JP6856620B2 - 薬剤搭載ナノ樹脂粒子 - Google Patents
薬剤搭載ナノ樹脂粒子 Download PDFInfo
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- JP6856620B2 JP6856620B2 JP2018504264A JP2018504264A JP6856620B2 JP 6856620 B2 JP6856620 B2 JP 6856620B2 JP 2018504264 A JP2018504264 A JP 2018504264A JP 2018504264 A JP2018504264 A JP 2018504264A JP 6856620 B2 JP6856620 B2 JP 6856620B2
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- YWIVKILSMZOHHF-QJZPQSOGSA-N sodium;(2s,3s,4s,5r,6r)-6-[(2s,3r,4r,5s,6r)-3-acetamido-2-[(2s,3s,4r,5r,6r)-6-[(2r,3r,4r,5s,6r)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2- Chemical compound [Na+].CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 YWIVKILSMZOHHF-QJZPQSOGSA-N 0.000 description 1
- ADWNFGORSPBALY-UHFFFAOYSA-M sodium;2-[dodecyl(methyl)amino]acetate Chemical compound [Na+].CCCCCCCCCCCCN(C)CC([O-])=O ADWNFGORSPBALY-UHFFFAOYSA-M 0.000 description 1
- 229940075554 sorbate Drugs 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 239000003549 soybean oil Substances 0.000 description 1
- 235000012424 soybean oil Nutrition 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 210000000952 spleen Anatomy 0.000 description 1
- 230000002269 spontaneous effect Effects 0.000 description 1
- 210000003802 sputum Anatomy 0.000 description 1
- 208000024794 sputum Diseases 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 238000010186 staining Methods 0.000 description 1
- 239000000021 stimulant Substances 0.000 description 1
- 239000012607 strong cation exchange resin Substances 0.000 description 1
- 239000006190 sub-lingual tablet Substances 0.000 description 1
- BAQAVOSOZGMPRM-QBMZZYIRSA-N sucralose Chemical compound O[C@@H]1[C@@H](O)[C@@H](Cl)[C@@H](CO)O[C@@H]1O[C@@]1(CCl)[C@@H](O)[C@H](O)[C@@H](CCl)O1 BAQAVOSOZGMPRM-QBMZZYIRSA-N 0.000 description 1
- 235000019408 sucralose Nutrition 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 229960002673 sulfacetamide Drugs 0.000 description 1
- SKIVFJLNDNKQPD-UHFFFAOYSA-N sulfacetamide Chemical compound CC(=O)NS(=O)(=O)C1=CC=C(N)C=C1 SKIVFJLNDNKQPD-UHFFFAOYSA-N 0.000 description 1
- 230000000475 sunscreen effect Effects 0.000 description 1
- 239000000516 sunscreening agent Substances 0.000 description 1
- 238000010557 suspension polymerization reaction Methods 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 230000001975 sympathomimetic effect Effects 0.000 description 1
- 229940064707 sympathomimetics Drugs 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 229960004458 tafluprost Drugs 0.000 description 1
- WSNODXPBBALQOF-VEJSHDCNSA-N tafluprost Chemical compound CC(C)OC(=O)CCC\C=C/C[C@H]1[C@@H](O)C[C@@H](O)[C@@H]1\C=C\C(F)(F)COC1=CC=CC=C1 WSNODXPBBALQOF-VEJSHDCNSA-N 0.000 description 1
- IWVCMVBTMGNXQD-UHFFFAOYSA-N terramycin dehydrate Natural products C1=CC=C2C(O)(C)C3C(O)C4C(N(C)C)C(O)=C(C(N)=O)C(=O)C4(O)C(O)=C3C(=O)C2=C1O IWVCMVBTMGNXQD-UHFFFAOYSA-N 0.000 description 1
- 210000000115 thoracic cavity Anatomy 0.000 description 1
- 229960004089 tigecycline Drugs 0.000 description 1
- 229940042585 tocopherol acetate Drugs 0.000 description 1
- 239000006208 topical dosage form Substances 0.000 description 1
- 229940042129 topical gel Drugs 0.000 description 1
- 229940100615 topical ointment Drugs 0.000 description 1
- 239000012049 topical pharmaceutical composition Substances 0.000 description 1
- 239000003204 tranquilizing agent Substances 0.000 description 1
- 230000002936 tranquilizing effect Effects 0.000 description 1
- 239000012780 transparent material Substances 0.000 description 1
- 229960002368 travoprost Drugs 0.000 description 1
- MKPLKVHSHYCHOC-AHTXBMBWSA-N travoprost Chemical compound CC(C)OC(=O)CCC\C=C/C[C@H]1[C@@H](O)C[C@@H](O)[C@@H]1\C=C\[C@@H](O)COC1=CC=CC(C(F)(F)F)=C1 MKPLKVHSHYCHOC-AHTXBMBWSA-N 0.000 description 1
- 229960002622 triacetin Drugs 0.000 description 1
- 150000003626 triacylglycerols Chemical class 0.000 description 1
- 239000000814 tuberculostatic agent Substances 0.000 description 1
- 238000002604 ultrasonography Methods 0.000 description 1
- 238000002562 urinalysis Methods 0.000 description 1
- 238000005353 urine analysis Methods 0.000 description 1
- 229940124549 vasodilator Drugs 0.000 description 1
- 239000003071 vasodilator agent Substances 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
- 230000009278 visceral effect Effects 0.000 description 1
- 239000004034 viscosity adjusting agent Substances 0.000 description 1
- 239000011709 vitamin E Substances 0.000 description 1
- 229940046009 vitamin E Drugs 0.000 description 1
- 235000019165 vitamin E Nutrition 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000002132 β-lactam antibiotic Substances 0.000 description 1
- 229940124586 β-lactam antibiotics Drugs 0.000 description 1
Images
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- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
- A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
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Description
i.イオン交換樹脂を洗浄し、かつ水性液体中で懸濁する工程、
ii.(i)の懸濁液を、粒子が、D90値が200ナノメートル〜900ナノメートルの間、およびD10値が50ナノメートル以上であることを特徴とする粒度分布を有するように、ある期間湿式粉砕に供する工程、
iii.(ii)の懸濁液を精製に供して不純物を除去する工程、
iv.精製した懸濁液を乾燥させてナノ樹脂粒子を乾燥粉末形態で得る工程
を含んでなる方法によって製造されたナノサイズ樹脂粒子を提供する。
i.イオン交換樹脂を洗浄し、かつ水性液体中で懸濁する工程、
ii.(i)の懸濁液を、粒子が、D90値が200ナノメートル〜900ナノメートルの間およびD10値が50ナノメートル以上であることを特徴とする粒度分布を有するように、ある期間湿式粉砕に供する工程、
iii.(ii)の懸濁液を精製に供して不純物を除去する工程、
iv.精製した懸濁液を乾燥させてナノ樹脂粒子を乾燥粉末形態で得る工程
を含んでなる方法に関する。
半固形の投薬形態は、クリーム、軟膏、ローション、エマルジョン、懸濁液、ペースト、塗布薬、ヒドロゲルまたはゲルのうちの1つでよい。
本発明による固形経口投薬形態は書籍、Remington: The Science and Practice of Pharmacy, 22nd Editionで言及されたものなどの経口投薬形態に好適な薬学的に許容可能な賦形剤を含んでなっていてもよい。これらには、制限することなく、希釈剤、崩壊剤、膨張性薬剤、バインダー、潤滑剤、流動促進剤、着色剤等が含まれる。
i.イオン交換樹脂を洗浄し、かつ水性液体中で懸濁する工程、
ii.(i)の懸濁液を、粒子が、D90値が200ナノメートル〜900ナノメートルの間、およびD10値が50ナノメートル以上であることを特徴とする粒度分布を有するように、ある期間湿式粉砕に供する工程、
iii.(ii)の懸濁液を精製に供して許容可能な限度内での不純物を達成する工程、
iv.精製した懸濁液を乾燥させてナノ樹脂粒子を、15%以下の水分含量の乾燥粉末形態で得る工程
を含んでなる方法であって、水抽出性不純物は樹脂の1重量%以下であり、有機不純物は3ppm以下である方法によって製造されたナノ樹脂粒子を提供する。
i.イオン交換樹脂を洗浄し、かつ水性液体中で懸濁する工程、
ii.(i)の懸濁液を、粒子が、D90値が200ナノメートル〜900ナノメートルの間およびD10値が50ナノメートル以上であることを特徴とする粒度分布を有するように、ある期間湿式粉砕に供する工程、
iii.(ii)の懸濁液を精製に供して水抽出性不純物および有機不純物を除去する工程、
iv.精製した懸濁液を乾燥させてナノ樹脂粒子を乾燥粉末形態で得る工程
を含んでなる方法によって製造される。
(a)工程(i)の樹脂を、ビーズ径が0.5mm〜1.25mmの範囲である製粉媒体を使用して粉砕する工程、および
(b)亜工程(a)の樹脂を、ビーズ径が0.1mm〜0.4mmの範囲である製粉媒体を使用して粉砕する工程。
一つの実施態様では、粉砕媒体のビーズ径は、およそ0.1mmから0.4mmの範囲、例えば、0.2または0.3mmである。
i.イオン交換樹脂を洗浄し、かつ水性液体中で懸濁する工程、
ii.(i)の懸濁液を、粒子が、D90値が200ナノメートル〜900ナノメートルの間およびD10値が50ナノメートル以上であることを特徴とする粒度分布を有するように、ある期間湿式粉砕に供する工程であって、当該湿式粉砕が、(a)工程(i)の樹脂を、ビーズ径が0.5mm〜1.25mmの範囲である製粉媒体を使用して粉砕する亜工程、および(b)亜工程(a)の樹脂を、ビーズ径が0.1mm〜0.4mmの範囲である製粉媒体を使用して粉砕する亜工程を含んでなる2つの亜工程で行われる、工程、
iii.(ii)の懸濁液を、孔径分画分子量が200kD〜750である限外濾過膜を使用して透析濾過に供して水抽出性不純物および有機不純物を除去する工程、
iv.(iii)の懸濁液を凍結乾燥させて自由流動性ナノ樹脂粒子を乾燥粉末形態で得る工程
を含んでなる方法によって製造される。
ナノ樹脂の調製:本発明によるナノ樹脂の調製方法は、イオン交換樹脂を洗浄する工程、好ましくは2つの異なるサイズの製粉媒体を使用した、洗浄樹脂を湿式粉砕する工程、続けて透析濾過する工程を含んでなる。本発明の一つの実施態様によれば、ナノ樹脂は下記の方法によって調製した。
生物学的反応性試験:実施例1により調製したナノ樹脂をin−vivoおよびin−vitroの生物学的反応性試験に供して生物学的反応性を決定した。下記の通りその試験を記載する。
1.in−vivo生物学的反応性:粉砕樹脂抽出物のin−vivo生物学的反応性をニュージーランドホワイトラビットの皮内試験によって評価した。USP<88>生物学的反応性in−vivoに言及されている手順の通り、AmberliteIRP 69の抽出を、0.9%塩化ナトリウム溶液中アルコール溶液20個で、1回で行った。生物学的反応性研究により、粉砕ナノ樹脂抽出物がUSP「皮内検査」に適合していたことが観察された。
2.in vitro生物学的反応性:粉砕樹脂抽出物のin vitro生物学的反応性を、NCTCクローン929(L細胞;L−929)ATCCでアガロース拡散アッセイによって評価した。粉砕樹脂抽出物に続き、哺乳動物細胞培養の生物学的反応性は観察されなかった。
本実施例は、ナノ樹脂粒子に抗緑内障薬ブリモニジンが載せられ、薬剤搭載薬ナノ樹脂粒子が眼科的使用に好適な水性懸濁液投与形態に製剤化された、本発明の特定の実施態様を提供する。
実施例3に記載の懸濁投薬形態の薬剤搭載ナノ樹脂粒子は、可逆的クラスターを形成した。本実施例では、せん断力(眼の瞬きによるせん断力など)に供した際に個々の薬剤搭載ナノ樹脂粒子に分解する、実施例3で懸濁したこれら薬剤搭載ナノ樹脂粒子の可逆的クラスターへのせん断力の効果を実証した。この効果は、最初の粒度分布およびせん断力を加えた粒度分布に関して測定した。
本実施例は、本発明の一つの実施態様によって調製した水性懸濁液投薬形態の安全性試験を提供する。(実施例3の)水性懸濁液投薬形態は、14日間連続して懸濁液製剤を毎日の眼内投与することによって安全試験に供した。以下の試験計画書に従った。
ニュージーランドホワイトラビット20個体;(雄10個体および雌10個体)を、体重に基づき、ランダムに以下の5つの研究グループに分けた。各グループには両性別の動物2個体が含まれていた。所望の容量を眼内注入により投与した。
G1(生理食塩水{対照}(360μL/動物/日))、1眼/1回当たり30μL×1日6回
G2(プラセボ(360μL/動物/日))、1眼/1回当たり30μL×1日6回
G3(低用量{試験}(60μL/動物/日))、1眼/1回当たり30μL×1日1回
G4(中用量{試験}(180μL/動物/日)); 1眼/1回当たり30μL×1日3回
G5(高用量{試験}(360μL/動物/日)); 1眼/1回当たり30μL×1日6回
G3、G4およびG5試験=本発明の0.35%のw/v酒石酸ブリモニジン水性懸濁液(実施例3)
ニュージーランドホワイトラビットに30日連続して毎日複数回注入した後に、実施例3の懸濁液の長期的な安全プロファイルを評価した。特に、血行力学パラメーターを評価した。このために、研究設計は次の通りであった:グループ1は1眼当たり30μLを1日6回(n=6)受け取り、グループ2は実施例3の懸濁液を1眼/1回当たり30μLを1日6回(n=6)受け取った。
本実施例は、本発明の一つの実施態様による、ドキシサイクリンの懸濁液製剤を提供する。
本実施例は、本発明の一つの実施態様によるマレイン酸アセナピンの懸濁液製剤を提供する。
本実施例は、本発明の一つの実施態様によるブロムフェナクナトリウムの水性懸濁液製剤を提供する。
本発明の一つの実施態様によれば、本実施は、アセナピンナノ樹脂複合体を有するマレイン酸アセナピンの懸濁液製剤を提供し、この懸濁液製剤は経口送達用のタブレット投薬形態に製剤化した。
本実施例は、アミトリプチリンナノ樹脂複合体を含んでなる懸濁液製剤を提供し、この懸濁液製剤はその後、局所的投薬形態(即ち、ゲル)に製剤化した。
実施例13〜14は、メトトレキセートおよびミノサイクリンの局所軟膏製剤を提供する。
Claims (7)
- 疾患の治療用の医薬組成物であって、D90値が200ナノメートル〜900ナノメートルの間およびD10値が50ナノメートル以上であることを特徴とする粒度分布を有する薬剤搭載ナノ樹脂粒子を含んでなり、前記ナノ樹脂粒子が、樹脂全体の1重量%以下の水抽出性不純物を含有し、かつ前記ナノ樹脂粒子が、HPLC技術によって分析された3ppm以下の全有機不純物を含有する、組成物。
- 前記粒度分布が、D50値が75ナノメートル〜300ナノメートルの間であることを特徴とする、請求項1に記載の組成物。
- 前記ナノ樹脂粒子が、カチオン交換樹脂またはアニオン交換樹脂から選択されるイオン交換樹脂である、請求項1または2に記載の組成物。
- 前記組成物が、水性懸濁液投薬形態であり、懸濁化剤および水性ビヒクルをさらに含んでなる、請求項1〜3のいずれか一項に記載の組成物。
- 前記組成物が、半固形投薬形態であり、水性または非水性ビヒクルをさらに含んでなる、請求項1〜3のいずれか一項に記載の組成物。
- 前記半固形投薬形態が、クリーム、軟膏、ローション、エマルジョン、懸濁液またはゲルである、請求項5に記載の組成物。
- 前記薬剤が経皮又は経口又は舌下の投与経路を介して送達される、請求項1〜6のいずれか一項に記載の組成物。
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FR3108841B1 (fr) * | 2020-04-06 | 2023-11-03 | Algotherapeutix | Composition pharmaceutique topique sous forme de gel aqueux comprenant au moins de l’amitriptyline |
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US20230330100A1 (en) * | 2022-02-17 | 2023-10-19 | Woolsey Pharmaceuticals, Inc. | Taste-masking oral formulations of fasudil |
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US7001615B1 (en) * | 2001-12-07 | 2006-02-21 | Alcon, Inc. | Sustained release ophthalmic, otic and nasal suspension |
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CA2733017A1 (en) | 2008-08-05 | 2010-02-11 | Mannkind Corporation | Improved powder dispenser modules and powder dispenser assemblies |
US9095506B2 (en) * | 2008-11-17 | 2015-08-04 | Allergan, Inc. | Biodegradable alpha-2 agonist polymeric implants and therapeutic uses thereof |
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US20130230587A1 (en) | 2010-11-10 | 2013-09-05 | Rubicon Research Private Limited | Sustained release compositions |
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WO2016016908A1 (en) * | 2014-07-28 | 2016-02-04 | Sun Pharma Advanced Research Company Limited | Method of increasing bioavailability and/or prolonging ophthalmic action of a drug |
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US11559487B2 (en) | 2023-01-24 |
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