BR112013017296B1 - composto e composição compreendendo oxicodona, método para reduzir o abuso potencial da referida composição, unidade de dose e método para a sua preparação, e método para identificar um composto e um inibidor de tripsina - Google Patents
composto e composição compreendendo oxicodona, método para reduzir o abuso potencial da referida composição, unidade de dose e método para a sua preparação, e método para identificar um composto e um inibidor de tripsina Download PDFInfo
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- BR112013017296B1 BR112013017296B1 BR112013017296-7A BR112013017296A BR112013017296B1 BR 112013017296 B1 BR112013017296 B1 BR 112013017296B1 BR 112013017296 A BR112013017296 A BR 112013017296A BR 112013017296 B1 BR112013017296 B1 BR 112013017296B1
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- Prior art keywords
- compound
- prodrug
- dose
- trypsin inhibitor
- oxycodone
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 444
- 239000002753 trypsin inhibitor Substances 0.000 title claims abstract description 157
- 229940122618 Trypsin inhibitor Drugs 0.000 title claims abstract description 138
- 101710162629 Trypsin inhibitor Proteins 0.000 title claims abstract description 138
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- 229960002085 oxycodone Drugs 0.000 title claims abstract description 127
- 239000000203 mixture Substances 0.000 title claims abstract description 123
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Images
Classifications
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- C07—ORGANIC CHEMISTRY
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- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/08—Tripeptides
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- 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
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
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- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
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| EP2475429B1 (en) | 2009-09-08 | 2015-07-29 | Signature Therapeutics, Inc. | Compositions comprising enzyme-cleavable ketone-modified opioid prodrugs and optional inhibitors thereof |
| US10668060B2 (en) | 2009-12-10 | 2020-06-02 | Collegium Pharmaceutical, Inc. | Tamper-resistant pharmaceutical compositions of opioids and other drugs |
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| US20130059914A1 (en) | 2010-04-21 | 2013-03-07 | Signature Therapeutics, Inc. | Compositions Comprising Enzyme-Cleavable Amphetamine Prodrugs and Inhibitors Thereof |
| CN103384472B (zh) | 2011-01-11 | 2016-01-20 | 特色疗法股份有限公司 | 包含酶可裂解的羟考酮药物前体的组合物 |
| AU2012225337B2 (en) | 2011-03-09 | 2016-04-28 | Signature Therapeutics, Inc. | Active agent prodrugs with heterocyclic linkers |
| WO2012122420A2 (en) | 2011-03-09 | 2012-09-13 | Pharmacofore, Inc. | Opioid prodrugs with heterocyclic linkers |
| AU2014359894B2 (en) | 2013-12-06 | 2020-09-17 | Baikang (Suzhou) Co., Ltd | Bioreversable promoieties for nitrogen-containing and hydroxyl-containing drugs |
| NZ731591A (en) * | 2014-11-25 | 2018-06-29 | Kempharm Inc | Benzoic acid, benzoic acid derivatives and heteroaryl carboxylic acid conjugates of oxycodone |
| US11634384B2 (en) | 2014-11-25 | 2023-04-25 | Concentric Analgesics, Inc. | Prodrugs of phenolic TRPV1 agonists |
| GB2556817B (en) | 2015-10-01 | 2019-11-06 | Elysium Therapeutics Inc | Polysubunit opioid prodrugs resistant to overdose and abuse |
| US10335406B2 (en) | 2015-10-01 | 2019-07-02 | Elysium Therapeutics, Inc. | Opioid compositions resistant to overdose and abuse |
| EP3210630A1 (en) * | 2016-02-29 | 2017-08-30 | G.L. Pharma GmbH | Abuse-deterrent pharmaceutical compositions |
| CA3025268A1 (en) | 2016-05-25 | 2017-11-30 | Concentric Analgesics, Inc. | Prodrugs of phenolic trpv1 agonists in combination with local anesthetics and vasoconstrictors for improved local anesthesia |
| WO2017222575A1 (en) | 2016-06-23 | 2017-12-28 | Collegium Pharmaceutical, Inc. | Process of making more stable abuse-deterrent oral formulations |
| US11879019B2 (en) | 2016-12-19 | 2024-01-23 | The Regents Of The University Of California | Dual-enzyme responsive peptides |
| WO2018118903A1 (en) | 2016-12-19 | 2018-06-28 | The Regents Of The University Of California | Noncrushable pill formulatiions |
| CA3056239C (en) | 2017-03-17 | 2023-09-12 | Elysium Therapeutics, Inc. | Polysubunit opioid prodrugs resistant to overdose and abuse |
| CN111683976B (zh) | 2018-02-05 | 2022-11-18 | 生物辐射实验室股份有限公司 | 具有阴离子交换-疏水混合模式配体的色谱树脂 |
| TW202019887A (zh) | 2018-07-27 | 2020-06-01 | 美商同心止痛劑股份有限公司 | 酚系trpv1促效劑之聚乙二醇化前藥 |
| US12384744B2 (en) | 2021-09-29 | 2025-08-12 | Ensysce Biosciences Inc. | Enzyme-cleavable methadone prodrugs and methods of use thereof |
Family Cites Families (58)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU527371B2 (en) | 1980-09-16 | 1983-03-03 | Torii & Co., Ltd. | Amidine |
| US5109118A (en) | 1989-07-06 | 1992-04-28 | Yutaka Mizushima | Modified biologically active proteins |
| US5217987A (en) | 1989-10-30 | 1993-06-08 | Berger Stephen P | Dopamine uptake inhibitors in reducing substance abuse and/or craving |
| CA2032420A1 (en) | 1989-12-22 | 1991-06-23 | Akira Okuyama | Guanidinobenzene derivatives |
| US6692766B1 (en) | 1994-06-15 | 2004-02-17 | Yissum Research Development Company Of The Hebrew University Of Jerusalem | Controlled release oral drug delivery system |
| EP0893437A4 (en) | 1996-04-10 | 2000-12-27 | Ono Pharmaceutical Co | GUANIDINO TRYPTASE INHIBITOR |
| WO2000028980A2 (en) | 1998-11-13 | 2000-05-25 | Eli Lilly And Company | Combination of duloxetine with non-steroidal antiinflammatory drug for treating pain |
| JP4668418B2 (ja) | 1998-12-15 | 2011-04-13 | アプライド バイオシステムズ リミテッド ライアビリティー カンパニー | 多種酵素アッセイ |
| US6849263B2 (en) | 1998-12-21 | 2005-02-01 | Generex Pharmaceutical Incorporated | Pharmaceutical compositions for buccal delivery of pain relief medications |
| AU3000800A (en) | 1999-02-18 | 2000-09-04 | Supergen, Inc. | Phosphocholine linked prodrug derivatives |
| US7060708B2 (en) | 1999-03-10 | 2006-06-13 | New River Pharmaceuticals Inc. | Active agent delivery systems and methods for protecting and administering active agents |
| KR20020059653A (ko) * | 1999-10-29 | 2002-07-13 | 그린 마틴, 브라이언 쥐 테슬리 | 서방성 하이드로코돈 제형 |
| US20030180352A1 (en) | 1999-11-23 | 2003-09-25 | Patel Mahesh V. | Solid carriers for improved delivery of active ingredients in pharmaceutical compositions |
| US6673574B2 (en) | 2000-11-30 | 2004-01-06 | Unigene Laboratories Inc. | Oral delivery of peptides using enzyme-cleavable membrane translocators |
| JP4541693B2 (ja) | 2001-06-11 | 2010-09-08 | メダレックス，インコーポレイティド | Ｃｄ１０活性化プロドラッグ化合物 |
| US7375082B2 (en) | 2002-02-22 | 2008-05-20 | Shire Llc | 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 |
| CA2477004C (en) | 2002-02-22 | 2011-05-10 | Thomas Piccariello | Novel sustained release pharmaceutical compounds to prevent abuse of controlled substances |
| US20100092562A1 (en) | 2002-11-26 | 2010-04-15 | Hollenbeck R Gary | Sustained-release drug delivery compositions and methods |
| EP1603597B1 (en) | 2003-03-13 | 2010-01-06 | Controlled Chemicals, Inc. | Oxycodone conjugates with lower abuse potential and extended duration of action |
| EP1782834A3 (en) * | 2003-03-13 | 2007-08-01 | Controlled Chemicals, Inc. | Oxycodone conjugates with lower abuse potential and extended duration of action |
| AU2004251647B2 (en) | 2003-05-29 | 2010-01-14 | Takeda Pharmaceutical Company Limited | Abuse resistant amphetamine compounds |
| AU2004277400B2 (en) | 2003-09-30 | 2009-01-22 | Shire Llc | Pharmaceutical compositions for prevention of overdose or abuse |
| EP1678321A1 (en) | 2003-10-24 | 2006-07-12 | Gilead Sciences, Inc. | Methods and compositions for identifying therapeutic compounds |
| EP1928881A2 (en) * | 2005-08-19 | 2008-06-11 | Pharmacofore, Inc. | Prodrugs of active agents |
| US20070054843A1 (en) | 2005-08-26 | 2007-03-08 | Yeomans David C | Methods for treatment of headaches by administration of oxytocin |
| BRPI0617987A2 (pt) | 2005-10-06 | 2011-08-16 | Auspex Pharmaceuticals Inc | composição, composição farmacêutica, forma de dosagem efervescente, composição farmacêutica oral de comprimidos unitários múltiplos, forma de dosagem farmacêutica de liberação prolongada, forma de dosagem farmacêutica revestida entérica, forma de dosagem farmacêutica estável para administração oral a sujeitos mamìferos, método para tratamento de doenças relacionadas a ácido gástrico pela inibição de secreção de ácido gástrico, método para tratamento de uma infecção bacteriana provocada ou mediada por helicobacter pylori, processo para preparar um composto da fórmula 3, processo para preparar um composto da fórmula 5, uso de um composto da fórmula 1 para a preparação de um medicamento para tratamento de doenças relacionadas a ácido gástrico, pela inibição de secreção de ácido gástrico, uso de um composto da fórmula 1 para a preparação de um medicamento para tratamento de uma infecção bacteriana provocada ou mediada por helicobacter pylori uso de um composto da fórmula 1 para a preparação de um medicamento para tratamento de doenças relecionadas a ácido gástrico pela inibição de secreção de ácido gástrico |
| ES2391575T3 (es) | 2005-12-05 | 2012-11-27 | Xenoport, Inc. | Mesilato de profármaco de Levodopa, sus composiciones y sus usos |
| CA2649360A1 (en) | 2006-04-10 | 2007-10-25 | Shire Llc | Mono and di-substituted oxycodone compounds and compositions |
| JP2009533459A (ja) | 2006-04-14 | 2009-09-17 | シャイア エルエルシー | 共有結合する化合物の鎮痛作用の増強と、有害な副作用の減衰と、前記化合物の乱用の予防とのための組成物及び方法 |
| DK2046393T3 (da) | 2006-05-26 | 2014-05-12 | Signature Therapeutics Inc | Kontrolleret frigivelse af phenol-opioider |
| TWI401237B (zh) | 2006-07-24 | 2013-07-11 | ３-〔（１ｒ，２ｒ）-３-（二甲基氨基）-１-乙基-２-甲基丙基〕酚之製備 | |
| US20100022792A1 (en) | 2006-09-14 | 2010-01-28 | Qionghua Shen | Synthetic process for cyclic organosilanes |
| WO2008101202A1 (en) | 2007-02-16 | 2008-08-21 | Pharmacofore, Inc. | N-17-alkylated prodrugs of opioids |
| US20110105381A2 (en) * | 2007-02-16 | 2011-05-05 | Pharmacofore, Inc. | Prodrugs of Peripheral Phenolic Opioid Antagonists |
| MX360289B (es) | 2007-11-23 | 2018-10-29 | Gruenenthal Gmbh | Composiciones de tapentadol. |
| US9023860B2 (en) | 2007-11-26 | 2015-05-05 | Signature Therapeutics, Inc. | Pro-drugs for controlled release of biologically active compounds |
| WO2009080030A1 (en) | 2007-12-21 | 2009-07-02 | Lifecycle Pharma A/S | Treatment of autoimmune hepatitis with a once daily oral dosage form comprising tacrolimus |
| WO2009092071A2 (en) | 2008-01-18 | 2009-07-23 | Shire Llc | Amino acid and peptide pro-drugs of phenolic analgesics and uses thereof |
| ES2671897T3 (es) | 2008-02-14 | 2018-06-11 | Alkermes, Inc. | Compuestos opioides selectivos |
| CA2723434C (en) | 2008-05-05 | 2018-01-23 | Oramed Ltd. | Methods and compositions for oral administration of exenatide |
| CN102186467B (zh) * | 2008-10-17 | 2014-06-04 | 特色疗法股份有限公司 | 具有减弱释放酚类阿片样物质的药用组合物 |
| US20100227921A1 (en) | 2009-03-03 | 2010-09-09 | Shire Llc | Amino acid and peptide carbamate prodrugs of tapentadol and uses thereof |
| AU2010231126A1 (en) * | 2009-04-02 | 2011-10-13 | Shire Llc | Novel dicarboxylic acid linked amino acid and peptide prodrugs of opioids and uses thereof |
| US20120270847A1 (en) | 2009-07-17 | 2012-10-25 | Shire Llc | Novel carbamate amino acid and peptide prodrugs of opiates and uses thereof |
| EP2475429B1 (en) | 2009-09-08 | 2015-07-29 | Signature Therapeutics, Inc. | Compositions comprising enzyme-cleavable ketone-modified opioid prodrugs and optional inhibitors thereof |
| US20110262355A1 (en) | 2010-04-21 | 2011-10-27 | Jenkins Thomas E | Compositions comprising enzyme-cleavable opioid prodrugs and inhibitors thereof |
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| EP2560491A1 (en) * | 2010-04-21 | 2013-02-27 | Signature Therapeutics, Inc. | Peripheral opioid agonists and peripheral opioid antagonists |
| EP2560489A4 (en) * | 2010-04-21 | 2014-01-22 | Signature Therapeutics Inc | COMPOSITIONS WITH ENZYMSPALTBAR OPIOID PRODRUGS AND HEMMER FOR THIS |
| US20110262360A1 (en) | 2010-04-21 | 2011-10-27 | Jenkins Thomas E | Compositions Comprising Enzyme-Cleavable Phenol-Modified Opioid Prodrugs and Inhibitors Thereof |
| US20130059914A1 (en) | 2010-04-21 | 2013-03-07 | Signature Therapeutics, Inc. | Compositions Comprising Enzyme-Cleavable Amphetamine Prodrugs and Inhibitors Thereof |
| US9238020B2 (en) | 2010-04-21 | 2016-01-19 | Signature Therapeutics, Inc. | Compositions comprising enzyme-cleavable phenol-modified tapentadol prodrug |
| EP2560490A1 (en) * | 2010-04-21 | 2013-02-27 | Signature Therapeutics, Inc. | Compositions comprising enzyme-cleavable prodrugs of active agents and inhibitors thereof |
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| WO2012122420A2 (en) | 2011-03-09 | 2012-09-13 | Pharmacofore, Inc. | Opioid prodrugs with heterocyclic linkers |
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- 2012-01-10 TW TW101100923A patent/TWI526209B/zh active
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2013
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- 2013-09-24 US US14/035,871 patent/US8962547B2/en active Active
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2015
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|---|---|
| AU2012205733B2 (en) | 2015-10-08 |
| US8569228B2 (en) | 2013-10-29 |
| BR112013017296A2 (pt) | 2017-09-05 |
| IL225904B (en) | 2020-03-31 |
| EP2663187B1 (en) | 2016-06-01 |
| JP2014502972A (ja) | 2014-02-06 |
| RU2013137452A (ru) | 2015-02-20 |
| WO2012096887A2 (en) | 2012-07-19 |
| EP2663187A2 (en) | 2013-11-20 |
| ES2584634T3 (es) | 2016-09-28 |
| JP6016810B2 (ja) | 2016-10-26 |
| AU2012205733A1 (en) | 2013-05-09 |
| CA2814763A1 (en) | 2012-07-19 |
| RU2609412C2 (ru) | 2017-02-01 |
| US20140162935A1 (en) | 2014-06-12 |
| CN103384472A (zh) | 2013-11-06 |
| HK1189763A1 (zh) | 2014-06-20 |
| TWI526209B (zh) | 2016-03-21 |
| WO2012096887A3 (en) | 2012-10-04 |
| DK2663187T3 (en) | 2016-08-29 |
| EP2663187A4 (en) | 2014-09-10 |
| CA2814763C (en) | 2019-05-28 |
| US20150197544A1 (en) | 2015-07-16 |
| CN103384472B (zh) | 2016-01-20 |
| US8962547B2 (en) | 2015-02-24 |
| TW201309297A (zh) | 2013-03-01 |
| US9499581B2 (en) | 2016-11-22 |
| US20120178772A1 (en) | 2012-07-12 |
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