JP5749881B2 - ポリラクチド組成物およびその使用 - Google Patents
ポリラクチド組成物およびその使用 Download PDFInfo
- Publication number
- JP5749881B2 JP5749881B2 JP2008507201A JP2008507201A JP5749881B2 JP 5749881 B2 JP5749881 B2 JP 5749881B2 JP 2008507201 A JP2008507201 A JP 2008507201A JP 2008507201 A JP2008507201 A JP 2008507201A JP 5749881 B2 JP5749881 B2 JP 5749881B2
- Authority
- JP
- Japan
- Prior art keywords
- substituted
- alkyl
- lactide
- pharmaceutical preparation
- polymer
- 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.)
- Expired - Fee Related
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- 229920000747 poly(lactic acid) Polymers 0.000 title claims description 210
- 239000000203 mixture Substances 0.000 title claims description 108
- 238000007151 ring opening polymerisation reaction Methods 0.000 claims description 104
- 239000003054 catalyst Substances 0.000 claims description 76
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 75
- 125000000217 alkyl group Chemical group 0.000 claims description 66
- 239000003814 drug Substances 0.000 claims description 49
- 150000001875 compounds Chemical class 0.000 claims description 48
- 229940079593 drug Drugs 0.000 claims description 47
- 239000003999 initiator Substances 0.000 claims description 41
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 35
- 229960000549 4-dimethylaminophenol Drugs 0.000 claims description 34
- 239000001257 hydrogen Substances 0.000 claims description 32
- 229910052739 hydrogen Inorganic materials 0.000 claims description 32
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 29
- 229920001223 polyethylene glycol Polymers 0.000 claims description 25
- 125000002877 alkyl aryl group Chemical group 0.000 claims description 21
- BSDLHDSKWLPXIW-UHFFFAOYSA-N 3-hexyl-6-methyl-1,4-dioxane-2,5-dione Chemical compound CCCCCCC1OC(=O)C(C)OC1=O BSDLHDSKWLPXIW-UHFFFAOYSA-N 0.000 claims description 17
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 16
- 125000003342 alkenyl group Chemical group 0.000 claims description 16
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 11
- RBGLVWCAGPITBS-UHFFFAOYSA-L bis(trifluoromethylsulfonyloxy)tin Chemical compound [Sn+2].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F RBGLVWCAGPITBS-UHFFFAOYSA-L 0.000 claims description 10
- 238000002156 mixing Methods 0.000 claims description 10
- 239000003960 organic solvent Substances 0.000 claims description 10
- TYKJTLOUDJNYRH-UHFFFAOYSA-N 3,3,6-trimethyl-1,4-dioxane-2,5-dione Chemical compound CC1OC(=O)C(C)(C)OC1=O TYKJTLOUDJNYRH-UHFFFAOYSA-N 0.000 claims description 9
- YERALMNRPJTTGO-UHFFFAOYSA-N 3-methyl-6-propan-2-yl-1,4-dioxane-2,5-dione Chemical group CC(C)C1OC(=O)C(C)OC1=O YERALMNRPJTTGO-UHFFFAOYSA-N 0.000 claims description 9
- 238000002347 injection Methods 0.000 claims description 9
- 239000007924 injection Substances 0.000 claims description 9
- KSBAEPSJVUENNK-UHFFFAOYSA-L tin(ii) 2-ethylhexanoate Chemical group [Sn+2].CCCCC(CC)C([O-])=O.CCCCC(CC)C([O-])=O KSBAEPSJVUENNK-UHFFFAOYSA-L 0.000 claims description 9
- VSORDMNKDOKERL-UHFFFAOYSA-N 3,6-dihexyl-1,4-dioxane-2,5-dione Chemical compound CCCCCCC1OC(=O)C(CCCCCC)OC1=O VSORDMNKDOKERL-UHFFFAOYSA-N 0.000 claims description 8
- DFYKCOWGIBSJOD-UHFFFAOYSA-N 3-benzyl-6-methyl-1,4-dioxane-2,5-dione Chemical compound O1C(=O)C(C)OC(=O)C1CC1=CC=CC=C1 DFYKCOWGIBSJOD-UHFFFAOYSA-N 0.000 claims description 7
- IRUSWOTYMUKTJX-UHFFFAOYSA-N 3-butyl-6-methyl-1,4-dioxane-2,5-dione Chemical compound CCCCC1OC(=O)C(C)OC1=O IRUSWOTYMUKTJX-UHFFFAOYSA-N 0.000 claims description 6
- 238000007911 parenteral administration Methods 0.000 claims description 5
- 150000002431 hydrogen Chemical class 0.000 claims description 4
- MVXNGTMKSZHHCO-UHFFFAOYSA-N 3-methyl-1,4-dioxane-2,5-dione Chemical compound CC1OC(=O)COC1=O MVXNGTMKSZHHCO-UHFFFAOYSA-N 0.000 claims 1
- 125000003358 C2-C20 alkenyl group Chemical group 0.000 claims 1
- 229920000642 polymer Polymers 0.000 description 148
- JJTUDXZGHPGLLC-UHFFFAOYSA-N lactide Chemical class CC1OC(=O)C(C)OC1=O JJTUDXZGHPGLLC-UHFFFAOYSA-N 0.000 description 121
- 238000006243 chemical reaction Methods 0.000 description 104
- 238000006116 polymerization reaction Methods 0.000 description 92
- 239000000178 monomer Substances 0.000 description 77
- 239000004626 polylactic acid Substances 0.000 description 77
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 60
- 230000015572 biosynthetic process Effects 0.000 description 58
- 239000000693 micelle Substances 0.000 description 57
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 56
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 51
- 238000003786 synthesis reaction Methods 0.000 description 51
- 238000006731 degradation reaction Methods 0.000 description 49
- 230000015556 catabolic process Effects 0.000 description 47
- 229920001577 copolymer Polymers 0.000 description 46
- 230000002209 hydrophobic effect Effects 0.000 description 45
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 45
- 238000000034 method Methods 0.000 description 42
- 239000000243 solution Substances 0.000 description 41
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 37
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 36
- 238000012377 drug delivery Methods 0.000 description 35
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 33
- 235000019441 ethanol Nutrition 0.000 description 33
- XMEVHPAGJVLHIG-FMZCEJRJSA-N chembl454950 Chemical compound [Cl-].C1=CC=C2[C@](O)(C)[C@H]3C[C@H]4[C@H]([NH+](C)C)C(O)=C(C(N)=O)C(=O)[C@@]4(O)C(O)=C3C(=O)C2=C1O XMEVHPAGJVLHIG-FMZCEJRJSA-N 0.000 description 32
- 239000000463 material Substances 0.000 description 32
- 229960004989 tetracycline hydrochloride Drugs 0.000 description 31
- 238000005481 NMR spectroscopy Methods 0.000 description 30
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 30
- 239000002904 solvent Substances 0.000 description 30
- JJTUDXZGHPGLLC-IMJSIDKUSA-N 4511-42-6 Chemical compound C[C@@H]1OC(=O)[C@H](C)OC1=O JJTUDXZGHPGLLC-IMJSIDKUSA-N 0.000 description 28
- -1 straight chain Chemical class 0.000 description 27
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 25
- WXZMFSXDPGVJKK-UHFFFAOYSA-N pentaerythritol Chemical compound OCC(CO)(CO)CO WXZMFSXDPGVJKK-UHFFFAOYSA-N 0.000 description 25
- IIUZTXTZRGLYTI-UHFFFAOYSA-N Dihydrogriseofulvin Natural products COC1CC(=O)CC(C)C11C(=O)C(C(OC)=CC(OC)=C2Cl)=C2O1 IIUZTXTZRGLYTI-UHFFFAOYSA-N 0.000 description 23
- UXWOXTQWVMFRSE-UHFFFAOYSA-N Griseoviridin Natural products O=C1OC(C)CC=C(C(NCC=CC=CC(O)CC(O)C2)=O)SCC1NC(=O)C1=COC2=N1 UXWOXTQWVMFRSE-UHFFFAOYSA-N 0.000 description 23
- DDUHZTYCFQRHIY-UHFFFAOYSA-N Negwer: 6874 Natural products COC1=CC(=O)CC(C)C11C(=O)C(C(OC)=CC(OC)=C2Cl)=C2O1 DDUHZTYCFQRHIY-UHFFFAOYSA-N 0.000 description 23
- DDUHZTYCFQRHIY-RBHXEPJQSA-N griseofulvin Chemical compound COC1=CC(=O)C[C@@H](C)[C@@]11C(=O)C(C(OC)=CC(OC)=C2Cl)=C2O1 DDUHZTYCFQRHIY-RBHXEPJQSA-N 0.000 description 23
- 229960002867 griseofulvin Drugs 0.000 description 23
- 230000037396 body weight Effects 0.000 description 22
- 150000002632 lipids Chemical class 0.000 description 22
- 230000009477 glass transition Effects 0.000 description 20
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 19
- 230000007246 mechanism Effects 0.000 description 19
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 18
- 238000002360 preparation method Methods 0.000 description 18
- 239000002202 Polyethylene glycol Substances 0.000 description 17
- VOFUROIFQGPCGE-UHFFFAOYSA-N nile red Chemical compound C1=CC=C2C3=NC4=CC=C(N(CC)CC)C=C4OC3=CC(=O)C2=C1 VOFUROIFQGPCGE-UHFFFAOYSA-N 0.000 description 16
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 15
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 15
- 238000010521 absorption reaction Methods 0.000 description 15
- 238000012512 characterization method Methods 0.000 description 15
- 238000005227 gel permeation chromatography Methods 0.000 description 14
- 230000035484 reaction time Effects 0.000 description 14
- NAKFRQULMGLXBT-UHFFFAOYSA-N 6-methoxyquinolin-8-ol Chemical compound N1=CC=CC2=CC(OC)=CC(O)=C21 NAKFRQULMGLXBT-UHFFFAOYSA-N 0.000 description 13
- 230000000694 effects Effects 0.000 description 13
- 229920001606 poly(lactic acid-co-glycolic acid) Polymers 0.000 description 13
- 239000003643 water by type Substances 0.000 description 13
- 241000282414 Homo sapiens Species 0.000 description 12
- 235000019445 benzyl alcohol Nutrition 0.000 description 12
- 238000009826 distribution Methods 0.000 description 12
- 239000003937 drug carrier Substances 0.000 description 12
- 150000002148 esters Chemical class 0.000 description 12
- 238000001914 filtration Methods 0.000 description 12
- 239000007788 liquid Substances 0.000 description 12
- 239000011159 matrix material Substances 0.000 description 12
- 229920001400 block copolymer Polymers 0.000 description 11
- 239000008194 pharmaceutical composition Substances 0.000 description 11
- 239000012071 phase Substances 0.000 description 11
- 230000000704 physical effect Effects 0.000 description 11
- 239000007787 solid Substances 0.000 description 11
- 125000001424 substituent group Chemical group 0.000 description 11
- NWXMGUDVXFXRIG-NAOJVREFSA-N (4s,4as,5as,12ar)-4-(dimethylamino)-1,6,10,11,12a-pentahydroxy-6-methyl-3,12-dioxo-4,4a,5,5a-tetrahydrotetracene-2-carboxamide Chemical compound C1=CC=C2C(O)(C)[C@H]3C[C@H]4[C@H](N(C)C)C(=O)C(C(N)=O)=C(O)[C@@]4(O)C(=O)C3=C(O)C2=C1O NWXMGUDVXFXRIG-NAOJVREFSA-N 0.000 description 10
- ILLHORFDXDLILE-UHFFFAOYSA-N 2-bromopropanoyl bromide Chemical compound CC(Br)C(Br)=O ILLHORFDXDLILE-UHFFFAOYSA-N 0.000 description 10
- 239000004480 active ingredient Substances 0.000 description 10
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 10
- 230000004580 weight loss Effects 0.000 description 10
- 229920001710 Polyorthoester Polymers 0.000 description 9
- 239000004098 Tetracycline Substances 0.000 description 9
- 239000003795 chemical substances by application Substances 0.000 description 9
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 9
- 238000002474 experimental method Methods 0.000 description 9
- 238000009472 formulation Methods 0.000 description 9
- 230000007062 hydrolysis Effects 0.000 description 9
- 238000006460 hydrolysis reaction Methods 0.000 description 9
- 238000002844 melting Methods 0.000 description 9
- 230000008018 melting Effects 0.000 description 9
- 229910052757 nitrogen Inorganic materials 0.000 description 9
- 239000008363 phosphate buffer Substances 0.000 description 9
- 239000000047 product Substances 0.000 description 9
- 239000011550 stock solution Substances 0.000 description 9
- 239000000126 substance Substances 0.000 description 9
- 229960002180 tetracycline Drugs 0.000 description 9
- 229930101283 tetracycline Natural products 0.000 description 9
- 235000019364 tetracycline Nutrition 0.000 description 9
- 150000003522 tetracyclines Chemical class 0.000 description 9
- RKDVKSZUMVYZHH-UHFFFAOYSA-N 1,4-dioxane-2,5-dione Chemical compound O=C1COC(=O)CO1 RKDVKSZUMVYZHH-UHFFFAOYSA-N 0.000 description 8
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 8
- 206010038933 Retinopathy of prematurity Diseases 0.000 description 8
- 239000002253 acid Substances 0.000 description 8
- 238000005538 encapsulation Methods 0.000 description 8
- 230000003628 erosive effect Effects 0.000 description 8
- 125000000524 functional group Chemical group 0.000 description 8
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- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 8
- 238000005580 one pot reaction Methods 0.000 description 8
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- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 7
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- SNRUBQQJIBEYMU-UHFFFAOYSA-N dodecane Chemical group CCCCCCCCCCCC SNRUBQQJIBEYMU-UHFFFAOYSA-N 0.000 description 7
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- 238000005809 transesterification reaction Methods 0.000 description 7
- QXJQHYBHAIHNGG-UHFFFAOYSA-N trimethylolethane Chemical compound OCC(C)(CO)CO QXJQHYBHAIHNGG-UHFFFAOYSA-N 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- NGEWQZIDQIYUNV-UHFFFAOYSA-N L-valinic acid Natural products CC(C)C(O)C(O)=O NGEWQZIDQIYUNV-UHFFFAOYSA-N 0.000 description 6
- 229920001244 Poly(D,L-lactide) Polymers 0.000 description 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
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- 125000003118 aryl group Chemical group 0.000 description 6
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- 239000000969 carrier Substances 0.000 description 6
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- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 6
- MZMWDTBBVARORD-UHFFFAOYSA-N 2-(2-bromopropanoyloxy)octanoic acid Chemical compound CCCCCCC(C(O)=O)OC(=O)C(C)Br MZMWDTBBVARORD-UHFFFAOYSA-N 0.000 description 5
- 230000002378 acidificating effect Effects 0.000 description 5
- HFBMWMNUJJDEQZ-UHFFFAOYSA-N acryloyl chloride Chemical compound ClC(=O)C=C HFBMWMNUJJDEQZ-UHFFFAOYSA-N 0.000 description 5
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- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 3
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- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 3
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 3
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- C08G63/00—Macromolecular compounds obtained by reactions forming a carboxylic ester link in the main chain of the macromolecule
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- C08G63/06—Polyesters derived from hydroxycarboxylic acids or from polycarboxylic acids and polyhydroxy compounds derived from hydroxycarboxylic acids
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- C—CHEMISTRY; METALLURGY
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- C08G63/00—Macromolecular compounds obtained by reactions forming a carboxylic ester link in the main chain of the macromolecule
- C08G63/78—Preparation processes
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- C08G63/823—Preparation processes characterised by the catalyst used for the preparation of polylactones or polylactides
Landscapes
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| PCT/IB2006/002849 WO2007012979A2 (en) | 2005-04-22 | 2006-04-21 | Polylactide compositions and uses thereof |
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| PT1883665T (pt) * | 2005-04-22 | 2017-11-14 | Univ Geneve | Composições polilactídeo e usos das mesmas |
| WO2008121702A2 (en) * | 2007-03-28 | 2008-10-09 | Boston Scientific Scimed, Inc. | Medical devices having bioerodable layers for the release of therapeutic agents |
| WO2009025719A1 (en) * | 2007-08-03 | 2009-02-26 | University Of Massachusetts Medical School | Polymer compositions for biomedical and material applications |
| US8697098B2 (en) * | 2011-02-25 | 2014-04-15 | South Dakota State University | Polymer conjugated protein micelles |
| CN101665566B (zh) * | 2008-09-01 | 2012-01-04 | 南京工业大学 | 一种利用双螺杆挤出机制备聚乳酸及其制品的方法 |
| FR2942800B1 (fr) * | 2009-03-06 | 2012-04-20 | Minasolve | Procede de polymerisation par voie catalytique de 1,4-dioxanes-2,5 diones et les polymeres correspondants |
| WO2011082479A1 (en) * | 2010-01-08 | 2011-07-14 | University Of Prince Edward Island | Star polymers having controlled tacticity and methods of making same |
| ES2581837T3 (es) | 2010-07-26 | 2016-09-07 | Université De Genève | Composiciones que comprenden polímeros preparados a partir de ácidos 2-hidroxi alquil |
| KR101952599B1 (ko) | 2011-02-25 | 2019-05-22 | 사우스다코타주립대학 | 고분자 컨쥬게이트화된 단백질 마이셀 |
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| ES2604837T3 (es) | 2012-02-02 | 2017-03-09 | Esbatech - A Novartis Company Llc | Formulación de liberación sostenida que contiene anticuerpos para administración ocular |
| AR090736A1 (es) * | 2012-04-20 | 2014-12-03 | Sucampo Ag | Conjugado de compuesto triciclo-polimero |
| AR092821A1 (es) * | 2012-04-20 | 2015-05-06 | Sucampo Ag | Conjugado de derivado de acido graso-polimero |
| EP2941422B1 (en) * | 2013-02-08 | 2017-04-05 | Total Research & Technology Feluy SA | Process for preparing cyclic esters and cyclic amides |
| US8975344B2 (en) * | 2013-07-10 | 2015-03-10 | Xerox Corporation | Polyester/polycarbonate block copolymers via one-pot, neat ring opening polymerization |
| US9080012B2 (en) * | 2013-07-10 | 2015-07-14 | Xerox Corporation | One-pot, neat ring opening polymerization to prepare resin |
| DE102013018193A1 (de) | 2013-10-30 | 2015-05-13 | Martin-Luther-Universität Halle-Wittenberg, Körperschaft des öffentlichen Rechts | Injizierbare Depotformulierungen zur kontrollierten Wirkstofffreisetzung |
| CA2940955C (en) * | 2014-02-26 | 2022-03-15 | University Of Massachusetts Medical School | Amphiphilic degradable polymers for immobilization and sustained delivery of biomolecules |
| DE102014005782A1 (de) | 2014-04-23 | 2015-10-29 | Martin-Luther-Universität Halle-Wittenberg | lnjizierbare und implantierbare Trägersysteme auf Basis von modifizierten Poly(dikarbonsäure-multiol estern) zur kontrollierten Wirkstofffreisetzung |
| CN106659731A (zh) * | 2014-05-30 | 2017-05-10 | 夏尔人类遗传性治疗公司 | 用于递送核酸的可生物降解脂质 |
| US10822491B2 (en) * | 2014-11-17 | 2020-11-03 | Roquette Freres | Composition of polyester and thermoplastic starch, having improved mechanical properties |
| WO2016100520A1 (en) * | 2014-12-16 | 2016-06-23 | Boston Scientific Scimed, Inc. | Bioerodible polymer compositions |
| US9260550B1 (en) | 2015-01-27 | 2016-02-16 | International Business Machines Corporation | Lactide-based acrylate polymers |
| JP6148701B2 (ja) * | 2015-07-31 | 2017-06-14 | ユニベルシテ ドゥ ジュネーブ | ２−ヒドロキシアルキル酸から調製されたポリマーを含む組成物 |
| US10570252B2 (en) | 2017-03-08 | 2020-02-25 | International Business Machines Corporation | Flame retardant lactide monomors for polylactide synthesis |
| US10202489B2 (en) | 2017-03-08 | 2019-02-12 | International Business Machines Corporation | Lactide copolymers and ring-opened lactide copolymers |
| US10072121B1 (en) | 2017-03-08 | 2018-09-11 | International Business Machines Corporation | Bottlebrush polymers derived from poly(methylidenelactide) |
| US10035877B1 (en) | 2017-03-08 | 2018-07-31 | International Business Machines Corporation | Matrix-bondable lactide monomors for polylactide synthesis |
| EP3743041A1 (en) | 2018-01-26 | 2020-12-02 | Apidel SA | New spironolactone formulations and their use |
| CA2994005A1 (fr) * | 2018-02-05 | 2019-08-05 | Hydro-Quebec | Copolymeres d'unites ester et ether, leurs procedes de fabrication et leurs utilisations |
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| US20160367680A1 (en) | 2016-12-22 |
| JP6491614B2 (ja) | 2019-03-27 |
| US20150073060A1 (en) | 2015-03-12 |
| US8741877B2 (en) | 2014-06-03 |
| JP2016128506A (ja) | 2016-07-14 |
| US20090281068A1 (en) | 2009-11-12 |
| EP1883665A2 (en) | 2008-02-06 |
| EP3339348B1 (en) | 2019-12-04 |
| JP2014065722A (ja) | 2014-04-17 |
| WO2007012979A2 (en) | 2007-02-01 |
| US20130331464A1 (en) | 2013-12-12 |
| US20180271984A1 (en) | 2018-09-27 |
| EP3339348A1 (en) | 2018-06-27 |
| EP1883665B1 (en) | 2017-10-11 |
| PT1883665T (pt) | 2017-11-14 |
| ES2646141T3 (es) | 2017-12-12 |
| CA2605652C (en) | 2016-05-24 |
| US10314913B2 (en) | 2019-06-11 |
| JP2017222712A (ja) | 2017-12-21 |
| DK1883665T3 (da) | 2017-11-13 |
| WO2007012979A3 (en) | 2007-05-03 |
| PL1883665T3 (pl) | 2018-05-30 |
| JP2015038121A (ja) | 2015-02-26 |
| JP6346540B2 (ja) | 2018-06-20 |
| US9925267B2 (en) | 2018-03-27 |
| US9375482B2 (en) | 2016-06-28 |
| CA2605652A1 (en) | 2007-02-01 |
| JP2008538589A (ja) | 2008-10-30 |
| JP6559198B2 (ja) | 2019-08-14 |
| US8466133B2 (en) | 2013-06-18 |
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