JP5439652B2 - 眼の表面の潤滑性の治療的調節 - Google Patents
眼の表面の潤滑性の治療的調節 Download PDFInfo
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- JP5439652B2 JP5439652B2 JP2011508633A JP2011508633A JP5439652B2 JP 5439652 B2 JP5439652 B2 JP 5439652B2 JP 2011508633 A JP2011508633 A JP 2011508633A JP 2011508633 A JP2011508633 A JP 2011508633A JP 5439652 B2 JP5439652 B2 JP 5439652B2
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Description
本出願は、その開示が参照により本明細書に組み込まれる、2008年5月7日出願の米国仮出願第61/051,112号の利益を主張する。
本発明は、眼の潤滑性の調節に関連するものである。詳細には、本発明は、角膜および結膜表面の潤滑性の欠乏により起こる疾患を治療するための製薬学的組成物、およびその使用方法に関するものである。
プロテオグリカン4(proteoglycan 4(prg4))遺伝子は、巨核球刺激因子(Megakaryocyte Stimulating Factor)(MSF)、ルブリシン(lubricin)、及び、スーパーフィシャル・ゾーン・プロテイン(Superficial Zone Protein)(SZP)を容易にコードする(1)。これらの分子は、集合的に、PRG4若しくはPRG4タンパク質と呼ばれている。PRG4は、髄液中に、そして、滑膜(2)、腱(3)、半月板(4)の表面に存在し、健康的な滑膜関節のために重要な構成要素であろうとされている。例えば、(5)及び(6)参照。
。
ヒト角膜および結膜上皮細胞におけるPRG4 mRNA発現
アンドロゲンによるインビトロでのPRG4発現の調節
アンドロゲンとPRG4を用いたインビボにおける眼の表面の境界潤滑欠失の治療
1. G. D. Jay, Curr Opin Orthop 15, 355 (2004).
2. Schumacher BL, Hughes CE, Kuettner KE, Caterson B, Aydelotte MB. Immunodetection and partial cDNA sequence of the proteoglycan, superficial zone protein, synthesized by cells lining synovial joints. J Orthop Res. 1999 Jan; 17(1): 110-20.
3. S. G. Rees et al., Matrix Biology 21, 593 (2002).
4. Schumacher BL, Schmidt TA, Voegtline MS, Chen AC, Sah RL. Proteoglycan 4 (PRG4) synthesis and immunolocalization in bovine meniscus. J Orthop Res. 2005 May; 23(3): 562-8.
5. J. Marcelino et al., Nat Genet 23, 319 (1999).
6. D. K. Rhee et al., J Clin Invest 115, 622 (2005).
7. Cutolo M, Capellino S, Sulli A, Serioli B, Secchi ME, Villaggio B, Straub RH. Estrogens and autoimmune diseases. Ann NY Acad Sci 2006; 1089: 538-547.
8. Cutolo M, Sulli A, Capellino S, Villaggio B, Montagna P, Pizzorni C, Paolino S, Seriolo B, Felli L, Straub RH. Anti-TNF and sex hormones. Ann NY Acad Sci 2006; 1069: 391-400.
9. Rontzsch A, Thoss K, Petrow PK, Henzgen S, Brauer R. Amelioration of murine antigen-induced arthritis by dehydroepiandrosterone (DHEA). Inflamm Res 2004; 53: 189-198.
10. Schwarz IM, Hills BA, Br. J. Rheum. 1998; 37: 21-26.
11. Jay GD, Hong BS. Connect Tissue Res, 1992; 28(1-2): 89-98.
12. Jones MB. et. al. Mathematical Medicine and Biology 2005; 22, 265.
13. E. Meyer, R. M. Overney, K. Dransfeld, T. Gyalog, Nanoscience: Friction and Rheology on the Nanometer Scale (World Scientific Publishing Co. Pte. Ltd, River Edge, New Jersey, 2002), pp.373.
14. D. Dowson, Proc Inst Mech Eng [H] 215, 335 (2001).
15. G. A. Ateshian, V. C. Mow, in Basic Orthopaedic Biomechanics and Mechano-Biology V. C. Mow, R. Huiskes, Eds. (Lippincott Williams & Wilkins, Philadelphia, 2005) pp.447-494.
16. F. Guilak, Arthritis Rheum 52, 1632 (Jun, 2005).
17. K. C. Morell, W. A. Hodge, D. E. Krebs, R. W. Mann, Proc Natl Acad Sci USA 102, 14819 (Oct 11, 2005).
18. S. A. V. Swanson, in Adult Articular Cartilage M. A. R. Freeman, Ed. (Pitman Medical, Tunbridge Wells, England, 1979) pp.415-460.
19. K. C. Morrell, W. A. Hodge, D. E. Krebs, R. W. Mann, Proc Natl Acad Sci USA 102, 14819 (Oct 11, 2005).
20. C. W. McCutchen, Fed Proceedings 25, 1061 (1966).
21. T. Murakami, Y. Sawae, M. Ihara, JSME Int J Series C-Mechanical Systems Machine Elements & Manufacturing 46, 594 (2003).
22. G. Meachim, Ann Rheum Dis 31, 457 (1972).
23. Schmidt M, Naumann H, Weidler C, Schellenberg M, Anders S, Straub RH. Inflammation and sex hormone metabolism. Ann NY Acad Sci 2006; 1069: 236-246.
Claims (11)
- 治療有効濃度のPRG4又はそのフラグメント、及び、アンドロゲン、17α−メチル−17β−ヒドロキシ−2−オキサ−5α−アンドロスタン−3−オン、テストステロン、4,5−αジヒドロテストステロン、不飽和A環を含む17β−ヒドロキシ−5α−アンドロスタン、及び19−ノルテストステロンからなる群より選択される化合物、又はS−3−(4−アセチルアミノ−フェノキシ)−2−ヒドロキシ−2−メチル−N−(4−ニトロ−3−トリフルオロメチル−フェニル)−プロピノアミド[S−4]及びS−3−(4−フルオェノキシ)−2−ヒドロキシ−2−メチル−N−(4−ニトロ−3−トリフルオロメチル−フェニル)−プロピオアミド[S−1])からなる群より選択される化合物を含むものであって、
眼の潤滑性欠乏症の治療
において使用するための製薬学的組成物。 - 請求項1に記載の製薬学的組成物であって、その組成物は10−10,000μg/mLのPRG4を含むことを特徴とする製薬学的組成物。
- 請求項1に記載の製薬学的組成物であって、その組成物は50−500μg/mLのPRG4を含むことを特徴とする製薬学的組成物。
- 請求項1の製薬学的組成物であって、その組成物は0.0001−0.1%w/vのアンドロゲン、17α−メチル−17β−ヒドロキシ−2−オキサ−5α−アンドロスタン−3−オン、テストステロン、4,5−αジヒドロテストステロン、不飽和A環を含む17β−ヒドロキシ−5α−アンドロスタン、及び19−ノルテストステロンからなる群より選択される化合物、又はS−3−(4−アセチルアミノ−フェノキシ)−2−ヒドロキシ−2−メチル−N−(4−ニトロ−3−トリフルオロメチル−フェニル)−プロピノアミド[S−4]及びS−3−(4−フルオェノキシ)−2−ヒドロキシ−2−メチル−N−(4−ニトロ−3−トリフルオロメチル−フェニル)−プロピオアミド[S−1])からなる群より選択される化合物を含むことを特徴とする製薬学的組成物。
- 請求項1〜3の何れかに記載の製薬学的組成物であって、PRG4又はそのフラグメントは、50kDa及び400kDaの間の平均分子量を持つものであることを特徴とする製薬学的組成物。
- 請求項1〜3の何れかに記載の製薬学的組成物であって、PRG4又はそのフラグメントは、遺伝子組換えによるもの又は単離されたポリペプチドであることを特徴とする製薬学的組成物。
- 請求項1の製薬学的組成物であって、10−100,000μg/mLの治療有効濃度のヒアルロン酸ナトリウム、又は、ヒアルロン酸を更に含むことを特徴とする製薬学的組成物。
- 請求項1の製薬学的組成物であって、1又はそれ以上の表面活性リン脂質を更に含み、この表面活性リン脂質は、10−10,000μg/mLの治療有効濃度の、L−α−ジパルミトイルフォスファジルコリン、ホスファチジルコリン、ホスファチジルエタノールアミン、及び、スフィンゴミエリンからなる群より選択されることを特徴とする製薬学的組成物。
- 請求項1の製薬学的組成物であって、リン酸緩衝生理食塩水、又は、オプサルミカリーに許容できる平衡塩類溶液を含み、この平衡塩類溶液は、リン酸ナトリウム、塩化ナトリウム、塩化カリウム、炭酸水素ナトリウム、炭酸水素カリウム、塩化カルシウム、塩化マグネシウム、クエン酸三ナトリウム、塩酸、及び、水酸化ナトリウムからなる群より選択されることを特徴とする製薬学的組成物。
- 請求項1の製薬学的組成物であって、更に、治療有効濃度の1又はそれ以上の眼科治療用の粘滑剤、賦形剤、収斂剤、血管収縮剤、軟化剤、又は、滞留時間増加剤を含み、オプションとして、その滞留時間増加剤は、ヒドロキシプロピルメチルセルロース、カルボキシメチルセルロース、カルボマー、アクリル酸ポリマー、ポリメチルメタクリレイト、ポリアクリルアミド、ポリカルボフィル、ポリエチレン・オキシド、アクリル酸/アクリル酸ブチル共重合物、アルギン酸ナトリウム、デキストラン、及びこれらの組合せからなる群から選択されることを特徴とする製薬学的組成物。
- 請求項1の製薬学的組成物であって、前記状態は、涙液欠乏性若しくは蒸発性ドライアイ症状、シェーグレン症候群、乾性角結膜炎、アンドロゲン欠乏症、マイボーム腺病、エストロゲン補充療法、コンタクトレンズ装着、屈折矯正手術、アレルギー、涙膜層破壊時間の減少、易感染涙膜、眼表面障害、涙膜内及び眼の表面でのプロテアーゼ・レベルの上昇、慢性炎症、高浸透度、加齢、又は、それらの組合せである製薬学的組成物。
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Families Citing this family (62)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20040082509A1 (en) | 1999-10-12 | 2004-04-29 | Christophe Bonny | Cell-permeable peptide inhibitors of the JNK signal transduction pathway |
US9884038B2 (en) | 2004-06-07 | 2018-02-06 | University Of Tennessee Research Foundation | Selective androgen receptor modulator and methods of use thereof |
WO2013003594A2 (en) | 2011-06-28 | 2013-01-03 | Tearscience, Inc. | Methods and systems for treating meibomian gland dysfunction using radio-frequency energy |
US20070016256A1 (en) | 2005-07-18 | 2007-01-18 | Korb Donald R | Method and apparatus for treating gland dysfunction |
US20070060988A1 (en) | 2005-07-18 | 2007-03-15 | Grenon Stephen M | Melting meibomian gland obstructions |
US8950405B2 (en) | 2006-05-15 | 2015-02-10 | Tearscience, Inc. | Treatment of obstructive disorders of the eye or eyelid |
US20080114423A1 (en) | 2006-05-15 | 2008-05-15 | Grenon Stephen M | Apparatus for inner eyelid treatment of meibomian gland dysfunction |
US7981146B2 (en) | 2006-05-15 | 2011-07-19 | Tearscience Inc. | Inner eyelid treatment for treating meibomian gland dysfunction |
US7981095B2 (en) | 2005-07-18 | 2011-07-19 | Tearscience, Inc. | Methods for treating meibomian gland dysfunction employing fluid jet |
US20090043365A1 (en) * | 2005-07-18 | 2009-02-12 | Kolis Scientific, Inc. | Methods, apparatuses, and systems for reducing intraocular pressure as a means of preventing or treating open-angle glaucoma |
US7981145B2 (en) | 2005-07-18 | 2011-07-19 | Tearscience Inc. | Treatment of meibomian glands |
WO2007031098A1 (en) | 2005-09-12 | 2007-03-22 | Xigen S.A. | Cell-permeable peptide inhibitors of the jnk signal transduction pathway |
US7981147B2 (en) | 2006-05-15 | 2011-07-19 | Tearscience, Inc. | Outer eyelid heat and pressure treatment for treating meibomian gland dysfunction |
US8128674B2 (en) | 2006-05-15 | 2012-03-06 | Tearscience, Inc. | System for outer eyelid heat and pressure treatment for treating meibomian gland dysfunction |
US8007524B2 (en) | 2006-05-15 | 2011-08-30 | Tearscience, Inc. | Heat treatment and heat loss reduction for treating meibomian gland dysfunction |
US9314369B2 (en) | 2006-05-15 | 2016-04-19 | Tearscience, Inc. | System for inner eyelid treatment of meibomian gland dysfunction |
US8128673B2 (en) | 2006-05-15 | 2012-03-06 | Tearscience, Inc. | System for inner eyelid heat and pressure treatment for treating meibomian gland dysfunction |
US8137390B2 (en) | 2006-05-15 | 2012-03-20 | Tearscience, Inc. | System for providing heat treatment and heat loss reduction for treating meibomian gland dysfunction |
US7976573B2 (en) | 2006-05-15 | 2011-07-12 | Tearscience, Inc. | Inner eyelid heat and pressure treatment for treating meibomian gland dysfunction |
US7968603B2 (en) | 2007-09-11 | 2011-06-28 | University Of Tennessee Research Foundation | Solid forms of selective androgen receptor modulators |
ES2633792T3 (es) * | 2008-05-07 | 2017-09-25 | The Regents Of The University Of California | Reposición y enriquecimiento terapéuticos de la lubricación de la superficie ocular |
US8506944B2 (en) * | 2008-05-07 | 2013-08-13 | The Regents Of The University Of California | Replenishment and enrichment of ocular surface lubrication |
WO2009143864A1 (en) | 2008-05-30 | 2009-12-03 | Xigen S.A. | Use of cell-permeable peptide inhibitors of the jnk signal transduction pathway for the treatment of chronic or non-chronic inflammatory digestive diseases |
WO2009143865A1 (en) | 2008-05-30 | 2009-12-03 | Xigen S.A. | Use of cell-permeable peptide inhibitors of the jnk signal transduction pathway for the treatment of various diseases |
WO2010072228A1 (en) | 2008-12-22 | 2010-07-01 | Xigen S.A. | Novel transporter constructs and transporter cargo conjugate molecules |
JP2012527485A (ja) | 2009-05-22 | 2012-11-08 | ルブリス,エルエルシー. | Prg4及びその治療調節作用の応用及び使用 |
MX2012008110A (es) | 2010-01-11 | 2012-10-03 | Gtx Inc | Metodos para tratar una disfuncion de glandula de meibomio. |
WO2011160653A1 (en) | 2010-06-21 | 2011-12-29 | Xigen S.A. | Novel jnk inhibitor molecules |
CA2807036C (en) | 2010-10-14 | 2018-01-16 | Xigen S.A. | Use of cell-permeable peptide inhibitors of the jnk signal transduction pathway for the treatment of chronic or non-chronic inflammatory eye diseases |
WO2012174123A1 (en) * | 2011-06-13 | 2012-12-20 | Allergan, Inc. | Treatment of psychological trauma |
CN103764120A (zh) * | 2011-06-29 | 2014-04-30 | 阿勒根公司 | 聚乙二醇15羟基硬脂酸酯制剂 |
US20130029919A1 (en) * | 2011-07-26 | 2013-01-31 | Allergan, Inc. | Two part formulation system for opthalmic delivery |
CA2855223A1 (en) * | 2011-11-30 | 2013-06-06 | Xigen Inflammation Ltd. | Use of cell-permeable peptide inhibitors of the jnk signal transduction pathway for the treatment of dry eye syndrome |
WO2013091670A1 (en) | 2011-12-21 | 2013-06-27 | Xigen S.A. | Novel jnk inhibitor molecules for treatment of various diseases |
US9827250B2 (en) * | 2012-07-31 | 2017-11-28 | Johnson & Johnson Vision Care, Inc. | Lens incorporating myopia control optics and muscarinic agents |
WO2014031857A2 (en) | 2012-08-22 | 2014-02-27 | Tearscience, Inc. | Apparatuses and methods for diagnosing and/or treating lipid transport deficiency in ocular tear films, and related components and devices |
US9763827B2 (en) | 2013-04-30 | 2017-09-19 | Tear Film Innovations, Inc. | Systems and methods for the treatment of eye conditions |
ES2942724T3 (es) | 2013-04-30 | 2023-06-06 | Alcon Inc | Sistemas para el tratamiento de enfermedades del ojo |
WO2015197097A1 (en) | 2014-06-26 | 2015-12-30 | Xigen Inflammation Ltd. | New use for jnk inhibitor molecules for treatment of various diseases |
WO2014206427A1 (en) | 2013-06-26 | 2014-12-31 | Xigen Inflammation Ltd. | New use of cell-permeable peptide inhibitors of the jnk signal transduction pathway for the treatment of various diseases |
PL3013353T3 (pl) | 2013-06-26 | 2021-09-20 | Xigen Inflammation Ltd. | Przenikające do komórki inhibitory peptydowe szlaku przekazywania sygnału jnk do leczenia zapalenia pęcherza |
WO2015060935A1 (en) | 2013-10-22 | 2015-04-30 | Lubris, Llc | Control of rheological properties of mixed hyaluronate/lubricin solutions |
US9668916B2 (en) | 2013-11-04 | 2017-06-06 | Vance M. Thompson | Conjunctival cover and methods therefor |
US20150141328A1 (en) * | 2013-11-18 | 2015-05-21 | The Schepens Eye Research Institute | Stimulation of human meibomian gland function |
JP6571101B2 (ja) | 2013-11-26 | 2019-09-04 | ルブリス,エルエルシー. | 細胞間相互作用を阻害するための組成物及び方法 |
EP3154413B1 (en) | 2014-06-15 | 2021-08-25 | Yeda Research and Development Co. Ltd. | Surface treatment of contact lens and treatment of ocular discomfort by water soluble polymers and lipids/liposomes |
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US9395557B2 (en) | 2014-11-12 | 2016-07-19 | Vance M. Thompson | Partial corneal conjunctival contact lens |
CA2972817A1 (en) * | 2015-01-26 | 2016-08-04 | Lubris Llc | Use of prg4 as an anti-inflammatory agent |
US9869883B2 (en) | 2015-03-11 | 2018-01-16 | Vance M. Thompson | Tear shaping for refractive correction |
AU2016240948A1 (en) * | 2015-04-03 | 2017-11-16 | Santen Pharmaceutical Co., Ltd. | Dry eye therapeutic agent having as active ingredient nandrolone or ester thereof or methenolone or ester thereof |
EP3300482B1 (en) * | 2015-05-19 | 2021-07-14 | Lubris LLC | Use of prg4 to improve dynamic visual acuity and higher order aberrations |
JP6718608B2 (ja) * | 2016-05-25 | 2020-07-08 | 国立大学法人愛媛大学 | 眼表面・眼瞼摩擦係数測定装置および眼表面・眼瞼摩擦係数評価方法 |
US10974063B2 (en) | 2016-06-30 | 2021-04-13 | Alcon Inc. | Light therapy for eyelash growth |
US10353220B2 (en) | 2016-10-17 | 2019-07-16 | Vance M. Thompson | Tear shaping for refractive correction |
US10678067B2 (en) | 2018-04-06 | 2020-06-09 | Vance M. Thompson | Tear shaping for refractive correction |
WO2019246522A1 (en) * | 2018-06-21 | 2019-12-26 | Lubris Llc | Lubricin for use in wound healing |
US20220008518A1 (en) * | 2018-11-08 | 2022-01-13 | The Schepens Eye Research Institute, Inc. | Therapeutic approaches for tissue reconstruction and wound healing treatment |
US20220127318A1 (en) * | 2019-01-15 | 2022-04-28 | Cornell University | Recombinant lubricins, and compositions and methods for using the same |
AU2020320507A1 (en) * | 2019-07-26 | 2022-02-17 | Pandorum Technologies Private Limited | Bio-ink formulations, bio-printed corneal lenticule, and applications thereof |
US20220347167A1 (en) * | 2019-10-05 | 2022-11-03 | The Schepens Eye Research Institute, Inc. | A new treatment for meibomian gland dysfunction |
US11609438B2 (en) * | 2019-10-31 | 2023-03-21 | Menicon Singapore Pte Ltd. | Ocular lens with friction control structures |
Family Cites Families (59)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4550022A (en) * | 1981-10-05 | 1985-10-29 | Alcon Laboratories, Inc. | Tissue irrigating solution |
SE8501723L (sv) * | 1985-04-09 | 1986-10-10 | Pharmacia Ab | Preparation att anvendas vid behandling av ledinflammation |
US4964206A (en) * | 1988-03-15 | 1990-10-23 | Minnesota Mining And Manufacturing Company | Intraocular lens anchoring filament to lens element fixation method |
US4964205A (en) * | 1988-06-13 | 1990-10-23 | Rampart Packaging Inc. | Method for making screw cap jar |
US6433142B1 (en) | 1989-08-08 | 2002-08-13 | Genetics Institute, Llc | Megakaryocyte stimulating factors |
US5326558A (en) | 1989-08-08 | 1994-07-05 | Genetics Institute, Inc. | Megakaryocytopoietic factor |
RU2033165C1 (ru) * | 1989-10-13 | 1995-04-20 | Межотраслевой научно-технический комплекс "Микрохирургия глаза" | Способ получения пластичного материала из коллагена |
US5688765A (en) | 1992-04-21 | 1997-11-18 | The Schepens Eye Research Institute, Inc. | Ocular therapy in Sjogren's syndrome using topically applied androgensor TGF-β |
US6107289A (en) * | 1992-04-21 | 2000-08-22 | The Schepens Eye Research Institute, Inc. | Ocular therapy in keratoconjunctivitis sicca using topically applied androgens or TGF-β |
DE69326836T2 (de) | 1992-04-21 | 2000-02-24 | The Schepens Eye Research Institute, Inc. | Androgentherapie am auge beim sjögrensyndrom |
IL106922A (en) * | 1992-09-14 | 1998-08-16 | Novartis Ag | Complex materials with one or more wettable surfaces and a process for their preparation |
US5351100A (en) * | 1992-12-09 | 1994-09-27 | Bmc Industries, Inc. | Glass multifocal ophthalmic lens with polarizing element and method of making |
US20030130324A1 (en) * | 1993-11-19 | 2003-07-10 | Johnston W. Mcavoy | Method for preventing or controlling cataract |
US5515590A (en) * | 1994-07-19 | 1996-05-14 | University Of Kentucky Research Foundation | Method for reducing the generation of wear particulates from an implant |
US5518732A (en) * | 1995-02-14 | 1996-05-21 | Chiron Vision, Inc. | Bio-erodible ophthalmic shield |
DE69629230D1 (de) * | 1995-03-24 | 2003-09-04 | Ocular Res Of Bonton Inc | Hydrogellinse mit Lipid-Vorbeschichtigung |
RU2207885C2 (ru) * | 1995-08-30 | 2003-07-10 | Фармация Аб | Способ подачи небольшого объема лечебного раствора к целевому месту |
US6689748B1 (en) * | 1998-04-08 | 2004-02-10 | Theoharis C. Theoharides | Method of treating mast cell activation-induced diseases with a proteoglycan |
WO2000027421A2 (en) * | 1998-11-06 | 2000-05-18 | The Schepens Eye Research Institute, Inc. | LOCAL USE OF SOLUBLE TUMOR NECROSIS RECEPTOR I (sTNFRI) FOR PROPHYLAXIS AND TREATMENT OF CORNEAL TRANSPLANT REJECTION AND OTHER DISORDERS OF THE EYE |
WO2000027405A1 (fr) * | 1998-11-10 | 2000-05-18 | Denki Kagaku Kogyo Kabushiki Kaisha | Gel d'acide hyaluronique son procede de preparation et produit medical le contenant |
US6960562B2 (en) | 1999-04-23 | 2005-11-01 | Rhode Island Hospital, A Lifespan Partner | Tribonectin polypeptides and uses thereof |
US6743774B1 (en) | 1999-04-23 | 2004-06-01 | Rhode Island Hospital | Tribonectins |
CA2399039C (en) | 2000-02-03 | 2009-09-22 | Denki Kagaku Kogyo Kabushiki Kaisha | Hyaluronic acid gel, method of its production and medical material containing it |
US7026500B2 (en) * | 2000-08-24 | 2006-04-11 | University Of Tennessee Research Foundation | Halogenated selective androgen receptor modulators and methods of use thereof |
KR20070087252A (ko) * | 2000-12-20 | 2007-08-27 | 알콘, 인코퍼레이티드 | 개선된 유동 특성을 갖는 안내 세척 용액 |
AU2002232437A1 (en) * | 2000-12-20 | 2002-07-01 | Alcon Universal Ltd. | Ophthalmic lubricating solution adapted for use in lasik surgery |
AU2002303438B2 (en) * | 2001-04-23 | 2007-10-25 | Smith & Nephew (Overseas) Limited | Therapeutic treatments using the direct application of antimicrobial metal compositions |
US6815074B2 (en) * | 2001-05-30 | 2004-11-09 | Novartis Ag | Polymeric materials for making contact lenses |
CN1980582B (zh) | 2001-08-17 | 2010-12-22 | 美你康株式会社 | 用于用后即弃式软隐形眼镜的包装 |
US20030134810A1 (en) * | 2001-10-09 | 2003-07-17 | Chris Springate | Methods and compositions comprising biocompatible materials useful for the administration of therapeutic agents |
TWI255224B (en) * | 2002-01-09 | 2006-05-21 | Novartis Ag | Polymeric articles having a lubricious coating and method for making the same |
AR038926A1 (es) * | 2002-03-13 | 2005-02-02 | Novartis Ag | Materiales con contenido de multiples capas de vesiculas |
SE0201479D0 (sv) * | 2002-05-16 | 2002-05-16 | Pharmacia Groningen Bv | Kit and method in eye surgery |
US20050196370A1 (en) | 2003-03-18 | 2005-09-08 | Zhi-Jian Yu | Stable ophthalmic oil-in-water emulsions with sodium hyaluronate for alleviating dry eye |
US20050074497A1 (en) | 2003-04-09 | 2005-04-07 | Schultz Clyde L. | Hydrogels used to deliver medicaments to the eye for the treatment of posterior segment diseases |
AU2004263130A1 (en) | 2003-08-06 | 2005-02-17 | Nirmal Mulye | Pharmaceutical composition containing water soluble drug |
US7642236B2 (en) | 2003-08-14 | 2010-01-05 | Wyeth | Recombinant lubricin molecules and uses thereof |
US7087237B2 (en) * | 2003-09-19 | 2006-08-08 | Advanced Ocular Systems Limited | Ocular solutions |
WO2005027933A1 (en) | 2003-09-23 | 2005-03-31 | The Corporation Of The Trustees Of The Order Of The Sisters Of Mercy In Queensland | Unsaturated phosphatidylcholines and uses thereof |
CA2558497A1 (en) * | 2004-03-05 | 2005-09-15 | Synthes (U.S.A.) | Use of a mixture for the production of an agent for treating defective or degenerated cartilage in the production of natural cartilage replacement in vitro |
US20090060933A1 (en) | 2004-06-14 | 2009-03-05 | Estell David A | Proteases producing an altered immunogenic response and methods of making and using the same |
US20050287223A1 (en) * | 2004-06-23 | 2005-12-29 | Peyman Gholam A | Use of amniotic membrane as biocompatible devices |
EP1768687A2 (en) * | 2004-06-29 | 2007-04-04 | Massachusetts Institute Of Technology | Methods and compositions related to the modulation of intercellular junctions |
AU2005267012A1 (en) * | 2004-07-23 | 2006-02-02 | Mucosal Therapeutics Llc | Compositions and methods for viscosupplementation |
US7662509B2 (en) * | 2004-10-29 | 2010-02-16 | Medtronic, Inc. | Lithium-ion battery |
AU2006218653A1 (en) * | 2005-03-02 | 2006-09-08 | Barnett, Gene Ph.D. | Pharmaceutically acceptable carrier for ophthalmic compositions |
JP5794721B2 (ja) * | 2005-05-17 | 2015-10-14 | サーコード バイオサイエンス インコーポレイテッド | 眼障害の治療のための組成物および方法 |
US20080213274A1 (en) * | 2005-10-28 | 2008-09-04 | Sabbadini Roger A | Compositions and methods for the treatment and prevention of fibrotic, inflammatory, and neovascularization conditions of the eye |
JP5549045B2 (ja) * | 2006-01-13 | 2014-07-16 | 大正製薬株式会社 | 蒸発亢進型ドライアイの予防又は改善用水性点眼剤 |
US20080094573A1 (en) * | 2006-04-04 | 2008-04-24 | Vermette Patrick | Surface-modified materials, such as contact lenses, methods and kits for their preparation, and uses thereof |
US9539202B2 (en) * | 2006-04-28 | 2017-01-10 | Universidad Complutense De Madrid | Formulation of liposomal vesicles in aqueous solutions with lachrymal film characteristics |
US20070264226A1 (en) * | 2006-05-10 | 2007-11-15 | Karagoezian Hampar L | Synergistically enhanced disinfecting solutions |
EA016853B1 (ru) * | 2006-08-24 | 2012-08-30 | Юниверсити Оф Теннесси Рисерч Фаундейшн | Замещенные ациланилиды и их применение |
US20080097606A1 (en) | 2006-10-19 | 2008-04-24 | Cragg Andrew H | Knee joint prosthesis and hyaluronate compositions for treatment of osteoarthritis |
US20080197324A1 (en) | 2007-02-20 | 2008-08-21 | Fang Zhao | Ophthalmic composition containing a polyol-acid copolymer |
US20090068247A1 (en) | 2007-09-12 | 2009-03-12 | Mucosal Therapeutics | Biocompatible devices coated with a tribonectin and methods for their production |
CA2704018C (en) | 2007-12-20 | 2016-01-19 | Novartis Ag | Method for making contact lenses |
US8506944B2 (en) * | 2008-05-07 | 2013-08-13 | The Regents Of The University Of California | Replenishment and enrichment of ocular surface lubrication |
ES2633792T3 (es) | 2008-05-07 | 2017-09-25 | The Regents Of The University Of California | Reposición y enriquecimiento terapéuticos de la lubricación de la superficie ocular |
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