CN1114401C - 11－(3－二甲氨基亚丙基)－6,11－二氢二苯并[b,e]噁庚英－2－乙酸用于制药的新用途 - Google Patents
11－(3－二甲氨基亚丙基)－6,11－二氢二苯并[b,e]噁庚英－2－乙酸用于制药的新用途 Download PDFInfo
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- A61K31/00—Medicinal preparations containing organic active ingredients
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- A—HUMAN NECESSITIES
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- A61P27/02—Ophthalmic agents
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- A—HUMAN NECESSITIES
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- A61P27/00—Drugs for disorders of the senses
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- Pain & Pain Management (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pyrane Compounds (AREA)
- Medicinal Preparation (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
含11-(3-二甲氨基亚丙基)-6，11-二氢二苯并[b，e]噁庚英-2-乙酸或其药用盐作活性成分的眼用制剂用于抑制细胞因子(如IL-6和IL-8)从人眼细胞中释放。该制剂用于治疗或预防眼部新血管生成和非过敏性炎性症状如干眼，角膜炎，睑炎，眼炎素层类和与感染有关的炎症。
Description
本发明涉及眼科用药物制剂。更具体讲，本发明涉及11-(3-二甲氨基亚丙基)-6，11-二氢二苯并[b，e]噁庚英-2-乙酸用于治疗和/或预防人体眼细胞的细胞因子释放以及形成新血管或非过敏性炎症疾病的治疗和预防用途。
美国专利US4,871,865和4,923,892，两者已转让给BurroughsWellcome公司(“Burroughs Wellcome专利”)，谈到一些多塞平(Doxepin)的羧酸衍生物，包括11-(3-二甲氨基亚丙基)-6，11-二氢二苯并[b，e]噁庚英-2-甲酸和11-(3-二甲氨基亚丙基)-6，11-二氢二苯并[b，e]噁庚英-2-(E)-丙烯酸具有抗组胺和止喘活性。这两个专利基于抗组胺作用，将多塞平羧酸衍生物分类为肥大细胞稳定剂，因为它们能抑制来自肥大细胞的自体有效物质(组胺，5-羟色胺等)的释放，以及直接抑制组胺对靶组织的效应。Burroughs Wellcome专利谈到了含有多塞平羧酸衍生物的不同药物制剂。在两个专利中的实施例8(I)中，透露了一个眼科用的溶液制剂。
转让给Kyowa Hakko Kogyo有限公司的美国专利US5,116,863(“Kyowa专利”)谈到多塞平的乙酸衍生物，其中包括Z-11-(3-二甲氨基亚丙基)-6，11-二氢二苯并[b，e]噁庚英-2-乙酸，具有抗过敏和抗炎活性。抗炎活性可归因于前列腺素生物合成的抑制作用(见栏28，51-57行)。Kyowa专利透露的多塞平衍生物用化合物I代表：
其中X表示＝N-，＝CH-或-CH2-的化合物被描述为具有强的抗过敏活性，而X代表＝N-的化合物被描述为具有强的抗炎活性(见栏24，20-57行)。于是，为了抗炎应用，Kyowa专利提出了化合物(I)的多塞平衍生物，其X为＝N-。
Kyowa专利显示出在Wistar雄性大鼠体上的抗过敏和抗炎活性。对于多塞平乙酸衍生物，从Kyowa专利中谈到的药物剂型包括广泛的药用载体；可是，仅仅供口服和注射给药的剂型被叙述到。在过敏性眼疾的治疗中，例如过敏性结膜炎，这样的给药方法要求大剂量的药物。
美国专利US5,641,805透露了眼科局部用药制剂，其含有11-(3-二甲氨基亚丙基-6，11-二氢二苯并[b，e]噁庚英-2-乙酸，用来治疗过敏性眼疾。
本发明提供了治疗和预防眼部新血管生成以及非过敏性炎症疾病，包括细胞因子从人眼细胞中释放的方法，该方法包括通过给予眼部含治疗有效剂量的11-(3-二甲氨基亚丙基)-6，11-二氢二苯并[b，e]噁庚英-2-乙酸(下文中称作“化合物A”)及其药用盐的眼用制剂来抑制人眼细胞中的细胞因子释放。该制剂可以含有化合物A(Z-11-(3-二甲氨基亚丙基)-6，11-二氢二苯并[b，e]噁庚英-2-乙酸)的顺式异构体，化合物A(E-11-(3-二甲氨基亚丙基)-6，11-二氢二苯并[b，e]噁庚英-2-乙酸)的反式异构体，或化合物A的顺式和反式异构体两者的混合物。除非在其它特定情况下，“11-(3-二甲氨基亚丙基)-6，11-二氢二苯并[b，e]噁庚英-2-乙酸”或“化合物A”意谓着顺式异构体，反式异构体或是两者的混合物。“顺式异构体”意谓着实质上不含反式异构体的顺式异构体；“反式异构体”意谓着实质上不含顺式异构体的反式异构体。此处所指的一种异构体实质上不含有其它异构体，假如所存在的不需要的异构体量少于大约2％。
化合物A是已知化合物，且化合物A的顺式和反式两者能通过美国专利US5,116,863披露的方法制得，其整个内容在此插入作为参考文献。
化合物A药用盐的实例，包括无机酸盐，如盐酸盐，溴氢酸盐，硫酸盐和磷酸盐；有机酸盐，如乙酸盐，马来酸盐，富马酸盐，酒石酸盐和柠檬酸盐；碱金属盐，如钠盐和钾盐；碱土金属盐，如镁盐和钙盐；金属盐，如铝盐和锌盐；以及有机胺加成盐，如三乙胺加成盐(已知的氨基丁三醇)，吗啉加成盐和哌啶加成盐。
化合物A可以多种多样方式给药于眼部。最可取的方式是采用常规的眼局部制剂，如溶液，悬浮液或凝胶。或者，化合物A可以经过注射或埋入给药。根据制剂的类型，常规的组分将与化合物A结合起来。化合物A优选的眼局部用制剂是滴眼剂溶液。在眼用制剂中，本发明化合物A优选的形式是顺式。本发明滴眼剂的制备通法，作为非限定的实施例被叙述于后。
化合物A和等渗剂被加到经过灭菌的纯水中，而且若有需要，防腐剂，缓冲剂，稳定剂，粘性赋形剂等被加到溶液中，并溶于其中。化合物A的浓度为0.0001-5w/v％，优选为0.0001-0.001w/v％，最优选约为0.0005w/v％，基于灭菌的纯水。在溶解后，用pH调节剂调节pH值到适用作眼用药物的范围内，优选pH4.5-8的范围。
氯化钠，甘油，甘露糖醇等可被用作为等渗剂；对羟基苯甲酸酯，氯化苄烷铵等作为防腐剂；磷酸氢钠，磷酸二氢钠，硼酸等作为缓冲剂；依地酸钠盐等作为稳定剂；聚乙烯醇，聚乙烯吡咯烷酮(PVP)，聚丙烯酸等作为粘性赋形剂；还有氢氧化钠，盐酸等作为pH调节剂。
假如有需要，可以加入其它眼科药物，如肾上腺素，萘甲唑林盐酸盐，盐酸黄连素，奥磺酸钠，盐酸溶菌酶，甘草酸盐等。
通过上述方法生产的滴眼剂，仅仅被典型地应用于眼睛。每日几次，用量为一至数滴，尽管在更严重的情况下，可使用滴剂，每天多次。典型的一滴为30微升。
按照本发明的方法，含有化合物A的眼科制剂，被用来抑制原炎性的细胞因子从人体眼细胞(例如人体结膜上皮细胞)分泌出来。这种类型的细胞因子分泌(例如，IL-6和IL-8)能刺激眼部新血管形成(例如，见于Yoshida et al.，IOVS，39：1097(1998))以及其它非过敏性炎症的疾病，如干眼，角膜炎，睑炎，眼色素层炎和与感染有关的炎症。
本发明一些实施方案被叙述于以下实施例中。
实施例1：优选的局部眼用的溶液制剂
组分 浓度(w/v％)
化合物A盐酸盐 0.111*
磷酸氢二钠(无水)，USP 0.5
氯化钠，USP 0.65
氯化苄烷铵 0.01
氢氧化钠，NF q.s.pH＝7.0
盐酸，NF q.s.pH＝7.0
纯水 q.s.100*0.111％化合物A盐酸盐相当于0.1％化合物A。
实施例2：眼科局部使用的凝胶制剂
组分 浓度(w/v％)
化合物A盐酸盐 0.11*
974P 0.8
EDTA二钠 0.01
吐温80 0.05
氯化苄烷铵，溶液 0.01+5xs
氢氧化钠 q.s.pH7.2
盐酸 q.s.pH7.2
*0.11％化合物A盐酸盐相当于0.1％化合物A。
实施例3：细胞因子释放的抑制作用A·人结膜上皮细胞(HCE)培养
详述原始上皮细胞培养物的制备方法，以及利用这些细胞作细胞因子释放的研究已被描述。参见Gamache et al.，“原炎性细胞素通过人结膜上皮细胞的分泌”Ocul.Immunol.Inflamm.，5：117-128(1997)。简言之，人结膜上皮细胞的培养物是通过各种眼库从在尸体解剖8小时内得到的供体组织引入的。该组织经酶消化过夜。上皮细胞和缓地从组织表面刮去，解离进入单一的细胞悬浮液中，并在角质化细胞生长培养基(Clonetics注册商标，圣迭戈，加州)中培养。所用细胞只是经过通道6。培养维持在预先的汇合状态，以防止分化。细胞经过阳性角蛋白染色法被鉴定为上皮细胞。B·细胞因子分析
几种具有组胺H1-拮抗活性的化合物在对组胺刺激的反应中，评价其抑制细胞因子(IL-6和IL-8)从培养的人结膜上皮细胞的分泌的能力。细胞被置于平皿(2×104个细胞/孔)，并在5％CO2 37℃下培养过夜。次日，将含有被测试化合物的新鲜培养基直接加到孔内，并且在用组胺(30μM)24小时刺激之前，将细胞孵育30分钟。三个单个的培养孔用于每个治疗组。在实验结束时，收集上清液，在200xg时离心，在-20℃下保存。样品通过该说明书的酶标记免疫测定法(ELISA，研究和发展系统，明尼阿波利斯，明尼苏达州)分析IL-6和IL-8，每个ELISA的灵敏度如下：IL-6 0.7pg/ml；IL-8 3.0pg/ml。C·数据分析
拮抗剂强度(IC50)定义为对激动剂刺激功能性反应产生50％抑制时所需的药物浓度。从细胞得来的数据以平均标准误(SEM)的值作计算，该值代表了经过同样处理的培养孔之间的有变性。药剂的剂量依赖效应和IC50值通过线性回归测定，数据取平均值±SEM，来自3-5个独立的实验。D·结果
人结膜上皮细胞(HCE)暴露于30μM组胺，增加了IL-6和IL-8的分泌，其量分别为1.59±0.19和1.80±0.28倍于基线水平。(细胞因子的基线水平是153±42pg/ml，n＝4(IL-6)；197±48pg/ml，n＝6(IL-8)。
用具有抗组胺活性，并且可用于眼局部给药(先于组胺暴露)的药物治疗HCE，导致IL-6和IL-8分泌浓度依赖的抑制作用。结果见如下表1所示。
依美斯汀在完整细胞中的强度，与应用组织匀浆在受体结合分析中所测得的活性是一致的。左卡巴斯汀也能在与H1-受体结合亲和力一致的水平上抑制IL-6和IL-8的分泌。安他心和抗感明(两个第一代的眼科局部使用的抗组胺化合物)作为IL-6和IL-8分泌的抑制剂，比起所预测的它们的与组胺H1-受体结合的亲和力来(20-140倍)讲，强度大大地减低。然而，奥洛派他定比上预测的，已被公布的组胺H1-受体结合亲和力(36nM)要强。奥洛派他定、安他心和抗感明显示出相似的H1-受体结合亲和力(32-39nM)。，到目前为止，奥洛派他定作为细胞因子分泌抑制剂，大体上要比由结合分析预测的数据强10倍，IC50分别为5.5nM(IL-6分泌)和1.7nM(IL-8分泌)。这些数据指出，并不象其它被测定的化合物那样，奥洛派他定抑制细胞因子分泌的能力，可以归因于比H1-受体结合亲和力更多的一些方面。表1：组胺H1拮抗剂：人结膜上皮细胞中IL-6和IL-8分泌的抑制作
用以及H1受体结合亲和力H1拮抗剂 IL-6 IL-8 H1结合
IC50(nM) IC50(nM) Ki(nM)依美斯汀a 2.5 4.0 1.22*奥洛派他定b 5.5 1.7 36.0**左卡巴斯汀c 25.1 11.9 52.6*安他心d 1014 652 38.4*抗感明e 4826 1216 33.9*
a 1H-苯并咪唑，1-(2-乙氧基乙基)-2-(六氢-4-甲基-1H-1，4-二氮杂卓-1-基)，
(E)-2-丁烯二酸酯(1∶2).
b Z-11-(3-二甲氨基亚丙基)-6，11-二氢二苯并[b，e]噁庚英-2-乙酸.
c (-)-反-1-[顺-4-氰基-4-(对-氟苯基)环己基]-3-甲基-4-苯基异-3-哌啶甲酸单
盐酸盐.
d 4，5-二氢-N-苯基-N-(苯甲基)-1H-咪唑-2-甲胺.
e N，N-二甲基-γ-苯基-2-吡啶-丙胺.
* Sharif et al.，J.Ocul.Pharmacol.，10：653-664(1994).
** Yanni et al.，Ann.Allergy Asthma Immunol.，79：541-545(1997).
Claims (14)
1.11-(3-二甲氨基亚丙基)-6，11-二氢二苯并[b，e]噁庚英-2-乙酸或其药用盐的组合物在制备治疗或预防包括细胞因子从人眼细胞释放的眼部新血管生成和非过敏性眼部炎症的药中的应用。
2.权利要求1的应用，其中组合物是局部给药的溶液，而且11-(3-二甲氨基亚丙基)-6，11-二氢二苯并[b，e]噁庚英-2-乙酸的量大约为0.0001％(w/v)至大约5％(w/v)。
3.权利要求2的应用，其中11-(3-二甲氨基亚丙基)-6，11-二氢二苯并[b，e]噁庚英-2-乙酸的量大约为0.0001％(w/v)至大约0.001％(w/v)。
4.权利要求3的应用，其中11-(3-二甲氨基亚丙基)-6，11-二氢二苯并[b，e]噁庚英-2-乙酸的量大约为0.0005％(w/v)。
5.权利要求1的应用，其中11-(3-二甲氨基亚丙基)-6，11-二氢二苯并[b，e]噁庚英-2-乙酸是(Z)-11-(3-二甲氨基亚丙基)-6，11-二氢二苯并[b，e]噁庚英-2-乙酸，实质上不含(E)-11-(3-二甲氨基亚丙基)-6，11-二氢二苯并[b，e]噁庚英-2-乙酸。
6.权利要求5的应用，其中组合物是局部给药的溶液，而且(Z)-11-(3-二甲氨基亚丙基)-6，11-二氢二苯并[b，e]噁庚英-2-乙酸的量大约为0.0001％(w/v)至大约5％(w/v)。
7.权利要求6的应用，其中(Z)-11-(3-二甲氨基亚丙基)-6，11-二氢二苯并[b，e]噁庚英-2-乙酸的量大约为0.0001％(w/v)至大约0.001％(w/v)。
8.权利要求7的应用，其中(Z)-11-(3-二甲氨基亚丙基)-6，11-二氢二苯并[b，e]噁庚英-2-乙酸的量大约为0.0005％(w/v)。
9.权利要求1的应用，其中11-(3-二甲氨基亚丙基)-6，11-二氢二苯并[b，e]噁庚英-2-乙酸是(E)-11-(3-二甲氨基亚丙基)-6，11-二氢二苯并[b，e]噁庚英-2-乙酸，实质上不含(Z)-11-(3-二甲氨基亚丙基)-6，11-二氢二苯并[b，e]噁庚英-2-乙酸。
10.权利要求9的应用，其中组合物是局部给药的组合物，而且(E)-11-(3-二甲氨基亚丙基)-6，11-二氢二苯并[b，e]噁庚英-2-乙酸的量大约为0.0001％(w/v)至大约5％(w/v)。
11.权利要求10的应用，其中(E)-11-(3-二甲氨基亚丙基)-6，11-二氢二苯并[b，e]噁庚英-2-乙酸的量大约为0.0001％(w/v)至大约0.001％(w/v)。
12.权利要求11的应用，其中(E)-11-(3-二甲氨基亚丙基)-6，11-二氢二苯并[b，e]噁庚英-2-乙酸的量大约为0.0005％(w/v)。
13.权利要求1的应用，其中非过敏性眼部炎症选自干眼、角膜炎、睑炎、眼色素层炎、以及和感染有关的炎症。
14.权利要求1的应用，其中眼部新血管生成和非过敏性眼部炎症包括人结膜上皮细胞的细胞因子释放。
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| CA2609053C (en) | 2005-05-17 | 2017-04-25 | Sarcode Corporation | Compositions and methods for treatment of eye disorders |
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| US5641805A (en) * | 1995-06-06 | 1997-06-24 | Alcon Laboratories, Inc. | Topical ophthalmic formulations for treating allergic eye diseases |
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| JPS6310784A (ja) * | 1986-03-03 | 1988-01-18 | Kyowa Hakko Kogyo Co Ltd | 抗アレルギー剤 |
| JPH02138215A (ja) * | 1988-08-05 | 1990-05-28 | Dai Ichi Seiyaku Co Ltd | 抗アレルギー・抗炎症剤 |
| IE920499A1 (en) * | 1991-02-21 | 1992-08-26 | Merck Frosst Canada Inc | Quinoline-containing ketoacids as leukotriene antagonists |
| ZA924953B (en) * | 1991-07-25 | 1993-04-28 | Univ Louisville Res Found | Method of treating ocular inflammation |
| JP3453152B2 (ja) * | 1992-04-06 | 2003-10-06 | 格 冨山 | 抗炎症点眼剤 |
| FR2701948B1 (fr) * | 1993-02-22 | 1996-07-26 | Exsymol Sa | Produit de couplage de l'histamine ou l'histamine méthyl-substituée et d'un acide aminé, procédé de préparation et applications thérapeutiques, cosmétologiques et agroalimentaires. |
| CA2159091C (en) * | 1993-03-26 | 2006-12-19 | Richard J. Sharpe | Topical and systemic application of buspirone or derivatives thereof for treatment of pathological conditions associated with immune responses |
| FR2711990B1 (fr) * | 1993-11-05 | 1995-12-08 | Exsymol Sa | Produit pseudodipeptide possédant un groupement imidazole, et applications thérapeutiques, cosmétologiques et agroalimentaires. |
| JP2852607B2 (ja) * | 1994-06-10 | 1999-02-03 | 雪印乳業株式会社 | ドライアイ治療剤 |
| JPH1067684A (ja) * | 1996-06-17 | 1998-03-10 | Mitsubishi Chem Corp | 涙液分泌促進剤 |
| JP2002514194A (ja) * | 1996-11-19 | 2002-05-14 | ザ スキーペンズ アイ リサーチ インスティテュート インコーポレイテッド | 角膜移植拒否又は眼疾におけるｉｌ―１ｒａの局所使用 |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5641805A (en) * | 1995-06-06 | 1997-06-24 | Alcon Laboratories, Inc. | Topical ophthalmic formulations for treating allergic eye diseases |
Also Published As
| Publication number | Publication date |
|---|---|
| JP2002520355A (ja) | 2002-07-09 |
| DK1037627T3 (da) | 2001-10-01 |
| CA2306393A1 (en) | 2000-01-27 |
| BR9906772A (pt) | 2000-09-26 |
| ATE203668T1 (de) | 2001-08-15 |
| DE69900207T2 (de) | 2001-11-22 |
| GR3036422T3 (en) | 2001-11-30 |
| AU742237B2 (en) | 2001-12-20 |
| KR100598723B1 (ko) | 2006-07-11 |
| CA2306393C (en) | 2008-12-23 |
| EP1037627B1 (en) | 2001-08-01 |
| EP1037627A1 (en) | 2000-09-27 |
| PT1037627E (pt) | 2001-11-30 |
| DE69900207D1 (de) | 2001-09-06 |
| CN1275078A (zh) | 2000-11-29 |
| AU4563499A (en) | 2000-02-07 |
| TW561046B (en) | 2003-11-11 |
| ES2159209T3 (es) | 2001-09-16 |
| KR20010024508A (ko) | 2001-03-26 |
| AR019916A1 (es) | 2002-03-27 |
| WO2000003705A1 (en) | 2000-01-27 |
| HK1030362A1 (en) | 2001-05-04 |
| ZA200001593B (en) | 2000-10-25 |
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