JP2014014694A - 血管拡張薬を含有する持続放出性眼内インプラント - Google Patents
血管拡張薬を含有する持続放出性眼内インプラント Download PDFInfo
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- JP2014014694A JP2014014694A JP2013170156A JP2013170156A JP2014014694A JP 2014014694 A JP2014014694 A JP 2014014694A JP 2013170156 A JP2013170156 A JP 2013170156A JP 2013170156 A JP2013170156 A JP 2013170156A JP 2014014694 A JP2014014694 A JP 2014014694A
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Abstract
【解決手段】ムスカリン薬、エンドセリン受容体拮抗薬及びホスホジエステラーゼ−5阻害薬から成る群から選択される血管拡張薬、並びにポリラクチド、ポリグリコリド、ポリ(ラクチド−コ−グリコリド)及びポリカプロラクトンから成る群から選択される生分解性ポリマーを含んで成る硝子体内インプラント。
【選択図】なし
Description
特に、本発明は、(a)ムスカリン薬、エンドセリン受容体拮抗薬およびホスホジエステラーゼ−5阻害薬から成る群から選択される血管拡張薬、並びに(b)血管拡張薬と組み合わされた、ポリラクチド(PLA)、ポリグリコリド(PGA)、ポリ(ラクチド−コ−グリコリド)(PLGA)およびポリカプロラクトンから成る群から選択される生分解性ポリマーを含んで成る、眼内圧降下薬を摂取し、正常な眼内圧を有している緑内障患者の網膜血流を増加させるための押出硝子体内インプラントを提供する
本明細書において使用される以下の語句または用語は、以下に示す意味を有する。
ブドウ膜炎/網膜炎/脈絡膜炎: 急性多発性小板状色素上皮症、ベーチェット病、バードショット脈絡網膜症、感染症(梅毒、ライム病、結核症、トキソプラスマ症)、ブドウ膜炎(中間部ブドウ膜炎(扁平部炎)および前部ブドウ膜炎を含む)、多病巣性脈絡膜炎、多発消失性白点症候群(MEWDS)、眼サルコイドーシス、後強膜炎、ほ行性脈絡膜炎、網膜下線維症、ブドウ膜炎症候群、およびフォークト−小柳−原田症候群。
血管疾患/滲出性疾患: 網膜動脈閉塞症、網膜中心静脈閉塞症、播種性血管内凝固症、網膜分岐静脈閉塞症、高血圧性眼底変化、眼虚血症候群、網膜動脈毛細血管瘤、コーツ病、傍中心窩毛細管拡張症、半網膜静脈閉塞症、乳頭静脈炎、網膜中心動脈閉塞症、網膜分岐動脈閉塞症、頸動脈疾患(CAD)、霜状分岐血管炎、鎌状赤血球網膜症および他の異常ヘモグロビン症、網膜色素線条症、家族性滲出性硝子体網膜症、イールズ病。
外傷性/外科手術性: 交感性眼炎、ブドウ膜炎網膜疾患、網膜剥離、外傷、レーザー、PDT、光凝固術、手術中の低灌流、放射線網膜症、骨髄移植網膜症。
増殖性疾患: 増殖性硝子体網膜症および網膜上膜、増殖性糖尿病性網膜症。
感染性疾患: 眼ヒストプラスマ症、眼トキソカラ症、推定眼ヒストプラスマ症候群(POHS)、眼内炎、トキソプラスマ症、HIV感染関連網膜疾患、HIV感染関連脈絡膜疾患、HIV感染関連ブドウ膜炎疾患、ウイルス性網膜炎、急性網膜壊死、進行性網膜外層壊死、真菌性網膜疾患、眼梅毒、眼結核症、びまん性片側性亜急性神経網膜炎、およびハエウジ病。
遺伝病: 色素性網膜炎、関連網膜ジストロフィーを伴う全身疾患、先天性停在夜盲症、錐体ジストロフィー、シュタルガルト病および黄色斑眼底、ベスト病、網膜色素上皮のパターンジストロフィー、X連鎖網膜分離症、ソーズビー眼底ジストロフィー、両性同心性黄斑症、ビエッティ(Biett's)結晶状ジストロフィー、弾性線維性仮性黄色腫。
網膜断裂/円孔: 網膜剥離、黄斑円孔、巨大網膜断裂。
腫瘍: 腫瘍に関連した網膜疾患、先天性RPE肥大、後部ブドウ膜メラノーマ、脈絡膜血管腫、脈絡膜骨腫、脈絡膜転移、網膜および網膜色素上皮の複合(combined)過誤腫、網膜芽細胞腫、眼底の血管増殖性腫瘍、網膜星状細胞腫、眼内リンパ性腫瘍。
その他: 点状内脈絡膜症、急性後極部多発性小板状色素上皮症、近視性網膜変性、急性網膜色素上皮炎など。
血管作動薬、例えばエンドセリン受容体拮抗薬(例えばボセンタン)、ホスホジエステラーゼ−5阻害薬(例えばバルデナフィル)またはピロカルピンを使用することができる。血管作動薬およびポリ(ラクチド−コ−グリコリド)(PLGA)を計量し、ステンレススチール混合容器に入れることができる。容器を密閉し、Turbulaミキサー上に置き、所定の強度、例えば96rpmで、約15分間混合することができる。得られる粉末ブレンドを、一度に1単位用量で、1個取りタブレットプレスに装填することができる。プレスを事前設定した圧力(例えば25psi)および時間(例えば6秒)で作動させ、タブレットを形成し、室温でプレスから取り出すことができる。血管拡張薬/PLGAの比率は、全ての圧縮タブレットインプラントについて70/30にすることができる。タブレットインプラントを眼内インプラントとして使用して、緑内障のような眼症状を治療するために治療レベルでの血管作動薬の持続放出を与えることができる。
血管作動薬、例えばエンドセリン受容体拮抗薬(例えばボセンタン)、ホスホジエステラーゼ−5阻害薬(例えばバルデナフィル)またはピロカルピン、およびポリ(ラクチド−コ−グリコリド)(PLGA)を計量し、ステンレススチール混合容器に入れることができる。容器を密閉し、Turbulaミキサー上に置き、所定の強度(例えば96rpm)および時間(例えば10〜15分間)で混合することができる。PLGAは、親水性末端PLGA(Boehringer Ingelheim, Wallingford, CT)および疎水性末端PLGA(Boehringer Ingelheim, Wallingford, CT)の30/10 w/w混合物を含んで成ることができる。得られた粉末ブレンドをDACA Microcompounder-Extruder(DACA, Goleta, CA)に供給し、事前設定温度(例えば115℃)およびスクリュー速度(例えば12rpm)に付すことができる。フィラメントを案内装置に押出し、指定インプラント重量に対応する正確な長さにカットすることができる。血管拡張薬/全PLGA(親水性および疎水性末端)の比率は、全ての押出インプラントについて60/40 w/wにすることができる。押出インプラントを眼内インプラントとして使用して、緑内障のような眼症状を治療するために治療レベルでの血管作動薬の持続放出を与えることができる。
血管拡張活性剤および生分解性ポリマー組成物を、ステンレススチール乳鉢において合わすことによって、インプラントを製造する。合わせたものを、96rpmに設定したTurbula振とう機で15分間混合する。粉末ブレンドを乳鉢の側壁からこすり落とし、次に、さらに15分間再混合する。混合した粉末ブレンドを、所定温度で合計30分間にわたって、半溶融状態に加熱し、ポリマー/薬剤メルトを形成する。
20ゲージの微小硝子体網膜(MVR)ナイフを使用して、結膜および強膜を10〜12時の位置で切開することによって、インプラントをニュージーランド白ウサギの右目の後区に配置することができる。27ゲージ針を取り付けた1-cc注射器で、50〜100μLの硝子体液を除去することができる。実施例1、2または3の1つまたは複数のインプラントを前もって装填した滅菌トロカールを、強膜切開を通して5mm挿入し、次に、プッシュワイヤで所定の位置に引き込み、インプラントを後区に残す。次に、7-0Vicryl縫合糸を使用して強膜および結膜を閉じる。
両眼が緑内障に罹患した72才の女性に、血管作動薬およびPLAとPLGAの組合せを含有する眼内インプラントを、各眼に投与する。インプラントは、重さが約1mgであり、約500mgの血管作動薬、例えば、ボセンタン、バルデナフィルまたはピロカルピンを含有する。1つのインプラントを、注射器で各眼の硝子体に配置する。約2日後に、患者が、眼の不快感のかなりの軽減を報告する。実験は、眼内圧が減少したことを示し、8:00AMに測定した平均眼内圧は、28mmHgから14.3mmHgに減少した。患者を約6ヵ月間にわたって毎月モニターする。眼内圧レベルは6ヵ月間にわたって15mmHg未満に維持され、患者は眼の不快感の減少を報告する。
62才の男性が、緑内障による左眼の周辺視野減少を示す。400mgのピロカルピンおよび600mgのPLAを含有するインプラントを、米国特許出願第10/917909号または第11/021947号に示されているアプリケーターによって、左眼の硝子体に挿入する。レーザードップラー流速計(HRF)を使用して、網膜の上窩および下窩領域における血流を測定した。埋め込みから30日後に、網膜血流が10%〜30%増加し、患者の視力はさらに低下していない。
69才の男性が、両眼において緑内障による周辺視野減少を示す。400mgのピロカルピンおよび600mgのPLGAを含有するインプラントを、米国特許出願第10/917909号または第11/021947号に示されているアプリケーターによって、各眼の硝子体に挿入する。レーザードップラー流速計(HRF)を使用して、網膜の上窩および下窩領域における血流を測定した。埋め込みから30日後に、網膜血流が各眼において10%〜30%増加し、6ヵ月間にわたって患者は失った視野の50%を回復する。
51才の男性が、22〜24mmHgのIOP、緑内障の家族歴および初期視神経陥没損傷の所見を包含する緑内障危険因子を有するが、視野欠損は有さない。その患者に、両眼に硝子体内インプラントを投与する。インプラントは、400mgのピロカルピンおよび600mgのPLGAを含んで成り、米国特許出願第10/917909号または第11/021947号に示されているアプリケーターによって、各眼の硝子体に挿入される。レーザードップラー流速計(HRF)を使用して、網膜の上窩および下窩領域における血流を測定した。埋め込みから30日後に、網膜血流が10%〜30%増加しうる。患者を2年間にわたって追跡調査し、その間に、患者は視力低下およびさらなる視神経損傷を示さない。このような危険因子を有する患者は緑内障によるいくらかの視力低下を示すと考えられるので、これは統計的に有意である。
血管作動薬を使用して、網膜組織血流を増加させることによって緑内障のような網膜障害を治療しうることを示す実験を行った。即ち、正常網膜および緑内障網膜の遺伝子発現を比較するために、微小配列試験を行った。2つの正常対照群および4つの緑内障群を比較した。これらの6つの群のそれぞれは、6人の患者からのプールRNAを有していた。この試験は、2つの遺伝子ファミリーが緑内障患者群において一貫して変化していることを見出した。即ち、全てのヘモグロビンファミリー遺伝子が緑内障群において減少していたが、大部分のメタロチオネインIファミリー遺伝子は緑内障群において増加していた。データを表1および表2に示す。
Claims (11)
- (a) ムスカリン薬、エンドセリン受容体拮抗薬およびホスホジエステラーゼ−5阻害薬から成る群から選択される血管拡張薬、並びに
(b) 血管拡張薬と組み合わされた、ポリラクチド(PLA)、ポリグリコリド(PGA)、ポリ(ラクチド−コ−グリコリド)(PLGA)およびポリカプロラクトンから成る群から選択される生分解性ポリマー
を含んで成る、眼内圧降下薬を摂取し、正常な眼内圧を有している緑内障患者の網膜血流を増加させるための押出硝子体内インプラント。 - インプラントの硝子体内配置後に、インプラントが、治療有効量の血管拡張薬を7日から40日の間の期間にわたって放出することができる請求項1に記載のインプラント。
- 血管拡張薬がムスカリン薬である請求項1に記載のインプラント。
- ムスカリン薬がピロカルピンである請求項3に記載のインプラント。
- 血管拡張薬がエンドセリン受容体拮抗薬である請求項1に記載のインプラント。
- エンドセリン受容体拮抗薬がシタクスセンタンまたはボセンタンである請求項5に記載のインプラント。
- 血管拡張薬がホスホジエステラーゼ−5阻害薬である請求項1に記載のインプラント。
- ホスホジエステラーゼ−5阻害薬がバルデナフィル、シルデナフィルまたはタダラフィルである請求項7に記載のインプラント。
- インプラントの重量に対して10wt%〜90wt%、好ましくは20wt%〜80wt%の血管拡張薬を含む請求項1〜8のいずれかに記載のインプラント。
- ムスカリン薬、エンドセリン受容体拮抗薬およびホスホジエステラーゼ−5阻害薬から成る群から選択される血管拡張薬およびポリラクチド(PLA)、ポリグリコリド(PGA)、ポリ(ラクチド−コ−グリコリド)(PLGA)およびポリカプロラクトンから成る群から選択される生分解性ポリマーの混合物を押出す工程を含んで成り、それによって眼内圧降下薬を摂取し、正常な眼内圧を有している緑内障患者の網膜血流を増加させるのに適した硝子体内インプラントを形成し、該インプラントの生体内配置後にインプラントが治療有効量の血管拡張薬を7から40日の間の期間にわたって放出する、生分解性硝子体内インプラントの製造法。
- 生分解性ポリマーが、ポリラクチド、ポリ(ラクチド−コ−グリコリド)およびそれらの組合せから成る群から選択されるポリマーを含んで成る請求項3に記載の方法。
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Families Citing this family (27)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6726918B1 (en) | 2000-07-05 | 2004-04-27 | Oculex Pharmaceuticals, Inc. | Methods for treating inflammation-mediated conditions of the eye |
ES2250504T3 (es) | 2000-11-29 | 2006-04-16 | Allergan Inc. | Prevencion del rechazo de injerto en el ojo. |
US7431710B2 (en) | 2002-04-08 | 2008-10-07 | Glaukos Corporation | Ocular implants with anchors and methods thereof |
US20050048099A1 (en) | 2003-01-09 | 2005-03-03 | Allergan, Inc. | Ocular implant made by a double extrusion process |
US20050244469A1 (en) | 2004-04-30 | 2005-11-03 | Allergan, Inc. | Extended therapeutic effect ocular implant treatments |
US20070178138A1 (en) * | 2006-02-01 | 2007-08-02 | Allergan, Inc. | Biodegradable non-opthalmic implants and related methods |
WO2009061988A1 (en) | 2007-11-08 | 2009-05-14 | Alimera Sciences, Inc. | Ocular implantation device |
DE102008040786A1 (de) * | 2008-07-28 | 2010-02-04 | Biotronik Vi Patent Ag | Biokorrodierbares Implantat mit einer Beschichtung enthaltend eine wirkstofftragende Polymermatrix |
US20100204325A1 (en) * | 2009-02-11 | 2010-08-12 | Allergan, Inc. | Valproic acid drug delivery systems and intraocular therapeutic uses thereof |
US10206813B2 (en) | 2009-05-18 | 2019-02-19 | Dose Medical Corporation | Implants with controlled drug delivery features and methods of using same |
US8529492B2 (en) | 2009-12-23 | 2013-09-10 | Trascend Medical, Inc. | Drug delivery devices and methods |
WO2011146483A1 (en) | 2010-05-17 | 2011-11-24 | Aerie Pharmaceuticals, Inc. | Drug delivery devices for delivery of ocular therapeutic agents |
WO2012149278A1 (en) * | 2011-04-29 | 2012-11-01 | Allergan, Inc. | Sustained release latanoprost implant |
US10245178B1 (en) | 2011-06-07 | 2019-04-02 | Glaukos Corporation | Anterior chamber drug-eluting ocular implant |
US8883189B2 (en) | 2011-09-27 | 2014-11-11 | The Regents Of The University Of Colorado, A Body Corporate | Intraocular encapsulation of oxygenic bacteria |
BR112015019546A2 (pt) * | 2013-02-15 | 2017-07-18 | Allergan Inc | implante de distribuição de drogas prolongado |
EP3677229A1 (en) | 2014-05-29 | 2020-07-08 | Glaukos Corporation | Implants with controlled drug delivery features |
US11925578B2 (en) | 2015-09-02 | 2024-03-12 | Glaukos Corporation | Drug delivery implants with bi-directional delivery capacity |
US11564833B2 (en) | 2015-09-25 | 2023-01-31 | Glaukos Corporation | Punctal implants with controlled drug delivery features and methods of using same |
JP7003110B2 (ja) | 2016-04-20 | 2022-01-20 | ドーズ メディカル コーポレーション | 生体吸収性眼球薬物送達デバイス |
AU2019275409A1 (en) | 2018-05-24 | 2020-07-16 | Celanese Eva Performance Polymers Llc | Implantable device for sustained release of a macromolecular drug compound |
SG11202005947RA (en) | 2018-05-24 | 2020-07-29 | Celanese Eva Performance Polymers Corp | Implantable device for sustained release of a macromolecular drug compound |
WO2020120480A1 (en) * | 2018-12-10 | 2020-06-18 | University Of Copenhagen | Vasodilators for use in the treatment of a retinal ischemic disorder |
AU2020302924A1 (en) | 2019-06-27 | 2022-02-17 | Layerbio, Inc. | Ocular device delivery methods and systems |
JP2022554277A (ja) | 2019-10-30 | 2022-12-28 | パフューズ セラピューティクス, インコーポレイテッド | エンドセリンレセプターアンタゴニストを使用する眼疾患の処置 |
US20210275638A1 (en) * | 2020-03-04 | 2021-09-09 | The Schepens Eye Research Institute, Inc. | Polyhedrin-based slow release growth factor system for neuroprotection of retinal ganglion cell neurons |
CA3218251A1 (en) | 2021-04-30 | 2022-11-03 | Perfuse Therapeutics, Inc. | Pharmaceutical compositions and intravitreal drug delivery systems for the treatment of ocular diseases |
Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2004513920A (ja) * | 2000-11-17 | 2004-05-13 | ノバルティス アクチエンゲゼルシャフト | 循環器系疾患のためのレニン阻害剤を含む相乗的組合せ剤 |
JP2004517896A (ja) * | 2000-12-01 | 2004-06-17 | オーエスアイ・ファーマスーティカルズ・インコーポレーテッド | アデノシンa1、a2a、およびa3受容体に特異的な化合物、ならびにそれらの使用 |
WO2005110424A1 (en) * | 2004-04-30 | 2005-11-24 | Allergan, Inc. | Biodegradable intraocular implants containing prostamides |
WO2005110420A1 (de) * | 2004-05-11 | 2005-11-24 | Bayer Healthcare Ag | Formulierungen mit kontrollierter wirkstofffreisetzung enthaltend vardenafil |
WO2005110362A1 (en) * | 2004-04-30 | 2005-11-24 | Allergan, Inc. | Biodegradable ocular implants with long-term release characteristics |
WO2006041942A2 (en) * | 2004-10-04 | 2006-04-20 | Qlt Usa, Inc. | Ocular delivery of polymeric delivery formulations |
Family Cites Families (34)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4327725A (en) * | 1980-11-25 | 1982-05-04 | Alza Corporation | Osmotic device with hydrogel driving member |
JPS58126435U (ja) * | 1982-02-19 | 1983-08-27 | オリンパス光学工業株式会社 | Ttlオ−トストロボ用絞り制御回路 |
US4521210A (en) * | 1982-12-27 | 1985-06-04 | Wong Vernon G | Eye implant for relieving glaucoma, and device and method for use therewith |
US4853224A (en) * | 1987-12-22 | 1989-08-01 | Visionex | Biodegradable ocular implants |
US4997652A (en) * | 1987-12-22 | 1991-03-05 | Visionex | Biodegradable ocular implants |
US5164188A (en) * | 1989-11-22 | 1992-11-17 | Visionex, Inc. | Biodegradable ocular implants |
KR0185215B1 (ko) * | 1990-11-30 | 1999-05-01 | 요시다 쇼오지 | 서방성 안구삽입용 약제 |
US5443505A (en) * | 1993-11-15 | 1995-08-22 | Oculex Pharmaceuticals, Inc. | Biocompatible ocular implants |
US5869079A (en) * | 1995-06-02 | 1999-02-09 | Oculex Pharmaceuticals, Inc. | Formulation for controlled release of drugs by combining hydrophilic and hydrophobic agents |
US6369116B1 (en) * | 1995-06-02 | 2002-04-09 | Oculex Pharmaceuticals, Inc. | Composition and method for treating glaucoma |
CA2300154C (en) * | 1997-08-11 | 2008-07-08 | Allergan Sales, Inc. | Sterile bioerodible implant device with improved biocompatability and method |
US6306426B1 (en) * | 1997-08-11 | 2001-10-23 | Allergan Sales, Inc. | Implant device with a retinoid for improved biocompatibility |
US6331313B1 (en) * | 1999-10-22 | 2001-12-18 | Oculex Pharmaceticals, Inc. | Controlled-release biocompatible ocular drug delivery implant devices and methods |
US6726918B1 (en) * | 2000-07-05 | 2004-04-27 | Oculex Pharmaceuticals, Inc. | Methods for treating inflammation-mediated conditions of the eye |
ES2250504T3 (es) * | 2000-11-29 | 2006-04-16 | Allergan Inc. | Prevencion del rechazo de injerto en el ojo. |
US6713081B2 (en) * | 2001-03-15 | 2004-03-30 | The United States Of America As Represented By The Department Of Health And Human Services | Ocular therapeutic agent delivery devices and methods for making and using such devices |
US6899717B2 (en) * | 2002-09-18 | 2005-05-31 | Allergan, Inc. | Methods and apparatus for delivery of ocular implants |
US20050203542A1 (en) * | 2002-09-18 | 2005-09-15 | Allergan, Inc. | Apparatus for delivery of ocular implants with reduced incidence of ocular adverse events |
US7468065B2 (en) * | 2002-09-18 | 2008-12-23 | Allergan, Inc. | Apparatus for delivery of ocular implants |
US20050048099A1 (en) * | 2003-01-09 | 2005-03-03 | Allergan, Inc. | Ocular implant made by a double extrusion process |
US20040137059A1 (en) * | 2003-01-09 | 2004-07-15 | Thierry Nivaggioli | Biodegradable ocular implant |
US20050101582A1 (en) * | 2003-11-12 | 2005-05-12 | Allergan, Inc. | Compositions and methods for treating a posterior segment of an eye |
US20050244469A1 (en) * | 2004-04-30 | 2005-11-03 | Allergan, Inc. | Extended therapeutic effect ocular implant treatments |
US20050244478A1 (en) * | 2004-04-30 | 2005-11-03 | Allergan, Inc. | Anti-excititoxic sustained release intraocular implants and related methods |
US20050244472A1 (en) * | 2004-04-30 | 2005-11-03 | Allergan, Inc. | Intraocular drug delivery systems containing excipients with reduced toxicity and related methods |
AU2005240078A1 (en) * | 2004-04-30 | 2005-11-17 | Allergan, Inc. | Retinoid-containing sustained release intraocular drug delivery systems and related methods of manufacturing |
US20050244463A1 (en) * | 2004-04-30 | 2005-11-03 | Allergan, Inc. | Sustained release intraocular implants and methods for treating ocular vasculopathies |
US7771742B2 (en) * | 2004-04-30 | 2010-08-10 | Allergan, Inc. | Sustained release intraocular implants containing tyrosine kinase inhibitors and related methods |
US8119154B2 (en) * | 2004-04-30 | 2012-02-21 | Allergan, Inc. | Sustained release intraocular implants and related methods |
US20050244471A1 (en) * | 2004-04-30 | 2005-11-03 | Allergan, Inc. | Estradiol derivative and estratopone containing sustained release intraocular implants and related methods |
WO2005107708A1 (en) * | 2004-04-30 | 2005-11-17 | Allergan, Inc. | Biodegradable intravitreal tyrosine kinase inhibitors implants |
US8425929B2 (en) * | 2004-04-30 | 2013-04-23 | Allergan, Inc. | Sustained release intraocular implants and methods for preventing retinal dysfunction |
US20050244458A1 (en) * | 2004-04-30 | 2005-11-03 | Allergan, Inc. | Sustained release intraocular implants and methods for treating ocular neuropathies |
EP1904108B1 (en) * | 2005-07-15 | 2011-11-30 | Chakshu Research, Inc. | Ophthalmological formulation comprising methylsulfonylmethane and ciprofloxacin |
-
2006
- 2006-05-04 US US11/417,420 patent/US20070260203A1/en not_active Abandoned
-
2007
- 2007-05-01 CA CA2651300A patent/CA2651300C/en active Active
- 2007-05-01 DK DK07761644.9T patent/DK2026764T3/en active
- 2007-05-01 AU AU2007248143A patent/AU2007248143B2/en active Active
- 2007-05-01 EP EP07761644.9A patent/EP2026764B1/en active Active
- 2007-05-01 WO PCT/US2007/067883 patent/WO2007130945A1/en active Application Filing
- 2007-05-01 BR BRPI0711311-0A patent/BRPI0711311A2/pt not_active IP Right Cessation
- 2007-05-01 JP JP2009510011A patent/JP2009535422A/ja active Pending
-
2013
- 2013-08-20 JP JP2013170156A patent/JP2014014694A/ja active Pending
Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2004513920A (ja) * | 2000-11-17 | 2004-05-13 | ノバルティス アクチエンゲゼルシャフト | 循環器系疾患のためのレニン阻害剤を含む相乗的組合せ剤 |
JP2004517896A (ja) * | 2000-12-01 | 2004-06-17 | オーエスアイ・ファーマスーティカルズ・インコーポレーテッド | アデノシンa1、a2a、およびa3受容体に特異的な化合物、ならびにそれらの使用 |
WO2005110424A1 (en) * | 2004-04-30 | 2005-11-24 | Allergan, Inc. | Biodegradable intraocular implants containing prostamides |
WO2005110362A1 (en) * | 2004-04-30 | 2005-11-24 | Allergan, Inc. | Biodegradable ocular implants with long-term release characteristics |
WO2005110420A1 (de) * | 2004-05-11 | 2005-11-24 | Bayer Healthcare Ag | Formulierungen mit kontrollierter wirkstofffreisetzung enthaltend vardenafil |
WO2006041942A2 (en) * | 2004-10-04 | 2006-04-20 | Qlt Usa, Inc. | Ocular delivery of polymeric delivery formulations |
Non-Patent Citations (5)
Title |
---|
JPN6012026349; 今日の治療指針2004年版 , 2004, p.986 * |
JPN6012026350; LAWS,H: 'Peripheral vasodilators in the treatment of macular degenerative changes in the eye' Canadian Medical Association journal Vol.91, No.7, 1964, p.325-330 * |
JPN6015015641; あたらしい眼科 21巻4号, 2004, p.535-538 * |
JPN6015015642; 臨床眼科 Vol.52, No.4, 1998, p.627-630 * |
JPN6015015644; あたらしい眼科 Vol.11 臨時増刊号, 1994, p.206-208 * |
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EP2026764A1 (en) | 2009-02-25 |
JP2009535422A (ja) | 2009-10-01 |
US20070260203A1 (en) | 2007-11-08 |
DK2026764T3 (en) | 2017-10-23 |
EP2026764B1 (en) | 2017-07-12 |
WO2007130945A1 (en) | 2007-11-15 |
CA2651300A1 (en) | 2007-11-15 |
CA2651300C (en) | 2015-09-15 |
AU2007248143A1 (en) | 2007-11-15 |
BRPI0711311A2 (pt) | 2011-12-06 |
AU2007248143B2 (en) | 2012-11-08 |
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