CN1111403C - 继发性白内障抑制剂 - Google Patents
继发性白内障抑制剂 Download PDFInfo
- Publication number
- CN1111403C CN1111403C CN97198769A CN97198769A CN1111403C CN 1111403 C CN1111403 C CN 1111403C CN 97198769 A CN97198769 A CN 97198769A CN 97198769 A CN97198769 A CN 97198769A CN 1111403 C CN1111403 C CN 1111403C
- Authority
- CN
- China
- Prior art keywords
- aftercataract
- tranilast
- inhibitor
- cell
- pharmaceutically acceptable
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
- 208000002177 Cataract Diseases 0.000 title abstract description 17
- 239000003112 inhibitor Substances 0.000 title abstract description 12
- 208000008516 Capsule Opacification Diseases 0.000 title description 8
- 206010036346 Posterior capsule opacification Diseases 0.000 claims abstract description 20
- 150000003839 salts Chemical class 0.000 claims abstract description 19
- RWZYAGGXGHYGMB-UHFFFAOYSA-N anthranilic acid Chemical compound NC1=CC=CC=C1C(O)=O RWZYAGGXGHYGMB-UHFFFAOYSA-N 0.000 claims abstract description 14
- 239000008194 pharmaceutical composition Substances 0.000 claims description 10
- 150000001875 compounds Chemical class 0.000 abstract description 5
- 210000001940 cystoblast Anatomy 0.000 abstract description 5
- 230000002401 inhibitory effect Effects 0.000 abstract description 5
- 230000002265 prevention Effects 0.000 abstract description 3
- NZHGWWWHIYHZNX-CSKARUKUSA-N tranilast Chemical compound C1=C(OC)C(OC)=CC=C1\C=C\C(=O)NC1=CC=CC=C1C(O)=O NZHGWWWHIYHZNX-CSKARUKUSA-N 0.000 description 20
- 229960005342 tranilast Drugs 0.000 description 20
- 210000001542 lens epithelial cell Anatomy 0.000 description 13
- 210000000695 crystalline len Anatomy 0.000 description 12
- 210000004027 cell Anatomy 0.000 description 11
- 239000001963 growth medium Substances 0.000 description 8
- 239000003814 drug Substances 0.000 description 7
- 238000000034 method Methods 0.000 description 7
- 206010020880 Hypertrophy Diseases 0.000 description 6
- 230000005764 inhibitory process Effects 0.000 description 6
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 4
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 4
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 4
- 229920000642 polymer Polymers 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- 210000001519 tissue Anatomy 0.000 description 4
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
- 102000004142 Trypsin Human genes 0.000 description 3
- 108090000631 Trypsin Proteins 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 229920001577 copolymer Polymers 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 206010020718 hyperplasia Diseases 0.000 description 3
- CGIGDMFJXJATDK-UHFFFAOYSA-N indomethacin Chemical compound CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 CGIGDMFJXJATDK-UHFFFAOYSA-N 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 239000003094 microcapsule Substances 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- 239000006187 pill Substances 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 230000001225 therapeutic effect Effects 0.000 description 3
- 239000012588 trypsin Substances 0.000 description 3
- IAKHMKGGTNLKSZ-INIZCTEOSA-N (S)-colchicine Chemical compound C1([C@@H](NC(C)=O)CC2)=CC(=O)C(OC)=CC=C1C1=C2C=C(OC)C(OC)=C1OC IAKHMKGGTNLKSZ-INIZCTEOSA-N 0.000 description 2
- NZHGWWWHIYHZNX-UHFFFAOYSA-N 2-((3-(3,4-dimethoxyphenyl)-1-oxo-2-propenyl)amino)benzoic acid Chemical compound C1=C(OC)C(OC)=CC=C1C=CC(=O)NC1=CC=CC=C1C(O)=O NZHGWWWHIYHZNX-UHFFFAOYSA-N 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 230000002421 anti-septic effect Effects 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 239000001569 carbon dioxide Substances 0.000 description 2
- 229910002092 carbon dioxide Inorganic materials 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 239000011521 glass Substances 0.000 description 2
- 230000001969 hypertrophic effect Effects 0.000 description 2
- 229960000905 indomethacin Drugs 0.000 description 2
- 239000007951 isotonicity adjuster Substances 0.000 description 2
- 239000004310 lactic acid Substances 0.000 description 2
- 235000014655 lactic acid Nutrition 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 2
- 231100000241 scar Toxicity 0.000 description 2
- 239000003381 stabilizer Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000001356 surgical procedure Methods 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 229940124597 therapeutic agent Drugs 0.000 description 2
- 238000012546 transfer Methods 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- STQGQHZAVUOBTE-UHFFFAOYSA-N 7-Cyan-hept-2t-en-4,6-diinsaeure Natural products C1=2C(O)=C3C(=O)C=4C(OC)=CC=CC=4C(=O)C3=C(O)C=2CC(O)(C(C)=O)CC1OC1CC(N)C(O)C(C)O1 STQGQHZAVUOBTE-UHFFFAOYSA-N 0.000 description 1
- 206010002945 Aphakia Diseases 0.000 description 1
- 102000008186 Collagen Human genes 0.000 description 1
- 108010035532 Collagen Proteins 0.000 description 1
- 206010010744 Conjunctivitis allergic Diseases 0.000 description 1
- 206010012438 Dermatitis atopic Diseases 0.000 description 1
- 206010048768 Dermatosis Diseases 0.000 description 1
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 208000002260 Keloid Diseases 0.000 description 1
- 206010023330 Keloid scar Diseases 0.000 description 1
- 229930192392 Mitomycin Natural products 0.000 description 1
- NWIBSHFKIJFRCO-WUDYKRTCSA-N Mytomycin Chemical compound C1N2C(C(C(C)=C(N)C3=O)=O)=C3[C@@H](COC(N)=O)[C@@]2(OC)[C@@H]2[C@H]1N2 NWIBSHFKIJFRCO-WUDYKRTCSA-N 0.000 description 1
- 206010039085 Rhinitis allergic Diseases 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 208000002205 allergic conjunctivitis Diseases 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 201000010105 allergic rhinitis Diseases 0.000 description 1
- 230000007815 allergy Effects 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- 208000024998 atopic conjunctivitis Diseases 0.000 description 1
- 201000008937 atopic dermatitis Diseases 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 229920002988 biodegradable polymer Polymers 0.000 description 1
- 239000004621 biodegradable polymer Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 229960001338 colchicine Drugs 0.000 description 1
- 229920001436 collagen Polymers 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 210000004087 cornea Anatomy 0.000 description 1
- 210000004351 coronary vessel Anatomy 0.000 description 1
- 239000006184 cosolvent Substances 0.000 description 1
- STQGQHZAVUOBTE-VGBVRHCVSA-N daunorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(C)=O)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 STQGQHZAVUOBTE-VGBVRHCVSA-N 0.000 description 1
- 229960000975 daunorubicin Drugs 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 238000002651 drug therapy Methods 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 210000002950 fibroblast Anatomy 0.000 description 1
- 229960002949 fluorouracil Drugs 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 238000003306 harvesting Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 239000007943 implant Substances 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 208000030603 inherited susceptibility to asthma Diseases 0.000 description 1
- 239000013010 irrigating solution Substances 0.000 description 1
- 210000001117 keloid Anatomy 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 206010025482 malaise Diseases 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 229960004857 mitomycin Drugs 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000001543 one-way ANOVA Methods 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 229920002401 polyacrylamide Polymers 0.000 description 1
- 230000002980 postoperative effect Effects 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 208000017520 skin disease Diseases 0.000 description 1
- 210000000329 smooth muscle myocyte Anatomy 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 238000007619 statistical method Methods 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 230000009978 visual deterioration Effects 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/196—Carboxylic acids, e.g. valproic acid having an amino group the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
- A61P27/12—Ophthalmic agents for cataracts
Landscapes
- Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Epidemiology (AREA)
- Ophthalmology & Optometry (AREA)
- General Chemical & Material Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
一种继发性白内障的抑制剂，它含有下式表示的N-(3，4-二甲氧基肉桂酰)氨茴酸或其药学上可接受的盐作为活性成分：该化合物对白内障手术后发生的后囊层浑浊化有抑制作用，因而可用于预防或治疗继发性白内障。
Description
技术领域
本发明涉及可用作继发性白内障抑制剂的药物组合物。
更具体地，本发明涉及用于白内障手术后继发性白内障的抑制剂，它含有下式表示的N-(3，4-二甲氧基肉桂酰)氨茴酸或其药学上可接受的盐作为活性成分：
背景技术
白内障是一种难治的眼科疾病，该病会因多种因素而发病和发展，随后因晶状体浑浊而导致视力下降。绝大多数是与年龄有关的高龄白内障。白内障的发病率在60多岁者中据信为60-70％，在80多岁或更高龄者接近100％。在逐渐迈向由大部分老年人所构成的社会过程中，预防和治疗白内障将会变得更加重要。然而，在目前，还没有对白内障的发展有确实抑制活性的治疗剂。因此，需要开发有效的治疗剂。所以，目前白内障的治疗最终取决于用眼镜、隐性眼镜等来矫正视力，或者用手术治疗，例如在囊外白内障摘除术之后将人工晶体插入到晶状体囊中。
在白内障手术中，已指出手术后的继发性白内障是一大问题。继发性白内障是指在囊外白内障摘除术之后残留的后囊层(posterior capsule)表面的浑浊。继发性白内障的机理基本如下所述。即，在切除了晶状体上皮细胞(前囊层)之后，会因残留晶状体上皮细胞(在摘除晶状体皮质时没有完全被去除)迁移到后囊层并增生而导致后囊层浑浊化，从而导致继发性白内障。此外，继发性白内障可起源于：残留的晶状体上皮细胞在赤道部异常增生，并随后形成Elschnig珠。
在白内障手术中，不可能完全去除晶状体上皮细胞，因此难以完全防止继发性白内障。据称，上述后囊层浑浊化的发生率在无晶状体眼中为40-50％，在人工晶状体眼(pseudophakic eye)中为7-20％。
另一方面，在白内障的药疗法领域，广泛的研究已经积极地进行，以便找到能够抑制继发性白内障的物质。迄今为止，例如已证实代谢拮抗剂如丝裂霉素、柔红霉素、5-氟尿嘧啶和秋水仙素均是有效的。然而，这些药物存在问题，例如严重的副作用[Atarashii Ganka，Vol.12，No.pp451-452(1995)；Japanese Journal ofOphthalmic Surgery，Vol.8，No.3，pp439-446(1995)]，而且在临床上还不足以应用。此外，已报道，当插入的人工晶体涂有吲哚美辛(indometacin)时，可显著抑制继发性白内障的形成，而且乙二胺四乙酸(EDTA)对继发性白内障也是有效的[Japanese Journal of Ophthalmic Surgery，Vol.8，No.3，pp439-446(1995)；IOL&RS，Vol.19 No.2 pp.78-82(1995)；日本专利申请出版(公开)No.Hei.8-175984]。然而，还未开发出防止和抑制继发性白内障的在临床上令人满意的药物。
本发明的由上式(I)表示的N-(3，4-二甲氧基肉桂酰)氨茴酸(一般名称：曲尼司特(Tranilast))，已经广泛地被用作药物治疗变态反应病如支气管哮喘、过敏性鼻炎、特异反应性皮炎和变态反应性结膜炎，以及治疗皮肤疾病如疤痕疙瘩和肥大性疤痕(hypertrophic scar)。例如，已知道曲尼司特对下列现象有抑制作用：变态反应造成的化学中介物释放，在皮肤组织中成纤维细胞造成的胶原过度堆积，和在冠状动脉血管中平滑肌细胞的过度增生。
然而，没有公开过曲尼司特对继发性白内障形成有抑制活性，而且也根本不知道曲尼司特可用作继发性白内障的抑制剂。
发明公开内容
本发明涉及一种继发性白内障抑制剂，它含有下式表示的N-(3，4-二甲氧基肉桂酰)氨茴酸或其药学上可接受的盐作为活性成分：
本发明涉及一种预防或治疗继发性白内障的方法，它包括施用上式(I)所表示的N-(3，4-二甲氧基肉桂酰)氨茴酸或其药学上可接受的盐。
本发明还涉及上式(I)所表示的N-(3，4-二甲氧基肉桂酰)氨茴酸或其药学上可接受的盐的用途，它们被用于制造用于预防或治疗继发性白内障的药物组合物。
此外，本发明涉及上式(I)所表示的N-(3，4-二甲氧基肉桂酰)氨茴酸或其药学上可接受的盐作为继发性白内障抑制剂的用途。
本发明人进行了广泛研究，以寻找对继发性白内障形成有抑制作用的化合物。结果，发现本发明由上式(I)表示的N-(3，4-二甲氧基肉桂酰)氨茴酸对晶状体上皮细胞增生有显著的抑制作用，因而可极为有效地作为继发性白内障抑制剂，由此构成了本发明的基础。
相应地，本发明人证实，在用大鼠晶状体上皮细胞进行体外试验中，证实了曲尼司特可明显地抑制晶状体上皮细胞的增生，从而证实了对细胞增生的抑制活性。
结果，曲尼司特对晶状体上皮细胞增生有优异的抑制作用，因而是极为有用的可用作继发性白内障抑制剂的化合物。
因此，可用作继发性白内障抑制剂的药物组合物可这样制备，即，使其含有曲尼司特或其药学上可接受的盐作为活性成分。
用作活性成分的曲尼司特及其盐的各种制备方法是已知的，这些化合物可方便地根据文献中所述的方法制得(日本专利申请出版物(kokoku)No.Sho.56-40710；同上(ibid)No.Sho.57-36905；同上No.Sho.58-17186；同上No.Sho.58-48545；同上No.Sho.58-55138；同上No.Sho.58-55139；同上No.Hei.01-28013；同上No.Hei.01-50219；同上No.Hei.03-37539等)。
作为曲尼司特的药学上可接受的盐的例子，可以例举的有与无机碱形成的盐如钠盐和钾盐，与有机胺(如吗啉、哌嗪和吡咯烷)形成的盐，以及与氨基酸形成的盐。
当本发明的药物组合物被用于实际治疗时，可根据使用情况而采用各种不同剂型的药物组合物。较佳地，可以例举的有眼药水、针剂、眼药膏，或者例如在掺入药丸或微囊后进行植入(plantation)，以及在预先涂于人工晶体之后再插入晶体的方法。
这些药物组合物可根据常规方法通过混合、稀释或溶解而进行配制，并且偶尔添加合适的药物添加剂，如赋形剂、崩解剂、粘合剂、润滑剂、稀释剂、缓冲剂、等渗剂(isotonicities)、防腐剂、润湿剂、乳化剂、分散剂、稳定剂和助溶剂，而且该配制过程可根据剂型用惯常方式进行。
例如，眼药水的配制可这样进行：将曲尼司特或其药学上可接受的盐与碱性物质(basic substance)一起通过加热溶解于无菌水(在无菌水中溶解有表面活性剂)中，加入聚乙烯吡咯烷酮，并可任意地加入合适的药物添加剂如防腐剂、稳定剂、缓冲剂和等渗剂、抗氧化剂和增粘剂，然后使其完全溶解。
可通过细针，将针剂直接注射入病理组织如角膜、晶状体和玻璃质中，或它们相邻的组织中。针剂还可被用作眼内灌注液。
本发明的药物组合物可以缓释剂形式给药。例如，曲尼司特或其盐可被掺入以缓释聚合物为载体的药丸或微囊中，然后将该药丸或微囊通过手术植入待治疗的组织。此外，曲尼司特或其盐还可通过插入预先涂有药物的人工晶体而得以应用。作为缓释聚合物的例子，可例举的有乙烯-乙烯基乙酸酯共聚物、聚羟基甲基丙烯酸酯(polyhydrometaacrylate)、聚丙烯酰胺、聚乙烯吡咯烷酮、甲基纤维素、乳酸聚合物、乳酸-乙醇酸共聚物等，较佳地可例举的是可生物降解的聚合物如乳酸聚合物和乳酸-乙醇酸共聚物。
当本发明的药物组合物被用于实际治疗时，作为活性成分的曲尼司特或其药学上可接受的盐的剂量，可根据待治疗的每个病人的体重、年龄、性别、症状程度而合理地加以确定。例如，当滴注入眼内时，这些化合物的给药量约为每个成人10微克-50毫克/天。
取决于待治疗病人的症状程度和治疗效果，曲尼司特或其药学上可接受盐的剂量可以适当地增加或减少。
实施例
接着，通过以下实施例更详细地阐述本发明。
实施例
对晶状体上皮细胞增生的抑制活性
(1)培养大鼠晶状体上皮细胞
采集大鼠晶状体，将其切成细长条。将细长条粘附于培养皿上并在含10％胎牛血清(FBS)的Dulbecco改进的Eagle培养基(DMEM)上，在含5％二氧化碳的空气中，于37℃继代培养4天。在第4天时(在晶状体上皮细胞从晶状体组织中迁移出并增生时)，培养基被吸去，用磷酸盐缓冲液(PBS(-))轻柔地洗涤细胞。然后，吸去PBS(-)，将一份含0.02％EDTA的0.25％胰蛋白酶溶液加至培养皿，在相差显微镜下观察细胞形态。当细胞变圆时，将等量的含10％FBS的DMEM加至胰蛋白酶溶液中以终止胰蛋白酶的作用。通过用细长的巴氏吸管吸取培养基，将贴壁细胞(attached cell)从培养皿上收集下来。细胞悬浮液被转移至一锥形容器(spit)，然后向该锥形容器中加入培养基，通过用巴氏吸管吸取而剧烈地混合细胞悬浮液约20次，然后100-110×g离心1分钟。在弃去上清液之后，向沉淀物加入新鲜的培养基，然后通过用巴氏吸管吸取而制备晶状体上皮细胞的悬浮液。该悬浮液在含10％FBS的DMEM中进一步进行继代培养，以备试验之用。
(2)制备测试药物
将曲尼司特加至1％碳酸氢钠水溶液中，在70℃下加温溶解而制备成1.0％溶液。溶液通过微孔滤器过滤而灭菌，并用含10％FBS的DMEM培养基稀释至最终的规定浓度。
(3)实验方法
将细胞悬浮液(2×104细胞/0.1毫升)以及含有各种浓度曲尼司特和10％FBS的DMEM培养基(1.9毫升)加至培养皿(60毫米)中，在含5％二氧化碳的空气中，于37℃进行培养。4天后，吸去培养基，用PBS(-)洗涤细胞，然后将1毫升含0.02％EDTA的0.25％胰蛋白酶溶液加至培养皿中。在通过巴氏吸管吸取而从培养皿收获细胞之后，用血细胞计数器对活细胞的数目进行计数。
(4)结果评估
计算每组的平均值和标准差数值。用单向方差分析方法进行显著性的统计分析，证实了统计显著性。之后，用Dunnett氏多重测试法对组之间的显著性进行分析。
(5)结果
如图1所示，曲尼司特以依赖于浓度的方式显著地抑制晶状体上皮细胞的增生。
附图简述
图1阐述了曲尼司特对大鼠晶状体上皮细胞增生的抑制活性。纵坐标显示了大鼠晶状体上皮细胞的数目(×104细胞)，横坐标显示了加入的曲尼司特浓度(微克/毫升)。在图中，符号*和**分别表示差异显著性为p＜0.05和p＜0.01。
工业应用性
含有曲尼司特或其药学上可接受盐作为活性成分的药物组合物，对晶状体上皮细胞增生有显著的抑制活性，因而适合用作继发性白内障的抑制剂。
Claims (1)
1.一种下式所表示的N-(3，4-二甲氧基肉桂酰)氨茴酸或其药学上可接受的盐的用途，其特征在于，被用于制造用于预防或治疗继发性白内障的药物组合物
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP306952/96 | 1996-10-14 | ||
| JP30695296 | 1996-10-14 | ||
| JP306952/1996 | 1996-10-14 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1233172A CN1233172A (zh) | 1999-10-27 |
| CN1111403C true CN1111403C (zh) | 2003-06-18 |
Family
ID=17963256
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN97198769A Expired - Fee Related CN1111403C (zh) | 1996-10-14 | 1997-10-09 | 继发性白内障抑制剂 |
Country Status (14)
| Country | Link |
|---|---|
| US (1) | US6376543B1 (zh) |
| EP (1) | EP0958815A4 (zh) |
| KR (1) | KR20000049136A (zh) |
| CN (1) | CN1111403C (zh) |
| AU (1) | AU745028B2 (zh) |
| BR (1) | BR9712308A (zh) |
| CA (1) | CA2267320A1 (zh) |
| CZ (1) | CZ127999A3 (zh) |
| EA (1) | EA001745B1 (zh) |
| HU (1) | HUP9904617A3 (zh) |
| IL (1) | IL129421A0 (zh) |
| NO (1) | NO991627L (zh) |
| NZ (1) | NZ335042A (zh) |
| WO (1) | WO1998016214A1 (zh) |
Families Citing this family (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1008347A4 (en) * | 1997-04-18 | 2002-02-06 | Kissei Pharmaceutical | REMEDIES FOR PROPHYLAXIS OR TREATMENT OF DISEASES RESULTING IN EXCESSIVE PROLIFERATION OF PIGMENTAL RETINE EPITHELIAL CELLS |
| US20060166879A1 (en) * | 2002-12-20 | 2006-07-27 | Chakshu Research Inc | Treatment of conditions associated with the presence of macromolecular aggregates, particularly ophthalmic disorders |
| US20060177430A1 (en) * | 2002-12-20 | 2006-08-10 | Chakshu Research Inc | Treatment of ocular disorders with ophthalmic formulations containing methylsulfonylmethane as a transport enhancer |
| US20060172972A1 (en) * | 2002-12-20 | 2006-08-03 | Chakshu Research Inc | Formulation and method for administration of ophthalmologically active agents |
| NZ540885A (en) * | 2002-12-20 | 2009-02-28 | Chakshu Res Inc | Ophthalmic formulation for the prevention and treatment of ocular conditions |
| US20050106230A1 (en) * | 2003-11-17 | 2005-05-19 | Young Janel E. | Drug-enhanced adhesion prevention |
| WO2006073126A1 (ja) * | 2005-01-06 | 2006-07-13 | Kissei Pharmaceutical Co., Ltd. | 慢性移植片対宿主症におけるドライアイの予防および治療剤 |
| WO2007011843A2 (en) * | 2005-07-15 | 2007-01-25 | Chakshu Research Inc. | Prevention and treatment of ophthalmic complications of diabetes |
| US8668703B2 (en) * | 2006-12-01 | 2014-03-11 | Wake Forest University Health Sciences | Medical devices incorporating collagen inhibitors |
| US8614233B2 (en) | 2007-05-29 | 2013-12-24 | Universite De Montreal | Cinnamoyl inhibitors of transglutaminase |
| EP2448948A4 (en) * | 2009-07-02 | 2013-04-10 | Oxigene Inc | COMBRETASTATINE FOR PREVENTING FUTURE |
| US9844556B2 (en) | 2015-03-25 | 2017-12-19 | Megumi Honjo | Preventive/therapeutic method and preventive/therapeutic agent for complications after cataract surgery |
| RU2622606C1 (ru) * | 2016-08-11 | 2017-06-16 | Федеральное государственное автономное учреждение "Межотраслевой научно-технический комплекс "Микрохирургия глаза" имени академика С.Н. Федорова" Министерства здравоохранения Российской Федерации | Способ медикаментозного лечения вторичной катаракты |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0391002A2 (en) * | 1989-04-04 | 1990-10-10 | Kissei Pharmaceutical Co., Ltd. | Pharmaceutical compositions containing N-(3,4-dimethoxycinnamoyl) anthranilic acid |
| WO1995013827A1 (en) * | 1993-11-19 | 1995-05-26 | The University Of Sydney | A method for preventing or controlling cataract |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2693107B1 (fr) * | 1992-07-01 | 1994-09-23 | Chauvin Laboratoire | Moyens pour la prévention de la cataracte secondaire. |
| BR9707514A (pt) * | 1996-02-15 | 1999-07-27 | Kissei Pharmaceutical | Inibidor de neovascularizacão |
-
1997
- 1997-10-09 NZ NZ335042A patent/NZ335042A/xx unknown
- 1997-10-09 BR BR9712308-0A patent/BR9712308A/pt not_active Application Discontinuation
- 1997-10-09 US US09/269,200 patent/US6376543B1/en not_active Expired - Fee Related
- 1997-10-09 WO PCT/JP1997/003630 patent/WO1998016214A1/ja not_active Application Discontinuation
- 1997-10-09 AU AU44718/97A patent/AU745028B2/en not_active Ceased
- 1997-10-09 EP EP97943164A patent/EP0958815A4/en not_active Withdrawn
- 1997-10-09 EA EA199900374A patent/EA001745B1/ru not_active IP Right Cessation
- 1997-10-09 IL IL12942197A patent/IL129421A0/xx unknown
- 1997-10-09 CA CA002267320A patent/CA2267320A1/en not_active Abandoned
- 1997-10-09 CZ CZ991279A patent/CZ127999A3/cs unknown
- 1997-10-09 HU HU9904617A patent/HUP9904617A3/hu unknown
- 1997-10-09 CN CN97198769A patent/CN1111403C/zh not_active Expired - Fee Related
- 1997-10-09 KR KR1019990703223A patent/KR20000049136A/ko not_active Application Discontinuation
-
1999
- 1999-04-06 NO NO991627A patent/NO991627L/no not_active Application Discontinuation
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0391002A2 (en) * | 1989-04-04 | 1990-10-10 | Kissei Pharmaceutical Co., Ltd. | Pharmaceutical compositions containing N-(3,4-dimethoxycinnamoyl) anthranilic acid |
| WO1995013827A1 (en) * | 1993-11-19 | 1995-05-26 | The University Of Sydney | A method for preventing or controlling cataract |
Non-Patent Citations (1)
| Title |
|---|
| JAPAN.J.PHARMACOL.1992,VOL.60 NO.2 1992-07-10 suzawa.h.et al inhibitory action of tranilast,an anti-alergic durg,on the release of cytokines and p * |
Also Published As
| Publication number | Publication date |
|---|---|
| EA001745B1 (ru) | 2001-08-27 |
| CN1233172A (zh) | 1999-10-27 |
| EP0958815A1 (en) | 1999-11-24 |
| NO991627L (no) | 1999-06-03 |
| CA2267320A1 (en) | 1998-04-23 |
| AU4471897A (en) | 1998-05-11 |
| BR9712308A (pt) | 1999-08-31 |
| WO1998016214A1 (fr) | 1998-04-23 |
| HUP9904617A2 (hu) | 2000-05-28 |
| NO991627D0 (no) | 1999-04-06 |
| AU745028B2 (en) | 2002-03-07 |
| NZ335042A (en) | 2001-01-26 |
| EP0958815A4 (en) | 2001-02-07 |
| KR20000049136A (ko) | 2000-07-25 |
| IL129421A0 (en) | 2000-02-17 |
| HUP9904617A3 (en) | 2000-07-28 |
| EA199900374A1 (ru) | 1999-12-29 |
| CZ127999A3 (cs) | 1999-07-14 |
| US6376543B1 (en) | 2002-04-23 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US4141973A (en) | Ultrapure hyaluronic acid and the use thereof | |
| KR0178544B1 (ko) | 안과용 순수 히알우론산 분류물 및 그의 정제방법 | |
| CN1111403C (zh) | 继发性白内障抑制剂 | |
| US6407139B1 (en) | Neovascularization inhibitor | |
| RU2207852C2 (ru) | Средства для предотвращения или лечения болезней, связанных с чрезмерной пролиферацией эпителиальных пигментных клеток сетчатки | |
| Kremer et al. | Toxic anterior segment syndrome following iris-supported phakic IOL implantation with viscoelastic Multivisc BD | |
| EP2525793A2 (en) | Alpha-2 adrenergic agonist having long duration of intraocular pressure-lowering effect | |
| EP4226924A1 (en) | Use of penehyclidine in treatment or prevention of vision-impairing eye diseases | |
| JPS5874609A (ja) | のう外摘出後における水晶体の残遺部上皮細胞の増殖を防止するための有糸分裂阻止剤 | |
| EP0974352B1 (en) | Drugs inhibiting progress of pterygium and postoperative recurrence of the same | |
| JP3603129B2 (ja) | 糖尿病性角膜症の治療剤 | |
| EP1380302B1 (en) | Remedies for retina and choroid diseases containing steroids as the active ingredient | |
| Fechner et al. | Comparison of hydroxypropyl methylcellulose 2%(Adatocel®) and hyaluronic acid 1%(Healon®) | |
| KR20230007963A (ko) | 이나보글리플로진을 포함하는 안질환의 예방 또는 치료용 약학적 조성물 | |
| CN114392230A (zh) | 雷公藤红素在制备抑制角膜基质纤维化药物中的应用 | |
| CN116172885A (zh) | 一种抗后发性白内障药物制剂及其制备方法 | |
| AU722807B2 (en) | Neovascularization inhibitor | |
| RU2135127C1 (ru) | Раствор для защиты и лечения заболеваний и повреждений роговицы "визитин" | |
| TW200906386A (en) | Compositions with anti-angiogenic activity | |
| JP2000169388A (ja) | 血管新生阻害剤 | |
| L-LYSOZYM | not only the non-pathogenic bacteria, but also many of the bacteria pathogenic for man in such concentration as exists in hu-man tears. | |
| JPH11255648A (ja) | 血管新生阻害剤 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| C19 | Lapse of patent right due to non-payment of the annual fee | ||
| CF01 | Termination of patent right due to non-payment of annual fee |