JP2018528305A - ポリマーおよびミクロスフェア - Google Patents
ポリマーおよびミクロスフェア Download PDFInfo
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- JP2018528305A JP2018528305A JP2018511446A JP2018511446A JP2018528305A JP 2018528305 A JP2018528305 A JP 2018528305A JP 2018511446 A JP2018511446 A JP 2018511446A JP 2018511446 A JP2018511446 A JP 2018511446A JP 2018528305 A JP2018528305 A JP 2018528305A
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- UUEVFMOUBSLVJW-UHFFFAOYSA-N oxo-[[1-[2-[2-[2-[4-(oxoazaniumylmethylidene)pyridin-1-yl]ethoxy]ethoxy]ethyl]pyridin-4-ylidene]methyl]azanium;dibromide Chemical compound [Br-].[Br-].C1=CC(=C[NH+]=O)C=CN1CCOCCOCCN1C=CC(=C[NH+]=O)C=C1 UUEVFMOUBSLVJW-UHFFFAOYSA-N 0.000 claims description 2
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- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 239000008367 deionised water Substances 0.000 description 1
- 229910021641 deionized water Inorganic materials 0.000 description 1
- 238000011026 diafiltration Methods 0.000 description 1
- 229960001259 diclofenac Drugs 0.000 description 1
- DCOPUUMXTXDBNB-UHFFFAOYSA-N diclofenac Chemical compound OC(=O)CC1=CC=CC=C1NC1=C(Cl)C=CC=C1Cl DCOPUUMXTXDBNB-UHFFFAOYSA-N 0.000 description 1
- 238000009792 diffusion process Methods 0.000 description 1
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 1
- 238000010494 dissociation reaction Methods 0.000 description 1
- 230000005593 dissociations Effects 0.000 description 1
- 238000007922 dissolution test Methods 0.000 description 1
- VSJKWCGYPAHWDS-UHFFFAOYSA-N dl-camptothecin Natural products C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)C5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-UHFFFAOYSA-N 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 238000011067 equilibration Methods 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000004052 folic acid antagonist Substances 0.000 description 1
- 229960003883 furosemide Drugs 0.000 description 1
- ZZUFCTLCJUWOSV-UHFFFAOYSA-N furosemide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC(C(O)=O)=C1NCC1=CC=CO1 ZZUFCTLCJUWOSV-UHFFFAOYSA-N 0.000 description 1
- UIWYJDYFSGRHKR-UHFFFAOYSA-N gadolinium atom Chemical compound [Gd] UIWYJDYFSGRHKR-UHFFFAOYSA-N 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 230000008570 general process Effects 0.000 description 1
- 238000004442 gravimetric analysis Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 230000036571 hydration Effects 0.000 description 1
- 238000006703 hydration reaction Methods 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 229960001680 ibuprofen Drugs 0.000 description 1
- 229960000905 indomethacin Drugs 0.000 description 1
- 229960004260 indomethacin sodium Drugs 0.000 description 1
- 238000005342 ion exchange Methods 0.000 description 1
- 230000005865 ionizing radiation Effects 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 229960002603 iopromide Drugs 0.000 description 1
- DGAIEPBNLOQYER-UHFFFAOYSA-N iopromide Chemical compound COCC(=O)NC1=C(I)C(C(=O)NCC(O)CO)=C(I)C(C(=O)N(C)CC(O)CO)=C1I DGAIEPBNLOQYER-UHFFFAOYSA-N 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- DKYWVDODHFEZIM-UHFFFAOYSA-N ketoprofen Chemical compound OC(=O)C(C)C1=CC=CC(C(=O)C=2C=CC=CC=2)=C1 DKYWVDODHFEZIM-UHFFFAOYSA-N 0.000 description 1
- 229960000991 ketoprofen Drugs 0.000 description 1
- 201000010260 leiomyoma Diseases 0.000 description 1
- 239000002502 liposome Substances 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 208000014018 liver neoplasm Diseases 0.000 description 1
- 239000013627 low molecular weight specie Substances 0.000 description 1
- 230000005291 magnetic effect Effects 0.000 description 1
- 229960003194 meglumine Drugs 0.000 description 1
- 229960000485 methotrexate Drugs 0.000 description 1
- 238000001000 micrograph Methods 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- VOAWOIGCXMLYFY-UHFFFAOYSA-N n-(2-oxoethyl)prop-2-enamide Chemical compound C=CC(=O)NCC=O VOAWOIGCXMLYFY-UHFFFAOYSA-N 0.000 description 1
- 230000017074 necrotic cell death Effects 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 108020004707 nucleic acids Proteins 0.000 description 1
- 102000039446 nucleic acids Human genes 0.000 description 1
- 150000007523 nucleic acids Chemical class 0.000 description 1
- 238000000879 optical micrograph Methods 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 230000005298 paramagnetic effect Effects 0.000 description 1
- 235000019371 penicillin G benzathine Nutrition 0.000 description 1
- 230000010412 perfusion Effects 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 229960002895 phenylbutazone Drugs 0.000 description 1
- VYMDGNCVAMGZFE-UHFFFAOYSA-N phenylbutazonum Chemical compound O=C1C(CCCC)C(=O)N(C=2C=CC=CC=2)N1C1=CC=CC=C1 VYMDGNCVAMGZFE-UHFFFAOYSA-N 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
- 229960004919 procaine Drugs 0.000 description 1
- 201000004240 prostatic hypertrophy Diseases 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 229960004432 raltitrexed Drugs 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000007873 sieving Methods 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000009518 sodium iodide Nutrition 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- JMHRGKDWGWORNU-UHFFFAOYSA-M sodium;2-[1-(4-chlorobenzoyl)-5-methoxy-2-methylindol-3-yl]acetate Chemical compound [Na+].CC1=C(CC([O-])=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 JMHRGKDWGWORNU-UHFFFAOYSA-M 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 229910001220 stainless steel Inorganic materials 0.000 description 1
- 239000010935 stainless steel Substances 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 229940124530 sulfonamide Drugs 0.000 description 1
- 150000003456 sulfonamides Chemical class 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 229920001059 synthetic polymer Polymers 0.000 description 1
- 235000013706 tagetes lucida Nutrition 0.000 description 1
- 125000000383 tetramethylene group Chemical group [H]C([H])([*:1])C([H])([H])C([H])([H])C([H])([H])[*:2] 0.000 description 1
- OEIXGLMQZVLOQX-UHFFFAOYSA-N trimethyl-[3-(prop-2-enoylamino)propyl]azanium;chloride Chemical compound [Cl-].C[N+](C)(C)CCCNC(=O)C=C OEIXGLMQZVLOQX-UHFFFAOYSA-N 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 229960000281 trometamol Drugs 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 229960005080 warfarin Drugs 0.000 description 1
- PJVWKTKQMONHTI-UHFFFAOYSA-N warfarin Chemical compound OC=1C2=CC=CC=C2OC(=O)C=1C(CC(=O)C)C1=CC=CC=C1 PJVWKTKQMONHTI-UHFFFAOYSA-N 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
Images
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- A61K49/0069—Preparation for luminescence or biological staining characterised by a special physical or galenical form, e.g. emulsions, microspheres the agent being in a particular physical galenical form
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- A61K9/1605—Excipients; Inactive ingredients
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- C08F290/126—Polymers of unsaturated carboxylic acids or derivatives thereof
Abstract
【選択図】なし
Description
Xは直鎖状または分岐したC1〜6アルキレン基、C2〜6アルケニレン基またはC2〜6アルキニレン基であり、
R1、R2およびR3は同一かまたは異なり、C1〜4アルキル基から選択され、
R4はHまたはC1〜4アルキルである。
Qは直鎖状または分岐したC1〜8アルキレン基であり、
R5はH、C1〜6アルキル、またはC3〜6シクロアルキルであり、
R6は25以下の炭素原子を有するオレフィン系不飽和電子吸引性共重合可能ラジカルであり、
R7はHまたはC1〜6アルキルである。
Qはメチレン基、エチレン基、またはプロピレン基であり、最も好ましくはメチレン基であり、R5はHまたはメチル、特にHであり、R7はHまたはメチル、特にHである。したがって、特にQはメチレン基であり、R5はHであり、R7はHであり、式IIbのようになる。
Xは直鎖状または分岐したC1〜4アルキレン、好ましくはエチレン、プロピレン、またはブチレンであり、
R1、R2およびR3は同一かまたは異なり、C1〜4アルキル基から選択され、好ましくはメチルまたはエチルであり、
R4はHまたはC1〜4アルキル、好ましくはHまたはメチルである。
実施例1
(i)PVAマクロマーの合成
マクロマーは、本質的にWO04071495の実施例1にしたがって調製されてよい。Mowiol 8−88 PVA粉末(88%加水分解度、12%アセテート含量、平均分子量約67,000D)(150g)(Clariant,Charlotte,NC USA)を2リットルガラス反応容器に加える。穏やかに撹拌しながら1000mlの水を加え、撹拌を400rpmまで増加させる。PVAを完全に溶解させるために、温度を99±9℃に2〜3時間昇温する。室温まで冷却し、PVA溶液にN−アクリロイルアミノアセトアルデヒド(NAAADA)(Ciba Vision,10 Germany)(2.49gまたは0.104mmol/gのPVA)を混合し、続いて濃塩酸(100ml)を加える。反応は室温で6〜7時間進行し、次いで2.5M NaOHを用いてpH7.4に中和することにより停止する。
ミクロスフェアを、「油中水」型の系において酸化還元触媒反応で合成した。
水中で完全に膨潤したミクロスフェアを分子量4kDa〜250kDaのFITC−デキストラン複合体(FITC−D)に暴露することによって、各マトリックス配合物について分子量カットオフデータを決定した。共焦点レーザー走査顕微鏡(CLSM)を使用してミクロスフェアの内部へのFITC−Dの拡散を観察した。APTA16、APTA43およびAPTA60について、対象の領域を中心とした代表的な画像を図3に示す。ミクロスフェアの中心にFITC−Dが観察されなかった最大分子量カットオフ範囲のまとめを表2に示す。
本発明のミクロスフェアの担持および溶出特性を、一連の市販のピレンスルホン酸ナトリウム塩をモデルアニオン性薬物として用いて特性決定した。1−ピレンスルホン酸ナトリウム塩(P1)、6,8−ジヒドロキシピレン−1,3−ジスルホン酸二ナトリウム塩(P2)、8−ヒドロキシピレン−1,3,6−トリスルホン酸三ナトリウム塩(P3)および1,3,6,8−ピレンテトラスルホン酸水和物四ナトリウム塩(P4)の各色素の化学構造を図4に示す。
メスシリンダーを使用して、生理食塩水(例えば、1mL)中で完全に水和したミクロスフェアの体積を等分した。その後ミクロスフェアをバイアルに移し、生理食塩水を除去した。モデル化合物の溶液を、化合物を脱イオン水中に溶解することによって調製した。その後、溶液をミクロスフェアのスラリーを含むバイアルに加えた。その後、バイアルを室温で回転させて混合し、担持溶液のアリコートを除去することによって担持を観察した。
各ポリマー配合物のミクロスフェアに、等量の各色素を担持した。色素担持ミクロスフェアの試料1mlを、褐色瓶中の200mLのPBSに加えた。ミクロスフェア懸濁液を回転させて連続混合した。各時点で溶離液を採取し、上記のようなUV/Vis分光光度法によってアッセイした。採取した溶離液の体積を新鮮なPBSと交換して溶出体積を維持した。図5は、APTA43ミクロスフェアからの各色素の溶出プロファイルを示す。
Claims (21)
- 前記マクロマーは1,3−ジオール基を含む、請求項1に記載のポリマー。
- 前記マクロマーはポリビニルアルコールを含む、請求項1または2に記載のポリマー。
- 前記ポリマーに共有結合した1つまたは複数のヨウ素をさらに含む、請求項1〜5に記載のポリマー。
- ヒドロゲルの形態である、請求項1〜7に記載のポリマー。
- 1つまたは複数の医薬活性物質を含む、請求項1〜8に記載のポリマー。
- 前記医薬活性物質は前記ポリマー内にイオン相互作用で結合している、請求項9に記載のポリマー。
- 請求項1〜8のいずれかに記載のポリマーを含む、ミクロスフェア。
- 前記ポリマーは5〜75重量%のカチオン性コモノマーを含む、請求項11に記載のミクロスフェア。
- 医薬活性物質および/または撮像剤をさらに含む、請求項11または12に記載のミクロスフェア。
- 前記医薬活性物質および/または撮像剤は前記ポリマー内にイオン相互作用で可逆的に結合している、請求項13に記載のミクロスフェア。
- 請求項11〜14に記載のミクロスフェアの1つまたは複数を含む、組成物。
- 破裂したミクロスフェアを含まない、請求項15に記載の組成物。
- 医薬的に許容される希釈剤を含む、請求項15または16に記載の組成物。
- 請求項11〜14のいずれかに記載のミクロスフェアを提供すること、および前記ミクロスフェアをそれを必要とする患者の血管に送達し、それによって血管に塞栓形成することを含む、処置の方法。
- 動脈塞栓術での使用ための、請求項11〜14に記載のミクロスフェア。
- 患者の体内の部位への前記ミクロスフェアの直接注入を含む方法での使用ための、請求項11〜14に記載のミクロスフェア。
- 凍結乾燥され、0.9bar未満の圧力下にされた、請求項11〜13に記載の1つまたは複数の無菌ミクロスフェアを含む、密封容器。
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PCT/EP2016/070808 WO2017037276A1 (en) | 2015-09-03 | 2016-09-05 | Polymers and microspheres |
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JP2022518586A (ja) * | 2019-03-22 | 2022-03-15 | バイオコンパティブルズ ユーケー リミテッド | 塞栓マイクロスフェア及び方法 |
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US10376469B2 (en) * | 2016-02-17 | 2019-08-13 | Biosphere Medical, Inc. | Microspheres containing therapeutic agents and related methods of use |
EP3668491A4 (en) * | 2017-08-16 | 2021-06-16 | Biosphere Medical, Inc. | MICROSPHERES CONTAINING THERAPEUTIC AGENTS AND RELATED METHODS OF USE |
CN109666098B (zh) * | 2017-10-17 | 2021-03-26 | 中国石油化工股份有限公司 | 双交联网络缓膨型聚合物微球及其制备方法和应用 |
US20230037198A1 (en) * | 2021-07-29 | 2023-02-02 | Varian Medical Systems, Inc. | Apparatuses and methods for producing embolic particles with activated loading sites |
CN114262279B (zh) * | 2021-12-30 | 2022-12-16 | 上海汇禾医疗科技有限公司 | 一种x射线可显影分子、栓塞微球及其制备方法 |
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JP2022518586A (ja) * | 2019-03-22 | 2022-03-15 | バイオコンパティブルズ ユーケー リミテッド | 塞栓マイクロスフェア及び方法 |
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CA2996692A1 (en) | 2017-03-09 |
WO2017037276A8 (en) | 2018-03-29 |
EP3344234A1 (en) | 2018-07-11 |
HK1254237A1 (zh) | 2019-07-12 |
JP7033530B2 (ja) | 2022-03-10 |
AU2016316807A1 (en) | 2018-03-08 |
CA2996692C (en) | 2023-09-05 |
TW201718016A (zh) | 2017-06-01 |
WO2017037276A1 (en) | 2017-03-09 |
GB201515602D0 (en) | 2015-10-21 |
US20180250230A1 (en) | 2018-09-06 |
EP3344234B1 (en) | 2021-11-24 |
KR20180050319A (ko) | 2018-05-14 |
CN107949376A (zh) | 2018-04-20 |
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