TW201720445A - Ophthalmic formulations of squalamine - Google Patents

Ophthalmic formulations of squalamine Download PDF

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TW201720445A
TW201720445A TW105137145A TW105137145A TW201720445A TW 201720445 A TW201720445 A TW 201720445A TW 105137145 A TW105137145 A TW 105137145A TW 105137145 A TW105137145 A TW 105137145A TW 201720445 A TW201720445 A TW 201720445A
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伊雷區 Ｂ 塔拉波瑞瓦拉
山謬爾 Ｉ 貝肯羅斯
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Ｏｈｒ製藥公司
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Abstract

Ophthalmic compositions containing squalamine dilactate were unexpectedly observed to effectively treat ophthalmic conditions. The ophthalmic compositions may also be used in combination with other ophthalmic therapies.

Description

角鯊胺之眼用調配物Squalamine eye ophthalmic formulation

本發明係關於用於治療眼科病況或病症之二乳酸角鯊胺調配物。The present invention relates to a dilactic acid squalamine formulation for use in the treatment of an ophthalmic condition or disorder.

在美國，年齡相關性黃斑變性(age-related macular degeneration；AMD)係52歲或以上人群中發生不可逆中心視覺損失之主要原因，且該疾病係美國、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。有兩種形式黃斑變性的存在：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)。乾型形式可能為濕型形式之前體，其係黃斑之色素上皮無法去除因視網膜生成之廢物所造成。濕型形式係在視網膜下面生長新血管發生，特定而言是黃斑。 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，其已以靜脈內輸注液形式用於有效治療濕型AMD，其中其係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10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。 從患者使用及風險之角度來看，顯然是期望局部調配物可直接施加至眼睛，而不是靜脈內輸注，或尤其需要每月直接注射至眼睛中之當前照護標準。與侵襲性較強之技術(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，該等侵襲性較強之技術需要在醫學監督下成本較高的投與且其會引起嚴重併發症(例如眼內炎及視網膜脫落)。然而，眼部滴眼劑一般問題係在於在其投與後，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 (2001))。 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。使用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，且其因為各種原因在商業基礎上係不可行的。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不足以阻斷脈絡膜新生血管形成(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，隨後在第五週後產生改良之速率下降。靜脈內投藥造成局部輸注位點反應(投藥較在局部調配物中使用之劑量高幾個數量級)。在「現實世界」情形中，期望患有濕型AMD之老年患者能夠每週訪視診所以進行延長時間輸注係不切實際的。大多數視網膜眼科實務上亦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，本發明是為供局部投與之安全且非刺激之眼部調配物之發現，該調配物能夠達成治療劑選擇性地遞送至眼睛之後部，以用於治療病症。In the United States, age-related macular degeneration (AMD) is the leading cause of irreversible central visual loss in people aged 52 years or older, and the disease is in the United States, Canada, Great Britain, and The most common cause of blindness in Australia (Australia). 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 may be a wet form precursor, which is a pigmented epithelium of the macula that cannot be removed from waste generated by the retina. The wet form is the growth of new blood vessels under the retina, in particular the macula. 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 in the form of intravenous infusion for the effective treatment of wet AMD, wherein Used to prevent 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 ://www.eyesightnews.com/topic/28.html (October 7, 2003)). The squalamine is awarded to the US Patent No. 5,192,756 by Zasloff et al. The disclosures are hereby incorporated by reference in its entirety, the entire disclosure of which is hereby incorporated by reference in its entirety in U.S. Pat. From the standpoint, it is clear that it is desirable that the topical formulation can be applied directly to the eye rather than intravenously, or in particular the current standard of care that is directly injected into the eye each month. Invasive techniques (eg, intravitreal injection) In contrast, topical formulations in the form of, for example, solutions, suspensions, creams or ointments are readily self-administered by the patient, and such aggressive techniques require costly administration under medical supervision and It can cause serious complications (such as endophthalmitis and retinal detachment). However, the general problem of eye drops is that after they are administered, usually less than 5% of the eye drops penetrate the cornea and reach the eye. organization. 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 (2001)). 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. Using pharmacokinetic analysis, IV formulations of IV formulations are considered to be suboptimal and are 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 insufficient concentration in the choroid after 4 to 6 days to block choroidal neovascularization (CNV). 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. Intravenous administration results in a local infusion site response (the administration is several orders of magnitude higher than the dose used in the topical formulation). In the "real world" situation, it is unrealistic to expect elderly patients with wet AMD to be able to visit the clinic weekly for extended time infusion. Most retinal ophthalmology practices are also not provided for such intravenous infusions. In contrast to the above indicated disadvantages associated with intravenous administration, the present invention is the discovery of a safe and non-irritating ocular formulation for topical administration that is capable of selectively delivering a therapeutic agent to the posterior portion of the eye. For the treatment of a condition.

本發明之一個態樣係眼用組合物，其包含選自由以下組成之群之組合物中之至少一者：如本文所闡述之調配物1、調配物2、調配物3、調配物4、調配物5及調配物6。 在本發明之另一態樣中，眼用組合物包含二乳酸角鯊胺；磷酸氫二鈉七水合物；磷酸二氫鈉二水合物；甘油；聚維酮K-30(Povidone K-30)；依地酸二鈉(edetate disodium)；氯苄烷銨；及水。 在本發明之另一態樣中，眼用組合物包含二乳酸角鯊胺；硼酸；硼酸鈉；羧甲基纖維素鈉；環糊精(例如2-羥丙基-β-環糊精)；氯化鈉；氯苄烷銨；及水。 在本發明之另一態樣中，眼用組合物包含二乳酸角鯊胺；硼酸；硼酸鈉；依地酸二鈉；甘油；丙二醇；羥丙甲纖維素；山梨酸；及水。 在本發明之另一態樣中，眼用組合物包含二乳酸角鯊胺；硼酸；硼酸鈉；氯化鈉；山梨醇；丙二醇；聚氧乙烯40氫化蓖麻油；正十二烷基-β-D-醣苷；氯苄烷銨；及水。 在本發明之另一態樣中，眼用組合物包含二乳酸角鯊胺；磷酸鈉七水合物；磷酸二氫鈉一水合物；聚維酮K-30；依地酸二鈉；氯化鈉；氯苄烷銨；環糊精(例如2-羥丙基-β-環糊精)；及水。 在本發明之另一態樣中，眼用組合物由以下組成：二乳酸角鯊胺；磷酸氫二鈉七水合物；磷酸二氫鈉二水合物；甘油；聚維酮K-30；依地酸二鈉；氯苄烷銨；及水。 在本發明之另一態樣中，眼用組合物由以下組成：二乳酸角鯊胺；硼酸；硼酸鈉；羧甲基纖維素鈉；環糊精(例如2-羥丙基-β-環糊精)；氯化鈉；氯苄烷銨；及水。 在本發明之另一態樣中，眼用組合物由以下組成：二乳酸角鯊胺；硼酸；硼酸鈉；依地酸二鈉；甘油；丙二醇；羥丙甲纖維素；山梨酸；及水。 在本發明之另一態樣中，眼用組合物由以下組成：二乳酸角鯊胺；硼酸；硼酸鈉；氯化鈉；山梨醇；丙二醇；聚氧乙烯40氫化蓖麻油；正十二烷基-β-D-醣苷；氯苄烷銨；及水。 在本發明之另一態樣中，眼用組合物由以下組成：二乳酸角鯊胺；磷酸鈉七水合物；磷酸二氫鈉一水合物；聚維酮K-30；依地酸二鈉；氯化鈉；氯苄烷銨；環糊精(例如2-羥丙基-β-環糊精)；及水。 在本發明之例示性實施例，本發明之組合物/調配物中之任一者均適於局部投與眼睛。 本發明之另一態樣係治療有需要之哺乳動物之眼科病況之方法，其包含向哺乳動物之一隻或兩隻眼睛投與治療有效量之選自由以下組成之群之組合物中之至少一者：如本文所闡述之調配物1、調配物2、調配物3、調配物4、調配物5及調配物6。 本發明之另一態樣係治療有需要之哺乳動物之眼科病況之方法，其包含向哺乳動物之一隻或兩隻眼睛投與治療有效量之包含以下之組合物：二乳酸角鯊胺；磷酸氫二鈉七水合物；磷酸二氫鈉二水合物；甘油；聚維酮K-30；依地酸二鈉；氯苄烷銨；及水。 本發明之另一態樣係治療有需要之哺乳動物之眼科病況之方法，其包含向哺乳動物之一隻或兩隻眼睛投與治療有效量之包含以下之組合物：二乳酸角鯊胺；硼酸；硼酸鈉；羧甲基纖維素鈉；環糊精(例如2-羥丙基-β-環糊精)；氯化鈉；氯苄烷銨；及水。 本發明之另一態樣係治療有需要之哺乳動物之眼科病況之方法，其包含向哺乳動物之一隻或兩隻眼睛投與治療有效量之包含以下之組合物：二乳酸角鯊胺；硼酸；硼酸鈉；依地酸二鈉；甘油；丙二醇；羥丙甲纖維素；山梨酸；及水。 本發明之另一態樣係治療有需要之哺乳動物之眼科病況之方法，其包含向哺乳動物之一隻或兩隻眼睛投與治療有效量之包含以下之組合物：二乳酸角鯊胺；硼酸；硼酸鈉；氯化鈉；山梨醇；丙二醇；聚氧乙烯40氫化蓖麻油；正十二烷基-β-D-醣苷；氯苄烷銨；及水。 本發明之另一態樣係治療有需要之哺乳動物之眼科病況之方法，其包含向哺乳動物之一隻或兩隻眼睛投與治療有效量之包含以下之組合物：二乳酸角鯊胺；磷酸鈉七水合物；磷酸二氫鈉一水合物；聚維酮K-30；依地酸二鈉；氯化鈉；氯苄烷銨；環糊精(例如2-羥丙基-β-環糊精)；及水。 本發明之另一態樣係治療有需要之哺乳動物之眼科病況之方法，其包含向哺乳動物之一隻或兩隻眼睛投與治療有效量之由以下組成之組合物：二乳酸角鯊胺；磷酸氫二鈉七水合物；磷酸二氫鈉二水合物；甘油；聚維酮K-30；依地酸二鈉；氯苄烷銨；及水。 本發明之另一態樣係治療有需要之哺乳動物之眼科病況之方法，其包含向哺乳動物之一隻或兩隻眼睛投與治療有效量之由以下組成之組合物：二乳酸角鯊胺；硼酸；硼酸鈉；羧甲基纖維素鈉；環糊精(例如2-羥丙基-β-環糊精)；氯化鈉；氯苄烷銨；及水。 本發明之另一態樣係治療有需要之哺乳動物之眼科病況之方法，其包含向哺乳動物之一隻或兩隻眼睛投與治療有效量之由以下組成之組合物：二乳酸角鯊胺；硼酸；硼酸鈉；依地酸二鈉；甘油；丙二醇；羥丙甲纖維素；山梨酸；及水。 本發明之另一態樣係治療有需要之哺乳動物之眼科病況之方法，其包含向哺乳動物之一隻或兩隻眼睛投與治療有效量之由以下組成之組合物：二乳酸角鯊胺；硼酸；硼酸鈉；氯化鈉；山梨醇；丙二醇；聚氧乙烯40氫化蓖麻油；正十二烷基-β-D-醣苷；氯苄烷銨；及水。 本發明之另一態樣係治療有需要之哺乳動物之眼科病況之方法，其包含向哺乳動物之一隻或兩隻眼睛投與治療有效量之由以下組成之組合物：二乳酸角鯊胺；磷酸鈉七水合物；磷酸二氫鈉一水合物；聚維酮K-30；依地酸二鈉；氯化鈉；氯苄烷銨；環糊精(例如2-羥丙基-β-環糊精)；及水。 本發明之另一態樣係治療有需要之哺乳動物之眼科病況之方法，其由向哺乳動物之一隻或兩隻眼睛投與治療有效量之組合物中之至少一者組成，該組合物選自由以下組成之群：如本文所闡述之調配物1、調配物2、調配物3、調配物4、調配物5及調配物6。 本發明之另一態樣係治療有需要之哺乳動物之眼科病況之方法，其由向哺乳動物之一隻或兩隻眼睛投與治療有效量之組合物組成，該組合物包含二乳酸角鯊胺；磷酸氫二鈉七水合物；磷酸二氫鈉二水合物；甘油；聚維酮K-30；依地酸二鈉；氯苄烷銨；及水。 本發明之另一態樣係治療有需要之哺乳動物之眼科病況之方法，其由向哺乳動物之一隻或兩隻眼睛投與治療有效量之組合物組成，該組合物包含二乳酸角鯊胺；硼酸；硼酸鈉；羧甲基纖維素鈉；環糊精(例如2-羥丙基-β-環糊精)；氯化鈉；氯苄烷銨；及水。 本發明之另一態樣係治療有需要之哺乳動物之眼科病況之方法，其由向哺乳動物之一隻或兩隻眼睛投與治療有效量之組合物組成，該組合物包含二乳酸角鯊胺；硼酸；硼酸鈉；依地酸二鈉；甘油；丙二醇；羥丙甲纖維素；山梨酸；及水。 本發明之另一態樣係治療有需要之哺乳動物之眼科病況之方法，其由向哺乳動物之一隻或兩隻眼睛投與治療有效量之組合物組成，該組合物包含二乳酸角鯊胺；硼酸；硼酸鈉；氯化鈉；山梨醇；丙二醇；聚氧乙烯40氫化蓖麻油；正十二烷基-β-D-醣苷；氯苄烷銨；及水。 本發明之另一態樣係治療有需要之哺乳動物之眼科病況之方法，其由向哺乳動物之一隻或兩隻眼睛投與治療有效量之組合物組成，該組合物包含二乳酸角鯊胺；磷酸鈉七水合物；磷酸二氫鈉一水合物；聚維酮K-30；依地酸二鈉；氯化鈉；氯苄烷銨；環糊精(例如2-羥丙基-β-環糊精)；及水。 本發明之另一態樣係治療有需要之哺乳動物之眼科病況之方法，其由向哺乳動物之一隻或兩隻眼睛投與治療有效量之組合物組成，該組合物由以下組成：二乳酸角鯊胺；磷酸氫二鈉七水合物；磷酸二氫鈉二水合物；甘油；聚維酮K-30；依地酸二鈉；氯苄烷銨；及水。 本發明之另一態樣係治療有需要之哺乳動物之眼科病況之方法，其由向哺乳動物之一隻或兩隻眼睛投與治療有效量之組合物組成，該組合物由以下組成：二乳酸角鯊胺；硼酸；硼酸鈉；羧甲基纖維素鈉；環糊精(例如2-羥丙基-β-環糊精)；氯化鈉；氯苄烷銨；及水。 本發明之另一態樣係治療有需要之哺乳動物之眼科病況之方法，其由向哺乳動物之一隻或兩隻眼睛投與治療有效量之組合物組成，該組合物由以下組成：二乳酸角鯊胺；硼酸；硼酸鈉；依地酸二鈉；甘油；丙二醇；羥丙甲纖維素；山梨酸；及水。 本發明之另一態樣係治療有需要之哺乳動物之眼科病況之方法，其由向哺乳動物之一隻或兩隻眼睛投與治療有效量之組合物組成，該組合物由以下組成：二乳酸角鯊胺；硼酸；硼酸鈉；氯化鈉；山梨醇；丙二醇；聚氧乙烯40氫化蓖麻油；正十二烷基-β-D-醣苷；氯苄烷銨；及水。 本發明之另一態樣係治療有需要之哺乳動物之眼科病況之方法，其由向哺乳動物之一隻或兩隻眼睛投與治療有效量之組合物組成，該組合物由以下組成：二乳酸角鯊胺；磷酸鈉七水合物；磷酸二氫鈉一水合物；聚維酮K-30；依地酸二鈉；氯化鈉；氯苄烷銨；環糊精(例如2-羥丙基-β-環糊精)；及水。 本發明之另一態樣係治療有需要之哺乳動物之眼科病況之方法，其包含向哺乳動物之一隻或兩隻眼睛投與治療有效量之眼用治療劑以及治療有效量之選自由以下組成之群之組合物中之至少一者：如本文所闡述之調配物1、調配物2、調配物3、調配物4、調配物5及調配物6。 本發明之另一態樣係治療有需要之哺乳動物之眼科病況之方法，其包含向哺乳動物之一隻或兩隻眼睛投與治療有效量之眼用治療劑以及治療有效量之包含以下之組合物：二乳酸角鯊胺；磷酸氫二鈉七水合物；磷酸二氫鈉二水合物；甘油；聚維酮K-30；依地酸二鈉；氯苄烷銨；及水。 本發明之另一態樣係治療有需要之哺乳動物之眼科病況之方法，其包含向哺乳動物之一隻或兩隻眼睛投與治療有效量之眼用治療劑以及治療有效量之包含以下之組合物：二乳酸角鯊胺；硼酸；硼酸鈉；羧甲基纖維素鈉；環糊精(例如2-羥丙基-β-環糊精)；氯化鈉；氯苄烷銨；及水。 本發明之另一態樣係治療有需要之哺乳動物之眼科病況之方法，其包含向哺乳動物之一隻或兩隻眼睛投與治療有效量之眼用治療劑以及治療有效量之包含以下之組合物：二乳酸角鯊胺；硼酸；硼酸鈉；依地酸二鈉；甘油；丙二醇；羥丙甲纖維素；山梨酸；及水。 本發明之另一態樣係治療有需要之哺乳動物之眼科病況之方法，其包含向哺乳動物之一隻或兩隻眼睛投與治療有效量之眼用治療劑以及治療有效量之包含以下之組合物：二乳酸角鯊胺；硼酸；硼酸鈉；氯化鈉；山梨醇；丙二醇；聚氧乙烯40氫化蓖麻油；正十二烷基-β-D-醣苷；氯苄烷銨；及水。 本發明之另一態樣係治療有需要之哺乳動物之眼科病況之方法，其包含向哺乳動物之一隻或兩隻眼睛投與治療有效量之眼用治療劑以及治療有效量之包含以下之組合物：二乳酸角鯊胺；磷酸鈉七水合物；磷酸二氫鈉一水合物；聚維酮K-30；依地酸二鈉；氯化鈉；氯苄烷銨；環糊精(例如2-羥丙基-β-環糊精)；及水。 本發明之另一態樣係治療有需要之哺乳動物之眼科病況之方法，其包含向哺乳動物之一隻或兩隻眼睛投與治療有效量之眼用治療劑以及治療有效量之由以下組成之組合物：二乳酸角鯊胺；磷酸氫二鈉七水合物；磷酸二氫鈉二水合物；甘油；聚維酮K-30；依地酸二鈉；氯苄烷銨；及水。 本發明之另一態樣係治療有需要之哺乳動物之眼科病況之方法，其包含向哺乳動物之一隻或兩隻眼睛投與治療有效量之眼用治療劑以及治療有效量之由以下組成之組合物：二乳酸角鯊胺；硼酸；硼酸鈉；羧甲基纖維素鈉；環糊精(例如2-羥丙基-β-環糊精)；氯化鈉；氯苄烷銨；及水。 本發明之另一態樣係治療有需要之哺乳動物之眼科病況之方法，其包含向哺乳動物之一隻或兩隻眼睛投與治療有效量之眼用治療劑以及治療有效量之由以下組成之組合物：二乳酸角鯊胺；硼酸；硼酸鈉；依地酸二鈉；甘油；丙二醇；羥丙甲纖維素；山梨酸；及水。 本發明之另一態樣係治療有需要之哺乳動物之眼科病況之方法，其包含向哺乳動物之一隻或兩隻眼投與治療有效量之眼睛用治療劑以及治療有效量之由以下組成之組合物：二乳酸角鯊胺；硼酸；硼酸鈉；氯化鈉；山梨醇；丙二醇；聚氧乙烯40氫化蓖麻油；正十二烷基-β-D-醣苷；氯苄烷銨；及水。 本發明之另一態樣係治療有需要之哺乳動物之眼科病況之方法，其包含向哺乳動物之一隻或兩隻眼睛投與治療有效量之眼用治療劑以及治療有效量之由以下組成之組合物：二乳酸角鯊胺；磷酸鈉七水合物；磷酸二氫鈉一水合物；聚維酮K-30；依地酸二鈉；氯化鈉；氯苄烷銨；環糊精(例如2-羥丙基-β-環糊精)；及水。 本發明之另一態樣係治療有需要之哺乳動物之眼科病況之方法，其由向哺乳動物之一隻或兩隻眼睛投與治療有效量之眼用治療劑以及治療有效量之組合物中之至少一者組成，該組合物選自由以下組成之群：如本文所闡述之調配物1、調配物2、調配物3、調配物4、調配物5及調配物6。 本發明之另一態樣係治療有需要之哺乳動物之眼科病況之方法，其向哺乳動物之一隻或兩隻眼睛投與治療有效量之眼用治療劑以及治療有效量之組合物組成，該組合物包含二乳酸角鯊胺；磷酸氫二鈉七水合物；磷酸二氫鈉二水合物；甘油；聚維酮K-30；依地酸二鈉；氯苄烷銨；及水。 本發明之另一態樣係治療有需要之哺乳動物之眼科病況之方法，其由向哺乳動物之一隻或兩隻眼睛投與治療有效量之眼用治療劑以及治療有效量之組合物組成，該組合物包含二乳酸角鯊胺；硼酸；硼酸鈉；羧甲基纖維素鈉；環糊精(例如2-羥丙基-β-環糊精)；氯化鈉；氯苄烷銨；及水。 本發明之另一態樣係治療有需要之哺乳動物之眼科病況之方法，其由向哺乳動物之一隻或兩隻眼睛投與治療有效量之眼用治療劑以及治療有效量之組合物組成，該組合物包含二乳酸角鯊胺；硼酸；硼酸鈉；依地酸二鈉；甘油；丙二醇；羥丙甲纖維素；山梨酸；及水。 本發明之另一態樣係治療有需要之哺乳動物之眼科病況之方法，其由向哺乳動物之一隻或兩隻眼睛投與治療有效量之眼用治療劑以及治療有效量之組合物組成，該組合物包含二乳酸角鯊胺；硼酸；硼酸鈉；氯化鈉；山梨醇；丙二醇；聚氧乙烯40氫化蓖麻油；正十二烷基-β-D-醣苷；氯苄烷銨；及水。 本發明之另一態樣係治療有需要之哺乳動物之眼科病況之方法，其由向哺乳動物之一隻或兩隻眼睛投與治療有效量之眼用治療劑以及治療有效量之組合物組成，該組合物包含二乳酸角鯊胺；磷酸鈉七水合物；磷酸二氫鈉一水合物；聚維酮K-30；依地酸二鈉；氯化鈉；氯苄烷銨；環糊精(例如2-羥丙基-β-環糊精)；及水。 本發明之另一態樣係治療有需要之哺乳動物之眼科病況之方法，其由向哺乳動物之一隻或兩隻眼睛投與治療有效量之眼用治療劑以及治療有效量之組合物組成，該組合物由以下組成：二乳酸角鯊胺；磷酸氫二鈉七水合物；磷酸二氫鈉二水合物；甘油；聚維酮K-30；依地酸二鈉；氯苄烷銨；及水。 本發明之另一態樣係治療有需要之哺乳動物之眼科病況之方法，其由向哺乳動物之一隻或兩隻眼睛投與治療有效量之眼用治療劑以及治療有效量之組合物組成，該組合物由以下組成：二乳酸角鯊胺；硼酸；硼酸鈉；羧甲基纖維素鈉；環糊精(例如2-羥丙基-β-環糊精)；氯化鈉；氯苄烷銨；及水。 本發明之另一態樣係治療有需要之哺乳動物之眼科病況之方法，其由向哺乳動物之一隻或兩隻眼睛投與治療有效量之眼用治療劑以及治療有效量之組合物組成，該組合物由以下組成：二乳酸角鯊胺；硼酸；硼酸鈉；依地酸二鈉；甘油；丙二醇；羥丙甲纖維素；山梨酸；及水。 本發明之另一態樣係治療有需要之哺乳動物之眼科病況之方法，其由向哺乳動物之一隻或兩隻眼睛投與治療有效量之眼用治療劑以及治療有效量之組合物組成，該組合物由以下組成：二乳酸角鯊胺；硼酸；硼酸鈉；氯化鈉；山梨醇；丙二醇；聚氧乙烯40氫化蓖麻油；正十二烷基-β-D-醣苷；氯苄烷銨；及水。 本發明之另一態樣係治療有需要之哺乳動物之眼科病況之方法，其由向哺乳動物之一隻或兩隻眼睛投與治療有效量之眼用治療劑以及治療有效量之組合物組成，該組合物由以下組成：二乳酸角鯊胺；磷酸鈉七水合物；磷酸二氫鈉一水合物；聚維酮K-30；依地酸二鈉；氯化鈉；氯苄烷銨；環糊精(例如2-羥丙基-β-環糊精)；及水。 在本發明之態樣中，眼用治療劑係在投與選自由以下組成之群之組合物中之至少一者之前投與哺乳動物：如本文所闡述之調配物1、調配物2、調配物3、調配物4、調配物5及調配物6。 在本發明之態樣中，眼用治療劑大約與選自由以下組成之群之組合物中之至少一者之投與同時投與哺乳動物：如本文所闡述之調配物1、調配物2、調配物3、調配物4、調配物5及調配物6。 在本發明之態樣中，眼用治療劑係在投與選自由以下組成之群之組合物中之至少一者後投與哺乳動物：如本文所闡述之調配物1、調配物2、調配物3、調配物4、調配物5及調配物6。 在本發明之態樣中，眼用治療劑係在投與本文所闡述組合物中之至少一者之前投與哺乳動物。 在本發明之態樣中，眼用治療劑大約與本文所闡述組合物中之至少一者之投與同時投與哺乳動物。 在本發明之態樣中，眼用治療劑係在投與本文所闡述組合物中之至少一者之後投與哺乳動物。 在本發明之態樣中，哺乳動物係人類。 在本發明之態樣中，眼用治療劑係任一眼用治療劑，例如(但不限於)選自由以下組成之群者：雷珠單抗(ranibizumab) (Lucentis®)、貝伐珠單抗(bevacizumab)(Avastin®)、阿柏西普(aflibercept) (Eylea®)、DARPin (Abicipar)及布羅西珠單抗(brolucizumab) (RTH-258)。 在本發明之態樣中，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(Vogt-Koyanagi-Harada Disease)、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。 在本發明之另一態樣中，本發明組合物中之每一者均可進一步包含以下各項中之至少一者或由其組成：黏膜黏著劑、滲透增強劑、黏度增加劑、滲性改良劑、抗微生物防腐劑、緩衝劑、表面活性劑、穩定劑、增溶及再懸浮劑(若該藥劑尚未存於組合物中)，且若該藥劑已存於組合物中，則組合物可包含另一該藥劑或由其組成。認識到存於本發明組合物中之任一者中之特定化學化合物可以一種以上能力起作用，亦即可主要用作(例如)黏膜黏著劑且在較低程度上用作(例如)穩定劑；或主要用作增溶劑但亦用作表面活性劑。 在例示性實施例中，該組合物可進一步包含黏膜黏著劑、滲透增強劑、黏度增加劑、滲性改良劑、抗微生物防腐劑、緩衝劑、表面活性劑、穩定劑、增溶劑及再懸浮劑中之至少兩者或至少三者或至少四者或至少五者。認識到就此而言特定化學化合物可以多種能力起作用。 在例示性實施例中，組合物呈滴眼劑形式。 本發明之態樣係將所闡述組合物/調配物中之一者以治療有效量遞送至哺乳動物眼睛之後鞏膜及/或脈絡膜之方法。 在例示性實施例中，本發明之組合物/調配物投與哺乳動物之眼睛之後，與眼睛內其他部位相比，該等組合物/調配物以顯著更低之濃度存於水狀液或玻璃體液中。 在例示性實施例中，眼科病況係濕型AMD。 在例示性實施例中，二乳酸角鯊胺係以0.01重量%至5.0重量%之量存在。在特定實施例中，重量%為0.05重量%或0.1重量%或0.2重量%或0.3重量%。 在例示性實施例中，鹽係以足以接近人類淚液之鹽濃度及/或滲性之量存在。 在例示性實施例中，鹽係以0.5重量%至1.0重量%範圍內之量存在。 在例示性實施例中，防腐劑係以足以生成微生物障壁以使微生物濃度維持或降低約12小時至約72小時之時段之量存在。 本發明之特定態樣係眼用組合物，其包含： 0.05 w/v%至0.25 w/v%二乳酸角鯊胺； 0.5 w/v%至1.5 w/v%硼酸及0.05 w/v%至0.30 w/v%硼酸鈉； 0.005 w/v%至0.03 w/v%依地酸二鈉； 0.5 w/v%至3.0 w/v%甘油； 0.20 w/v%至1.0 w/v%丙二醇； 0.3 w/v%至2.0 w/v%羥丙甲纖維素； 0.005 w/v%至0.3 w/v%山梨酸；及 充足量之注射用水或純化水USP。 本發明之另一特定態樣係眼用組合物，其包含： 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。 本發明之特定態樣係眼用組合物，其係由以下組成： 0.05 w/v%至0.25 w/v%二乳酸角鯊胺； 0.5 w/v%至1.5 w/v%硼酸及0.05 w/v%至0.30 w/v%硼酸鈉； 0.005 w/v%至0.03 w/v%依地酸二鈉； 0.5 w/v%至3.0 w/v%甘油； 0.20 w/v%至1.0 w/v%丙二醇； 0.3 w/v%至2.0 w/v%羥丙甲纖維素； 0.005 w/v%至0.3 w/v%山梨酸；及 充足量之注射用水或純化水USP。 本發明之另一特定態樣係眼用組合物，其係由以下組成： 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。 在例示性實施例中，上述組合物中之任一者係局部投與需要其之哺乳動物的眼睛。 在例示性實施例中，組合物呈滴眼劑之形式。 在例示性實施例中，哺乳動物罹患眼科病況，例如選自由以下組成之群者：濕型年齡相關性黃斑變性(濕型AMD)、脈絡膜新生血管形成及乾型年齡相關性黃斑變性(乾型AMD)。 本發明之態樣係將角鯊胺或其醫藥上可接受之鹽以治療上有效治療眼科病況之量選擇性地遞送至需要其之哺乳動物的眼睛之後鞏膜及脈絡膜之方法，該方法包含：向哺乳動物之眼睛投與組合物，其中眼科病況係選自由濕型年齡相關性黃斑變性(濕型AMD)、脈絡膜新生血管形成及乾型年齡相關性黃斑變性(乾型AMD)組成之群。An aspect of the invention is an ophthalmic composition comprising at least one selected from the group consisting of: Formulation 1, Formulation 2, Formulation 3, Formulation 4, as set forth herein Formulation 5 and Formulation 6. In another aspect of the invention, the ophthalmic composition comprises diacetamide squalamine; disodium hydrogen phosphate heptahydrate; sodium dihydrogen phosphate dihydrate; glycerin; povidone K-30 (Povidone K-30) ); edetate disodium; benzalkonium chloride; and water. In another aspect of the invention, the ophthalmic composition comprises dihydrostamol; boric acid; sodium borate; sodium carboxymethylcellulose; cyclodextrin (eg, 2-hydroxypropyl-beta-cyclodextrin) Sodium chloride; benzalkonium chloride; and water. In another aspect of the invention, the ophthalmic composition comprises diacetamide squalamine; boric acid; sodium borate; disodium edetate; glycerin; propylene glycol; hypromellose; sorbic acid; In another aspect of the invention, the ophthalmic composition comprises diacetamide squalamine; boric acid; sodium borate; sodium chloride; sorbitol; propylene glycol; polyoxyethylene 40 hydrogenated castor oil; n-dodecyl-beta -D-glycoside; benzalkonium chloride; and water. In another aspect of the invention, the ophthalmic composition comprises dihydrostamol; sodium phosphate heptahydrate; sodium dihydrogen phosphate monohydrate; povidone K-30; disodium edetate; chlorination Sodium; benzalkonium chloride; cyclodextrin (eg 2-hydroxypropyl-β-cyclodextrin); and water. In another aspect of the present invention, the ophthalmic composition is composed of: diacetamide squalamine; disodium hydrogen phosphate heptahydrate; sodium dihydrogen phosphate dihydrate; glycerin; povidone K-30; Disodium glutamate; benzalkonium chloride; and water. In another aspect of the invention, the ophthalmic composition consists of diacetamide, boric acid; boric acid; sodium borate; sodium carboxymethylcellulose; cyclodextrin (eg, 2-hydroxypropyl-beta-ring) Dextrin); sodium chloride; benzalkonium chloride; and water. In another aspect of the invention, the ophthalmic composition consists of diacetamide, boric acid, boric acid, sodium borate, disodium edetate, glycerin, propylene glycol, hypromellose, sorbic acid, and water. . In another aspect of the invention, the ophthalmic composition is comprised of: diacetamide squalamine; boric acid; sodium borate; sodium chloride; sorbitol; propylene glycol; polyoxyethylene 40 hydrogenated castor oil; n-dodecane Benzyl-β-D-glycoside; benzalkonium chloride; and water. In another aspect of the invention, the ophthalmic composition consists of diacetamide squalamine; sodium phosphate heptahydrate; sodium dihydrogen phosphate monohydrate; povidone K-30; disodium edetate Sodium chloride; benzalkonium chloride; cyclodextrin (eg 2-hydroxypropyl-β-cyclodextrin); and water. In an exemplary embodiment of the invention, any of the compositions/formulations of the invention are suitable for topical administration to the eye. Another aspect of the invention is a method of treating an ophthalmic condition in a mammal in need thereof, comprising administering to one or both of the mammals a therapeutically effective amount of at least one selected from the group consisting of: One: Formulation 1, Formulation 2, Formulation 3, Formulation 4, Formulation 5, and Formulation 6 as set forth herein. Another aspect of the invention is a method of treating an ophthalmic condition in a mammal in need thereof, comprising administering to the mammal one or both of the eyes a therapeutically effective amount of a composition comprising: sulphate; Disodium hydrogen phosphate heptahydrate; sodium dihydrogen phosphate dihydrate; glycerin; povidone K-30; disodium edetate; benzalkonium chloride; Another aspect of the invention is a method of treating an ophthalmic condition in a mammal in need thereof, comprising administering to the mammal one or both of the eyes a therapeutically effective amount of a composition comprising: sulphate; Boric acid; sodium borate; sodium carboxymethylcellulose; cyclodextrin (eg 2-hydroxypropyl-β-cyclodextrin); sodium chloride; benzalkonium chloride; and water. Another aspect of the invention is a method of treating an ophthalmic condition in a mammal in need thereof, comprising administering to the mammal one or both of the eyes a therapeutically effective amount of a composition comprising: sulphate; Boric acid; sodium borate; disodium edetate; glycerin; propylene glycol; hypromellose; sorbic acid; Another aspect of the invention is a method of treating an ophthalmic condition in a mammal in need thereof, comprising administering to the mammal one or both of the eyes a therapeutically effective amount of a composition comprising: sulphate; Boric acid; sodium borate; sodium chloride; sorbitol; propylene glycol; polyoxyethylene 40 hydrogenated castor oil; n-dodecyl-β-D-glycoside; benzalkonium chloride; Another aspect of the invention is a method of treating an ophthalmic condition in a mammal in need thereof, comprising administering to the mammal one or both of the eyes a therapeutically effective amount of a composition comprising: sulphate; Sodium phosphate heptahydrate; sodium dihydrogen phosphate monohydrate; povidone K-30; disodium edetate; sodium chloride; benzalkonium chloride; cyclodextrin (eg 2-hydroxypropyl-β-ring Dextrin); and water. Another aspect of the invention is a method of treating an ophthalmic condition in a mammal in need thereof, comprising administering to one or both of the mammals a therapeutically effective amount of a composition consisting of: lysine disqualate ; disodium hydrogen phosphate heptahydrate; sodium dihydrogen phosphate dihydrate; glycerin; povidone K-30; disodium edetate; benzalkonium chloride; Another aspect of the invention is a method of treating an ophthalmic condition in a mammal in need thereof, comprising administering to one or both of the mammals a therapeutically effective amount of a composition consisting of: lysine disqualate Boric acid; sodium borate; sodium carboxymethylcellulose; cyclodextrin (eg 2-hydroxypropyl-β-cyclodextrin); sodium chloride; benzalkonium chloride; and water. Another aspect of the invention is a method of treating an ophthalmic condition in a mammal in need thereof, comprising administering to one or both of the mammals a therapeutically effective amount of a composition consisting of: lysine disqualate Boric acid; sodium borate; disodium edetate; glycerin; propylene glycol; hypromellose; sorbic acid; Another aspect of the invention is a method of treating an ophthalmic condition in a mammal in need thereof, comprising administering to one or both of the mammals a therapeutically effective amount of a composition consisting of: lysine disqualate Boric acid; sodium borate; sodium chloride; sorbitol; propylene glycol; polyoxyethylene 40 hydrogenated castor oil; n-dodecyl-β-D-glycoside; benzalkonium chloride; Another aspect of the invention is a method of treating an ophthalmic condition in a mammal in need thereof, comprising administering to one or both of the mammals a therapeutically effective amount of a composition consisting of: lysine disqualate Sodium phosphate heptahydrate; sodium dihydrogen phosphate monohydrate; povidone K-30; disodium edetate; sodium chloride; benzalkonium chloride; cyclodextrin (eg 2-hydroxypropyl-β- Cyclodextrin); and water. Another aspect of the invention is a method of treating an ophthalmic condition in a mammal in need thereof, comprising administering to the mammal one or both of the eyes a therapeutically effective amount of at least one of the composition, the composition Groups of the following composition are selected: Formulation 1, Formulation 2, Formulation 3, Formulation 4, Formulation 5, and Formulation 6 as set forth herein. Another aspect of the invention is a method of treating an ophthalmic condition in a mammal in need thereof, which comprises administering to a mammal one or both eyes a therapeutically effective amount of a composition comprising a dilactine shark Amine; disodium hydrogen phosphate heptahydrate; sodium dihydrogen phosphate dihydrate; glycerin; povidone K-30; disodium edetate; benzalkonium chloride; Another aspect of the invention is a method of treating an ophthalmic condition in a mammal in need thereof, which comprises administering to a mammal one or both eyes a therapeutically effective amount of a composition comprising a dilactine shark Amine; boric acid; sodium borate; sodium carboxymethylcellulose; cyclodextrin (eg 2-hydroxypropyl-β-cyclodextrin); sodium chloride; benzalkonium chloride; Another aspect of the invention is a method of treating an ophthalmic condition in a mammal in need thereof, which comprises administering to a mammal one or both eyes a therapeutically effective amount of a composition comprising a dilactine shark Amine; boric acid; sodium borate; disodium edetate; glycerin; propylene glycol; hypromellose; sorbic acid; Another aspect of the invention is a method of treating an ophthalmic condition in a mammal in need thereof, which comprises administering to a mammal one or both eyes a therapeutically effective amount of a composition comprising a dilactine shark Amine; boric acid; sodium borate; sodium chloride; sorbitol; propylene glycol; polyoxyethylene 40 hydrogenated castor oil; n-dodecyl-β-D-glycoside; benzalkonium chloride; Another aspect of the invention is a method of treating an ophthalmic condition in a mammal in need thereof, which comprises administering to a mammal one or both eyes a therapeutically effective amount of a composition comprising a dilactine shark Amine; sodium phosphate heptahydrate; sodium dihydrogen phosphate monohydrate; povidone K-30; disodium edetate; sodium chloride; benzalkonium chloride; cyclodextrin (eg 2-hydroxypropyl-β - cyclodextrin); and water. Another aspect of the invention is a method of treating an ophthalmic condition in a mammal in need thereof, which comprises administering to a mammal one or both of the eyes a therapeutically effective amount of a composition consisting of the following: Salicylamine squalamine; disodium hydrogen phosphate heptahydrate; sodium dihydrogen phosphate dihydrate; glycerin; povidone K-30; disodium edetate; benzalkonium chloride; Another aspect of the invention is a method of treating an ophthalmic condition in a mammal in need thereof, which comprises administering to a mammal one or both of the eyes a therapeutically effective amount of a composition consisting of the following: Salicyl squalamine; boric acid; sodium borate; sodium carboxymethylcellulose; cyclodextrin (eg 2-hydroxypropyl-β-cyclodextrin); sodium chloride; benzalkonium chloride; Another aspect of the invention is a method of treating an ophthalmic condition in a mammal in need thereof, which comprises administering to a mammal one or both of the eyes a therapeutically effective amount of a composition consisting of the following: Salicyl squalamine; boric acid; sodium borate; disodium edetate; glycerin; propylene glycol; hypromellose; sorbic acid; Another aspect of the invention is a method of treating an ophthalmic condition in a mammal in need thereof, which comprises administering to a mammal one or both of the eyes a therapeutically effective amount of a composition consisting of the following: Salicyl squalamine; boric acid; sodium borate; sodium chloride; sorbitol; propylene glycol; polyoxyethylene 40 hydrogenated castor oil; n-dodecyl-β-D-glycoside; benzalkonium chloride; Another aspect of the invention is a method of treating an ophthalmic condition in a mammal in need thereof, which comprises administering to a mammal one or both of the eyes a therapeutically effective amount of a composition consisting of the following: Salicyl squalamine; sodium phosphate heptahydrate; sodium dihydrogen phosphate monohydrate; povidone K-30; disodium edetate; sodium chloride; benzalkonium chloride; cyclodextrin (eg 2-hydroxypropane) Base-β-cyclodextrin); and water. Another aspect of the invention is a method of treating an ophthalmic condition in a mammal in need thereof, comprising administering to the mammal one or both of the eyes a therapeutically effective amount of an ophthalmic therapeutic agent and a therapeutically effective amount selected from the group consisting of At least one of the compositions of the composition: Formulation 1, Formulation 2, Formulation 3, Formulation 4, Formulation 5, and Formulation 6 as set forth herein. Another aspect of the invention is a method of treating an ophthalmic condition in a mammal in need thereof, comprising administering to the mammal one or both of the eyes a therapeutically effective amount of an ophthalmic therapeutic agent and a therapeutically effective amount comprising the Composition: dibasic squalamine; disodium hydrogen phosphate heptahydrate; sodium dihydrogen phosphate dihydrate; glycerin; povidone K-30; disodium edetate; benzalkonium chloride; Another aspect of the invention is a method of treating an ophthalmic condition in a mammal in need thereof, comprising administering to the mammal one or both of the eyes a therapeutically effective amount of an ophthalmic therapeutic agent and a therapeutically effective amount comprising the Composition: squalinamin; boric acid; sodium borate; sodium carboxymethylcellulose; cyclodextrin (eg 2-hydroxypropyl-β-cyclodextrin); sodium chloride; benzalkonium chloride; . Another aspect of the invention is a method of treating an ophthalmic condition in a mammal in need thereof, comprising administering to the mammal one or both of the eyes a therapeutically effective amount of an ophthalmic therapeutic agent and a therapeutically effective amount comprising the Composition: diacetamide squalamine; boric acid; sodium borate; disodium edetate; glycerin; propylene glycol; hypromellose; sorbic acid; Another aspect of the invention is a method of treating an ophthalmic condition in a mammal in need thereof, comprising administering to the mammal one or both of the eyes a therapeutically effective amount of an ophthalmic therapeutic agent and a therapeutically effective amount comprising the Composition: diacetamide squalamine; boric acid; sodium borate; sodium chloride; sorbitol; propylene glycol; polyoxyethylene 40 hydrogenated castor oil; n-dodecyl-β-D-glycoside; benzalkonium chloride; . Another aspect of the invention is a method of treating an ophthalmic condition in a mammal in need thereof, comprising administering to the mammal one or both of the eyes a therapeutically effective amount of an ophthalmic therapeutic agent and a therapeutically effective amount comprising the Composition: sodium sulphate diamine; sodium phosphate heptahydrate; sodium dihydrogen phosphate monohydrate; povidone K-30; disodium edetate; sodium chloride; benzalkonium chloride; cyclodextrin (eg 2-hydroxypropyl-β-cyclodextrin); and water. Another aspect of the invention is a method of treating an ophthalmic condition in a mammal in need thereof, comprising administering to the mammal one or both of the eyes a therapeutically effective amount of an ophthalmic therapeutic agent and a therapeutically effective amount consisting of Composition: dihedral squalamine; disodium hydrogen phosphate heptahydrate; sodium dihydrogen phosphate dihydrate; glycerin; povidone K-30; disodium edetate; benzalkonium chloride; Another aspect of the invention is a method of treating an ophthalmic condition in a mammal in need thereof, comprising administering to the mammal one or both of the eyes a therapeutically effective amount of an ophthalmic therapeutic agent and a therapeutically effective amount consisting of Composition: squalinamin; boric acid; sodium borate; sodium carboxymethylcellulose; cyclodextrin (eg 2-hydroxypropyl-β-cyclodextrin); sodium chloride; benzalkonium chloride; water. Another aspect of the invention is a method of treating an ophthalmic condition in a mammal in need thereof, comprising administering to the mammal one or both of the eyes a therapeutically effective amount of an ophthalmic therapeutic agent and a therapeutically effective amount consisting of Composition: diacetamide squalamine; boric acid; sodium borate; disodium edetate; glycerin; propylene glycol; hypromellose; sorbic acid; Another aspect of the invention is a method of treating an ophthalmic condition in a mammal in need thereof, comprising administering to the mammal one or both of the eye a therapeutically effective amount of an ocular therapeutic agent and a therapeutically effective amount consisting of the following Composition: diacetamide squalamine; boric acid; sodium borate; sodium chloride; sorbitol; propylene glycol; polyoxyethylene 40 hydrogenated castor oil; n-dodecyl-β-D-glycoside; benzalkonium chloride; . Another aspect of the invention is a method of treating an ophthalmic condition in a mammal in need thereof, comprising administering to the mammal one or both of the eyes a therapeutically effective amount of an ophthalmic therapeutic agent and a therapeutically effective amount consisting of Composition: diacetamide squalamine; sodium phosphate heptahydrate; sodium dihydrogen phosphate monohydrate; povidone K-30; disodium edetate; sodium chloride; benzalkonium chloride; cyclodextrin For example, 2-hydroxypropyl-β-cyclodextrin); and water. Another aspect of the invention is a method of treating an ophthalmic condition in a mammal in need thereof, which comprises administering to the mammal one or both of the eyes a therapeutically effective amount of an ophthalmic therapeutic agent and a therapeutically effective amount of the composition At least one of the compositions consisting of a composition consisting of Formulation 1, Formulation 2, Formulation 3, Formulation 4, Formulation 5, and Formulation 6 as set forth herein. Another aspect of the invention is a method of treating an ophthalmic condition in a mammal in need thereof, which comprises administering to a mammal one or both eyes a therapeutically effective amount of an ophthalmic therapeutic agent and a therapeutically effective amount of a composition, The composition comprises diacetamide squalamine; disodium hydrogen phosphate heptahydrate; sodium dihydrogen phosphate dihydrate; glycerin; povidone K-30; disodium edetate; benzalkonium chloride; Another aspect of the invention is a method of treating an ophthalmic condition in a mammal in need thereof, which comprises administering to the mammal one or both of the eyes a therapeutically effective amount of an ophthalmic therapeutic agent and a therapeutically effective amount of a composition. The composition comprises diacetamide squalamine; boric acid; sodium borate; sodium carboxymethylcellulose; cyclodextrin (eg 2-hydroxypropyl-β-cyclodextrin); sodium chloride; benzalkonium chloride; And water. Another aspect of the invention is a method of treating an ophthalmic condition in a mammal in need thereof, which comprises administering to the mammal one or both of the eyes a therapeutically effective amount of an ophthalmic therapeutic agent and a therapeutically effective amount of a composition. The composition comprises diacetamide squalamine; boric acid; sodium borate; disodium edetate; glycerin; propylene glycol; hypromellose; sorbic acid; Another aspect of the invention is a method of treating an ophthalmic condition in a mammal in need thereof, which comprises administering to the mammal one or both of the eyes a therapeutically effective amount of an ophthalmic therapeutic agent and a therapeutically effective amount of a composition. The composition comprises diacetamide squalamine; boric acid; sodium borate; sodium chloride; sorbitol; propylene glycol; polyoxyethylene 40 hydrogenated castor oil; n-dodecyl-β-D-glycoside; And water. Another aspect of the invention is a method of treating an ophthalmic condition in a mammal in need thereof, which comprises administering to the mammal one or both of the eyes a therapeutically effective amount of an ophthalmic therapeutic agent and a therapeutically effective amount of a composition. The composition comprises diacetamide squalamine; sodium phosphate heptahydrate; sodium dihydrogen phosphate monohydrate; povidone K-30; disodium edetate; sodium chloride; benzalkonium chloride; cyclodextrin (eg 2-hydroxypropyl-β-cyclodextrin); and water. Another aspect of the invention is a method of treating an ophthalmic condition in a mammal in need thereof, which comprises administering to the mammal one or both of the eyes a therapeutically effective amount of an ophthalmic therapeutic agent and a therapeutically effective amount of a composition. The composition consists of: diacetamide squalamine; disodium hydrogen phosphate heptahydrate; sodium dihydrogen phosphate dihydrate; glycerin; povidone K-30; disodium edetate; benzalkonium chloride; And water. Another aspect of the invention is a method of treating an ophthalmic condition in a mammal in need thereof, which comprises administering to the mammal one or both of the eyes a therapeutically effective amount of an ophthalmic therapeutic agent and a therapeutically effective amount of a composition. The composition consists of: dibasic squalamine; boric acid; sodium borate; sodium carboxymethylcellulose; cyclodextrin (eg 2-hydroxypropyl-β-cyclodextrin); sodium chloride; Alkyl ammonium; and water. Another aspect of the invention is a method of treating an ophthalmic condition in a mammal in need thereof, which comprises administering to the mammal one or both of the eyes a therapeutically effective amount of an ophthalmic therapeutic agent and a therapeutically effective amount of a composition. The composition consists of diacetate squalamine; boric acid; sodium borate; disodium edetate; glycerin; propylene glycol; hypromellose; sorbic acid; Another aspect of the invention is a method of treating an ophthalmic condition in a mammal in need thereof, which comprises administering to the mammal one or both of the eyes a therapeutically effective amount of an ophthalmic therapeutic agent and a therapeutically effective amount of a composition. The composition consists of: diacetamide squalamine; boric acid; sodium borate; sodium chloride; sorbitol; propylene glycol; polyoxyethylene 40 hydrogenated castor oil; n-dodecyl-β-D-glycoside; Alkyl ammonium; and water. Another aspect of the invention is a method of treating an ophthalmic condition in a mammal in need thereof, which comprises administering to the mammal one or both of the eyes a therapeutically effective amount of an ophthalmic therapeutic agent and a therapeutically effective amount of a composition. The composition consists of: diacetamide squalamine; sodium phosphate heptahydrate; sodium dihydrogen phosphate monohydrate; povidone K-30; disodium edetate; sodium chloride; benzalkonium chloride; Cyclodextrin (eg 2-hydroxypropyl-β-cyclodextrin); and water. In an aspect of the invention, the ophthalmic therapeutic agent is administered to the mammal prior to administration of at least one selected from the group consisting of: Formulation 1, Formulation 2, Formulation as set forth herein Compound 3, Formulation 4, Formulation 5, and Formulation 6. In an aspect of the invention, the ophthalmic therapeutic agent is administered to the mammal simultaneously with administration of at least one selected from the group consisting of: Formulation 1, Formulation 2 as set forth herein Formulation 3, Formulation 4, Formulation 5, and Formulation 6. In an aspect of the invention, the ophthalmic therapeutic agent is administered to the mammal after administration of at least one of a composition selected from the group consisting of: Formulation 1, Formulation 2, Formulation as set forth herein Compound 3, Formulation 4, Formulation 5, and Formulation 6. In aspects of the invention, the ophthalmic therapeutic agent is administered to the mammal prior to administration of at least one of the compositions set forth herein. In aspects of the invention, the ophthalmic therapeutic agent is administered to the mammal simultaneously with administration of at least one of the compositions set forth herein. In aspects of the invention, the ophthalmic therapeutic agent is administered to the mammal after administration of at least one of the compositions set forth herein. In the aspect of the invention, the mammal is a human. In an aspect of the invention, the ophthalmic therapeutic agent is any ophthalmic therapeutic agent such as, but not limited to, selected from the group consisting of ranibizumab (Lucentis®), bevacizumab (bevacizumab) (Avastin®), abelibercept (Eylea®), DARPin (Abicipar), and brolucizumab (RTH-258). In an aspect of the invention, 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 Diabetic retinopathy, ischemic retinopathy (including retinal artery occlusion and carotid occlusion), cystoid macular edema, diabetic macular edema, iris reddening, retinopathy of prematurity, retinal vascular obstructive disease (including central and branch) Retinal vein occlusion), inflammatory/infectious retinal neovascularization/edema (including posterior uveitis, sarcoidosis, toxoplasmosis, histoplasmosis, Vogt-Koyanagi-Harada disease) 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 another aspect of the invention, each of the compositions of the present invention may further comprise or consist of at least one of: a mucoadhesive, a penetration enhancer, a viscosity increasing agent, a osmoticity a modifying agent, an antimicrobial preservative, a buffering agent, a surfactant, a stabilizer, a solubilizing and resuspending agent (if the agent is not already present in the composition), and if the agent is already present in the composition, the composition Another agent may be included or consist of. It is recognized that a particular chemical compound present in any of the compositions of the present invention may function at more than one capacity, i.e., may be used primarily as, for example, a mucoadhesive agent and, to a lesser extent, as a stabilizer, for example. Or mainly used as a solubilizer but also as a surfactant. In an exemplary embodiment, the composition may further comprise a mucoadhesive, an infiltration enhancer, a viscosity increasing agent, a permeability improving agent, an antimicrobial preservative, a buffering agent, a surfactant, a stabilizer, a solubilizing agent, and a resuspension. At least two or at least three or at least four or at least five of the agents. It is recognized that certain chemical compounds can function in a variety of capacities in this regard. In an exemplary embodiment, the composition is in the form of an eye drop. A mode of the invention is a method of delivering one of the compositions/formulations described in a therapeutically effective amount to the sclera and/or choroid of the eye of a mammal. In an exemplary embodiment, after administration of the compositions/formulations of the invention to the eye of a mammal, the compositions/formulations are present in the aqueous solution at a significantly lower concentration than other sites in the eye or In the vitreous humor. In an exemplary embodiment, the ophthalmic condition is wet AMD. In an exemplary embodiment, the diacetin squalamine is present in an amount from 0.01% to 5.0% by weight. In a particular embodiment, the weight % is 0.05% by weight or 0.1% by weight or 0.2% by weight or 0.3% by weight. In an exemplary embodiment, the salt is present in an amount sufficient to approximate the salt concentration and/or permeability of the human tear fluid. In an exemplary embodiment, the salt is present in an amount ranging from 0.5% to 1.0% by weight. In an exemplary embodiment, the preservative is present in an amount sufficient to create a microbial barrier to maintain or reduce the microbial concentration for a period of from about 12 hours to about 72 hours. A particular aspect of the invention is an ophthalmic composition comprising: 0.05 w/v% to 0.25 w/v% di-squalate squalamine; 0.5 w/v% to 1.5 w/v% boric acid and 0.05 w/v% To 0.30 w/v% sodium borate; 0.005 w/v% to 0.03 w/v% disodium edetate; 0.5 w/v% to 3.0 w/v% glycerol; 0.20 w/v% to 1.0 w/v% Propylene glycol; 0.3 w/v% to 2.0 w/v% hypromellose; 0.005 w/v% to 0.3 w/v% sorbic acid; and a sufficient amount of water for injection or purified water USP. Another particular aspect of the invention is an ophthalmic composition comprising: 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% Disodium edetate; 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-hydroxyl Propyl-β-cyclodextrin; and sufficient purified water. A particular aspect of the invention is an ophthalmic composition consisting of: 0.05 w/v% to 0.25 w/v% di-squalate squalamine; 0.5 w/v% to 1.5 w/v% boric acid and 0.05 w /v% to 0.30 w/v% sodium borate; 0.005 w/v% to 0.03 w/v% disodium edetate; 0.5 w/v% to 3.0 w/v% glycerol; 0.20 w/v% to 1.0 w /v% propylene glycol; 0.3 w/v% to 2.0 w/v% hypromellose; 0.005 w/v% to 0.3 w/v% sorbic acid; and a sufficient amount of water for injection or purified water USP. Another particular aspect of the invention is an ophthalmic composition consisting of: 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% disodium edetate; 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. In an exemplary embodiment, any of the above compositions is administered topically to the eye of a mammal in need thereof. In an exemplary embodiment, the composition is in the form of an eye drop. In an exemplary embodiment, the mammal has an ophthalmic condition, such as selected from the group consisting of: wet age-related macular degeneration (wet AMD), choroidal neovascularization, and dry age-related macular degeneration (dry type) AMD). The aspect of the invention is a method of selectively delivering squalamine or a pharmaceutically acceptable salt thereof to the sclera and choroid of the eye of a mammal in need thereof in a therapeutically effective amount for treating an ophthalmic condition, the method comprising: The composition is administered to the eye of a mammal, wherein the ophthalmic condition is selected from the group consisting of wet age-related macular degeneration (wet AMD), choroidal neovascularization, and dry age-related macular degeneration (dry AMD).

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。 根據所獲得之數據，本發明之局部調配物似乎靶向眼睛之後部。局部調配物為有利地靶向眼睛之後部，其應具有能夠以充足濃度到達眼睛之後鞏膜之性質。理想地，調配物在角膜上之滯留時間應增強而不會在擴散至眼睛之後部(例如自前鞏膜至後鞏膜)之前被眼淚沖掉。由於藥物分子可因(例如)使眼睛之晶狀體模糊而不利地影響該晶狀體，故該藥物分子不應自眼睛之前部進入眼球中並且進入眼球內之水狀液及玻璃體液至任一顯著程度。本發明調配物具有有效遞送藥物分子(例如二乳酸角鯊胺)所需要之期望且獨特之特徵，將該藥物分子施加至眼睛前部至需要治療濃度之藥物分子之眼睛後部用於治療靶向病症。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。 在投與至眼睛之表面上後，組合物進入結膜及前鞏膜並進入角膜層中。在存在時，黏膜黏著劑似乎增加在角膜中之滯留時間，使得藥物可隨時間緩慢擴散至後鞏膜，從而在後鞏膜中遞送持續濃度之角鯊胺或其醫藥上可接受之鹽。黏膜黏著劑因阻止(例如)由流淚及眼淚翻轉自鼻淚管排出引起之藥物損失實現了此目標。黏膜黏著劑亦通常具有可引起合意之舒緩或潤滑效應之黏度增強性質。視情況添加至調配物中之滲透增強劑可增強調配物滲透至角膜上皮層中，從而進一步增強角鯊胺或其醫藥上可接受之鹽在眼睛中之滯留時間。穩定劑可充當抗氧化劑或以其他方式阻止角鯊胺調配物之化學降解。緩衝劑將調配物緩衝至與眼部投與相容之舒適的近中性pH。調配物中之滲性改良劑產生眼用調配物之適當滲透壓。 所得調配物係穩定的，且其在滅菌後可包裝、儲存及直接使用。在例示性實施例中，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。在例示性實施例中，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。在各個例示性實施例中，抗微生物防腐劑係以足以使微生物濃度降低約12小時至約1個月(例如約12小時至約3週、例如約12小時至約2週、例如約12小時至約1週、例如約12小時至約3天、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。 在例示性實施例中，彼等不含防腐劑之調配物係包裝在單位劑量容器中，亦即其中給定容器僅提供單一劑量。一旦消費者首次開封容器時，該等不含防腐劑之組合物會經受失控之微生物生長。因此，要指導消費者處理第一次劑量後的容器。對於不含防腐劑之調配物而言，通常使用適當單位劑量系統(例如吹瓶-填充-密封單位劑量不含防腐劑之包裝系統)。 可在習用的眼科上相容之媒劑(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)中調配用於局部眼科投與本發明二乳酸角鯊胺之醫藥組合物。 如本文所使用之術語「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。 如本文所使用之術語「黃斑變性」意欲涵蓋黃斑變性之所有形式且包括尤其在老年人中發生之通常影響一隻或兩隻眼睛之中心視覺逐漸損失。黃斑變性之緩慢進展形式通常稱作乾型形式，其特徵尤其在於黃斑中累積黃色沈積物及黃斑之薄化。黃斑變性之快速進展形式通常稱作濕型形式，其特徵在於因出血產生之結瘢及在黃斑下方形成之新血管之流體滲漏。黃斑變性可以濕型形式或乾型形式存在。 如本文所使用之片語「醫藥上可接受之鹽」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存於化學化合物中之酸基團及/或鹼基團之鹽。例示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%。 在各個例示性實施例中，二乳酸角鯊胺鹽係以約0.1至約5 w/v%之濃度使用，例如約0.1w/v%至約4.5 w/v%，例如約0.1w/v%至約4.0 w/v%，例如約0.1w/v%至約3.5 w/v%，例如約0.1w/v%至約3.0 w/v%，例如約0.1w/v%至約2.5 w/v%，例如約0.1w/v%至約2.0 w/v%，例如約0.1w/v%至約1.5 w/v%，例如約0.1w/v%至約1.0 w/v%，例如約0.1w/v%至約0.8 w/v%，例如約0.1w/v%至約0.7 w/v%，例如約0.1w/v%至約0.6 w/v%，例如約0.1w/v%至約0.5 w/v%，例如約0.1w/v%至約0.4 w/v%，例如約0.1w/v%至約0.3 w/v%，例如約0.1w/v%至約0.2 w/v%。 視情況，本發明調配物含有滲性改良劑。 在例示性實施例中，滲性改良劑係非離子型的。滲性改良劑可選自(但不限於)甘露醇、山梨醇、右旋糖、蔗糖、尿素、甘油、聚乙二醇及其任一混合物。在例示性實施例中，滲性改良劑係以足以生成約250毫滲量/公斤(mOsmol/kg)至約350毫滲量/公斤(mOsmol/kg) (例如約265 mOsmol/kg至約325 mOsmol/kg，例如約280 mOsmol/kg至約310 mOsmol/kg，例如約295 mOsmol/kg至約315 mOsmol/kg)之滲性之量存在。 調配物亦可含有在約0.3重量%至約1重量%之範圍內或足以接近人類淚液之鹽濃度及/或滲性之量的選自(但不限於)鹼金屬鹵化物(例如，NaCl、KCl、NaBr等)之離子鹽。來自此群組之所選鹽亦可稱作離子滲性改良劑。 倘若在本發明調配物中使用防腐劑，則抗微生物係以足以生成微生物障壁以使微生物濃度維持或降低以下時段之量存在：約12小時至約1月，例如約12小時至約3週，例如約12小時至約2週，例如約12小時至約1週，例如約12小時至約3天，例如約12小時至約48小時，例如約12小時至約24小時。適宜防腐劑包括(但不限於)、氯苄烷銨、苄醇、山梨酸、氯丁醇、西曲銨(cetrimonium)、對羥基苯甲酸甲酯、對羥基苯甲酸丙酯、聚胺基丙基雙胍、苯乙醇、洛赫西定(chlorhexidine)、二葡萄糖酸洛赫西定、氯代季銨(chloroquat)、經穩定氧氯複合物或其任一組合。 可用於本發明調配物中之緩衝劑包括(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。在例示性實施例中，緩衝劑係磷酸二氫鈉或磷酸二鈉或硼酸/硼酸鈉。本發明之緩衝劑應以足以產生及維持約5.0至約8.0之調配物pH之量存在，例如約5.5至約7.7、例如約6.0至約7.5、例如約6.3至約7.5、例如約6.7至7.5、例如約6.7至約7.1，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。 亦可向本發明組合物中添加表面活性劑。在例示性實施例中，表面活性劑係以約0.001%至約0.3% (例如約0.005%至約0.2%、例如約0.01%至約0.1%、例如約0.05%至約0.1%)之濃度範圍存在以為調配物提供增強之潤濕特徵。表面活性劑可包括(但不限於)泊洛沙姆(poloxamer)、聚山梨醇酯80、聚山梨醇酯20、泰洛沙泊(tyloxapol)、聚氧化乙烯、Brij 35、Brij 58、Brij 78、Aptet 100、G 1045、Spans 20、40及85、Tweens 20、40、80或81、月桂醯基肌胺酸鈉、月桂醯基-L-麩胺酸三乙醇胺、肉豆蔻基肌胺酸鈉及月桂基硫酸鈉、聚氧乙烯山梨醇酐脂肪酸酯、聚氧乙烯氫化蓖麻油、聚乙二醇脂肪酸酯(例如，聚氧乙烯硬脂酸酯)、聚氧乙烯聚氧丙烯烷基醚、聚氧化烯烷基苯基醚、聚甘油脂肪酸酯(例如，十聚甘油單月桂酸酯)、甘油脂肪酸酯、山梨醇酐脂肪酸酯及聚氧乙烯聚氧丙二醇(泊洛沙姆)、聚氧乙烯硬脂酸酯40及/或其任一組合。 亦可將穩定劑添加至本發明調配物中。適宜穩定劑包括(但不限於)偏亞硫酸氫鈉、硫酸氫鈉、乙醯基半胱胺酸、抗壞血酸、硫代硫酸鈉、α-生育酚、肌肽、棕櫚酸視黃酯、乙二胺四乙酸(EDTA)之鹽(例如，依地酸二鈉鹽、依地酸四鈉鹽、依地酸鈣鹽或依地酸鈣鈉鹽)或其任一組合。 黏膜黏著劑在存於所闡述調配物中時增加角膜接觸時間，增強生物利用度及/或產生潤滑效應，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。 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、環糊精(CD)或其任一組合。 另外，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-CD (Cavasol®)、磺丁基醚4 β-CD (Captisol®)及羥丙基β-CD (Kleptose®))、聚山梨醇酯80 (Tween80® )或玻尿酸或玻尿酸鹽。環糊精特定而言亦可展現滲透增強性質，但在其他情況中，已知環糊精可阻止類固醇化合物(例如氫化可體松(hydrocortisone))吸收至眼部組織中。M. Masson等人，Proc. of the 9th Intl. Symposium on Cyclodextrins, Kluwer Academic Publishers (1999), 363-369；T. Loftsson等人，Acta Ophthalmologica Scandinavica (2003), 144-150；International Journal of Pharmaceutics 156 (1997), 201–209。 角鯊胺之二乳酸鹽可以非晶形形式或結晶形式存在。在本發明之例示性實施例，二乳酸鹽之結晶形式以溶劑合物形式存在。在另一例示性實施例中，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。 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、穩定劑及佐劑之例示性清單可參見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。實例 實例1 -調配物1 調配物1含有以下各項： 0.05 w/v%至0.25 w/v%二乳酸角鯊胺； 0.20w/v%至0.30w/v%磷酸氫二鈉七水合物及0.10 w/v%至0.20w/v%磷酸二氫鈉二水合物； 0.15 w/v%至0.45 w/v%甘油； 0.5 w/v%至2.5 w/v%聚維酮K-30； 0.005 w/v%至0.05 w/v%依地酸二鈉； 0.001 w/v%至0.010 w/v%氯苄烷銨；及 充足量之注射用水或純化水USP。 pH = 6.5至7.5且滲透壓 = 260 mOsm/kg至340 mOsm/kg。 調配物1之特定實施例含有0.2 w/v%二乳酸角鯊胺；027 w/v%磷酸氫二鈉七水合物及0.13 w/v%磷酸二氫鈉二水合物；0.3 w/v%甘油；1.4 w/v%聚維酮K-30；0.01 w/v%依地酸二鈉；0.005 w/v%氯苄烷銨；及充足量之注射用水或純化水USP。pH = 6.8且滲透壓 = 280 mOsm/kg。 調配物1之製備. 將約50 mL純化水置於具有攪拌棒之250 mL刻度燒杯中。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0.13 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0.3 g甘油添加至燒杯中並攪拌直至其溶解為止。將1.4 g聚維酮K-30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6.8 (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。 實例2 -調配物2 調配物2含有以下各項： 0.05 w/v%至0.25 w/v%二乳酸角鯊胺； 1.0 w/v%至1.5 w/v%硼酸及0.10 w/v%至0.15w/v%硼酸鈉； 0.1 w/v%至1.0 w/v%羧甲基纖維素鈉； 0.2 w/v%至1.5 w/v% 2-羥丙基-β-環糊精； 0.3 w/v%至1.5 w/v%氯化鈉； 0.03w/v%至0.15w/v%氯苄烷銨；及 足量純化水。 PH = 7.3且滲透壓 = 310 mOsm/kg。 調配物2之特定實施例含有0.2 w/v%二乳酸角鯊胺；1.18 w/v%硼酸；0.12 w/v%硼酸鈉；0.4 w/v%羧甲基纖維素鈉；0.9 w/v% 2-羥丙基-β-環糊精；0.85w/v%氯化鈉；0.08 w/v%氯苄烷銨；及足量純化水。PH = 7.3且滲透壓 = 310 mOsm/kg。 調配物2之製備.將約50 mL純化水置於具有攪拌棒之250 mL刻度燒杯中。將1.18 g硼酸及0.12 g硼酸鈉添加至燒杯中並攪拌直至其溶解位置。將0.85 g氯化鈉添加至燒杯中並攪拌直至其溶解為止。將0.4 g羧甲基纖維素鈉添加至燒杯中並攪拌直至其溶解為止。將0.08 g氯苄烷銨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0.9 g羥丙基-β-環糊精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 (若需要)將pH調節至7.3。將體積補足至100 mL且使用0.22微米過濾器之無菌過濾總成過濾溶液。 實例3 -調配物3 調配物3含有以下各項： 0.05 w/v%至0.25 w/v%二乳酸角鯊胺； 0.5 w/v%至1.5 w/v%硼酸及0.05 w/v%至0.30 w/v%硼酸鈉； 0.005 w/v%至0.03 w/v%依地酸二鈉； 0.5 w/v%至3.0 w/v%甘油； 0.20 w/v%至1.0 w/v%丙二醇； 0.3 w/v%至2.0 w/v%羥丙甲纖維素； 0.005 w/v%至0.3 w/v%山梨酸；及 充足量之注射用水或純化水USP。 PH = 6.5至7.5且滲透壓 = 280 mOsm/kg至340 mOsm/kg。 調配物3之特定實施例含有0.2 w/v%二乳酸角鯊胺；1.15 w/v%硼酸；0.13 w/v%硼酸鈉；0.01 w/v%依地酸二鈉；1.0 w/v%甘油；0.45 w/v%丙二醇；0.7 w/v%羥丙甲纖維素；0.1 w/v%山梨酸；及充足量之注射用水或純化水USP。 調配物3之製備. 將約50 mL純化水置於具有攪拌棒之250 mL刻度燒杯中。將1.15 g硼酸及0.13 g硼酸鈉添加至燒杯中並攪拌直至其溶解位置。將1.0 g甘油添加至燒杯中並攪拌直至其溶解為止。將0.45 g丙二醇添加至燒杯中並攪拌直至其溶解為止。將0.1 g EDTA二鈉添加至燒杯中並攪拌直至其溶解為止。將0.700 g羥丙甲纖維素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0.1 g山梨酸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7.4 (若需要)。將體積補足至100 mL且使用0.22微米過濾器之無菌過濾總成過濾溶液。 實例4 -調配物4 調配物4含有以下各項： 0.05 w/v%至0.25 w/v%二乳酸角鯊胺； 0.5 w/v%至1.5 w/v%硼酸及0.05w/v%至0.5 w/v%硼酸鈉； 0.5w/v%至2.0w/v% NaCl； 2.5w/v%至4.0w/v%山梨醇； 0.2 w/v%至1.5 w/v%丙二醇； 0.2 w/v%至1.5w/v%聚氧乙烯40氫化蓖麻油； 0.01w/v%至0.1 w/v%正十二烷基-β-D-醣苷； 0.001 w/v%至0.01 w/v%氯苄烷銨；及 充足量之注射用水或純化水USP。 PH = 6.5至7.5且滲透壓 = 250 mOsm/kg至340 mOsm/kg。 調配物4之特定實施例含有0.2 w/v%二乳酸角鯊胺；1.18 w/v%硼酸；0.12 w/v%硼酸鈉；0.75w/v % NaCl；3.5w/v%山梨醇；0.45 w/v%丙二醇；0.5w/v %聚氧乙烯40氫化蓖麻油；0.05w/v %正十二烷基-β-D-醣苷；0.005 w/v%氯苄烷銨；及充足量之注射用水或純化水USP。PH = 6.9且滲透壓 = 305 mOsm/kg。 調配物4之製備.將約50 mL純化水置於具有攪拌棒之250 mL刻度燒杯中。將1.18 g硼酸及0.12 g硼酸鈉添加至燒杯中並攪拌直至其溶解位置。將0.5 g聚氧乙烯40氫化蓖麻油添加至燒杯中並攪拌直至其溶解為止。將0.4 g丙二醇添加至燒杯中並攪拌直至其溶解為止。將0.3 g山梨醇添加至燒杯中並攪拌直至其溶解為止。將0.05 g正十二烷基-β-D-醣苷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0.005 g氯苄烷銨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6.9 (若需要)。將體積補足至100 mL且使用0.22微米過濾器之無菌過濾總成過濾溶液。 實例5 -調配物5 調配物5含有以下各項： 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5之特定實施例含有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；0.80w/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5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。 實例6 -調配物6 調配物6含有以下各項： 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6之製備. 此調配物係以與調配物5類似之方式來製備。 實例7 –調配物6之臨床前測試– 生物分佈研究 QD (每24小時)或BID (每12小時)雙側投與雄性荷蘭黑帶兔(Dutch belted rabbit) (n=24)調配物6滴眼劑(40 µL)達1天、7天及14天(n=4隻/組/劑量)。對動物實施安樂死且分別在QD或BID組中在最後投藥後24 (±2)或12(±1)小時收集眼部組織。使用經驗證LC-MS/MS方法分析後鞏膜/脈絡膜、水狀液及玻璃體液及血漿之角鯊胺濃度，且量化下限(LLOQ)為10ng/g組織。將低於LLOQ之值報告為可量化下限或BQL。亦藉助臨床觀察及狹縫燈眼底鏡檢查評估調配物之眼部毒性及刺激。結果為QD或BID給予之調配物6滴眼劑耐受良好且無不利臨床效應。QD給予時，在1天、7天及14天群組中後鞏膜/脈絡膜中角鯊胺之濃度分別為9.5ng/g、21.9ng/g及39.8 ng/g (圖 1 ，下部曲線)。BID給予時，在1天、7天及14天群組中後鞏膜/脈絡膜中角鯊胺之濃度分別為21.7ng/g、62.6ng/g及68 ng/g (圖 1 ，上部曲線)。值代表在最後投與之後一個完全投藥間隔(QD 24(+2)小時，BID 12(+1)小時)之含量。QD及BID值證明後鞏膜/脈絡膜中角鯊胺之含量遠高於抑制組織血管生成之臨限值(約11 ng/g)。相比之下，角鯊胺濃度在水狀液及玻璃體液中之在所有動物中皆＜LLOQ (10 ng/mL)且在血漿中在23/24動物中＜LLOQ(表1)。 表1 BQL =量化下限(在組織中10 ng/g；在血漿中10 ng/mL) 調配物6滴眼劑證實無害且在眼科狹縫燈眼部檢查中未產生可辨別變化。 實例8 –調配物5之臨床測試 下文所闡述之臨床研究使用調配物5之以下實施例：0.2 w/v%二乳酸角鯊胺；0.27 w/v%磷酸鈉七水合物及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；0.80w/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 6.7至7.1。 下文所闡述之研究代表調配物5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5滴劑加Lucentis® (「調配物5」臂或組，在圖中標記為「形式-5」)對每日兩次投與安慰劑滴眼劑加Lucentis® (「Lucentis®單一療法」臂或組，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5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 (在經改良意向治療或mITT群體中)之患者之視覺敏銳度結果。在具有含有經典脈絡膜新生血管形成(CNV)之病灶(含有經典之病灶)之mITT群體(調配物5，n=37；Lucentis®單一療法，n=28)中，第9個月時視覺敏銳度之平均增加為OHR-102組合臂之+11個字母及利用Lucentis®單一療法之+5個字母，在臨床上有意義之益處為6個字母(圖 2A )。另外，如與在Lucentis®單一療法組中之28%相比，在9個月時44%的接受調配物5組合療法之患者達成≥3行視覺增加(圖 2B )。在含有經典之病灶中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。含有經典之CNV群體代表總濕型AMD患者群體之約2/3。 在含有經典之病灶中之mITT數據亦顯示對於達成≥4及≥5行視覺增加之彼等患者，在調配物5與Lucentis®單一療法組之間之分離更顯著。如與對於接受Lucentis®單一療法之彼等具有≥4行增加之7%及具有≥5行增加之7%相比，在接受調配物5之患者中，在9個月時22%達成≥4行增加且17%達成≥5行增加(圖 2C )。 分析在意向治療(ITT-LOCF)群體(調配物5，n=38；Lucentis®單一療法，n=32)中具有含有經典之病灶之患者之數據。在此組中，視覺敏銳度之平均增加為調配物5組合臂之+10.5個字母及利用Lucentis®單一療法之+5.4個字母，在臨床上有意義之益處為+5.1個字母(圖 3A )。另外，如與在Lucentis®單一療法組中之25%相比，在9個月時31%的接受調配物5之患者達成≥3行增加(圖 3B )。 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. Based on the data obtained, the topical formulations of the invention appear to be targeted to the posterior portion of the eye. The topical formulation is advantageously targeted to the posterior portion of the eye, which should have the property of being able to reach the sclera after the eye in sufficient concentration. Ideally, the residence time of the formulation on the cornea should be enhanced without being washed away by tears before spreading to the back of the eye (eg, from the anterior sclera to the posterior sclera). Since the drug molecule can adversely affect the lens due to, for example, blurring the lens of the eye, the drug molecule should not enter the eyeball from the front of the eye and enter the aqueous humor and vitreous humor in the eyeball to any significant extent. The formulation of the present invention has the desirable and unique characteristics required for the effective delivery of a drug molecule (e.g., diacetamide), which is applied to the anterior portion of the eye to the back of the eye of the drug molecule in need of therapeutic concentration for therapeutic targeting. Illness. 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. Upon administration to the surface of the eye, the composition enters the conjunctiva and anterior sclera and enters the corneal layer. When present, the mucoadhesive appears to increase the residence time in the cornea so that the drug can slowly diffuse over time to the posterior sclera, thereby delivering a sustained concentration of squalamine or a pharmaceutically acceptable salt thereof in the posterior sclera. Mucosal adhesives achieve this goal by preventing drug loss caused, for example, by tearing and tearing over the nasolacrimal duct. Mucoadhesives also typically have viscosity-enhancing properties that cause a desirable soothing or lubricating effect. The penetration enhancer added to the formulation as appropriate enhances penetration of the formulation into the corneal epithelial layer, thereby further enhancing the residence time of squalamine or a pharmaceutically acceptable salt thereof in the eye. The stabilizer acts as an antioxidant or otherwise prevents chemical degradation of the squalamine formulation. The buffer buffers the formulation to a comfortable near neutral pH compatible with ocular administration. The osmotic modifier in the formulation produces an appropriate osmotic pressure for the ophthalmic formulation. The resulting formulation is 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 an eye drop 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 various exemplary embodiments, the antimicrobial preservative is sufficient to reduce the microbial concentration for from about 12 hours to about 1 month (eg, from about 12 hours to about 3 weeks, such as from about 12 hours to about 2 weeks, such as about 12 hours). An amount is present for a period of from about 1 week, such as from about 12 hours to about 3 days, such as from about 12 hours to about 48 hours, such as from about 12 hours to about 24 hours. In an exemplary embodiment, the preservative-free formulation is packaged in a unit dose container, i.e., wherein a given container provides only a single dose. Once the consumer first unpacks the container, the preservative-free composition will undergo uncontrolled microbial growth. Therefore, the consumer is to be instructed to handle the container after the first dose. For preservative-free formulations, an appropriate unit dose system (eg, a blow-fill-seal unit dose of a preservative-free packaging system) is typically used. Formulated for use in topical ophthalmic administration in conventional ophthalmologically compatible vehicles (eg, ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols or oils) And a pharmaceutical composition of the diacetamide of the present invention. The term "ophthalmic condition" or "ophthalmic condition" as used herein 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. The term "macular degeneration" as used herein is intended to encompass all forms of macular degeneration and includes gradual loss of central vision that typically affects one or both eyes, particularly in the elderly. The slow progression of macular degeneration is commonly referred to as the dry form and is characterized, inter alia, by the accumulation of yellow deposits in the macula and thinning of the macula. The rapidly progressing form of macular degeneration is commonly referred to as the wet form and is characterized by scarring of the scar caused by bleeding and fluid leakage of new blood vessels formed under the macula. Macular degeneration can exist in either wet or dry form. The phrase "pharmaceutically acceptable salt" as used herein refers to any salt of a chemical compound that can be safely used in mammals. Pharmaceutically acceptable salts include 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. 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 is also an amount 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- lysamine is typically 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. In various exemplary embodiments, the dilacsamine salt is used at a concentration of from about 0.1 to about 5 w/v%, such as from about 0.1 w/v% to about 4.5 w/v%, such as about 0.1 w/v. % to about 4.0 w/v%, such as from about 0.1 w/v% to about 3.5 w/v%, such as from about 0.1 w/v% to about 3.0 w/v%, such as from about 0.1 w/v% to about 2.5 w. /v%, for example from about 0.1 w/v% to about 2.0 w/v%, such as from about 0.1 w/v% to about 1.5 w/v%, such as from about 0.1 w/v% to about 1.0 w/v%, for example From about 0.1 w/v% to about 0.8 w/v%, such as from about 0.1 w/v% to about 0.7 w/v%, such as from about 0.1 w/v% to about 0.6 w/v%, such as about 0.1 w/v. % to about 0.5 w/v%, such as from about 0.1 w/v% to about 0.4 w/v%, such as from about 0.1 w/v% to about 0.3 w/v%, such as from about 0.1 w/v% to about 0.2 w. /v%. Optionally, the formulation of the present invention contains a permeability improving agent. In an exemplary embodiment, the osmotic modifier is non-ionic. The osmoticity improver can be selected from, but not limited to, mannitol, sorbitol, dextrose, sucrose, urea, glycerol, polyethylene glycol, and any mixture thereof. In an exemplary embodiment, the osmotic modifier is sufficient to produce from about 250 milliosmoles per kilogram (mOsmol/kg) to about 350 milliosmoles per kilogram (mOsmol/kg) (eg, from about 265 mOsmol/kg to about 325). An amount of osmoticity of mOsmol/kg, for example from about 280 mOsmol/kg to about 310 mOsmol/kg, for example from about 295 mOsmol/kg to about 315 mOsmol/kg, is present. The formulation may also contain, in the range of from about 0.3% to about 1% by weight or sufficient to approximate the salt concentration and/or permeability of the human tear fluid, selected from, but not limited to, an alkali metal halide (eg, NaCl, Ionic salt of KCl, NaBr, etc.). Selected salts from this group may also be referred to as ion permeability improvers. If a preservative is used in the formulation of the invention, the antimicrobial system is present in an amount sufficient to produce a microbial barrier to maintain or reduce the microbial concentration for a period of from about 12 hours to about 1 month, such as from about 12 hours to about 3 weeks, For example, from about 12 hours to about 2 weeks, such as from about 12 hours to about 1 week, such as from about 12 hours to about 3 days, such as from about 12 hours to about 48 hours, such as from about 12 hours to about 24 hours. Suitable preservatives include, but are not limited to, benzalkonium chloride, benzyl alcohol, sorbic acid, chlorobutanol, cetrimonium, methyl paraben, propyl paraben, polyaminopropyl Bismuth, phenylethyl alcohol, chlorhexidine, lohexidine digluconate, chloroquat, stabilized oxychloride complex, or any combination thereof. Buffering agents which may be used in the formulations of the present invention include, but are not limited to, sodium bicarbonate, potassium, sodium, potassium, sodium, potassium, sodium citrate, potassium, sodium borate A buffer prepared from potassium salts 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 buffer of the present invention should be present in an amount sufficient to produce and maintain a pH of the formulation of from about 5.0 to about 8.0, such as from about 5.5 to about 7.7, such as from about 6.0 to about 7.5, such as from about 6.3 to about 7.5, such as from about 6.7 to 7.5. For example, from about 6.7 to about 7.1, and including 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. Surfactants can also be added to the compositions of the invention. In an exemplary embodiment, the surfactant is in a concentration range of from about 0.001% to about 0.3% (eg, from about 0.005% to about 0.2%, such as from about 0.01% to about 0.1%, such as from about 0.05% to about 0.1%). There is a wetting feature that provides enhanced formulation. Surfactants may include, but are not limited to, poloxamer, polysorbate 80, polysorbate 20, tyloxapol, polyethylene oxide, Brij 35, Brij 58, Brij 78. , Aptte 100, G 1045, Spans 20, 40 and 85, Tweens 20, 40, 80 or 81, sodium lauryl sarcosinate, lauryl-L-glutamic acid triethanolamine, myristyl-sodium myristate And sodium lauryl sulfate, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene hydrogenated castor oil, polyethylene glycol fatty acid ester (for example, polyoxyethylene stearate), polyoxyethylene polyoxypropylene alkyl Ether, polyoxyalkylene alkylphenyl ether, polyglycerol fatty acid ester (for example, decaglycerin monolaurate), glycerin fatty acid ester, sorbitan fatty acid ester, and polyoxyethylene polyoxypropylene glycol (poloxa) M), polyoxyethylene stearate 40 and/or any combination thereof. Stabilizers can also be added to the formulations of the present invention. Suitable stabilizers include, but are not limited to, sodium metabisulfite, sodium hydrogen sulfate, acetylcysteine, ascorbic acid, sodium thiosulfate, alpha-tocopherol, carnosine, retinyl palmitate, ethylenediamine A salt of tetraacetic acid (EDTA) (for example, disodium edetate, tetrasodium edetate, calcium edetate or sodium edetate) or any combination thereof. The mucoadhesive agent increases corneal contact time, enhances bioavailability and/or produces a lubricating effect when present in the formulation as described, and includes, but is not limited to, acrylic acid polymers, methyl cellulose, ethyl cellulose, Povidone K-30, hydroxypropyl methylcellulose, hydroxyethylcellulose, 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 sulfate or any combination thereof. Permeation enhancers which are optionally present in the formulation include, but are not limited to, laurocapram (azone), bile acids and their alkali metal salts, including chenodeoxycholic acid, cholic acid , taurocholic acid, taurodeoxycholic acid, tauroursodeoxycholic acid or ursodeoxycholic acid, glycocholate, n-dodecyl-β-D-maltoside, sucrose dodecanoic acid Ester, octyl maltoside, decyl maltoside, tridecyl maltoside, tetradecyl maltoside, hexamethylene laurylamine, hexamethylene octylamine, glycerol monolaurate, PGML ( Polyethylene glycol monolaurate), dimethylhydrazine, methylsulfonyl methane, sodium fusidate, saponin, cyclodextrin (CD), or any combination thereof. Additionally, solubilizers or resuspension agents can also be added to the formulations of the present invention. Suitable solubilizing or resuspension agents include, but are not limited to, cyclodextrin (CD) (eg, hydroxypropyl γ-CD (Cavasol®), sulfobutyl ether 4 β-CD (Captisol®), and hydroxypropyl β- CD (Kleptose®), Polysorbate 80 (Tween80 ® ) or Hyaluronic Acid or Hyaluronic Acid. Cyclodextrins may also exhibit osmotic enhancing properties in particular, but in other instances, cyclodextrins are known to prevent absorption of steroid compounds, such as hydrocortisone, into ocular tissues. M. Masson et al., Proc of the 9 th Intl Symposium on Cyclodextrins, Kluwer Academic Publishers (1999), 363-369;... T Loftsson et al, Acta Ophthalmologica Scandinavica (2003), 144-150; International Journal of Pharmaceutics 156 (1997), 201–209. The squalamine dilactate 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. An illustrative list of typical carriers, stabilizers, and adjuvants known to those skilled in the art for use in the ophthalmic compositions described herein can be found in Gennaro (2005) Remington: The Science and Practice of Pharmacy, Mack Publishing, 21 edition. In vivo Administration of the Compositions The invention may be practiced in one dose, multiple doses, continuously or intermittently throughout the course of the treatment. Methods for determining the most effective dosage to be administered are well known to those skilled in the art and will vary with the composition used in the therapy, the purpose of the therapy, and the individual being treated. Single or multiple administrations can be performed, with the dosage amount and pattern being selected by the treating physician. Various specific and non-limiting formulations are set forth in the Examples below. The formulations are only illustrative of the invention as set forth and are not intended to limit the scope of the invention as set forth. EXAMPLES Example 1 - Formulation 1 Formulation 1 contains the following: 0.05 w/v% to 0.25 w/v% di-squalate squalamine; 0.20 w/v% to 0.30 w/v% disodium hydrogen phosphate heptahydrate And 0.10 w/v% to 0.20 w/v% sodium dihydrogen phosphate dihydrate; 0.15 w/v% to 0.45 w/v% glycerol; 0.5 w/v% to 2.5 w/v% povidone K-30 0.005 w/v% to 0.05 w/v% disodium edetate; 0.001 w/v% to 0.010 w/v% benzalkonium chloride; and a sufficient amount of water for injection or purified water USP. pH = 6.5 to 7.5 and osmotic pressure = 260 mOsm/kg to 340 mOsm/kg. A specific example of Formulation 1 contains 0.2 w/v% dihrolyl squalamine; 027 w/v% disodium hydrogen phosphate heptahydrate and 0.13 w/v% sodium dihydrogen phosphate dihydrate; 0.3 w/v% Glycerol; 1.4 w/v% povidone K-30; 0.01 w/v% disodium edetate; 0.005 w/v% benzalkonium chloride; and a sufficient amount of water for injection or purified water USP. pH = 6.8 and osmotic pressure = 280 mOsm/kg. Preparation of Formulation 1. Approximately 50 mL of purified water was placed in a 250 mL graduated beaker with a stir bar. 0.27 g of sodium phosphate heptahydrate was added to the beaker and stirred until it dissolved. 0.13 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. Add 0.3 g of glycerol to the beaker and stir until it dissolves. 1.4 g of povidone K-30 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 6.8 (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. Example 2 - Formulation 2 Formulation 2 contained the following: 0.05 w/v% to 0.25 w/v% di-squalate squalamine; 1.0 w/v% to 1.5 w/v% boric acid and 0.10 w/v% to 0.15 w/v% sodium borate; 0.1 w/v% to 1.0 w/v% sodium carboxymethylcellulose; 0.2 w/v% to 1.5 w/v% 2-hydroxypropyl-β-cyclodextrin; w/v% to 1.5 w/v% sodium chloride; 0.03 w/v% to 0.15 w/v% benzalkonium chloride; and sufficient purified water. PH = 7.3 and osmotic pressure = 310 mOsm/kg. A particular example of Formulation 2 contains 0.2 w/v% di-squalate squalamine; 1.18 w/v% boric acid; 0.12 w/v% sodium borate; 0.4 w/v% sodium carboxymethylcellulose; 0.9 w/v % 2-hydroxypropyl-β-cyclodextrin; 0.85 w/v% sodium chloride; 0.08 w/v% benzalkonium chloride; and sufficient purified water. PH = 7.3 and osmotic pressure = 310 mOsm/kg. Preparation of Formulation 2. Approximately 50 mL of purified water was placed in a 250 mL graduated beaker with a stir bar. Add 1.18 g of boric acid and 0.12 g of sodium borate to the beaker and stir until it dissolves. 0.85 g of sodium chloride was added to the beaker and stirred until it dissolved. 0.4 g of sodium carboxymethylcellulose was added to the beaker and stirred until it dissolved. 0.08 g of benzalkonium chloride 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. 0.9 g of hydroxypropyl-β-cyclodextrin 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 7.3 using 2 N NaOH and 1 N HCl (if needed). The volume was made up to 100 mL and the solution was filtered using a sterile filter assembly of 0.22 micron filter. Example 3 - Formulation 3 Formulation 3 contained the following: 0.05 w/v% to 0.25 w/v% di-squalate squalamine; 0.5 w/v% to 1.5 w/v% boric acid and 0.05 w/v% to 0.30 w/v% sodium borate; 0.005 w/v% to 0.03 w/v% disodium edetate; 0.5 w/v% to 3.0 w/v% glycerol; 0.20 w/v% to 1.0 w/v% propylene glycol 0.3 w/v% to 2.0 w/v% hypromellose; 0.005 w/v% to 0.3 w/v% sorbic acid; and a sufficient amount of water for injection or purified water USP. PH = 6.5 to 7.5 and osmotic pressure = 280 mOsm/kg to 340 mOsm/kg. A specific example of Formulation 3 contains 0.2 w/v% di-squalate squalamine; 1.15 w/v% boric acid; 0.13 w/v% sodium borate; 0.01 w/v% disodium edetate; 1.0 w/v% Glycerin; 0.45 w/v% propylene glycol; 0.7 w/v% hypromellose; 0.1 w/v% sorbic acid; and a sufficient amount of water for injection or purified water USP. Preparation of Formulation 3. Approximately 50 mL of purified water was placed in a 250 mL graduated beaker with a stir bar. 1.15 g of boric acid and 0.13 g of sodium borate were added to the beaker and stirred until it dissolved. Add 1.0 g of glycerin to the beaker and stir until it dissolves. 0.45 g of propylene glycol was added to the beaker and stirred until it dissolved. 0.1 g of disodium EDTA was added to the beaker and stirred until it dissolved. 0.700 g of hypromellose 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. 0.1 g of sorbic acid 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 7.4 (if needed) using 2 N NaOH and 1 N HCl. The volume was made up to 100 mL and the solution was filtered using a sterile filter assembly of 0.22 micron filter. Example 4 - Formulation 4 Formulation 4 contained the following: 0.05 w/v% to 0.25 w/v% di-squalate squalamine; 0.5 w/v% to 1.5 w/v% boric acid and 0.05 w/v% to 0.5 w/v% sodium borate; 0.5 w/v% to 2.0 w/v% NaCl; 2.5 w/v% to 4.0 w/v% sorbitol; 0.2 w/v% to 1.5 w/v% propylene glycol; 0.2 w /v% to 1.5w/v% polyoxyethylene 40 hydrogenated castor oil; 0.01w/v% to 0.1 w/v% n-dodecyl-β-D-glycoside; 0.001 w/v% to 0.01 w/v % benzylammonium chloride; and a sufficient amount of water for injection or purified water USP. PH = 6.5 to 7.5 and osmotic pressure = 250 mOsm/kg to 340 mOsm/kg. A particular example of Formulation 4 contains 0.2 w/v% di-squalate squalamine; 1.18 w/v% boric acid; 0.12 w/v% sodium borate; 0.75 w/v % NaCl; 3.5 w/v% sorbitol; w/v% propylene glycol; 0.5 w/v % polyoxyethylene 40 hydrogenated castor oil; 0.05 w/v % n-dodecyl-β-D-glycoside; 0.005 w/v% benzalkonium chloride; and sufficient amount Water for injection or purified water USP. PH = 6.9 and osmotic pressure = 305 mOsm/kg. Preparation of Formulation 4. Approximately 50 mL of purified water was placed in a 250 mL graduated beaker with a stir bar. Add 1.18 g of boric acid and 0.12 g of sodium borate to the beaker and stir until it dissolves. 0.5 g of polyoxyethylene 40 hydrogenated castor oil was added to the beaker and stirred until it dissolved. 0.4 g of propylene glycol was added to the beaker and stirred until it dissolved. 0.3 g of sorbitol was added to the beaker and stirred until it dissolved. 0.05 g of n-dodecyl-β-D-glycoside 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. 0.005 g of benzalkonium chloride 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 6.9 (if needed) using 2 N NaOH and 1 N HCl. The volume was made up to 100 mL and the solution was filtered using a sterile filter assembly of 0.22 micron filter. Example 5 - Formulation 5 Formulation 5 contains the following: 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 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. 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 5 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% polydimension Ketone 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-hydroxypropyl-β-cyclodide Fine; and sufficient purified water. PH = 6.70 and osmotic pressure = 315 mOsm/kg. Preparation of Formulation 5. 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. Example 6 - Formulation 6 Formulation 6 contains the following: 0.2% dihrolyl squalamine; 0.188 w/v% sodium phosphate heptahydrate and 0.1 w/v% sodium dihydrogen phosphate monohydrate; 1.2 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 purified water. PH = 6.70 and osmotic pressure = 315 mOsm/kg. Preparation of Formulation 6. This formulation was prepared in a similar manner to Formulation 5. Example 7 - Preclinical Testing of Formulation 6 - Biodistribution Study QD (every 24 hours) or BID (every 12 hours) bilateral dosing of Dutch Dutch rabbits (n=24) formulation 6 drops Eye drops (40 μL) for 1 day, 7 days, and 14 days (n=4/group/dose). Animals were euthanized and ocular tissue was collected in the QD or BID group at 24 (±2) or 12 (±1) hours after the last administration, respectively. The squalamine concentrations in the posterior sclera/choroid, aqueous and vitreous humor and plasma were analyzed using a validated LC-MS/MS method with a lower limit of quantitation (LLOQ) of 10 ng/g tissue. Values below LLOQ are reported as quantifiable lower limits or BQL. The eye toxicity and irritation of the formulation were also evaluated by clinical observation and slit lamp ophthalmoscopy. Results Formulations administered with QD or BID 6 eye drops were well tolerated and had no adverse clinical effects. At the time of QD administration, the concentrations of squalamine in the posterior sclera/choroid in the 1 day, 7 days, and 14 day groups were 9.5 ng/g, 21.9 ng/g, and 39.8 ng/g, respectively ( Fig. 1 , lower curve). At the time of BID administration, the concentrations of squalamine in the posterior sclera/choroid in the 1 day, 7 days, and 14 day groups were 21.7 ng/g, 62.6 ng/g, and 68 ng/g, respectively ( Fig. 1 , upper curve). The value represents the content of a complete dosing interval (QD 24 (+2) hours, BID 12 (+1) hours) after the last administration. The QD and BID values demonstrate that the content of squalamine in the posterior sclera/choroid is much higher than the threshold for inhibition of tissue angiogenesis (approximately 11 ng/g). In contrast, squalamine concentrations were <LLOQ (10 ng/mL) in all animals and <LLOQ in plasma in 23/24 animals in aqueous and vitreous humor (Table 1). Table 1 BQL = lower limit of quantitation (10 ng/g in tissue; 10 ng/mL in plasma) Formulation 6 eye drops proved harmless and did not produce discernable changes in ophthalmic slit lamp eye examination. Example 8 - Clinical Test of Formulation 5 The clinical studies set forth below use the following examples of Formulation 5: 0.2 w/v% dibasic squalamine; 0.27 w/v% sodium phosphate heptahydrate and 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-hydroxypropyl-β-cyclodextrin; and sufficient purified water, pH 6.7 to 7.1. The studies set forth below represent a 9-month Phase II clinical trial evaluation of Formulation 5 for the safety and efficacy of wet AMD. Two treatment arms were administered twice daily with 5 drops of formulation plus Lucentis® ("Condition 5" arm or group, labeled "Form-5" in the figure). Placebo drops twice daily. Eye drops plus Lucentis® ("Lucentis® Monotherapy" arm or group, 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 5 was generally well tolerated and there were only two treatment related discontinuations in this study. The visual acuity results of patients who completed the 9-month treatment period (in the modified intention-to-treat or mITT population) were analyzed. Visual acuity at 9th month in the mITT population (preparation 5, n=37; Lucentis® monotherapy, n=28) with lesions containing classical choroidal neovascularization (CNV) (with classic lesions) The average increase was +11 letters for the OHR-102 combination arm and +5 letters for Lucentis® monotherapy, with a clinically meaningful benefit of 6 letters ( Figure 2A ). In addition, 44% of patients receiving Formulation 5 combination therapy achieved a visual increase of ≥3 lines at 9 months compared to 28% in the Lucentis® monotherapy group ( Fig. 2B ). This positive effect on visual acuity in classic lesions has been observed both early in the course of treatment and continues to increase until the end of the study. The classical CNV population is representative of approximately 2/3 of the total wet AMD patient population. The mITT data in the classic lesions also showed a more significant separation between Formulation 5 and the Lucentis® monotherapy group for those patients who achieved a visual increase of ≥4 and ≥5 lines. As compared to 7% with ≥4 lines of increase and ≥5 lines of 7% for those receiving Lucentis® monotherapy, 22% achieved ≥4 at 9 months in patients receiving Formulation 5 The line increases and 17% achieves an increase of ≥5 lines ( Fig. 2C ). Data were analyzed in patients with intentional lesions in the intention to treat (ITT-LOCF) population (Formulation 5, n=38; Lucentis® monotherapy, n=32). In this group, the average increase in visual acuity was +10.5 letters for the combination arm of Formulation 5 and +5.4 letters for Lucentis® monotherapy, with a clinically meaningful benefit of +5.1 letters ( Figure 3A ). In addition, 31% of patients receiving Formulation 5 achieved an increase of ≥3 lines at 9 months compared to 25% in the Lucentis® monotherapy group ( Fig. 3B ). 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特定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 圖解說明在第1天、第7天及第14天、在所指示投藥間隔下、兔眼中調配物6之後鞏膜及脈絡膜中之角鯊胺濃度。圖 2A 圖解說明使用調配物5與Lucentis®之組合(標記為「形式-5」)治療對利用Lucentis®及安慰劑調配物(標記為「安慰劑」)治療，直至第36週在患者群體中視覺敏銳度(增加之字母)之平均變化。圖 2B 圖解說明使用調配物5與Lucentis®之組合(標記為「形式-5」)治療對利用Lucentis®及安慰劑調配物(標記為「安慰劑」)治療，直至第36週在視覺敏銳度方面增加≥3行之患者之百分比。圖 2C 圖解說明使用調配物5與Lucentis®之組合(標記為「形式-5」)治療對利用Lucentis®及安慰劑調配物(標記為「安慰劑」)治療，在視覺敏銳度方面增加≥ 4行及增加≥ 5行之患者之百分比。圖 3A 圖 解說明使用調配物5與Lucentis®之組合(標記為「形式-5」)治療對利用Lucentis®及安慰劑調配物(標記為「安慰劑」)治療，直至第36週在患者群體中視覺敏銳度之平均變化。圖 3B 圖解說明使用調配物5與Lucentis®之組合(標記為「形式-5」)治療對利用Lucentis®及安慰劑調配物(標記為「安慰劑」)治療，直至第36週在視覺敏銳度方面增加≥ 3行之患者之百分比。The drawings illustrate only a particular embodiment of the invention and are not intended to limit the scope of the invention as set forth herein. Figure 1 illustrates the concentration of squalamine in the sclera and choroid after Formulation 6 in rabbit eyes on Days 1, 7 and 14 at the indicated dosing interval. Figure 2A illustrates treatment with Lucentis® and a placebo formulation (labeled "placebo") using a combination of Formulation 5 and Lucentis® (labeled "Form-5") until week 36 in the patient population The average change in visual acuity (increasing letters). Figure 2B illustrates treatment with Lucentis® and placebo formulation (labeled "placebo") using a combination of Formulation 5 and Lucentis® (labeled "Form-5") until visual acuity at week 36 Increase the percentage of patients with ≥3 lines. Figure 2C illustrates treatment with Lucentis® and a placebo formulation (labeled "placebo") using a combination of Formulation 5 and Lucentis® (labeled "Form-5") with an increase in visual acuity ≥ 4 The percentage of patients who progressed and increased ≥ 5 lines. FIG 3A described FIG solution (labeled as "form -5") using the therapeutic composition of the formulations 5 and Lucentis® Lucentis® use of formulations and placebo (labeled as "placebo") treatment until week 36 in patient populations The average change in visual acuity. Figure 3B illustrates treatment with Lucentis® and a placebo formulation (labeled "placebo") using a combination of Formulation 5 and Lucentis® (labeled "Form-5") until visual acuity at week 36 Increase the percentage of patients with ≥ 3 lines.

Claims (19)

一種眼用組合物，其包含： 0.05 w/v%至0.25 w/v%二乳酸角鯊胺； 0.5 w/v%至1.5 w/v%硼酸及0.05 w/v%至0.30 w/v%硼酸鈉； 0.005 w/v%至0.03 w/v%依地酸二鈉(edetate disodium)； 0.5 w/v%至3.0 w/v%甘油； 0.20 w/v%至1.0 w/v%丙二醇； 0.3 w/v%至2.0 w/v%羥丙甲纖維素； 0.005 w/v%至0.3 w/v%山梨酸；及 充足量之注射用水或純化水USP。An ophthalmic composition comprising: 0.05 w/v% to 0.25 w/v% dihrolyser squalamine; 0.5 w/v% to 1.5 w/v% boric acid and 0.05 w/v% to 0.30 w/v% Sodium borate; 0.005 w/v% to 0.03 w/v% edetate disodium; 0.5 w/v% to 3.0 w/v% glycerol; 0.20 w/v% to 1.0 w/v% propylene glycol; 0.3 w/v% to 2.0 w/v% hypromellose; 0.005 w/v% to 0.3 w/v% sorbic acid; and a sufficient amount of water for injection or purified water USP. 一種眼用組合物，其包含： 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(Povidone)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。An ophthalmic composition comprising: 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% disodium edetate; 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. 一種眼用組合物，其係由以下組成： 0.05 w/v%至0.25 w/v%二乳酸角鯊胺； 0.5 w/v%至1.5 w/v%硼酸及0.05 w/v%至0.30 w/v%硼酸鈉； 0.005 w/v%至0.03 w/v%依地酸二鈉； 0.5 w/v%至3.0 w/v%甘油； 0.20 w/v%至1.0 w/v%丙二醇； 0.3 w/v%至2.0 w/v%羥丙甲纖維素； 0.005 w/v%至0.3 w/v%山梨酸；及 充足量之注射用水或純化水USP。An ophthalmic composition consisting of: 0.05 w/v% to 0.25 w/v% di-squalate squalamine; 0.5 w/v% to 1.5 w/v% boric acid and 0.05 w/v% to 0.30 w /v% sodium borate; 0.005 w/v% to 0.03 w/v% disodium edetate; 0.5 w/v% to 3.0 w/v% glycerol; 0.20 w/v% to 1.0 w/v% propylene glycol; w/v% to 2.0 w/v% hypromellose; 0.005 w/v% to 0.3 w/v% sorbic acid; and a sufficient amount of water for injection or purified water USP. 一種眼用組合物，其係由以下組成： 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。An ophthalmic composition consisting of: 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% disodium edetate; 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. 如請求項1之組合物，其中該組合物適於局部投與需要其之哺乳動物眼睛。The composition of claim 1 wherein the composition is suitable for topical administration to a mammalian eye in need thereof. 如請求項2之組合物，其中該組合物適於局部投與需要其之哺乳動物眼睛。The composition of claim 2, wherein the composition is suitable for topical administration to a mammalian eye in need thereof. 如請求項3之組合物，其中該組合物適於局部投與需要其之哺乳動物眼睛。The composition of claim 3, wherein the composition is suitable for topical administration to a mammalian eye in need thereof. 如請求項4之組合物，其中該組合物適於局部投與需要其之哺乳動物眼睛。The composition of claim 4, wherein the composition is suitable for topical administration to a mammalian eye in need thereof. 如請求項1至4中任一項之組合物，其中該組合物係呈滴眼劑形式。The composition of any one of claims 1 to 4, wherein the composition is in the form of an eye drop. 如請求項5至8中任一項之組合物，其中該組合物在投與後選擇性地存於該哺乳動物眼睛的後鞏膜及脈絡膜中。The composition of any one of claims 5 to 8, wherein the composition is selectively present in the posterior sclera and choroid of the mammalian eye after administration. 如請求項5至8中任一項之組合物，其中該哺乳動物罹患眼科病況。The composition of any one of claims 5 to 8, wherein the mammal has an ophthalmic condition. 如請求項11之組合物，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 composition of claim 11, 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 retina Lesions, 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11之組合物，其中該眼科病況係濕型AMD。The composition of claim 11, wherein the ophthalmic condition is wet AMD. 如請求項5至8中任一項之組合物，其中該哺乳動物係人類。The composition of any one of claims 5 to 8, wherein the mammal is a human. 一種如請求項1至4中任一項之組合物之用途，其用於製造用以治療眼科病況之藥劑，其中該組合物中之角鯊胺或其醫藥上可接受之鹽係選擇性遞送至有需要之哺乳動物眼睛的後鞏膜及脈絡膜。Use of a composition according to any one of claims 1 to 4 for the manufacture of a medicament for the treatment of an ophthalmic condition, wherein the squalamine or a pharmaceutically acceptable salt thereof is selectively delivered in the composition The posterior sclera and choroid of the mammalian eye to the eye. 如請求項15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 15, 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, retina Shedding, myopic neovascularization, vascular lesions, Iles disease, choroidal rupture, and any combination thereof. 如請求項15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 15, wherein the ophthalmic condition is wet age-related macular degeneration (wet AMD). 如請求項15之用途，其中該組合物係局部投與眼睛。The use of claim 15, wherein the composition is administered topically to the eye. 如請求項15之用途，其中該哺乳動物係人類。The use of claim 15, wherein the mammal is a human.
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