JP5312720B2 - ポリアルキレングリコールを含むインスリン薬物−オリゴマー結合体の混合物、これらの使用、及びこれらの製造方法 - Google Patents
ポリアルキレングリコールを含むインスリン薬物−オリゴマー結合体の混合物、これらの使用、及びこれらの製造方法 Download PDFInfo
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- JP5312720B2 JP5312720B2 JP2001316998A JP2001316998A JP5312720B2 JP 5312720 B2 JP5312720 B2 JP 5312720B2 JP 2001316998 A JP2001316998 A JP 2001316998A JP 2001316998 A JP2001316998 A JP 2001316998A JP 5312720 B2 JP5312720 B2 JP 5312720B2
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- insulin
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- conjugate
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- 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
- A61K47/56—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 an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
- A61K47/59—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 an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
- A61K47/60—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 an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
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- A61P5/50—Drugs for disorders of the endocrine system of the pancreatic hormones for increasing or potentiating the activity of insulin
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| US09/873899 | 2001-06-04 |
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| US7169889B1 (en) | 1999-06-19 | 2007-01-30 | Biocon Limited | Insulin prodrugs hydrolyzable in vivo to yield peglylated insulin |
| US7060675B2 (en) | 2001-02-15 | 2006-06-13 | Nobex Corporation | Methods of treating diabetes mellitus |
| US6867183B2 (en) | 2001-02-15 | 2005-03-15 | Nobex Corporation | Pharmaceutical compositions of insulin drug-oligomer conjugates and methods of treating diseases therewith |
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| US7713932B2 (en) | 2001-06-04 | 2010-05-11 | Biocon Limited | Calcitonin drug-oligomer conjugates, and uses thereof |
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| US7196059B2 (en) * | 2001-09-07 | 2007-03-27 | Biocon Limited | Pharmaceutical compositions of insulin drug-oligomer conjugates and methods of treating diseases therewith |
| US7166571B2 (en) * | 2001-09-07 | 2007-01-23 | Biocon Limited | Insulin polypeptide-oligomer conjugates, proinsulin polypeptide-oligomer conjugates and methods of synthesizing same |
| US7312192B2 (en) * | 2001-09-07 | 2007-12-25 | Biocon Limited | Insulin polypeptide-oligomer conjugates, proinsulin polypeptide-oligomer conjugates and methods of synthesizing same |
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| US20030198666A1 (en) * | 2002-01-07 | 2003-10-23 | Richat Abbas | Oral insulin therapy |
| US7601688B2 (en) | 2002-06-13 | 2009-10-13 | Biocon Limited | Methods of reducing hypoglycemic episodes in the treatment of diabetes mellitus |
| WO2004043396A2 (en) * | 2002-11-09 | 2004-05-27 | Nobex Corporation | Modified carbamate-containing prodrugs and methods of synthesizing same |
| DE60331584D1 (de) * | 2002-11-26 | 2010-04-15 | Biocon Ltd | Modifizierte natriuretic verbindungen, konjugate und ihre verwendungen |
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| US7384914B2 (en) * | 2003-01-06 | 2008-06-10 | Emisphere Technologies, Inc. | Night-time oral insulin therapy |
| US20060241019A1 (en) * | 2003-07-25 | 2006-10-26 | Bridon Dominique P | Long lasting insulin derivatives and methods thereof |
| US20050203001A1 (en) * | 2004-03-05 | 2005-09-15 | Emisphere Technologies, Inc. | Oral insulin therapies and protocol |
| US8329958B2 (en) | 2004-07-02 | 2012-12-11 | Biocon Limited | Combinatorial synthesis of PEG oligomer libraries |
| PT1773878E (pt) * | 2004-07-19 | 2015-06-05 | Biocon Ltd | Conjugados de insulina-oligómero, formulaçôes e usos dos mesmos |
| WO2006076471A2 (en) * | 2005-01-12 | 2006-07-20 | Nobex Corporation | Bnp conjugates and methods of use |
| TWI376234B (en) | 2005-02-01 | 2012-11-11 | Msd Oss Bv | Conjugates of a polypeptide and an oligosaccharide |
| ES2490243T3 (es) * | 2005-02-02 | 2014-09-03 | Novo Nordisk A/S | Derivados de insulina |
| KR101225679B1 (ko) * | 2005-07-08 | 2013-01-23 | 바이오콘 리미티드 | 인슐린 복합체의 제조 |
| JP5047978B2 (ja) | 2005-10-13 | 2012-10-10 | バイオコン・リミテッド | インスリン複合体の調製のための方法 |
| CN100362916C (zh) * | 2006-06-07 | 2008-01-23 | 南京医科大学 | 糜蛋白酶作为有机杀虫剂降解剂的应用 |
| JP5048283B2 (ja) * | 2006-07-20 | 2012-10-17 | キヤノン株式会社 | 偏向器アレイ、描画装置およびデバイス製造方法 |
| CN101573133B (zh) | 2006-07-31 | 2014-08-27 | 诺沃-诺迪斯克有限公司 | Peg化延长的胰岛素 |
| PL2074141T3 (pl) * | 2006-09-22 | 2017-02-28 | Novo Nordisk A/S | Analogi insuliny oporne na proteazę |
| JP5496082B2 (ja) * | 2007-04-30 | 2014-05-21 | ノボ・ノルデイスク・エー/エス | タンパク質組成物を乾燥させる方法、乾燥タンパク質組成物、及び乾燥タンパク質を含有する薬学的組成物 |
| MX2009012789A (es) * | 2007-06-01 | 2009-12-10 | Novo Nordisk As | Composiciones farmaceuticas no acuosas estables. |
| NZ585135A (en) | 2007-10-16 | 2012-08-31 | Biocon Ltd | An orally administerable solid pharmaceutical composition comprising in-105 and a process thereof |
| IL188647A0 (en) * | 2008-01-08 | 2008-11-03 | Orina Gribova | Adaptable structured drug and supplements administration system (for oral and/or transdermal applications) |
| WO2009112583A2 (en) * | 2008-03-14 | 2009-09-17 | Novo Nordisk A/S | Protease-stabilized insulin analogues |
| JP5749155B2 (ja) | 2008-03-18 | 2015-07-15 | ノボ・ノルデイスク・エー/エス | プロテアーゼ安定化アシル化インスリンアナログ |
| MY155612A (en) * | 2008-07-14 | 2015-11-13 | Biocon Ltd | A method of synthesizing a substantially monodispersed mixture of oligomers |
| EP2898900B1 (en) | 2008-09-19 | 2017-11-15 | Nektar Therapeutics | Polymer conjugates of ziconotide |
| US20110171312A1 (en) * | 2008-09-19 | 2011-07-14 | Nektar Therapeutics | Modified therapeutic peptides, methods of their preparation and use |
| DE102008056086A1 (de) * | 2008-11-06 | 2010-05-12 | Gp Solar Gmbh | Additiv für alkalische Ätzlösungen, insbesondere für Texturätzlösungen sowie Verfahren zu dessen Herstellung |
| US9060932B2 (en) | 2009-07-09 | 2015-06-23 | Oshadi Drug Administration Ltd. | Matrix carrier compositions, methods and uses |
| EP2504019A2 (en) | 2009-11-25 | 2012-10-03 | ArisGen SA | Mucosal delivery composition comprising a peptide complexed with a crown compound and/or a counter ion |
| US8575124B2 (en) | 2010-02-18 | 2013-11-05 | Anthony P. Shuber | Compositions and methods for treating cancer |
| CN102675452B (zh) * | 2011-03-17 | 2015-09-16 | 重庆富进生物医药有限公司 | 具持续降血糖和受体高结合的人胰岛素及类似物的偶联物 |
| JP6329486B2 (ja) | 2011-10-21 | 2018-05-23 | シーチェイド ファーマシューティカルズ,インコーポレーテッド | 医薬組成物及びそれらの使用 |
| CA2870313A1 (en) | 2012-04-11 | 2013-10-17 | Novo Nordisk A/S | Insulin formulations |
| EP2861065B1 (en) * | 2012-06-18 | 2017-03-15 | Basf Se | Agroformulations containing a lactone based alkoxylate |
| US9457096B2 (en) | 2012-07-06 | 2016-10-04 | Consejo Nacional De Investigaciones Cientificas Y Tecnicas (Concet) | Protozoan variant-specific surface proteins (VSP) as carriers for oral drug delivery |
| CN105636979B (zh) | 2013-10-07 | 2020-01-10 | 诺和诺德股份有限公司 | 胰岛素类似物的新衍生物 |
| CN104447981B (zh) * | 2014-12-25 | 2015-07-08 | 重庆浦诺维生物科技有限公司 | 端羟基聚乙二醇化的人胰岛素及其类似物的偶联物 |
| US20180169190A1 (en) | 2016-12-16 | 2018-06-21 | Novo Nordisk A/S | Insulin containing pharmaceutical compositions |
| TWI839327B (zh) | 2017-03-22 | 2024-04-21 | 美商建南德克公司 | 用於治療眼部病症之最佳化之抗體組合物 |
| CN113087623A (zh) * | 2021-04-13 | 2021-07-09 | 苏州昊帆生物股份有限公司 | 一种8-溴辛酸乙酯的合成方法 |
| US20240315972A1 (en) | 2021-07-12 | 2024-09-26 | Zidkiyahu Simenhaus | Protein containing bio-active compositions comprising cellulose microparticle carriers |
Family Cites Families (188)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US1801575A (en) * | 1927-11-04 | 1931-04-21 | Delco Remy Corp | Molding press |
| US3256153A (en) | 1963-02-08 | 1966-06-14 | Smith Kline French Lab | Method of stabilizing wax-fat coating materials and product thereof |
| US4003792A (en) | 1967-07-01 | 1977-01-18 | Miles Laboratories, Inc. | Conjugates of acid polysaccharides and complex organic substances |
| US3950517A (en) | 1970-05-08 | 1976-04-13 | National Research Development Corporation | Insulin derivatives |
| GB1381274A (en) | 1971-01-28 | 1975-01-22 | Nat Res Dev | Insulin derivatives |
| US3919411A (en) | 1972-01-31 | 1975-11-11 | Bayvet Corp | Injectable adjuvant and compositions including such adjuvant |
| US4044196A (en) | 1972-03-30 | 1977-08-23 | Bayer Aktiengesellschaft | Crosslinked copolymers of α,β-olefinically unsaturated dicarboxylic anhydrides |
| US4179337A (en) | 1973-07-20 | 1979-12-18 | Davis Frank F | Non-immunogenic polypeptides |
| FR2408387A2 (fr) | 1975-06-30 | 1979-06-08 | Oreal | Compositions a base de dispersions aqueuses de spherules lipidiques |
| US4087390A (en) | 1977-02-02 | 1978-05-02 | Eli Lilly And Company | Somatostatin analogs and intermediates thereto |
| US4093574A (en) | 1977-02-02 | 1978-06-06 | Eli Lilly And Company | Somatostatin analogs and intermediates thereto |
| GB1492997A (en) | 1976-07-21 | 1977-11-23 | Nat Res Dev | Insulin derivatives |
| US4223163A (en) | 1976-12-10 | 1980-09-16 | The Procter & Gamble Company | Process for making ethoxylated fatty alcohols with narrow polyethoxy chain distribution |
| JPS53116315A (en) | 1977-03-17 | 1978-10-11 | Ueno Seiyaku Oyo Kenkyujo Kk | Powder or granular containing improved sorbinic acid |
| US4100117A (en) | 1977-04-21 | 1978-07-11 | Eli Lilly And Company | Somatostatin analogs and intermediates thereto |
| US4253998A (en) | 1979-03-09 | 1981-03-03 | American Home Products Corporation | Peptides related to somatostatin |
| JPS54148722A (en) | 1978-05-12 | 1979-11-21 | Takeda Chem Ind Ltd | Nonapeptide and its preparation |
| US4277394A (en) | 1979-04-23 | 1981-07-07 | Takeda Chemical Industries, Ltd | Tetrapeptidehydrazide derivatives |
| GB2051574B (en) | 1979-05-10 | 1984-01-18 | Kyoto Pharma Ind | Adjuvant for promoting absorption of pharmacologically active substances through the rectum |
| US4348387A (en) | 1979-07-31 | 1982-09-07 | The Rockefeller University | Method and system for the controlled release of biologically active substances to a body fluid |
| US4469681A (en) | 1979-07-31 | 1984-09-04 | The Rockefeller University | Method and system for the controlled release of biologically active substances to a body fluid |
| FR2465486A1 (fr) | 1979-09-21 | 1981-03-27 | Roussel Uclaf | Nouvelle application utilisant la lh-rh ou des agonistes |
| JPS5692846A (en) | 1979-12-27 | 1981-07-27 | Takeda Chem Ind Ltd | Tetrapeptide derivative and its preparation |
| US4554101A (en) | 1981-01-09 | 1985-11-19 | New York Blood Center, Inc. | Identification and preparation of epitopes on antigens and allergens on the basis of hydrophilicity |
| IT1144743B (it) | 1981-07-09 | 1986-10-29 | Mario Cane | Apparecchio infusore di insulina perfezionato |
| US4698264A (en) | 1982-08-02 | 1987-10-06 | Durkee Industrial Foods, Corp. | Particulate composition and process for making same |
| IL68769A (en) | 1983-05-23 | 1986-02-28 | Hadassah Med Org | Pharmaceutical compositions containing insulin for oral administration |
| US4602043A (en) | 1983-07-18 | 1986-07-22 | Technology Unlimited Inc. | Treatment for hypoglycemia |
| JPS6028025A (ja) * | 1983-07-26 | 1985-02-13 | Fuji Photo Film Co Ltd | 磁気記録媒体 |
| US4585754A (en) | 1984-01-09 | 1986-04-29 | Valcor Scientific, Ltd. | Stabilization of proteins and peptides by chemical binding with chondroitin |
| US4684524A (en) | 1984-03-19 | 1987-08-04 | Alza Corporation | Rate controlled dispenser for administering beneficial agent |
| US4717566A (en) | 1984-03-19 | 1988-01-05 | Alza Corporation | Dosage system and method of using same |
| US4704394A (en) | 1984-04-25 | 1987-11-03 | Technology Unlimited, Inc. | Treatment for hyperactivity |
| US4963367A (en) | 1984-04-27 | 1990-10-16 | Medaphore, Inc. | Drug delivery compositions and methods |
| US4849405A (en) | 1984-05-09 | 1989-07-18 | Synthetic Blood Corporation | Oral insulin and a method of making the same |
| US4863896A (en) | 1984-05-03 | 1989-09-05 | Technology Unlimited, Inc. | Diabetic control by combined insulin forms |
| US4761287A (en) | 1984-05-03 | 1988-08-02 | Technology Unlimited, Inc. | Diabetes control by serotonin |
| US4963526A (en) | 1984-05-09 | 1990-10-16 | Synthetic Blood Corporation | Oral insulin and a method of making the same |
| US4839341A (en) | 1984-05-29 | 1989-06-13 | Eli Lilly And Company | Stabilized insulin formulations |
| US4622392A (en) | 1984-06-21 | 1986-11-11 | Health Research Inc. (Roswell Park Division) | Thiophospholipid conjugates of antitumor agents |
| US4629621A (en) | 1984-07-23 | 1986-12-16 | Zetachron, Inc. | Erodible matrix for sustained release bioactive composition |
| US4797288A (en) | 1984-10-05 | 1989-01-10 | Warner-Lambert Company | Novel drug delivery system |
| US4946828A (en) | 1985-03-12 | 1990-08-07 | Novo Nordisk A/S | Novel insulin peptides |
| US5157021A (en) | 1985-03-15 | 1992-10-20 | Novo Nordisk A/S | Insulin derivatives and pharmaceutical preparations containing these derivatives |
| US4917888A (en) | 1985-06-26 | 1990-04-17 | Cetus Corporation | Solubilization of immunotoxins for pharmaceutical compositions using polymer conjugation |
| SE457326B (sv) | 1986-02-14 | 1988-12-19 | Lejus Medical Ab | Foerfarande foer framstaellning av en snabbt soenderfallande kaerna innehaallande bl a mikrokristallin cellulosa |
| US4801575A (en) | 1986-07-30 | 1989-01-31 | The Regents Of The University Of California | Chimeric peptides for neuropeptide delivery through the blood-brain barrier |
| CA1339955C (en) | 1986-10-14 | 1998-07-14 | Richard Eugene Heiney | Process for transforming a human insulin precursor to human insulin |
| GB8706313D0 (en) | 1987-03-17 | 1987-04-23 | Health Lab Service Board | Treatment & prevention of viral infections |
| US5093198A (en) | 1987-06-19 | 1992-03-03 | Temple University | Adjuvant-enhanced sustained release composition and method for making |
| US4822337A (en) | 1987-06-22 | 1989-04-18 | Stanley Newhouse | Insulin delivery method and apparatus |
| DE3721721C1 (de) | 1987-07-01 | 1988-06-09 | Hoechst Ag | Verfahren zur Umhuellung von Granulaten |
| US5080891A (en) | 1987-08-03 | 1992-01-14 | Ddi Pharmaceuticals, Inc. | Conjugates of superoxide dismutase coupled to high molecular weight polyalkylene glycols |
| JPH01207320A (ja) | 1988-02-15 | 1989-08-21 | Daicel Chem Ind Ltd | 芳香族ポリエーテルの製造方法 |
| JPH01308231A (ja) | 1988-06-03 | 1989-12-12 | Takeda Chem Ind Ltd | 安定化された医薬組成物および製造法 |
| US5055300A (en) | 1988-06-17 | 1991-10-08 | Basic Bio Systems, Inc. | Time release protein |
| DK336188D0 (da) | 1988-06-20 | 1988-06-20 | Nordisk Gentofte | Propeptider |
| US5349052A (en) * | 1988-10-20 | 1994-09-20 | Royal Free Hospital School Of Medicine | Process for fractionating polyethylene glycol (PEG)-protein adducts and an adduct for PEG and granulocyte-macrophage colony stimulating factor |
| US5162430A (en) | 1988-11-21 | 1992-11-10 | Collagen Corporation | Collagen-polymer conjugates |
| US5306500A (en) | 1988-11-21 | 1994-04-26 | Collagen Corporation | Method of augmenting tissue with collagen-polymer conjugates |
| KR910700262A (ko) | 1988-12-23 | 1991-03-14 | 안네 제케르 | 사람 인슐린 유사체 |
| US4994439A (en) | 1989-01-19 | 1991-02-19 | California Biotechnology Inc. | Transmembrane formulations for drug administration |
| US5089261A (en) | 1989-01-23 | 1992-02-18 | Cetus Corporation | Preparation of a polymer/interleukin-2 conjugate |
| US5182258A (en) | 1989-03-20 | 1993-01-26 | Orbon Corporation | Systemic delivery of polypeptides through the eye |
| US5122614A (en) * | 1989-04-19 | 1992-06-16 | Enzon, Inc. | Active carbonates of polyalkylene oxides for modification of polypeptides |
| US5324844A (en) | 1989-04-19 | 1994-06-28 | Enzon, Inc. | Active carbonates of polyalkylene oxides for modification of polypeptides |
| US5286637A (en) | 1989-08-07 | 1994-02-15 | Debiopharm, S.A. | Biologically active drug polymer derivatives and method for preparing same |
| US5013556A (en) | 1989-10-20 | 1991-05-07 | Liposome Technology, Inc. | Liposomes with enhanced circulation time |
| DE3937797A1 (de) | 1989-11-14 | 1991-05-16 | Basf Ag | Verfahren zur herstellung von polyetherglykolen |
| US5650388A (en) | 1989-11-22 | 1997-07-22 | Enzon, Inc. | Fractionated polyalkylene oxide-conjugated hemoglobin solutions |
| US5312808A (en) | 1989-11-22 | 1994-05-17 | Enzon, Inc. | Fractionation of polyalkylene oxide-conjugated hemoglobin solutions |
| CA2030174C (en) | 1990-01-10 | 1996-12-24 | Anthony H. Cincotta | Process for the long term reduction of body fat stores, insulin resistance, hyperinsulinemia and hypoglycemia in vertebrates |
| US5545618A (en) | 1990-01-24 | 1996-08-13 | Buckley; Douglas I. | GLP-1 analogs useful for diabetes treatment |
| US5126324A (en) | 1990-06-07 | 1992-06-30 | Genentech, Inc. | Method of enhancing growth in patients using combination therapy |
| IE912365A1 (en) * | 1990-07-23 | 1992-01-29 | Zeneca Ltd | Continuous release pharmaceutical compositions |
| DD297249A5 (de) | 1990-08-07 | 1992-01-02 | Veb Mineralwollewerk Flechtingen Bereich F/E Mineralwolle,De | Verfahren zur automatischen ueberwachung des aushaertegrades an materialbahnen |
| IL99699A (en) | 1990-10-10 | 2002-04-21 | Autoimmune Inc | Drug with the option of oral, intra-intestinal, or inhaled dosing for suppression of autoimmune response associated with type I diabetes |
| US5468727A (en) | 1990-12-13 | 1995-11-21 | Board Of Regents, The University Of Texas System | Methods of normalizing metabolic parameters in diabetics |
| US5595732A (en) | 1991-03-25 | 1997-01-21 | Hoffmann-La Roche Inc. | Polyethylene-protein conjugates |
| US5321009A (en) | 1991-04-03 | 1994-06-14 | American Home Products Corporation | Method of treating diabetes |
| CA2108266C (en) | 1991-04-19 | 2003-06-03 | Albert J. Owen | Convertible microemulsion formulations |
| FR2675807B1 (fr) | 1991-04-23 | 1994-07-01 | Medgenix Group Sa | Conjugue de calcitonine et de polyethylene glycol. |
| US5304473A (en) | 1991-06-11 | 1994-04-19 | Eli Lilly And Company | A-C-B proinsulin, method of manufacturing and using same, and intermediates in insulin production |
| CH683149A5 (fr) | 1991-07-22 | 1994-01-31 | Debio Rech Pharma Sa | Procédé pour la préparation de microsphères en matériau polymère biodégradable. |
| AU667316B2 (en) | 1991-07-26 | 1996-03-21 | Smithkline Beecham Corporation | W/O microemulsions |
| US5206219A (en) | 1991-11-25 | 1993-04-27 | Applied Analytical Industries, Inc. | Oral compositions of proteinaceous medicaments |
| US5693769A (en) | 1991-12-13 | 1997-12-02 | Transcell Technologies, Inc. | Glycosylated steroid derivatives for transport across biological membranes and process for making and using same |
| US5320094A (en) | 1992-01-10 | 1994-06-14 | The Johns Hopkins University | Method of administering insulin |
| DE59309678D1 (de) | 1992-01-17 | 1999-08-05 | Alfatec Pharma Gmbh | Verfahren zur Herstellung von Wirkstoff enthaltenden Pulvern, Granulaten oder Pellets mit einem Gerüst aus hydrophilen Makromolekülen und ihre Verwendung |
| GB9212511D0 (en) | 1992-06-12 | 1992-07-22 | Cortecs Ltd | Pharmaceutical compositions |
| US5262172A (en) | 1992-06-19 | 1993-11-16 | Digestive Care Inc. | Compositions of gastric acid-resistant microspheres containing buffered bile acids |
| US5415872A (en) | 1992-06-22 | 1995-05-16 | Digestive Care Inc. | Compositions of gastric acid-resistant microspheres containing salts of bile acids |
| US5420108A (en) | 1992-09-14 | 1995-05-30 | Shohet; Isaac H. | Method of controlling diabetes mellitus |
| US6093391A (en) | 1992-10-08 | 2000-07-25 | Supratek Pharma, Inc. | Peptide copolymer compositions |
| GB9316895D0 (en) | 1993-08-13 | 1993-09-29 | Guy S And St Thomas Hospitals | Hepatoselective insulin analogues |
| US5298643A (en) | 1992-12-22 | 1994-03-29 | Enzon, Inc. | Aryl imidate activated polyalkylene oxides |
| US5349001A (en) | 1993-01-19 | 1994-09-20 | Enzon, Inc. | Cyclic imide thione activated polyalkylene oxides |
| US5364838A (en) | 1993-01-29 | 1994-11-15 | Miris Medical Corporation | Method of administration of insulin |
| US5321095A (en) | 1993-02-02 | 1994-06-14 | Enzon, Inc. | Azlactone activated polyalkylene oxides |
| US5298410A (en) | 1993-02-25 | 1994-03-29 | Sterling Winthrop Inc. | Lyophilized formulation of polyethylene oxide modified proteins with increased shelf-life |
| US6191105B1 (en) | 1993-05-10 | 2001-02-20 | Protein Delivery, Inc. | Hydrophilic and lipophilic balanced microemulsion formulations of free-form and/or conjugation-stabilized therapeutic agents such as insulin |
| US5359030A (en) | 1993-05-10 | 1994-10-25 | Protein Delivery, Inc. | Conjugation-stabilized polypeptide compositions, therapeutic delivery and diagnostic formulations comprising same, and method of making and using the same |
| US5681811A (en) | 1993-05-10 | 1997-10-28 | Protein Delivery, Inc. | Conjugation-stabilized therapeutic agent compositions, delivery and diagnostic formulations comprising same, and method of making and using the same |
| US5621039A (en) | 1993-06-08 | 1997-04-15 | Hallahan; Terrence W. | Factor IX- polymeric conjugates |
| AU7113594A (en) * | 1993-06-21 | 1995-01-17 | Enzon, Inc. | Site specific synthesis of conjugated peptides |
| US5506203C1 (en) | 1993-06-24 | 2001-02-06 | Astra Ab | Systemic administration of a therapeutic preparation |
| US5830853A (en) | 1994-06-23 | 1998-11-03 | Astra Aktiebolag | Systemic administration of a therapeutic preparation |
| TW402506B (en) | 1993-06-24 | 2000-08-21 | Astra Ab | Therapeutic preparation for inhalation |
| US5747445A (en) | 1993-06-24 | 1998-05-05 | Astra Aktiebolag | Therapeutic preparation for inhalation |
| IS1796B (is) | 1993-06-24 | 2001-12-31 | Ab Astra | Fjölpeptíð lyfjablanda til innöndunar sem einnig inniheldur eykjaefnasamband |
| US6342225B1 (en) | 1993-08-13 | 2002-01-29 | Deutshces Wollforschungsinstitut | Pharmaceutical active conjugates |
| EP0792290B1 (en) | 1993-09-17 | 2001-08-29 | Novo Nordisk A/S | Acylated insulin |
| SI0722434T1 (en) | 1993-10-06 | 1998-12-31 | Nicox S.A. | Nitric esters having anti-inflammatory and/or analgesic activity and process for their preparation |
| US5643575A (en) | 1993-10-27 | 1997-07-01 | Enzon, Inc. | Non-antigenic branched polymer conjugates |
| US5919455A (en) | 1993-10-27 | 1999-07-06 | Enzon, Inc. | Non-antigenic branched polymer conjugates |
| US5605976A (en) | 1995-05-15 | 1997-02-25 | Enzon, Inc. | Method of preparing polyalkylene oxide carboxylic acids |
| US5951974A (en) | 1993-11-10 | 1999-09-14 | Enzon, Inc. | Interferon polymer conjugates |
| AU692506B2 (en) | 1993-11-17 | 1998-06-11 | Ibah, Inc. | Transparent liquid for encapsulated drug delivery |
| KR100419037B1 (ko) | 1994-03-07 | 2004-06-12 | 넥타르 테라퓨틱스 | 폐를통한인슐린의전달방법및그조성물 |
| GB9406094D0 (en) | 1994-03-28 | 1994-05-18 | Univ Nottingham And University | Polymer microspheres and a method of production thereof |
| CA2190087C (en) | 1994-05-10 | 2005-08-02 | Piero Del Soldato | Nitro compounds and their compositions having anti-inflammatory, analgesic and anti-thrombotic activities |
| AU2455295A (en) | 1994-05-20 | 1995-12-18 | Hisamitsu Pharmaceutical Co., Inc. | Protein or polypeptide, process for producing the same, and intermediate compound tehrefor |
| US5461031A (en) | 1994-06-16 | 1995-10-24 | Eli Lilly And Company | Monomeric insulin analog formulations |
| US5504188A (en) | 1994-06-16 | 1996-04-02 | Eli Lilly And Company | Preparation of stable zinc insulin analog crystals |
| US6165976A (en) | 1994-06-23 | 2000-12-26 | Astra Aktiebolag | Therapeutic preparation for inhalation |
| US5730990A (en) | 1994-06-24 | 1998-03-24 | Enzon, Inc. | Non-antigenic amine derived polymers and polymer conjugates |
| GB9417524D0 (en) | 1994-08-31 | 1994-10-19 | Cortecs Ltd | Pharmaceutical compositions |
| US5738846A (en) | 1994-11-10 | 1998-04-14 | Enzon, Inc. | Interferon polymer conjugates and process for preparing the same |
| US5693609A (en) | 1994-11-17 | 1997-12-02 | Eli Lilly And Company | Acylated insulin analogs |
| US5646242A (en) | 1994-11-17 | 1997-07-08 | Eli Lilly And Company | Selective acylation of epsilon-amino groups |
| JPH10510516A (ja) | 1994-12-07 | 1998-10-13 | ノボ ノルディスク アクティーゼルスカブ | アレルゲン性を減らしたポリペプチド |
| GB9424902D0 (en) | 1994-12-09 | 1995-02-08 | Cortecs Ltd | Solubilisation Aids |
| SE9404468D0 (sv) | 1994-12-22 | 1994-12-22 | Astra Ab | Powder formulations |
| US5843866A (en) | 1994-12-30 | 1998-12-01 | Hampshire Chemical Corp. | Pesticidal compositions comprising solutions of polyurea and/or polyurethane |
| US5932462A (en) | 1995-01-10 | 1999-08-03 | Shearwater Polymers, Inc. | Multiarmed, monofunctional, polymer for coupling to molecules and surfaces |
| US5907030A (en) | 1995-01-25 | 1999-05-25 | University Of Southern California | Method and compositions for lipidization of hydrophilic molecules |
| KR0150565B1 (ko) | 1995-02-15 | 1998-08-17 | 김정재 | 유전자 조환에 의한 사람 인슐린 전구체의 제조 및 이를 이용한 인슐린의 제조방법 |
| US6251856B1 (en) | 1995-03-17 | 2001-06-26 | Novo Nordisk A/S | Insulin derivatives |
| AR002976A1 (es) | 1995-03-31 | 1998-05-27 | Lilly Co Eli | Formulaciones farmaceuticas parenterales de efecto prolongado de insulina; cristales de dichos analogos aplicables en dichas formulaciones yprocedimiento de las formulaciones mencionadas |
| US5606038A (en) | 1995-04-10 | 1997-02-25 | Competitive Technologies, Inc. | Amphiphilic polyene macrolide antibiotic compounds |
| EP0741187A2 (en) | 1995-05-05 | 1996-11-06 | F. Hoffmann-La Roche Ag | Recombinant obese (Ob) proteins |
| US5824638A (en) | 1995-05-22 | 1998-10-20 | Shire Laboratories, Inc. | Oral insulin delivery |
| US5704910A (en) | 1995-06-05 | 1998-01-06 | Nephros Therapeutics, Inc. | Implantable device and use therefor |
| US5631347A (en) | 1995-06-07 | 1997-05-20 | Eli Lilly And Company | Reducing gelation of a fatty acid-acylated protein |
| US5700904A (en) | 1995-06-07 | 1997-12-23 | Eli Lilly And Company | Preparation of an acylated protein powder |
| US5714519A (en) | 1995-06-07 | 1998-02-03 | Ergo Science Incorporated | Method for regulating glucose metabolism |
| GB9516268D0 (en) | 1995-08-08 | 1995-10-11 | Danbiosyst Uk | Compositiion for enhanced uptake of polar drugs from the colon |
| DK0851925T3 (da) | 1995-09-21 | 2005-11-28 | Genentech Inc | Humane Væksthormonvarianter |
| WO1997014740A1 (en) * | 1995-10-19 | 1997-04-24 | Receptagen Corporation | Discrete-length polyethylene glycols |
| US5766620A (en) | 1995-10-23 | 1998-06-16 | Theratech, Inc. | Buccal delivery of glucagon-like insulinotropic peptides |
| US5639705A (en) | 1996-01-19 | 1997-06-17 | Arco Chemical Technology, L.P. | Double metal cyanide catalysts and methods for making them |
| US5866538A (en) | 1996-06-20 | 1999-02-02 | Novo Nordisk A/S | Insulin preparations containing NaCl |
| US5948751A (en) | 1996-06-20 | 1999-09-07 | Novo Nordisk A/S | X14-mannitol |
| GB9613858D0 (en) | 1996-07-02 | 1996-09-04 | Cortecs Ltd | Hydrophobic preparations |
| US5905140A (en) | 1996-07-11 | 1999-05-18 | Novo Nordisk A/S, Novo Alle | Selective acylation method |
| US5856369A (en) | 1996-07-30 | 1999-01-05 | Osi Specialties, Inc. | Polyethers and polysiloxane copolymers manufactured with double metal cyanide catalysts |
| DE19632440A1 (de) | 1996-08-12 | 1998-02-19 | Basf Ag | Verfahren zur Herstellung von aus Polykationen aufgebauten, geformten Mischhydroxiden |
| US6180604B1 (en) | 1996-08-21 | 2001-01-30 | Micrologix Biotech Inc. | Compositions and methods for treating infections using analogues of indolicidin |
| US5874111A (en) | 1997-01-07 | 1999-02-23 | Maitra; Amarnath | Process for the preparation of highly monodispersed polymeric hydrophilic nanoparticles |
| US6011008A (en) | 1997-01-08 | 2000-01-04 | Yissum Research Developement Company Of The Hebrew University Of Jerusalem | Conjugates of biologically active substances |
| US5830918A (en) | 1997-01-15 | 1998-11-03 | Terrapin Technologies, Inc. | Nonpeptide insulin receptor agonists |
| DE69829763T2 (de) | 1997-02-05 | 2006-04-13 | F. Hoffmann-La Roche Ag | Verwendung von tetrahydolipstatin in der behandlung von diabetes typ ii |
| US6043214A (en) | 1997-03-20 | 2000-03-28 | Novo Nordisk A/S | Method for producing powder formulation comprising an insulin |
| US6310038B1 (en) | 1997-03-20 | 2001-10-30 | Novo Nordisk A/S | Pulmonary insulin crystals |
| US5898028A (en) | 1997-03-20 | 1999-04-27 | Novo Nordisk A/S | Method for producing powder formulation comprising an insulin |
| CO4750643A1 (es) | 1997-06-13 | 1999-03-31 | Lilly Co Eli | Formulacion estable de la insulina que contiene l-arginina y protamina |
| BR9813111A (pt) | 1997-10-24 | 2000-08-15 | Lilly Co Eli | Composições de insulina insolúveis |
| ZA989744B (en) | 1997-10-31 | 2000-04-26 | Lilly Co Eli | Method for administering acylated insulin. |
| US5981709A (en) | 1997-12-19 | 1999-11-09 | Enzon, Inc. | α-interferon-polymer-conjugates having enhanced biological activity and methods of preparing the same |
| US5985263A (en) | 1997-12-19 | 1999-11-16 | Enzon, Inc. | Substantially pure histidine-linked protein polymer conjugates |
| US6495514B1 (en) | 1998-01-21 | 2002-12-17 | Mercer University | Method for reducing inflammation and inducing an analgesic effect and compounds thereof |
| JP2002518408A (ja) | 1998-06-12 | 2002-06-25 | キングス・カレツジ・ロンドン | インスリン類似体 |
| US6211144B1 (en) | 1998-10-16 | 2001-04-03 | Novo Nordisk A/S | Stable concentrated insulin preparations for pulmonary delivery |
| DE19908041A1 (de) | 1999-02-24 | 2000-08-31 | Hoecker Hartwig | Kovalent verbrückte Insulindimere |
| US6248363B1 (en) | 1999-11-23 | 2001-06-19 | Lipocine, Inc. | Solid carriers for improved delivery of active ingredients in pharmaceutical compositions |
| US6309633B1 (en) | 1999-06-19 | 2001-10-30 | Nobex Corporation | Amphiphilic drug-oligomer conjugates with hydroyzable lipophile components and methods for making and using the same |
| KR100345214B1 (ko) | 1999-08-17 | 2002-07-25 | 이강춘 | 생체적합성 고분자가 수식된 펩타이드의 비점막 전달 |
| US6323311B1 (en) | 1999-09-22 | 2001-11-27 | University Of Utah Research Foundation | Synthesis of insulin derivatives |
| US6867183B2 (en) | 2001-02-15 | 2005-03-15 | Nobex Corporation | Pharmaceutical compositions of insulin drug-oligomer conjugates and methods of treating diseases therewith |
| US7060675B2 (en) * | 2001-02-15 | 2006-06-13 | Nobex Corporation | Methods of treating diabetes mellitus |
| US6828305B2 (en) | 2001-06-04 | 2004-12-07 | Nobex Corporation | Mixtures of growth hormone drug-oligomer conjugates comprising polyalkylene glycol, uses thereof, and methods of making same |
| US6835802B2 (en) | 2001-06-04 | 2004-12-28 | Nobex Corporation | Methods of synthesizing substantially monodispersed mixtures of polymers having polyethylene glycol moieties |
| US6858580B2 (en) * | 2001-06-04 | 2005-02-22 | Nobex Corporation | Mixtures of drug-oligomer conjugates comprising polyalkylene glycol, uses thereof, and methods of making same |
| US6828297B2 (en) * | 2001-06-04 | 2004-12-07 | Nobex Corporation | Mixtures of insulin drug-oligomer conjugates comprising polyalkylene glycol, uses thereof, and methods of making same |
| US6713452B2 (en) | 2001-06-04 | 2004-03-30 | Nobex Corporation | Mixtures of calcitonin drug-oligomer conjugates comprising polyalkylene glycol, uses thereof, and methods of making same |
| US6770625B2 (en) | 2001-09-07 | 2004-08-03 | Nobex Corporation | Pharmaceutical compositions of calcitonin drug-oligomer conjugates and methods of treating diseases therewith |
| US6913903B2 (en) | 2001-09-07 | 2005-07-05 | Nobex Corporation | Methods of synthesizing insulin polypeptide-oligomer conjugates, and proinsulin polypeptide-oligomer conjugates and methods of synthesizing same |
| US7196059B2 (en) * | 2001-09-07 | 2007-03-27 | Biocon Limited | Pharmaceutical compositions of insulin drug-oligomer conjugates and methods of treating diseases therewith |
-
2001
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- 2002-06-04 DK DK02737359.6T patent/DK1404178T3/en active
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- 2002-06-04 AR ARP020102080A patent/AR034356A1/es unknown
- 2002-06-04 MY MYPI20022069A patent/MY139375A/en unknown
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- 2004-04-29 US US10/835,018 patent/US7084114B2/en not_active Expired - Lifetime
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|---|---|
| US7470663B2 (en) | 2008-12-30 |
| EP1404178A1 (en) | 2004-04-07 |
| DK1404178T3 (en) | 2016-03-07 |
| BR0106851A (pt) | 2003-04-08 |
| CA2449426A1 (en) | 2002-12-12 |
| US20060199759A1 (en) | 2006-09-07 |
| US20030027748A1 (en) | 2003-02-06 |
| CN1538809A (zh) | 2004-10-20 |
| ES2564820T3 (es) | 2016-03-29 |
| KR20040004692A (ko) | 2004-01-13 |
| AR034356A1 (es) | 2004-02-18 |
| CA2449426C (en) | 2013-12-03 |
| WO2002098232A1 (en) | 2002-12-12 |
| AU2002310291B2 (en) | 2007-09-20 |
| JP2003113113A (ja) | 2003-04-18 |
| EP1404178A4 (en) | 2010-05-26 |
| MY139375A (en) | 2009-09-30 |
| US20040198949A1 (en) | 2004-10-07 |
| US6828297B2 (en) | 2004-12-07 |
| EP1404178B1 (en) | 2016-01-20 |
| US7084114B2 (en) | 2006-08-01 |
| MXPA03011284A (es) | 2004-03-26 |
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