CN100341498C - 含有2－氨基－3－(4－溴苯甲酰基)苯乙酸的水成液制剂 - Google Patents
含有2－氨基－3－(4－溴苯甲酰基)苯乙酸的水成液制剂 Download PDFInfo
- Publication number
- CN100341498C CN100341498C CNB2004800009763A CN200480000976A CN100341498C CN 100341498 C CN100341498 C CN 100341498C CN B2004800009763 A CNB2004800009763 A CN B2004800009763A CN 200480000976 A CN200480000976 A CN 200480000976A CN 100341498 C CN100341498 C CN 100341498C
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- Prior art keywords
- aqueous liquid
- liquid preparation
- amino
- hydrate
- phenylacetic acid
- 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 - Lifetime
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- 238000002360 preparation method Methods 0.000 title claims abstract description 83
- 239000007788 liquid Substances 0.000 title claims abstract description 74
- ZBPLOVFIXSTCRZ-UHFFFAOYSA-N bromfenac Chemical compound NC1=C(CC(O)=O)C=CC=C1C(=O)C1=CC=C(Br)C=C1 ZBPLOVFIXSTCRZ-UHFFFAOYSA-N 0.000 title abstract description 3
- MDYZKJNTKZIUSK-UHFFFAOYSA-N tyloxapol Chemical compound O=C.C1CO1.CC(C)(C)CC(C)(C)C1=CC=C(O)C=C1 MDYZKJNTKZIUSK-UHFFFAOYSA-N 0.000 claims abstract description 40
- 150000003839 salts Chemical class 0.000 claims abstract description 33
- 239000003889 eye drop Substances 0.000 claims abstract description 26
- 229920000642 polymer Polymers 0.000 claims abstract description 16
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 14
- 239000004721 Polyphenylene oxide Substances 0.000 claims abstract description 14
- 125000002877 alkyl aryl group Chemical group 0.000 claims abstract description 14
- 229920000570 polyether Polymers 0.000 claims abstract description 14
- 239000007923 nasal drop Substances 0.000 claims abstract description 5
- WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical compound OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 claims description 70
- 229960003424 phenylacetic acid Drugs 0.000 claims description 35
- 239000003279 phenylacetic acid Substances 0.000 claims description 35
- 230000002421 anti-septic effect Effects 0.000 claims description 28
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims description 14
- 238000000034 method Methods 0.000 claims description 6
- VSMUFFIEXQUZPA-UHFFFAOYSA-M sodium 2-phenylacetate hydrate Chemical compound [OH-].[Na+].C1(=CC=CC=C1)CC(=O)O VSMUFFIEXQUZPA-UHFFFAOYSA-M 0.000 claims description 4
- 159000000000 sodium salts Chemical class 0.000 claims description 4
- 230000000087 stabilizing effect Effects 0.000 claims description 2
- -1 fatty acid ester Chemical class 0.000 abstract description 22
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- 239000002202 Polyethylene glycol Substances 0.000 abstract description 13
- 229920001223 polyethylene glycol Polymers 0.000 abstract description 13
- 206010039083 rhinitis Diseases 0.000 abstract description 9
- 230000002757 inflammatory effect Effects 0.000 abstract description 7
- 206010010741 Conjunctivitis Diseases 0.000 abstract description 5
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- 235000014113 dietary fatty acids Nutrition 0.000 abstract description 5
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- 208000000592 Nasal Polyps Diseases 0.000 abstract description 3
- 206010039085 Rhinitis allergic Diseases 0.000 abstract description 3
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- 239000003755 preservative agent Substances 0.000 abstract 2
- RFVNOJDQRGSOEL-UHFFFAOYSA-N 2-hydroxyethyl octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCCO RFVNOJDQRGSOEL-UHFFFAOYSA-N 0.000 abstract 1
- 230000002980 postoperative effect Effects 0.000 abstract 1
- ITIONVBQFUNVJV-UHFFFAOYSA-N Etomidoline Chemical compound C12=CC=CC=C2C(=O)N(CC)C1NC(C=C1)=CC=C1OCCN1CCCCC1 ITIONVBQFUNVJV-UHFFFAOYSA-N 0.000 description 16
- 229940006198 sodium phenylacetate Drugs 0.000 description 16
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- 229960000686 benzalkonium chloride Drugs 0.000 description 13
- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 description 13
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- 239000000203 mixture Substances 0.000 description 10
- 229920001246 polyethylene glycol monostearate Polymers 0.000 description 10
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 8
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- RYYKJJJTJZKILX-UHFFFAOYSA-M sodium octadecanoate Chemical class [Na+].CCCCCCCCCCCCCCCCCC([O-])=O RYYKJJJTJZKILX-UHFFFAOYSA-M 0.000 description 6
- 239000002351 wastewater Substances 0.000 description 6
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- 239000003109 Disodium ethylene diamine tetraacetate Substances 0.000 description 4
- ZGTMUACCHSMWAC-UHFFFAOYSA-L EDTA disodium salt (anhydrous) Chemical compound [Na+].[Na+].OC(=O)CN(CC([O-])=O)CCN(CC(O)=O)CC([O-])=O ZGTMUACCHSMWAC-UHFFFAOYSA-L 0.000 description 4
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- 235000019301 disodium ethylene diamine tetraacetate Nutrition 0.000 description 4
- 150000004665 fatty acids Chemical class 0.000 description 4
- 239000002054 inoculum Substances 0.000 description 4
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 4
- 229920006316 polyvinylpyrrolidine Polymers 0.000 description 4
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 4
- 238000013112 stability test Methods 0.000 description 4
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- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
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- 235000021355 Stearic acid Nutrition 0.000 description 3
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- 125000000217 alkyl group Chemical group 0.000 description 3
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- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 239000007951 isotonicity adjuster Substances 0.000 description 3
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 3
- 239000002997 ophthalmic solution Substances 0.000 description 3
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 3
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 3
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- 239000004094 surface-active agent Substances 0.000 description 3
- 239000002562 thickening agent Substances 0.000 description 3
- RJWUMFHQJJBBOD-UHFFFAOYSA-N 2-methylheptadecane Chemical compound CCCCCCCCCCCCCCCC(C)C RJWUMFHQJJBBOD-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- 241000233866 Fungi Species 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 239000004743 Polypropylene Substances 0.000 description 2
- 239000004372 Polyvinyl alcohol Substances 0.000 description 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 150000001721 carbon Chemical group 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 238000012937 correction Methods 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- SFNALCNOMXIBKG-UHFFFAOYSA-N ethylene glycol monododecyl ether Chemical compound CCCCCCCCCCCCOCCO SFNALCNOMXIBKG-UHFFFAOYSA-N 0.000 description 2
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 125000002960 margaryl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 125000001421 myristyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 125000001400 nonyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
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- 125000002958 pentadecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 229940112041 peripherally acting muscle relaxants other quaternary ammonium compound in atc Drugs 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
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- 235000010265 sodium sulphite Nutrition 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 150000003431 steroids Chemical class 0.000 description 2
- LSNNMFCWUKXFEE-UHFFFAOYSA-L sulfite Chemical compound [O-]S([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-L 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 125000002948 undecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- DTGKSKDOIYIVQL-WEDXCCLWSA-N (+)-borneol Chemical compound C1C[C@@]2(C)[C@@H](O)C[C@@H]1C2(C)C DTGKSKDOIYIVQL-WEDXCCLWSA-N 0.000 description 1
- NOOLISFMXDJSKH-KXUCPTDWSA-N (-)-Menthol Chemical compound CC(C)[C@@H]1CC[C@@H](C)C[C@H]1O NOOLISFMXDJSKH-KXUCPTDWSA-N 0.000 description 1
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- ZVUNTIMPQCQCAQ-UHFFFAOYSA-N 2-dodecanoyloxyethyl dodecanoate Chemical compound CCCCCCCCCCCC(=O)OCCOC(=O)CCCCCCCCCCC ZVUNTIMPQCQCAQ-UHFFFAOYSA-N 0.000 description 1
- 125000006176 2-ethylbutyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(C([H])([H])*)C([H])([H])C([H])([H])[H] 0.000 description 1
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- WLJVXDMOQOGPHL-PPJXEINESA-N 2-phenylacetic acid Chemical compound O[14C](=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-PPJXEINESA-N 0.000 description 1
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Abstract
本发明涉及一种稳定的水成液制剂，含有2-氨基-3-(4-溴苯甲酰基)苯乙酸或其药用盐或其水合物，诸如四丁酚醛(tyloxapol)的烷芳基聚醚醇型聚合物，或者诸如聚乙二醇一硬脂酸酯的聚乙二醇脂肪酸酯。甚至在将防腐剂掺入至所述水成液制剂的情况下，防腐剂也可长期显示出充分的防腐效果，因而滴眼剂形式的所述水成液制剂可用于睑炎、结膜炎、巩膜炎和术后炎症的治疗。同样，滴鼻剂形式的本发明的水成液制剂可用于过敏性鼻炎、炎性鼻炎(例如慢性鼻炎、肥厚性鼻炎、鼻息肉等)的治疗。
Description
技术领域
本发明涉及一种含有2-氨基-3-(4-溴苯甲酰基)苯乙酸或其药用盐或其水合物的水成液制剂。更具体地，本发明涉及一种含有2-氨基-3-(4-溴苯甲酰基)苯乙酸的水成液制剂或其药用盐或其水合物，以及烷芳基聚醚醇类型的聚合物或聚乙二醇脂肪酸酯。
背景技术
苯甲酰基苯乙酸衍生物包括通式(I)的溴芬酸(属名)：
该通式化学名为2-氨基-3-(4-溴苯甲酰基)苯乙酸，被认为是公开于JP-A-23052/1977和对应的美国专利4.045,576中。2-氨基-3-(4-溴苯甲酰基)苯乙酸，其药用盐和其水合物被认为是非甾类抗炎症试剂，能够有效抵抗眼睛前段和后段的炎性疾病，例如睑炎、结膜炎、巩膜炎和眼科学领域中的术后炎症，其盐已被实践以滴眼剂的形式(“New Drugs in Japan，2001”，2001版，Yakuji Nippo Ltd.出版，2001年5月11日，27-29页)使用。
如上提及的滴眼剂通过加入水溶性聚合物(例如聚乙烯吡咯烷酮，聚乙烯醇等)和亚硫酸盐(例如亚硫酸钠，亚硫酸钾等)而用以稳定2-氨基-3-(4-溴苯甲酰基)苯乙酸(日本专利号2,683,676和其对应的美国专利号4,910,225)。
另外，作为不同于前面提及的一种滴眼剂，日本专利号2,954,356(对应于美国专利号5,603,929和5,653,972)公开了一种稳定的眼用组合物，所述组合物包含将抗细菌的季铵聚合物和硼酸掺入酸性眼用试剂。该处描述的酸性试剂包括，例如2-氨基-3-(4-溴苯甲酰基)苯乙酸。
进一步地，在日本专利2,954,356中有如下描述“杀藻胺(benzalkonium chloride)是眼用溶液中广泛使用的一种防腐剂”。然而，一般认为杀藻胺(benzalkonium chloride)和其他季铵化合物与诸如非甾类抗炎症药物的带有酸性基团的眼用药物组合物不相容。这些防腐剂即失去了与带电药物化合物形成复合物的能力。
在这些现有技术的参考文献中，并没有烷芳基聚醚醇类型的聚合物或聚乙二醇脂肪酸酯能够稳定2-氨基-3-(4-溴苯甲酰基)苯乙酸或其药用盐，以及抑制杀藻胺(benzalkonium chloride)和其他季铵化合物的防腐效果减少的公开内容。
发明内容
本发明的一个目的是提供一种含有2-氨基-3-(4-溴苯甲酰基)苯乙酸或其药用盐或其水合物的水成液制剂，所述水成液制剂在对眼睛无刺激的pH范围内是稳定的，并且其中将诸如杀藻胺(benzalkoniumchloride)的防腐剂掺入时，防腐剂的防腐效果基本不会减弱。
本发明的另一目的是提供一种稳定2-氨基-3-(4-溴苯甲酰基)苯乙酸或其药用盐或其水合物的水成液制剂的方法。
本发明的进一步目的是提供一种含有2-氨基-3-(4-溴苯甲酰基)苯乙酸或其药用盐或其水合物和防腐剂的水成液制剂，其中当特别地将诸如杀藻胺(benzalkonium chloride)的季铵盐作为防腐剂掺入时，所述防腐剂的防腐效果的减少被抑制。
作为各种研究的结果，本发明的发明人发现，例如通过将诸如四丁酚醛(tyloxapol)的烷芳基聚醚醇类型的聚合物，或者诸如聚乙二醇一硬脂酸酯的聚乙二醇脂肪酸酯，加入至2-氨基-3-(4-溴苯甲酰基)苯乙酸或其药用盐或其水合物的水成液制剂中，该水溶液在对眼睛无刺激的pH范围内变得稳定，并且2-氨基-3-(4-溴苯甲酰基)苯乙酸随时间的变化可被抑制，此外，当水溶液含有防腐剂时，所述防腐剂的防腐效果的恶化可长时间被抑制。本发明的发明人作了进一步的广泛研究并完成了本发明。
换句话说，本发明涉及：
(1)一种含有2-氨基-3-(4-溴苯甲酰基)苯乙酸或其药用盐或其水合物，以及烷芳基聚醚醇类型的聚合物或聚乙二醇脂肪酸酯的水成液制剂。
(2)根据上述(1)的水成液制剂，其中烷芳基聚醚醇类型的聚合物具有3-10的聚合度，烷基含有1-18个碳原子，芳香基是苯基残基，聚醚醇以通式O(CH2CH2O)xH表示，其中X是5-100的整数，
(3)根据上述(1)的水成液制剂，其中烷芳基聚醚醇类型的聚合物是四丁酚醛(tyloxapol)，
(4)根据上述(1)的水成液制剂，其中聚乙二醇脂肪酸酯中的脂肪酸的碳原子数为12-18，
(5)根据上述(1)的水成液制剂，其中的聚乙二醇脂肪酸酯是聚乙二醇一硬脂酸酯，
(6)根据上述(1)至(3)任一项中的水成液制剂，其中烷芳基聚醚醇型聚合物的浓度范围选自0.01w/v％的最小浓度至0.5w/v％的最大浓度，
(7)根据上述(1)、(2)或(4)任一项中的水成液制剂，其中聚乙二醇脂肪酸酯的浓度范围选自0.02w/v％的最小浓度至0.1w/v％的最大浓度，
(8)根据上述(1)至(7)任一项中的水成液制剂，其中2-氨基-3-(4-溴苯甲酰基)苯乙酸或其药用盐或其水合物的浓度为0.01-0.5w/v％，
(9)根据上述(1)至(8)任一项中的水成液制剂，其中含有作为防腐剂的杀藻胺(benzalkonium chloride)，
(10)根据上述(1)至(9)任一项中的水成液制剂，其中可作药用的2-氨基-3-(4-溴苯甲酰基)苯乙酸的盐是钠盐，
(11)根据上述(1)至(10)任一项中的水成液制剂，其中水成液制剂的pH处于7-9的范围，
(12)根据上述(11)的水成液制剂，其中水成液制剂的pH处于7.5-8.5的范围，
(13)根据上述(1)至(12)任一项中的水成液制剂，其中的水成液制剂是滴眼剂，
(14)根据上述(1)至(12)任一项中的水成液制剂，其中的水成液制剂是滴鼻剂，
(15)一种滴眼剂，含有2-氨基-3-(4-溴苯甲酰基)苯乙酸钠水合物和0.01-0.5w/v％的四丁酚醛(tyloxapol)，
(16)一种滴眼剂，含有2-氨基-3-(4-溴苯甲酰基)苯乙酸钠水合物和0.02-0.1w/v％的聚乙二醇一硬脂酸酯，
(17)一种使水成液制剂中2-氨基-3-(4-溴苯甲酰基)苯乙酸或其药用盐或其水合物稳定化的方法，包含将四丁酚醛(tyloxapol)或聚乙二醇一硬脂酸酯掺入含有2-氨基-3-(4-溴苯甲酰基)苯乙酸或其药用盐或其水合物的水成液制剂中，以及
(18)一种2-氨基-3-(4-溴苯甲酰基)苯乙酸或其药用盐或其水合物的水成液制剂中防腐剂的防腐效果减少的抑制方法，包含将四丁酚醛(tyloxapol)或聚乙二醇一硬脂酸酯掺入含有2-氨基-3-(4-溴苯甲酰基)苯乙酸或其药用盐或其水合物和防腐剂的水成液制剂中。
根据本发明，通过将诸如四丁酚醛(tyloxapol)的烷芳基聚醚醇类型的聚合物，或者将诸如聚乙二醇一硬脂酸酯的聚乙二醇脂肪酸酯，掺入至含有2-氨基-3-(4-溴苯甲酰基)苯乙酸或其药用盐或其水合物的水成液制剂中，可制备出含有2-氨基-3-(4-溴苯甲酰基)苯乙酸或其药用盐或其水合物的稳定水成液制剂。同样，其中掺入防腐剂的本发明水成液制剂，具有充分的防腐效果。
因而，本发明的水成液制剂可方便地用作为滴眼剂，用于诸如睑炎、结膜炎、巩膜炎和术后炎症的治疗。另外，此类水成液制剂可用作为滴鼻剂，用于诸如过敏性鼻炎、炎性鼻炎(例如慢性鼻炎、肥厚性鼻炎、鼻息肉等)的治疗。
2-氨基-3-(4-溴苯甲酰基)苯乙酸的可作药用的盐包括，例如碱金属盐，如钠盐和钾盐，以及碱土金属盐，如钙盐和镁盐，其中特别优选的是钠盐。
可根据JP-A-23052/1977(对应于美国专利4,045,576)或通过其类似方法，制备出2-氨基-3-(4-溴苯甲酰基)苯乙酸及其可作药用的盐。根据合成条件和重结晶条件，这些化合物可以其水合物的形式得到。水合物包括1/2水合物，1水合物，和3/2水合物，其中优选为3/2水合物。
在本发明的水成液制剂中，2-氨基-3-(4-溴苯甲酰基)苯乙酸及可作药用的其盐或其水合物的含量(浓度范围)通常为约0.05-0.5w/v％，优选为约0.05-0.2w/v％，尤其是约0.1w/v％，根据使用目的和待治疗的疾病程度，优选地对含量进行改变。
作为非离子表面活性剂，用作2-氨基-3-(4-溴苯甲酰基)苯乙酸及可作药用的其盐或其水合物的稳定剂的烷芳基聚醚醇型聚合物，其中烷基的碳原子数约为1-18。特别地，该烷基包括，例如甲基，乙基，丙基，异丙基，环丙基，丁基，异丁基，仲丁基，叔丁基，环丁基，戊基，异戊基，新戊基，叔戊基，1-乙基丙基，4-甲基戊基，1，1-二甲基丁基，2，2-二甲基丁基，1，2-二甲基丁基，2-乙基丁基，环戊基，己基，环己基，庚基，异庚基，辛基，异辛基，壬基，异壬基，癸基，异癸基，十一烷基，异十一烷基，十二烷基，异十二烷基，十三烷基，异十三烷基，十四烷基，异十四烷基，十五烷基，异十五烷基，十六烷基，异十六烷基，十七烷基，异十七烷基，十八烷基，异十八烷基，以及其异构体，其中优选为辛基和其异构体(如异辛基，仲辛基，1-甲基庚基，1-乙基己基，2-乙基己基，1-丙基戊基，1，5-二甲基己基，1，1，3，3，-四甲基丁基，等)，尤其优选为作为辛基异构体的1，1，3，3，-四甲基丁基。
烷芳基聚醚醇型聚合物中的芳香基可优选为苯基残基。聚醚醇可以通式O(CH2CH2O)xH表示，其中X是5-100的整数，优选为5-30，更优选为8-10。平均聚合度优选为约3-10。
在上面提及的烷芳基聚醚醇型聚合物中，尤其优选的是具有如下通式的四丁酚醛(tyloxapol)：
R＝(CH2CH20)xHx＝8-10m＜6
作为非离子表面活性剂，用作2-氨基-3-(4-溴苯甲酰基)苯乙酸及可作药用的其盐或其水合物的稳定剂的聚乙二醇脂肪酸酯的脂肪酸，其脂肪酸可优选为带有12-18碳原子的脂肪酸。此类聚乙二醇脂肪酸酯的特定实例有聚乙二醇一硬脂酸酯(如聚乙二醇8硬脂酸酯，聚乙二醇40硬脂酸酯，等)，聚乙二醇一月桂酸酯，聚乙二醇一油酸酯，聚乙二醇二异硬脂酸酯，聚乙二醇二月桂酸酯，聚乙二醇二油酸酯，等。这些化合物中，优选的是聚乙二醇一硬脂酸酯，尤其优选的是聚乙二醇四零硬脂酸酯。聚乙二醇四零硬脂酸酯是环氧乙烷缩合聚合物的一硬脂酸酯，可以通式C17H35COO(CH2CH2O)nH表示，是非离子表面活性剂，n约为40。
虽然本发明的水成液制剂中烷芳基聚醚醇型聚合物的含量依赖于所使用的化合物种类，但最小浓度约为0.01w/v％，最大浓度约为0.5w/v％。至于四丁酚醛(tyloxapol)的含量(浓度范围)，例如，其最小含量约为0.01w/v％，0.02w/v％或0.03w/v％，最大含量约为0.05w/v％，0.1w/v％，0.3w/v％，或0.5w/v％，优选地最小含量约为0.02w/v％，最大含量约为0.05w/v％。
虽然本发明的水成液制剂中聚乙二醇脂肪酸酯的含量(浓度范围)依赖于所使用的化合物种类，但其所处范围为约0.02w/v％的最小浓度至约0.1w/v％的最大浓度。例如，聚乙二醇一硬脂酸酯含量(浓度范围)所处范围为约0.02w/v％的最小含量至约0.1w/v％的最大含量，优选范围为约0.02w/v％的最小含量至约0.05w/v％的最大含量。
本发明的水成液制剂中，相对于1个重量份的2-氨基-3-(4-溴苯甲酰基)苯乙酸及可作药用的其盐或其水合物，四丁酚醛(tyloxapol)的掺入比例范围为约0.1或0.2重量份的最小含量至0.5，1，3或5重量份的最大含量。
本发明的水成液制剂中，相对于1个重量份的2-氨基-3-(4-溴苯甲酰基)苯乙酸及可作药用的其盐或其水合物，聚乙二醇一硬脂酸酯的掺入比例为约0.2重量份的最小含量至约0.5或1重量份的最大含量。
本发明中使用的防腐剂包括，例如叔铵盐(如杀藻胺(benzalkoniumchloride)，苄索氯铵等)，氯己定葡萄糖酸酯等，其中特别优选为杀藻胺(benzalkonium chloride)。
进一步地，只要达到了本发明目的，可适当地将常规的各种添加剂加入至本发明的水成液制剂中，所述添加剂例如等渗剂，缓冲液，增稠剂，稳定剂，螯合剂，pH控制剂，芳香剂等。等渗剂包括氯化钠，氯化钾，甘油，甘露糖醇，山梨糖醇，硼酸，葡萄糖，丙二醇等。缓冲液包括，例如磷酸盐缓冲液，硼酸盐缓冲液，柠檬酸盐缓冲液，酒石酸盐缓冲液，醋酸盐缓冲液，硼酸，硼砂，氨基酸等。增稠剂包括聚乙烯吡咯烷酮，羧甲基纤维素，羧丙基纤维素，羟乙基纤维素，羟丙基纤维素，羟丙基甲基纤维素，聚乙烯醇，聚丙烯酸钠等。稳定剂包括诸如亚硫酸钠的亚硫酸盐等。螯合剂包括乙二胺四乙酸钠，柠檬酸钠，缩合磷酸钠等。pH控制剂包括盐酸，氢氧化钠，磷酸，醋酸等。芳香剂包括1-薄荷醇，龙脑，樟脑，桉油等。
至于本发明的水成液制剂中上述各种添加剂的浓度，等渗剂掺入后的渗透压为约0.8-1.2，待添加的缓冲液和增稠剂各自浓度为约0.01-2w/v％和0.1-10w/v％。
本发明的水成液制剂的pH调节至约6-9，优选为约7-9，尤其是约7.5-8.5。
只要本发明目的已达到，可适当加入其他相同或不同种类的活性成分。
本发明的水成液制剂可通过本身已知的方法，或根据日本药典第14版，制备溶液或眼用溶液的一般规则(General Rules for Preparations，Solutions or Ophthalmic solutions)来制备。
本发明的水成液制剂可施用于温血动物，例如人体，老鼠，小鼠，兔子，母牛，猪，狗，猫等。
本发明的水成液制剂可容易地通过将上述组分溶解于例如蒸馏水或无菌净化水中而制备得到。例如，滴眼剂形式的水成液制剂可用于眼睛前段或后段中炎症疾病的治疗，如睑炎、结膜炎、巩膜炎和术后炎症等。含有0.1w/v％ 2-氨基-3-(4-溴苯甲酰基)苯乙酸钠水合物的水成液制剂的剂量为，例如成人每天给药3-6次，每次用量1-2滴。根据疾病程度，可对定量给药的频率进行适当控制。
本发明最佳实施方案
本发明将通过如下实验性实施例和实施例来进行例述，但并不受这些实施例的限制。
实验性实施例1：2-氨基-3-(4-溴苯甲酰基)苯乙酸钠的稳定性试验
制备含有表1中所示组分的四种2-氨基-3-(4-溴苯甲酰基)苯乙酸钠滴眼剂，分别装入聚丙烯容器中，并在60℃下进行稳定性试验。
表1
| 组分 | 对比实施例1 | A-01 | A-02 | A-03 |
| 2-氨基-3-(4-溴苯甲酰基)苯乙酸钠 | 0.1g | 0.1g | 0.1g | 0.1g |
| 硼酸 | 1.5g | 1.5g | 1.5g | 1.5g |
| 杀藻胺(benzalkoniumchloride) | 0.005g | 0.005g | 0.005g | 0.005g |
| 聚山梨醇酯80 | 0.15g | - | - | - |
| 硬脂酸40聚烃氧基酯 | - | 0.15g | - | - |
| 四丁酚醛(tyloxapol) | - | - | 0.15g | 0.02g |
| 无菌净化水 | 适量 | 适量 | 适量 | 适量 |
| 总体积 | 100mL | 100mL | 100mL | 100mL |
| pH | 7.0 | 7.0 | 7.0 | 7.0 |
| 60℃下4周后的剩余比率(％) | 51.3 | 63.7 | 73.8 | 89.6 |
上述表1中的剩余比率(％)指代通过修正从容器的水分蒸发所得数值。从表1可明显看出，在pH7.0、60℃下持续4星期实施稳定性试验，各滴眼剂中2-氨基-3-(4-溴苯甲酰基)苯乙酸钠的稳定性次序为：含四丁酚醛(tyloxapol)的制剂＞硬脂酸40聚烃氧基酯的制剂＞含聚山梨醇酯80的制剂。
进一步地，对于含有四丁酚醛(tyloxapol)的滴眼剂(组合物A-02和A-03)，含0.02w/v％四丁酚醛(tyloxapol)的组合物A-03中的2-氨基-3-(4-溴苯甲酰基)苯乙酸钠比含有0.15w/v％四丁酚醛(tyloxapol)的组合物A-02中的更稳定。
实验性实施例2：2-氨基-3-(4-溴苯甲酰基)苯乙酸钠的稳定性试验
制备含有表2中所示组分的五种2-氨基-3-(4-溴苯甲酰基)苯乙酸钠滴眼剂，分别装入聚丙烯容器中，并在60℃下保存4星期，然后测量各滴眼剂中2-氨基-3-(4-溴苯甲酰基)苯乙酸钠的含量和pH。
表2
| 组分 | A-04 | A-05 | A-06 | A-07 | A-08 | |
| 2-氨基-3-(4-溴苯甲酰基)苯乙酸钠 | 0.1g | 0.1g | 0.1g | 0.1g | 0.1g | |
| 硼酸 | 1.1g | 1.1g | 1.1g | 1.1g | 1.1g | |
| 硼砂 | 1.1g | 1.1g | 1.1g | 1.1g | 1.1g | |
| 杀藻胺(benzalkoniumchloride) | 0.005g | 0.005g | 0.005g | 0.005g | 0.005g | |
| 聚山梨醇酯80 | - | - | - | - | - | |
| 四丁酚醛(tyloxapol) | 0.02g | 0.05g | 0.03g | - | - | |
| 硬脂酸40聚烃氧基酯 | - | - | - | 0.02g | 0.05g | |
| 聚乙烯吡咯烷酮(K-30) | 2.0g | 2.0g | 2.0g | 2.0g | 1.0g | |
| 乙二胺四乙酸钠盐 | 0.02g | 0.02g | 0.02g | 0.02g | 0.02g | |
| 氢氧化钠 | 适量 | 适量 | 适量 | 适量 | 适量 | |
| 无菌净化水 | 适量 | 适量 | 适量 | 适量 | 适量 | |
| 总体积 | 100mL | 100mL | 100mL | 100mL | 100mL | |
| pH | 8.17 | 8.16 | 8.15 | 8.19 | 8.19 | |
| 60℃，4周 | 剩余比率(％) | 92.6 | 90.9 | 92.0 | 93.4 | 93.1 |
| pH | 8.15 | 8.16 | 8.15 | 8.13 | 8.14 | |
表2所示为60℃下贮存4周后2-氨基-3-(4-溴苯甲酰基)苯乙酸钠的剩余比率和pH，滴眼剂生产出来时2-氨基-3-(4-溴苯甲酰基)苯乙酸钠的剩余比率设为100％。剩余比率(％)是通过修正容器的水分蒸发所得的数值。从表2可明显看出，60℃下贮存4周后，含有0.02w/v％，0.03w/v％，0.05w/v％四丁酚醛(tyloxapol)或0.02w/v％和0.05w/v％聚乙二醇40硬脂酸酯的组合物A-04，A-05，A-06，A-07和A-08中，2-氨基-3-(4-溴苯甲酰基)苯乙酸钠的剩余比率不低于90％，这表明这些组合物具有用于滴眼剂的充分稳定性。
实验性实施例3：含有2-氨基-3-(4-溴苯甲酰基)苯乙酸钠的水成液制剂的防腐效果试验
以金黄色酿脓葡萄球菌、大肠杆菌、绿脓假单胞菌、白色念珠菌和黑曲霉来实施实验性实施例2的组合物A-04，A-05和A-07的防腐效果试验。
结果示于表3-1，3-2和3-3中。
表3-1
| A-04 | 细胞计数(CFU/mL) | ||||||
| 接种物接种物计数 | 接种后6小时 | 接种后24小时 | 接种后7天 | 接种后14天 | 接种后21天 | 接种后28天 | |
| 金黄色酿脓葡萄球菌 | 2.1×106 | 3.0×101 | 0 | 0 | 0 | 0 | 0 |
| 大肠杆菌 | 6.5×106 | 0 | 0 | 0 | 0 | 0 | 0 |
| 绿脓假单胞菌 | 5.8×106 | 0 | 0 | 0 | 0 | 0 | 0 |
| 白色念珠菌 | 3.2×105 | - | - | 0 | 0 | 0 | 0 |
| 黑曲霉 | 1.8×105 | - | - | 0 | 0 | 0 | 0 |
表3-2
| A-05 | 细胞计数(CFU/mL) | ||||||
| 接种物计数 | 接种后6小时 | 接种后24小时 | 接种后7天 | 接种后14天 | 接种后21天 | 接种后28天 | |
| 金黄色酿脓葡萄球菌 | 2.1×106 | 1.7×105 | 2.0×101 | 0 | 0 | 0 | 0 |
| 大肠杆菌 | 6.5×106 | 0 | 0 | 0 | 0 | 0 | 0 |
| 绿脓假单胞菌 | 5.8×106 | 0 | 0 | 0 | 0 | 0 | 0 |
| 白色念珠菌 | 3.2×105 | - | - | 0 | 0 | 0 | 0 |
| 黑曲霉 | 1.8×105 | - | - | 0 | 0 | 0 | 0 |
表3-3
| A-07 | 细胞计数(CFU/mL) | ||||||
| 接种物计数 | 接种后6小时 | 接种后24小时 | 接种后7天 | 接种后14天 | 接种后21天 | 接种后28天 | |
| 金黄色酿脓葡萄球菌 | 2.7×106 | 3.1×104 | 0 | 0 | 0 | 0 | 0 |
| 大肠杆菌 | 7.4×106 | 0 | 0 | 0 | 0 | 0 | 0 |
| 緑脓假单胞菌 | 8.8×106 | 0 | 0 | 0 | 0 | 0 | 0 |
| 白色念珠菌 | 4.6×105 | - | - | 0 | 0 | 0 | 0 |
| 黑曲霉 | 1.0×105 | - | - | 0 | 0 | 0 | 0 |
从表3-1，3-2和3-3可明显看出，组合物A-04的防腐效果发现与欧洲药典(EP)中的EP-标准A一致，组合物A-05和A-07的防腐效果发现与EP-标准B一致。
如下给出EP-标准A和EP-标准B。
EP-标准A：
接种后6小时，24小时和28天，细菌(金黄色酿脓葡萄球菌、绿脓假单胞菌)的活细胞计数分别减少至不超过1/100，不超过1/1000和无法检测出。
接种后7小时，真菌(白色念珠菌、黑曲霉)的活细胞计数减少至不超过1/100，此后细胞计数平稳或减少。
EP-标准B：
接种后24小时和7天，细菌(金黄色酿脓葡萄球菌、绿脓假单胞菌)的活细胞计数分别减少至不超过1/10，不超过1/1000，此后细胞计数平稳或减少。
接种后14天，真菌(白色念珠菌、黑曲霉)的活细胞计数减少至不超过1/10，此后细胞计数与接种后14天保持相同水平。
实施例1：滴眼剂
| 2-氨基-3-(4-溴苯甲酰基)苯乙酸钠3/2水合物 | 0.1g |
| 硼酸 | 1.1g |
| 硼砂 | 1.1g |
| 杀藻胺(benzalkonium chloride) | 0.005g |
| 四丁酚醛(tyloxapol) | 0.02g |
| 聚乙烯吡咯烷酮(K-30) | 2.0g |
| 乙二胺四乙酸钠盐 | 0.02g |
| 氢氧化钠 | 适量 |
| 无菌净化水 | 使总体积达到100mL |
| pH8.17 |
以常规方式，使用上述组分制备滴眼剂。
实施例2：滴眼剂
| 2-氨基-3-(4-溴苯甲酰基)苯乙酸钠3/2水合物 | 0.1g |
| 硼酸 | 1.1g |
| 硼砂 | 1.1g |
| 杀藻胺(benzalkonium chloride) | 0.005g |
| 四丁酚醛(tyloxapol) | 0.05g |
| 聚乙烯吡咯烷酮(K-30) | 2.0g |
| 乙二胺四乙酸钠盐 | 0.02g |
| 氢氧化钠 | 适量 |
| 无菌净化水 | 使总体积达到100mL |
| pH 8.16 |
以常规方式，使用上述组分制备滴眼剂。
实施例3：滴眼剂
| 2-氨基-3-(4-溴苯甲酰基)苯乙酸钠3/2水合物 | 0.1g |
| 硼酸 | 1.1g |
| 硼砂 | 1.1g |
| 杀藻胺(benzalkonium chloride) | 0.005g |
| 聚乙二醇40硬脂酸酯 | 0.02g |
| 聚乙烯吡咯烷酮(K-30) | 2.0g |
| 乙二胺四乙酸钠盐 | 0.02g |
| 氢氧化钠 | 适量 |
| 无菌净化水 | 使总体积达到100mL |
| pH 8.19 |
以常规方式，使用上述组分制备滴眼剂。
工业适用性
本发明滴眼剂形式的水成液制剂，可用于睑炎、结膜炎、巩膜炎和术后炎症的治疗。此类制剂也可用作滴鼻剂，用于诸如过敏性鼻炎、炎性鼻炎(例如慢性鼻炎、肥厚性鼻炎、鼻息肉等)的治疗。
本发明基于在日本提交的申请12427/2003之上，并包括该申请的全部内容。此处引用的包括专利和专利申请的参考文献，以与其内容公开时的相同水平引入本申请作为参考。此外，由于很明显地，可超出上述例解和实施例范围而实施本发明，按照前面的描述，可对本发明作各种其他修正和改变，因而应认为这些修正和改变是处于所附权利要求范围内的。
Claims (13)
1.一种水成液制剂，含有2-氨基-3-(4-溴苯甲酰基)苯乙酸或其药用盐或其水合物，以及四丁酚醛作为烷芳基聚醚醇型聚合物。
2.根据权利要求1的水成液制剂，其中四丁酚醛的浓度选择范围为0.01w/v％的最小浓度至0.5w/v％的最大浓度。
3.根据权利要求1和2任一项的水成液制剂，其中2-氨基-3-(4-溴苯甲酰基)苯乙酸或其药用盐或其水合物的浓度为0.01-0.5w/v％。
4.根据权利要求1和2任一项的水成液制剂，其中含有作为防腐剂的杀藻胺。
5.根据权利要求1和2任一项的水成液制剂，其中2-氨基-3-(4-溴苯甲酰基)苯乙酸的药用盐是钠盐。
6.根据权利要求1和2任一项的水成液制剂，其中水成液制剂的pH在7-9的范围内。
7.根据权利要求6的水成液制剂，其中水成液制剂的pH在7.5-8.5的范围内。
8.根据权利要求1和2任一项的水成液制剂，其中水成液制剂是滴眼剂。
9.根据权利要求1和2任一项的水成液制剂，其中水成液制剂是滴鼻剂。
10.根据权利要求1和2任一项的水成液制剂，其中的水成液制剂是滴眼剂，含有2-氨基-3-(4-溴苯甲酰基)苯乙酸钠水合物和0.01-0.5w/v％的四丁酚醛。
11.一种使水成液制剂中的2-氨基-3-(4-溴苯甲酰基)苯乙酸或其药用盐或其水合物稳定化的方法，包含将四丁酚醛掺入至含有2-氨基-3-(4-溴苯甲酰基)苯乙酸或其药用盐或其水合物的水成液制剂中。
12.一种抑制在2-氨基-3-(4-溴苯甲酰基)苯乙酸或其药用盐或其水合物的水成液制剂中的防腐剂的防腐效果降低的方法，包含将四丁酚醛掺入至含有2-氨基-3-(4-溴苯甲酰基)苯乙酸或其药用盐或其水合物和防腐剂的水成液制剂中。
13.根据权利要求1的水成液制剂在制备滴眼剂中的应用。
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP12427/2003 | 2003-01-21 | ||
| JP2003012427 | 2003-01-21 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1700913A CN1700913A (zh) | 2005-11-23 |
| CN100341498C true CN100341498C (zh) | 2007-10-10 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB2004800009763A Expired - Lifetime CN100341498C (zh) | 2003-01-21 | 2004-01-16 | 含有2－氨基－3－(4－溴苯甲酰基)苯乙酸的水成液制剂 |
Country Status (15)
| Country | Link |
|---|---|
| US (9) | US8129431B2 (zh) |
| EP (1) | EP1586316B1 (zh) |
| JP (1) | JP4500261B2 (zh) |
| KR (1) | KR101059711B1 (zh) |
| CN (1) | CN100341498C (zh) |
| AT (1) | ATE393627T1 (zh) |
| BE (1) | BE2011C027I2 (zh) |
| CA (2) | CA3043910A1 (zh) |
| DE (2) | DE602004013420T2 (zh) |
| ES (1) | ES2301964T3 (zh) |
| HK (1) | HK1083468A1 (zh) |
| HU (1) | HUS1100022I1 (zh) |
| MX (1) | MX2016014404A (zh) |
| PT (1) | PT1586316E (zh) |
| WO (2) | WO2004064828A1 (zh) |
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- 2004-01-16 US US10/525,006 patent/US8129431B2/en active Active
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