AREA)
  • Pain & Pain Management (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

The invention generally relates to compositions and methods with covalently bound compounds, such as controlled substances covalently attached to a chemical moiety, and opioid antagonists or covalently bound opioid antagonists to enhance analgesic potency and/or attenuate one or more adverse effects of covalently bound compounds, including adverse side effect(s) in humans such as nausea, vomiting, dizziness, headache, sedation (somnolence), physical dependence or pruritis. This invention relates to compositions and methods for selectively enhancing the analgesic potency of a covalently bound compound and simultaneously attenuating anti-analgesia, hyperalgesia, hyperexcitability, physical dependence and/or tolerance effects associated with the administration of a covalently bound compound. The methods of the invention comprise administering to a subject an analgesic or sub-analgesic amount of a covalently bound compound and an amount of excitatory opioid receptor antagonist such as naltrexone or nalmefene effective to enhance the analgesic potency of a covalently bound compound and attenuate the anti-analgesia, hyperalgesia, hyperexcitability, physical dependence and/or tolerance effects of covalently bound compound. The invention also relates to the addition of covalently-bound opioid antagonists to the compositions containing covalently bound compounds such that if the compositions are subjected to manipulation by illicit chemists, the opioid antagonist is released effectively reducing or eliminating the euphoric effect of the covalently bound compounds.
PCT/US2007/009220 2006-04-14 2007-04-16 Compositions and methods for enhancing analgesic potency of covalently bound compounds, attenuating its adverse side effects, and preventing their abuse Ceased WO2007120864A2 (en)

Priority Applications (6)

Application Number Priority Date Filing Date Title
CA002648659A CA2648659A1 (en) 2006-04-14 2007-04-16 Compositions and methods for enhancing analgesic potency of covalently bound compounds, attenuating its adverse side effects, and preventing their abuse
AU2007238625A AU2007238625A1 (en) 2006-04-14 2007-04-16 Compositions and methods for enhancing analgesic potency of covalently bound compounds, attenuating its adverse side effects, and preventing their abuse
JP2009505510A JP2009533459A (en) 2006-04-14 2007-04-16 Compositions and methods for enhancing analgesic action of covalently bound compounds, attenuating harmful side effects and preventing abuse of said compounds
US12/296,715 US20100144645A1 (en) 2006-04-14 2007-04-16 Compositions and methods for enhancing analgesic potency of covalently bound-compounds, attenuating its adverse side effects, and preventing their abuse
EP07755474A EP2007389A2 (en) 2006-04-14 2007-04-16 Compositions and methods for enhancing analgesic potency of covalently bound compounds, attenuating its adverse side effects, and preventing their abuse
IL194651A IL194651A0 (en) 2006-04-14 2008-10-07 Compositions and methods for enhancing analgesic potency of covalently bound compounds, attenuating its adverse side effects, and preventing their abuse

Applications Claiming Priority (10)

Application Number Priority Date Filing Date Title
US79189206P 2006-04-14 2006-04-14
US60/791,892 2006-04-14
US79635206P 2006-05-01 2006-05-01
US60/796,352 2006-05-01
US84977606P 2006-10-06 2006-10-06
US84977506P 2006-10-06 2006-10-06
US84977406P 2006-10-06 2006-10-06
US60/849,776 2006-10-06
US60/849,774 2006-10-06
US60/849,775 2006-10-06

Publications (2)

Publication Number Publication Date
WO2007120864A2 WO2007120864A2 (en) 2007-10-25
WO2007120864A3 true WO2007120864A3 (en) 2008-08-28

Family

ID=38610227

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2007/009220 Ceased WO2007120864A2 (en) 2006-04-14 2007-04-16 Compositions and methods for enhancing analgesic potency of covalently bound compounds, attenuating its adverse side effects, and preventing their abuse

Country Status (7)

Country Link
US (1) US20100144645A1 (en)
EP (1) EP2007389A2 (en)
JP (1) JP2009533459A (en)
AU (1) AU2007238625A1 (en)
CA (1) CA2648659A1 (en)
IL (1) IL194651A0 (en)
WO (1) WO2007120864A2 (en)

Families Citing this family (31)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8394813B2 (en) 2000-11-14 2013-03-12 Shire Llc Active agent delivery systems and methods for protecting and administering active agents
US7169752B2 (en) * 2003-09-30 2007-01-30 New River Pharmaceuticals Inc. Compounds and compositions for prevention of overdose of oxycodone
US8133881B2 (en) 2003-01-13 2012-03-13 Shire Llc Carbohydrate conjugates to prevent abuse of controlled substances
US20090192095A1 (en) * 2008-01-18 2009-07-30 Shire Llc Amino acid and peptide prodrugs of opioid analgesics with reduced gi side-effects
WO2010045599A1 (en) 2008-10-17 2010-04-22 Pharmacofore, Inc. Pharmaceutical compositions with attenuated release of phenolic opioids
US20120302590A1 (en) * 2009-08-13 2012-11-29 The General Hospital Corporation Methods and compositions to prevent addiction
CN102695545B (en) 2009-09-08 2016-08-17 特色疗法股份有限公司 Compositions comprising enzymatically cleavable ketone-modified opioid prodrugs and optional inhibitors thereof
CA2785056A1 (en) 2009-12-22 2011-07-21 Pondera Biotechnologies, LLC Methods and compositions for treating distress dysfunction and enhancing safety and efficacy of specific medications
US20130059914A1 (en) 2010-04-21 2013-03-07 Signature Therapeutics, Inc. Compositions Comprising Enzyme-Cleavable Amphetamine Prodrugs and Inhibitors Thereof
US20110262355A1 (en) 2010-04-21 2011-10-27 Jenkins Thomas E Compositions comprising enzyme-cleavable opioid prodrugs and inhibitors thereof
AU2012205733B2 (en) 2011-01-11 2015-10-08 Signature Therapeutics, Inc. Compositions comprising enzyme-cleavable oxycodone prodrug
JP6148182B2 (en) 2011-03-09 2017-06-14 シグネーチャー セラピューティクス, インク.Signature Therapeutics, Inc. Active drug prodrugs with heterocyclic linkers
WO2012122420A2 (en) 2011-03-09 2012-09-13 Pharmacofore, Inc. Opioid prodrugs with heterocyclic linkers
SG11201401856VA (en) * 2011-10-26 2014-05-29 Kempharm Inc Benzoic acid, benzoic acid derivatives and heteroaryl carboxylic acid conjugates of hydromorphone, prodrugs, methods of making and use thereof
ITRM20130223A1 (en) * 2013-04-15 2014-10-16 Rosario Nicoletti CODEINE DERIVATIVES AS INHIBITORS OF MORUCINE GLUCURONATION
JP6449272B2 (en) * 2013-07-08 2019-01-09 ナンジン レジェンド バイオテック カンパニー，リミテッドＮａｎｊｉｎｇ Ｌｅｇｅｎｄ Ｂｉｏｔｅｃｈ Ｃｏ．，Ｌｔｄ． Compositions and methods for increasing the serum half-life of proteins
CA2875384A1 (en) 2013-12-20 2015-06-20 AntiOP, Inc. Intranasal naloxone compositions and methods of making and using same
CA2910865C (en) 2014-07-15 2016-11-29 Isa Odidi Compositions and methods for reducing overdose
WO2016064914A1 (en) * 2014-10-20 2016-04-28 Elysium Therapeutics, Inc. Diversion-resistant opioid formulations
RU2683274C2 (en) 2014-12-02 2019-03-27 Кемфарм, Инк. Benzoic acid, benzoic acid derivatives and conjugates of heteroaryl carboxylic acid and oxymorphone, prodrugs, methods for obtaining and use thereof
US10226456B2 (en) * 2015-04-27 2019-03-12 3St Research Llc Methods and compositions for preventing opioid abuse
US10449190B2 (en) * 2015-04-27 2019-10-22 John K. Thottathil Alpha-hydroxy carboxylic acid and derivatives and other GRAS-based prodrugs of opioids and uses thereof
US10017519B2 (en) * 2015-04-27 2018-07-10 3St Research Llc Alpha-hydroxy carboxylic acid and derivatives and other GRAS based prodrugs of oxycodone and uses thereof
US10335406B2 (en) 2015-10-01 2019-07-02 Elysium Therapeutics, Inc. Opioid compositions resistant to overdose and abuse
AU2016332071B2 (en) * 2015-10-01 2019-04-18 Elysium Therapeutics, Inc. Polysubunit opioid prodrugs resistant to overdose and abuse
EP3595663A4 (en) 2017-03-17 2021-01-13 Elysium Therapeutics, Inc. MULTI-UNIT OPIOID MEDICINES RESISTANT TO OVERDOSE AND ABUSE
WO2020012245A1 (en) 2018-07-13 2020-01-16 Alkermes Pharma Ireland Limited Thienothiophene-naltrexone prodrugs for long-acting injectable compositions
US10799496B2 (en) 2018-07-13 2020-10-13 Alkermes Pharma Ireland Limited Naphthylenyl compounds for long-acting injectable compositions and related methods
US10975099B2 (en) 2018-11-05 2021-04-13 Alkermes Pharma Ireland Limited Thiophene compounds for long-acting injectable compositions and related methods
IL305493A (en) 2021-03-09 2023-10-01 Ensysce Biosciences Inc Compositions Containing Enzyme-Degradable Drug Enzymes and Controlled-Release Nemostat and Methods for Using Them
CA3230025A1 (en) 2021-09-29 2023-04-06 Lynn Kirkpatrick Enzyme-cleavable methadone prodrugs and methods of use thereof

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20020094947A1 (en) * 1992-09-21 2002-07-18 Crain Stanley M. Method of simultaneously enhancing analgesic potency and attenuating dependence liability caused by morphine and other bimodally-acting opioid agonists
US20030004177A1 (en) * 2001-05-11 2003-01-02 Endo Pharmaceuticals, Inc. Abuse-resistant opioid dosage form
US20040106636A1 (en) * 2002-04-26 2004-06-03 Kream Richard M. Method of inhibiting opioid tolerance with chimeric hybrid analgesics

Family Cites Families (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4587046A (en) * 1982-05-18 1986-05-06 The Regents Of The University Of California Drug-carrier conjugates
CA2132342A1 (en) * 1992-04-06 1993-10-14 Kenneth F. Buechler Novel opiate derivatives and protein and polypeptide opiate derivative conjugates and labels
US5472943A (en) * 1992-09-21 1995-12-05 Albert Einstein College Of Medicine Of Yeshiva University, Method of simultaneously enhancing analgesic potency and attenuating dependence liability caused by morphine and other opioid agonists
US5580876A (en) * 1992-09-21 1996-12-03 Albert Einstein College Of Medicine Of Yeshiva University, A Division Of Yeshiva University Method of simultaneously enhancing analgesic potency and attenuating dependence liability caused by morphine and other bimodally-acting opioid agonists
US20010006967A1 (en) * 1992-09-21 2001-07-05 Stanley M. Crain Method of simultaneously enhancing analgesic potency and attenuating adverse side effects caused by tramadol and other bimodally-acting opioid agonists
US5512578A (en) * 1992-09-21 1996-04-30 Albert Einstein College Of Medicine Of Yeshiva University, A Division Of Yeshiva University Method of simultaneously enhancing analgesic potency and attenuating dependence liability caused by exogenous and endogenous opiod agonists
US6716452B1 (en) * 2000-08-22 2004-04-06 New River Pharmaceuticals Inc. Active agent delivery systems and methods for protecting and administering active agents
US7060708B2 (en) * 1999-03-10 2006-06-13 New River Pharmaceuticals Inc. Active agent delivery systems and methods for protecting and administering active agents
US7375082B2 (en) * 2002-02-22 2008-05-20 Shire Llc Abuse-resistant hydrocodone compounds
US7338939B2 (en) * 2003-09-30 2008-03-04 New River Pharmaceuticals Inc. Abuse-resistant hydrocodone compounds
US7169752B2 (en) * 2003-09-30 2007-01-30 New River Pharmaceuticals Inc. Compounds and compositions for prevention of overdose of oxycodone
US20060014697A1 (en) * 2001-08-22 2006-01-19 Travis Mickle Pharmaceutical compositions for prevention of overdose or abuse
KR100822498B1 (en) * 2002-02-22 2008-04-16 샤이어 엘엘씨 New sustained-release pharmaceutical compounds to prevent abuse of regulated substances
US7399488B2 (en) * 2002-07-05 2008-07-15 Collegium Pharmaceutical, Inc. Abuse-deterrent pharmaceutical compositions of opiods and other drugs
US6913768B2 (en) * 2002-09-24 2005-07-05 Shire Laboratories, Inc. Sustained release delivery of amphetamine salts
EA008864B1 (en) * 2003-09-30 2007-08-31 Нью Ривер Фармасьютикалз Инк. Pharmaceutical compositions for of overdose or abuse

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20020094947A1 (en) * 1992-09-21 2002-07-18 Crain Stanley M. Method of simultaneously enhancing analgesic potency and attenuating dependence liability caused by morphine and other bimodally-acting opioid agonists
US20030004177A1 (en) * 2001-05-11 2003-01-02 Endo Pharmaceuticals, Inc. Abuse-resistant opioid dosage form
US20040106636A1 (en) * 2002-04-26 2004-06-03 Kream Richard M. Method of inhibiting opioid tolerance with chimeric hybrid analgesics

Also Published As

Publication number Publication date
AU2007238625A1 (en) 2007-10-25
IL194651A0 (en) 2009-08-03
EP2007389A2 (en) 2008-12-31
US20100144645A1 (en) 2010-06-10
CA2648659A1 (en) 2007-10-25
JP2009533459A (en) 2009-09-17
WO2007120864A2 (en) 2007-10-25

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