DK2741765T3 - Injicerbar opløsning af i det mindste én type basal-insulin - Google Patents
Injicerbar opløsning af i det mindste én type basal-insulin Download PDFInfo
- Publication number
- DK2741765T3 DK2741765T3 DK12758562.8T DK12758562T DK2741765T3 DK 2741765 T3 DK2741765 T3 DK 2741765T3 DK 12758562 T DK12758562 T DK 12758562T DK 2741765 T3 DK2741765 T3 DK 2741765T3
- Authority
- DK
- Denmark
- Prior art keywords
- insulin
- group
- radical
- lantus
- dextran
- Prior art date
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Claims (18)
1. Sammensætning i form af en injicerbar vandig opløsning, hvis pH er imellem 6,0 og 8,0, omfattende i det mindste: a) en basal-insulin, hvis isoelektriske punkt pi er imellem 5,8 og 8,5; b) en dextran, som er substitueret med radikaler, som bærer carboxylatladninger og hydrofobe radikaler af formlen I eller formlen II:
Formel I hvor: • R er -OH eller valgt fra gruppen bestående af radikalerne: o -(f-[A]-COOH)n; o -(g-[B]-/c-[D])m, hvor D omfatter i det mindste én alkylkæde omfattende i det mindste 8 kulstofatomer; • n repræsenterer graden af substitution af glucosidenhederne med -/-[A]-COOH og 0,1 <n<2; • m repræsenterer graden af substitution af glucosidenhederne med -g-[B]-/r-[D] og 0 < m < 0,5; • q repræsenterer graden af polymerisering som glucosidenheder, dvs. det gennemsnitlige antal af glucosidenheder pr. polysaccharidkæde, og 3 < q < 50; • -(f-[A]-COOH)n: o -A- er et lineært eller forgrenet radikal omfattende fra 1 til 4 kulstofatomer; det nævnte -A-radikal: o er bundet til en glucosidenhed via en funktionel gruppe f valgt fra gruppen bestående af ether-, ester- og carbamatfunktionelle grupper; • -(g-[B]-/f-[D])m: o -B- er et lineært eller forgrenet, i det mindste divalent, radikal omfattende fra 1 til 4 kulstofatomer; det nævnte -B-radikal: o er bundet til en glucosidenhed via en funktionel gruppe g valgt fra gruppen bestående af ether-, ester- og carbamatfunktionelle grupper; o er bundet til et -D radikal via en funktionel gruppe k\ k er valgt fra gruppen bestående af ester-, amid- og carbamatfunktionelle grupper; det nævnte -D radikal: • er et -X(-/-Y)p radikal, X er et i det mindst divalent radikal omfattende fra 1 til 12 atomer valgt fra gruppen bestående af C-, N- og O-atomer, eventuelt bærende carboxyl- eller aminfunktionelle grupper og/eller resulterende af en aminosyre, en dialkohol, en diamin eller en mono- eller polyethylenglykolmono- eller -diamin; Y er en lineær eller cyclisk alkylgruppe, en alkylaryl eller en arylalkyl, af 8 til 30 kulstofatomer, eventuelt substitueret med én eller flere Ci- til C3-alkylgrupper; p > 1 og / en funktionel gruppe valgt fra gruppen bestående af ester-, amid- og carbamat-funktionelle grupper; • f, g og k er identiske eller forskellige; • de frie syrefunktionelle grupper foreligger i form af salte af alkalimetalkationer valgt fra gruppen bestående af Na+ og K+; • og når p = 1, hvis Y er en Ce- til Ci4-alkyl, så q*m > 2, hvis Y er en Cis-alkyl, så q*m > 2; og hvis Y er en Ci6- til C2o-alkyl, så q*m > 1; • og når p > 2, hvis Y er en Ce-til Cg-alkyl, så q*m > 2 og, hvis Y er en C10- til Ci6-alkyl, så q*m > 0,2;
Formel II hvor: • R er -OH eller en -(/-[A]-COOH)n-radikal: o -A- er et lineært eller forgrenet radikal omfattende fra 1 til 4 kulstofatomer; det nævnte radikal -A-: o er bundet til en glucosidenhed via en funktionel gruppe f valgt fra gruppen bestående af ether-, ester- eller carbamatfunktionelle grupper; o n repræsenterer graden af substitution af glucosidenhederne med -f-[A]-COOH og 0,1 <n<2; • R' er valgt fra gruppen bestående af radikalerne: o -C(0)NH-[E]-(o-[F])t; o -CH2N(L)z-[E]-(o-[F])t; hvor: o z er et positivt helt tal lig med 1 eller 2, o L er valgt fra gruppen bestående af: -H og z er lig med 1, og/eller -[AJ-COOH og z er lig med 1 eller 2, hvis fer en etherfunktionel gruppe, -CO-[A]-COOH og z er lig med 1, hvis fer en esterfunktionel gruppe, og -CO-NH-[A]-COOH og z er lig med 1, hvis fer en carbamatfunktionel gruppe; o -[E]-(o-[F]),: -E- er et lineært eller forgrenet, i det mindste divalent, radikal omfattende fra 1 til 8 kulstofatomer og eventuelt omfattende heteroatomer såsom O, N eller S; -F- er en lineær eller cyclisk alkylgruppe, en alkylaryl eller en arylalkyl, af 12 til 30 kulstofatomer, eventuelt substitueret med én eller flere Ci- til C3-alkylgrupper; o er en funktionel gruppe valgt fra gruppen bestående af ether-, ester-, amideller carbamatfunktionelle grupper; t er et positivt helt tal lig med 1 eller 2; • q repræsenterer graden af polymerisation som glucosidenheder, dvs. det gennemsnitlige antal glucosidenheder pr. polysaccharidkæde, og 3 < q < 50; • de frie syrefunktionelle gruppe foreligger i form af salte af alkalimetalkationer valgt fra gruppen bestående af Na+ og K+; • når z = 2, foreligger nitrogenatomet i form af en kvaternær ammonium.
2. Sammensætning ifølge krav 1, kendetegnet ved, at dextranet, som er substitueret med radikaler, som bærer carboxylatladninger, og hydrofobe radikaler vælges fra dextraner af formel I.
3. Sammensætning ifølge et af kravene 1 og 2, kendetegnet ved, at dextranet, som er substitueret med radikaler, som bærer carboxylatladninger, og hydrofobe radikaler vælges fra dextranerne af formel I, i hvilke -(/-[A]-COOH)n-radikalet vælges fra gruppen bestående af følgende sekvenser, hvor f har en betydning, som er defineret i krav 1:
4. Sammensætning ifølge ethvert af kravene 1 til 3, kendetegnet ved, at dextranet, som er substitueret med radikaler, som bærer carboxylatladninger, og hydrofobe radikaler, vælges fra dextranerne af formel I, i hvilke -(g-[B]-/r-[D])m-radikalet vælges fra gruppen bestående af følgende sekvenser, idet g, k og D har de betydninger, som er definerede i krav 1:
5. Sammensætning ifølge ethvert af kravene 1 til 4, kendetegnet ved, at dextranerne, som er substituerede med radikaler, som bærer carboxylatladninger, og hydrofobe radikaler vælges fra dextranerne af formel I, i hvilke -(g-[B]-/c-[D])m-radikalet er således, at: • -B- er et radikal omfattende ét kulstofatom; det nævnte -B-radikal er bundet til en glucosidenhed via en etherfunktionel gruppe g, og X er et radikal, som stammer fra en aminosyre.
6. Sammensætning ifølge ethvert af kravene 1 til 5, kendetegnet ved, at dextranet, som er substitueret med radikaler, som bærer carboxylatladninger, og hydrofobe radikaler, vælges fra dextranerne af formel I, i hvilke X-radikalet er et i det mindste divalent radikal, som stammer fra en aminosyre valgt fra gruppen bestående af glycin, leucin, phenylalanin, lysin, isoleucin, alanin, valin, asparaginsyre og glutaminsyre.
7. Sammensætning ifølge ethvert af kravene 1 til 6, kendetegnet ved, at dextranet, som er substitueret med radikaler, som bærer carboxylatladninger, og hydrofobe radikaler, vælges fra dextranerne af formel I, i hvilke Y-gruppen vælges fra gruppen bestående af en hydrofob alkohol, en hydrofob syre, en sterol eller en tocopherol.
8. Sammensætning ifølge ethvert af kravene 1 til 7, kendetegnet ved, at dextranet, som er substitueret med radikaler, som bærer carboxylatladninger, og hydrofobe radikaler, vælges fra dextranerne af formel I, i hvilke Y-gruppen er en sterol valgt blandt cholesterolderivater.
9. Sammensætning ifølge ethvert af kravene 1 til 8, kendetegnet ved, at dextranet, som er substitueret med radikaler, som bærer carboxylatladninger, og hydrofobe radikaler, vælges fra gruppen bestående af følgende dextraner af formel I: - natriumdextranmethylcarboxylat modificeret med octylglycinat, - natriumdextranmethylcarboxylat modificeret med cetylglycinat, - natriumdextranmethylcarboxylat modificeret med octylphenylalaninat, - natriumdextranmethylcarboxylat modificeret med 3,7-dimethyl-1 -octylphenylalaninat, - natriumdextranmethylcarboxylat modificeret med dioctylaspartat, - natriumdextranmethylcarboxylat modificeret med didecylaspartat, - natriumdextranmethylcarboxylat modificeret med dilaurylaspartat, - natriumdextranmethylcarboxylat modificeret med N-(2-aminoethyl)dodecanamid, - natriumdextransuccinat modificeret med laurylglycinat, - N-(natriummethylcarboxylat)dextrancarbamat modificeret med dioctylaspartat, - natriumdextranmethylcarboxylat modificeret med 2-(2-aminoethoxy)ethyl-dodecanoat, - natriumdextranmethylcarboxylat modificeret med 2-(2-{2-[dodecanoylamino]-ethoxy}ethoxy)ethylamin, - natriumdextranmethylcarboxylat modificeret med 2-(2-{2-[hexadecanoylamino]-ethoxy}ethoxy)ethylamin, - natriumdextranmethylcarboxylat modificeret med cholesterylleucinat, - natriumdextranmethylcarboxylat modificeret med cholesteryl-1-ethylendiamin-carboxylat, - N-(natriummethylcarboxylat)dextrancarbamat modificeret med cholesterylleucinat.
10. Sammensætning ifølge ethvert af de foregående krav, kendetegnet ved, at basalinsulinet, hvis isoelektriske punkt er imellem 5,8 og 8,5 er insulin-glargin.
11. Sammensætning ifølge ethvert af de foregående krav, kendetegnet ved, at den omfatter imellem 40 lU/ml og 500 lU/ml af basal-insulin, hvis isoelektriske punkt er imellem 5,8 og 8,5.
12. Sammensætning ifølge ethvert af de foregående krav, kendetegnet ved, at den yderligere omfatter en prandial-insulin.
13. Sammensætning ifølge ethvert af de foregående krav, kendetegnet ved, at den omfatter imellem 40 og 800 lU/ml af total-insulin.
14. Sammensætning ifølge et af kravene 12 og 13, kendetegnet ved, at den omfatter proportioner, udtrykt som procentdel, imellem basal-insulinen hvis isoelektriske punkt er imellem 5,8 og 8,5 og en prandial-insulin på 25/75, 30/70, 40/60, 50/50, 60/40, 70/30, 80/20 og 90/10.
15. Sammensætning ifølge ethvert af kravene 1 til 11, kendetegnet ved, at den yderligere omfatter en GLP-1, en GLP-1 analog eller et GLP-1-derivat.
16. Sammensætning ifølge ethvert af de foregående krav, kendetegnet ved, at den yderligere omfatter zinksalte i en koncentration på imellem 0 og 5000 μΜ.
17. Sammensætning ifølge ethvert af kravene 12 til 14, kendetegnet ved, at den nævnte prandial-insulin vælges fra gruppen dannet af human-insulin, insulin-glulisin, insulin-lispro og insulinaspart.
18. Enkeltdosisformulering omfattende en sammensætning ifølge ethvert af kravene 1 til 14 og 16 til 17 ved en pH på imellem 6,6 og 7,8 og en prandial-insulin.
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US201161522031P | 2011-08-10 | 2011-08-10 | |
| FR1157291A FR2978918B1 (fr) | 2011-08-10 | 2011-08-10 | Solution injectable a ph7 comprenant au moins une insuline basale dont le pi est compris entre 5,8 et 8,5 |
| US201161579966P | 2011-12-23 | 2011-12-23 | |
| FR1162445A FR2984749A1 (fr) | 2011-12-23 | 2011-12-23 | Solution injectable a ph 7 comprenant au moins une insuline basale dont le pi est compris entre 5,8 et 8,5 en combinaison avec une hormone gastro-intestinale a visee therapeutique |
| PCT/FR2012/051880 WO2013021143A1 (fr) | 2011-08-10 | 2012-08-09 | Solution injectable d'au moins une insuline basale |
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Families Citing this family (42)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DK2741765T3 (da) | 2011-08-10 | 2016-06-13 | Adocia | Injicerbar opløsning af i det mindste én type basal-insulin |
| US9198971B2 (en) | 2012-01-09 | 2015-12-01 | Adocia | Injectable solution at pH 7 comprising at least one basal insulin the pI of which is between 5.8 and 8.5 and a substituted co-polyamino acid |
| US20150314003A2 (en) | 2012-08-09 | 2015-11-05 | Adocia | Injectable solution at ph 7 comprising at least one basal insulin the isoelectric point of which is between 5.8 and 8.5 and a hydrophobized anionic polymer |
| UA116217C2 (uk) | 2012-10-09 | 2018-02-26 | Санофі | Пептидна сполука як подвійний агоніст рецепторів glp1-1 та глюкагону |
| CN104902922B (zh) | 2012-11-13 | 2017-12-12 | 阿道恰公司 | 包含经取代阴离子化合物的速效胰岛素制剂 |
| FR3001895B1 (fr) * | 2013-02-12 | 2015-07-03 | Adocia | Solution injectable a ph7 comprenant au moins une insuline basale dont le point isoelectrique est compris en 5,8 et 8,5 et un compose anionique porteur de charges carboxylates et de radicaux hydrophobes |
| AU2013366692B2 (en) | 2012-12-21 | 2017-11-23 | Sanofi | Dual GLP1/GIP or trigonal GLP1/GIP/Glucagon agonists |
| AU2014326181A1 (en) | 2013-09-30 | 2016-03-17 | Wockhardt Limited | Pharmaceutical composition |
| WO2015086733A1 (en) | 2013-12-13 | 2015-06-18 | Sanofi | Dual glp-1/glucagon receptor agonists |
| EP3080154B1 (en) | 2013-12-13 | 2018-02-07 | Sanofi | Dual glp-1/gip receptor agonists |
| EP3080152A1 (en) | 2013-12-13 | 2016-10-19 | Sanofi | Non-acylated exendin-4 peptide analogues |
| WO2015086728A1 (en) | 2013-12-13 | 2015-06-18 | Sanofi | Exendin-4 peptide analogues as dual glp-1/gip receptor agonists |
| TW201625670A (zh) | 2014-04-07 | 2016-07-16 | 賽諾菲公司 | 衍生自ｅｘｅｎｄｉｎ－４之雙重ｇｌｐ－１／升糖素受體促效劑 |
| TW201625669A (zh) | 2014-04-07 | 2016-07-16 | 賽諾菲公司 | 衍生自艾塞那肽－４（Ｅｘｅｎｄｉｎ－４）之肽類雙重ＧＬＰ－１／升糖素受體促效劑 |
| TW201625668A (zh) | 2014-04-07 | 2016-07-16 | 賽諾菲公司 | 作為胜肽性雙重ｇｌｐ－１／昇糖素受體激動劑之艾塞那肽－４衍生物 |
| US9795678B2 (en) * | 2014-05-14 | 2017-10-24 | Adocia | Fast-acting insulin composition comprising a substituted anionic compound and a polyanionic compound |
| FR3020947B1 (fr) | 2014-05-14 | 2018-08-31 | Adocia | Composition aqueuse comprenant au moins une proteine et un agent solubilisant, sa preparation et ses utilisations |
| FR3020952B1 (fr) * | 2014-05-14 | 2017-09-08 | Adocia | Formulation a action rapide d'insuline comprenant un compose anionique substitue et un compose polyanionique |
| US9932381B2 (en) | 2014-06-18 | 2018-04-03 | Sanofi | Exendin-4 derivatives as selective glucagon receptor agonists |
| AR105319A1 (es) | 2015-06-05 | 2017-09-27 | Sanofi Sa | Profármacos que comprenden un conjugado agonista dual de glp-1 / glucagón conector ácido hialurónico |
| TW201706291A (zh) | 2015-07-10 | 2017-02-16 | 賽諾菲公司 | 作為選擇性肽雙重ｇｌｐ－１／升糖素受體促效劑之新毒蜥外泌肽（ｅｘｅｎｄｉｎ－４）衍生物 |
| JP7001584B2 (ja) * | 2015-09-04 | 2022-01-19 | ラティチュード ファーマシューティカルズ インコーポレイテッド | 安定化されたグルカゴン溶液 |
| EP3377038A1 (fr) * | 2015-11-16 | 2018-09-26 | Adocia | Composition a action rapide d'insuline comprenant un compose anionique substitue et un compose polyanionique |
| FR3043557B1 (fr) | 2015-11-16 | 2019-05-31 | Adocia | Composition a action rapide d'insuline comprenant un citrate substitue |
| WO2017145104A1 (en) * | 2016-02-25 | 2017-08-31 | Wockhardt Limited | Pharmaceutical composition of insulin glargine and amino acids |
| GB201607918D0 (en) | 2016-05-06 | 2016-06-22 | Arecor Ltd | Novel formulations |
| FR3052072A1 (fr) | 2016-06-07 | 2017-12-08 | Adocia | Solution injectable a ph 7 comprenant au moins une insuline basale dont le pi est compris entre 5,8 et 8,5 et un co-polyaminoacide porteur de charges carboxylates et de radicaux hydrophobes |
| JP2019529506A (ja) | 2016-09-29 | 2019-10-17 | アレコル リミテッド | 新規の製剤 |
| US10463717B2 (en) * | 2016-12-27 | 2019-11-05 | Adocia | Compositions in the form of an injectable aqueous solution comprising amylin, an amylin receptor agonist or an amylin analog, and a co-polyamino acid |
| FR3070264A1 (fr) | 2017-08-24 | 2019-03-01 | Adocia | Solution injectable a ph 7 comprenant au moins une insuline basale dont le pi est compris de 5,8 a 8,5 et un co-polyaminoacide porteur de charges carboxylates et de radicaux hydrophobes |
| WO2019110625A1 (fr) | 2017-12-06 | 2019-06-13 | Adocia | Solution injectable a ph 7 comprenant au moins une insuline basale dont le pi est compris entre 5,8 et 8,5 et un co-polyaminoacide porteur de charges carboxylates et de radicaux hydrophobes |
| FR3083089A1 (fr) | 2018-06-29 | 2020-01-03 | Adocia | Solution injectable a ph 7 comprenant au moins une insuline basale dont le pi est compris entre 5,8 et 8,5 et un co-polyaminoacide porteur de charges carboxylates et de radicaux hydrophobes |
| FR3083088B1 (fr) | 2018-06-29 | 2020-10-02 | Adocia | Solution injectable a ph 7 comprenant au moins une insuline basale dont le pi est compris entre 5,8 et 8,5 et un co-polyaminoacide porteur de charges carboxylates et de radicaux hydrophobes |
| IL275192B2 (en) | 2017-12-07 | 2025-06-01 | Adocia | Injectable solution at ph 7 comprising at least one basal insulin having a pi of between 5.8 and 8.5 and a copolyamino acid carrying carboxylate charges and hydrophobic radicals |
| TW201938190A (zh) | 2017-12-07 | 2019-10-01 | 法商阿道洽公司 | 包含至少一具有pi從5.8至8.5之基礎胰島素以及一帶有羧酸鹽電荷及疏水基之共聚胺基酸的ph 7之可注射溶液 |
| TWI813604B (zh) | 2017-12-07 | 2023-09-01 | 法商阿道洽公司 | 包含至少一具有pi從5.8至8.5之基礎胰島素以及一帶有羧酸鹽電荷及疏水基之共聚胺基酸的可注射ph7溶液 |
| KR102833828B1 (ko) * | 2018-04-04 | 2025-07-15 | 아레콜 리미티드 | 인슐린 화합물의 전달을 위한 의료용 주입 펌프 시스템 |
| US12357562B2 (en) | 2018-04-04 | 2025-07-15 | Arecor Limited | Injection pen system for the delivery of an insulin compound |
| US20210113763A1 (en) * | 2018-04-04 | 2021-04-22 | Arecor Limited | Medical infusion pump system for the delivery of an insulin compound |
| CN112313206B (zh) * | 2018-06-29 | 2023-09-12 | 巴斯夫欧洲公司 | 酯胺盐 |
| FR3083700B1 (fr) * | 2018-07-13 | 2021-03-12 | Adocia | Formulation thermostable d'insuline humaine a21g |
| US20200179489A1 (en) | 2018-12-07 | 2020-06-11 | Adocia | Injectable solution at ph 7 comprising at least one basal insulin which pi is from 5.8 to 8.5 and a co-polyamino-acid bearing carboxylate charges and hydrophobic radicals and a limited amount of m-cresol |
Family Cites Families (56)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2387201A (en) | 1942-01-12 | 1945-10-16 | Bonneville Ltd | Mono-acyl ethylene diamines |
| WO1985001890A1 (fr) | 1983-10-26 | 1985-05-09 | Kanebo, Ltd. | Agent emulsifiant proteique, son procede de preparation et preparation cosmetique emulsifiee le contenant |
| DE3837825A1 (de) | 1988-11-08 | 1990-05-10 | Hoechst Ag | Neue insulinderivate, ihre verwendung und eine sie enthaltende pharmazeutische zubereitung |
| WO2000061191A2 (en) | 1999-04-09 | 2000-10-19 | Advanced Magnetics, Inc. | Heat stable coated colloidal iron oxides |
| FR2801226B1 (fr) | 1999-11-23 | 2002-01-25 | Flamel Tech Sa | Suspension colloidale de particules submicroniques de vectorisation de principes actifs et son mode de preparation |
| IL140844A0 (en) | 2001-01-10 | 2002-02-10 | Polygene Ltd | Cationic polysaccharide compositions |
| CZ2004710A3 (cs) | 2001-12-20 | 2005-02-16 | Eli Lilly And Company | Inzulínová sloučenina s protrahovaným účinkem |
| FR2840614B1 (fr) | 2002-06-07 | 2004-08-27 | Flamel Tech Sa | Polyaminoacides fonctionnalises par de l'alpha-tocopherol et leurs applications notamment therapeutiques |
| DE10227232A1 (de) * | 2002-06-18 | 2004-01-15 | Aventis Pharma Deutschland Gmbh | Saure Insulinzubereitungen mit verbesserter Stabilität |
| WO2004060968A1 (fr) | 2002-12-04 | 2004-07-22 | Flamel Technologies | Polyaminoacides fonctionnalises par au moins un groupement (oligo)aminoacide et leurs applications notamment therapeutiques |
| EP1620465A2 (en) | 2003-04-29 | 2006-02-01 | Eli Lilly And Company | Insulin analogs having protracted time action |
| DK3300721T4 (da) * | 2003-11-20 | 2025-03-03 | Novo Nordisk As | Propylenglycol-holdige peptidformuleringer hvilke er optimale til fremstilling og til anvendelse i injektionsindretninger |
| FR2862536B1 (fr) | 2003-11-21 | 2007-11-23 | Flamel Tech Sa | Formulations pharmaceutiques pour la liberation prolongee de principe(s) actif(s), ainsi que leurs applications notamment therapeutiques |
| FR2873040B1 (fr) | 2004-07-19 | 2007-11-30 | Flamel Technologies Sa | Formulation colloidale d'insuline longue action et sa preparation |
| WO2006051103A2 (en) | 2004-11-12 | 2006-05-18 | Novo Nordisk A/S | Stable formulations of peptides |
| CA2593112A1 (en) | 2005-01-21 | 2006-07-27 | Alza Corporation | Therapeutic peptide formulations for coating microneedles with improved stability containing at least one counterion |
| CN101460523A (zh) * | 2006-04-07 | 2009-06-17 | 阿道恰公司 | 双官能化多糖 |
| EP2012817A2 (en) | 2006-04-12 | 2009-01-14 | Biodel, Inc. | Rapid acting and long acting insulin combination formulations |
| US8679540B2 (en) | 2006-06-09 | 2014-03-25 | Flamel Technologies | Pharmaceutical formulations for the prolonged release of active principle(s), and their applications, especially therapeutic applications |
| FR2902007B1 (fr) | 2006-06-09 | 2012-01-13 | Flamel Tech Sa | Formulations pharmaceutiques pour la liberation prolongee de principe(s) actif(s) ainsi que leurs applications notamment therapeutiques |
| NZ575365A (en) | 2006-09-07 | 2012-02-24 | Ind Res Ltd | Acyclic amine inhibitors of nucleoside phosphorylases and hydrolases |
| FR2915683B1 (fr) | 2007-05-03 | 2009-08-07 | Flamel Technologies Sa | Formulations pharmaceutiques auto-precipitantes pour la liberation modifiee de principe actif |
| FR2919188B1 (fr) | 2007-07-27 | 2010-02-26 | Proteins & Peptides Man | Complexes entre un polymere amphiphile et une proteine osteogenique appartenant a la famille des bmps |
| JP5710253B2 (ja) | 2007-08-13 | 2015-04-30 | ノボ・ノルデイスク・エー／エス | 速効型インスリンアナログ |
| BRPI0820535B8 (pt) * | 2007-11-16 | 2021-05-25 | Novo Nordisk As | composições farmacêuticas contendo insulina e um peptídeo insulinotrópico |
| TWI394580B (zh) * | 2008-04-28 | 2013-05-01 | Halozyme Inc | 超快起作用胰島素組成物 |
| TWI451876B (zh) * | 2008-06-13 | 2014-09-11 | Lilly Co Eli | 聚乙二醇化之離脯胰島素化合物 |
| WO2010028055A1 (en) * | 2008-09-02 | 2010-03-11 | Biodel, Inc. | Insulin with a basal release profile |
| US20100167984A1 (en) | 2008-09-26 | 2010-07-01 | Adocia | Complex between human insulin and an amphiphilic polymer and use of this complex in the preparation of a fast-acting human insulin formulation |
| FR2940802A1 (fr) * | 2008-10-10 | 2010-07-09 | Adocia | Complexe entre l'insuline humaine et un polymere amphiphile et utilisation de ce complexe pour la preparation d'une formulation d'insuline humaine rapide. |
| US8426382B2 (en) * | 2008-10-06 | 2013-04-23 | Adocia | Polysaccharides comprising carboxyl functional groups substituted by a hydrophobic alcohol derivative |
| FR2936800B1 (fr) * | 2008-10-06 | 2010-12-31 | Adocia | Polysaccharide comportant des groupes fonctionnels carboxyles substitues par un derive d'alcool hydrophobe |
| US8759322B2 (en) | 2008-11-05 | 2014-06-24 | National University Corporation Tokyo Medical And Dental University | Hyaluronic acid derivative and pharmaceutical composition thereof |
| US20110305769A1 (en) | 2008-11-17 | 2011-12-15 | Enzon Pharmaceuticals, Inc. | Branched cationic lipids for nucleic acids delivery system |
| FR2948573B1 (fr) * | 2009-07-31 | 2011-11-18 | Adocia | Nouvelle forme d'administration de complexes de proteines osteogeniques |
| FR2944448B1 (fr) * | 2008-12-23 | 2012-01-13 | Adocia | Composition pharmaceutique stable comprenant au moins un anticorps monodonal et au moins un polysacharide amphiphile comprenant des substituants derives d'alcools hydrofobes ou d'amines hydrophobes. |
| CN102272146A (zh) * | 2009-01-13 | 2011-12-07 | 通用电气健康护理生物科学股份公司 | 用带负电的聚合物沉淀生物分子 |
| US9060927B2 (en) * | 2009-03-03 | 2015-06-23 | Biodel Inc. | Insulin formulations for rapid uptake |
| FR2943538B1 (fr) | 2009-03-27 | 2011-05-20 | Adocia | Formulation a action rapide d'insuline recombinante humaine |
| US9018190B2 (en) | 2009-03-27 | 2015-04-28 | Adocia | Functionalized oligosaccharides |
| FR2956116A1 (fr) * | 2010-02-09 | 2011-08-12 | Adocia | Complexes polysaccharide/bmp-7 solubles a ph physiologique |
| FR2958646B1 (fr) | 2010-04-07 | 2012-05-18 | Adocia | Polysaccharides comportant des groupes fonctionnels carboxyles substitues par un derive d'acide hydrophobe. |
| BR112012019580A2 (pt) * | 2010-02-09 | 2020-08-18 | Adocia | "polissacarídeos antônicos funcionalizados por pelo menos dois grupos hidrofóbicos carreados por pelo menos um espaçador trivalente |
| FR2958647B1 (fr) | 2010-04-08 | 2013-08-23 | Adocia | Polysaccharides comportant des groupes fonctionnels carboxyles substitues par un derive hydrophobe porte par un spacer au moins trivalent. |
| EP2388723A1 (en) | 2010-05-18 | 2011-11-23 | University College Cork-National University of Ireland, Cork | Method of assessing allergic status in a subject |
| AU2011202239C1 (en) | 2010-05-19 | 2017-03-16 | Sanofi | Long-acting formulations of insulins |
| EP2389945A1 (en) | 2010-05-28 | 2011-11-30 | Sanofi-Aventis Deutschland GmbH | Pharmaceutical composition comprising AVE0010 and insulin glargine |
| US20120295833A1 (en) | 2011-05-10 | 2012-11-22 | Adocia | Polysaccharides having an adjustable degree of functionalization |
| EP2828297A1 (fr) | 2011-05-10 | 2015-01-28 | Adocia | Oligosaccharides fonctionnalisés |
| DK2741765T3 (da) | 2011-08-10 | 2016-06-13 | Adocia | Injicerbar opløsning af i det mindste én type basal-insulin |
| FR2985428B1 (fr) | 2012-01-09 | 2016-05-27 | Adocia | Solution injectable a ph 7 comprenant au moins une insuline basale dont le pi est compris entre 5,8 et 8,5 et un polyaminoacide substitue |
| US9198971B2 (en) | 2012-01-09 | 2015-12-01 | Adocia | Injectable solution at pH 7 comprising at least one basal insulin the pI of which is between 5.8 and 8.5 and a substituted co-polyamino acid |
| FR2985429B1 (fr) | 2012-01-09 | 2016-07-29 | Adocia | Solution injectable a ph 7 comprenant au moins une insuline basale dont le pi est compris entre 5,8 et 8,5 et un polyaminoacide substitue obtenu par un procede de polymerisation controle |
| US9994615B2 (en) | 2012-02-17 | 2018-06-12 | Massachusetts Institute Of Technology | Self-regulated peptide hydrogel for insulin delivery |
| EP2920200A1 (fr) | 2012-11-13 | 2015-09-23 | Adocia | Composes anioniques substitues constitues d'un squelette forme d'un nombre discret d'unites saccharidiques |
| CN104902922B (zh) | 2012-11-13 | 2017-12-12 | 阿道恰公司 | 包含经取代阴离子化合物的速效胰岛素制剂 |
-
2012
- 2012-08-09 DK DK12758562.8T patent/DK2741765T3/da active
- 2012-08-09 RU RU2014108829/15A patent/RU2578460C2/ru not_active IP Right Cessation
- 2012-08-09 AU AU2012293463A patent/AU2012293463B2/en not_active Ceased
- 2012-08-09 US US13/571,026 patent/US9089476B2/en not_active Expired - Fee Related
- 2012-08-09 WO PCT/FR2012/051880 patent/WO2013021143A1/fr not_active Ceased
- 2012-08-09 JP JP2014524435A patent/JP5950477B2/ja not_active Expired - Fee Related
- 2012-08-09 CN CN201280038926.9A patent/CN103889442B/zh not_active Expired - Fee Related
- 2012-08-09 EP EP12758562.8A patent/EP2741765B9/fr not_active Not-in-force
- 2012-08-09 EP EP16162474.7A patent/EP3053590A1/fr not_active Withdrawn
- 2012-08-09 BR BR112014002986A patent/BR112014002986A2/pt active Search and Examination
- 2012-08-09 KR KR1020147005655A patent/KR101810055B1/ko not_active Expired - Fee Related
- 2012-08-09 MX MX2014001190A patent/MX2014001190A/es active IP Right Grant
- 2012-08-09 CA CA2843586A patent/CA2843586A1/fr not_active Abandoned
-
2014
- 2014-01-23 IL IL230611A patent/IL230611A/en not_active IP Right Cessation
- 2014-01-31 ZA ZA2014/00773A patent/ZA201400773B/en unknown
-
2015
- 2015-05-26 US US14/721,889 patent/US20170182131A9/en not_active Abandoned
-
2018
- 2018-07-02 US US16/025,832 patent/US20180311316A1/en not_active Abandoned
Also Published As
| Publication number | Publication date |
|---|---|
| KR101810055B1 (ko) | 2017-12-18 |
| IL230611A (en) | 2016-10-31 |
| US20130065826A1 (en) | 2013-03-14 |
| EP2741765B9 (fr) | 2016-09-28 |
| AU2012293463B2 (en) | 2016-08-04 |
| KR20140051384A (ko) | 2014-04-30 |
| MX2014001190A (es) | 2014-05-12 |
| JP2014521716A (ja) | 2014-08-28 |
| US20180311316A1 (en) | 2018-11-01 |
| RU2014108829A (ru) | 2015-09-20 |
| JP5950477B2 (ja) | 2016-07-13 |
| US20170182131A9 (en) | 2017-06-29 |
| IL230611A0 (en) | 2014-03-31 |
| CA2843586A1 (fr) | 2013-02-14 |
| WO2013021143A1 (fr) | 2013-02-14 |
| ZA201400773B (en) | 2016-11-30 |
| EP2741765B1 (fr) | 2016-03-30 |
| CN103889442A (zh) | 2014-06-25 |
| RU2578460C2 (ru) | 2016-03-27 |
| EP3053590A1 (fr) | 2016-08-10 |
| EP2741765A1 (fr) | 2014-06-18 |
| BR112014002986A2 (pt) | 2017-06-13 |
| US9089476B2 (en) | 2015-07-28 |
| AU2012293463A1 (en) | 2014-03-06 |
| US20150250858A1 (en) | 2015-09-10 |
| CN103889442B (zh) | 2016-12-28 |
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