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Publication numberCN101043884 A
Publication typeApplication
Application numberCN 200580028729
PCT numberPCT/US2005/023113
Publication date26 Sep 2007
Filing date30 Jun 2005
Priority date1 Jul 2004
Also published asCA2572344A1, EP1781278A1, EP1781278A4, EP1781278B1, US20060009522, US20080153909, WO2006007510A1
Publication number200580028729.9, CN 101043884 A, CN 101043884A, CN 200580028729, CN-A-101043884, CN101043884 A, CN101043884A, CN200580028729, CN200580028729.9, PCT/2005/23113, PCT/US/2005/023113, PCT/US/2005/23113, PCT/US/5/023113, PCT/US/5/23113, PCT/US2005/023113, PCT/US2005/23113, PCT/US2005023113, PCT/US200523113, PCT/US5/023113, PCT/US5/23113, PCT/US5023113, PCT/US523113
InventorsR达纳, D肖姆伯格, F莫洛克, L库珀, S马哈德文, KO罗伦兹, S拉什德
Applicant谢彭斯眼科研究公司, 庄臣及庄臣视力保护公司
Export CitationBiBTeX, EndNote, RefMan
External Links: SIPO, Espacenet
Compositions and methods for treating eye disorders and conditions
CN 101043884 A
Abstract
The present invention relates to compositions comprising omega-6 and/or omega-3 fatty acids and uses thereof. The present invention also relates to methods of treatment using such compositions.
Claims(44)  translated from Chinese
1.一种眼科用组合物,含有至少一种ω-6脂肪酸和至少一种ω-3脂肪酸。 An ophthalmic composition, comprising at least one ω-6 fatty acids and at least one ω-3 fatty acids.
2.权利要求1的组合物,其中所述的ω-6脂肪酸是非促炎性的。 The composition of claim 1, wherein said ω-6 fatty acid is non-pro-inflammatory.
3.权利要求1的组合物,其中所述的组合物基本上不含有亚油酸和/或花生四烯酸。 The composition of claim 1, wherein said composition is substantially free of linoleic acid and / or arachidonic acid.
4.权利要求1的组合物,其中所述的组合物含有表面活性剂。 The composition of claim 1, wherein the composition contains a surfactant.
5.权利要求4的组合物,其中所述表面活性剂占约1至约15重量%。 The composition of claim 4, wherein said surfactant comprises from about 1% to about 15 wt.
6.权利要求4的组合物,其中所述表面活性剂占约1至约10重量%。 The composition of claim 4, wherein said surfactant comprises from about 1 to about 10% by weight.
7.权利要求1的组合物,其中所述的表面活性剂是乙氧基化的脱水山梨糖醇一油酸酯、乙氧基化的甲基葡糖苷、DOE 120、反相普流尼克表面活性剂、司盘表面活性剂或其混合物。 The composition of claim 1, wherein said surfactant is ethoxylated sorbitan monooleate, ethoxylated methyl glucoside, 120, inverting pluronic surface DOE active agents, Span surfactant or mixtures thereof.
8.权利要求1的组合物,其中所述的组合物适合眼部给药。 The composition of claim 1, wherein said composition is suitable for ophthalmic administration.
9.权利要求1的组合物,其中所述的组合物包括滴眼剂。 The composition of claim 1, wherein said composition comprises eye drops.
10.权利要求1的组合物,其中所述的ω-6脂肪酸化合物是亚油酸的非致炎性衍生物。 10. The composition of claim 1, ω-6 fatty acids, wherein said compound is non-inflammatory and linoleic acid derivative.
11.权利要求1的组合物,其中所述的ω-3脂肪酸化合物是γ亚麻酸或其衍生物。 11. The composition of claim 1, wherein said ω-3 fatty acid compound is γ-linolenic acid or a derivative thereof.
12.权利要求1的组合物其中所述的ω-6脂肪酸化合物是γ亚麻酸、二高γ亚麻酸或两者。 12. The composition of claim 1 ω-6 fatty acids, wherein said compound is γ-linolenic acid, di high γ-linolenic acid or both.
13.权利要求1的组合物,其中所述的ω-3脂肪酸化合物是二十碳五烯酸、二十二碳六烯酸或两者。 13. The composition of claim 1, wherein said compound is ω-3 fatty acids eicosapentaenoic acid, docosahexaenoic acid, or both.
14.权利要求1的组合物,其中所述的组合物被配制为用于局部给药。 14. The composition of claim 1, wherein said composition is formulated for topical administration.
15.权利要求1的组合物,其中所述的药物组合物是可注射的组合物。 15. The composition of claim 1, wherein said pharmaceutical composition is an injectable composition.
16.权利要求1的组合物,其中所述的组合物含有缓释装置。 The composition of claim 1, wherein said composition contains sustained release device.
17.权利要求1的组合物,其中所述ω-3脂肪酸与ω-6脂肪酸的比例是约10∶1至约1∶1。 17. The composition of claim 1, wherein the ω-3 and ω-6 fatty acid ratio of fatty acids is about 10 to about 1.
18.权利要求1的组合物,其中所述ω-3脂肪酸与ω-6脂肪酸的比例是约5∶1至约1∶1。 18. The composition of claim 1, wherein the ω-3 and ω-6 fatty acid ratio of fatty acids is about 5 to about 1.
19.权利要求1的组合物,其中所述ω-3脂肪酸与ω-6脂肪酸的比例是约5∶1。 19. The composition of claim 1, wherein the ω-3 fatty acids and ω-6 fatty acid ratio is about 5.
20.权利要求1的组合物,其中所述ω-3脂肪酸与ω-6脂肪酸的比例是约1∶1。 20. The composition of claim 1, wherein the ω-3 fatty acid ratio of ω-6 fatty acids is about 1:1.
21.一种治疗个体中的干眼的方法,包括使所述个体的眼表面与含有治疗有效量的权利要求1的组合物的组合物接触。 21. A method of treating dry eye in an individual comprising contacting the individual with the ocular surface comprising a therapeutically effective amount of the composition of claim 1 in contact with the composition.
22.权利要求21的方法,其中所述的ω-3脂肪酸是二十碳五烯酸、二十二碳六烯酸或其组合。 22. The method of claim 21, wherein the ω-3 fatty acids, eicosapentaenoic acid, docosahexaenoic acid, or combinations thereof.
23.权利要求21的方法,其中所述的ω-6脂肪酸是γ亚麻酸、二高γ亚麻酸或其组合。 23. The method of claim 21, wherein said ω-6 fatty acid is γ-linolenic acid, di high γ-linolenic acid or combinations thereof.
24.权利要求21的方法,其中所述的组合物包括滴眼剂。 24. The method of claim 21, wherein said composition comprises eye drops.
25.一种治疗附属器炎症的方法,包括给个体的受感染眼睛施用治疗有效量的权利要求1的组合物。 25. A method of treating adnexal inflammation, comprising administering to an individual infected eye administering a therapeutically effective amount of a composition of claim 1.
26.权利要求25的方法,其中所述的个体被确定为需要所述的治疗。 26. The method of claim 25, wherein said individual has been identified as in need of such treatment.
27.权利要求25的方法,其中所述的ω-3脂肪酸是二十碳五烯酸、二十二碳六烯酸或两者。 27. The method of claim 25, wherein the ω-3 fatty acids, eicosapentaenoic acid, docosahexaenoic acid, or both.
28.权利要求25的方法,其中所述的ω-6脂肪酸是γ亚麻酸、二高γ亚麻酸或两者。 28. The method of claim 25, wherein said ω-6 fatty acid is γ-linolenic acid, di high γ-linolenic acid or both.
29.权利要求25的方法其中所述的组合物包括滴眼剂。 29. The composition of method of claim 25 wherein said include eye drops.
30.一种提高个体眼睛舒适性的方法,包括局部施用含有治疗有效量的权利要求1的组合物的组合物。 30. A method for an individual to improve the comfort of the eye, comprising topically administering a composition comprising a therapeutically effective amount of the composition of claim 1.
31.权利要求30的方法,其中所述的组合物作为滴眼剂被施用。 31. The method of claim 30, wherein said composition is administered as an eye drop.
32.一种用于向眼睛施用的无菌制剂,其中含有至少一种ω-6脂肪酸和至少一种ω-3脂肪酸。 32. A sterile preparation for administration to the eye, comprising at least one ω-6 fatty acids and at least one ω-3 fatty acids.
33.权利要求32的无菌制剂,其中所述的制剂基本上不含有亚油酸和/或花生四烯酸。 33. The sterile preparation of claim 32, wherein said formulation is substantially free of linoleic acid and / or arachidonic acid.
34.权利要求32的无菌制剂,其中所述的ω-3脂肪酸含有二十碳五烯酸、二十二碳六烯酸或两者。 34. The sterile preparation of claim 32, wherein said ω-3 fatty acids containing eicosapentaenoic acid, docosahexaenoic acid, or both.
35.权利要求32的无菌制剂,其中所述的ω-6脂肪酸含有γ亚麻酸、二高γ亚麻酸,或两者。 35. The sterile preparation of claim 32, wherein said ω-6 fatty acids containing γ-linolenic acid, di high γ-linolenic acid, or both.
36.权利要求32的无菌制剂,其中所述的施用是局部施用。 36. The sterile preparation of claim 32, wherein said administering is topical administration.
37.一种使个体的眼睛中的ω-3脂肪酸与ω-6脂肪酸的比例正常化的方法,包括施用权利要求1的组合物。 37. A so that the individual's eyes in ω-3 and ω-6 fatty acids, fatty acid ratio normalization, comprising administering the composition of claim 1.
38.权利要求37的方法,其中所述的正常化的比例是约1∶1至约10∶1。 38. The method of claim 37, wherein said normalized ratio is from about 1:1 to about 10.
39.一种制备含有ω-6和/或ω-3脂肪酸的组合物的方法,包括a)将第一表面活性剂与盐水溶液混合;b)使至少一种ω-6酸和/或至少一种ω-3脂肪酸与步骤a)的溶液接触。 39. A preparation containing and / or ω-3 fatty acids in a composition of ω-6, comprising a) mixing a first surfactant with a saline solution; b) reacting at least one ω-6 acid and / or at least a fatty acid of step a) contacting a solution-3 ω.
40.权利要求39的方法,其中所述的混合和/或所述的接触在室温下进行。 40. The method of claim 39, contact and / or wherein said mixing at room temperature.
41.权利要求39的方法,其中使所述的至少ω-6脂肪酸和/或至少一种ω-3脂肪酸与步骤a)的溶液接触1小时。 41. The method of claim 39, wherein said at least a ω-6 fatty acids and / or at least one ω-3 fatty acids and in step a) is contacted with a solution for one hour.
42.权利要求39的方法,其中第二表面活性剂与步骤a)的溶液在步骤c)之前接触。 42. The method of claim 39, wherein the second surfactant of step a) prior to contacting the solution of step c).
43.权利要求39的方法,其中所述的第一表面活性剂是乙氧基化的脱水山梨糖醇一油酸酯、乙氧基化的甲基葡糖苷、DOE 120、反相普流尼克表面活性剂、司盘表面活性剂或其混合物。 43. The method of claim 39, wherein said first surfactant is ethoxylated sorbitan monooleate, ethoxylated methyl glucoside, DOE 120, reverse phase pluronic surfactant, Span surfactant or mixtures thereof.
44.权利要求42的方法,其中所述的第二表面活性剂是乙氧基化的脱水山梨糖醇一油酸酯、乙氧基化的甲基葡糖苷、DOE 120、反相普流尼克表面活性剂、司盘表面活性剂或其混合物。 44. The method of claim 42, wherein said second surfactant is ethoxylated sorbitan monooleate, ethoxylated methyl glucoside, DOE 120, reverse phase pluronic surfactant, Span surfactant or mixtures thereof.
Description  translated from Chinese
用于治疗眼部疾病和病症的组合物和方法 Compositions and methods for treating ocular diseases and disorders for

交叉参考的相关申请本申请请求享受2004年7约1日提交的美国临时申请系列号60/584,514的优先权,其在此全文引入作为参考。 CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Application Serial No. 7 about 1 priority 2004, filed 60 / 584,514, which is hereby incorporated by reference.

发明领域本发明涉及通过施用含有脂肪酸的组合物对眼部病症和疾病进行治疗。 Field of the Invention The present invention relates to a composition comprising fatty acids by administering the eye conditions and diseases for treatment.

发明背景干眼综合征(DES)在美国是相当流行的眼科病症并且是寻找眼部护理的常见原因。 Background of the Invention Dry eye syndrome (DES) is very popular in the United States and is a common cause of ophthalmic disorders seek eye care. 眼部不适是普通患者的一种主诉。 Eye irritation is a common chief complaint of the patient. 此外,DES可以导致功能性视觉分辩力减弱,阅读、使用计算机、夜间驾驶和进行职业工作出现问题。 In addition, DES may lead to functional visual differentiate weakened, reading, using a computer, night driving and vocational work problems.

尽管有关判断DES的病因学和病理学有进步,但现有知识仍不充分并且对于DES最常见的疗法,人造眼泪只能提供暂时性和不完全的症状缓解。 Although DES judgment about the etiology and pathology progress, but still insufficient, and the existing knowledge of the most common therapy for DES, artificial tears, provides only temporary and incomplete symptomatic relief. 所以,需要确定新形式的DES治疗方法。 Therefore, the need to identify new forms of DES treatment.

被称作″必需″脂肪酸的某些化合物,不是由人体产生的,并且通过饮食摄取被引入到系统中。 Called "essential" fatty acids, some of the compounds, not produced by the body, and is introduced into the system through diet. 必需脂肪酸被机体用于产生多种类型的以脂质为基础的代谢产物,这些代谢产物被机体用于多种必不可少的功能。 Essential fatty acids used by the body to produce lipid-based metabolites of various types, these metabolites are essential for a variety of body functions.

眼表面一般被泪膜湿润,泪膜由三层组成,最上面的是脂质层,它覆盖在泪膜的水层上。 Ocular tear film surface is generally wet, tear film consists of three layers, the top is the lipid layer, which covers the aqueous layer of the tear film. 泪膜本身的脂质层由许多彼此相互作用的极性和非极性脂质元素组成。 Lipid layer of the tear film itself is composed of many polar and non-polar lipid elements interact with one another composition. 它还含有存在于泪膜的其他层中的蛋白质和肽。 It also contains other layers present in the tear film of proteins and peptides. 所示脂质层具有与其位于泪膜上的物理存在有关的功能(例如,延迟蒸发)以及其生物化学性质(例如,给表面提供参与炎症调节的分子)。 Located in the lipid layer has shown its physical presence tear film related functions (eg, delay evaporation) as well as its biochemical properties (for example, to provide a surface molecule involved in inflammation regulation). 另外在脂质层中已知与多种眼科表面疾病有关,包括干眼综合征。 Also known in the lipid layer surface with a variety of ophthalmic diseases, including dry eye syndrome. 大多数干眼综合征与脂质异常有关,包括″典型″形式的水分或泪水缺乏性干眼,被称作斯耶格伦氏综合征。 Most dry eye syndrome with lipid abnormalities, including the "typical" in the form of moisture or tear-deficient dry eye, Sjogren's syndrome is referred to.

不饱和脂肪酸的特征在于其烃链的长度和其双键的数目和位置。 Unsaturated fatty acids characterized in that the length of the hydrocarbon chains and the number and location of their double bonds. 两组的脂肪酸被认为是人体健康所必需的并且从饮食中摄取,因为它们无法从其他脂肪酸合成。 Two fatty acids are considered essential to human health and the intake from the diet because they can not be synthesized from other fatty acids. 这些包括衍生自亚油酸(LA)的ω-6脂肪酸和衍生自γ亚麻酸(ALA)的ω-3脂肪酸。 These include those derived from linoleic acid (LA) of ω-6 fatty acids and are derived from γ-linolenic acid (ALA) of ω-3 fatty acids. LA以高水平存在于典型美国饮食中,可以在植物性烹饪油、牛肉和乳制品中发现,并且被认为能够部分负责促炎作用,通过抵消ω-3FA的有益作用,主要是经过使LA转化为花生四烯酸(AA)。 LA present at high levels in the typical American diet, can be found in vegetable cooking oil, beef and dairy products, and is thought to be partially responsible for the pro-inflammatory effect, by offsetting the beneficial effects of ω-3FA, primarily through conversion to make LA arachidonic acid (AA). AA也直接从肉源被消耗。 AA can also be consumed directly from meat sources. 它通过在环加氧酶(COX-2)和脂氧合酶(两者在眼表面激活)作用下代谢形成多种强力促炎的花生酸,包括前列腺素E2(PGE2)和白三烯B4(LTB4)。 It is through the cyclooxygenase (COX-2) and lipoxygenase (both in the ocular surface activation) under the effect of a variety of metabolic formation of a strong pro-inflammatory eicosanoids, including prostaglandin E2 (PGE2) and leukotriene B4 (LTB4). γ亚麻酸(GLA)是另一种ω-6脂肪酸,它可以从LA在酶δ-6去饱和酶作用下生成,并且可以进一步延长为二高γ亚麻酸(DGLA),也是ω-6脂肪酸。 γ-linolenic acid (GLA) is another ω-6 fatty acids, which is available from LA desaturase enzyme δ-6 in the next generation, and may further be extended to two high γ-linolenic acid (DGLA), also the ω-6 fatty acids . 与AA形成对照,GLA和DGLA被认为造成炎症活性降低。 In contrast with the AA, GLA and DGLA is considered cause inflammation activity. 然而,δ-6去饱和酶的活性似乎在数种疾病中受损。 However, δ-6 desaturase activity appears impaired in several diseases. 尽管观察ω-6脂肪酸的代谢途径将会揭示GLA的增加应当导致AA增加,但研究表明这不一定发生。 Although the observed metabolic pathways ω-6 fatty acid GLA will reveal an increase should lead to increase in AA, but research shows that this need not happen. 这是一个重要的观察结果,因为与AA竞争氧化酶的DGLA代谢生成前列腺素El(PGE1),已知具有抗炎和免疫调节性质的类花生酸。 This is an important observation, since the resulting prostaglandin El compete with AA oxidase DGLA metabolism (PGE1), known to have anti-inflammatory eicosanoids and immunomodulatory properties. 事实上,口服GLA补剂的研究已经证实PGE1的生产增加并且致炎性花生酸,包括PGE2和LTB4的生产减少。 In fact, studies have demonstrated that oral administration of GLA supplements PGE1 production increases and proinflammatory eicosanoids, including the reduction of PGE2 and LTB4 production. DGLA还可以以前列腺素依赖性方式通过作用于T-淋巴细胞而调节免疫反应,这被认为在干眼综合征的病理学中起关键作用。 DGLA can also modulate the immune response in lymphocytes and T-, which is thought to play a key role in the pathology of dry eye syndrome to prostaglandin-dependent manner by the action.

GLA的抗炎作用在有足够的ω-3脂肪酸供应的情况下可以得到增强,因为这些脂肪酸也与AA竞争成为酶底物。 Anti-inflammatory effects of GLA there is sufficient supply of ω-3 fatty acids, the situation can be enhanced, because these fatty acids and AA competition to become the enzyme substrate. 据报道ω-3脂肪酸的摄取使膜AA的水平降低并由此减少促炎的花生酸的生产。 It is reported that ω-3 fatty acid intake reduce the horizontal membrane AA and thereby reducing the production of proinflammatory eicosanoids. 这与二十碳五烯酸(EPA)-衍生的类花生酸的生产增加并行进行,包括3-系列的前列腺素和血栓烷(TXs)和5-系列的白三烯类(LTs),这实质上不是炎症。 This and eicosapentaenoic acid (EPA) - derived eicosanoid production increased in parallel, including 3- series prostaglandins and thromboxane (TXs) and 5-series leukotrienes (LTs), which essentially not inflammation. 人体主要通过消耗油性鱼类而得到ω-3脂肪酸EPA和二十二碳六烯酸(DHA),但它们还可以在体内经过某些种子(例如,亚麻、油菜、芡欧鼠尾草、紫苏和黑醋栗)或叶子(例如,马齿苋)内的ALA转化合成。 The body primarily through consumption of oily fish and get ω-3 fatty acids EPA and docosahexaenoic acid (DHA), but they can also be in the body after some seeds (such as flax, canola, chia, purple Sue and black currant) or leaves (eg, ALA purslane) within the conversion of synthesis. EPA和DHA还竞争性抑制AA通过环加氧酶的氧合作用,EPA可以充当脂氧合酶的底物,由此进一步减少有效致炎的性AA-衍生的类花生酸的生产。 EPA and DHA are also competitive inhibition of AA by oxygenation of cyclooxygenase, EPA can act as lipoxygenase substrate, thereby further reducing the production of proinflammatory effective sexual AA- derived eicosanoids. ω-3脂肪酸还被证实减少粘附分子的表达和促炎细胞因子白介素1β(IL-1)、白介素6(IL-6)13和肿瘤坏死因子α(TNF-α)的生产。 ω-3 fatty acids has also been shown to reduce the expression of adhesion molecules and proinflammatory cytokines interleukin-1β (IL-1), interleukin-6 (IL-6) 13 and tumor necrosis factor-α (TNF-α) production. 这些分子参与干眼综合征的发病。 These molecules are involved in the pathogenesis of dry eye syndrome.

口服摄取脂肪酸与高热量摄取有关并且常常由于胃肠道副作用而无法忍受。 Oral intake of fatty and high calorie intake and often related to the gastrointestinal tract due to intolerable side effects. 所以,需要治疗多种眼部疾病和病症的组合物和方法,包括但不限于,干眼综合征和眼部的炎症。 Therefore, in need of treatment a variety of compositions and methods for ocular diseases and disorders, including but not limited to, dry eye syndrome and ocular inflammation.

发明概述在一些实施方式中,本发明提供含有至少一种ω-6脂肪酸和至少一种ω-3脂肪酸的眼科用组合物。 SUMMARY OF THE INVENTION In some embodiments, the present invention provides comprising at least one ω-6 fatty acids and at least one ω-3 fatty acids in an ophthalmic composition.

在一些实施方式中,本发明提供治疗个体中干眼的方法,包括使个体的眼睛表面与含有治疗有效量的含有至少一种ω-6脂肪酸和至少一种ω-3脂肪酸的组合物的组合物接触。 In some embodiments, the present invention provides a treatment of dry eye in an individual comprising contacting the surface of the eye of an individual a combination comprising at least one ω-6 fatty acids and at least one ω-3 fatty acid composition containing a therapeutically effective amount of a in contact.

在一些实施方式中,本发明提供治疗附属器炎症的方法,包括给个体的感染眼睛施用治疗有效量的含有至少一种ω-6脂肪酸和至少一种ω-3脂肪酸的组合物。 In some embodiments, the present invention provides a method of treating adnexal inflammation, comprising administering to an individual for the infection of the eye comprising a therapeutically effective amount of at least one ω-6 fatty acids and at least one ω-3 fatty acid composition.

在一些实施方式中,本发明提供在个体中提高眼睛舒适性的方法,包括局部施用含有治疗有效量的含有至少一种ω-6脂肪酸和至少一种ω-3脂肪酸的组合物的组合物。 In some embodiments, the present invention provides improved eye comfort in an individual, comprising a composition for topical administration comprising a therapeutically effective amount of at least one ω-6 fatty acids and at least one ω-3 fatty acid composition.

在一些实施方式中,本发明提供含有至少一种ω-6脂肪酸和至少一种ω-3脂肪酸的无菌制剂用于施用到眼睛。 In some embodiments, the present invention comprises providing at least one ω-6 fatty acids and at least one ω-3 fatty acids sterile preparation for administration to the eye.

在一些实施方式中,本发明提供个体眼睛中的ω-3脂肪酸与ω-6脂肪酸的比例正常化的方法,包括施用含有至少一种ω-6脂肪酸和至少一种ω-3脂肪酸的组合物。 In some embodiments, the present invention provides an individual eye of ω-3 fatty acid ratio of ω-6 fatty acids normalization method, comprising administering a composition comprising at least one ω-6 fatty acids and at least one ω-3 fatty acids composition .

在一些实施方式中,本发明提供制备含有ω-6和/或ω-3脂肪的方法。 In some embodiments, the present invention provides processes for preparing ω-6 and / or ω-3 fatty method comprising.

附图简述图1:在特定条件下的眼泪试验:单独的干眼隔室(″隔室″)、单独的东莨菪碱,以及隔室加东莨菪碱。 BRIEF DESCRIPTION Figure 1: Tears tests under specific conditions: separate compartment dry eye ("compartments"), a separate scopolamine and scopolamine plus compartment.

图2:按照国立眼睛研究所(NEI)分级方案将角膜分为5个部分,并且根据角膜荧光素染色的程度将5个部分中的每一部分评为0-3分。 Figure 2: According to the National Eye Institute (NEI) grading program will be divided into five parts of the cornea and corneal fluorescein staining according to the degree of each part of the five sections of the rated 0-3 points.

图3:三组的角膜荧光素染色得分,将小鼠暴露在单独的隔室下,或单独的东莨菪碱或混合隔室和东莨菪碱,保持6天的持续时间。 Figure 3: Three groups of corneal fluorescein staining score, the mice were exposed to a single compartment, or scopolamine alone or mixed compartments and scopolamine, keeping six days duration.

图4:四组的眼泪测定时间,没有接受滴眼剂、接受载体或两个接受含有ω-3和ω-6脂肪酸的组。 Figure 4: Determination of the time four tears, eye drops did not accept, accept acceptable carriers or both groups containing ω-3 and ω-6 fatty acids. 使小鼠连续暴露在混合的隔室和东莨菪碱下6天。 The mice were exposed to continuous mixing compartment and scopolamine next six days. 在48小时时,开始滴注滴眼剂并且持续至多至第6天,在此时测定眼泪的分泌。 At 48 hours, eye drop instillation began and continued up to Day 6, tear secretion was measured at this time. 这是治疗手段,其中首先在48小时时诱导干眼并且随后测试制剂和载体。 This is a treatment in which the induction of dry eye and then the first test formulations and vehicle at 48 hours.

图5:三组的角膜荧光素染色得分,没有接受滴眼剂、接受载体或接受制剂1(含有ω-3和ω-6脂肪酸)的组。 Figure 5: Three groups of corneal fluorescein staining scores, there is no accepted eye drops, preparations or accept group received vehicle (containing ω-3 and ω-6 fatty acids) 1. 使小鼠连续暴露在混合的隔室和东莨菪碱下6天。 The mice were exposed to continuous mixing compartment and scopolamine next six days. 在48小时时,开始滴注滴眼剂并且持续至多至第6天,记录角膜荧光素染色。 At 48 hours, eye drop instillation began and continued up to day 6, corneal fluorescein staining recorded. 这是治疗手段,其中干眼首先在48小时时诱导并且随后测试制剂和载体。 This is a treatment in which the induction of dry eye and then the first test formulations and vehicle at 48 hours.

图6:三组的角膜荧光素染色得分,没有接受滴眼剂、接受载体或接受制剂2(含有ω-3和ω-6脂肪酸)的组。 Figure 6: Three groups of corneal fluorescein staining scores, eye drops did not accept to accept acceptable carrier or formulation 2 group (containing ω-3 and ω-6 fatty acids). 在48小时时,开始滴注滴眼剂并且持续至多至第6天,记录角膜荧光素染色。 At 48 hours, eye drop instillation began and continued up to day 6, corneal fluorescein staining recorded. 这是治疗手段,其中首先在48小时时诱导干眼并且随后测试制剂和载体。 This is a treatment in which the induction of dry eye and then the first test formulations and vehicle at 48 hours.

图7:表示用荧光素染色的角膜的代表性图谱,显示使用含有ω-3和ω-6脂肪酸的制剂的表面的正常化。 Figure 7: shows the cornea stained with fluorescein representative map, the normalization of the display containing ω-6 surface and the formulation of ω-3 fatty acids.

图8:三组的角膜荧光素染色得分,没有接受滴眼剂、接受载体或接受制剂2(含有ω-3和ω-6脂肪酸)的组。 Figure 8: Three groups of corneal fluorescein staining scores, eye drops did not accept to accept acceptable carrier or formulation 2 group (containing ω-3 and ω-6 fatty acids). 使小鼠连续暴露在混合的隔室和东莨菪碱下6天。 The mice were exposed to continuous mixing compartment and scopolamine next six days. 在0小时时,开始滴注滴眼剂。 At 0 hours, eye drop instillation began. 在第6天,记录角膜荧光素染色。 In the first six days, recording corneal fluorescein staining. 这是研究的预防手段,其中从开始暴露于干眼刺激下开始测试制剂和载体。 This is a means of prevention research, which from the beginning of exposure to the dry eye irritation test preparation and vehicle start.

发明详述本发明部分涉及发现了眼部的疾病和病症与必需脂肪酸(例如ω-6和/或ω-3脂肪酸)的缺乏或不平衡有关。 DETAILED DESCRIPTION The present invention relates to the discovery of the part of the eye diseases and disorders associated with essential fatty acids (e.g., ω-6 and / or ω-3 fatty acids) related to deficiency or imbalance.

本发明提供含有至少一种必需脂肪酸的眼科用组合物。 The present invention provides at least one essential fatty acid containing ophthalmic composition. 所述的组合物可以含有至少一种ω-6脂肪酸和/或至少一种ω-3脂肪酸。 The compositions can contain at least one ω-6 fatty acids and / or at least one ω-3 fatty acids. 然而,组合物中可以包括任意数量的脂肪酸(例如必需脂肪酸)。 However, the composition may include any number of fatty acids (e.g. essential fatty acids). 所以,施用至少一种ω-6、一种ω-3脂肪酸或其组合物应当是使眼表面环境向减少促炎介质的产生的方向移动的有效策略。 Therefore, administering at least one ω-6, one kind of ω-3 fatty acids, or combinations thereof the surface of the eye should be moved to reduce the production environment of proinflammatory mediators in the direction of an effective strategy. 在一些实施方式中,所述组合物基本上不含有花生四烯酸或亚油酸。 In some embodiments, the composition is substantially free of arachidonic acid or linoleic acid.

如本文所使用的,术语″眼科用组合物″是指适合眼睛或或眼表面给药的组合物。 As used herein, the term "ophthalmic composition" means a surface suitable for the eye or ocular administration, or compositions. 所述组合物可以是本文所述的任何形式及其等效物。 The composition may be in any form as described herein and equivalents thereof.

如本文所使用的,术语″约″是指数字可以改变5%的范围。 As used herein, the term "about" means the number can change the range of 5%. 例如,短语″约10″应当包括9.5和10.5两者。 For example, the phrase "about 10" shall include both 9.5 and 10.5.

在一些实施方式中,本发明提供含有至少一种ω-6脂肪酸和至少一种ω-3脂肪酸的眼科用组合物。 In some embodiments, the present invention comprises providing at least one ω-6 fatty acids and at least one ω-3 fatty acids in an ophthalmic composition.

本文所使用的,术语″不饱和脂肪酸″是指含有至少一种双键或叁键的脂肪酸。 As used herein, the term "unsaturated fatty acid" means a fatty acid containing at least one double or triple bond. 此类脂肪酸中使用希腊γ字母来确定双键的位置。 Such fatty acid γ Greek alphabet used to determine the position of the double bond. ″γ″碳是与羧基最接近的碳并且″ω″碳是链最后的碳。 "Γ" is the carbon closest to the carboxyl carbon, and "ω" is the last carbon of the carbon chain. 例如,亚油酸和γ-亚麻酸(分别是LA和GLA)是ω-6脂肪酸,因为它们具有距其ω碳有6个碳的双键。 For example, linoleic acid and γ- linolenic acid (LA, respectively and GLA) are ω-6 fatty acids, because they have, from its ω has six carbon carbon double bonds. γ-亚麻酸是ω3-脂肪酸,因为它们具有距ω碳有3个碳原子的双键。 γ- linolenic acid is ω3- fatty acids, because they have from the ω carbon double bond three carbon atoms. 如本文所使用的,术语″ω-3脂肪酸″是指具有距其ω碳原子有3个碳原子的双键的脂肪酸。 As used herein, the term "ω-3 fatty acid" refers to a carbon atom from which ω fatty acid double bonds three carbon atoms. 例如,ω-3脂肪酸包括,但不限于γ亚麻酸(ALA)。 For example, ω-3 fatty acids include, but are not limited to γ-linolenic acid (ALA). 其他ω-3脂肪酸包括ALA的衍生物。 Other ω-3 fatty acids include derivatives of ALA. ALA的″衍生物″是在γ亚麻酸上进行的化学修饰制成的脂肪酸,例如,通过酶或通过有机合成。 ALA "derivatives" of the γ-linolenic acid is performed chemically modified fatty acids formed, e.g., by enzymatic or organic synthesis. ω-3脂肪酸的实例是ALA的衍生物,包括但不限于,二十碳五烯酸(EPA)、二十二碳六烯酸(DHA)等。 Examples of ω-3 fatty acids are ALA derivatives, including, but not limited to, eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA) and so on. ″ω-3脂肪酸″可以包括一种或多种ω-3脂肪酸。 "Ω-3 fatty acids" may include one or more ω-3 fatty acids.

如本文所使用的,术语″ω-6脂肪酸″是指一种或多种距其ω碳原子有6个碳原子的双键的脂肪酸。 As used herein, the term "ω-6 fatty acid" refers to one or more carbon atoms, from its ω fatty acid double bonds 6 carbon atoms. 例如,ω-6脂肪酸包括,但不限于亚油酸(LA)。 For example, ω-6 fatty acids include, but are not limited to linoleic acid (LA). 其他ω-6脂肪酸包括亚油酸的衍生物。 Other ω-6 fatty acids include derivatives of linoleic acid. 亚油酸的″衍生物″是在亚油酸上进行化学修饰制成的脂肪酸。 Linoleic acid "derivative" is a chemically modified fatty acids were made on the linoleic acid. ω-6脂肪酸的实例是亚麻酸的衍生物,包括但不限于,γ亚麻酸(GLA)、二高γ亚麻酸(DGLA)等。 Examples of ω-6 fatty acid is linolenic acid derivatives, including but not limited to, γ-linolenic acid (GLA), two high γ-linolenic acid (DGLA) and the like. 在一些实施方式中,所述组合物含有至少一种非炎性ω-6脂肪酸。 In some embodiments, the composition contains at least one non-inflammatory ω-6 fatty acids. 非炎性ω-6脂肪酸是不会引发或引起炎症的ω脂肪酸。 Noninflammatory ω-6 fatty acids is not initiated or caused by inflammation ω fatty acids. 在一些实施方式中炎症位于眼睛内或感染眼表面。 In some embodiments, the inflammation is located within the eye or ocular surface infections. 本领域技术人员可以判断脂肪酸是否引起或促使炎症。 Skilled in the art can determine whether fatty acids cause or contribute to inflammation. 如果脂肪酸引起或促使炎症,脂肪酸可以不被包括在组合物中。 If fatty acids cause or contribute to inflammation, the fatty acid may not be included in the composition.

任何方法可以用于判断脂肪酸是否促使或引起炎症。 Any method can be used to determine whether fatty acids induce or cause inflammation.

判断脂肪酸可以促使或引起炎症的方法可以基于某些组织中亲核性细胞或其他细胞因子的侵润的增多或减少(参见,例如,Hong S等,JBiol Chem.2003 Apr 25;278(17):14677-87;Serhan CN等.J Exp Med.2002 Oct 21;196(8):1025-37;Marcheselli VL等,J Biol Chem.2003 Oct31;278(44):43807-17;Serhan CN等,J Immunol.2003 Dec 15;171(12):6856-65;Hamrah P等,Arch Ophthalmol.2003;121:1132-40;或Luo L等Invest Ophthalmol Vis Sci.2004 Dec;45(12):4293-301.)。 Analyzing a fatty acid can promote or cause inflammation can be based on a method nucleophilic certain tissues or cells of other cytokines invasion of increase or decrease (see, e.g., Hong S, etc., JBiol Chem.2003 Apr 25; 278 (17) : 14677-87; Serhan CN, etc. .J Exp Med.2002 Oct 21; 196 (8): 1025-37; Marcheselli VL like, J Biol Chem.2003 Oct31; 278 (44): 43807-17; Serhan CN et al., J Immunol.2003 Dec 15; 171 (12): 6856-65; Hamrah P, etc., Arch Ophthalmol.2003; 121: 1132-40; or Luo L, etc. Invest Ophthalmol Vis Sci.2004 Dec; 45 (12): 4293- 301.). 眼睛的角膜和结膜中的炎症细胞的侵润和活化可以通过,例如,对体外的组织切片上的炎症细胞的标记物进行免疫组织化学染色来评估炎症细胞的标记物,和随后用扫描激光同焦显微镜分析染色的组织。 Corneal and conjunctival inflammatory cell infiltration and activation of the eye can be produced by, for example, for markers of inflammatory cells on tissue sections in vitro was assessed by immunohistochemistry markers of inflammatory cells, and followed by a scanning laser with confocal microscopy analysis of stained tissue. 这些标记物包括CD 3(T-细胞标记)、GR-1(嗜中性粒细胞标记物)、CD11b(单核细胞标记物)、F4/80(巨噬细胞标记物)和炎症细胞活化的标记物(MHC种类II、CD 80、CD 86、CD 40)。 These markers include CD 3 (T- cell marker), GR-1 (neutrophil marker), CD11b (monocyte marker), F4 / 80 (macrophage marker) and inflammatory cell activation markers (MHC types II, CD 80, CD 86, CD 40). T细胞、嗜中性粒细胞、单核细胞和巨噬细胞都是炎症细胞。 T cells, neutrophils, monocytes and macrophages are inflammatory cells.

药物对眼睛的促或抗炎作用还可以通过,例如,测定蛋白质水平和不同促炎细胞因子例如肿瘤坏死因子α(TNF-α)和白介素-1β(IL-1b)在体外眼睛组织(角膜和结膜)中的基因表达来评估。 Pro or anti-inflammatory drugs to the eye can also, for example, determination of protein levels and different pro-inflammatory cytokines such as tumor necrosis factor-α (TNF-α) and interleukin -1β (IL-1b) in vitro ocular tissue (cornea and conjunctiva) Gene expression evaluated. 在角膜和结膜中促炎细胞因子的蛋白质水平可通过进行酶联免疫吸附测定(ELISA)来评估,并且基因表达水平可以通过mRNA分离、反转录聚合酶链反应(PCR)和实时PCR来评估。 Pro-inflammatory cytokines in the cornea and conjunctiva protein levels can be assessed by performing enzyme-linked immunosorbent assay (ELISA), and gene expression levels by mRNA isolation, reverse transcription polymerase chain reaction (PCR) and real-time PCR to assess . 引发或促使炎症的脂肪酸的实例是亚油酸或花生四烯酸。 Examples of fatty acids induce inflammation is initiated or linoleic acid or arachidonic acid. 如果TNF-[γ]和/或IL-l[β]的量增加,说明该药物是促炎的。 If TNF- [γ] and / or the amount of IL-l [β] is increased, indicating that the drug is proinflammatory.

在一些实施方式中,ω-6脂肪酸不是AA或本文所述的组合物不含有或基本上不含有LA或AA。 In some embodiments, ω-6 fatty acid is not AA or the compositions described herein contain no or substantially free of LA or AA. 在一些实施方式中,ω-3或ω-6脂肪酸具有下面的结构。 In some embodiments, ω-3 or ω-6 fatty acid has the following structure.

上面的结构是ω-3脂肪酸的一种实例。 The above structure is an instance of ω-3 fatty acids. 下面的结构是ω-6脂肪酸的一个实例。 The following structure is an example of ω-6 fatty acids. 这些结构仅仅用于举例并且可以进行其他修饰。 These structures are merely by way of example and may be other modifications. 修饰可以发生在例如脂肪酸的羧基处。 Modifications can occur, for example, fatty acids at the carboxyl group.

如上所述,所述组合物可以含有至少一种ω-3脂肪酸和/或至少一种ω-6脂肪酸。 As described above, the composition may contain at least one ω-3 fatty acids and / or at least one ω-6 fatty acids. 在一些实施方式中,所述组合物含有至少两种ω-6脂肪酸和/或至少两种ω-3脂肪酸。 In some embodiments, the composition contains at least two kinds of ω-6 fatty acids and / or at least two kinds of ω-3 fatty acids. 在一些实施方式中,所述组合物含有至少3种、至少4种、至少5种或至少6种ω-6脂肪酸和/或至少3种、至少4种、至少5种或至少6种ω3脂肪酸。 In some embodiments, the composition comprises at least 3, at least 4, at least 5 or at least 6 kinds of ω-6 fatty acids and / or at least 3, at least 4, at least 5 or at least 6 ω3 fatty acids . 在一些实施方式中,所述组合物含有2、3、4、5或6种ω-6脂肪酸。 In some embodiments, the composition contains 4, 5 or 6 ω-6 fatty acids. 所述组合物还可以包括2、3、4、5或6种ω-3脂肪酸。 The composition may also include five or six kinds of ω-3 fatty acids.

如本文所探讨的,本发明公开的制剂可以被制成眼科用组合物。 As discussed herein, the present invention is disclosed formulations can be prepared ophthalmic composition. 本发明还可以在清醒的个体种作为清洗或冲洗任意用于手术期间,或者治疗昏迷患者的干眼或那些有益肌肉或神经损伤、神经肌肉阻滞或眼皮损失而无法眨眼的人。 The present invention may also be used as washing or rinsing operation for a given period, or the treatment of dry eye or comatose patients who benefit muscle or nerve damage, neuromuscular blockade or loss of the eyelids unable to blink in awake individuals species. 本发明组合物的局部给药包括制剂、组合物的输注,或从装置内局部给药,所述装置选自泵-导管系统、基质模型或缓释装置。 Topical compositions of the present invention includes infusion formulation, composition, or topical administration from the apparatus, the apparatus is selected from a pump - the catheter system, the matrix model, or sustained release device. 局部给药的制剂可以包括制剂在载体媒介中的分散体,所述载体媒介选自液体、凝胶、软膏和脂质体。 Formulations for topical administration may include formulation in a carrier medium in the dispersion, the carrier medium is selected from liquids, gels, ointments, and liposomes.

本文所使用的,术语″缓释装置″是在一段时期内输送活性剂或组合物的装置。 As used herein, the term "sustained release device" is a device or composition of the active agent delivery over a period of time. 所述″缓释装置″在一段时期内释放小于全部量的活性剂或组合物,与一次性释放全部量的组合物或活性剂不同。 The "sustained release device" release less than the entire amount of the active agent or composition over a period of time, and the time release of different composition or the whole amount of the active agent. ″基质″可以由任何适合眼部制剂或给药的材料制成。 "Substrate" may be made of any material suitable for ocular formulation or administration.

通过非限定说明,本发明的制剂或组合物可以用于动物和人体中的眼睛(例如眼表面)作为对应于或存在于软膏、凝胶或脂质体中。 By non-limiting description, preparation or composition of the present invention can be used in animals and humans in the eye (e.g. ocular surface) as corresponds to or is present in the ointment, gel or liposomes. 所述的组合物还可以包含表面活性剂。 Said compositions may further comprise a surfactant. 此外,所述组合物可以用泵-导管系统注入到泪膜内。 In addition, the composition may be pumped - injected into the lacrimal duct system film. 在其他实施方式中,所述的组合物可以含在连续或其他选择性释放的装置中,例如,膜。 In other embodiments, the composition may contain in a continuous or selective release of other devices, e.g., films. 通常,希望施用的模式是这样的,它使化合物进入到泪膜或与眼睛的表面接触。 Typically, the mode of administration is hoped such that the compound into the tear film or contact with the surface of the eye. 在一些实施方式中,所述组合物或制剂可以含在可以用于眼表面的擦子或海绵中。 In some embodiments, the composition or formulation may contain the eraser or sponge may be used for ocular surface. 在一些实施方式中,本发明的组合物或制剂可以含在可以用于眼表面的液体喷雾剂中。 In some embodiments, the compositions or formulations of the present invention may be contained in the liquid sprays may be used for ocular surface. 在一些实施方式中,组合物或制剂可以被直接注射到泪腺组织中或眼表面上。 In some embodiments, the composition or formulation may be injected directly into the lacrimal tissues or ocular surface.

手术移植的眼内装置或基质可以是具有聚乙烯醇或醋酸聚乙烯的可扩散壁的储库容器。 Ophthalmic device surgically implanted within or matrix may be a polyvinyl alcohol or polyvinyl acetate may diffusing wall of the reservoir container. 含有一定量的本发明所述组合物的此类装置或基质可以被植入到巩膜内。 Contain an amount of the composition of the present invention such devices can be implanted into the substrate or within the sclera. 作为另一实例,一定量的组合物可以被掺混在具有约2mm4mm的面积的聚合物基质内,聚合物由例如聚己内酯、聚(羟乙)酸、聚(乳)酸、聚酐制成,或由脂质例如癸二酸制成,并且可以被植入到巩膜上或眼睛内。 As another example, a certain amount of the composition can be blended in a polymer matrix having about 2mm 4mm area of, for example, polycaprolactone polymers, poly (glycolate) acid, poly (lactate) acid, poly anhydride made, or made of lipids such as sebacic acid, and can be implanted on the sclera or within the eye. 这通常由接受局部或定位麻醉的患者且采用在角膜后的小(3-4mm)切口完成。 This usually consists of patients receiving local anesthesia and the use or location of the cornea after a small (3-4mm) incision is completed. 含有组合物的基质经切口被插入并用9-0尼龙缝合到巩膜。 A matrix containing the composition to be inserted through the incision and sutured to the sclera using 9-0 nylon.

定时释放活性剂给药体系可以被植入眼内而得到ω-6和/或ω-3脂肪酸在一段时间内的控释。 Timed release of the active agent delivery system to obtain ω-6 and / or ω-3 fatty acids, controlled release over a period of time may be implanted in the eye. 可植入制剂可以是任何上面所公开的聚合物(例如,聚己内酯、聚(羟乙)酸、聚(乳)酸、聚酐)或可以配制为微球的脂质的胶囊的形式。 In the form of implantable formulations may be any of the above disclosed polymers (e.g., polycaprolactone, poly (glycolate) acid, poly (lactate) acid, polyanhydride) or may be formulated as microspheres lipid capsules . 如实例所示,活性剂(例如,ω-6和/或ω-3脂肪酸)可以与聚乙烯醇(PVA)混合,随后干燥该混合物并且用乙烯-醋酸乙烯基酯包衣,此后在此与PVA冷却。 As illustrated example, the active agent (e.g., ω-6 and / or ω-3 fatty acids) may be (PVA) mixing polyvinyl alcohol, and then drying the mixture with ethylene - vinyl acetate coating, and thereafter this PVA cool. 与脂质体结合的活性剂可以以滴眼剂或者水基霜剂的形式被局部给药,或者可以眼内注射。 Liposomes may be bound to the active agent in the form of eye drops or water based cream to be administered topically, or may intraocular injections. 在局部给药的制剂中,活性剂随着时间缓慢释放而脂质体胶囊由于冲洗和眼泪而从眼表面降解。 In topical formulations, the active agent is released slowly over time as the liposome capsule degradation due to the rinse and tears from the eye surface. 在眼内注射的制剂中,脂质体胶囊由于细胞消化而降解。 Intraocular injection formulation, a liposome capsule due to digestion and degradation of the cell. 这两种制剂提供了缓释活性剂给药体系的优越性,给患者提供了在一段时间内剂量稳定的活性剂。 Both formulations offer the advantage of sustained release of an active agent delivery system, providing the patient with a period of time on a stable dose of an active agent. 缓释的制剂通过例如载体的多种制剂来实现,例如,包衣或未包衣微球、包衣或未包衣胶囊、脂质或聚合物组分、单室或多室结构和上述的组合物等。 Sustained release formulation is prepared by a variety of formulations such as carriers to achieve, for example, coated or uncoated 衣微 ball, coated or uncoated capsule, lipid or polymer components, single-chamber or multi-chamber structure and above the compositions and the like. 其他变量可以包括患者的药动学-药效学参数(例如,体重、性别、血浆清除率、肝功能等)。 Other variables may include the patient's drug pharmacokinetic - pharmacodynamic parameters (e.g., weight, gender, plasma clearance rate, hepatic function, etc.). 微球、微囊、脂质体等的形成和负载及其眼内植入是本领域技术人员已知的标准技术,例如,使用无环鸟苷含水植入物以治疗巨细胞病毒视网膜炎,公开在Vitreoretinal Surgical Techniques中,Peyman等编辑(Martin Dunitz,London 2001,chapter 45);Handbook ofPharmaceutical Controlled Release Technology,Wise,Ed.(MarcelDekker,New York 2000),其相关部分在此全文引入作为参考。 Microspheres, microcapsules, liposomes, etc. and their formation and load intraocular implants are known to those skilled in the standard techniques, e.g., using acyclovir aqueous implant to treat cytomegalovirus retinitis, disclosed in Vitreoretinal Surgical Techniques in, Peyman et al, eds (Martin Dunitz, London 2001, chapter 45); Handbook ofPharmaceutical Controlled Release Technology, Wise, Ed (MarcelDekker, New York 2000), the pertinent portions of which are hereby incorporated by reference.

可以通过将所选的脂肪酸分散或溶解在适当的载体中来制备本发明的眼科用组合物。 Can be prepared by dispersing or dissolving the selected fatty acids in a suitable carrier to prepare an ophthalmic composition of the present invention. 任何已知的眼科相容的载体可以用于制备本发明的眼科用组合物。 Any known carrier may be used in ophthalmic compatible ophthalmic preparation of the present invention compositions. 适当的载体包括水、盐水溶液、矿物油、凡士林、C15-20醇、C15-20酰胺、被两性离子取代的C15-20醇、其组合等等。 Suitable carriers include water, saline solution, mineral oil, petroleum jelly, C15-20 alcohols, C15-20 amides, substituted zwitterionic C15-20 alcohols, combinations thereof and the like. 当所选的载体无法溶解脂肪酸时,可以加入表面活性剂。 When the selected carrier can not dissolve the fatty acids a surfactant may be added.

在其中脂肪酸不溶于所选载体中的实施方式中,希望将脂肪酸、载体和表面活性剂活化,如果可能,形成乳液并且在一些实施方式中形成微乳。 In which the fatty acid is insoluble in the selected carrier embodiments, it is desirable to fatty acids, the carrier and surfactants activation, if possible, to form an emulsion and microemulsion is formed in some embodiments. 适当的微乳可以具有小于约1微米、小于约0.1微米或小于约0.005微米的液滴尺寸。 Suitable microemulsion may have less than about 1 micron, less than about 0.1 microns, or less than about 0.005 micrometers droplet size. 所述组合物还可以含有表面活性剂以帮助″溶解″所述的脂肪酸(例如必须和/或非必需脂肪酸),使它们输送到个体的眼睛内。 The composition may also contain a surfactant to assist in the fatty acid "dissolved" (such as the need and / or non-essential fatty acids), so that they convey into the eye of an individual.

所述脂肪酸一般是非水溶性的并且当置于盐水(盐水)溶液中时将更加不溶;所以,它们需要用表面活性剂和乳化体系乳化,所述表面活性剂与所述ω-3和6脂肪酸的脂族非极性长链基团极其相容并且所述乳化体系应当缓慢释放这些非水溶性脂肪酸到其外部环境中。 The fatty acids will generally not water-soluble and when placed in saline (saline) solution will be even more insoluble when; therefore, they need to use a surfactant and an emulsifying system emulsification, the surfactant with the ω-3 and 6 fatty acids aliphatic non-polar long chain group of the emulsifying system is extremely compatible and should release the non-water soluble fatty acids slowly to the outside environment.

表面活性剂的使用可能根据其HLB值而变化很大。 Use of surfactants may vary according to their HLB value greatly. 表面活性剂的性质可以包括,但不限于,表面活性的和将表面张力降低到低于10达因/cm;快速吸附在分散的液体四周成为浓缩的、非粘附性薄膜,它可以防止聚结;使液滴具有足够的电势从而出现相互排斥;增加乳液的粘度;和/或在合理低的浓度下有效。 Nature of the surfactant may include, but are not limited to, surfactants, and the surface tension is reduced to less than 10 dynes / cm; fast adsorption in the liquid become concentrated around the dispersed, non-tacky film, it is possible to prevent polymerization knot; droplet has sufficient potential which appears mutually exclusive; increased viscosity of the emulsion; and / or effective in a reasonable low concentration.

药学和/或眼科可接受表面活性剂还可以是稳定的、与其他组分相容的、无毒的、没有气味、味道和颜色的;和/或不干扰活性剂的效价稳定性。 Pharmaceutical and / or ophthalmic acceptable surfactant can also be stable, compatible with the other ingredients, non-toxic, no odor, taste and color; and / or potency does not interfere with the stability of the active agent.

油也具有指定的HLB值;然而,这种″HLB″是对于水包油乳液是否被稳定化也是相对的。 Oil also has an HLB value specified; however, this "HLB" for oil in water emulsion is stabilized is relative. 通常,表面活性剂应当具有与各种油的HLB相似的HLB值,从而获得最大的稳定作用。 Typically, the surfactant should have HLB of various oils with a similar HLB values, for maximum stability. 矿物油具有2-5之间的指定HLB,这取决于其数均分子量(Mn)。 Mineral oil having a specified HLB 2-5 between, depending on its number average molecular weight (Mn). 所以,对于矿物油而言,表面活性剂的HLB数应当分别为约4和10.5。 Therefore, for the purposes of mineral oil, HLB number of the surfactant should be between about 4 and 10.5, respectively. 也可以通过将亲脂性和亲水性表面活性剂混合来获得所需HLB数。 Also can be obtained by mixing the lipophilic and hydrophilic surfactants to obtain the desired HLB number. 该混合物的总HLB值计算为分数乘以各个HLB值之和。 Overall HLB value of the mixture was calculated to be multiplied by the fraction of the sum of the individual HLB values. 示例表面活性剂是吐温80(乙氧基化的脱水山梨糖醇一油酸酯)、Glucam E-20(乙氧基化甲基葡糖苷)、基于甲基葡糖苷的二油酸酯乙氧基化物,例如但不限于DOE 120、含有嵌有疏水性聚环氧丙烷(PPO)亚基的亲水性聚环氧乙烷(PEO)核的嵌段共聚物(反普流尼克)、山梨糖醇酯表面活性剂(″司盘″类表面活性剂)和其组合物等等。 Example surfactant is Tween 80 (ethoxylated sorbitan monooleate), Glucam E-20 (ethoxylated methyl glucoside), based on methyl glucoside dioleate B alkoxylates, such as, but not limited to DOE 120, is embedded with a hydrophobic polypropylene oxide (PPO) subunits hydrophilic polyethylene oxide (PEO) block copolymer containing nuclei (anti pluronic), sorbitan ester surfactant ("Span" type surfactants) and combinations thereof and the like. 表1表示了在乳化脂肪酸时,可以使用的多种乳液和表面活性剂的量的实例。 Table 1 shows the fatty acid at the time of emulsification, the emulsion may be used and multiple instances of the amount of surface active agent. 然而,也可以采用其他用量。 However, other dosage may be used.

表1:用于乳化ω-3和ω-6脂肪酸的组合物的实例 Table 1: Examples of emulsifying ω-3 and ω-6 fatty acid composition

ω-6和/或ω-3脂肪酸的用量可以被表示为占组合物总量的百分率。 ω-6 and / or the amount of ω-3 fatty acids can be represented as the percentage of the total composition,. ω-6和/或ω-3脂肪酸的百分率可以通过任何方法测定,但可以例如是通过将脂肪酸的重量除以组合物的总重量。 ω-6 and / or the percentage of ω-3 fatty acids can be measured by any method, but can be, for example, by the weight divided by the total weight of the fatty acid composition. 组合物中任何组分的百分率可以以类似方式测定。 Any percentage of the components can be determined in a similar manner the composition. 例如,所述组分的重量除以所述组合物的总重量得到该组分在所述组合物中的百分率。 For example, the weight of the component divided by the total weight of the composition obtained in the percentage component of the composition.

在一些实施方式中,ω-6和ω-3脂肪酸的总量以等于约0.01,约10重量%的量存在,在一些实施方式中以介于约0.01至约6重量%的量存在,并且在其他实施方式中是约0.05重量%,至约5重量%的量存在。 In some embodiments, ω-6 and ω-3 fatty acids in the total amount equal to about 0.01, from about 10 wt%, by weight, in some embodiments in the range of from about 0.01 to about 6% by weight present in an amount, and In other embodiments from about 0.05% by weight, to an amount of about 5% by weight. ω-3脂肪酸在本发明眼科用组合物中存在的量包括约0.01至约10重量%,在一些实施方式中包括约0.05重量%,至约5重量%,,基于眼科制剂中所有组分计。 ω-3 fatty acids in the present invention is an ophthalmic composition in an amount comprising from about 0.01 to about 10% by weight, including from about 0.05 wt% in some embodiments, to about 5% by weight ,, based on the count of all components in the ophthalmic formulation .

ω-6脂肪酸在本发明的眼科用组合物中可以存在的量包括约0至约10重量%,在一些实施方式中约0.01重量%,至约5重量%,基于所述眼科制剂中所有组分计。 ω-6 fatty acids in an amount in the ophthalmic composition of the present invention may be present include from about 0 to about 10 wt.%, in some embodiments from about 0.01 wt% to about 5% by weight, based on the ophthalmic preparation for all groups meter.

在一些实施方式中,希望提供一种使眼睛内ω-3脂肪酸∶ω-6脂肪酸的平衡恢复到约1∶1的组合物。 In some embodiments, it is desirable to provide an ω-3 fatty acids in the eye :ω-6 fatty acids to restore balance to the composition of approximately 1:1. 为了使西方国家如美国和欧洲的许多人实现这种情况,需要提供富含ω-3脂肪酸的制剂。 In order to make the Western countries such as the United States and Europe many people realize this, it is necessary to provide rich in ω-3 fatty acid preparations. 所以,在这个实施方式中希望提供的眼科用组合物,其具有的ω-3脂肪酸∶ω-6脂肪酸的比例是约10∶约1至不小于约1∶约1并且是从约5∶1至约1∶1,约4∶1至约1∶1,从约3∶1至约1∶1,从约2∶1至约1∶1,约1∶1,约2∶1,约3∶1,约4∶1,约5∶1,约6∶1,约7∶1,约8∶1,约9∶1,或约10∶1。 Therefore, it is desirable in this embodiment to provide an ophthalmic composition having the ω-3 fatty acids :ω-6 fatty acid ratio is from about 1 to about 10: 1: about not less than about 1 and from about 5 to about 1, about 4 to about 1, from about 3 to about 1, from about 2 to about 1, about 1:1, about 2, about 3 :1, about 4, about 5, about 6, about 7, about 8, about 9, or about 10. 该比例基于各个类型的ω脂肪酸的总量计。 The proportion of each type of ω based on the total amount of fatty acids.

本发明的眼科用组合物还可以含有至少一种表面活性剂。 Ophthalmic composition of the present invention may also contain at least one surfactant. 适合本发明的眼科用组合物的表面活性剂具有类似于ω-6和/或ω-3脂肪酸的非极性脂族尾端。 Suitable for the present invention is an ophthalmic composition having similar surfactant and ω-6 / ω-3 fatty acids or non-polar aliphatic tail. 采用具有相似脂族尾端的表面活性剂得到更加稳定的乳液并且有助于与乳液稳定性所需的分散力匹配。 Surfactants are used in a similar aliphatic tail end to be more stable emulsion and helps with the stability of the emulsion required dispersancy match. 表面活性剂和脂肪酸的″相似″非极性尾端也有助于在高浓度下产生稳定的乳液。 Surfactant and fatty acids "similar" nonpolar tails also help produce a stable emulsion at a high concentration. 根据分子的亲水性和亲脂性部分之间的平衡描述表面活性剂的特征。 Describe the characteristics of the surfactant molecules according to the balance of hydrophilic and lipophilic portions. 亲水性和亲脂性平衡(″HLB″)是分子的极性在1-40的范围内的一个指标,并且绝大多数常用的表面活性剂具有1至20的值。 Hydrophilic and lipophilic balance ("HLB") is an indicator of the polarity of the molecule in the range of 1 to 40, and the vast majority of conventional surfactants having a value of 1 to 20. HLB值随着亲水性的增高而增加。 HLB value increases with increasing hydrophilicity. 对于聚合物表面活性剂而言,HLB值可以利用下列公式计算:20(亲水性单体的重量/聚合物表面活性剂的重量)20(1-S/A)S=酯的皂化值A=酸的酸值皂化值是脂肪、蜡和树脂中游离和结合的酸的总数,表示成1克底物完全被皂化所需的KOH的毫克数。 For the purposes of polymeric surfactants, HLB value may use the following formula: 20 (wt wt hydrophilic monomer / polymer surfactant) 20 (1-S / A) S = saponification number of the ester A = acid number of the acid saponification value of fats, waxes, and the total number of free and bound resin acids, expressed as milligrams of 1 g substrate completely saponified KOH required to neutralize.

酸值是中和1克底物中游离酸所需的KOH的毫克数。 The acid value was 1 gram of substrate in the number of milligrams of KOH required to neutralize the free acid. 当无法得到皂化值时,可以利用下列公式测定HLB。 When it is impossible to obtain a saponification value, HLB can be determined using the following formula.

HLB=(E+P)/5其中E是氧化乙烯的重量%P是多元醇的重量百分比。 HLB = (E + P) / 5 where E is ethylene oxide wt% P is the percentage by weight of polyol. 通常,适用于本发明的眼科用组合物中的表面活性剂具有的HLB值为约10至约20,在一些实施方式中为约12至约18,并且在其他实施方式中为约14至约16。 Typically, the present invention is suitable for ophthalmic composition of a surfactant having an HLB value of from about 10 to about 20, in some embodiments from about 12 to about 18, and in other embodiments from about 14 to about 16. 在一些实施方式中,所述组合物含有约0.5至20.0重量%的表面活性剂,基于所述组合物的所有组分计。 In some embodiments, the composition contains from about 0.5 to 20.0% by weight of surfactant, based on the count of all the components of the composition. 在一些实施方式中,表面活性剂的百分率是约1至约15重量%,约1至约10重量%,约1至约5重量%,等。 In some embodiments, the percentage of surfactant is from about 1 to about 15% by weight, from about 1 to about 10% by weight, from about 1 to about 5% by weight, and the like.

所述组合物可以含有不止一种表面活性剂。 The composition may contain more than one surfactant. 本发明的组合物可以含有能够输送活性剂(例如,ω-6和/或ω-3脂肪酸)的其他组分。 The compositions of the invention may contain an active agent capable of transporting (e.g., ω-6 and / or ω-3 fatty acids) of the other components. 本发明的组合物可以进一步含有附加组分例如抗氧剂、缓冲剂、张力调节剂、螯合剂、防腐剂、湿润剂、增稠剂、其组合等。 The compositions of the invention may further contain additional ingredients such as antioxidants, buffers, tonicity adjusting agents, chelating agents, preservatives, wetting agents, thickeners, combinations thereof and the like. 适当实例是本领域已知的那些。 Suitable examples are those known in the art. 在一些实施方式中,所述组合物含有盐水。 In some embodiments, the composition comprises brine. 在一些实施方式中,所述组合物含有维生素E。 In some embodiments, the composition comprises vitamin E. 在一些实施方式中,在所述组合物中维生素E的量等于1滴(约50μL)。 In some embodiments, the composition in the amount of vitamin E is equal to 1 drop (approximately 50μL).

所述组合物还具有其他可以影响增溶型和活性剂输送性的性质,并且由此可以改变它们。 The compositions also have other properties can affect the type and solubilization of the active agent delivery, and thus can change them. 此类可以改进的性质的实例如表2中所示。 Such examples can be improved properties as shown in Table 2.

表2:表1中所示的制剂1-4的性质。 Table 2: Properties of formulations shown in Table 1 1-4.

在一些实施方式中,所述组合物的pH是约5至约8,约5.5至约7.5,约6至约7.5,约6.5至约7.5,约6.9至约7.3,约6.95至约7.2,约7.2,约6.95,约6.12,约5.54。 In some embodiments, pH of the composition is from about 5 to about 8, from about 5.5 to about 7.5, from about 6 to about 7.5, from about 6.5 to about 7.5, from about 6.9 to about 7.3, from about 6.95 to about 7.2, from about 7.2, about 6.95, about 6.12 to about 5.54. 在一些实施方式中,组合物的电导率可以是约10至约14,约10至约12,约10至约14,约13至约14,约13至约13.5,约13.5至约14,约12至约13,约10.5,约11,约13.5,约13.75,约14等。 In some embodiments, the conductivity of the composition may be from about 10 to about 14, from about 10 to about 12, from about 10 to about 14, from about 13 to about 14, from about 13 to about 13.5, from about 13.5 to about 14, from about 12 to about 13, about 10.5, about 11, about 13.5, about 13.75, about 14 and so on. 在一些实施方式中,所述组合物的pH是5至8,5.5至7.5,6至7.5,6.5至7.5,6.9至7.3,6.95至7.2,7.2,6.95,6.12,5.54。 In some embodiments, pH of the composition is 5 to 8,5.5 to 7.5,6 to 7.5,6.5 to 7.5,6.9 to 7.3,6.95 to 7.2,7.2,6.95,6.12,5.54. 在一些实施方式中,所述组合物的电导率可以是10至14,10至12,10至14,13至14,13至13.5,13.5至14,12至13,10.5,11,13.5,13.75,14等。 In some embodiments, the conductivity of the composition may be from 10 to 14,10 to 12,10 to 14,13 to 14,13 to 14,12 to 13,10.5,11,13.5,13.75 to 13.5,13.5 , 14 and so on.

在一些实施方式中,所述组合物的摩尔渗透压浓度是约100至约600,约150至约500,约200至约300.在一些实施方式中,所述组合物的摩尔渗透压浓度是400至600,400至550,450至525,100,200,300,400,500,150,250,300,350等。 In some embodiments, the osmolality of the composition is from about 100 to about 600, from about 150 to about 500, from about 200 to about 300. In some embodiments, the osmolality of the composition is 400 to 600,400 to 550,450 to 525,100,200,300,400,500,150,250,300,350 like. 在一些实施方式中,摩尔渗透压浓度小于550,525,500或450。 In some embodiments, the osmolality is less than 550,525,500, or 450. 在一些实施方式中,所述摩尔渗透压浓度大于400,425,450,475,500,或525。 In some embodiments, the osmolality is greater than 400,425,450,475,500, or 525.

在一些实施方式中,本发明涉及局部施用组合物,所述组合物含有至少一种ω-6脂肪酸(例如,GLA和DGLA)和至少一种ω-3脂肪酸(例如,包括ALA、EPA和/或DHA)的组合作为减少眼表面炎症的有效策略。 In some embodiments, the present invention relates to a composition for topical application, said composition comprising at least one ω-6 fatty acids (e.g., GLA and DGLA) and at least one ω-3 fatty acids (e.g., including ALA, EPA and / or DHA) combination as the reduction of ocular surface inflammation effective strategy. 如本文所探讨的,眼表面的炎症可以在例如干眼综合征、睑板腺机能障碍、眼睑炎、特应性角膜结膜炎和许多其他病症中发现。 As discussed herein, the inflammation of the ocular surface in dry eye syndrome, for example, meibomian gland dysfunction, blepharitis, atopic keratoconjunctivitis and many other disorders found. 本发明包括治疗有效量的治疗性脂肪酸化合物并且可以分散在适合眼科给药的药学可接受载体媒介中,例如,但不限于透明质酸或其他基于甲基纤维素的载体。 The present invention comprises a therapeutically effective amount of a therapeutic compound and a fatty acid may be dispersed in a suitable ophthalmic administration of a pharmaceutically acceptable carrier medium, such as, but not limited to, hyaluronic acid or other methylcellulose based carrier. 还考虑控释制剂。 Also consider the controlled release formulations. 例如,本发明的组合物可以以缓释制剂采用生物可降解聚合物给药,或利用胶束、凝胶和脂质体就地给药。 For example, the compositions of the present invention may be a sustained release formulation using a biodegradable polymer is administered, or the use of micelles, gels and liposomes in situ administration. 通过口服,本发明的组合物中所含的脂肪酸似乎在高达数克/天的剂量下都可以被很好地耐受。 By the oral, the fatty acid composition of the present invention contained seemed up to several grams / day doses may be well tolerated. 局部使用本发明组合物的最佳给药剂量和方式可以很容易地由常规方案来判断。 Topical compositions of the present invention is optimal dosage and mode can be easily judged by a conventional scheme.

在一些实施方式中,ω-6脂肪酸化合物是DGLA并且ω-3脂肪酸化合物是EPA和DHA。 In some embodiments, ω-6 fatty acid compound is DGLA and ω-3 fatty acid compounds are EPA and DHA. 在一些实施方式中,EPA和ALA可以作为ω-3脂肪酸的组合形式使用。 In some embodiments, EPA and ALA can be used as ω-3 fatty acids in the form of combination use. 在一些实施方式中,所述组合物含有GLA或DGLA或两者、EPA或ALA5或两者。 In some embodiments, the composition comprising GLA or DGLA or both, EPA or ALA5 or both.

此外,本发明包括治疗眼部病症和疾病的方法,包括给眼表面施用本发明所述的组合物。 Further, the present invention comprises a method of ocular disorders and treatment of diseases, comprising administering to the ocular surface composition of the present invention. 在一些实施方式中,本发明提供增加个体可以佩戴隐形眼睛的年龄的方法,包括将组合物施用到眼表面。 In some embodiments, the present invention provides an individual may wear contact lenses increasing age, comprising the composition is applied to the surface of the eye. 在一些实施方式中,所述给药包括局部给药。 In some embodiments, the administering comprises topical administration. 本发明的组合物还可以用于制备治疗例如,但不限于,附属器炎症。 The compositions of the invention may also be used to prepare the treatment such as, but not limited to, adnexal inflammation.

术语″眼部病症和疾病″包括干眼综合征。 The term "ocular conditions and diseases," including dry eye syndrome. 根据National EyeInstitute Workshop有关干眼的临床试验,干眼综合征(DES)被定义为泪膜的疾病,其由眼泪缺乏和/或过度眼泪蒸发造成,对眼(眼睛)表面造成损伤并且带来眼睛不适的症状。 According to clinical trials National EyeInstitute Workshop related dry eye, dry eye syndrome (DES) is defined as the tear film diseases, it lacks the tear and / or cause excessive tear evaporation, ocular (eye) surface and causing damage to bring eyes symptoms of discomfort. The National Eye InstituteIndustry Workshop还制定了分类,它主要将干眼综合征划分为两个主要类型:缺泪型(包括斯耶格伦氏综合征和非斯耶格伦氏综合征眼泪缺乏)和蒸发型。 The National Eye InstituteIndustry Workshop also developed a classification, it is mainly dry eye syndrome is divided into two main types: lack of tears type (including Sjogren's syndrome, Sjogren's syndrome and non-tear deficiency) and evaporation type. 泪膜通常覆盖在被称作角膜和结膜的眼睛的前部。 Tear film normally covers the front of the eye is called the cornea and conjunctiva. 泪膜持续暴露在多种环境因素下,包括改变的温度、气流和湿度,这些可以刺激或延迟泪膜的蒸发。 Tear film left exposed to various environmental factors, including changes in temperature, air flow and humidity, which may stimulate or delay the evaporation of the tear film. 特别是,在明显气流条件下低湿度条件增加了眼泪的蒸发率,处于干燥环境下的主体常常报告这种情况。 In particular, under conditions of low humidity air flow conditions significantly increases the tear evaporation rate, in a dry environment of the body often report it. 实际上,即使具有正常眼泪分泌速率的人当暴露在干燥环境下,例如飞机中和干燥工作环境下时,也可能经历干眼症状。 Indeed, even people with a normal tear secretion rate when exposed to dry environments, such as aircraft and dried under working conditions, but also may experience dry eye symptoms. 有趣的是,已经证实干眼的眼表面试验结果,例如Schirmer试验和泪水消散时间,在生活在干燥气候下的对象中有所减小。 Interestingly, it has been confirmed that ocular surface tests results for dry eye, e.g., Schirmer test and tear break up time, in the object living in a dry climate in decreased. 本发明提供了对于此类病症和其他被认为不同原因造成的部分干眼的病症的方法,所有干眼都存在眼表面干燥和上皮损伤的共同特点,测定的终点作为本发明所包括数据的一部分。 The present invention provides a method for such disorders, and other various causes are considered part of the dry eye condition, there are all dry eye ocular surface dryness and epithelial damage of the common characteristics, as measured by the present invention, the end portion of data comprises .

″眼部病症和疾病″还可以是指,但不限于:角膜结膜炎(KCS)、与年龄有关的干眼、Stevens-Johnson综合征、斯耶格伦氏综合征、眼瘢痕天疱疮、眼睑炎、角膜损伤、感染、Riley-Day综合征、先天性无泪、营养疾病或缺乏(包括维生素)、药物副作用、眼睛应激、腺和组织破坏、环境接触(例如烟雾、吸烟、非常干的空气、空中的微粒)、自身免疫和其他免疫缺损疾病,以及无法眨眼的昏迷患者。 "Eye disorders and diseases" can also refer to, but not limited to: keratoconjunctivitis sicca (KCS), age-related dry eye, Stevens-Johnson syndrome, Sjogren's syndrome, ocular pemphigoid scar, blepharitis, corneal injury, infection, Riley-Day syndrome, congenital absence of tears, nutritional disorders or deficiencies (including vitamins), drug side effects, eye stress, glandular and tissue destruction, environmental exposure (such as smoke, smoking, very dry air, air particulates), autoimmune and other immune deficiency diseases, and comatose patients unable to blink. 干眼还可以定义为在角膜和结膜病灶存在或不存在的情况下眼泪质量降低或改变的病症。 Dry eye can also be defined as a decrease or change in the cornea and conjunctiva lesion presence or absence of tears quality conditions. 这包括在少泪、无泪、眼干燥和糖尿病、HIV/AIDS等中发现的干眼;白内障手术后的干眼;与变应性结膜炎相关的干眼;和与年龄相关的干眼综合征。 This includes small tears, no tears, dry eye and diabetes, HIV / AIDS, such as found in dry eye; dry eye after cataract surgery; associated with allergic conjunctivitis, dry eye; and age-related dry eye Integrated sign. 干眼还可以包括在由于长时间看显示器终端(VDT)操作、空调造成的室内干燥等引起的少泪患者中发现的病症。 Dry eye can also include a small tear in the patient due to the long time to see the display terminal (VDT) operations, room air conditioner caused by drying conditions found caused.

本发明还可以在清醒个体中、手术期间用作洗涤或冲洗溶液或者用于维持昏迷患者或那些由于肌肉或神经损伤、神经进入阻滞和眼皮损失造成的无法眨眼的患者。 The present invention may also be in conscious individuals, during surgery or as detergent or rinsing solution for comatose patients or patients who can not blink due to muscle or nerve damage, nerve damage caused to enter the block and eyelids to maintain.

本发明还可以施用给已经确定需要本发明的组合物的个体。 The present invention may also be administered to a need has been determined that compositions of the present invention an individual. 如果个体已经被确定为患有或具有干眼综合征的话,所述个体需要它们。 If the individual has been identified as suffering from or having dry eye syndrome words, the individual in need them. 本领域技术人员懂得如何确定需要治疗干眼综合征的患者。 Skilled in the art knows how to identify patients in need of treatment of dry eye syndrome.

在一些实施方式中,本发明还可以用于治疗眼睛炎症的方法。 In some embodiments, the present invention can also be used a method of treating ocular inflammation.

在一些实施方式中,本发明提供使眼内的ω-3与ω-6脂肪酸的比例正常化的方法。 In some embodiments, the present invention provides a method for normalizing the ratio of ω-6 fatty acid-3 ω eye. 如本文所述,ω-3与ω-6脂肪酸的比例可以通过个体的饮食来测定。 As described herein, ω-3 and ω-6 fatty acid ratio can be determined by the individual's diet. 在某些群体中,减少ω-3脂肪酸的量,它可能具有有害作用例如,但不限于干眼综合征或病症。 In some groups, the reduction of the amount of ω-3 fatty acids, it may have deleterious effects such as, but not limited to dry eye syndrome or condition. 所以,包括施用至少一种ω-3脂肪酸和/或至少一种ω-6脂肪酸到眼表面或眼睛的方法可以用于使ω-3脂肪酸与ω-6脂肪酸的比例正常化。 Therefore, comprising administering at least one ω-3 fatty acids and / or at least one ω-6 fatty acids to the surface of the eye or eye method may be used to ω-3 fatty acid ratio of ω-6 normalization fatty acids. 所述比例可以正常化至,例如,但不限于约1∶1,约2∶1,约3∶1,约4∶1,约5∶1,约1∶1至约10∶1,约5∶1至约10∶1,或约1∶1至约5∶1。 The ratio can be normalized to, for example, but not limited to about 1:1, about 2, about 3, about 4, about 5, about 1:1 to about 10, from about 5 :1 to about 10, or about 1 to about 5 to 1.

本发明的组合物可以作为局部制剂被施用到眼睛。 The compositions of the invention may be administered as a topical formulation to the eye. 在一些实施方式中,含有本发明所述组合物的局部制剂可以通过将组合物(例如含有ω-6和/或ω-3脂肪酸)与适当的防腐剂混合而制成。 In some embodiments, the topical formulation containing the composition of the invention may be prepared by the composition (e.g., containing ω-6 and / or ω-3 fatty acid) were mixed with a suitable preservative made. 所述制剂一般还可以含有生理相容性载体,本领域技术人员可以利用常规标准进行选择。 The formulations in general may also contain a physiologically compatible carrier, those skilled in the art can select using conventional criteria. 载体可以选自已知的眼科载体,其包括,但不限于,水,聚醚例如聚乙二醇,乙烯类聚合物例如聚乙烯醇和吡咯烷酮,纤维素衍生物例如甲基纤维素和羟丙基甲基纤维素,石油衍生物例如矿物油、白凡士林,动物脂肪例如羊毛脂,植物脂肪例如花生油、丙烯酸的聚合物例如羧基聚亚甲基凝胶,多糖例如葡聚糖,糖胺聚糖泪例如透明质酸钠和盐例如氯化钠、氯化钾,和其组合。 Ophthalmic carrier may be selected from known vectors, including, but not limited to, water, polyethers such as polyethylene glycol, ethylene-based polymers such as polyvinyl alcohol and polyvinylpyrrolidone, cellulose derivatives such as methyl cellulose and hydroxypropyl methyl cellulose, petroleum derivatives such as mineral oil, white petrolatum, animal fats such as lanolin, vegetable fats such as peanut oil, polymers of acrylic acid such as carboxypolymethylene gel, polysaccharides such as dextran, glycosaminoglycans tears e.g. sodium hyaluronate and salts such as sodium chloride, potassium chloride, and combinations thereof. 在一些实施方式中,载体是无毒眼科制剂,其具有下列组分:约22.0至43.0毫摩尔钾/升;约29.0至50.0毫摩尔碳酸氢盐/升;约130.0至140.0毫摩尔钠/升;和约118.0至136.5毫摩尔的氯化物/升。 In some embodiments, the carrier is a non-toxic ophthalmic preparation having the following composition: about 22.0 to 43.0 millimoles of potassium / liter; from about 29.0 to 50.0 millimoles of bicarbonate / liter; about 130.0 to 140.0 mmol of sodium / liter ; about 118.0 to 136.5 millimoles of chloride / liter.

在一些实施方式中,虽然一般希望制剂是等渗的,但是溶液的最终摩尔渗透压浓度和张度是可以改变的。 In some embodiments, the formulation is isotonic, although it is generally desirable, but a final osmolality and tonicity of the solution can be changed. 在一些实施方式中,当治疗需要时,所述的制剂或组合物可以被稀释到低等渗浓度。 In some embodiments, when the treatment desired, the formulation or composition can be diluted to a low osmolarity. 在一些实施方式中,当治疗需要时,所述制剂或组合物还可以被浓缩到高等渗浓度。 In some embodiments, when the treatment desired, the formulation or composition may also be concentrated to a higher osmolarity.

组合物的″治疗有效量″或″有效量″是组合提供所需结果的量。 "Therapeutically effective amount" or "effective amount" of the composition is a combination of an amount to provide the desired result. 本领域技术人员应当很容易测定治疗有效量或有效量是多少。 Those skilled in the art should readily determined therapeutically effective amount or effective amount is. 治疗有效量可以是指组合物有效预防、缓解或改善个体的疾病、障碍或病症的症状的量。 A therapeutically effective amount may refer to the compositions effective to prevent, alleviate or ameliorate symptoms of an individual amount of disease, disorder or condition.

在一些实施方式中,本发明的组合物可以是眼科制剂。 In some embodiments, the compositions of the present invention may be ophthalmic preparations. 可以根据所用的给药方式配制眼科用组合物或制剂。 Ophthalmic composition can be formulated or administered according to the formulation used. 通常,等渗所用的添加剂可以包括氯化钠、葡萄糖、甘露糖醇、山梨糖醇和乳糖。 Typically, isotonic additives may be used include sodium chloride, dextrose, mannitol, sorbitol and lactose. 在一些实施方式中,可以使用等渗溶液例如磷酸盐缓冲的盐水。 In some embodiments, can be used isotonic solutions such as phosphate buffered saline. 稳定剂包括明胶和白蛋白。 Stabilizers include gelatin and albumin. 在一些实施方式中,将血管收缩剂加入到制剂中。 In some embodiments, a vasoconstriction agent is added to the formulation. 本发明的眼科制剂可以是灭菌和无致热原的。 Ophthalmic formulations of the present invention may be sterilized and non-pyrogenic. 本发明的药物(例如眼科)组合物包括递送组分与本文所述的进一步含有眼科可接受载体或媒介的组合物的组合,所述载体或媒介例如是盐水溶液。 Medicament of the present invention (e.g. ophthalmic) compositions containing composition further comprises a delivery composition ophthalmically acceptable carriers or media components as described herein, the carrier or medium such as a saline solution. 可以使用任何能够成功递送本发明组合物的介质。 You can use any successful delivery of compositions of the present invention medium. 本领域技术人员应当很容易理解许多本领域可以使用的药学(例如,眼科)可接受介质。 Those skilled in the art should readily appreciate that many in the art can be used pharmaceutically (e.g., ophthalmic) acceptable medium. 适当的眼科载体如Remington′sPharmaceutical Sciences,A.Osol所述,它是该领域的标准参考书,其被引入作为参考。 Suitable ophthalmic carriers such as Remington'sPharmaceutical Sciences, A.Osol said, it is a standard reference book in this field, which is incorporated herein by reference.

本发明的组合物和/或眼科用组合物可以以单剂量或多剂量给药。 The compositions of the invention and / or ophthalmic may be administered in single or multiple doses composition. 本发明的眼科用组合物可以以单个治疗剂或者与其他治疗剂的组合给药。 Ophthalmic composition of the present invention may be a single therapeutic agent or in combination with other therapeutic agents administered in combination. 本发明的治疗可以与常规疗法结合,它们可以顺序或同时给药。 Treatment of the invention may be combined with conventional therapies, which may be administered sequentially or simultaneously.

剂量根据已知的因素而变化,例如特定药物的药代动力学特性,和给药的方式和途径;患者的年龄、健康和体重;症状的性质和程度;并行治疗的类型;治疗的频率;和所需作用。 Dose according to known factors, such as the pharmacokinetic properties of the particular drug, and the mode and route of administration; the age, health and weight; the nature and extent of symptoms; type of concurrent treatment; frequency of treatment; and the desired effect. 治疗组合物的配制及其随后的给药属于本领域技术人员的范畴内。 Formulation and subsequent administration of therapeutic compositions are within the scope of the skilled in the art. 通常,剂量可以是约1至3000毫克/50千克的体重;10至1000毫克/50千克的体重;25至800毫克/50千克的体重。 Typically, the dose may be about 1 to 3000 mg / 50 kg of body weight; 10 to 1000 mg / 50 kg of body weight; 25 to 800 mg / 50 kg body weight. 剂量还可以被配制为活性成分(例如ω-6和/或ω-3脂肪酸)在溶液中的浓度,例如滴眼剂。 Dose may also be formulated as an active ingredient (e.g., ω-6 and / or ω-3 fatty acids) in a concentration in the solution, such as eye drops.

本发明还提供制备或制造含有ω-6和/或ω-3脂肪酸的组合物的方法(例如药物)。 The present invention also provides a preparation or manufacture and / or methods (e.g., drug) ω-3 fatty acids compositions containing ω-6. 在一些实施方式中,所述方法包括将至少一种或第一种表面活性剂与盐水溶液混合(例如,搅拌)。 In some embodiments, the method comprises at least one first surfactant with a saline solution, or mixing (e.g., stirring). 该盐水溶液可以是适合所述组合物的任何溶液,例如,但不限于硼酸盐缓冲的盐水溶液。 The salt solution may be any solution suitable for the composition, for example, but not limited to a borate buffered saline solution. 在一些实施方式中,第二表面活性剂与含有第一表面活性剂和所述盐水溶液的溶液接触(例如混合)。 In some embodiments, a second contact with a surfactant solution containing the first surfactant and the saline solution (e.g., mixed). 在一些实施方式中,该方法发生在室温下。 In some embodiments, the process occurs at room temperature. 在一些实施方式中,将所述脂肪酸(例如,ω-6和/或ω)-3)在一定时间内加入。 In some embodiments, the fatty acids (e.g., ω-6 and / or ω) -3) in a certain period of time. 在一些实施方式中,该时间为约30分钟、约1小时、约2小时、约3小时、约4小时、约5小时。 In some embodiments, the time is about 30 minutes, about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours. 当物质(溶液或固体)在一定时间内被加入时,在该时间内以大致相等的量加入。 When a substance (solution or solid) is added in a certain period of time, during which time approximately equal to the amount added. 可以在任何时间间隔(例如,5分钟、10分钟、15分钟、20分钟、30分钟、40分钟、60分钟等)加入。 May be spaced (e.g., 5 minutes, 10 minutes, 15 minutes, 20 minutes, 30 minutes, 40 minutes, 60 minutes, etc.) is added at any time.

还可以调整混合速度,由此首先缓慢混合并且随后提高混合设备的RPM。 The mixing speed can also be adjusted, whereby the first mixed and then slowly increase RPM mixing device. 可以采用任何混合设备。 Any mixing apparatus can be employed. 在一些实施方式中,混合设备是在磁搅拌机顶部在溶液中的磁搅拌棒(或桨)。 In some embodiments, the mixing apparatus is at the top of a magnetic stirrer in a solution with a magnetic stir bar (or paddle). 其他混合设备包括安装有搅拌轴的机械搅拌器。 Other mixing devices include equipped with a mechanical stirrer shaft. 在一些实施方式中,在5RPM下开始混合并且以每2分钟5rpm的速度提高。 In some embodiments, at 5RPM beginning and every 2 minutes mixing speed of 5rpm improved. 在一些实施方式中,混合步骤的最大RPM是5、10、15、20、25、30、35、40、45、50、60、70、80、90、100、150、200、小于200、小于150、小于100、小于50、小于25。 In some embodiments, the maximum RPM of the mixing step is 5,10,15,20,25,30,35,40,45,50,60,70,80,90,100,150,200, less than 200, less than 150, less than 100, less than 50, less than 25. 在一些实施方式中、混合步骤的rpm是约50至约75、50至75、约40至约100、约50至约100、50至100、40至100等。 In some embodiments, rpm mixing step is from about 50 to about 75, 50 to 75, from about 40 to about 100, from about 50 to about 100, 50 to 100,40 to 100 and so on. 在一些实施方式中混合设备的rpm被提高到100rpm。 In some embodiments the rpm of the mixing apparatus is increased to 100rpm. 在混合步骤的过程中,将混合停止一段时间。 During the mixing step, the mixing is stopped for some time. 在一些实施方式中,停止搅拌约5、约10、约15、约20、约30、约40、约50、约60、约70、约80、约90、少于30、超过30、少于60、超过60、5、10、15、20、30、40、50、60、70、80、90分钟等。 In some embodiments, the stirring is stopped for about 5, about 10, about 15, about 20, about 30, about 40, about 50, about 60, about 70, about 80, about 90, less than 30, more than 30, less than 60, more than 60,5,10,15,20,30,40,50,60,70,80,90 minutes and so on.

在一些实施方式中,将维生素E加入到含有第一表面活性剂和脂肪酸的溶液中。 In some embodiments, the vitamin E is added to a solution of a first surfactant and a fatty acid solution.

本发明所述的搅拌(例如混合)步骤可以持续任何时间段,它彻底混合所述溶液达到所需状态。 Stirring of the present invention (e.g., mixing) step may last any period of time, the solution was thoroughly mixed it reaches the desired state. 可以由本领域技术人员测定所得状态或条件。 The resulting state or condition can be determined by one skilled in the art. 在一些实施方式中,将所述溶液搅拌约5分钟、约10分钟、约15分钟、约20分钟、约30分钟、约40分钟、约50分钟、约60分钟、约1至约2小时、约1至约3小时、约1至约4小时、约1至约5小时、约3至约4小时、约2至约4小时、约6小时、超过2小时、超过3小时、超过4小时、过夜(例如约8至约12小时)等。 In some embodiments, the solution was stirred for about 5 minutes, about 10 minutes, about 15 minutes, about 20 minutes, about 30 minutes, about 40 minutes, about 50 minutes, about 60 minutes, from about 1 to about 2 hours, from about 1 to about 3 hours, from about 1 to about 4 hours, from about 1 to about 5 hours, from about 3 to about 4 hours, from about 2 to about 4 hours, about 6 hours, more than 2 hours, more than three hours, more than 4 hours , overnight (e.g. about 8 to about 12 hours) and the like.

在一些实施方式中,将第一表面活性剂加入到盐水溶液中而制成表面活性剂-盐水溶液。 In some embodiments, the first surfactant is added to the aqueous salt solution made Surfactants - saline solution. 在一些实施方式中,将第二表面活性剂加入到上述溶液中而制成含有两种表面活性剂-盐水溶液的体系。 In some embodiments, the second surfactant is added to the above solution containing a surfactant made of two - System saline solution. 在一些实施方式中,将至少一种ω-6脂肪酸和/或至少一种ω-3脂肪酸加入到两种-表面活性剂-盐水溶液而制成含有至少一种脂肪酸和两种表面活性剂-盐水溶液的溶液。 In some embodiments, at least one ω-6 fatty acids and / or at least one ω-3 fatty acids added to the two kinds of - surfactant - containing saline solution made of at least one fatty acid and two surfactants - solution of brine solution. 在一些实施方式中,将约1滴、约2滴、约3滴、约4滴、约5滴、至少5滴、至少10滴、至少1drop、至少2滴、至少3滴、至少4滴、至少20滴、1滴、2滴、3滴、4滴、5滴、6滴、7滴、8滴、9滴或10滴的维生素E加入到所述脂肪酸-表面活性剂-盐水溶液中。 In some embodiments, about 1 drop, about 2 drops, about 3 drops, about 4 drops, about 5 drops, at least 5 drops, at least 10 drops, at least 1drop, at least 2 drops, at least 3 drops, at least 4 drops, at least 20 drops, 1 drop, 2 drops, 3 drops, 4 drops, 5 drops, 6 drops, 7 drops, 8 drops, 9 drops, or 10 drops of Vitamin E is added to the fatty acid - Surfactant - saline solution. 在一些实施方式中,加入其他抗氧剂以防止脂肪酸的氧化。 In some embodiments, an antioxidant is added to prevent the oxidation of other fatty acids. 其他抗氧剂可以用于代替维生素E液体或者除维生素E液滴以外还加入其它抗氧化剂,从而防止或延迟脂肪酸的氧化。 Other antioxidants may be used in place of or in addition to vitamin E Vitamin E liquid droplets also added other antioxidants, to prevent or delay the oxidation of fatty acids.

现在参照下列实施例对本发明进行说明。 Referring now to the following examples of the present invention will be described. 这些实施例仅仅出于举例说明的目的而被提供,并且本发明不应受这些实施例的限定,但应包括根据本文中的教导变得显而易见的任何和所有变化方案。 These examples are merely for purposes of illustration and is provided, and the present invention should not be limited by these embodiments, but should include become apparent according to the teachings herein, any and all variations.

实施例实施例1:干眼动物模型:可以通过连续暴露在下述控制环境隔室(CEC)中的干燥环境中来诱发正常健康小鼠患上干眼。 Examples Example 1: Dry Eye Animal Model: The following control can continuously exposed to the environment through the compartment (CEC) in a dry environment to induce normal healthy mice suffering from dry eye. 使CEC中的小鼠在试验的整个过程中持续暴露在相对湿度小于30%(平均和标准偏差19%4%)、高气流(15升/分钟)和恒定温度(21-23摄氏度)下。 Mice in CEC makes the entire process in continuous exposure tests relative humidity less than 30% (mean and standard deviation 19% 4%), high airflow (15 l / min) and constant temperature (21-23 C) under . 将正常笼内的小鼠暴露在约70%的相对湿度(平均和SD 78%5%)、无气流和相同的温度下。 The cage of mice were exposed to normal at about 70% relative humidity (mean and SD 78% 5%), no air flow and the same temperature. 此外,置于CEC内的小鼠也用东莨菪碱处理,这种碱是一种药理学上抑制眼泪分泌的活性剂。 In addition, mice were placed within the CEC also treated with scopolamine, which inhibit the secretion of tears in the base is a pharmacologically active agent. CEC和东莨菪碱导致严重的干眼。 CEC and scopolamine cause severe dry eye.

缓释透皮东莨菪碱贴剂(scop贴)得自Novartis(Summit,NJ)。 Sustained-release transdermal scopolamine patch (scop paste) from Novartis (Summit, NJ). 每48小时将贴剂的四分之一涂覆在小鼠的脱毛中尾部。 Fourth coating every 48 hours in the tail of the patch epilation mice.

控制的环境隔室:营造了CEC,允许调节气流和湿度并且控制温度。 Controlled environment compartments: create a CEC, allows adjustment of airflow and humidity and temperature control. 隔室由改造过的能够使用干燥剂的笼子(Lab Products Inc.,Seaford,DE)组成。 Compartment can be used by the transformation of the desiccant cages (Lab Products Inc., Seaford, DE) components. 我们改造的笼子的可利用地面是725cm2。 We can take advantage of the transformation of the cage floor is 725cm2. 笼子的顶部用隔离材料密封,从而使该隔室独立于其所放置的室内的湿度。 The top of the cage with the separator material of the sealing, so that the compartment is independent of its placement of the indoor humidity. 顶部开孔允许空气从CEC向外流动。 Top openings allow air to flow outward from the CEC. 将不锈钢屏障体系放置在隔室内从而在放置干燥剂时不会出现与小鼠接触的危险性。 Stainless steel barrier system will be placed in the compartment so that when the mouse is placed in contact with the desiccant does not appear dangerous. 对于干燥剂,是指硅胶,包装在直径114mm的筒内(Cole-Parmer Instrument Company,Vernon Hills,IL),并且指示燥石膏(无水CaSO4;WAHammond Drierite Co.,Xenia,OH),这两者均常用于除去环境中的水分,并且对于人体和动物无毒。 For desiccant, means silica gel, packed in the cylinder diameter 114mm (Cole-Parmer Instrument Company, Vernon Hills, IL), and indicating Drierite (anhydrous CaSO4; WAHammond Drierite Co., Xenia, OH), both of are commonly used to remove moisture in the environment, and non-toxic for humans and animals. CEC与空气管道接触并且记录温度和湿度。 CEC in contact with the air duct and recording temperature and humidity. 将小型低噪(38dB)无油线性泵(38升/分钟开管流动,26瓦特;Gast Manufacturing Inc.,Benton Harbor,MI)置于离隔室1m处用作空气来源。 The (open tube 38 l / min flow, 26 watts; Gast Manufacturing Inc., Benton Harbor, MI) small low-noise (38dB) Oil-free linear pump placed at 1m from the compartment as an air source. 通过流量计调节气流(0-50l/min,精度5%)并且将阀门置于空气管上。 By adjusting the air flow meter (0-50l / min, accuracy 5%) and the valve placed on the air tube. 将空气经4个位于两个相反侧壁上的尖端(直径1mm)泵入隔室,从而获得一种层状空气流,并且避免湍流。 The air through 4 located on the two opposite side walls of the tip (diameter 1mm) was pumped into the compartment, whereby a laminar flow of air, and avoid turbulence. 选择尖端的高度(一侧为3.5和4.5cm,另一侧为3和4cm)使其对应于小鼠眼睛的高度。 Select tip height (side 3.5 and 4.5cm, and the other side for 3 4cm) to correspond to the height of the eyes of mice. 可以用阀门调节泵入隔室的空气湿度,它可以直接进入到水分离器(SMC Corporation,Tokyo,Japan)的干燥剂体系中,并且空气干燥柱含有燥石膏。 Can be pumped into the valve adjustment compartment air humidity, it can go directly to a water separator (SMC Corporation, Tokyo, Japan) desiccant systems, and air drying columns containing Drierite. 在CEC中,温度(范围是5-45℃,精度1℃),和湿度(0-100%,精度2%)始终由探针监测,用温度湿度记录仪记录在圆形图表中(Supco,Allenwood,NJ)。 In CEC, the temperature (range 5-45 ℃, accuracy 1 ℃), and humidity (0-100%, accuracy 2%) is always monitored by the probe, with temperature and humidity loggers record in circular chart ( Supco, Allenwood, NJ).

干眼征兆的眼表面试验:干眼的征兆通过进行下列来评估:a)测量泪水产生的棉线试验,在患有DES的患者中一般减少;和b)角膜荧光素染色,它是角膜表面损伤的一个标记物,并且在患有DES的患者中一般增多。 Ocular surface signs of dry eye test: dry eye signs evaluated by the following: cotton test a) measuring the tears produced in patients with DES in the general reduction; and b) corneal fluorescein staining, it is the corneal surface damage a marker, and in patients with DES in general increased.

棉线试验:用棉线试验测定眼泪的产生,将棉线浸渍在酚红中(Zone-Quick,Lacrimedics,Eastsound,WA)。 Cotton test: test measures tears with cotton production, the cotton soaked in phenol red in (Zone-Quick, Lacrimedics, Eastsound, WA). 这个试验在小鼠中的有效性如上所述。 The effectiveness of the test in mice described above. 在放大的荧光灯下,用珠宝钳夹住棉线并且置于右眼结膜穹隆的外眦达60秒。 Under fluorescent amplification, jewelry clamp to live with cotton and placed in the right eye conjunctival fornix outer canthus up to 60 seconds. 在显微镜(Zeiss S4,West Germany)下眼泪的距离以mm利用血小板计数规模读取。 Microscope (Zeiss S4, West Germany) under the tear distance in mm utilizing platelet count scale reading. 测定三组小鼠的眼泪分泌(图1)。 Tear secretion was measured three groups of mice (Fig. 1). 在用CEC单独处理6天的小鼠中,在第3天和第6天眼泪分泌与基线(第0天)相比明显减少(图1)。 In six days of treatment in mice with CEC alone, compared to the 3rd and 6th day of tears secretion baseline (day 0) was significantly reduced (Figure 1). 将第二族小鼠用Scop贴剂单独处理6天(图1)并且第三组同时用CEC和Scop贴剂处理6天(图1)。 The Group II mice were treated with Scop patch alone six days (FIG. 1) and a third group treated simultaneously with CEC and Scop patch 6 days (Figure 1). 在第二和第三组的小鼠中,眼泪分泌与基线相比在第3和第6天都明显减少,这种效应比单独隔室处理更加严重并且在整个试验期间持续。 In the second and third groups of mice, tear secretion were significantly reduced compared with baseline at 3 and 6 days, this effect is more serious than a separate compartment treatment and continued throughout the test period.

角膜荧光素染色:角膜荧光素染色通过用微量吸移管将1.0μl的5%荧光素涂覆在眼睛的下结膜囊内。 Corneal fluorescein staining: corneal fluorescein staining by micro pipette 5% fluorescein coated 1.0μl in under the conjunctiva of the eye. 用裂隙灯生物显微镜和钴蓝灯在将角膜注入荧光素后3分钟对其进行检验。 With a slit lamp biomicroscopy and cobalt blue light in the cornea after fluorescein injection three minutes to check this. 在已经划分的角膜表面中的5个区域的每个区域内利用标准化国立眼科协会(NEI)的0-3的等级体系以隐蔽方式记录点染色(图2)。 Within each region has been divided in five corneal surface area using standardized National Eye Institute (NEI) of the hierarchy 0-3 record points to covert manner staining (Figure 2). 如图3所示,单独的隔室或单独的东莨菪碱处理与对照相比,在第3天和第6天使角膜荧光素染色明显增加。 As shown in Figure 3, a separate compartment or separate scopolamine treatment compared with the control, in the first three days and six angels corneal fluorescein staining was significantly increased. 然而,在各个时间点东莨菪碱和隔室染色的组合效果增加得最明显。 However, the combined effect at various points in time scopolamine and compartments stained increase was most pronounced.

这个模型在正常小鼠内重现了临床干眼。 The model in the normal mice reproduce clinical dry eye.

实施例2:制剂制剂3含有1%EPA+DHA和1%GLA,而制剂1含有0.1%的脂肪酸。 Example 2: Formulation Formulation 3 comprises 1% EPA + DHA and 1% GLA, whereas Formulation 1 containing 0.1% fatty acid. 制剂2和4含有4∶1的ω-3与ω-6。 Formulation 2 and 4 containing 4 to 1 ω-3 and ω-6. 所述制剂含有矿物油作为载体并且加入维生素E作为抗氧剂。 The formulations containing mineral oil as the carrier and adding vitamin E as an antioxidant. 将脂肪酸储存在黑暗中以进一步降低氧化的危险性。 Fatty acid stored in the dark in order to further reduce the risk of oxidation. 所述制剂公开在表3中。 The formulation disclosed in Table 3 below.

表3:脂肪酸制剂 Table 3: Fatty Acid Formulation

EPA∶DHA在所用制剂中的比例是1∶1。 EPA:DHA ratio used in the formulation is 1:1. EPA的分子量:302.5;DHA的分子量:328.6;GLA的分子量是:278.4实施例3:活性剂研究设计该研究是前瞻性掩蔽试验。 The molecular weight of EPA: 302.5; molecular weight of DHA: 328.6; the molecular weight is GLA: 278.4 Example 3: Active Agent Study Design The study was a prospective masked trial. 使各小鼠的一只眼睛随机接受载体(阴性对照),或一种制剂。 So that one eye of each mouse was randomized to receive either vehicle (negative control), or a formulation. 以掩蔽方式施用活性剂。 To mask the active agent administered. 在一只眼睛中施用5μl滴,每天2次,给药的间隔是12小时。 Administered 5μl drop in one eye, twice a day dosing interval is 12 hours.

由组合的环境和药理学作用(将小鼠置于CEC中并且涂覆东莨菪碱贴剂6天)诱发干眼。 By a combination of environmental and pharmacological effects of (the mice were placed in the CEC and coated with scopolamine patch 6 days) induced dry eye. 存在两个主要的活性试验组。 There are two principal active test group. 处理组:在暴露CEC+Scop贴剂48小时后滴注滴眼剂至第6天。 Treatment groups: exposure CEC + Scop patch 48 hours after instillation of eye drops to 6 days. 从48小时到第6天施用活性剂。 From 48 hours to 6 days on administration of the active agent. 在第6天结束时在最后一次给药12小时后评估干眼。 In the first six days after the end of the last dose 12 hours evaluation of dry eye. 预防组:从第0天连续到第6天滴注滴眼剂。 Prevention group: from day 0 to the first six days of continuous infusion of eye drops. 在第6天结束时在最后一次给药12小时后评估干眼。 In the first six days after the end of the last dose 12 hours evaluation of dry eye.

统计学分析泪水产生的学生t试验和角膜荧光素染色的Mann-Whitney试验用于对比载体和制剂组制剂的差异。 Statistical analysis Student t test produced tears and corneal fluorescein staining of the Mann-Whitney test is used to compare differences between carriers and agents group preparations. 在组内,通过成对t试验(泪水产生)和Wilcoxon试验(角膜荧光素染色)分析相对于基线的变化。 Within the group, by paired t test (tear production) and Wilcoxon test (corneal fluorescein staining) changes relative to baseline analysis. 所有试验是双尾的,并且p值小于0.05被视为具有统计学意义:结果眼泪试验:用制剂1和制剂2处理。 All tests were two-tailed, and a p-value less than 0.05 was regarded as statistically significant: Results tear test: treated with Formulation 1 and Formulation 2. 图4概括对于4组在第0天、第2天和第6天进行眼泪测量的结果,这些组是没有接受滴眼剂的组、接受载体的组、接受制剂1或制剂2的组。 Figure 4 summarizes the four groups for day 0, 2 days and 6 days were tears measurement result, these groups are not accepted eye drop group, the group receiving vehicle, acceptable formulation 1 or formulation 2 group. 在第0天,所有四组具有正常的眼泪分泌。 On day 0, all four groups had normal tear secretion. 暴露在CEC+Scop贴剂下48小时后,所有四组出现干眼的征兆,也就是,与基线(第0天)相比眼泪的分泌明显减少。 Exposed for 48 hours CEC + Scop patch, all four groups appears dry eye symptom, i.e., the secretion compared to the baseline (day 0) was significantly reduced tears. 此时(48小时),当小鼠连续暴露在CEC+Scop下的同时每12小时给每只眼睛施用5ul的滴眼剂。 At this time (48 hours), when the mice were continuously exposed to CEC + Scop simultaneously under each eye every 12 hours administered to 5ul of eye drops. 在第6天,没有接受滴眼剂的组与基线(第0天)和用载体或制剂1或制剂3处理的组相比,眼泪分泌明显减少。 On day 6, the group did not receive an eye drop with baseline (day 0), and compared with vehicle or formulation 1 or formulation 3 treated group, significantly reduced secretion of tears. 接受载体或制剂的组与48小时(施用活性剂之前的干眼)相比眼泪分泌增加,但眼泪值没有达到基线(第0天)。 Acceptable carrier or formulation group and 48 hours (before the administration of the active agent dry eye) compared tear secretion, but the tear values did not reach the baseline (day 0). 所以在眼泪试验(第二个终点)中,制剂1和2两者有效逆转了干眼中的眼泪分泌减少。 So tear test (second end), the formulation and 2 both an effective reversal of reduced secretion of tears dry eyes.

角膜荧光素染色:用制剂1和2的治疗图5和6概括了没有接受滴眼剂、接受载体、接受制剂1或制剂2的眼睛的角膜荧光素得分。 Corneal fluorescein staining: Treatment with Formulation 1 and 2 of FIG. 5 and 6 did not accept summarized eye drop, received vehicle, accepted eye formulation 1 or formulation 2 of corneal fluorescein scores. 所有组在第0天(相似)相似。 Similar in all groups at day 0 (or similar). 暴露在CEC+Scop贴剂下48小时后,所有组与基线(第0天)相比角膜荧光素染色增加。 Exposed for 48 hours CEC + Scop patch, all groups with baseline (day 0) corneal fluorescein staining as compared to the increase. 从48小时开始滴注滴眼剂并且连续6天,所有组的小鼠持续接触CEC+Scop贴剂。 48 hours from the start of infusion of eye drops and six days in a row, all groups of mice in constant contact CEC + Scop patch.

在第4天和第6天两天,接受载体的组与没有接受滴眼剂的组相比,并且与第2天(图5和6)相比,角膜荧光素染色没有明显减少。 At the 4th and 6th day for two days, the group receiving vehicle compared to the group received no eye drops, and as compared with the first two days (Figures 5 and 6), corneal fluorescein staining not significantly reduced. 在第4天和第6天,载体组中的角膜荧光素染色始终明显高于基线(第0天)。 In the first 4 days and 6 days, the carrier group corneal fluorescein staining is always significantly higher than baseline (day 0).

制剂1组在第4天和第6天与第2天相比并且与接受载体或没有接受滴眼剂的相比,角膜荧光素染色明显降低(图5)。 Preparation of a group compared to the first four days and six days in the first two days and compared with the acceptable carrier or did not receive eye drops, corneal fluorescein staining was significantly reduced (Fig. 5). 此外,接受了制剂1的眼睛中角膜荧光素染色得分在第6天恢复到基线(正常值)。 Furthermore, accepted formulation of the eye corneal fluorescein staining score in the first 6 days returned to baseline (normal).

接受了制剂2的眼睛(图6)在第4天与在第4天的接受载体和没有接受滴眼剂的眼睛相比,角膜荧光素染色明显减少。 Accepted the eye preparations 2 (Fig. 6) in the first four days than in the first four days of the acceptance of the carrier and did not receive eye drops eye, corneal fluorescein staining was significantly reduced. 与第2天(48小时)相比,该组明显减少。 Compared with the first two days (48 hours), which was significantly reduced. 在第6天,荧光素染色得分略微增高,然而制剂2与载体相比仍然降低了(虽然没有统计学意义)染色评分。 On day 6, fluorescein staining scores increased slightly, however formulation 2 still reduced as compared with a carrier (although not statistically significant) staining scores. 在第4天和第6天两天,制剂2组与没有接受滴眼剂的眼睛样本具有明显低的染色得分。 In the 4th and 6th day two days, the formulation 2 group did not receive eye drops and eye samples stained with a significantly lower score.

图7表示用荧光素染色的角膜的代表性图像,证明使用制剂1和2对角膜表面的正常化。 Figure 7 shows Corneal staining with fluorescein representative images, using Formulation 1 proved normalization and two pairs of the corneal surface.

制剂1和2两者在抑制角膜上皮疾病中显著地具有深厚和持久的作用(如通过染色测定)。 Formulation 1 and 2 in the inhibition of both corneal epithelial disease significantly with deep and lasting effects (such as measured by staining). 这种在治疗干眼中的抑制作用比单独的试验载体明显地更加有效。 This clearly more effective in treating dry eye inhibition than single test vector.

角膜荧光素染色:用制剂2的预防。 Corneal fluorescein staining: Prevention with Formulation 2. 图8概括了没有接受滴眼剂、接受载体、接受制剂1的眼睛的角膜荧光素得分。 Figure 8 summarizes the eye drop did not accept, accept carriers, accepted eye formulation of corneal fluorescein scores. 在预防组中,在第0天开始滴注滴眼剂并且持续至第6天。 In the prevention group, the eye drop instillation began on day 0 and continued until day 6. 所有小鼠在这个期间接触CEC+Scop贴剂。 During this period all mice contact CEC + Scop patch. 在第6天,接受载体的组与没有接受滴眼剂的组相比,表现出荧光素染色得分的界限明显减小。 On day 6, compared with the group receiving vehicle is not receiving eye drop group showed a fluorescein score boundaries significantly reduced. 在第6天,制剂2与接受载体和没有接受滴眼剂的组相比,表现出染色得分明显减小。 On day 6, formulation 2 than those who did not receive the carrier and the eye drop group showed a significantly reduced staining score.

所以,制剂1和2使干眼症状减弱。 Therefore, the formulations 1 and 2 so that dry eye symptoms diminish. 制剂1和2证实就初步的角膜染色结果来说,与施用载体相比具有治疗功效。 Formulation 1 and 2 confirm the preliminary results of corneal staining, compared with administration of a carrier having a therapeutic effect.

实施例4:制剂的制备在典型乳液中将溶解的物质Glucam E-20加入到硼酸盐缓冲的盐水中(各组分的%wt:NaCl 0.83;H3BO30.89;Na2B4O710H2O 0.23;EDTA 0.01;H2O 98.04)。 Example 4: Preparation of a typical formulation will be an emulsion in dissolved substances Glucam E-20 was added to the borate buffered saline (each component% wt: NaCl 0.83; H3BO30.89; Na2B4O7 10H2O 0.23; EDTA 0.01 ; H2O 98.04). 将此溶液在室温下搅拌至少30分钟,此后溶液变均匀。 The solution was stirred for at least 30 minutes at room temperature, after which the solution became homogeneous. 开始搅拌并且以每2分钟提高5rpm的间隔时间直至达到100rpm。 Stirring was started and every two minutes improved 5rpm intervals until 100rpm. 搅拌叶应当是桨叶形的,从而在搅拌过程中达到高剪切搅拌。 Stirring blade should be paddle shaped, so as to achieve high shear agitation in the mixing process. 将该溶液在100rpm下搅拌至少30分钟后得到澄清溶液。 To give a clear solution and the solution was stirred at 100rpm at least 30 minutes.

将该澄清溶液放置且不搅拌10分钟,此时加入吐温80。 The clear solution was left without stirring for 10 minutes, at which time Tween 80. 首先出现不溶的物质并且包裹在搅拌轴四周,但加入吐温后重新开始搅拌并且利用与Glucam-E相同的搅拌方法在室温下溶解吐温80。 First appeared insoluble material and wrapped around the stirring shaft, but resumed stirring and after the addition of Tween and Glucam-E use the same method of dissolving Tween 80 was stirred at room temperature.

在50-75rpm之间搅拌该溶液,将脂肪酸在1小时内缓慢加入,此后该反应可表现为乳白色。 The solution was stirred between 50-75rpm, the fatty acid was slowly added over 1 hour, after which the reaction can be expressed as a cream. 此后在1小时内在50-75rpm的持续搅拌下加入所述的脂肪酸。 Subsequent addition of the fatty acids in the one hour of continuous stirring inherent 50-75rpm. 此时如果采用高浓度的脂肪酸,该反应表现为白色。 In this case if a high concentration of fatty acid, the reaction performance of white. 低浓度溶液产生微乳液并且看似透明。 Low concentration of the solution and produce seemingly transparent microemulsion. 此后搅拌该溶液并且加入1滴维生素E,将该反应在已经达到的剪切速度如75rpm下持续搅拌3-4小时。 Thereafter the solution was stirred and 1 drop of vitamin E, the reaction has reached the stirring was continued at a shear rate of 75rpm as 3-4 hours.

本文引入的各个专利、专利申请和文献的内容在此全文引入作为参考。 Each is incorporated by the content of the patent application and are hereby incorporated by reference.

虽然本发明参考具体实施方式进行说明,显然本领域其他技术人员在不脱离本发明的实质和范围下可以设计其他实施方式和本发明的变化方案。 While the present invention will be described with reference to specific embodiments, it is clear that others skilled person without departing from the spirit and scope of the present invention may be designed under the other embodiments and variations of the present invention. 所附权利要求数用于解释包括所有此类实施方式和等同方案。 Number of the appended claims serve to explain the embodiments and includes all such equivalents.

Referenced by
Citing PatentFiling datePublication dateApplicantTitle
CN104994911A *5 Sep 201321 Oct 2015尊贵科学有限公司Cosmetic compositions comprising epa and gla and methods of making and using same
Classifications
International ClassificationA61K31/19
Cooperative ClassificationA61K31/202, A61K9/107, A61K9/0048
European ClassificationA61K31/202, A61K9/00M16
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