TW201720446A - Occult CNV size as a predictor for treatment with squalamine - Google Patents

Occult CNV size as a predictor for treatment with squalamine Download PDF

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TW201720446A
TW201720446A TW105137146A TW105137146A TW201720446A TW 201720446 A TW201720446 A TW 201720446A TW 105137146 A TW105137146 A TW 105137146A TW 105137146 A TW105137146 A TW 105137146A TW 201720446 A TW201720446 A TW 201720446A
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agent
administered
mammal
squalamine
cyclodextrin
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TW105137146A
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Chinese (zh)
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傑森 Ｓ 史雷克特
山謬爾 Ｉ 貝肯羅斯
葛林 Ｌ 史托樂
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Ｏｈｒ製藥公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/40—Cyclodextrins; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0048—Eye, e.g. artificial tears
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Inorganic Chemistry (AREA)
  • Ophthalmology & Optometry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Medicinal Preparation (AREA)

Abstract

The invention relates to the discovery of occult CNV size as a predictor for the level of success to be achieved in treating eye conditions by administration of ophthalmic formulations of squalamine dilactate alone or in combination with therapeutic agents. The invention also relates to a method of preventing or delaying the development of an ophthalmic condition in at risk patients by administration of ophthalmic formulations of squalamine dilactate.

Description

非典型脈絡膜新生血管（ＣＮＶ）之大小做為以角鯊胺治療之預測子The size of atypical choroidal neovascularization (CNV) as a predictor of squalamine treatment

本發明係關於非典型CNV大小作為在藉由二乳酸角鯊胺之眼用調配物單獨或與諸如抗血管生成劑等治療劑組合投與以治療眼科病況中達成之成功程度之預測子的發現。本發明亦係關於藉由投與二乳酸角鯊胺之眼用調配物延遲或預防有風險患者發生眼科病況之方法。The present invention relates to the discovery of atypical CNV size as a predictor of success in the treatment of ophthalmic conditions by administration of an ophthalmic formulation of squalamine disqualamine alone or in combination with a therapeutic agent such as an anti-angiogenic agent. . The invention also relates to a method of delaying or preventing the occurrence of an ophthalmic condition in a at-risk patient by administering an ophthalmic formulation of dihydrostamol.

年齡相關性黃斑變性(AMD)係52歲或以上之美國(United States)人中不可逆中心視覺損失之主要原因，且係美國、加拿大(Canada)、英國(Great Britain)及澳大利亞(Australia)最常見之失明原因。AMD涵蓋在受影響個體之黃斑中發展之若干類型之異常。存在兩種形式之黃斑變性：乾型(亦稱為萎縮性)及濕型(亦稱為盤狀、滲出性、視網膜下新生血管或脈絡膜新生血管)。乾型形式可為濕型形式之前體，其係由黃斑之色素上皮無法去除由視網膜生成之廢料造成。濕型形式在視網膜下生長新血管、特定而言黃斑時發生。 多種遺傳變體以及環境及生活方式因素促成AMD之風險，其每一者均添加少量至中等量之增加之風險(Seddon, J.M.等人，「Epidemiology of age-related macular degeneration」, Albert & Jakobiec’s Principles and Practice of Ophthalmology, Philadelphia:WB Saunders；413-422 (2007))。在具有患有AMD之家族成員之人中發生該疾病之風險較沒有患有AMD之一級親屬之彼等高三倍(Seddon, J.M.等人，「Familial aggregation of age-related maculopathy」, Am. J. Ophthalmol. 123(2):199-206 (1997))。 自2005年以來，若干遺傳變體始終與AMD相關。補體因子H (CFH)基因中之共同編碼變體Y402H係首次鑒定的。據估計與對於所有類別AMD之風險變體為純合的相關的勝算比在2.45與3.33之間；對於AMD之晚期乾型及濕型形式，勝算比更高，在3.5與7.4之間(Edwards, A.O.等人，「Complement factor H polymorphism and age-related macular degeneration」, Science 308(5720): 421-4 (2005)；Klein, R.J.等人，「Complement factor H polymorphism in age-related macular degeneration」, Science 308(5720): 385-9 (2005)；Haines, J.L.等人，「Complement factor H variant increases the risk of age-related macular degeneration」, Science 308(5720): 419-21 (2005)；Hageman, G.S.等人，「A common haplotype in the complement regulatory gene factor H (HF1/CFH) predisposes individuals to age-related macular degeneration」, Proc. Natl. Acad. Sci. USA 102(20): 7227-32 (2005)；Jorgenson, E.等人，「B4-4: Genome-Wide Association Study of Macular Degeneration: Early Results from the Kaiser Permanente Research Program on Genes, Environment, and Health (RPGEH)」, Clin. Med. Res. 11(3): 146-7 (2013))。 替代補體級聯中之若干其他基因座亦始終顯示可影響AMD風險。該等包括CFH中之其他變體(Maller, J.等人，「Common variation in three genes, including a noncoding variant in CFH, strongly influences risk of age-related macular degeneration」, Nat. Genet. 38(9): 1055-9 (2006))以及其他基因：因子B (BF)/補體組份2 (C2) (Maller, J.等人，「Common variation in three genes, including a noncoding variant in CFH, strongly influences risk of age-related macular degeneration」, Nat. Genet. 38(9): 1055-9 (2006)；Gold, B.等人，「Variation in factor B (BF) and complement component 2 (C2) genes is associated with age-related macular degeneration」, Nat. Genet. 38(4): 458-62 (2006))補體組份3 (C3) (Maller, J.B.等人，「Variation in complement factor 3 is associated with risk of age-related macular degeneration」, Nat. Genet. 39(10): 1200-1(2007)；Yates, J.R.等人，「Complement C3 variant and the risk of age-related macular degeneration」, N. Engl. J. Med. 357(6): 553-61 (2007))及補體因子I (CFI) (Fagerness, J.A.等人，「Variation near complement factor I is associated with risk of advanced AMD」, Eur. J. Hum. Genet. 17(1): 100-4 (2009)；Seddon, J.M.等人，「Rare variants in CFI, C3 and C9 are associated with high risk of advanced age-related macular degeneration」, Nat. Genet. 45(11): 1366-70 (2013)；Helgason, H.等人，「A rare nonsynonymous sequence variant in C3 is associated with high risk of age-related macular degeneration」, Nat. Genet. 45(11):1371-4 (2013)；Zhan, X.等人，「Identification of a rare coding variant in complement 3 associated with age-related macular degeneration」, Nat. Genet. 45(11): 1375-9 (2013))。 亦已涉及不參與補體級聯之若干基因。染色體10上HTRA1/ARMS2基因座中之變化已令人信服地與AMD相關，其中效應大小與利用CFH所觀察到者類似或大於其(Jakobsdottir, J.等人，「Susceptibility genes for age-related maculopathy on chromosome 10q26」, Am. J. Hum. Genet. 77(3): 389-407 (2005)；Dewan, A等人，「HTRA1 promoter polymorphism in wet age-related macular degeneration」, Science 314(5801): 989-92 (2006)；Yang, Z.等人，「A variant of the HTRA1 gene increases susceptibility to age-related macular degeneration」, Science 314(5801): 992-3 (2006))。此基因之功能尚未完全瞭解，但有證據表明其賦予濕型AMD較地圖狀萎縮更大之風險(Sobrin, L.等人，「ARMS2/HTRA1 locus can confer differential susceptibility to the advanced subtypes of age-related macular degeneration」, Am. J. Ophthalmol. (2010))。 目前，在大型全基因組關聯研究中報導肝脂酶C (LIPC)及金屬蛋白酶3 (TIMP3)之組織抑制劑與AMD相關(Neale, B.M.等人，「Genome-wide association study of advanced age-related macular degeneration identifies a role of the hepatic lipase gene (LIPC)」, Proc. Natl. Acad. Sci. USA. 107(16): 7395-400 (2010)；Chen, W.等人，「Genetic variants near TIMP3 and high-density lipoprotein-associated loci influence susceptibility to age-related macular degeneration」, Proc. Natl. Acad. Sci. USA. 107(16): 7401-6 (2010))。LIPC係新穎AMD基因，其參與高密度脂蛋白膽固醇(HDL)代謝(Neale, B.M.等人，「Genome-wide association study of advanced age-related macular degeneration identifies a role of the hepatic lipase gene (LIPC)」, Proc. Natl. Acad. Sci. USA. 107(16): 7395-400 (2010)；Reynolds, R.等人，「Serum lipid biomarkers and hepatic lipase gene associations with age-related macular degeneration」, Ophthalmology 117(10): 1989-95 (2010))，且TIMP3參與黃斑變性之孟德爾早發形式(Mendelian early-onset form)(稱為索斯比眼底營養不良(Sorsby's fundus dystrophy)) (Weber, B.H.等人，「Mutations in the tissue inhibitor of metalloproteinases-3 (TIMP3) in patients with Sorsby's fundus dystrophy」, Nat. Genet. 8(4):352-6 (1994))。 亦已探究環境風險因素、該等遺傳變體與AMD之間之關係。在一個研究中，與CFH Y402H相關之晚期AMD之易感性隨體重指數(BMI)變化，且BMI及抽煙在同一基因型內增加晚期AMD之風險(Seddon, J.M.等人，「CFH gene variant, Y402H, and smoking, body mass index, environmental associations with advanced age-related macular degeneration」, Hum. Hered. 61(3): 157-65 (2006))。然而，尚未觀察到抽煙與CFH Y402H或HTRA1/ARMS2基因型之間之統計相互作用(Seddon, J.M.等人，「CFH gene variant, Y402H, and smoking, body mass index, environmental associations with advanced age-related macular degeneration」, Hum. Hered. 61(3): 157-65 (2006)；Francis, P.J.等人，「The LOC387715 gene, smoking, body mass index, environmental associations with advanced age-related macular degeneration」, Hum. Hered. 63(3-4): 212-8 (2007))。 具有發生可引起新生血管併發症(例如與AMD相關之彼等)之眼科病況之風險之患者展現眼睛變化，其指示受影響組織中之病理學程度，包括玻璃疣之數量、類型及程度以及色素變化之存在或不存在。研究已顯示基於該等特徵對眼睛進行分類可提供發生晚期AMD (包括新生血管疾病)之風險概況(Ophthalmology 112(4): 533-539 (2005)；及Arch Ophthalmol. 123(11): 1570-1574 (2005))。考慮到每一個體中之風險因素係系統性的，眼睛中新生血管形成之最大風險係在對側眼中存在CNV (Ophthalmology 120(10): 2035-2041 (2013)；Ophthalmologica 226(3): 110-8 (2011)；及Arch Ophthalmol. 115(6): 741-747 (1997))。 影響身體中除眼睛以外之部分之許多疾病對研究具有直接或間接影響。具有眼部表現之已知之全身疾病包括(但不限於)皮膚及黏膜疾病、酒渣性痤瘡、白化病、異位性皮膚炎、貝賽特氏病(Behçet's disease)、疤痕性類天皰瘡、埃-當症候群(Ehlers-Danlos syndrome)、水皰性表皮松解症、多形性紅斑、戈爾茨-戈林症候群(Goltz-Gorlin syndrome)、魚鱗癬、色素失調症、太田痣(Nevus of Ota)、天皰瘡、彈性纖維假黃瘤、牛皮癬、史-約症候群(Stevens-Johnson syndrome) (重症多形性紅斑)、伏格特-小柳-原田三氏症候群(Vogt-Koyanagi-Harada syndrome)、著色性乾皮病、母斑症、視網膜血管瘤病(逢希伯-林道病(Von Hippel-Lindau disease)) (小腦視網膜毛細血管瘤病)、共濟失調毛細血管擴張(路易斯-巴症候群(Louis-Bar syndrome))、大腦三叉神經性血管瘤病(斯特奇-韋伯症候群(Sturge-Weber syndrome)) (腦顏面海綿狀血管瘤病)、神經纖維瘤病(範-瑞克林豪森氏病(von Recklinghausen's disease))、結節性硬化症(伯恩維爾症候群(Bourneville's syndrome))、威布恩-馬森症候群(Wyburn-Mason syndrome) (葡萄狀血管瘤病)、膠原疾病、關節黏連性脊椎炎、皮肌炎、結節性動脈周圍炎、反應性關節炎、類風濕性關節炎、類肉瘤病、硬皮症、全身性紅斑狼瘡、顳動脈炎、復發型多發性軟骨炎、具有多血管炎之肉芽腫病、全身性病毒感染、水痘(varicella、chickenpox)、紅疹(麻疹)、風疹(德國麻疹(German measles))、天花(variola、smallpox)、牛痘、單純皰疹、帶狀皰疹、流行性腮腺炎、傳染性單核白血球增多症、流行性感冒、巨細胞性包涵體病、咽結膜熱(腺病毒3)、流行性角膜結膜炎(腺病毒8)、人類免疫缺失病毒(獲得性免疫缺失症候群)、全身性細菌感染、淋病(新生兒眼炎)、布氏桿菌病(brucellosis)、白喉、萊姆病(Lyme disease)、敗血症細菌轉移性眼內炎、土拉菌病(tularemia)、麻瘋病(漢森氏病(Hansen's disease))、結核症、梅毒、全身性原生動物感染、性病性淋巴肉芽腫(披衣菌(chlamydial))、包涵體結膜炎(披衣菌)、瘧疾、弓蟲症、全身性真菌感染、白色念珠菌、組織胞漿菌病、球黴菌病、隱球菌(cryptococcus)病、轉移性真菌眼內炎、放線菌屬(actinomyces)病、鏈絲菌屬(streptothrix)病、全身性絛蟲及線蟲感染、囊蟲症(絛蟲)、包蟲病(包囊蟲)、蛔蟲症(蛔蟲屬(toxocara))、旋毛蟲症(旋毛蟲屬(trichinella))、蟠尾絲蟲病、羅阿絲蟲病(Loiasis) (羅阿絲狀蟲(loa loa))、染色體病症及遺傳症候群、貓叫症候群(Cri-du chat syndrome)、施-弗症候群(Schmid-Fraccaro syndrome)、特納氏症候群(Turner's syndrome)、環D染色體、單染色體-G症候群、三染色體症13 (帕塔氏症候群(Patau's syndrome)，D-症候群)、三染色體症18 (愛德華症候群(Edwards' syndrome)，E-症候群)、三染色體症21 (唐氏症候群(Down's syndrome))、染色體18長臂缺失、纖毛病遺傳症候群、血液疾病、貧血、心血管疾病、動脈硬化、高血壓、子癇前期(懷孕毒血症)、阻塞性血管疾病(突髮型)、栓子及血栓、視網膜中央動脈堵塞、心臟黏液瘤、顱動脈炎、鐮狀細胞攻擊、阻塞性血管疾病(緩慢、進展性)、頸動脈疾病、動脈痙攣(TIA)、糖尿病、靜脈阻塞疾病、血栓形成、心內膜炎、黏液瘤、主動脈弧症候群(高安(takayasu))、子癇前期(懷孕毒血症)、閉塞性血栓性脈管炎、遺傳性毛細血管擴張(朗-奧-韋症候群(Rendu-Osler-Weber syndrome))、內分泌疾病、庫欣氏病(Cushing's disease)、艾迪森氏病(Addison's disease)、副甲狀腺機能亢進症、副甲狀腺低能症、甲狀腺高能症、甲狀腺低能症、胃腸及營養病症、酒精中毒、克隆氏病(Crohn's disease)、肝病、營養不良、消化性潰瘍疾病、胰臟疾病、局部性腸炎或潰瘍性結腸炎、維生素A缺乏、維生素B缺乏、維生素C缺乏、維生素A、B及D過多症、惠普爾氏病(Whipple's disease)、代謝失調、白化病、黑尿症、類澱粉變性、切東症候群(Chediak-Higashi syndrome)、胱胺酸症、法布瑞氏病(Fabry's disease)、半乳糖血症、高雪氏病(Gaucher's disease)、痛風、血色素沉著症、組織球增生症、高胱胺酸尿症、脂肪代謝病、馬凡氏症候群(Marfan's syndrome)、韋-馬二氏症候群(Weill-Marchesani syndrome)、黏多糖病、尼曼-皮克病(Niemann-Pick disease)、骨發生不全、威爾森氏症(Wilson's disease)、肌肉骨骼疾病、奧爾布賴特氏病(Albright's disease) (骨纖維發育不良)、阿佩爾症候群(Apert syndrome)、康拉迪氏症候群(Conradi's syndrome)、顱面症候群、面部畸形症候群、肌肉營養不良症、重症肌無力、骨發生不全、柏哲德氏病(Paget's disease)、肺病、氣喘、支氣管癌、支氣管擴張、胰臟囊性纖維化、肺氣腫、肺炎、腎病、奧爾波特氏症候群(Alport's syndrome)、氮血症(急性及慢性腎盂腎炎)、勞氏症候群(Lowe's syndrome)、髓質囊性病、腎病症候群(急性腎小球性腎炎、糖尿病腎、全身性紅斑狼瘡)、腎移植、維爾姆斯瘤(Wilms' tumor) (腎胚細胞瘤)、贅瘤性病及癌及原發性病灶位點。 滲出性AMD在脈絡膜毛細血管穿過布魯赫膜(Bruch’s membrane)時開始生長發生，此現象通常稱作脈絡膜新生血管形成(CNV)。新生血管(濕型) AMD係使用螢光血管造影之照相成像技術根據其外觀而分類為經典病灶類型及非典型病灶類型。侵襲性更強之經典病灶類型通常與由直接光受體損害引起之早期及實質視覺損失相關，而非典型病灶類型通常在視網膜下色素上皮(sub-RPE)中且與較低程度之視覺損失相關。 端視新生血管病灶之組成而定，AMD之非典型及經典新生血管形成之自然過程存在顯著變化。另外，病灶相對於中央黃斑之大小及部位係決定病況病程之因素。在具有經典脈絡膜新生血管形成且沒有非典型新生血管形成或具有主要經典脈絡膜新生血管形成(亦即，經典脈絡膜新生血管形成之面積≥整個病灶面積之50%)之患者中，視覺敏銳度損失得最快。相比之下，在具有非典型脈絡膜新生血管形成且沒有經典新生血管形成或具有主要非典型脈絡膜新生血管形成(亦即，非典型脈絡膜新生血管形成之面積＞整個病灶面積之50%)之患者中，視覺敏銳度損失得較慢。 在維替泊芬(verteporfin) (Visudyne®)光動力學療法試驗中觀察到，在具有由年齡相關性黃斑變性引起之窩下鱗CNV且具有非典型且沒有經典病灶組成及最低限度經典病灶組成之患者中，病灶大小為治療益處量值之預測子。(K.J. Blinder等人，Am. J. Ophthalmol. 136(3): 407-18 (2003))。 角鯊胺(IUPAC名稱：(硫酸氫[6-[(3S,5R,7R,10S,13R,14S)-3-[3-(4-胺基丁基胺基)丙基胺基]-7-羥基-10,13-二甲基-2,3,4,5,6,7,8,9,11,12,14,15,16,17-十四氫-lH-環戊[a]菲-17-基]-2-甲基庚-3-基]酯)係展現抗血管生成性質之胺基固醇，其已用作靜脈內輸注用於有效治療濕型AMD，其中其用於防止視網膜中表徵疾病進展之新生血管形成及異常血管形成(Sills Jr.等人，「Squalamine Inhibits Angiogenesis and Solid Tumor Growth in Vivo Perturbs Embryonic Vasculature」, Cancer Research 58: 2784-2792 (1998)；Higgins等人，「Squalamine Improves Retinal Neovascularization」, Investigative Ophthalmology & Visual Science 41(6): 1507-1512 (2000)；PRNEWSWIRE, 「Genaera Reports Squalamine Continues to Improve Vision at Four Months Timepoint in Age-Related Macular Degeneration」, http://www.eyesightnews.com/topic/28.html(2003年8月7日))。角鯊胺係頒予Zasloff等人之美國專利第5,192,756號之標的，其揭示內容係以全文引用方式併入本文中。角鯊胺之總化學合成闡述於美國專利第6,262,283號及第6,610,866號中，該等案件係以全文引用方式併入本文中。 自患者使用及風險之角度來看，顯然期望局部調配物可用於直接施加至眼睛，而不是靜脈內輸注，或尤其需要每月直接注射至眼中之當前照護標準。與侵襲性更強之技術(例如玻璃體內注射)相比，呈(例如)溶液、懸浮液、乳霜或軟膏形式之局部調配物易於由患者自投與，該等侵襲性更強之技術需要在醫學監督下成本較高的投與且其可引起嚴重併發症(例如眼內炎及視網膜脫落)。然而，眼部滴眼劑之一般問題在於在其投與後，通常滴眼劑中不到5%之藥物穿透角膜且到達眼內組織。而是，所投與劑量之主要部分因溶液排出及全身吸收而消除(Jarvinen K.等人，「Ocular absorption following topical delivery」, Adv. Drug Deliv. Rev. 16(1): 3-19 (1995)；Conroy C.W., 「Sulfonamides do not reach the retina in therapeutic amounts after topical application to the cornea」, Ocul. Pharmacol.Ther. 13(5): 465- 472 (1997)；及Maurice D.M., 「Drug delivery to the posterior segment from drops」, Surv. Ophthalmol. 47 (增刊1): S41- S52 (2002))。 另外，用於測試角鯊胺藉由IV輸注治療AMD之效能之先前臨床試驗揭露長期使用之潛在問題。基於藥物代謝動力學分析，IV調配物之靜脈內投藥方案被認為是次佳的，且因為各種原因被確定為不具有商業可行性。舉例而言，人類個體在40 mg劑量下角鯊胺之短血漿半衰期導致在4至6天後脈絡膜中之濃度可能不足以阻斷CNV。當投藥間隔為每月「維持」輸注時，可能僅存在最長一週之CNV抑制，隨後三週或更長時間之活性新血管生成。此方案在投與的前四週至五週後在視覺敏銳度方面產生良好增加，隨後在第五週後改良之速率下降。由於靜脈內投藥較在局部調配物中投與之劑量高幾個數量級，故該投藥造成局部輸注位點反應。在「現實世界」情形中，期望患有濕型AMD之老年及/或殘疾患者每週前往診所延長輸注時間係不切實際的。另外，大多數視網膜眼科實務上未設置用於該等靜脈內輸注。 與靜脈內投藥相關之上文所指示缺點相比，本發明是為用於局部投與之安全眼用調配物，其可將治療劑選擇性地遞送至眼睛之後部，用於治療與(例如)部分或完全非典型CNV相關之眼科病症。 針對濕型AMD之目前照護標準係向眼睛中直接注射抗VEGF化合物(例如雷珠單抗(ranibizumab) (Lucentis))。此治療雖可有效減緩疾病之進展，但通常需要重複注射。由患者視情況與抗VEGF及/或抗血小板源性生長因子(抗PDGF)化合物或其他治療劑(例如其他抗血管生成化合物)組合重複性地進行局部投與之安全且有效之滴眼劑可提供高度合意且能顯著改善之治療方法。 本發明係關於意外地發現非典型CNV大小可作為在藉由二乳酸角鯊胺之眼用調配物視情況與其他治療劑(例如抗血管生成劑(包括抗VEGF化合物及/或抗PDGF藥物))組合投與以治療眼睛病況(例如與脈絡膜新生血管形成相關之病況)中達到成功程度的可靠預測子。 除治療及/或預防已確立眼科病況以外，亦可高度期望藉由預防為此疾病之公認標誌之脈絡膜新生血管複合物之發生來預防與該等病況(例如新生血管AMD)相關之視覺損失。所有目前療法皆針對展現相關之滲出性及纖維變性前特徵之已確立之新生血管複合物，該等特徵即便在最大治療干預下亦限制改善視覺之有效性。因此，為在患有AMD之患者中提供視覺敏銳度之最佳結果，需要抑制新生血管病灶之初始形成。 利用目前治療劑，此目標在理論上在易受高風險乾型AMD影響之患者中利用玻璃體內抗VEGF藥劑之預防性固定投藥可達成。然而，此方法基於若干原因係不切實際的，該等原因包括與玻璃體內注射相關之固有風險使得此策略對在其他方面展現良好視覺功能之大量患者有危險的事實。此外，將照護負擔轉移給患者及醫師會使得此治療方法無法持續且無法維持。相比之下，患者自行以局部方式投與抗血管生成滴眼劑可理想地適於此適應症。此方法可為患者提供安全且非侵襲性的遞送方法，該方法可在患者家中及在正常日常活動期間實施。 具有其鈣調蛋白介導之多靶生長因子抑制之局部角鯊胺獨特地非常適合停止早期眼部血管生成(Grossniklaus, H.E.等人，「Clinicopathologic correlations of surgically excised type 1 and type 2 submacular choroidal neovascular membranes」, Am. J. Ophthalmol. 126: 59-69 (1998))。2期數據支持角鯊胺藉由改變患有已確立CNV之患者之新生血管過程來改良視覺結果之能力。因此，角鯊胺將為用作抑制乾型AMD轉化為該疾病之更嚴重新生血管形式(濕型AMD)之預防性療法之良好候選者。 脈絡膜血管生成係濕型AMD之標誌且通常亦稱作脈絡膜新生血管形成(CNV)。眾所周知CNV病灶在隨螢光素血管造影(FA)、吲哚菁綠血管造影(ICG)、組織切片及最近光學同調斷層掃瞄-血管造影(OCTA)上之外觀各不相同。CNV病灶最初係基於其在FA上之外觀來分類，此取決於CNV相對於視網膜色素上皮(RPE)之部位。典型CNV膜在FA上清晰可見且傾向於較快地發展且顯著洩露，從而導致在視網膜下空間中(亦即，在RPE與光受體之間)之流體累積及視覺敏銳度之快速變化。相比之下，非典型CNV膜在FA上較不可見且傾向於更慢地發展，且洩露較少，且在RPE下空間中(亦即，不中斷RPE與光受體之間之接觸)。另外，經典及非典型病灶可一起存在。 CNV膜之組織病理學評估證實典型CNV對應於視網膜下空間中之纖維小管組織(亦即，2型病灶)，且非典型CNV對應於RPE下空間中之纖維小管組織(亦即，1型病灶) (Grossniklaus, H.E.等人，「Clinicopathologic correlations of surgically excised type 1 and type 2 submacular choroidal neovascular membranes」, Am. J. Ophthalmol. 126: 59-69 (1998)；Lafaut, B.A等人，「Clinicopathological correlation in exudative age related macular degeneration: histological differentiation between classic and occult choroidal neovascularisation」, Br. J. Ophthalmol. 84: 239-243 (2000))。值得注意地，RPE層完整性可能存留於純非典型病灶中。FA數據之回顧性分析表明一些CNV病灶自疾病早期階段之非典型進展至晚期階段之經典可能由RPE完整性損失引起(Schneider, U.等人，「Natural course of occult choroidal neovascularization in age-related macular degeneration: development of classic lesions in fluorescein angiography」, Acta Ophthalmol. Scand. 83: 141-147 (2005)；Pieramici, D.J.等人，「Occult with no classic subfoveal choroidal neovascular lesions in age-related macular degeneration: clinically relevant natural history information in larger lesions with good vision from the Verteporfin in Photodynamic Therapy (VIP) Trial: VIP Report No. 4」, Arch. Ophthalmol. 124: 660-664 (2006))。 亦已使用光學同調斷層掃瞄(OCT)證實了病灶相對於RPE之部位。此外，亦已利用多種治療模式(例如熱雷射，「Occult choroidal neovascularization. Influence on visual outcome in patients with age-related macular degeneration. Macular Photocoagulation Study Group, Arch Ophthalmol. 114(4): 400-12 (1996)；Reichel, E.等人，「Transpupillary thermotherapy of occult subfoveal choroidal neovascularization in patients with age related macular degeneration」, Ophthalmology 106(10):1908-1914 (1999)，及利用Visudyne之光動力學療法(PDT))證明在經典與非典型CNV療法之間對治療性干預之差異反應。在治療及預防(TAP)研究中，PDT顯著降低患有主要典型CNV之患者之視覺損失速率(Bressler, N.M.等人，「Treatment of Age-Related Macular Degeneration with Photodynamic Therapy (TAP) Study Group). Photodynamic therapy of subfoveal choroidal neovascularization in age-related macular degeneration with verteporfin: two-year results of 2 randomized clinical trials-tap report 2」, Arch. Ophthalmol. 119: 198-207 (2001))。 相比之下，藉由如在Visudyne®產物標記上所指示之比較，具有純非典型及最低限度經典病灶之患者之視覺結果較差(Bressler, N.M.等人，「Treatment of Age-Related Macular Degeneration with Photodynamic Therapy (TAP) Study Group). Photodynamic therapy of subfoveal choroidal neovascularization in age-related macular degeneration with verteporfin: two-year results of 2 randomized clinical trials-tap report 2」, Arch. Ophthalmol. 119: 198-207 (2001))。然而，光動力學療法(VIP)研究中之維替泊芬揭露，與具有主要經典病灶之患者類似，具有較小純非典型病灶(例如，≤4個視盤面積[10.16 mm2 ])之患者亦得益於PDT，但具有較大非典型病灶之患者不能(Arnold等人，2001)。在經典與非典型CNV之間之反應差異擴展至抗VEGF療法。非反應與非典型(1型) CNV (Otsuji, T.等人，「Initial non-responders to ranibizumab in the treatment of age-related macular degeneration (AMD)」, Clin. Ophthalmol. 7 :1487-1490 (2013))及纖維小管色素上皮脫落(PED，一類非典型CNV)之存在相關，且RPE下流體較視網膜下流體消退得更慢(Freeman, W.R.等人，「Prognostic implications of pigment epithelial detachment in bevacizumab (avastin)-treated eyes with age-related macular degeneration and choroidal neovascularization」, Retina 31:1812-1818 (2011))。此觀察結果可反映該等病灶中RPE障壁功能之保存，該障壁功能可限制藥物滲透(Suzuki, M.等人，「Predictive factors for non-response to intravitreal ranibizumab treatment in age-related macular degeneration」, Br. J. Ophthalmol. 98:1186-1191 (2014))。 考慮到經典對非典型CNV之解剖學及組織學之差異以及其對治療性干預之差異反應的許多引用的先前實例，端視CNV病灶類型，角鯊胺已證明效能有差異係不足為奇的。更特定而言，來自2期試驗之數據表明，在與Lucentis® PRN治療組合使用時，含有經典之非典型病灶及純的非典型病灶對角鯊胺之反應不同。此外，該數據亦表明，獨立於經典組份之存在，非典型病灶組份之大小係對角鯊胺組合療法之臨床反應之決定因素。此反應亦獨立於Lucentis®注射之次數。因此，角鯊胺對非典型CNV之效應似乎可能僅基於其獨特作用機制，但亦基於其生理化學性質，例如展現疏水性及親水性要素之角鯊胺之兩親性性質。此性質使得角鯊胺極其適合到達由RPE細胞環繞及經RPE細胞包圍之非典型血管。(Miller等人，「Newly-formed subretinal vessels. Fine structure and fluorescein leakage」, Invest Ophthalmol. Vis. Sci. 27: 204-213 (1986)；Miller等人，「The role of the retinal pigment epithelium in the involution of subretinal neovascularization」, Invest. Ophthalmol. Vis. Sci. 27:1644-1652 (1986))。RPE細胞及可能的布魯赫膜之多個層充當針對限制其效能之目前生物抗VEGF藥劑的物理障壁。然而，角鯊胺由於其具有兩親性而能夠自由滲透此障壁且攻擊非典型脈絡膜新生血管複合物。角鯊胺亦可藉助抗PDGF性質增強對非典型CNV之效應。已知RPE細胞特別係在參與傷口癒合時或在潛在視網膜脫落存在下分泌PDGF (Campochiaro等人，「Platelet-derived growth factor is an antocrine stimulator in retinal pigmented epithelial cells」, J. Cell Sci. 107(9): 2459-6 (1994))。該等情況在非典型CNV中較在典型CNV中更常見，且因此非典型CNV可能處於較典型CNV更高之PDGF環境中。在已確立新生血管組織中之此治療效應將為角鯊胺在抑制小的新生血管病灶(特別係位於脈絡膜位準處之彼等，亦即，新血管生長之初始位點)中之作用提供基礎。 除該等效應以外，在先前未揭示之研究中，吾人觀察到新穎非鈣調蛋白介導之作用機制，其特異性靶向乾型AMD過渡至濕型AMD中之最早期事件。在McLean等人(未公開結果)之研究中，融合人類臍靜脈內皮細胞(HUVEC)用作在已確立血管中發現之成熟內皮細胞之模型，將該等融合HUVEC與次融合HUVEC相比較，該等次融合HUVEC用作在不成熟及新長出血管中發現之內皮細胞之模型。研究者在次融合積極分化之HUVEC中觀察到新穎角鯊胺細胞吸收機制及新穎細胞形態變化，該等在融合HUVEC中未觀察到。次融合細胞展現角鯊胺遍及該等細胞以彌漫方式定位，而不僅僅在如在鈣調蛋白介導之結合吸收下通常觀察到之近核部位定位。在融合HUVEC中未觀察到此彌漫性吸收。此外，次融合細胞證明在融合細胞中不發生之明顯細胞病理學及總體形態變化。此性質代表新穎抗血管生成作用機制，其中角鯊胺選擇性靶向稀疏平鋪之內皮細胞(圖 1 )，代表形成新生血管小管所需要之內皮細胞之最早期儲存器，該等新生血管小管最後組裝成脈絡膜新生血管複合物。積極分化之不成熟內皮細胞經由由血漿及核膜之滲透性增加引起之腫瘤病而被殺死。該等觀察結果代表角鯊胺針對積極分化之不成熟血管內皮細胞之新穎抗血管生成作用機制，其最終導致形成CNV及因此新生血管AMD及涉及血管生成之其他眼科病況之臨床病況。 總之，關於角鯊胺在改良患有已確立CNV之患者之視覺結果中之效能的現有臨床數據、關於角鯊胺對不成熟內皮細胞之效應之活體外數據，及藉由所述二乳酸角鯊胺眼用溶液使得藥物遞送可能之患者偏愛之非侵襲性局部方法，提供用於治療具有增加之發生新生血管相關性眼科病況(例如與AMD相關之併發症)之風險之患者的理想潛在治療劑。Age-related macular degeneration (AMD) is the leading cause of irreversible central visual loss in the United States of 52 years or older and is most common in the United States, Canada, Great Britain, and Australia. The cause of blindness. AMD covers several types of abnormalities that develop in the macula of affected individuals. There are two forms of macular degeneration: dry (also known as atrophic) and wet (also known as discoid, exudative, subretinal neovascularization or choroidal neovascularization). The dry form can be a wet form precursor which is caused by the inability of the pigment epithelium of the macula to remove the waste generated by the retina. The wet form occurs when new blood vessels, in particular the macula, are grown under the retina. Multiple genetic variants, as well as environmental and lifestyle factors contribute to the risk of AMD, each with a small to moderate increase in risk (Seddon, JM et al., "Epidemiology of age-related macular degeneration", Albert &Jakobiec's Principles And Practice of Ophthalmology, Philadelphia: WB Saunders; 413-422 (2007)). The risk of developing the disease in a person with a family member of AMD is three times higher than that of a relative with no AMD (Seddon, JM et al., "Familial aggregation of age-related maculopathy", Am. J. Ophthalmol. 123(2): 199-206 (1997)). Since 2005, several genetic variants have been associated with AMD. The co-coding variant Y402H in the complement factor H (CFH) gene was first identified. It is estimated that the odds ratio associated with homozygous for all types of AMD risk variants is between 2.45 and 3.33; for AMD's late dry and wet forms, the odds ratio is higher, between 3.5 and 7.4 (Edwards) , AO et al., "Complement factor H polymorphism and age-related macular degeneration", Science 308 (5720): 421-4 (2005); Klein, RJ et al., "Complement factor H polymorphism in age-related macular degeneration", Science 308 (5720): 385-9 (2005); Haines, JL, et al., "Complement factor H variant increases the risk of age-related macular degeneration", Science 308 (5720): 419-21 (2005); Hageman, GS et al., "A common haplotype in the complement regulatory gene factor H (HF1/CFH) predisposes individuals to age-related macular degeneration", Proc. Natl. Acad. Sci. USA 102(20): 7227-32 (2005) Jorgenson, E. et al., "B4-4: Genome-Wide Association Study of Macular Degeneration: Early Results from the Kaiser Permanente Research Program on Genes, Environment, and Health (RPGEH)", Clin. Med. Res. 11(3): 146-7 (2013)). Several other loci in the surrogate cascade have also been shown to affect AMD risk. These include other variants in CFH (Maller, J. et al., "Common variation in three genes, including a noncoding variant in CFH, strongly influences risk of age-related macular degeneration", Nat. Genet. 38(9) : 1055-9 (2006)) and other genes: Factor B (BF) / Complement 2 (C2) (Maller, J. et al., "Common variation in three genes, including a noncoding variant in CFH, strongly influences risk Of age-related macular degeneration", Nat. Genet. 38(9): 1055-9 (2006); Gold, B. et al., "Variation in factor B (BF) and complement component 2 (C2) genes is associated with Age-related macular degeneration", Nat. Genet . 38(4): 458-62 (2006)) Complement component 3 (C3) (Maller, JB et al., "Variation in complement factor 3 is associated with risk of age- Related macular degeneration", Nat. Genet. 39(10): 1200-1 (2007); Yates, JR et al., "Complement C3 variant and the risk of age-related macular degeneration", N. Engl. J. Med. 357(6): 553-61 (2007)) and complement factor I (CFI) (Fagerness, JA et al. "Variation near complement factor I is associated with risk of advanced AMD", Eur. J. Hum. Genet. 17(1): 100-4 (2009); Seddon, JM, et al., "Rare variants in CFI, C3 and C9 "Associated with high risk of advanced age-related macular degeneration", Nat. Genet. 45(11): 1366-70 (2013); Helgason, H. et al., "A rare nonsynonymous sequence variant in C3 is associated with high risk Of age-related macular degeneration", Nat. Genet. 45(11): 1371-4 (2013); Zhan, X. et al., "Identification of a rare coding variant in complement 3 associated with age-related macular degeneration", Nat. Genet. 45(11): 1375-9 (2013)). Several genes that are not involved in the complement cascade have also been involved. Changes in the HTRA1/ARMS2 locus on chromosome 10 have been convincingly associated with AMD, where the effect size is similar to or greater than that observed with CFH (Jakobsdottir, J. et al., "Susceptibility genes for age-related maculopathy" On chromosome 10q26", Am. J. Hum. Genet. 77(3): 389-407 (2005); Dewan, A et al., "HTRA1 promoter polymorphism in wet age-related macular degeneration", Science 314 (5801): 989-92 (2006); Yang, Z., et al., "A variant of the HTRA1 gene increases susceptibility to age-related macular degeneration", Science 314 (5801): 992-3 (2006)). The function of this gene is not fully understood, but there is evidence that it confers greater risk of wet AMD than map atrophy (Sobrin, L. et al., "ARMS2/HTRA1 locus can confer differential susceptibility to the advanced subtypes of age-related Macular degeneration", Am. J. Ophthalmol. (2010)). Currently, tissue inhibitors of hepatic lipase C (LIPC) and metalloproteinase 3 (TIMP3) are reported to be associated with AMD in large genome-wide association studies (Neale, BM et al., "Genome-wide association study of advanced age-related macular Degeneration identifies a role of the hepatic lipase gene (LIPC)", Proc. Natl. Acad. Sci. USA. 107(16): 7395-400 (2010); Chen, W. et al., "Genetic variants near TIMP3 and high -density lipoprotein-associated loci influence susceptibility to age-related macular degeneration", Proc. Natl. Acad. Sci. USA. 107(16): 7401-6 (2010)). LIPC is a novel AMD gene involved in high density lipoprotein cholesterol (HDL) metabolism (Neale, BM et al., "Genome-wide association study of advanced age-related macular degeneration identification a role of the hepatic lipase gene (LIPC)", Proc. Natl. Acad. Sci. USA. 107(16): 7395-400 (2010); Reynolds, R. et al., "Serum lipid biomarkers and hepatic lipase gene associations with age-related macular degeneration", Ophthalmology 117 (10 ): 1989-95 (2010)), and TIMP3 is involved in the Mendelian early-onset form of the macular degeneration (called Sorsby's fundus dystrophy) (Weber, BH et al. "Mutations in the tissue inhibitor of metalloproteinases-3 (TIMP3) in patients with Sorsby's fundus dystrophy", Nat. Genet . 8(4): 352-6 (1994)). Environmental risk factors, the relationship between these genetic variants and AMD have also been explored. In one study, the susceptibility of advanced AMD associated with CFH Y402H varied with body mass index (BMI), and BMI and smoking increased the risk of advanced AMD in the same genotype (Seddon, JM et al., "CFH gene variant, Y402H , and smoking, body mass index, environmental associations with advanced age-related macular degeneration", Hum. Hered . 61(3): 157-65 (2006)). However, statistical interactions between smoking and the CFH Y402H or HTRA1/ARMS2 genotype have not been observed (Seddon, JM et al., "CFH gene variant, Y402H, and smoking, body mass index, environmental associations with advanced age-related macular Degeneration", Hum. Hered . 61(3): 157-65 (2006); Francis, PJ, et al., "The LOC387715 gene, smoking, body mass index, environmental associations with advanced age-related macular degeneration", Hum. Hered 63 (3-4): 212-8 (2007)). Patients with a risk of developing an ophthalmic condition that can cause neovascular complications (such as those associated with AMD) exhibit eye changes indicative of the degree of pathology in the affected tissue, including the number, type and extent of drusen, and pigmentation The existence or absence of change. Studies have shown that classifying eyes based on these characteristics can provide a risk profile for the development of advanced AMD (including neovascular disease) (Ophthalmology 112(4): 533-539 (2005); and Arch Ophthalmol. 123(11): 1570- 1574 (2005)). Considering that the risk factors in each individual are systemic, the greatest risk of neovascularization in the eye is the presence of CNV in the contralateral eye (Ophthalmology 120(10): 2035-2041 (2013); Ophthalmologica 226(3): 110 -8 (2011); and Arch Ophthalmol. 115(6): 741-747 (1997)). Many diseases affecting the body other than the eye have direct or indirect effects on the study. Known systemic diseases with ocular manifestations include, but are not limited to, skin and mucosal diseases, rosacea, albinism, atopic dermatitis, Behçet's disease, scar pemphigoid, Ehlers-Danlos syndrome, vesicular epidermolysis, erythema multiforme, Goltz-Gorlin syndrome, ichthyosis, pigmentation disorder, Nevus of Ota ), pemphigus, elastic fiber pseudo-xanthoma, psoriasis, Stevens-Johnson syndrome (severe polymorphic erythema), Vogt-Koyanagi-Harada syndrome , xeroderma pigmentosum, maternal plaque, retinal angiomatosis (Von Hippel-Lindau disease) (cerebellar retinal capillary angiomatosis), ataxia telangiectasia (Louis-Barr syndrome) (Louis-Bar syndrome)), brain trigeminal angiomatosis (Sturge-Weber syndrome) (brain facial cavernous hemangioma), neurofibromatosis (Van-Ricklinhausen)病 (von Recklinghausen's disease)), knot Tuberous sclerosis (Bourneville's syndrome), Wyburn-Mason syndrome (glucovascular angiomatosis), collagen disease, joint adhesion spondylitis, dermatomyositis, Nodular periarteritis, reactive arthritis, rheumatoid arthritis, sarcoma-like disease, scleroderma, systemic lupus erythematosus, temporal arteritis, relapsing polychondritis, granulomatous disease with polyangiitis, Systemic viral infections, chickenpox (varicella, chickenpox), rash (measles), rubella (German measles), variola (smallpox), vaccinia, herpes simplex, herpes zoster, mumps , infectious mononucleosis, influenza, giant cell inclusion disease, pharyngeal conjunctival fever (adenovirus 3), epidemic keratoconjunctivitis (adenovirus 8), human immunodeficiency virus (acquired immunodeficiency syndrome) , systemic bacterial infection, gonorrhea (neonatal ophthalmia), brucellosis, diphtheria, Lyme disease, sepsis bacterial metastatic endophthalmitis, tularemia, leprosy Hansen Hansen's disease), tuberculosis, syphilis, systemic protozoal infection, sexually transmitted lymphogranuloma (chlamydial), inclusion body conjunctivitis (Chlamydia), malaria, toxoplasmosis, systemic Fungal infection, Candida albicans, histoplasmosis, coccidiosis, cryptococcus disease, metastatic fungal endophthalmitis, actinomyces disease, streptothrix disease, systemic Aphid and nematode infection, cysticercosis (aphid), echinococcosis (cysticer), ascariasis (toxocara), trichinella (trichinella), onchocerciasis, Luo Loiasis (loa loa), chromosomal disorders and genetic syndrome, Cri-du chat syndrome, Schmid-Fraccaro syndrome, Turner's disease Turner's syndrome, ring D chromosome, single chromosome-G syndrome, trisomy 13 (Patau's syndrome, D-symptoms), trisomy 18 (Edwards' syndrome, E- Syndrome), Trisomy 21 (Down's syndro Me)), chromosome 18 long arm loss, cilia genetic syndrome, blood disease, anemia, cardiovascular disease, arteriosclerosis, hypertension, preeclampsia (pregnancy toxemia), obstructive vascular disease (burst), embolus And thrombosis, central retinal artery occlusion, cardiac myxoma, cranial arteritis, sickle cell attack, obstructive vascular disease (slow, progressive), carotid artery disease, arterial spasm (TIA), diabetes, venous obstruction, thrombosis , endocarditis, myxoma, aortic arc syndrome (takayasu), preeclampsia (pregnancy toxemia), occlusive thrombotic vasculitis, hereditary telangiectasia (lang-au-wei syndrome) Rendu-Osler-Weber syndrome)), endocrine disease, Cushing's disease, Addison's disease, parathyroidism, parathyroid hypoxia, thyroid hyperactivity, thyroid dystrophy, Gastrointestinal and nutritional disorders, alcoholism, Crohn's disease, liver disease, malnutrition, peptic ulcer disease, pancreatic disease, local enteritis or ulcerative colitis, dimensional Vitamin A deficiency, vitamin B deficiency, vitamin C deficiency, vitamin A, B and D hyperactivity, Whipple's disease, metabolic disorders, albinism, black urine, amyloidosis, cut east syndrome (Chediak- Higashi syndrome), cysteine, Fabry's disease, galactosemia, Gaucher's disease, gout, hemochromatosis, glomerular hyperplasia, homocystinuria , Fat Metabolism Disease, Marfan's Syndrome, Weill-Marchesani Syndrome, Mucopolysaccharidosis, Niemann-Pick Disease, Bone Insufficiency, Weir Wilson's disease, musculoskeletal disease, Albright's disease (bone fiber dysplasia), Apert syndrome, Conradi's syndrome, cranial Facial syndrome, facial deformity syndrome, muscular dystrophy, myasthenia gravis, osteogenesis imperfecta, Paget's disease, lung disease, asthma, bronchial carcinoma, bronchiectasis, pancreatic cystic fibrosis, Emphysema, pneumonia, kidney disease, Alport's syndrome, nitrogenemia (acute and chronic pyelonephritis), Lowe's syndrome, medullary cystic disease, renal syndrome (acute glomerular Nephritis, diabetic kidney, systemic lupus erythematosus, kidney transplantation, Wilms' tumor (renal blastoma), neoplastic disease and cancer, and primary lesion sites. Exudative AMD begins to grow as choroidal capillaries pass through Bruch's membrane, a phenomenon commonly referred to as choroidal neovascularization (CNV). Neovascularization (wet type) AMD is classified into a classic lesion type and an atypical lesion type according to its appearance using angiographic imaging techniques of fluorescein angiography. The more aggressive type of classic lesion is usually associated with early and substantial visual loss caused by direct photoreceptor damage, while the typical type of lesion is usually in the subretinal pigment epithelium (sub-RPE) with a lower degree of visual loss. Related. Depending on the composition of the neovascular lesions, there is a significant change in the natural processes of AMD's atypical and classical neovascularization. In addition, the size and location of the lesion relative to the central macula are factors that determine the course of the disease. In patients with classical choroidal neovascularization without atypical neovascularization or with major classical choroidal neovascularization (ie, area of classical choroidal neovascularization ≥ 50% of the total lesion area), visual acuity is lost The fastest. In contrast, patients with atypical choroidal neovascularization and no classical neovascularization or with major atypical choroidal neovascularization (ie, area of atypical choroidal neovascularization > 50% of the total lesion area) Among them, visual acuity is lost more slowly. In the photodynamic therapy trial of verteporfin (Visudyne®), it was observed that there was a subtle squamous CNV caused by age-related macular degeneration and had atypical and no classical lesion composition and minimal classical lesion composition. In patients, the lesion size is a predictor of the therapeutic benefit magnitude. (KJ Blinder et al., Am. J. Ophthalmol. 136(3): 407-18 (2003)). Squalamine (IUPAC name: (hydrogen sulfate [6-[(3S,5R,7R,10S,13R,14S)-3-[3-(4-aminobutylamino)propylamino]-7 -hydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-lH-cyclopenta[a] Phenanthroline-yl-2-methylheptan-3-yl] ester is an amine steroid exhibiting anti-angiogenic properties, which has been used as an intravenous infusion for the effective treatment of wet AMD, wherein it is used for Prevents neovascularization and abnormal angiogenesis in the retina that characterize disease progression (Sills Jr. et al., "Squalamine Inhibits Angiogenesis and Solid Tumor Growth in Vivo Perturbs Embryonic Vasculature", Cancer Research 58: 2784-2792 (1998); Higgins et al. , "Squalamine Improves Retinal Neovascularization", Investigative Ophthalmology & Visual Science 41(6): 1507-1512 (2000); PRNEWSWIRE, "Genaera Reports Squalamine Continues to Improve Vision at Four Months Timepoint in Age-Related Macular Degeneration", http:/ </ br></br></br> The entire chemical synthesis of squalamine is described in U.S. Patent Nos. 6,262,283 and 6,610,866, each of which is incorporated herein by reference in its entirety. It will be apparent that it is expected that topical formulations can be used for direct application to the eye rather than intravenous infusion, or in particular the current standard of care for direct injection into the eye each month. Compared to more aggressive techniques (eg intravitreal injection) Topical formulations in the form of, for example, solutions, suspensions, creams or ointments are readily self-administered by the patient, and such more aggressive techniques require costly administration under medical supervision and can cause serious Complications (such as endophthalmitis and retinal detachment). However, a general problem with ocular eye drops is that typically less than 5% of the drug in the eye drops penetrates the cornea and reaches the tissues of the eye after it is administered. Rather, the major portion of the dose administered is eliminated by solution excretion and systemic absorption (Jarvinen K. et al., "Ocular absorption following topical delivery", Adv. Drug Deliv. Rev. 16(1): 3-19 (1995) ); Conroy CW, "Sulfonamides do not reach the retina in therapeutic amounts after topical application to the cornea", Ocul. Pharmacol. Ther. 13(5): 465-472 (1997); and Maurice DM, "Drug delivery to the Posterior segment from drops", Surv. Ophthalmol. 47 (suppl. 1): S41-S52 (2002)). In addition, previous clinical trials to test the efficacy of squalamine by IV infusion for the treatment of AMD revealed potential problems with long-term use. Based on pharmacokinetic analysis, the IV formulation of the IV formulation was considered to be sub-optimal and was determined to be not commercially viable for various reasons. For example, a short plasma half-life of squalamine at a dose of 40 mg in a human subject results in a concentration in the choroid that may not be sufficient to block CNV after 4 to 6 days. When the dosing interval is a monthly "maintenance" infusion, there may be only a maximum of one week of CNV inhibition, followed by active neovascularization for three weeks or longer. This regimen produced a good increase in visual acuity between the first four weeks and five weeks after the administration, followed by a decrease in the rate of improvement after the fifth week. Since the intravenous administration is several orders of magnitude higher than the dose administered in the topical formulation, the administration causes a local infusion site reaction. In the "real world" scenario, it is unrealistic to expect elderly and/or disabled patients with wet AMD to travel to the clinic each week to extend the infusion time. In addition, most retinal ophthalmology practices are not provided for such intravenous infusions. In contrast to the above indicated disadvantages associated with intravenous administration, the present invention is a topical administration of a safe ophthalmic formulation that selectively delivers a therapeutic agent to the back of the eye for treatment and (eg, Partial or complete atypical CNV-related ophthalmic conditions. The current standard of care for wet AMD is the direct injection of an anti-VEGF compound (e.g., ranibizumab (Lucentis)) into the eye. Although this treatment can effectively slow the progression of the disease, it usually requires repeated injections. Repeated topical administration of a safe and effective eye drop by a patient in combination with an anti-VEGF and/or anti-platelet-derived growth factor (anti-PDGF) compound or other therapeutic agent (eg, other anti-angiogenic compounds) Provides a highly desirable and significantly improved treatment. The present invention relates to the unexpected discovery that atypical CNV size can be used as an ophthalmic formulation by dihydrosqualamine and other therapeutic agents (eg, anti-angiogenic agents (including anti-VEGF compounds and/or anti-PDGF drugs). The combination is administered to provide a reliable predictor of success in treating eye conditions, such as conditions associated with choroidal neovascularization. In addition to the treatment and/or prevention of established ophthalmic conditions, it is highly desirable to prevent visual loss associated with such conditions (e.g., neovascular AMD) by preventing the development of a choroidal neovascular complex that is a recognized hallmark of the disease. All current therapies are directed to established neovascular complexes that exhibit associated exudative and pre-fibrotic features that limit the effectiveness of visual improvement even under maximum therapeutic intervention. Therefore, in order to provide optimal results for visual acuity in patients with AMD, it is desirable to inhibit the initial formation of neovascular lesions. With current therapeutic agents, this goal is theoretically achievable with prophylactic fixed administration of intravitreal anti-VEGF agents in patients susceptible to high risk dry AMD. However, this approach is impractical for several reasons, including the inherent risks associated with intravitreal injection making this strategy dangerous for a large number of patients who otherwise exhibit good visual function. In addition, transferring the burden of care to patients and physicians can make this treatment unsustainable and unsustainable. In contrast, the patient's own local administration of an anti-angiogenic eye drop is ideally suited for this indication. This method can provide a safe and non-invasive delivery method for a patient that can be performed at the patient's home and during normal daily activities. Local squalamine with its calmodulin-mediated inhibition of multiple target growth factors is uniquely suited to stop early ocular angiogenesis (Grossniklaus, HE et al., "Clinicopathologic correlations of surgically excised type 1 and type 2 submacular choroidal neovascular membranes Am. J. Ophthalmol. 126: 59-69 (1998)). Phase 2 data supports the ability of squalamine to improve visual outcomes by altering the neovascularization process in patients with established CNV. Therefore, squalamine will be a good candidate for prophylactic therapy to inhibit the conversion of dry AMD into a more severe neovascular form of the disease (wet AMD). The choroidal angiogenesis is a hallmark of wet AMD and is also commonly referred to as choroidal neovascularization (CNV). It is well known that CNV lesions vary in appearance with luciferin angiography (FA), indocyanine green angiography (ICG), tissue sections, and recent optical tonal tomography-angiography (OCTA). CNV lesions were originally classified based on their appearance on FA, depending on the location of CNV relative to the retinal pigment epithelium (RPE). A typical CNV membrane is clearly visible on the FA and tends to develop faster and significantly leak, resulting in rapid fluid accumulation and rapid changes in visual acuity in the subretinal space (ie, between the RPE and the photoreceptor). In contrast, atypical CNV membranes are less visible on FA and tend to develop more slowly, with less leakage and in the space under the RPE (ie, without interrupting the contact between the RPE and the photoreceptor) . In addition, classic and atypical lesions can exist together. Histopathological evaluation of the CNV membrane confirmed that typical CNV corresponds to fibrous tubule tissue in the subretinal space (ie, type 2 lesion), and atypical CNV corresponds to fibrous tubule tissue in the space under the RPE (ie, type 1 lesion) (Grossniklaus, HE et al., "Clinicopathologic correlations of surgically excised type 1 and type 2 submacular choroidal neovascular membranes", Am. J. Ophthalmol. 126: 59-69 (1998); Lafaut, BA et al., "Clinicopathological correlation in Exudative age related macular degeneration: histological differentiation between classic and occult choroidal neovascularisation", Br. J. Ophthalmol . 84: 239-243 (2000)). Notably, RPE layer integrity may persist in pure atypical lesions. Retrospective analysis of FA data suggests that the classic progression of some CNV lesions from the atypical progression to the late phase of the disease may be caused by loss of RPE integrity (Schneider, U. et al., "Natural course of occult choroidal neovascularization in age-related macular Degeneration: development of classic lesions in fluorescein angiography", Acta Ophthalmol. Scand. 83: 141-147 (2005); Piermici, DJ et al., "Occult with no classic subfoveal choroidal neovascular lesions in age-related macular degeneration: clinically relevant natural History information in larger lesions with good vision from the Verteporfin in Photodynamic Therapy (VIP) Trial: VIP Report No. 4", Arch. Ophthalmol. 124: 660-664 (2006)). Optical coherence tomography (OCT) has also been used to confirm the location of the lesion relative to the RPE. In addition, a variety of treatment modalities have been utilized (eg, heat laser, "Occult choroidal neovascularization. Influence on visual outcome in patients with age-related macular degeneration. Macular Photocoagulation Study Group, Arch Ophthalmol. 114(4): 400-12 (1996). Reichel, E., et al., "Transpupillary thermotherapy of occult subfoveal choroidal neovascularization in patients with age related macular degeneration", Ophthalmology 106(10): 1908-1914 (1999), and photodynamic therapy (PDT) using Visudyne ) demonstrates a differential response to therapeutic intervention between classical and atypical CNV therapy. In treatment and prevention (TAP) studies, PDT significantly reduced the rate of visual loss in patients with predominantly typical CNV (Bressler, NM et al., "Treatment of Age-Related Macular Degeneration with Photodynamic Therapy (TAP) Study Group). Photodynamic Therapy of subfoveal choroidal neovascularization in age-related macular degeneration with verteporfin: two-year results of 2 randomized clinical trials-tap report 2", Arch. Ophthalmol . 119: 198-207 (2001)). In contrast, patients with pure atypical and minimally classic lesions have poor visual outcomes as indicated by the Visudyne® product markers (Bressler, NM et al., "Treatment of Age-Related Macular Degeneration with Photodynamic Therapy (TAP) Study Group). Photodynamic therapy of subfoveal choroidal neovascularization in age-related macular degeneration with verteporfin: two-year results of 2 randomized clinical trials-tap report 2", Arch. Ophthalmol. 119: 198-207 (2001 )). However, verteporfin in photodynamic therapy (VIP) studies revealed similar small atypical atypical lesions (eg, ≤ 4 optic disc areas [10.16 mm 2 ]) similar to patients with major classic lesions. Patients also benefit from PDT, but patients with larger atypical lesions cannot (Arnold et al., 2001). The difference in response between classical and atypical CNV extends to anti-VEGF therapy. Non-reactive and atypical (type 1) CNV (Otsuji, T. et al., "Initial non-responders to ranibizumab in the treatment of age-related macular degeneration (AMD)", Clin. Ophthalmol . 7 : 1487-1490 (2013 )) and the presence of fibroin pigment epithelial shedding (PED, a class of atypical CNV), and the fluid under RPE dissipates more slowly than the subretinal fluid (Freeman, WR et al., "Prognostic implications of pigment epithelial detachment in bevacizumab (avastin) )-treated eyes with age-related macular degeneration and choroidal neovascularization", Retina 31:1812-1818 (2011)). This observation may reflect the preservation of RPE barrier function in these lesions, which may limit drug penetration (Suzuki, M. et al., "Predictive factors for non-response to intravitreal ranibizumab treatment in age-related macular degeneration", Br J. Ophthalmol. 98: 1186-1191 (2014)). Given the classic anatomical and histological differences in atypical CNV and its many previous examples of differential responses to therapeutic interventions, it is not surprising that squalamine has demonstrated a difference in potency depending on the type of CNV lesion. . More specifically, data from Phase 2 trials showed that in combination with Lucentis® PRN treatment, classic atypical lesions and pure atypical lesions responded differently to squalamine. In addition, the data also indicate that the size of the atypical lesion component is a determining factor in the clinical response to squalamine combination therapy, independent of the presence of the classical component. This response is also independent of the number of Lucentis® injections. Thus, the effect of squalamine on atypical CNV seems likely to be based solely on its unique mechanism of action, but also on its physiochemical properties, such as the amphipathic nature of squalamine, which exhibits hydrophobic and hydrophilic elements. This property makes squalamine extremely suitable for reaching atypical blood vessels surrounded by RPE cells and surrounded by RPE cells. (Miller et al., "Newly-formed subretinal vessels. Fine structure and fluorescein leakage", Invest Ophthalmol. Vis. Sci. 27: 204-213 (1986); Miller et al., "The role of the retinal pigment epithelium in the involution Of subretinal neovascularization", Invest. Ophthalmol. Vis. Sci. 27:1644-1652 (1986)). Multiple layers of RPE cells and possibly Bruch's membrane act as physical barriers to current biological anti-VEGF agents that limit their potency. However, squalamine is able to freely penetrate this barrier and attack atypical choroidal neovascular complexes due to its amphiphilic nature. Squalamine can also enhance the effect on atypical CNV by virtue of its anti-PDGF properties. It is known that RPE cells specifically secrete PDGF when involved in wound healing or in the presence of potential retinal detachment (Campochiaro et al., "Platelet-derived growth factor is an antocrine stimulator in retinal pigmented epithelial cells", J. Cell Sci. 107 (9 ): 2459-6 (1994)). These conditions are more common in atypical CNVs than in typical CNVs, and thus atypical CNVs may be in a higher PDGF environment than typical CNVs. This therapeutic effect in established neovascular tissue will provide for the role of squalamine in inhibiting small neovascular lesions, particularly at the choroidal level, ie, the initial site of neovascular growth. basis. In addition to these effects, in a previously undisclosed study, we observed a novel non-calmodulin-mediated mechanism of action that specifically targets the transition of dry AMD to the earliest events in wet AMD. In a study by McLean et al. (unpublished results), fusion human umbilical vein endothelial cells (HUVEC) was used as a model for mature endothelial cells found in established blood vessels, and the fusion HUVECs were compared to sub-fused HUVECs. Homogeneous fusion HUVEC is used as a model for endothelial cells found in immature and newly emerging vessels. The researchers observed novel squalamine cell uptake mechanisms and novel cell morphological changes in HUVECs that were actively differentiated, which were not observed in fused HUVECs. Sub-fusion cells demonstrate that squalamine is localized throughout the cells in a diffuse manner, not just in the near nucleus site as commonly observed in calmodulin-mediated binding. This diffuse absorption was not observed in the fused HUVEC. In addition, secondary fusion cells demonstrate significant cytopathology and overall morphological changes that do not occur in fused cells. This property represents a novel anti-angiogenic mechanism in which squalamine selectively targets sparsely tiled endothelial cells ( Fig. 1 ), representing the earliest reservoir of endothelial cells required for the formation of neovascular tubules, such neovascular tubules. Finally assembled into a choroidal neovascular complex. The actively differentiated immature endothelial cells are killed by tumor diseases caused by increased permeability of plasma and nuclear membrane. These observations represent a novel anti-angiogenic mechanism of squalamine against actively differentiated immature vascular endothelial cells, which ultimately leads to the development of clinical conditions of CNV and thus neovascular AMD and other ophthalmic conditions involving angiogenesis. In summary, prior clinical data on the efficacy of squalamine in improving the visual outcome of patients with established CNV, in vitro data on the effects of squalamine on immature endothelial cells, and by the dilactic acid angle A non-invasive topical method of squalamine ophthalmic solution that allows for drug delivery to be preferred by patients, providing an ideal potential treatment for patients at increased risk of developing neovascular-related ophthalmic conditions (eg, AMD-related complications) Agent.

本發明之態樣係以治療有效量向有需要之哺乳動物之眼睛之後鞏膜及脈絡膜選擇性遞送角鯊胺或其醫藥上可接受之鹽以治療眼科病況之方法，該方法包含：向哺乳動物之一隻或兩隻眼睛投與包含以下之組合物：二乳酸角鯊胺；緩衝劑；黏膜黏著劑；及環糊精，其中該哺乳動物具有一或多個具有小於10 mm2 面積之非典型CNV之病灶。 本發明之另一態樣係治療哺乳動物之眼科病況之方法，該方法包含：向有需要之哺乳動物之眼睛投與足以治療該病況之量之組合物，該組合物包含：二乳酸角鯊胺；緩衝劑；黏膜黏著劑；及環糊精，其中該哺乳動物具有一或多個具有小於10 mm2 面積之非典型CNV之病灶。 在實例性實施例中，該等組合物係水性組合物。 在實例性實施例中，具有非典型CNV之病灶具有小於9 mm2 之面積，例如小於8 mm2 之面積，例如小於7 mm2 之面積，例如小於6 mm2 之面積，例如小於5 mm2 之面積，例如小於4 mm2 之面積，例如小於3 mm2 之面積，例如小於2 mm2 之面積，例如小於1 mm2 之面積。 在實例性實施例中，病灶係作為眼科病況之結果存在。 在實例性實施例中，病灶具有非典型CNV但不含有任一典型CNV。 在實例性實施例中，病灶亦含有典型CNV。 在實例性實施例中，組合物係以局部方式投與哺乳動物之眼睛。 在實例性實施例中，組合物呈滴眼劑之形式。 在實例性實施例中，在將組合物投與哺乳動物之眼睛後，與眼睛內其他部位相比，在水狀液或玻璃體液中存在顯著更低濃度之組合物。 在實例性實施例中，組合物中之黏膜黏著劑為聚維酮(Povidone) K-30。 在實例性實施例中，組合物中之環糊精為2-羥丙基-β-環糊精。 在實例性實施例中，緩衝劑為磷酸鹽，例如鹼金屬(例如，鋰、鈉或鉀)磷酸鹽，例如磷酸鈉，例如磷酸鈉七水合物及/或磷酸二氫鈉一水合物。 在實例性實施例中，眼科病況係選自由以下組成之群：濕型年齡相關性黃斑變性(濕型AMD)、乾型年齡相關性黃斑變性(乾型AMD)、糖尿病視網膜病變、增殖性糖尿病視網膜病變、缺血性視網膜病變(其包括視網膜動脈阻塞及頸動脈阻塞)、囊樣黃斑水腫、糖尿病黃斑水腫、虹膜紅變、早產兒視網膜病變、視網膜血管阻塞性疾病(其包括中央及分支視網膜靜脈阻塞)、炎性/傳染性視網膜新生血管形成/水腫(其包括後眼色素層炎、肉狀瘤、弓蟲症、組織胞漿菌病、伏格特-小柳-原田三氏病、慢性後眼色素層炎、點狀及多病灶內部脈絡膜病變)、視網膜母細胞瘤、眼黑色素瘤、眼腫瘤、視網膜脫落、近視性新生血管形成、血管狀痕、伊爾斯病(Eales disease)、脈絡膜破裂及其任一組合。 在實例性實施例中，眼科病況係濕型年齡相關性黃斑變性(濕型AMD)。 在實例性實施例中，哺乳動物係人類。 在實例性實施例中，組合物進一步包含中之一或多者依地酸二鈉(edetate disodium)、氯化鈉及氯苄烷銨。 在實例性實施例中，組合物係與抗血管生成劑組合投與。 在實例性實施例中，抗血管生成劑係選自由以下組成之群：阿必西帕(Abicipar)、培格蘭尼(Pegpleranib) (Fovista®)、Zimura®、RTH258 (曾用名，ESBA1008)、X-82、耐斯伐庫單抗(Nesvacumab) + 阿柏西普(Aflibercept) (EYLEA®)、RG7716、rAAV.sFlt-1、瑞他奈(Retaane) (阿奈可他(Anecortave Acetate))、斥消靈(Rapamune) (西羅莫司(Sirolimus))、美加明(Inversine) (美卡拉明(Mecamylamine))、伊旦替克斯(Idantirx) (AGX-51)、NT-503-3、iSONEP、Palomid 529、帕唑帕尼(Pazopanib) (VOTRIENT®)、AdGVPEDF.11D、JSM6427、TK001、PAN-90806、魯米那特(Luminate)、APL-2R、庫柏西普(Conbercept)、瓦他拉尼(Vatalanib) (PTK787)及ALG-1001。 在實例性實施例中，抗血管生成劑係抗VEGF藥物。在具體實施例中，抗VEGF藥物係選自由以下組成之群：蘭尼單抗(Ranibizumab) (Lucentis®)、貝伐珠單抗(Bevacizumab) (Avastin®)、阿柏西普(EYLEA®)、DARPin® MP0112及RTH258 (曾用名，ESBA1008)。 在實例性實施例中，抗血管生成劑係抗PDGF藥物。在具體實施例中，抗PDGF藥物係培格蘭尼(Fovista®)。 在實例性實施例中，抗血管生成劑係藉由任何習用方式投與哺乳動物眼睛中。在具體實施例中，該等習用方式包括藉由直接注射或藉由局部投與。 在實例性實施例中，組合物係在投與抗血管生成劑之前投與。 在實例性實施例中，組合物係與抗血管生成劑之投與同時投與。 在實例性實施例中，組合物係在投與抗血管生成劑之後投與。 在實例性實施例中，組合物係在投與抗血管生成劑之後以BID方式投與。 在實例性實施例中，抗血管生成劑係抗VEGF藥物或抗PDGF藥物。 本發明之另一態樣係降低在哺乳動物之眼睛中發生眼科病況之風險之方法，其中眼科病況已存於哺乳動物之另一隻眼睛中，該方法包含：向不具有眼科病況之眼睛中投與足以預防或延遲眼科病況發生之量之組合物，該組合物包含：二乳酸角鯊胺；緩衝劑；黏膜黏著劑；及環糊精。 本發明之另一態樣係降低哺乳動物發生眼科病況之風險之方法，其中在哺乳動物之一隻或兩隻眼睛中檢測到可導致眼科病況之異常病理或血管生成過程，該方法包含：向一隻或兩隻眼睛投與足以預防或延遲異常病理或血管生成過程進一步進展之量之組合物，該組合物包含：二乳酸角鯊胺；緩衝劑；黏膜黏著劑；及環糊精。 本發明之另一態樣係基於全身病況或病症、家族病史或遺傳預先傾向性來預防性治療在一隻或兩隻眼睛中具有異常致病或血管生成過程之風險之哺乳動物之方法，該方法包含：向一隻或兩隻眼睛投與足以預防或延遲異常病理或血管生成過程之量之組合物，該組合物包含：二乳酸角鯊胺；緩衝劑；黏膜黏著劑；及環糊精。 在實例性實施例中，該組合物包含：二乳酸角鯊胺；磷酸鈉；依地酸二鈉；氯化鈉；氯苄烷銨；2-羥丙基-β-環糊精；及水。 在實例性實施例中，該組合物由以下組成：二乳酸角鯊胺；磷酸鈉；依地酸二鈉；氯化鈉；氯苄烷銨；2-羥丙基-β-環糊精；及水。 在實例性實施例中，病灶中之一或多者具有唯一的典型CNV (亦即，100%)或小於100%，例如95%，例如90%，例如85%，例如80%，例如75%，例如70%，例如65%，例如60%，例如55%，例如50%，例如45%，例如40%，例如35%，例如30%，例如25%，例如20%，例如15%，例如10%，例如5%，例如大於0%。 在實例性實施例中，藉由螢光素血管造影測得治療開始時病灶中所存在之非典型CNV之面積小於10 mm2 ，例如9 mm2 ，例如8 mm2 ，例如7 mm2 ，例如6 mm2 ，例如5 mm2 ，例如4 mm2 ，例如3 mm2 ，例如2 mm2 ，例如1 mm2 ，且包括在病灶中零量之非典型CNV。 在實例性實施例中，組合物係調配物1之組合物。 在具體實施例中，組合物係調配物1A之組合物。 在具體實施例中，組合物係調配物1B之組合物。 在實例性實施例中，調配物1、調配物1A或調配物1B之組合物係以滴眼劑之形式投與。 在具體實施例中，組合物(式1)包含： 0.05 w/v%至0.3 w/v%二乳酸角鯊胺； 0.15 w/v%至0.35 w/v%磷酸鈉七水合物； 0.03 w/v%至0.12 w/v%磷酸二氫鈉一水合物； 0.8 w/v%至1.4 w/v%聚維酮K-30 ； 0.005 w/v%至0.05 w/v%依地酸二鈉； 0.3 w/v%至1.5 w/v%氯化鈉； 0.001 w/v%至0.01 w/v%氯苄烷銨； 0.5 w/v%至2.0 w/v% 2-羥丙基-β-環糊精；及 足量純化水， 其中pH = 6.5至7.5或6.7至7.1且滲透壓 = 280 mOsm/kg至340 mOsm/kg。 在具體實施例中，組合物(調配物1A)包含： 0.2 w/v%二乳酸角鯊胺； 0.27 w/v%磷酸鈉七水合物； 0.06 w/v%磷酸二氫鈉一水合物； 1.2 w/v%聚維酮K-30； 0.01 w/v%依地酸二鈉； 0.80 w/v%氯化鈉； 0.005 w/v%氯苄烷銨； 1.0 w/v% 2-羥丙基-β-環糊精；及 足量純化水， 其中pH = 6.70且滲透壓 = 315 mOsm/kg。 在另一具體實施例中，組合物(調配物1B)包含： 0.2%二乳酸角鯊胺； 0.188 w/v%磷酸鈉七水合物； 0.1 w/v%磷酸二氫鈉一水合物； 1.2 w/v%聚維酮K-30； 0.01%依地酸二鈉； 0.005 w/v%氯苄烷銨； 1.0 w/v% 2-羥丙基-β-環糊精；及 足量純化水， 其中pH = 6.70且滲透壓 = 315 mOsm/kg。 在本發明之實施例中，與眼睛內其他部位相比，在向哺乳動物之眼睛中投與組合物之後，在水狀液或玻璃體液中存在顯著更低濃度之調配物1、調配物1A或調配物1B之組合物。 本發明之態樣係以治療有效量向有需要之哺乳動物眼睛之後鞏膜及脈絡膜中選擇性遞送存於調配物1、調配物1A或調配物1B之組合物中之角鯊胺以治療眼科病況之方法，該方法包含：視情況與抗血管生成劑組合向哺乳動物之眼睛局部投與調配物1、調配物1A或調配物1B之組合物，其中眼科病況係選自由以下組成之群：濕型年齡相關性黃斑變性(濕型AMD)、乾型年齡相關性黃斑變性(乾型AMD)、糖尿病視網膜病變、增殖性糖尿病視網膜病變、缺血性視網膜病變(其包括視網膜動脈阻塞及頸動脈阻塞)、囊樣黃斑水腫、糖尿病黃斑水腫、虹膜紅變、早產兒視網膜病變、視網膜血管阻塞性疾病(其包括中央及分支視網膜靜脈阻塞)、炎性/傳染性視網膜新生血管形成/水腫(其包括後眼色素層炎、肉狀瘤、弓蟲症、組織胞漿菌病、伏格特-小柳-原田三氏病、慢性後眼色素層炎、點狀及多病灶內部脈絡膜病變)、視網膜母細胞瘤、眼黑色素瘤、眼腫瘤、視網膜脫落、近視性新生血管形成、血管狀痕、伊爾斯病、脈絡膜破裂及其任一組合。 本發明之態樣係在具有發生晚期AMD之風險之患者中預防發生AMD之方法，其包含向有需要之患者之一隻或兩隻眼睛投與治療有效量之調配物1、調配物1A或調配物1B之組合物。A method of the present invention is a method for the selective delivery of squalamine or a pharmaceutically acceptable salt thereof to the sclera and choroid of a mammal in need thereof in a therapeutically effective amount to treat an ophthalmic condition, the method comprising: to a mammal One or both of the eyes are administered a composition comprising: diacetamide, a buffer; a mucoadhesive; and a cyclodextrin, wherein the mammal has one or more SARS having an area of less than 10 mm 2 Type CNV lesions. Another aspect of the invention is a method of treating an ophthalmic condition in a mammal, the method comprising: administering to the eye of a mammal in need thereof a composition sufficient to treat the condition, the composition comprising: diacetate shark An amine; a buffer; a mucoadhesive; and a cyclodextrin wherein the mammal has one or more lesions having an atypical CNV of less than 10 mm 2 area. In an exemplary embodiment, the compositions are aqueous compositions. In an exemplary embodiment, the lesion having an atypical CNV has an area of less than 9 mm 2 , such as an area of less than 8 mm 2 , such as an area of less than 7 mm 2 , such as an area of less than 6 mm 2 , such as less than 5 mm 2 The area, for example less than 4 mm 2 , for example less than 3 mm 2 , for example less than 2 mm 2 , for example less than 1 mm 2 . In an exemplary embodiment, the lesion is present as a result of an ophthalmic condition. In an exemplary embodiment, the lesion has an atypical CNV but does not contain any typical CNV. In an exemplary embodiment, the lesion also contains a typical CNV. In an exemplary embodiment, the composition is administered to the eye of a mammal in a localized manner. In an exemplary embodiment, the composition is in the form of an eye drop. In an exemplary embodiment, after administration of the composition to the eye of a mammal, a significantly lower concentration of the composition is present in the aqueous or vitreous humor as compared to other sites in the eye. In an exemplary embodiment, the mucoadhesive agent in the composition is Povidone K-30. In an exemplary embodiment, the cyclodextrin in the composition is 2-hydroxypropyl-beta-cyclodextrin. In an exemplary embodiment, the buffer is a phosphate such as an alkali metal (eg, lithium, sodium or potassium) phosphate such as sodium phosphate, such as sodium phosphate heptahydrate and/or sodium dihydrogen phosphate monohydrate. In an exemplary embodiment, the ophthalmic condition is selected from the group consisting of wet type age-related macular degeneration (wet AMD), dry age-related macular degeneration (dry AMD), diabetic retinopathy, proliferative diabetes Retinopathy, ischemic retinopathy (including retinal artery occlusion and carotid occlusion), cystoid macular edema, diabetic macular edema, iris reddening, retinopathy of prematurity, retinal vascular occlusive disease (including central and branch retina) Venous obstruction), inflammatory/infectious retinal neovascularization/edema (including posterior uveitis, sarcoidosis, toxoplasmosis, histoplasmosis, Vogt-Koyanagi-Harada disease, chronic Posterior uveitis, punctate and multifocal internal choroidal lesions, retinoblastoma, ocular melanoma, ocular tumor, retinal detachment, myopic neovascularization, vascular lesions, Eales disease, Choroidal rupture and any combination thereof. In an exemplary embodiment, the ophthalmic condition is wet age-related macular degeneration (wet AMD). In an exemplary embodiment, the mammal is a human. In an exemplary embodiment, the composition further comprises one or more of edetate disodium, sodium chloride, and benzalkonium chloride. In an exemplary embodiment, the composition is administered in combination with an anti-angiogenic agent. In an exemplary embodiment, the anti-angiogenic agent is selected from the group consisting of Abicipar, Pegpleranib (Fovista®), Zimura®, RTH258 (formerly known as ESBA1008) , X-82, Nesvacumab + Aflibercept (EYLEA®), RG7716, rAAV.sFlt-1, Retaane (Anecortave Acetate) ), Rapamune (Sirolimus), Inversine (Mecamylamine), Idantirx (AGX-51), NT-503- 3, iSONEP, Palomid 529, Pazopanib (VOTRIENT®), AdGVPEDF.11D, JSM6427, TK001, PAN-90806, Luminate, APL-2R, Cobercy (Conbercept) , Vatalanib (PTK787) and ALG-1001. In an exemplary embodiment, the anti-angiogenic agent is an anti-VEGF drug. In a specific embodiment, the anti-VEGF drug is selected from the group consisting of Ranibizumab (Lucentis®), Bevacizumab (Avastin®), and EYLEA®. , DARPin® MP0112 and RTH258 (formerly known as ESBA1008). In an exemplary embodiment, the anti-angiogenic agent is an anti-PDGF drug. In a specific embodiment, the anti-PDGF drug is Fovista®. In an exemplary embodiment, the anti-angiogenic agent is administered to the mammalian eye by any conventional means. In a particular embodiment, such practices include direct injection or by topical administration. In an exemplary embodiment, the composition is administered prior to administration of the anti-angiogenic agent. In an exemplary embodiment, the composition is administered concurrently with administration of an anti-angiogenic agent. In an exemplary embodiment, the composition is administered after administration of an anti-angiogenic agent. In an exemplary embodiment, the composition is administered in a BID manner following administration of the anti-angiogenic agent. In an exemplary embodiment, the anti-angiogenic agent is an anti-VEGF drug or an anti-PDGF drug. Another aspect of the invention is a method of reducing the risk of developing an ophthalmic condition in the eye of a mammal, wherein the ophthalmic condition is already present in the other eye of the mammal, the method comprising: in an eye that does not have an ophthalmic condition A composition is administered in an amount sufficient to prevent or delay the onset of an ophthalmic condition comprising: diacetamide squalamine; a buffer; a mucoadhesive; and a cyclodextrin. Another aspect of the invention is a method of reducing the risk of developing an ophthalmic condition in a mammal, wherein an abnormal pathology or angiogenic process that results in an ophthalmic condition is detected in one or both of the mammals, the method comprising: One or both of the eyes are administered in an amount sufficient to prevent or delay the progression of the abnormal pathology or angiogenic process, the composition comprising: diacetamide squalamine; a buffer; a mucoadhesive; and a cyclodextrin. Another aspect of the invention is a method of prophylactically treating a mammal having an abnormal pathogenic or angiogenic process in one or both eyes based on a systemic condition or disorder, a family history, or a genetic predisposition. The method comprises: administering to one or both eyes a composition sufficient to prevent or delay an abnormal pathology or angiogenic process, the composition comprising: diacetamide squalamine; a buffer; a mucoadhesive; and a cyclodextrin . In an exemplary embodiment, the composition comprises: dibasic squalamine; sodium phosphate; disodium edetate; sodium chloride; benzalkonium chloride; 2-hydroxypropyl-β-cyclodextrin; . In an exemplary embodiment, the composition consists of: diacetamide squalamine; sodium phosphate; disodium edetate; sodium chloride; benzalkonium chloride; 2-hydroxypropyl-β-cyclodextrin; And water. In an exemplary embodiment, one or more of the lesions have a unique typical CNV (ie, 100%) or less than 100%, such as 95%, such as 90%, such as 85%, such as 80%, such as 75%. , for example 70%, such as 65%, such as 60%, such as 55%, such as 50%, such as 45%, such as 40%, such as 35%, such as 30%, such as 25%, such as 20%, such as 15%, for example 10%, such as 5%, such as greater than 0%. In an exemplary embodiment, the area of the atypical CNV present in the lesion at the onset of treatment is less than 10 mm 2 by lucifer angiography, for example 9 mm 2 , for example 8 mm 2 , for example 7 mm 2 , for example 6 mm 2 , for example 5 mm 2 , for example 4 mm 2 , for example 3 mm 2 , for example 2 mm 2 , for example 1 mm 2 , and includes a small amount of atypical CNV in the lesion. In an exemplary embodiment, the composition is a composition of Formulation 1. In a particular embodiment, the composition is a composition of Formulation 1A. In a particular embodiment, the composition is a composition of Formulation 1B. In an exemplary embodiment, the formulation of Formulation 1, Formulation 1A or Formulation 1B is administered as an eye drop. In a particular embodiment, the composition (Formula 1) comprises: 0.05 w/v% to 0.3 w/v% di-squalate squalamine; 0.15 w/v% to 0.35 w/v% sodium phosphate heptahydrate; 0.03 w /v% to 0.12 w/v% sodium dihydrogen phosphate monohydrate; 0.8 w/v% to 1.4 w/v% povidone K-30; 0.005 w/v% to 0.05 w/v% edetic acid Sodium; 0.3 w/v% to 1.5 w/v% sodium chloride; 0.001 w/v% to 0.01 w/v% benzalkonium chloride; 0.5 w/v% to 2.0 w/v% 2-hydroxypropyl- --cyclodextrin; and sufficient purified water, wherein pH = 6.5 to 7.5 or 6.7 to 7.1 and osmotic pressure = 280 mOsm/kg to 340 mOsm/kg. In a particular embodiment, the composition (Formulation 1A) comprises: 0.2 w/v% di-squalate squalamine; 0.27 w/v% sodium phosphate heptahydrate; 0.06 w/v% sodium dihydrogen phosphate monohydrate; 1.2 w/v% povidone K-30; 0.01 w/v% disodium edetate; 0.80 w/v% sodium chloride; 0.005 w/v% benzalkonium chloride; 1.0 w/v% 2-hydroxyl Propyl-β-cyclodextrin; and sufficient purified water, pH = 6.70 and osmotic pressure = 315 mOsm/kg. In another embodiment, the composition (Formulation 1B) comprises: 0.2% diamine squalamin; 0.188 w/v% sodium phosphate heptahydrate; 0.1 w/v% sodium dihydrogen phosphate monohydrate; w/v% povidone K-30; 0.01% disodium edetate; 0.005 w/v% benzalkonium chloride; 1.0 w/v% 2-hydroxypropyl-β-cyclodextrin; and sufficient purification Water, where pH = 6.70 and osmotic pressure = 315 mOsm/kg. In an embodiment of the invention, a significantly lower concentration of Formulation 1, Formulation 1A is present in the aqueous or vitreous humor following administration of the composition to the mammalian eye compared to other parts of the eye. Or the composition of Formulation 1B. The aspect of the invention is the selective delivery of squalamine in a composition of Formulation 1, Formulation 1A or Formulation 1B to the sclera and choroid of a mammalian eye after treatment in a therapeutically effective amount to treat an ophthalmic condition. A method comprising: topically administering to a mammalian eye, a combination of Formulation 1, Formulation 1A or Formulation 1B, in combination with an anti-angiogenic agent, wherein the ophthalmic condition is selected from the group consisting of: wet Age-related macular degeneration (wet AMD), dry age-related macular degeneration (dry AMD), diabetic retinopathy, proliferative diabetic retinopathy, ischemic retinopathy (including retinal artery occlusion and carotid artery occlusion) ) cystic macular edema, diabetic macular edema, iris reddening, retinopathy of prematurity, retinal vascular occlusive disease (including central and branch retinal vein occlusion), inflammatory/infectious retinal neovascularization/edema (including Posterior uveitis, sarcoma, toxoplasmosis, histoplasmosis, Vogt-Koyanagi-Harada disease, chronic posterior uveitis Point and multifocal internal choroidopathy), retinoblastoma, intraocular melanoma, ocular tumors, retinal detachment, myopic neovascularization, vascular marks, Eales disease, choroidal rupture, and any combination thereof. A method of the invention is a method of preventing the onset of AMD in a patient at risk of developing advanced AMD comprising administering to a patient in need thereof only or both eyes a therapeutically effective amount of Formulation 1, Formulation 1A or Composition of Formulation 1B.

相關申請案交叉參考 此申請案在技術上與美國公開專利申請案第20130281420號及美國專利第5,192,756號、第6,962,909號、第7,981,876號及第8,716,270號相關，該等案件中之每一者均以全文引用方式併入。 本發明之調配物/組合物具有有效遞送角鯊胺所需要之期望且獨特之特徵，經由本文所闡述之眼用組合物將該角鯊胺施加至眼睛之前部，至眼睛之後部，其中角鯊胺之治療濃度係治療靶向病症所需要之彼等。本發明者出乎意料地發現來自存於本發明眼用調配物中之每一個別賦形劑之貢獻之總和與角鯊胺分子本身之固有理化性質一致，例如該分子之兩性離子特徵，在治療量下在眼睛中達成高度合意之選擇性生物利用度/生物分佈/耐受性性質。因此，儘管常規技術可單獨闡述本發明眼用調配物之賦形劑中之一或多者係為人熟知的，但先前未評價或預測本文所闡述眼用調配物之發明者觀察到之該等特定賦形劑之總成之獨特性質。 所闡述調配物/組合物係穩定的，且其在滅菌後可包裝、儲存及直接使用。在實例性實施例中，調配物呈滴劑形式，按照該方式通常用於施加滴眼劑。正常擠壓型液體滴劑施加裝置完全適合用於施加本發明之眼用調配物。在實例性實施例中，調配物藉由將調配物逐滴添加至使用者之受影響眼睛中來便利地投與。 含有防腐劑之本發明調配物尤其有利地在多劑量容器中使用。如本文所使用之多劑量容器係指容許兩次或更多次單獨施用存於容器內之眼用調配物之容器。該等容器係可再密封的，亦即可去除容器蓋用於第一次施用，且然後可將蓋再置於容器上，藉此再次提供實質上液體不可滲透性密封。在實例性實施例中，抗微生物防腐劑係以足以降低微生物濃度達約12小時至約72小時(例如約12小時至約48小時，例如約12小時至約24小時)之時段之量存在。 本發明之醫藥組合物可在任何習用的眼科上相容之媒劑中調配，例如，軟膏、乳霜、懸浮液、洗劑、粉末、溶液、糊劑、凝膠、噴霧劑、氣溶膠或油。 如本文所定義，「治療有效量」係完全或部分地抑制病況之進展或至少部分地緩解病況之一或多種症狀之活性劑(例如角鯊胺)之量。治療有效量亦可為在預防上有效之量。治療上有效之量將取決於患者之重量及性別、欲治療之病況、病況之嚴重性及尋求結果。對於給定患者，治療有效量可藉由業內已知之方法來確定。二乳酸角鯊胺之濃度通常將為約0.01重量%至約5.0重量%，例如約0.01重量%至約4.0重量%，例如約0.02重量%至約3.0重量%，例如約0.03重量%至約2.0重量%，例如約0.05重量%至約1.0重量%。 存於本發明組合物中之角鯊胺之二乳酸鹽可以非晶形形式或以結晶形式存在。在本發明之實例性實施例，二乳酸鹽之結晶形式以溶劑合物形式存在。在另一實例性實施例中，結晶形式以水合物形式存在，且在另一實施例中，二乳酸鹽以溶劑合物及水合物形式存在。二乳酸角鯊胺之結晶形式可以溶劑合物形式存在，其中溶劑分子納入晶體結構內。例如，當溶劑含有乙醇時，晶體可含有乙醇分子。在另一實施例中，溶劑合物可含有水，且晶體可為在晶體結構中含有水之水合物。在另一實施例中，晶體可為溶劑合物及水合物。二乳酸角鯊胺之各種結晶形式之論述可參見美國專利第7,981,876號，其係以全文引用方式併入。 如本文所定義，術語「眼科病況」或「眼科病症」包括(但不限於)濕型年齡相關性黃斑變性(濕型AMD)、乾型年齡相關性黃斑變性(乾型AMD)、糖尿病視網膜病變、增殖性糖尿病視網膜病變、缺血性視網膜病變(其包括視網膜動脈阻塞及頸動脈阻塞)、囊樣黃斑水腫、糖尿病黃斑水腫、虹膜紅變、早產兒視網膜病變、視網膜血管阻塞性疾病(其包括中央及分支視網膜靜脈阻塞)、炎性/傳染性視網膜新生血管形成/水腫(其包括後眼色素層炎、肉狀瘤、弓蟲症、組織胞漿菌病、伏格特-小柳-原田三氏病、慢性後眼色素層炎、點狀及多病灶內部脈絡膜病變)、視網膜母細胞瘤、眼黑色素瘤、眼腫瘤、視網膜脫落、近視性新生血管形成、血管狀痕、伊爾斯病、脈絡膜破裂及其任一組合。 如本文所使用之片語「醫藥上可接受之鹽」為人熟知且係指可安全用於哺乳動物中之化學化合物之任一鹽。醫藥上可接受之鹽包括(但不限於)存於化學化合物中之酸基團及/或鹼基團之鹽。實例性醫藥上可接受之酸加成鹽包括(但不限於)鹽酸鹽、氫溴酸鹽、氫碘酸鹽、硝酸鹽、硫酸鹽、硫酸氫鹽、磷酸鹽、乙酸鹽、乳酸鹽、柳酸鹽、檸檬酸鹽、酒石酸鹽、抗壞血酸鹽、琥珀酸鹽、馬來酸鹽、富馬酸鹽、葡萄糖酸鹽、甲酸鹽、苯甲酸鹽、甲磺酸鹽、乙磺酸鹽、苯磺酸鹽及對甲苯磺酸鹽。醫藥上可接受之鹽化合物亦包括式-NRR'R''+ Z- 之四級銨鹽，其中R、R'及R''中之每一者獨立地係(例如)氫、烷基或烷基芳基，且Z係相對離子，包括(但不限於)氯離子、溴離子、碘離子、烷氧離子、對甲苯磺酸根、甲基磺酸根、磺酸根、磷酸根或羧酸根。 如本文所用片語「家族病史」已為人熟知且係指家族內遺傳關係與個別家族成員之病史之組合。 如本文所用片語「遺傳預先傾向性」已為人熟知且係指使人易患具體疾病或病症之遺傳性遺傳型式。 用於本發明之眼用調配物中之適宜緩衝劑包括(但不限於)自碳酸氫鈉鹽、鉀鹽、磷酸鈉鹽、鉀鹽、乙酸鈉鹽、鉀鹽、檸檬酸鈉鹽、鉀鹽、硼酸鈉鹽、鉀鹽及/或磷酸、乙酸、檸檬酸或硼酸製備之緩衝劑。在實例性實施例中，緩衝劑係磷酸二氫鈉或磷酸二鈉或硼酸/硼酸鈉。緩衝劑應以足以產生及維持約5.5至約8.0之產物pH之量存在，例如約5.7至約7.7，例如約6.0至約7.4，例如約6.3至約7.1，例如約6.7至7.1，例如約6.7至約6.8，且包括約5.7、約5.9、約6.1、約6.3、約6.5、約6.7、約6.9、約7.1、約7.3、約7.5、約7.7或約7.9之pH。 適宜黏膜黏著劑在存於所闡述調配物中時通常增加角膜接觸時間、生物利用度及/或提供潤滑效應，且其包括(但不限於)丙烯酸聚合物、甲基纖維素、乙基纖維素、聚維酮K-30、羥丙基甲基纖維素、羥基乙基纖維素、Carbopol®聚合物(例如Carbopol® 674、676、690、980 NF、EZ-2、EZ-3、EZ-4、Aqua 30及Novethix™ L-10)、羥丙基纖維素、聚乙烯醇、明膠、軟骨素硫酸鈉或其任一組合。 亦可將增溶劑或再懸浮劑添加至本發明調配物中。適宜增溶劑或再懸浮劑包括(但不限於)環糊精(CD)(例如羥丙基γ-環糊精(Cavasol®)、磺丁基醚4 β-環糊精(Captisol®)及羥丙基β-環糊精(Kleptose®)(例如2-羥丙基β-環糊精)、聚山梨醇酯80 (Tween80® )或玻尿酸或玻尿酸鹽。具體而言，環糊精亦可展現滲透增強性質，但亦已知環糊精阻止類固醇化合物(例如氫化可的松(hydrocortisone))吸收至眼部組織中(Masson, M.等人，Proc. of the 9th Intl. Symposium on Cyclodextrins, Kluwer Academic Publishers 363-369 (1999)；Loftsson, T.等人，Acta Ophthalmologica Scandinavica 144-150 (2003)；International Journal of Pharmaceutics 156, 201-209 (1997))。 可視情況存於所述調配物中之滲透增強劑包括(但不限於)月桂氮酮(laurocapram) (氮酮(azone))、膽汁酸及其鹼金屬鹽，包括鵝去氧膽酸、膽酸、牛磺膽酸、牛磺去氧膽酸、牛磺熊去氧膽酸或熊去氧膽酸、甘膽酸鹽、正十二烷基-β-D-麥芽糖苷、蔗糖十二烷酸酯、辛基麥芽糖苷、癸基麥芽糖苷、十三烷基麥芽糖苷、十四烷基麥芽糖苷、六亞甲基月桂醯胺、六亞甲基辛醯胺、甘油單月桂酸酯、PGML (聚乙二醇單月桂酸酯)、二甲基亞碸、甲基磺醯基甲烷、夫西地酸鈉(sodium fusidate)、皂素或其任一組合。 可用於本文所闡述眼用組合物中之熟習此項技術者已知之典型載劑、穩定劑及佐劑之實例性清單可參見Gennaro (2005) Remington: The Science and Practice of Pharmacy, Mack Publishing, 第21版。 活體內投與組合物本發明可在整個治療過程期間以一個劑量、多個劑量、連續或間歇性地實現。測定最有效投與劑量之方法為熟習此項技術者熟知且將隨療法所用組合物、療法目的及所治療個體而變化。可實施單次或多次投與，其中劑量量及型式由治療醫師選擇。 各種特定化及非限制性調配物闡述於下文實例中。該等調配物僅圖解說明所闡述發明且並非意欲限制所闡述發明之範圍。 在實例性實施例中，本發明反映如下出乎意料之觀察結果：當患者具有小於10 mm2 面積之非典型CNV時，針對眼科病況使用如本文所闡述之抗VEGF藥物(例如Lucentis®)及式1組合物之組合療法進行治療之患者經歷較高成功率。當僅使用Lucentis®單一療法時，未觀察到此現象。 在另一實例性實施例中，本發明係關於使用如本文所闡述之抗PDGF藥物及式1組合物之組合療法對患者之眼科病況之治療，其中患者具有小於10 mm2 面積之非典型CNV。 所觀察到之結果容許使用非典型CNV大小作為在視情況與抗血管生成劑(例如習用抗血管生成劑)組合使用二乳酸角鯊胺之眼用調配物治療與脈絡膜新生血管形成相關之眼睛病況中達成之成功程度的預測子。實例 實例1 -調配物1 調配物1含有以下組份： 0.05 w/v%至0.25 w/v%二乳酸角鯊胺； 0.15 w/v%至0.35 w/v%磷酸鈉七水合物及0.03 w/v%至0.12 w/v%磷酸二氫鈉一水合物； 0.8 w/v%至1.4 w/v%聚維酮K-30 ； 0.005 w/v%至0.05 w/v%依地酸二鈉； 0.3 w/v%至1.5 w/v%氯化鈉； 0.001 w/v%至0.01 w/v%氯苄烷銨； 0.5 w/v%至2.0 w/v% 2-羥丙基-β-環糊精；及 足量純化水。 pH = 6.5至7.5或6.7至7.1且滲透壓 = 280 mOsm/kg至340 mOsm/kg。 調配物1之具體實施例(稱作調配物1A)含有0.2 w/v%二乳酸角鯊胺；0.27 w/v%磷酸鈉七水合物；0.06 w/v%磷酸二氫鈉一水合物；1.2 w/v%聚維酮K-30；0.01 w/v%依地酸二鈉；0.80 w/v%氯化鈉；0.005 w/v%氯苄烷銨；1.0 w/v% 2-羥丙基-β-環糊精；及足量純化水。pH = 6.70且滲透壓 = 315 mOsm/kg。 調配物1之另一具體實施例(稱作調配物1B)含有0.2%二乳酸角鯊胺；0.188 w/v%磷酸鈉七水合物及0.1 w/v%磷酸二氫鈉一水合物；1.2 w/v %聚維酮K-30；0.01%依地酸二鈉；0.005 w/v%氯苄烷銨；1.0 w/v% 2-羥丙基-β-環糊精；及足量純化水。pH = 6.70且滲透壓 = 315 mOsm/kg。 調配物1A之製備. 將約50 mL純化水置於具有攪拌棒之250 mL刻度玻璃燒杯中。將0.27 g磷酸鈉七水合物添加至燒杯中並攪拌直至其溶解為止。將0.06 g磷酸二氫鈉一水合物添加至燒杯中並攪拌直至其溶解為止。將0.005 g氯苄烷銨添加至燒杯中並攪拌直至其溶解為止。將0.01 g EDTA二鈉添加至燒杯中並攪拌直至其溶解為止。將0.8 g氯化鈉添加至燒杯中並攪拌直至其溶解為止。將1.2 g聚維酮K-30添加至燒杯中並攪拌直至其溶解為止。將1.0 g 2-羥丙基-β-環糊精添加至燒杯中並攪拌直至其溶解為止。將0.200 g二乳酸角鯊胺添加至燒杯中並攪拌直至其溶解為止。將約40 mL純化無菌水添加至燒杯中並使用2 N NaOH及1 N HC1將pH調節至6.7 (若需要)。利用充足量之注射用水或純化水USP將體積補足至100 mL。使用前藉助0.22微米過濾器無菌過濾溶液。 調配物1B之製備.  此調配物係以與調配物1A類似之來製備。 實例2 -調配物1之臨床測試 下文所闡述之研究代表調配物1A用於治療濕型AMD之安全性及效能之9個月的II期臨床試驗評估。兩個治療臂為每日兩次投與調配物1A滴劑加Lucentis® (「調配物1A」臂或組，且在圖中標記為「形式-1A」)對每日兩次投與安慰劑滴眼劑加Lucentis® (「Lucentis®單一療法」臂或組，且在圖中標記為「安慰劑」)。該研究中之所有患者皆接受初始Lucentis®注射。將142名患者隨機化至該研究中，其中90%之患者完成該9個月的治療方案。調配物1A通常耐受良好，且在該研究中僅兩例治療相關之中斷。 分析完成9個月治療時段之患者之視覺敏銳度結果。在具有帶有小於10 mm2 面積之非典型CNV之病灶之群體(94名患者)中，在第9個月時視覺敏銳度之平均增加為調配物1A臂之+11個字母及Lucentis®單一療法之+5.7個字母，在臨床上有意義之益處為5.3個字母(圖 2A )。另外，如與在Lucentis®單一療法組中之26%相比，在9個月時40%的接受調配物1A組合療法之該等患者達成≥3行視覺增加(圖 2B )。對視覺敏銳度之此正面效應在治療過程早期既已觀察到且其繼續增加直至研究結束為止。 具有含有小於10 mm2 面積之非典型CNV之病灶之患者之數據亦顯示，對於彼等達成≥4行及≥5行視覺增加之患者，在調配物1A組與Lucentis®單一療法組之間之分離更為顯著。如與對於接受Lucentis®單一療法之彼等具有≥4行增加之6%及具有≥5行增加之4%相比，在接受調配物1A之患者中，在9個月時17%達成≥4行增加且10%達成≥5行增加(圖 2C )。 非典型CNV大小對視覺敏銳度之結果之效應繪示於圖 3A 及3B 中，該等圖顯示具有帶有5 mm2 面積之非典型CNV之病灶的患者經歷顯著好於具有帶有12.5 mm2 面積之非典型CNV之病灶的患者的結果。在非典型CNV之基線大小與視覺敏銳度結果之間觀察到強烈關聯。值得注意的，在僅接受Lucentis®單一療法之患者中未觀察到非典型CNV大小對視覺敏銳度之結果之影響。因此，在臨床結果之子集評估後，確定具有帶有經量測面積小於10 mm2 之非典型CNV之病灶之患者代表較佳患者群體。 本文引用之所有專利/公開案皆以全文引用方式併入。 CROSS REFERENCE TO RELATED APPLICATIONS This application is related to U.S. Patent Application Serial No. 20,130, 281, 420 and U.S. Patent Nos. 5,192,756, 6,962, 909, 7,981, 876, and 8, 716, 270, each of which The full text is incorporated by reference. The formulations/compositions of the present invention have the desirable and unique characteristics required for effective delivery of squalamine, which is applied to the front of the eye via the ophthalmic composition set forth herein to the back of the eye, where The therapeutic concentration of squalamine is required for the treatment of targeted conditions. The inventors have unexpectedly discovered that the sum of the contributions from each of the individual excipients present in the ophthalmic formulations of the present invention is consistent with the inherent physicochemical properties of the squalamine molecule itself, such as the zwitterionic character of the molecule, A highly desirable selective bioavailability/biodistribution/tolerance property is achieved in the eye at therapeutic doses. Thus, while one or more of the excipients of the ophthalmic formulations of the present invention are individually well-known by conventional techniques, it has been previously observed by the inventors of the ophthalmic formulations not described herein. The unique nature of the assembly of a particular excipient. The formulations/compositions described are stable and can be packaged, stored and used directly after sterilization. In an exemplary embodiment, the formulation is in the form of a drop, which is typically used to apply eye drops in this manner. The normally extruded liquid drop application device is fully suitable for applying the ophthalmic formulation of the present invention. In an exemplary embodiment, the formulation is conveniently administered by dropwise adding the formulation to the affected eye of the user. Formulations of the invention containing a preservative are especially advantageously used in multi-dose containers. A multi-dose container as used herein refers to a container that allows two or more separate administrations of an ophthalmic formulation contained in a container. The containers are resealable, i.e., the container lid can be removed for the first application, and the lid can then be placed over the container, again providing a substantially liquid impermeable seal. In an exemplary embodiment, the antimicrobial preservative is present in an amount sufficient to reduce the microbial concentration for a period of from about 12 hours to about 72 hours (eg, from about 12 hours to about 48 hours, such as from about 12 hours to about 24 hours). The pharmaceutical compositions of the present invention can be formulated in any conventional ophthalmically compatible vehicle, for example, ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols or oil. As defined herein, a "therapeutically effective amount" is an amount of an active agent (eg, squalamine) that completely or partially inhibits progression of a condition or at least partially alleviates one or more symptoms of the condition. The therapeutically effective amount can also be an amount that is effective in preventing. The therapeutically effective amount will depend on the weight and sex of the patient, the condition to be treated, the severity of the condition, and the search for results. For a given patient, a therapeutically effective amount can be determined by methods known in the art. The concentration of di- squalamin will generally range from about 0.01% to about 5.0% by weight, such as from about 0.01% to about 4.0% by weight, such as from about 0.02% to about 3.0% by weight, such as from about 0.03% to about 2.0%. % by weight, for example from about 0.05% by weight to about 1.0% by weight. The dicalcium salt of squalamine present in the composition of the present invention may be present in an amorphous form or in a crystalline form. In an exemplary embodiment of the invention, the crystalline form of the dilactalate is in the form of a solvate. In another exemplary embodiment, the crystalline form is in the form of a hydrate, and in another embodiment, the dilactate is in the form of a solvate and a hydrate. The crystalline form of the di-saltamine can be present in the form of a solvate in which the solvent molecules are incorporated into the crystal structure. For example, when the solvent contains ethanol, the crystals may contain ethanol molecules. In another embodiment, the solvate may contain water, and the crystal may be a hydrate containing water in the crystal structure. In another embodiment, the crystals can be solvates and hydrates. A discussion of various crystalline forms of di-squalic acid squalamine can be found in U.S. Patent No. 7,981,876, which is incorporated by reference in its entirety. As defined herein, the term "ophthalmic condition" or "ophthalmic condition" includes, but is not limited to, wet age-related macular degeneration (wet AMD), dry age-related macular degeneration (dry AMD), diabetic retinopathy. Proliferative diabetic retinopathy, ischemic retinopathy (including retinal artery occlusion and carotid occlusion), cystoid macular edema, diabetic macular edema, iris reddening, retinopathy of prematurity, retinal vascular occlusive disease (including Central and branch retinal vein occlusion), inflammatory/infectious retinal neovascularization/edema (including posterior uveitis, sarcoidosis, toxoplasmosis, histoplasmosis, Vogt-Koyanagi-Harada Disease, chronic posterior uveitis, punctate and multifocal internal choroidal lesions, retinoblastoma, ocular melanoma, ocular tumor, retinal detachment, myopic neovascularization, vascular lesions, Iles disease, Choroidal rupture and any combination thereof. As used herein, the phrase "pharmaceutically acceptable salts" is well known and refers to any salt of a chemical compound that can be safely used in mammals. Pharmaceutically acceptable salts include, but are not limited to, the acid groups and/or salts of base groups present in the chemical compound. Exemplary pharmaceutically acceptable acid addition salts include, but are not limited to, hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, hydrogen sulfate, phosphate, acetate, lactate, Salicylate, citrate, tartrate, ascorbate, succinate, maleate, fumarate, gluconate, formate, benzoate, methanesulfonate, ethanesulfonate , besylate and p-toluenesulfonate. Pharmaceutically acceptable salts also include compounds of formula -NRR'R '' + Z - the quaternary ammonium salts, wherein R, R 'and each R''independently of the system (e.g.) hydrogen, alkyl, or Alkylaryl, and Z is a relative ion, including but not limited to chloride, bromide, iodide, alkoxide, p-toluenesulfonate, methanesulfonate, sulfonate, phosphate or carboxylate. The phrase "family history" as used herein is well known and refers to a combination of genetic relationships within a family and the history of individual family members. The phrase "genetic predisposition" as used herein is well known and refers to a hereditary genetic pattern that predisposes a person to a particular disease or condition. Suitable buffering agents for use in the ophthalmic formulations of the present invention include, but are not limited to, sodium bicarbonate, potassium, sodium, potassium, sodium, potassium, sodium citrate, potassium salts A buffer prepared from sodium borate, potassium salt and/or phosphoric acid, acetic acid, citric acid or boric acid. In an exemplary embodiment, the buffer is sodium dihydrogen phosphate or disodium phosphate or boric acid/sodium borate. The buffering agent should be present in an amount sufficient to produce and maintain a pH of the product of from about 5.5 to about 8.0, such as from about 5.7 to about 7.7, such as from about 6.0 to about 7.4, such as from about 6.3 to about 7.1, such as from about 6.7 to 7.1, such as about 6.7. To about 6.8, and includes a pH of about 5.7, about 5.9, about 6.1, about 6.3, about 6.5, about 6.7, about 6.9, about 7.1, about 7.3, about 7.5, about 7.7, or about 7.9. Suitable mucoadhesive agents generally increase corneal contact time, bioavailability, and/or provide a lubricating effect when present in the formulations described, and include, but are not limited to, acrylic polymers, methylcellulose, ethylcellulose , Povidone K-30, Hydroxypropyl Methyl Cellulose, Hydroxyethyl Cellulose, Carbopol® Polymers (eg Carbopol® 674, 676, 690, 980 NF, EZ-2, EZ-3, EZ-4 , Aqua 30 and NovethixTM L-10), hydroxypropylcellulose, polyvinyl alcohol, gelatin, sodium chondroitin or any combination thereof. Solubilizers or resuspension agents can also be added to the formulations of the invention. Suitable solubilizing or resuspension agents include, but are not limited to, cyclodextrin (CD) (eg, hydroxypropyl gamma-cyclodextrin (Cavasol®), sulfobutyl ether 4 beta-cyclodextrin (Captisol®), and hydroxy Propyl β-cyclodextrin (Kleptose®) (eg 2-hydroxypropyl β-cyclodextrin), polysorbate 80 (Tween 80 ® ) or hyaluronic acid or hyaluronic acid. In particular, cyclodextrin can also exhibit permeation enhancing properties, but cyclodextrins are also known to prevent steroid (e.g. hydrocortisone (hydrocortisone)) absorbed to the eye tissue (Masson, M. et al., Proc. of the 9 th Intl . Symposium on cyclodextrins, Kluwer Academic Publishers 363-369 (1999); Loftsson, T. et al., Acta Ophthalmologica Scandinavica 144-150 (2003); International Journal of Pharmaceutics 156, 201-209 (1997)). Permeation enhancers include, but are not limited to, laurocapram (azone), bile acids and their alkali metal salts, including chenodeoxycholic acid, cholic acid, taurocholic acid, taurofen Oxycholic acid, tauroursodeoxycholic acid or ursodeoxycholic acid, glycocholate, n-dodecyl-β-D-maltoside, Sucrose dodecanoate, octyl maltoside, mercapto maltoside, tridecyl maltoside, tetradecyl maltoside, hexamethylene laurylamine, hexamethylene octylamine, glycerol single laurel Acid ester, PGML (polyethylene glycol monolaurate), dimethyl azine, methylsulfonyl methane, sodium fusidate, saponin or any combination thereof. An exemplary list of typical carriers, stabilizers, and adjuvants known to those skilled in the art for use in ophthalmic compositions can be found in Gennaro (2005) Remington: The Science and Practice of Pharmacy, Mack Publishing, 21st Edition. In Vivo Administration Compositions The present invention can be practiced in one dose, multiple doses, continuously or intermittently throughout the course of the treatment. Methods for determining the most effective dosage are those well known to those skilled in the art and which will be used with therapies. Depending on the purpose of the therapy and the individual being treated, single or multiple administrations may be administered, wherein the dosage and form are selected by the treating physician. Various specific and non-limiting formulations are set forth in the Examples below. Description of the Solution of the invention and are not intended to limit the scope of the invention as set forth in the exemplary embodiment illustrated embodiment, the present invention reflects the observation of the following unexpected results: When the patient has an atypical CNV area 2 is less than 10 mm, for ophthalmic condition Patients treated with combination therapy with an anti-VEGF drug (eg, Lucentis®) as described herein and a combination of Formula 1 compositions experience a higher success rate. This phenomenon was not observed when using only Lucentis® monotherapy. In another exemplary embodiment, the invention relates to the treatment of an ophthalmic condition of a patient using a combination therapy of an anti-PDGF drug and a composition of formula 1 as set forth herein, wherein the patient has an atypical CNV of less than 10 mm 2 area . The observed results allow the use of atypical CNV size as an eye condition associated with choroidal neovascularization in the ophthalmic formulation of dicyanosalamine in combination with an anti-angiogenic agent (eg, a conventional anti-angiogenic agent). A predictor of the degree of success achieved in the middle. EXAMPLES Example 1 - Formulation 1 Formulation 1 contains the following components: 0.05 w/v% to 0.25 w/v% di-squalate squalamine; 0.15 w/v% to 0.35 w/v% sodium phosphate heptahydrate and 0.03 w/v% to 0.12 w/v% sodium dihydrogen phosphate monohydrate; 0.8 w/v% to 1.4 w/v% povidone K-30; 0.005 w/v% to 0.05 w/v% edetic acid Disodium; 0.3 w/v% to 1.5 w/v% sodium chloride; 0.001 w/v% to 0.01 w/v% benzalkonium chloride; 0.5 w/v% to 2.0 w/v% 2-hydroxypropyl -β-cyclodextrin; and sufficient purified water. pH = 6.5 to 7.5 or 6.7 to 7.1 and osmotic pressure = 280 mOsm/kg to 340 mOsm/kg. A specific example of Formulation 1 (referred to as Formulation 1A) contains 0.2 w/v% dihrolyl squalamine; 0.27 w/v% sodium phosphate heptahydrate; 0.06 w/v% sodium dihydrogen phosphate monohydrate; 1.2 w/v% povidone K-30; 0.01 w/v% disodium edetate; 0.80 w/v% sodium chloride; 0.005 w/v% benzalkonium chloride; 1.0 w/v% 2-hydroxyl Propyl-β-cyclodextrin; and sufficient purified water. pH = 6.70 and osmotic pressure = 315 mOsm/kg. Another embodiment of Formulation 1 (referred to as Formulation 1B) contains 0.2% dihrolyl squalamine; 0.188 w/v% sodium phosphate heptahydrate and 0.1 w/v% sodium dihydrogen phosphate monohydrate; w/v % povidone K-30; 0.01% disodium edetate; 0.005 w/v% benzalkonium chloride; 1.0 w/v% 2-hydroxypropyl-β-cyclodextrin; and sufficient purification water. pH = 6.70 and osmotic pressure = 315 mOsm/kg. Preparation of Formulation 1A. Approximately 50 mL of purified water was placed in a 250 mL graduated glass beaker with a stir bar. 0.27 g of sodium phosphate heptahydrate was added to the beaker and stirred until it dissolved. 0.06 g of sodium dihydrogen phosphate monohydrate was added to the beaker and stirred until it dissolved. 0.005 g of benzalkonium chloride was added to the beaker and stirred until it dissolved. Add 0.01 g of disodium EDTA to the beaker and stir until it dissolves. 0.8 g of sodium chloride was added to the beaker and stirred until it dissolved. 1.2 g of povidone K-30 was added to the beaker and stirred until it dissolved. 1.0 g of 2-hydroxypropyl-β-cyclodextrin was added to the beaker and stirred until it dissolved. 0.200 g of di-squalic acid squalamine was added to the beaker and stirred until it dissolved. Approximately 40 mL of purified sterile water was added to the beaker and the pH was adjusted to 6.7 (if needed) using 2 N NaOH and 1 N HCl. The volume is made up to 100 mL with a sufficient amount of water for injection or purified water USP. The solution was sterile filtered using a 0.22 micron filter prior to use. Preparation of Formulation 1B. This formulation was prepared analogously to Formulation 1A. Example 2 - Clinical Testing of Formulation 1 The studies set forth below represent a 9-month Phase II clinical trial evaluation of Formulation 1A for the safety and efficacy of Wet AMD. Two treatment arms were administered twice daily with Formulation 1A drops plus Lucentis® ("Condition 1A" arm or group, and labeled "Form-1A" in the figure) to place twice daily with placebo Eye drops plus Lucentis® ("Lucentis® Monotherapy" arm or group and labeled "Placebo" in the figure). All patients in the study received an initial Lucentis® injection. 142 patients were randomized to the study, and 90% of the patients completed the 9-month treatment regimen. Formulation 1A was generally well tolerated and there were only two treatment related interruptions in this study. The visual acuity results of patients who completed the 9-month treatment period were analyzed. In the population (94 patients) with lesions with atypical CNV of less than 10 mm 2 area, the average increase in visual acuity at 9 months was +11 letters of the 1A arm of the formulation and the Lucentis® single The +5.7 letters of therapy have a clinically meaningful benefit of 5.3 letters ( Figure 2A ). In addition, 40% of those receiving Formulation 1A combination therapy achieved a visual increase of ≥3 lines at 9 months compared to 26% in the Lucentis® monotherapy group ( Figure 2B ). This positive effect on visual acuity has been observed both early in the treatment process and continues to increase until the end of the study. Data from patients with lesions containing atypical CNV of less than 10 mm 2 area also showed that between patients with ≥4 lines and ≥5 lines of visual increase, between Formulation 1A and Lucentis® monotherapy groups The separation is more pronounced. 17% achieved ≥ 4 at 9 months in patients receiving Formulation 1A compared to 6% with ≥4 lines of increase and 4% of ≥5 lines for those who received Lucentis® monotherapy The line increases and 10% achieves an increase of ≥5 lines ( Fig. 2C ). The effect of atypical CNV size on the results of visual acuity is shown in Figures 3A and 3B , which show that patients with lesions with atypical CNV of 5 mm 2 area experience significantly better than with 12.5 mm 2 The results of patients with atypical CNV lesions in the area. A strong correlation was observed between the baseline size of the atypical CNV and the visual acuity results. Notably, the effect of atypical CNV size on visual acuity was not observed in patients receiving only Lucentis® monotherapy. Thus, after a subset of clinical outcomes, patients with lesions with atypical CNVs with a measured area of less than 10 mm 2 are identified as representing a preferred patient population. All patents/published references cited herein are hereby incorporated by reference in their entirety.

各圖僅圖解說明本發明之具體實施例且並非意欲以任一方式限制如本文所闡述之整體發明之範圍。圖 1 圖解說明角鯊胺處理之(1 µM角鯊胺)、稀疏平鋪之HUVAC細胞對碘化丙啶(PrI)之選擇性吸收，其可指示細胞腫瘤病。圖 2 圖解說明在接受利用Lucentis®及調配物1A之組合物之組合治療之患者中在具有非典型CNV之病灶之面積(mm2 )與所觀察到的視覺敏銳度之間的關聯。圖 3A 圖解說明在利用Lucentis®及調配物1A之組合物(標記為「形式-1A」)組合治療對利用Lucentis®及安慰劑調配物(標記為「安慰劑」)治療之後，在含有具有經量測面積小於10 mm2 之非典型CNV之病灶之患者群體中，直至第36週視覺敏銳度之平均變化。圖 3B 圖解說明在利用Lucentis®及調配物1A之組合物(標記為「形式-1A」)組合治療對利用Lucentis®及安慰劑調配物(標記為「安慰劑」)治療之後，直至第36週視覺敏銳度增加≥ 3行之患者之百分比，其中患者群體限於含有具有經量測面積小於10 mm2 之非典型CNV之病灶之彼等個體。圖 3C 圖解說明在利用Lucentis®及調配物1A之組合物(標記為「形式-1A」)組合治療對利用Lucentis®及安慰劑調配物(標記為「安慰劑」)治療之後，在第36週視覺敏銳度增加≥ 4行或增加≥ 5行之患者之百分比，其中患者群體限於含有具有經量測面積小於10 mm2 之非典型CNV之病灶之彼等個體。圖 4A 圖解說明在利用Lucentis®及調配物1A之組合物(標記為「形式-1A」)組合治療之後在第36週後，非典型CNV大小(5 mm2 、7.5 mm2 、10 mm2 及12.5 mm2 )對視覺敏銳度結果之效應。圖 4B 圖解說明直至第36週得益於利用Lucentis®及調配物1A之組合物(標記為「形式-1A」)之組合治療之患者的百分比，其中患者群體係藉由5 mm2 、7.5 mm2 、10 mm2 及12.5 mm2 之非典型CNV大小分開。The drawings are merely illustrative of specific embodiments of the invention and are not intended to limit the scope of the invention as set forth herein. Figure 1 illustrates the selective uptake of propidium iodide (PrI) by squalamine treated (1 μM squalamine), sparsely tiled HUVAC cells, which may be indicative of a cell tumor disease. Figure 2 illustrates the use of a combination in patients receiving Lucentis® 1A and formulations of the composition in the treatment of atypical CNV lesion area having the correlation between the observed visual acuity (mm 2). Figure 3A illustrates the combination therapy with Lucentis® and Formulation 1A (labeled "Form-1A") for treatment with Lucentis® and a placebo formulation (labeled "Placebo"). Mean changes in visual acuity up to week 36 were measured in a population of patients with lesions of atypical CNV with an area of less than 10 mm 2 . Figure 3B illustrates the combination treatment with Lucentis® and Formulation 1A (labeled "Form-1A") for treatment with Lucentis® and placebo formulations (labeled "Placebo") until week 36 The percentage of patients with visual acuity increased by ≥ 3 lines, wherein the patient population is limited to those individuals with lesions having atypical CNV having a measured area of less than 10 mm 2 . Figure 3C illustrates the combination treatment with Lucentis® and Formulation 1A (labeled "Form-1A") for treatment with Lucentis® and a placebo formulation (labeled "Placebo") at week 36. The percentage of patients whose visual acuity is increased by ≥ 4 lines or increased by ≥ 5 lines, wherein the patient population is limited to those individuals with lesions having atypical CNV having a measured area of less than 10 mm 2 . Figure 4A illustrates atypical CNV size (5 mm 2 , 7.5 mm 2 , 10 mm 2 and after 36 weeks after treatment with a combination of Lucentis® and Formulation 1A (labeled "Form-1A"). 12.5 mm 2 ) Effect on visual acuity results. Figure 4B illustrates the percentage of patients who benefited from the combination of Lucentis® and Formulation 1A (labeled "Form-1A") up to week 36, with a patient population system of 5 mm 2 , 7.5 mm 2 , 10 mm 2 and 12.5 mm 2 of atypical CNV size are separated.

Claims (36)

一種組合物之用途，其用於製造用以向需要其之哺乳動物眼睛之後鞏膜及脈絡膜選擇性遞送角鯊胺或其醫藥上可接受之鹽之藥劑，其中該組合物包含： 二乳酸角鯊胺； 緩衝劑； 黏膜黏著劑；及 環糊精， 其中該哺乳動物具有一或多個具有小於10 mm2 面積之非典型CNV之病灶。Use of a composition for the manufacture of a medicament for the selective delivery of squalamine or a pharmaceutically acceptable salt thereof to the sclera and choroid of a mammalian eye in need thereof, wherein the composition comprises: An amine; a buffer; a mucoadhesive; and a cyclodextrin, wherein the mammal has one or more lesions having an atypical CNV of less than 10 mm 2 area. 一種組合物之用途，其用於製造用以治療哺乳動物之眼科病況之藥劑，其中該組合物包含： 二乳酸角鯊胺； 緩衝劑； 黏膜黏著劑；及 環糊精， 其中該哺乳動物具有一或多個具有小於10 mm2 面積之非典型CNV之病灶。Use of a composition for the manufacture of a medicament for treating an ophthalmic condition in a mammal, wherein the composition comprises: diacetamide, a buffer; a mucoadhesive; and a cyclodextrin, wherein the mammal has One or more lesions having an atypical CNV of less than 10 mm 2 area. 如請求項1或2之用途，其中該哺乳動物具有一或多個具有小於8mm2 面積之非典型CNV之病灶。The use of claim 1 or 2, wherein the mammal has one or more lesions having an atypical CNV of less than 8 mm 2 area. 如請求項1或2之用途，其中該哺乳動物具有一或多個具有小於5mm2 面積之非典型CNV之病灶。The use of claim 1 or 2, wherein the mammal has one or more lesions having an atypical CNV of less than 5 mm 2 area. 如請求項1或2之用途，其中該等病灶亦含有典型CNV。The use of claim 1 or 2, wherein the lesions also contain a typical CNV. 如請求項1或2之用途，其中該藥劑係以局部方式投與該哺乳動物之眼睛。The use of claim 1 or 2, wherein the agent is administered to the eye of the mammal in a localized manner. 如請求項1或2之用途，其中該藥劑係呈滴眼劑形式。The use of claim 1 or 2, wherein the agent is in the form of an eye drop. 如請求項1或2之用途，其中該黏膜黏著劑係聚維酮(Povidone) K-30。The use of claim 1 or 2, wherein the mucoadhesive agent is Povidone K-30. 如請求項1或2之用途，其中該環糊精係2-羥丙基-β-環糊精。The use of claim 1 or 2, wherein the cyclodextrin is 2-hydroxypropyl-β-cyclodextrin. 如請求項1或2之用途，其中該緩衝劑係磷酸鹽。The use of claim 1 or 2, wherein the buffer is a phosphate. 如請求項1或2之用途，其中該眼科病況係選自由以下組成之群：濕型年齡相關性黃斑變性、乾型年齡相關性黃斑變性、糖尿病視網膜病變、增殖性糖尿病視網膜病變、缺血性視網膜病變、囊樣黃斑水腫、糖尿病黃斑水腫、虹膜紅變、早產兒視網膜病變、視網膜血管阻塞性疾病、炎性/傳染性視網膜新生血管形成/水腫、視網膜母細胞瘤、眼黑色素瘤、眼腫瘤、視網膜脫落、近視性新生血管形成、血管狀痕、伊爾斯病(Eales disease)、脈絡膜破裂及其任一組合。The use of claim 1 or 2, wherein the ophthalmic condition is selected from the group consisting of wet type age-related macular degeneration, dry age-related macular degeneration, diabetic retinopathy, proliferative diabetic retinopathy, ischemic Retinopathy, cystoid macular edema, diabetic macular edema, iris reddening, retinopathy of prematurity, retinal vascular obstructive disease, inflammatory/infectious retinal neovascularization/edema, retinoblastoma, ocular melanoma, ocular tumor Retinal detachment, myopic neovascularization, vascular lesions, Eales disease, choroidal rupture, and any combination thereof. 如請求項1或2之用途，其中該眼科病況係濕型年齡相關性黃斑變性(濕型AMD)。The use of claim 1 or 2, wherein the ophthalmic condition is wet age-related macular degeneration (wet AMD). 如請求項1或2之用途，其中該哺乳動物係人類。The use of claim 1 or 2, wherein the mammal is a human. 如請求項1或2之用途，其中該藥劑進一步包含依地酸二鈉(edetate disodium)、氯化鈉及氯苄烷銨中之一或多者。The use of claim 1 or 2, wherein the agent further comprises one or more of edetate disodium, sodium chloride, and benzalkonium chloride. 如請求項1或2之用途，其中該藥劑係與抗血管生成劑組合投與。The use of claim 1 or 2, wherein the agent is administered in combination with an anti-angiogenic agent. 如請求項15之用途，其中該藥劑係在投與該抗血管生成劑之前投與。The use of claim 15, wherein the agent is administered prior to administration of the anti-angiogenic agent. 如請求項15之用途，其中該藥劑係與投與該抗血管生成劑之同時投與。The use of claim 15, wherein the agent is administered concurrently with administration of the anti-angiogenic agent. 如請求項15之用途，其中該藥劑係在投與該抗血管生成劑之後投與。The use of claim 15, wherein the agent is administered after administration of the anti-angiogenic agent. 如請求項15之用途，其中該抗血管生成劑係抗VEGF藥物或抗PDGF藥物。The use of claim 15, wherein the anti-angiogenic agent is an anti-VEGF drug or an anti-PDGF drug. 一種組合物之用途，其用於製造用以降低哺乳動物一隻眼睛發生眼科病況之風險之藥劑，其中眼科病況已存在於該哺乳動物另一隻眼睛中， 其中該藥劑係投與未具該眼科病況之眼睛中以預防或延遲該眼科病況之發生，且其中該組合物包含： 二乳酸角鯊胺； 緩衝劑； 黏膜黏著劑；及 環糊精。Use of a composition for the manufacture of an agent for reducing the risk of an ophthalmic condition occurring in one eye of a mammal, wherein an ophthalmic condition is already present in the other eye of the mammal, wherein the agent is not administered Preventing or delaying the occurrence of the ophthalmic condition in the eye of an ophthalmic condition, and wherein the composition comprises: diacetamide squalamine; a buffer; a mucoadhesive; and a cyclodextrin. 一種組合物之用途，其用於製造用以降低哺乳動物發生眼科病況之風險之藥劑，其中在該哺乳動物一隻或兩隻眼睛中檢測到可導致該眼科病況之異常病理或血管生成過程， 其中該藥劑係投與該一隻或該兩隻眼睛中以預防或延遲該異常病理或血管生成過程進一步進展，且其中該組合物包含： 二乳酸角鯊胺； 緩衝劑； 黏膜黏著劑；及 環糊精。Use of a composition for the manufacture of a medicament for reducing the risk of developing an ophthalmic condition in a mammal, wherein an abnormal pathology or angiogenic process that causes the ophthalmic condition is detected in one or both of the mammalian eyes, Wherein the agent is administered to the one or both eyes to prevent or delay further progression of the abnormal pathology or angiogenesis process, and wherein the composition comprises: diacetamide squalamine; a buffer; a mucoadhesive; Cyclodextrin. 一種組合物之用途，其用於製造基於全身病況或病症、家族病史或遺傳預先傾向性來預防性治療在一隻或兩隻眼睛中具有異常致病或血管生成過程之風險之哺乳動物之藥劑， 其中該藥劑係投與該一隻或該兩隻眼睛以預防或延遲該異常病理或血管生成過程，且其中該組合物包含： 二乳酸角鯊胺； 緩衝劑； 黏膜黏著劑；及 環糊精。Use of a composition for the manufacture of a medicament for the prophylactic treatment of a mammal having an abnormal pathogenic or angiogenic process in one or both eyes based on a systemic condition or disorder, family history or genetic predisposition Wherein the agent is administered to the one or both eyes to prevent or delay the abnormal pathology or angiogenesis process, and wherein the composition comprises: diacetamide squalamine; a buffer; a mucoadhesive; and a cyclodextrin fine. 如請求項20至22中任一項之用途，其中該藥劑係以局部方式投與該哺乳動物之眼睛。The use of any one of claims 20 to 22, wherein the agent is administered to the eye of the mammal in a localized manner. 如請求項20至22中任一項之用途，其中該藥劑係呈滴眼劑形式。The use of any one of claims 20 to 22, wherein the medicament is in the form of an eye drop. 如請求項20至22中任一項之用途，其中該黏膜黏著劑係聚維酮K-30。The use of any one of claims 20 to 22, wherein the mucoadhesive agent is povidone K-30. 如請求項20至22中任一項之用途，其中該環糊精係2-羥丙基-β-環糊精。The use of any one of claims 20 to 22, wherein the cyclodextrin is 2-hydroxypropyl-β-cyclodextrin. 如請求項20至22中任一項之用途，其中該緩衝劑係磷酸鹽。The use of any one of claims 20 to 22, wherein the buffer is a phosphate. 如請求項20或21之用途，其中該眼科病況係選自由以下組成之群：濕型年齡相關性黃斑變性、乾型年齡相關性黃斑變性、糖尿病視網膜病變、增殖性糖尿病視網膜病變、缺血性視網膜病變、囊樣黃斑水腫、糖尿病黃斑水腫、虹膜紅變、早產兒視網膜病變、視網膜血管阻塞性疾病、炎性/傳染性視網膜新生血管形成/水腫、視網膜母細胞瘤、眼黑色素瘤、眼腫瘤、視網膜脫落、近視性新生血管形成、血管狀痕、伊爾斯病、脈絡膜破裂及其任一組合。The use of claim 20 or 21, wherein the ophthalmic condition is selected from the group consisting of wet type age-related macular degeneration, dry age-related macular degeneration, diabetic retinopathy, proliferative diabetic retinopathy, ischemic Retinopathy, cystoid macular edema, diabetic macular edema, iris reddening, retinopathy of prematurity, retinal vascular obstructive disease, inflammatory/infectious retinal neovascularization/edema, retinoblastoma, ocular melanoma, ocular tumor Retinal detachment, myopic neovascularization, vascular lesions, Iles disease, choroidal rupture, and any combination thereof. 如請求項20至22中任一項之用途，其中該藥劑進一步包含依地酸二鈉、氯化鈉及氯苄烷銨中之一或多者。The use of any one of claims 20 to 22, wherein the medicament further comprises one or more of disodium edetate, sodium chloride, and benzalkonium chloride. 如請求項20至22中任一項之用途，其中該藥劑係與抗血管生成劑組合投與。The use of any one of claims 20 to 22, wherein the agent is administered in combination with an anti-angiogenic agent. 如請求項30之用途，其中該藥劑係在投與該抗血管生成劑之前投與。The use of claim 30, wherein the agent is administered prior to administration of the anti-angiogenic agent. 如請求項30之用途，其中該藥劑係與投與該抗血管生成劑之同時投與。The use of claim 30, wherein the agent is administered concurrently with administration of the anti-angiogenic agent. 如請求項30之用途，其中該藥劑係在投與該抗血管生成劑之後投與。The use of claim 30, wherein the agent is administered after administration of the anti-angiogenic agent. 如請求項30之用途，其中該抗血管生成劑係抗VEGF藥物或抗PDGF藥物。The use of claim 30, wherein the anti-angiogenic agent is an anti-VEGF drug or an anti-PDGF drug. 2、20、21及22中任一項之用途，其中該等藥劑係水性組合物。The use of any of items 2, 20, 21 and 22, wherein the agents are aqueous compositions. 2、20、21及22中任一項之用途，其中該組合物包含： 二乳酸角鯊胺； 磷酸鈉； 依地酸二鈉； 氯化鈉； 氯苄烷銨；及 2-羥丙基-β-環糊精。The use of any one of 2, 20, 21 and 22, wherein the composition comprises: diacetamide squalamine; sodium phosphate; disodium edetate; sodium chloride; benzalkonium chloride; and 2-hydroxypropyl -β-cyclodextrin.
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