JP5253159B2 - 熱応答性バイオポリマーに基づく直接的ドラッグデリバリーシステム - Google Patents
熱応答性バイオポリマーに基づく直接的ドラッグデリバリーシステム Download PDFInfo
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Description
本出願は、2005年6月24日に出願された米国特許仮出願第60/693,966号の利益を主張し、その開示は全体として参照することにより本明細書の一部をなすものとする。
エラスチン様ポリペプチド(ELP)は遺伝子組換えバイオポリマーであり、上記に規定したペンタペプチド繰り返しユニットで構成されており、温度の上昇に応答して凝集する。ELPは、転移温度(Tt)未満の温度では可溶性であるが、Ttを超える温度では不溶性になり、ミクロンサイズの凝集体を形成する。本発明者らは、本明細書において、この薬物担体に付着したタンパク質薬が注射時点で凝集して注射部位で薬剤「デポー」を形成し、その後持続的に関節腔内へ緩徐に解離することを開示する(例えば、図1を参照されたい)。これらの実施例において、本発明者らはTtを超える温度でのELPのインビトロにおける解離、ならびに関節内注射後の凝集性ELP(Tt<30℃)および非凝集性ELP(Tt>50℃)のインビボ生体内分布および関節半減期を評価する。さらに、本発明者らはELP融合タンパク質薬物担体システムについて実証するために、ELPおよびIL1Raの融合タンパク質を設計し、それらのIL−1受容体への結合親和性およびIL−1を阻害する生物活性を評価する。
変形性関節症などの局所性疾患を治療するために提案されたデリバリーシステムの機能検証として、エラスチン様ポリペプチド(ELP)もしくはバイオエラスティックポリマーを、凝集体形態から「遊離」ポリマーの徐放を提供する能力について評価した。ドラッグデリバリーシステムは、速やかに熱による誘導で凝集して大きな粒子を形成し、その後にバルク凝集した大きな粒子から「遊離」形態と呼ばれるELPの徐放が行われるという固有のELP特性を利用している。これを評価するために、遺伝子組換え技術を利用して2つのELP分子:(1)ELP4〜90=[(VPGVG)10]9(配列番号1)、Tt=30.6℃、MW=37kDa;および(2)ELP4〜120=[(VPGVG)10]12(配列番号2)、Tt=28.6℃、MW=49kDaを、既知の技術(Urryへの米国特許第6,699,294号およびChilkotiへの米国特許第6,852,834号を参照されたい)にしたがって合成し、熱的に精製した。インビトロ試験のために、1.5mLの濃度30mg/mLのいずれかのELPを円錐管内に入れて、37℃で24時間インキュベートした。この時間の終了時に、上清を37℃のPBSと完全に交換し、上清中のELPの量を280nmでの吸光度によって出発ELP(図2、t=0時間)の関数として定量した。サンプルを37℃へ戻し、遊離ELPの量を経時的に7μLアリコートの上清で定量した。平衡の時間定数は、遊離ELP濃度についてのデータを一次指数関数へ数値的にフィッティングすることによって決定した。
凝集性ELP4−120([(VPGVG)10]12、配列番号2、Tt<32℃、MW 47kDa)および非凝集性ELP2([(VPGVG)1(VPGAG)8(VPGGG)7]10、配列番号18、MW 61kDa、Tt>50℃)の生体内分布および関節半減期。関節内注射後のELPをラット動物モデルにおいて評価した。ELPは、32〜37mCi/mmoleの比放射能を生じさせるように[14C]を用いて標識した。標識したELPを透析し、無菌濾過し(0.22μmフィルター)、約650μMのいずれかのペプチドを容量30μLでWistar系ラットの右膝の関節腔内へ注射した。注射後、動物をケージ内で4週間まで飼育した。各時点において5匹のラットを致死させ、それらの右および左膝(滑液、半月、軟骨、滑膜)、血液、心臓、肺、肝臓、脾臓、腎臓、および膀胱を採取し、消化した。各組織の放射能は、液体βシンチレーション計数を用いて決定した。組織重量当たりの総計数を各動物および各組織もしくは体液(1群当たりおよび1時点当たりn=5の動物)について測定し、各組織について時間の関数としてプロットした。関節組織および関節液についての数値を総計「関節」値(滑液、半月、関節軟骨、滑膜)に合計した。
図6は、本発明の方法および組成物による捕捉を実証している。図6は、インビトロでELPと混合した後に溶液へ放出された放射標識化合物の定量の結果を示している。2.5μg/mLでの[3H]rhIL1Raを、37℃で濃度の相違する様々なELP調製物(ELP4−120[(VPGVG)10]12、配列番号2、およびELP5[(VPGVG)6(VPGKG)]16、配列番号19)と混合した。ELP溶液は、200μLの全反応液量で0mg/mL(コントロール)、20mg/mL、および50mg/mLの濃度で調製した。ELP−IL1Ra混合物は、凝集体に複合体化することが観察された。上清のアリコート(5μL)を上清中のrhIL1Ra濃度の尺度として、経時的にシンチレーション計数によって[3H]についてアッセイした。測定結果は、溶液中のrhIL1Ra遊離率%=(サンプルのCPM/コントロールのCPM)×100を決定するためにコントロール(0mg/mL)に対して標準化した。データは、捕捉後24時間以内は安定性である。ここで示されるデータは平衡化の96時間後のものである。結果は、ELPが混合後にこの化合物の25〜55%まで取り込まれ得ることを示している。
このドラッグデリバリーシステムの機能検証試験では、ELPおよびIL1Raの2つの凝集性融合タンパク質を以下のように遺伝子組換えにより合成した。ヒトIL1Raの遺伝子は、Carter et al.(1990)Nature 344:633−8によって以前に記載されたように、LPS活性化U937細胞からPCRクローニングした。2つのELP調製物は、Chilkotiへの米国特許第6,852,834号によって記載されたように合成した:ELP1[(VPGVG)5(VPGGG)3(VPGAG)2]9、(配列番号20)、MW 36kDa、およびELP4[(VPGVG)10]3、(配列番号21)、MW 14.5kDa。各ELP遺伝子は、次に30.2kDaおよび53kDaの分子量をもつ2つのELP−IL1Ra融合タンパク質(表1〜2を参照)を生成するために、伝統的な分子生物学技術を用いてIL1Raを含むベクター(pET−25b+)にサブクローニングした。融合タンパク質は次に大腸菌(E.coli)内で発現させ、公知の技術であるUrryへの米国特許第6,699,294号およびChilkotiへの米国特許第6,852,834号に従って熱的に精製した。融合タンパク質のサイズおよび純度は、SDS−PAGEによって試験して、図7Aに示した。ここで使用した熱的な精製法は、95%を超える純度の、細菌増殖1リットル当たり50mgより多い融合タンパク質を産生した。
代表的な融合タンパク質(ELP4−IL1Ra)の生物活性を、以前に記載されたように、Con A−刺激マウスC57初代胸腺細胞のIL−1β増強の増大を阻害する能力について試験した。簡単には、初代胸腺細胞は新たに致死させた5〜7週齢のC57マウスから機械的に単離して、5% FCS、1μg/mL ConA(Sigma社)および1ng/mLのrmIL−1β(Pierce)が添加されたRPMI 1640中に約2×106cells/200μLの密度で懸濁させた。これらの細胞を48時間にわたり市販のrhIL1Ra(R&D Systems社)もしくはELP4−IL1Ra融合タンパク質(上述したように)いずれかの連続希釈液の存在下でインキュベートした。胸腺細胞の増殖を[3H]−チミジン(0.5μCi/ウエル)の取込みによって評価した。データは、6個の同型培養の[3H]−チミジン取込みの平均CPM±SDとして表示した。50%阻害(IC50)を引き起こす最高濃度は、データをシグモイド関数にフィッティングすることによって決定した。ELP4−IL1Ra融合タンパク質は、52pMのrmIL−1βを阻害する61.4±19.8nMのIC50を備える有意な生物活性を示した。図8を参照されたい。
本発明の組成物を投与する実施例は、図9に提供されている。凝集性ELP(黒棒)および非凝集性ELP(斜線棒)の腫瘍内における注射用量の百分率(%ID)が示されている。両方のタイプのELPをヌードマウス(Balb/c nu/nu)の脚のヒト扁平上皮癌(FaDu)腫瘍内へ注入した(4μL/分)。データは平均値±SEMであり、n=1〜9である。非凝集性ELPと比較して、凝集性ELPの用量の方がはるかに多いことに留意されたい。
Claims (24)
- 被験対象における選択された領域に治療用タンパク質を送達するための組成物であって、前記組成物が、前記治療用タンパク質と、前記被験対象の体温において逆温度相転移をするポリマーとを含む組換え融合体を含み、前記組成物が溶液相中で前記選択された領域に注射されると、結果として前記選択された領域内で前記組換え融合体が凝集し、その後徐々に凝集体から解離し、前記選択された領域での前記治療用タンパク質の徐放を提供する組成物。
- 前記注射が、針、シリンジ、シャント、又はカニューレによって実施される、請求項1に記載の組成物。
- 前記注射が、7〜33ゲージの針又はシリンジによって実施される、請求項1に記載の組成物。
- 前記治療用タンパク質が、抗炎症性タンパク質である、請求項1に記載の組成物。
- 前記選択された領域が、関節、滑膜性関節、又は関節腔である、請求項4に記載の組成物。
- 前記被験対象が、変形性関節疾患を有する、請求項5に記載の組成物。
- 前記被験対象が、変形性関節症に罹患している、請求項6に記載の組成物。
- 前記被験対象が、可動関節障害および/または椎間板病変に罹患している、請求項5に記載の組成物。
- 前記選択された領域が椎間板腔である、請求項8に記載の組成物。
- 前記組成物が、関節内注射によって注射される、請求項5に記載の組成物。
- 前記注射が、1カ月に1〜4回の頻度で繰り返される、請求項1に記載の組成物。
- 前記抗炎症性タンパク質が、抗体である、請求項4に記載の組成物。
- 前記抗体が、抗原に結合する抗体フラグメントである、請求項12に記載の組成物。
- 前記抗炎症性タンパク質が、TNFブロッキング抗体、IL−1抗体、可溶性TNF受容体、可溶性IL−1受容体、TNF受容体アンタゴニスト、およびIL−1受容体アンタゴニストから選択される、請求項4に記載の組成物。
- 前記抗炎症性タンパク質が、ヒトIL−1受容体アンタゴニストである、請求項4に記載の組成物。
- 前記ポリマーが、ペンタペプチド、テトラペプチド、および/またはノナペプチドのエラストマーユニットを含むバイオエラスティックポリマーである、請求項1に記載の組成物。
- 前記ポリマーが、VPGXGのユニット(式中、各々のXは独立してプロリン以外のアミノ酸である)を含む、請求項16に記載の組成物。
- 前記各々のXが、独立してV、A、G、L、またはFである、請求項17に記載の組成物。
- 前記ポリマーが、配列番号4〜17の1つ以上によって定義されるエラストマーユニットを含む、請求項1に記載の組成物。
- 前記ポリマーが、[(VPGXG) n ] m (式中、Xは独立してプロリン以外のアミノ酸であり、nは20以下であり、mは60以下である)によって定義される少なくとも1つのブロック構造を含む、請求項19に記載の組成物。
- 前記ポリマーが、ブロック構造の繰り返しを9個含む、請求項19に記載の組成物。
- 前記ポリマーが、少なくとも80個のエラストマーユニットを含む、請求項1に記載の組成物。
- 前記被験対象がヒトである、請求項1に記載の組成物。
- 前記ヒトが関節炎を有する、請求項23に記載の組成物。
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PCT/US2006/024427 WO2007002362A2 (en) | 2005-06-24 | 2006-06-21 | A direct drug delivery system based on thermally responsive biopolymers |
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Families Citing this family (35)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20130172274A1 (en) | 2005-12-20 | 2013-07-04 | Duke University | Methods and compositions for delivering active agents with enhanced pharmacological properties |
US8841255B2 (en) | 2005-12-20 | 2014-09-23 | Duke University | Therapeutic agents comprising fusions of vasoactive intestinal peptide and elastic peptides |
WO2007073486A2 (en) * | 2005-12-20 | 2007-06-28 | Duke University | Methods and compositions for delivering active agents with enhanced pharmacological properties |
US7709227B2 (en) * | 2006-01-04 | 2010-05-04 | Phasebio Pharmaceuticals, Inc. | Multimeric ELP fusion constructs |
US20090202645A1 (en) * | 2008-02-08 | 2009-08-13 | Acme Drugs S.R.L. | Intrasynovial formulations of stanozolol |
CA2953975C (en) * | 2008-06-27 | 2019-11-26 | Duke University | Therapeutic agents comprising elastin-like peptides |
CN102215901B (zh) * | 2008-11-07 | 2014-12-03 | 联合生物医学系统有限公司 | 用于治疗和/或预防疾病的装置和方法 |
KR101943420B1 (ko) | 2009-08-14 | 2019-04-17 | 파세비오 파마수티컬스 인코포레이티드 | 변형된 혈관활성 장 펩티드 |
AU2011323508B2 (en) | 2010-11-01 | 2017-04-27 | Peptimed, Inc. | Compositions of a peptide targeting system for treating cancer |
US9561262B2 (en) | 2011-06-06 | 2017-02-07 | Phasebio Pharmaceuticals, Inc. | Use of modified vasoactive intestinal peptides in the treatment of hypertension |
WO2013028989A1 (en) * | 2011-08-24 | 2013-02-28 | Phasebio Pharmaceuticals, Inc. | Formulations of active agents for sustained release |
JP6157877B2 (ja) * | 2012-02-28 | 2017-07-05 | 三洋化成工業株式会社 | 組織再生用ゲル、組織再生用タンパク質溶液及び組織再生用ゲルの製造方法 |
EP2668962B1 (en) * | 2012-05-29 | 2016-10-26 | Albert-Ludwigs-Universität Freiburg | Protein assembler |
CA2947982C (en) | 2014-05-08 | 2022-11-29 | Phasebio Pharmaceuticals, Inc. | Methods and compositions for treating cystic fibrosis |
EP3220936A4 (en) | 2014-11-21 | 2018-08-22 | Phasebio Pharmaceuticals, Inc. | Elp fusion proteins for controlled and sustained release |
US9932443B2 (en) * | 2014-12-05 | 2018-04-03 | University Of South Florida | Peptide-based materials |
AU2016219513B2 (en) | 2015-02-09 | 2021-09-30 | Immunoforge Co., Ltd. | Methods and compositions for treating muscle disease and disorders |
JP6882782B2 (ja) | 2015-08-04 | 2021-06-02 | デューク ユニバーシティ | 遺伝子コードされた本質的に無秩序な送達用ステルスポリマーおよびその使用方法 |
EP3373954A4 (en) * | 2015-11-10 | 2019-07-03 | Proteothera, Inc. | PROCESS FOR PREPARING AND CLEANING MATRIX-BINDING FUSION PROTEINS BY ION EXCHANGE CHROMATOGRAPHY |
US11752213B2 (en) | 2015-12-21 | 2023-09-12 | Duke University | Surfaces having reduced non-specific binding and antigenicity |
MX2018013546A (es) | 2016-05-06 | 2019-04-22 | Phasebio Pharmaceuticals Inc | Proteinas de fusion de elp para liberacion controlada y sostenida. |
US11467156B2 (en) | 2016-06-01 | 2022-10-11 | Duke University | Nonfouling biosensors |
CN109890833A (zh) | 2016-09-14 | 2019-06-14 | 杜克大学 | 用于递送亲水性药物的基于三嵌段多肽的纳米粒子 |
KR20190064600A (ko) | 2016-09-23 | 2019-06-10 | 듀크 유니버시티 | Lcst 거동을 갖는 비구조화된 비-반복적 폴리펩티드 |
US11648200B2 (en) | 2017-01-12 | 2023-05-16 | Duke University | Genetically encoded lipid-polypeptide hybrid biomaterials that exhibit temperature triggered hierarchical self-assembly |
WO2018213320A1 (en) | 2017-05-15 | 2018-11-22 | Duke University | Recombinant production of hybrid lipid-biopolymer materials that self-assemble and encapsulate agents |
WO2019006374A1 (en) | 2017-06-30 | 2019-01-03 | Duke University | ORDER AND DISORDER AS A DESIGN PRINCIPLE FOR STIMULI-SENSITIVE BIOPOLYMER NETWORKS |
EP3829622A4 (en) | 2018-08-02 | 2022-05-11 | Duke University | DUAL AGONIST FUSION PROTEINS |
WO2020048996A1 (en) | 2018-09-06 | 2020-03-12 | ETH Zürich | Self-assembling globular proteins and uses thereof |
KR102173702B1 (ko) * | 2018-11-27 | 2020-11-03 | 가톨릭대학교 산학협력단 | 피부 세포 표적용 펩타이드 및 이의 용도 |
US11512314B2 (en) | 2019-07-12 | 2022-11-29 | Duke University | Amphiphilic polynucleotides |
CN112521514A (zh) * | 2020-12-21 | 2021-03-19 | 清华大学 | 一种蛋白复合物及其制备方法和应用 |
CN113350563B (zh) * | 2021-03-01 | 2022-09-06 | 清华大学 | 一种组织粘合剂及其制备方法和应用 |
CN114470155A (zh) * | 2022-01-29 | 2022-05-13 | 清华大学 | 新冠病毒重组蛋白复合物药物及其制备方法与应用 |
CN117777303A (zh) * | 2022-09-27 | 2024-03-29 | 北京大学 | 一种高亲和力pd1蛋白偶联物及其应用 |
Family Cites Families (42)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6699A (en) | 1849-09-04 | Improvement in street-sweeping machines | ||
US294A (en) | 1837-07-22 | Improvement in modes of constructing and connecting together the cars or carriages | ||
US4132746A (en) | 1976-07-09 | 1979-01-02 | University Of Alabama, Birmingham Medical & Education Foundation | Synthetic elastomeric insoluble cross-linked polypentapeptide |
US4187852A (en) | 1976-07-09 | 1980-02-12 | The University Of Alabama | Synthetic elastomeric insoluble cross-linked polypentapeptide |
US4474851A (en) | 1981-10-02 | 1984-10-02 | The University Of Alabama In Birmingham | Elastomeric composite material comprising a polypeptide |
US4500700A (en) | 1981-10-02 | 1985-02-19 | The Board Of Trustees Of The University Of Alabama For The University Of Alabama In Birmingham | Elastomeric composite material comprising a polypentapeptide having an amino acid of opposite chirality in position three |
US4589882A (en) | 1983-09-19 | 1986-05-20 | Urry Dan W | Enzymatically crosslinked bioelastomers |
US4870055A (en) | 1986-04-17 | 1989-09-26 | University Of Alabama At Birmingham | Segmented polypeptide bioelastomers to modulate elastic modulus |
US5514581A (en) * | 1986-11-04 | 1996-05-07 | Protein Polymer Technologies, Inc. | Functional recombinantly prepared synthetic protein polymer |
US6184348B1 (en) * | 1986-11-04 | 2001-02-06 | Protein Polymer Technologies | Functional recombinantly prepared synthetic protein polymer |
US4787852A (en) * | 1987-04-24 | 1988-11-29 | Melnick David W | Multicolor interactive notepad |
US5075222A (en) | 1988-05-27 | 1991-12-24 | Synergen, Inc. | Interleukin-1 inhibitors |
ATE114458T1 (de) | 1990-03-27 | 1994-12-15 | Bioelastics Res Ltd | Bioelastomeres arzneimittelabgabesystem. |
US5595732A (en) * | 1991-03-25 | 1997-01-21 | Hoffmann-La Roche Inc. | Polyethylene-protein conjugates |
US5393602A (en) | 1991-04-19 | 1995-02-28 | Bioelastics Research Ltd. | Superabsorbent materials and uses thereof |
CA2166692C (en) | 1993-07-23 | 1999-01-26 | David R. Borcherding | Novel 9-n-bicyclic nucleoside agents useful as selective inhibitors of proinflammatory cytokines |
IL112834A (en) * | 1995-03-01 | 2000-12-06 | Yeda Res & Dev | Pharmaceutical compositions for controlled release of soluble receptors |
US6004782A (en) * | 1995-04-14 | 1999-12-21 | Bioelastics Research Ltd. | Hyperexpression of bioelastic polypeptides |
JPH11503752A (ja) * | 1995-04-20 | 1999-03-30 | ザ ケネディー インスティチュート オブ リューマトロジー | 抗tnf抗体の複数回投与 |
RU2270030C2 (ru) * | 1996-02-09 | 2006-02-20 | Абботт Байотекнолоджи эЛтиди. | СПОСОБ ИНГИБИРОВАНИЯ АКТИВНОСТИ ЧЕЛОВЕЧЕСКОГО TNFα (ВАРИАНТЫ), ПРИМЕНЕНИЕ ВЫДЕЛЕННОГО АНТИТЕЛА ЧЕЛОВЕКА ИЛИ ЕГО АНТИГЕНСВЯЗЫВАЮЩЕГО ФРАГМЕНТА В КАЧЕСТВЕ КОМПОНЕНТА ДЛЯ ПРОИЗВОДСТВА ЛЕКАРСТВЕННОГО СРЕДСТВА (ВАРИАНТЫ) И ВЫДЕЛЕННОЕ ЧЕЛОВЕЧЕСКОЕ АНТИТЕЛО ИЛИ ЕГО АНТИГЕНСВЯЗЫВАЮЩИЙ ФРАГМЕНТ |
KR20040010739A (ko) * | 1996-02-09 | 2004-01-31 | 암젠 인코포레이티드 | 인터루킨-1 수용체 길항물질을 포함하는 융합 단백질 및 이를 포함하는 제약학적 조성물 |
US5972880A (en) * | 1996-03-07 | 1999-10-26 | Arthro Lab Inc. | Method of treatment of osteoarthritis with interleuken-1 receptor antagonist |
US6063061A (en) | 1996-08-27 | 2000-05-16 | Fusion Medical Technologies, Inc. | Fragmented polymeric compositions and methods for their use |
EP1056413A4 (en) * | 1998-02-27 | 2003-08-20 | Bioelastics Res Ltd | INJECTABLE IMPLANTS FOR TISSUE ENHANCEMENT AND RESTORATION |
DK1073847T3 (da) * | 1998-04-24 | 2003-07-14 | Ebara Corp | Halvaksial centrifugalpumpe |
US6541033B1 (en) * | 1998-06-30 | 2003-04-01 | Amgen Inc. | Thermosensitive biodegradable hydrogels for sustained delivery of leptin |
EP1127054A4 (en) | 1998-10-29 | 2006-11-02 | Bristol Myers Squibb Co | INHIBITORS OF IMPDH ENZYME |
AU3867400A (en) * | 1999-03-19 | 2000-10-09 | Duke University | Methods of using bioelastomers |
RU2312860C2 (ru) | 1999-04-15 | 2007-12-20 | Бристол-Маерс Сквибб Компани | Циклические ингибиторы протеинтирозинкиназ |
US6498165B1 (en) | 1999-06-30 | 2002-12-24 | Merck & Co., Inc. | Src kinase inhibitor compounds |
WO2001041735A2 (en) * | 1999-12-07 | 2001-06-14 | Amgen Inc. | Thermosensitive biodegradable hydrogels based on low molecular weight pluronics |
US6593394B1 (en) | 2000-01-03 | 2003-07-15 | Prosperous Kingdom Limited | Bioactive and osteoporotic bone cement |
US6852834B2 (en) | 2000-03-20 | 2005-02-08 | Ashutosh Chilkoti | Fusion peptides isolatable by phase transition |
WO2002000149A1 (en) | 2000-06-23 | 2002-01-03 | Drexel University | Polymeric, fiber matrix delivery systems for bioactive compounds |
ATE392898T1 (de) | 2000-10-26 | 2008-05-15 | Amgen Inc | Antiphlogistische mittel |
US6575986B2 (en) | 2001-02-26 | 2003-06-10 | Ethicon, Inc. | Scaffold fixation device for use in articular cartilage repair |
US20050075488A1 (en) * | 2001-07-26 | 2005-04-07 | Bright Stuart Willis | Interleukin-1 beta antibodies |
US6852926B2 (en) * | 2002-03-26 | 2005-02-08 | Intel Corporation | Packaging microelectromechanical structures |
US8226715B2 (en) | 2003-06-30 | 2012-07-24 | Depuy Mitek, Inc. | Scaffold for connective tissue repair |
US8361467B2 (en) * | 2003-07-30 | 2013-01-29 | Depuy Spine, Inc. | Trans-capsular administration of high specificity cytokine inhibitors into orthopedic joints |
WO2006078629A2 (en) * | 2005-01-18 | 2006-07-27 | Duke University | In-situ crosslinkable elastin-like polypeptides for defect filling in cartilaginous tissue repair |
WO2007073486A2 (en) * | 2005-12-20 | 2007-06-28 | Duke University | Methods and compositions for delivering active agents with enhanced pharmacological properties |
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2006
- 2006-06-21 EP EP20156624.7A patent/EP3725299A1/en active Pending
- 2006-06-21 EP EP13176325.2A patent/EP2664340B1/en active Active
- 2006-06-21 EP EP06785402A patent/EP1896072A4/en not_active Withdrawn
- 2006-06-21 CN CN2006800223535A patent/CN101500606B/zh active Active
- 2006-06-21 JP JP2008518416A patent/JP5253159B2/ja active Active
- 2006-06-21 CA CA2613355A patent/CA2613355C/en active Active
- 2006-06-21 KR KR1020087001872A patent/KR101446503B1/ko active IP Right Grant
- 2006-06-21 WO PCT/US2006/024427 patent/WO2007002362A2/en active Application Filing
- 2006-06-21 US US11/472,113 patent/US20070009602A1/en not_active Abandoned
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2011
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EP1896072A4 (en) | 2013-01-09 |
CA2613355A1 (en) | 2007-01-04 |
EP1896072A2 (en) | 2008-03-12 |
EP2664340B1 (en) | 2020-02-12 |
CN101500606B (zh) | 2013-12-04 |
WO2007002362A3 (en) | 2009-04-16 |
CA2613355C (en) | 2014-04-22 |
EP2664340A2 (en) | 2013-11-20 |
KR20080045118A (ko) | 2008-05-22 |
WO2007002362A2 (en) | 2007-01-04 |
US20070009602A1 (en) | 2007-01-11 |
US20140364371A1 (en) | 2014-12-11 |
JP2009501703A (ja) | 2009-01-22 |
EP3725299A1 (en) | 2020-10-21 |
KR101446503B1 (ko) | 2014-10-06 |
US20110236384A1 (en) | 2011-09-29 |
EP2664340A3 (en) | 2013-12-11 |
CN101500606A (zh) | 2009-08-05 |
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