CN1228047C - 含有法呢基乙酸作为活性成分的角膜结膜疾病治疗药物 - Google Patents
含有法呢基乙酸作为活性成分的角膜结膜疾病治疗药物 Download PDFInfo
- Publication number
- CN1228047C CN1228047C CNB018185592A CN01818559A CN1228047C CN 1228047 C CN1228047 C CN 1228047C CN B018185592 A CNB018185592 A CN B018185592A CN 01818559 A CN01818559 A CN 01818559A CN 1228047 C CN1228047 C CN 1228047C
- Authority
- CN
- China
- Prior art keywords
- salt
- heratoconjunctival
- remedies
- farnesylacetic acid
- diseases
- 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
- 201000010099 disease Diseases 0.000 title claims abstract description 14
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 title claims abstract description 14
- 239000004480 active ingredient Substances 0.000 title abstract 2
- ZGIGZINMAOQWLX-NCZFFCEISA-N 3,7,11-Trimethyl-2,6,10-dodecatrienyl acetate Chemical compound CC(C)=CCC\C(C)=C\CC\C(C)=C\COC(C)=O ZGIGZINMAOQWLX-NCZFFCEISA-N 0.000 title 1
- ZGIGZINMAOQWLX-UHFFFAOYSA-N Farnesyl acetate Natural products CC(C)=CCCC(C)=CCCC(C)=CCOC(C)=O ZGIGZINMAOQWLX-UHFFFAOYSA-N 0.000 title 1
- 229940007703 farnesyl acetate Drugs 0.000 title 1
- VOKDWPMRYSKGTB-NCZFFCEISA-N (4e,8e)-5,9,13-trimethyltetradeca-4,8,12-trienoic acid Chemical compound CC(C)=CCC\C(C)=C\CC\C(C)=C\CCC(O)=O VOKDWPMRYSKGTB-NCZFFCEISA-N 0.000 claims abstract description 33
- 150000003839 salts Chemical class 0.000 claims abstract description 18
- 206010010741 Conjunctivitis Diseases 0.000 claims abstract description 6
- 206010023332 keratitis Diseases 0.000 claims abstract description 6
- 206010064996 Ulcerative keratitis Diseases 0.000 claims abstract description 5
- 201000007717 corneal ulcer Diseases 0.000 claims abstract description 5
- 210000004087 cornea Anatomy 0.000 claims description 19
- 208000005494 xerophthalmia Diseases 0.000 claims description 16
- 208000016134 Conjunctival disease Diseases 0.000 claims description 10
- 208000021921 corneal disease Diseases 0.000 claims description 9
- 210000003560 epithelium corneal Anatomy 0.000 claims description 6
- 238000002360 preparation method Methods 0.000 claims description 6
- 206010040844 Skin exfoliation Diseases 0.000 claims description 5
- 238000004299 exfoliation Methods 0.000 claims description 5
- 239000002552 dosage form Substances 0.000 claims description 4
- 102000015728 Mucins Human genes 0.000 abstract description 15
- 108010063954 Mucins Proteins 0.000 abstract description 15
- 230000028327 secretion Effects 0.000 abstract description 9
- 239000003814 drug Substances 0.000 abstract description 4
- 208000003556 Dry Eye Syndromes Diseases 0.000 abstract description 2
- 206010013774 Dry eye Diseases 0.000 abstract description 2
- 229940124597 therapeutic agent Drugs 0.000 abstract 2
- 206010011013 Corneal erosion Diseases 0.000 abstract 1
- 239000000126 substance Substances 0.000 abstract 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 11
- ZPACYDRSPFRDHO-ROBAGEODSA-N Gefarnate Chemical compound CC(C)=CCC\C(C)=C\CC\C(C)=C\CCC(=O)OC\C=C(/C)CCC=C(C)C ZPACYDRSPFRDHO-ROBAGEODSA-N 0.000 description 10
- 229920001386 Gefarnate Polymers 0.000 description 10
- 229960003779 gefarnate Drugs 0.000 description 10
- 210000000795 conjunctiva Anatomy 0.000 description 9
- 239000003889 eye drop Substances 0.000 description 9
- 229930187593 rose bengal Natural products 0.000 description 8
- AZJPTIGZZTZIDR-UHFFFAOYSA-L rose bengal Chemical compound [K+].[K+].[O-]C(=O)C1=C(Cl)C(Cl)=C(Cl)C(Cl)=C1C1=C2C=C(I)C(=O)C(I)=C2OC2=C(I)C([O-])=C(I)C=C21 AZJPTIGZZTZIDR-UHFFFAOYSA-L 0.000 description 8
- 229940081623 rose bengal Drugs 0.000 description 8
- STRXNPAVPKGJQR-UHFFFAOYSA-N rose bengal A Natural products O1C(=O)C(C(=CC=C2Cl)Cl)=C2C21C1=CC(I)=C(O)C(I)=C1OC1=C(I)C(O)=C(I)C=C21 STRXNPAVPKGJQR-UHFFFAOYSA-N 0.000 description 8
- 230000000694 effects Effects 0.000 description 7
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 210000001508 eye Anatomy 0.000 description 6
- 239000007924 injection Substances 0.000 description 6
- 238000002347 injection Methods 0.000 description 6
- 238000000034 method Methods 0.000 description 6
- 230000000144 pharmacologic effect Effects 0.000 description 5
- 210000001519 tissue Anatomy 0.000 description 5
- 210000004561 lacrimal apparatus Anatomy 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 238000002835 absorbance Methods 0.000 description 3
- 210000002919 epithelial cell Anatomy 0.000 description 3
- 239000000284 extract Substances 0.000 description 3
- 239000003885 eye ointment Substances 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- ZEMPKEQAKRGZGQ-AAKVHIHISA-N 2,3-bis[[(z)-12-hydroxyoctadec-9-enoyl]oxy]propyl (z)-12-hydroxyoctadec-9-enoate Chemical class CCCCCCC(O)C\C=C/CCCCCCCC(=O)OCC(OC(=O)CCCCCCC\C=C/CC(O)CCCCCC)COC(=O)CCCCCCC\C=C/CC(O)CCCCCC ZEMPKEQAKRGZGQ-AAKVHIHISA-N 0.000 description 2
- TYJOQICPGZGYDT-UHFFFAOYSA-N 4-methylsulfonylbenzenesulfonyl chloride Chemical compound CS(=O)(=O)C1=CC=C(S(Cl)(=O)=O)C=C1 TYJOQICPGZGYDT-UHFFFAOYSA-N 0.000 description 2
- GSDSWSVVBLHKDQ-UHFFFAOYSA-N 9-fluoro-3-methyl-10-(4-methylpiperazin-1-yl)-7-oxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylic acid Chemical compound FC1=CC(C(C(C(O)=O)=C2)=O)=C3N2C(C)COC3=C1N1CCN(C)CC1 GSDSWSVVBLHKDQ-UHFFFAOYSA-N 0.000 description 2
- 206010002091 Anaesthesia Diseases 0.000 description 2
- OVBJJZOQPCKUOR-UHFFFAOYSA-L EDTA disodium salt dihydrate Chemical compound O.O.[Na+].[Na+].[O-]C(=O)C[NH+](CC([O-])=O)CC[NH+](CC([O-])=O)CC([O-])=O OVBJJZOQPCKUOR-UHFFFAOYSA-L 0.000 description 2
- GLZPCOQZEFWAFX-UHFFFAOYSA-N Geraniol Chemical compound CC(C)=CCCC(C)=CCO GLZPCOQZEFWAFX-UHFFFAOYSA-N 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- YQEZLKZALYSWHR-UHFFFAOYSA-N Ketamine Chemical compound C=1C=CC=C(Cl)C=1C1(NC)CCCCC1=O YQEZLKZALYSWHR-UHFFFAOYSA-N 0.000 description 2
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 230000037005 anaesthesia Effects 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- 238000011156 evaluation Methods 0.000 description 2
- 230000003203 everyday effect Effects 0.000 description 2
- 230000024278 histolysis Effects 0.000 description 2
- 229940116314 ketaject Drugs 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 210000004877 mucosa Anatomy 0.000 description 2
- 229960001699 ofloxacin Drugs 0.000 description 2
- 230000003204 osmotic effect Effects 0.000 description 2
- WEXRUCMBJFQVBZ-UHFFFAOYSA-N pentobarbital Chemical compound CCCC(C)C1(CC)C(=O)NC(=O)NC1=O WEXRUCMBJFQVBZ-UHFFFAOYSA-N 0.000 description 2
- -1 polyoxyethylene Polymers 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 229960004175 xylazine hydrochloride Drugs 0.000 description 2
- 206010015548 Euthanasia Diseases 0.000 description 1
- GLZPCOQZEFWAFX-YFHOEESVSA-N Geraniol Natural products CC(C)=CCC\C(C)=C/CO GLZPCOQZEFWAFX-YFHOEESVSA-N 0.000 description 1
- 239000005792 Geraniol Substances 0.000 description 1
- 102000003886 Glycoproteins Human genes 0.000 description 1
- 108090000288 Glycoproteins Proteins 0.000 description 1
- 208000011671 Lacrimal disease Diseases 0.000 description 1
- 229920001214 Polysorbate 60 Polymers 0.000 description 1
- 208000003251 Pruritus Diseases 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- 241000425571 Trepanes Species 0.000 description 1
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 1
- 208000025865 Ulcer Diseases 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 230000002421 anti-septic effect Effects 0.000 description 1
- 230000003816 axenic effect Effects 0.000 description 1
- 229960000686 benzalkonium chloride Drugs 0.000 description 1
- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 description 1
- 210000000988 bone and bone Anatomy 0.000 description 1
- 210000005252 bulbus oculi Anatomy 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 230000008260 defense mechanism Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- 238000004043 dyeing Methods 0.000 description 1
- 210000000981 epithelium Anatomy 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 210000003499 exocrine gland Anatomy 0.000 description 1
- 229940012356 eye drops Drugs 0.000 description 1
- 210000000744 eyelid Anatomy 0.000 description 1
- 229940113087 geraniol Drugs 0.000 description 1
- 210000004907 gland Anatomy 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 239000007951 isotonicity adjuster Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- TZBAVQKIEKDGFH-UHFFFAOYSA-N n-[2-(diethylamino)ethyl]-1-benzothiophene-2-carboxamide;hydrochloride Chemical compound [Cl-].C1=CC=C2SC(C(=O)NCC[NH+](CC)CC)=CC2=C1 TZBAVQKIEKDGFH-UHFFFAOYSA-N 0.000 description 1
- PRGUDWLMFLCODA-UHFFFAOYSA-N oxybuprocaine hydrochloride Chemical compound [Cl-].CCCCOC1=CC(C(=O)OCC[NH+](CC)CC)=CC=C1N PRGUDWLMFLCODA-UHFFFAOYSA-N 0.000 description 1
- 230000000149 penetrating effect Effects 0.000 description 1
- 229960001412 pentobarbital Drugs 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
- 230000001737 promoting effect Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 230000035807 sensation Effects 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 238000002798 spectrophotometry method Methods 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 231100000397 ulcer Toxicity 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
- A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
- A61K31/202—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids having three or more double bonds, e.g. linolenic
-
- 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
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0048—Eye, e.g. artificial tears
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Ophthalmology & Optometry (AREA)
- Emergency Medicine (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明提供了能促进眼组织中粘蛋白产生和分泌的新物质。本发明的角膜结膜疾病治疗药物含有法呢基乙酸或其盐作为活性成分。这些角膜结膜疾病治疗药物可用于干眼病、角膜炎、结膜炎、角膜上皮脱落、角膜溃疡等。
Description
技术领域
本发明涉及一种含有法呢基乙酸或其盐作为活性成分的角膜结膜疾病治疗药物。
背景技术
生物体具有保护黏膜的防御机制。黏膜的上皮细胞上总是覆盖着粘性外分泌液，这种外分泌液中含有外分泌腺分泌的粘蛋白。在眼睛中，眼泪发挥着这样的作用。泪液层由三层组成，即脂层、水层和粘蛋白层，角膜结膜上皮细胞与粘蛋白层接触。构成粘蛋白层的粘蛋白是由结膜杯型细胞和角膜结膜上皮细胞所分泌的一种糖蛋白，它使泪液能良好保留，保持角膜和结膜湿润。
干眼病是一种具有眼干症状并由于泪液异常造成角膜上皮障碍的疾病。干眼病症状的例子有眼干、角膜充血、痒、异物感等。当干眼病严重时，有时会造成失明。泪液分泌的降少、泪液层的不稳定等被认为是造成干眼病发病的原因，但这些病因还未得到确认。
因此，如果有一种物质能够促进粘蛋白分泌到泪液中，这种物质可望用于治疗角膜结膜上皮上有问题的角膜结膜疾病，例如干眼病、角膜炎、结膜炎、角膜上皮脱落和角膜溃疡。
日本公开的专利申请194363/1997号公开了元白菜素，它是法呢基乙酸与香叶醇的一种酯，它具有促进眼组织中粘蛋白产生和分泌的作用，对治疗角膜结膜疾病如干眼病有效。
但是，没有关于元白菜素游离羧酸法呢基乙酸应用于眼科领域的报道，根本不知道法呢基乙酸如何作用于角膜结膜疾病。
因此，发现法呢基乙酸对角膜结膜疾病的药理作用是一项很有意义的课题。
发明内容
本发明人研究了法呢基乙酸对粘蛋白产生和分泌的促进作用，以发现其新的药理作用，结果发现，法呢基乙酸对粘蛋白的产生和分泌具有显著的促进作用。证明法呢基乙酸甚至在比元白菜素低得多的浓度下也具有与元白菜素同等的效果。
本发明涉及含有下式代表的法呢基乙酸或其盐作为活性成分的角膜结膜疾病治疗药物，所述角膜结膜疾病例如为干眼病、角膜炎、结膜炎、角膜上皮脱落和角膜溃疡。它们的效果将在药理试验部分详细描述。
本发明化合物的盐可以是任何药物可接受的盐，例如与碱金属或碱土金属的盐，如钠盐、钾盐或钙盐，铵盐，和与有机胺如二乙胺或三乙醇胺的盐。
法呢基乙酸或其盐的剂型的例子有眼科制剂如滴眼液和眼膏，以及注射液。法呢基乙酸或其盐可以利用广泛使用的方法配制成这种制剂。例如，滴眼液可以用下列物质制备：任选的等渗剂如氯化钠和浓甘油；缓冲剂如磷酸钠和乙酸钠；表面活性剂如聚山梨酯80、聚氧乙烯氢化蓖麻油60和聚乙二醇4000；稳定剂如柠檬酸钠和乙二胺四乙酸二钠；防腐剂如苯扎氯铵和对羟基苯甲酸酯类；pH调节剂如氢氧化钠和盐酸。最好将pH调节到中性左右，最好将渗透压调节到约1.0。
本发明还涉及一种治疗角膜结膜疾病的方法，其包括给予患者有效量的法呢基乙酸或其盐；还涉及一种促进粘蛋白产生的方法或一种治疗涉及粘蛋白产生的疾病的方法，其包括给予患者有效量的法呢基乙酸或其盐。
可以根据症状、年龄、剂型等适当地选择剂量。对于滴眼液，0.0001％到3(w/v)、优选0.001％到1％(w/v)的溶液，每天可以滴1次到数次。
本发明的最佳实施方式
药理试验：利用泪腺-瞬眼膜-副泪腺摘除的兔干眼病模型研究了法呢基乙酸对干眼病的作用。
兔干眼病模型的制备
参照Girbard等(Invest.Ophthalmol.Vis.Sci.，28：225-228(1987))的方法制备了泪腺-瞬眼膜-副泪腺摘除的兔干眼病模型。即，给兔子以1ml/kg的量注射5％盐酸氯胺酮注射液和2％盐酸赛拉嗪注射液的7∶1混合物，系统麻醉兔子。给兔子滴注0.4％的盐酸奥布卡因滴眼液，沿眶骨将下眼睑皮肤切开约5毫米，然后从结膜袋的外侧摘除泪腺。将切开位置的皮肤用4-0缝线缝合，在切口位置施用氧氟沙星眼膏。然后，摘除副泪腺，将其与瞬眼膜一起拉出。最后，在摘除位置施用氧氟沙星眼膏。
滴眼液的制备
通过用下述载体稀释法呢基乙酸达到0.75、7.5和75μM的浓度，来制备法呢基乙酸滴眼液。通过用同样的载体稀释元白菜素到7.5mM的浓度，制备元白菜素滴眼液。所有获得的滴眼液的pH为7.4，渗透压为1.0。
载体(100毫升中)
聚氧乙烯氢化蓖麻油40 0.3g
NaH2PO4·2HO2 1.0g
乙二胺四乙酸二钠 0.05g
NaCl 0.4g
无菌纯化水 足量
给药
将每种法呢基乙酸滴眼液(50μl)滴注给泪腺-瞬眼膜-副泪腺摘除的兔子，每天6次，共2周(每组4只兔子，8只眼)。在对照组和比较组中，分别类似地滴注载体和元白菜素。
评价方法
通过测定四氯四碘荧光素的吸收评价对干眼病的效果。给兔子以1ml/kg的量注射5％盐酸氯胺酮注射液和2％盐酸赛拉嗪注射液的7∶1混合物，系统麻醉兔子，然后用开睑器切开眼睑，并在结膜袋中注满含1％四氯四碘荧光素的生理盐水。将这样处理的眼睛保持10秒钟，然后用生理盐水洗涤。给兔子注射5％戊巴比妥注射液进行安乐死，摘下眼球。使用8毫米内径的环钻制备角膜片，将它们放置在1毫升2M氢氧化钠溶液中，然后避光静置一天，以将角膜组织完全溶解。用分光光度计测定所得组织溶解溶液在560纳米波长处的吸光度。
四氯四碘荧光素对角膜结膜中无粘蛋白层的部分染色。如果粘蛋白层存在，四氯四碘荧光素将被阻止不能透入角膜结膜组织，但如果粘蛋白层不存在，四氯四碘荧光素容易到达角膜结膜组织。因此，当粘蛋白层由于干眼病而减少时，角膜组织的四氯四碘荧光素吸收增加，从而所述组织溶解溶液的吸光度增加。
结果
吸光度的测定结果显示在表1中。法呢基乙酸给药组中的四氯四碘荧光素吸收显著少于载体对照组，在各法呢基乙酸给药组中，四氯四碘荧光素的吸收大致呈浓度依赖性降低。另外，结果证明，甚至在元白菜素浓度的约1/100的浓度下，法呢基乙酸(75μM给药组)显示与元白菜素(7.5mM给药组)同等的效果。从上述结果可知，因为法呢基乙酸促进粘蛋白的产生和分泌，法呢基乙酸可望用于防治角膜结膜疾病，如干眼病。
| 吸光度 | |
| 对照组(载体) | 0.236 |
| 法呢基乙酸0.75μM7.5μM75μM | 0.1690.1390.093 |
| 比较组(元白菜素7.5mM) | 0.075 |
工业实用性
上述药理试验的结果明确显示，法呢基乙酸对粘蛋白的产生和分泌具有促进作用，可用作角膜结膜疾病的治疗药物，例如对干眼病、角膜炎、结膜炎、角膜上皮脱落和角膜溃疡。
Claims (8)
1.角膜结膜疾病治疗药物，其含有浓度为0.001％到1％w/v的法呢基乙酸或其盐作为活性成分。
2.如权利要求1所述的角膜结膜疾病治疗药物，其中角膜结膜疾病为干眼病、角膜炎、结膜炎、角膜上皮脱落或角膜溃疡。
3.如权利要求1或2所述的角膜结膜疾病治疗药物，其中剂型为眼科制剂。
4.如权利要求1所述的角膜结膜疾病治疗药物，其中法呢基乙酸或其盐为粘蛋白产生促进剂。
5.法呢基乙酸或其盐在制造角膜结膜疾病治疗药物中的应用。
6.如权利要求5所述的法呢基乙酸或其盐的应用，其中角膜结膜疾病为干眼病、角膜炎、结膜炎、角膜上皮脱落或角膜溃疡。
7.如权利要求5或6所述的法呢基乙酸或其盐的应用，其中剂型为眼科制剂。
8.如权利要求5所述的法呢基乙酸或其盐的应用，其中法呢基乙酸或其盐为粘蛋白产生促进剂。
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP340115/00 | 2000-11-08 | ||
| JP2000340115 | 2000-11-08 | ||
| JP340115/2000 | 2000-11-08 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1473039A CN1473039A (zh) | 2004-02-04 |
| CN1228047C true CN1228047C (zh) | 2005-11-23 |
Family
ID=18815078
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB018185592A Expired - Fee Related CN1228047C (zh) | 2000-11-08 | 2001-11-08 | 含有法呢基乙酸作为活性成分的角膜结膜疾病治疗药物 |
Country Status (8)
| Country | Link |
|---|---|
| US (1) | US20040014812A1 (zh) |
| EP (1) | EP1338279A1 (zh) |
| KR (1) | KR20030048129A (zh) |
| CN (1) | CN1228047C (zh) |
| AU (1) | AU2002214267A1 (zh) |
| CA (1) | CA2428207A1 (zh) |
| NO (1) | NO20032035L (zh) |
| WO (1) | WO2002038149A1 (zh) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20080153908A1 (en) * | 2006-12-20 | 2008-06-26 | Jani Dharmendra M | Method of Treating Mucin Deficiency with an Active Pharmaceutical and Related Composition |
| JP5758501B2 (ja) * | 2012-08-10 | 2015-08-05 | 三菱重工業株式会社 | 浮体式風力発電装置 |
| JP6760275B2 (ja) * | 2015-05-12 | 2020-09-23 | ライオン株式会社 | 眼科用組成物 |
Family Cites Families (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5573642A (en) * | 1978-11-28 | 1980-06-03 | Kuraray Co Ltd | Farnesyl-acetic ester derivative |
| GB8710780D0 (en) * | 1987-05-07 | 1987-06-10 | Scras | Opthalmological application of eicosapentaenoic acid |
| US5567729A (en) * | 1993-10-28 | 1996-10-22 | David L. Bradfute | Farnesyl compounds as farnesyl protein transferase inhibitors to treat ras induced tumor growth |
| JP3136352B2 (ja) * | 1996-01-22 | 2001-02-19 | 参天製薬株式会社 | 角結膜疾患治療剤 |
| JPH10265378A (ja) * | 1997-03-25 | 1998-10-06 | Ofutekusu:Kk | 角膜上皮損傷治療剤 |
| US6303654B1 (en) * | 1998-03-12 | 2001-10-16 | Wisconsin Alumni Research Foundation | Acyclic monoterpenoid derivatives |
| JP2002519305A (ja) * | 1998-06-24 | 2002-07-02 | メルク エンド カムパニー インコーポレーテッド | 骨吸収阻害用の組成物および方法 |
-
2001
- 2001-11-08 WO PCT/JP2001/009760 patent/WO2002038149A1/ja active Application Filing
- 2001-11-08 AU AU2002214267A patent/AU2002214267A1/en not_active Abandoned
- 2001-11-08 US US10/415,725 patent/US20040014812A1/en not_active Abandoned
- 2001-11-08 CN CNB018185592A patent/CN1228047C/zh not_active Expired - Fee Related
- 2001-11-08 CA CA002428207A patent/CA2428207A1/en not_active Abandoned
- 2001-11-08 EP EP01982746A patent/EP1338279A1/en not_active Withdrawn
- 2001-11-08 KR KR10-2003-7006263A patent/KR20030048129A/ko not_active Application Discontinuation
-
2003
- 2003-05-06 NO NO20032035A patent/NO20032035L/no not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| US20040014812A1 (en) | 2004-01-22 |
| NO20032035L (no) | 2003-06-20 |
| CA2428207A1 (en) | 2002-05-16 |
| WO2002038149A1 (fr) | 2002-05-16 |
| AU2002214267A1 (en) | 2002-05-21 |
| CN1473039A (zh) | 2004-02-04 |
| KR20030048129A (ko) | 2003-06-18 |
| NO20032035D0 (no) | 2003-05-06 |
| EP1338279A1 (en) | 2003-08-27 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| DE69917040T2 (de) | Augenlösung mit tetracyclin für behandlung von trockenen augen | |
| JP5673531B2 (ja) | 眼科用組成物 | |
| CN102639136A (zh) | 前列腺素F2α及类似物用于愈合角膜和结膜损害的用途 | |
| JP2811036B2 (ja) | ビタミンｅ点眼剤 | |
| CA2807081A1 (en) | Preservative free bimatoprost and timolol solutions | |
| JP3362501B2 (ja) | 角膜障害治療剤 | |
| WO2010150812A1 (ja) | 眼科用組成物及び白濁・沈殿抑制方法 | |
| KR102657652B1 (ko) | 눈 통증의 예방 및 치료를 위한 아미노포스핀산 유도체 | |
| US6476039B1 (en) | Ophthalmic composition | |
| US20150099807A1 (en) | Preservative free bimatoprost solutions | |
| WO2019230834A1 (ja) | 涙液層安定化剤及びマイバム分泌促進剤、ならびに眼科用組成物 | |
| EP1408929B1 (en) | Ophthalmic composition containing n-acetylcysteine for the treatment of dry-eye syndrom | |
| CN1228047C (zh) | 含有法呢基乙酸作为活性成分的角膜结膜疾病治疗药物 | |
| JP7404658B2 (ja) | 涙液層安定化剤及びマイバム分泌促進剤 | |
| JPWO2018074421A1 (ja) | 眼科用剤及び眼科用薬 | |
| JP2003055201A (ja) | ビタミンａ類含有可溶化組成物及びビタミンａ類の安定化方法 | |
| RU2464985C1 (ru) | Композиция для комплексного лечения больных с первичной открытоугольной глаукомой и заболеваниями глазной поверхности | |
| JP3845767B2 (ja) | ファルネシル酢酸を有効成分とする角結膜疾患治療剤 | |
| JP4249185B2 (ja) | 涙液異常の治療のための眼科用組成物 | |
| US20140302099A1 (en) | Ophthalmic Composition Containing Cyclosporine And method For Preparing Same | |
| JP2005187354A (ja) | 水性外用剤組成物 | |
| JP2005200411A (ja) | 涙液層安定化剤 | |
| WO2005058932A1 (ja) | 涙液層安定化剤 | |
| TR201615165A1 (tr) | Oftalmi̇k farmasöti̇k bi̇leşi̇mler |
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 |