CN110013464A - 一种滴眼液及其制备方法 - Google Patents
一种滴眼液及其制备方法 Download PDFInfo
- Publication number
- CN110013464A CN110013464A CN201810017324.4A CN201810017324A CN110013464A CN 110013464 A CN110013464 A CN 110013464A CN 201810017324 A CN201810017324 A CN 201810017324A CN 110013464 A CN110013464 A CN 110013464A
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- Prior art keywords
- eye drops
- sodium
- amphoteric ion
- ion polymer
- gram
- Prior art date
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- 239000003889 eye drop Substances 0.000 title claims abstract description 47
- 229940012356 eye drops Drugs 0.000 title claims abstract description 47
- 238000002360 preparation method Methods 0.000 title abstract description 13
- 229920000642 polymer Polymers 0.000 claims abstract description 31
- 210000001508 eye Anatomy 0.000 claims abstract description 11
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 40
- 235000002639 sodium chloride Nutrition 0.000 claims description 30
- 150000002500 ions Chemical class 0.000 claims description 27
- 239000011780 sodium chloride Substances 0.000 claims description 19
- 239000000178 monomer Substances 0.000 claims description 10
- 239000000203 mixture Substances 0.000 claims description 9
- 239000000022 bacteriostatic agent Substances 0.000 claims description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- 239000002202 Polyethylene glycol Substances 0.000 claims description 5
- 229960000686 benzalkonium chloride Drugs 0.000 claims description 5
- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 claims description 5
- 239000001257 hydrogen Substances 0.000 claims description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims description 5
- 229920001223 polyethylene glycol Polymers 0.000 claims description 5
- YWIVKILSMZOHHF-QJZPQSOGSA-N sodium;(2s,3s,4s,5r,6r)-6-[(2s,3r,4r,5s,6r)-3-acetamido-2-[(2s,3s,4r,5r,6r)-6-[(2r,3r,4r,5s,6r)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2- Chemical compound [Na+].CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 YWIVKILSMZOHHF-QJZPQSOGSA-N 0.000 claims description 5
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 4
- -1 hydrogen sodium-disodium hydrogen phosphate Chemical class 0.000 claims description 4
- 230000003204 osmotic effect Effects 0.000 claims description 4
- 239000003795 chemical substances by application Substances 0.000 claims description 3
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims description 2
- 229960002233 benzalkonium bromide Drugs 0.000 claims description 2
- KHSLHYAUZSPBIU-UHFFFAOYSA-M benzododecinium bromide Chemical compound [Br-].CCCCCCCCCCCC[N+](C)(C)CC1=CC=CC=C1 KHSLHYAUZSPBIU-UHFFFAOYSA-M 0.000 claims description 2
- 229910021538 borax Inorganic materials 0.000 claims description 2
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 claims description 2
- 239000004327 boric acid Substances 0.000 claims description 2
- SEGLCEQVOFDUPX-UHFFFAOYSA-N di-(2-ethylhexyl)phosphoric acid Chemical compound CCCCC(CC)COP(O)(=O)OCC(CC)CCCC SEGLCEQVOFDUPX-UHFFFAOYSA-N 0.000 claims description 2
- 229960001617 ethyl hydroxybenzoate Drugs 0.000 claims description 2
- NUVBSKCKDOMJSU-UHFFFAOYSA-N ethylparaben Chemical compound CCOC(=O)C1=CC=C(O)C=C1 NUVBSKCKDOMJSU-UHFFFAOYSA-N 0.000 claims description 2
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 2
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 2
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 2
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 claims description 2
- GYCKQBWUSACYIF-UHFFFAOYSA-N o-hydroxybenzoic acid ethyl ester Natural products CCOC(=O)C1=CC=CC=C1O GYCKQBWUSACYIF-UHFFFAOYSA-N 0.000 claims description 2
- 239000004328 sodium tetraborate Substances 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims 4
- 125000000547 substituted alkyl group Chemical group 0.000 claims 3
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 claims 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 claims 2
- 235000009508 confectionery Nutrition 0.000 claims 2
- WRMNZCZEMHIOCP-UHFFFAOYSA-N 2-phenylethanol Chemical compound OCCC1=CC=CC=C1 WRMNZCZEMHIOCP-UHFFFAOYSA-N 0.000 claims 1
- CYDQOEWLBCCFJZ-UHFFFAOYSA-N 4-(4-fluorophenyl)oxane-4-carboxylic acid Chemical compound C=1C=C(F)C=CC=1C1(C(=O)O)CCOCC1 CYDQOEWLBCCFJZ-UHFFFAOYSA-N 0.000 claims 1
- NIXOWILDQLNWCW-UHFFFAOYSA-N Acrylic acid Chemical compound OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 claims 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 claims 1
- QFOHBWFCKVYLES-UHFFFAOYSA-N Butylparaben Chemical compound CCCCOC(=O)C1=CC=C(O)C=C1 QFOHBWFCKVYLES-UHFFFAOYSA-N 0.000 claims 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 claims 1
- 229920002307 Dextran Polymers 0.000 claims 1
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims 1
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 claims 1
- 108010039918 Polylysine Proteins 0.000 claims 1
- 229920000289 Polyquaternium Polymers 0.000 claims 1
- 229920002125 Sokalan® Polymers 0.000 claims 1
- PTQWFLCGYPLVQU-UHFFFAOYSA-M [Na+].CC([O-])=O.OB(O)O Chemical compound [Na+].CC([O-])=O.OB(O)O PTQWFLCGYPLVQU-UHFFFAOYSA-M 0.000 claims 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 claims 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 claims 1
- 239000000337 buffer salt Substances 0.000 claims 1
- 239000001110 calcium chloride Substances 0.000 claims 1
- 229910001628 calcium chloride Inorganic materials 0.000 claims 1
- 235000011148 calcium chloride Nutrition 0.000 claims 1
- 229960001631 carbomer Drugs 0.000 claims 1
- 229960002152 chlorhexidine acetate Drugs 0.000 claims 1
- 229960002086 dextran Drugs 0.000 claims 1
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 claims 1
- 239000008103 glucose Substances 0.000 claims 1
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 claims 1
- FZWBNHMXJMCXLU-BLAUPYHCSA-N isomaltotriose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1OC[C@@H]1[C@@H](O)[C@H](O)[C@@H](O)[C@@H](OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O)O1 FZWBNHMXJMCXLU-BLAUPYHCSA-N 0.000 claims 1
- 229910001629 magnesium chloride Inorganic materials 0.000 claims 1
- 235000011147 magnesium chloride Nutrition 0.000 claims 1
- 125000004430 oxygen atom Chemical group O* 0.000 claims 1
- PDTFCHSETJBPTR-UHFFFAOYSA-N phenylmercuric nitrate Chemical compound [O-][N+](=O)O[Hg]C1=CC=CC=C1 PDTFCHSETJBPTR-UHFFFAOYSA-N 0.000 claims 1
- 229920001983 poloxamer Polymers 0.000 claims 1
- 229960000502 poloxamer Drugs 0.000 claims 1
- 229920000656 polylysine Polymers 0.000 claims 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims 1
- 239000001103 potassium chloride Substances 0.000 claims 1
- 235000011164 potassium chloride Nutrition 0.000 claims 1
- 229940069328 povidone Drugs 0.000 claims 1
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 claims 1
- MCSINKKTEDDPNK-UHFFFAOYSA-N propyl propionate Chemical compound CCCOC(=O)CC MCSINKKTEDDPNK-UHFFFAOYSA-N 0.000 claims 1
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 claims 1
- 229960003415 propylparaben Drugs 0.000 claims 1
- 239000001540 sodium lactate Substances 0.000 claims 1
- 229940005581 sodium lactate Drugs 0.000 claims 1
- 235000011088 sodium lactate Nutrition 0.000 claims 1
- 239000001488 sodium phosphate Substances 0.000 claims 1
- 229910000162 sodium phosphate Inorganic materials 0.000 claims 1
- POECFFCNUXZPJT-UHFFFAOYSA-M sodium;carbonic acid;hydrogen carbonate Chemical compound [Na+].OC(O)=O.OC([O-])=O POECFFCNUXZPJT-UHFFFAOYSA-M 0.000 claims 1
- 239000004334 sorbic acid Substances 0.000 claims 1
- 235000010199 sorbic acid Nutrition 0.000 claims 1
- 229940075582 sorbic acid Drugs 0.000 claims 1
- RTKIYNMVFMVABJ-UHFFFAOYSA-L thimerosal Chemical compound [Na+].CC[Hg]SC1=CC=CC=C1C([O-])=O RTKIYNMVFMVABJ-UHFFFAOYSA-L 0.000 claims 1
- 229940033663 thimerosal Drugs 0.000 claims 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 claims 1
- XPFJYKARVSSRHE-UHFFFAOYSA-K trisodium;2-hydroxypropane-1,2,3-tricarboxylate;2-hydroxypropane-1,2,3-tricarboxylic acid Chemical compound [Na+].[Na+].[Na+].OC(=O)CC(O)(C(O)=O)CC(O)=O.[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O XPFJYKARVSSRHE-UHFFFAOYSA-K 0.000 claims 1
- 230000001934 delay Effects 0.000 abstract 1
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 18
- 239000000243 solution Substances 0.000 description 15
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical class CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 13
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 12
- 238000006243 chemical reaction Methods 0.000 description 12
- 229940090044 injection Drugs 0.000 description 12
- 239000007924 injection Substances 0.000 description 12
- 238000002347 injection Methods 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 12
- 239000003999 initiator Substances 0.000 description 9
- 150000003839 salts Chemical class 0.000 description 9
- 238000003756 stirring Methods 0.000 description 9
- 208000005494 xerophthalmia Diseases 0.000 description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- 239000003643 water by type Substances 0.000 description 8
- 239000000843 powder Substances 0.000 description 7
- LSXWFXONGKSEMY-UHFFFAOYSA-N di-tert-butyl peroxide Chemical compound CC(C)(C)OOC(C)(C)C LSXWFXONGKSEMY-UHFFFAOYSA-N 0.000 description 6
- 229940079593 drug Drugs 0.000 description 6
- 239000003814 drug Substances 0.000 description 6
- 229910052757 nitrogen Inorganic materials 0.000 description 6
- 238000006116 polymerization reaction Methods 0.000 description 6
- 229910052708 sodium Inorganic materials 0.000 description 6
- 239000011734 sodium Substances 0.000 description 6
- NOOLISFMXDJSKH-UTLUCORTSA-N (+)-Neomenthol Chemical compound CC(C)[C@@H]1CC[C@@H](C)C[C@@H]1O NOOLISFMXDJSKH-UTLUCORTSA-N 0.000 description 5
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- KIUKXJAPPMFGSW-DNGZLQJQSA-N (2S,3S,4S,5R,6R)-6-[(2S,3R,4R,5S,6R)-3-Acetamido-2-[(2S,3S,4R,5R,6R)-6-[(2R,3R,4R,5S,6R)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylic acid Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 KIUKXJAPPMFGSW-DNGZLQJQSA-N 0.000 description 3
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Abstract
本发明公开了一种滴眼液及其制备方法，其主要有效成分为两性离子聚合物，在滴入眼睛后形成亲水超滑层，增加眼泪粘度，延缓泪膜破裂时间，降低眼睛的摩擦，缓解疲劳。
Description
技术领域
本发明涉及一种滴眼液，具体地是一种含有两性离子聚合物，具有润滑性能，延缓泪膜破裂时间，可以缓解眼睛疲劳的滴眼液。
技术背景
干眼症影响10～20％的人群，随着年龄的增长，分泌眼泪的数量和质量下降，患干眼症的比例也随之上升。近年来由于电脑和智能手机的普及，使用视屏操作的人数、时间和强度明显增加，以致现代干眼症的发病率逐年上升，严重影响到青少年视力的正常发育和成年人的用眼健康。
根据2017年第二次国际干眼症研讨会的定义，干眼症是一种多因素的眼表疾病，以泪膜动态平衡损失为特征，并伴随着眼部症状，其中泪膜不稳定和高渗性，眼表炎症和损伤，以及神经感觉异常起病因作用。干眼症的定义从1995年到2007年，再到2017年的多次变更，反应了干眼症的复杂性和人们对其认识的不断加深。常见的干眼症症状包括眼睛干涩、容易疲倦、眼痒、有异物感、痛灼热感、分泌物黏稠、怕风、畏光、对外界刺激很敏感；有时眼睛太干，基本泪液不足，反而刺激反射性泪液分泌，而造成常常流泪；较严重者眼睛会红肿、充血、角质化、角膜上皮破皮而有丝状物黏附，这种损伤日久则可造成角结膜病变，并会造成视力的永久性损伤。
干眼症最直观的检测可以通过泪膜的破裂时间来判断，即泪膜从开始形成到出现干燥斑点的时间，一般小于秒为10泪膜不稳定，由于泪膜破裂，造成眼睛感觉干涩。泪膜不稳定一般是由于眼泪分泌不足，或眼泪质量问题(例如渗透压过高)。
缓解干眼症最直接易行的方法是使用人工眼泪，用来补充水分，增加眼泪粘度延长泪膜破裂时间，刺激泪液分泌，或者添加各种成分的药物来治疗眼科疾病。
中国专利号“1943650B”公布了一种玫瑰水滴眼液，该滴眼液是以水和玫瑰花蒸馏制得的玫瑰水为主要原料，添加马来那敏、甘草酸二钾、氯化钠、L-谷氨酸钠、苯扎氯铵、氯丁醇溶和薄荷醇，用氢氧化钠调整pH值到5.5，得到所述滴眼液。
中国专利号“101961486B”公布了含一种内源性激肽释放酶结合蛋白SA3K，(SERPINA3K，亦称为KBP kallikrein-binding protein)的滴眼液，其辅助成分包括胎牛血清、低分子右旋糖酐、羟乙基哌嗪乙硫磺酸、渗透压缓冲剂、抗生素妥布霉素以及平衡盐溶液。
中国专利号“102579599B”公布了一种含夏天无(一种植物块茎提取物，主要有效成分普鲁托品)的滴眼液，含稀磷酸溶液及辅料：磷酸二氢钠、增溶剂、依地酸二钠、抑菌剂、增稠剂、药用乙醇、磷酸氢二钠、甘油以及注射用水。
中国专利号“102670494B”公布了一种含玻璃酸钠和左氧氟沙星以及辅料磷酸二氢钠、磷酸氢二钠、羟苯甲酯、羟苯乙酯、氯化钠以及注射用水的滴眼液，具有增黏作用和保湿作用的水溶性辅料与药物以分子形式混合存在于水溶液中。
中国专利号“102697713B”公布了一种玻璃酸钠滴眼液及其制备方法。该滴眼液每100毫升由以下的组分构成：玻璃酸钠80～150毫克、硼酸130～200毫克，硼砂10～20毫克，依地酸二钠8～15毫克，6-氨基己酸80～160毫克、甘露醇80～160毫克、氯化钠600～800毫克、苯扎氯铵3～10毫克、冰片8～15毫克，注射用水加至100毫升，并调节pH为6.0～7.8。
中国专利号“102793786B”公布了一种防眼疲劳的滴眼液，各成份如下：熊胆粉2～4克、决明子5～8克、黄柏2～5克，白菊花8～10克、龙胆草2～4克、金银花4～6克、冬虫夏草1～2克；按照上述重量，取清洗、去杂、炮制好的药材，加入适量的水浸泡2小时，加热煎煮2次，每次30分钟至50分钟，后冷却、过滤、浓缩至100ml，加入PH值调节剂调节PH值至4～9；所述pH值调节剂可以是磷酸盐缓冲剂或硼酸盐缓冲液。
中国专利号“102961399B”公布了一种氯化钠滴眼液及其制备方法，该滴眼液包含氯化钠、羟丙甲纤维素和注射用水，还可以添加抑菌剂和酸碱调节剂。
中国专利号“103608000B”公布了一种含有透明质酸(即玻璃酸)或其盐以及丙二醇的滴眼液，该滴眼液采用0.001～0.002％(w/v)的浓度的苯扎氯铵作为防腐剂。
中国专利号“103623003B”公布了一种珍珠明目滴眼液及其制备方法，具体是在该制剂处方中加入丁二醇，减少原有配方中乙醇带来的刺激反应。
中国专利号“104069118B”公布了一种滴眼液及其制备方法，其中妥布霉素、盐酸莫西沙星和牛磺酸以特定比例组合。
中国专利号“104127441B”公布了一种抗眼疲劳的滴眼液及其制备方法。滴眼液由下列成份组成：氨碘肽滴眼液、肌苷注射液、三磷酸腺苷二钠注射液、消旋山莨菪碱注射液、维生素B6注射液，牛磺酸滴眼液和眼用助剂，其中眼用助剂是以下至少一种：注射用水或等渗调节剂，等渗调节剂是以下至少一种：氯化钠生理盐水、葡萄糖注射液、山梨醇滴眼液、硼酸盐缓冲液、甘露醇注射液或聚乙二醇滴眼液。
美国厂商Alcon Laboratories生产一种以聚乙二醇(PEG400)为基础的滴眼液。
上面所述的各种滴眼液以及市场上的其它滴眼液虽然对缓解眼疲劳有一定的作用，但是大多含有各种药物，长期使用容易产生药物依赖，疗效也会越来越不明显，更严重的会导致眼睛的器质性变化，产生严重的后果。
有的药物，例如玻璃酸，为一种生物大分子粘多糖，易被污染长菌。为了防止细菌感染，滴眼液中多需添加抑菌剂，比如苯扎氯铵、苯扎溴铵等。长期使用这些抑菌剂会带给患者一些毒理作用及不良反应，如角结膜膜上皮细胞损伤，甚至脱落，还包括刺激性、变态反应、角化、角膜变性和眼脸炎等。
很多药物还存在稳定性的问题，例如玻璃酸钠在光、热下不稳定，易降解，不宜在室温下长期保存。聚乙二醇在室温下长期保存会氧化或水解，增加溶液中醛类，羟化物和过氧化物的浓度，并会导致pH值的改变。
技术内容
为了解决滴眼液存在的不稳定，易感染，不能长期使用等问题，本发明的一个目的是提供一种长期稳定安全无毒性的滴眼液。
两性离子聚合物是一类同时带有阴、阳离子基团的聚合物，依据分子结构它主要包括磷酰胆碱型、磺基甜菜碱型、羧基甜菜碱型以及混合型两性离子聚合物等。两性离子聚合物具有极强的亲水性、优良的热和化学稳定性、优异的生物相容性以及良好的抗污染性能等特性。由于两性离子聚合物优良的亲水性，使得其与水结合，能形成一层水膜，具有优异的润滑性能，可以用作滴眼液的主要成分，显著缓解因为泪膜破裂而引起的干眼症问题。
两性离子聚合物的合成大多采用自由基聚合的方法，它与离子型聚合相比具有反应条件温和，单体种类多等优点。自由基聚合过程的例子包括但不限于紫外、热或氧化还原引发的过程。
(i)紫外引发剂
在一种实施方案中，将紫外引发剂与两性离子单体溶解在水溶液中，然后暴露于紫外光中，引发接自由基聚合反应。
紫外自由基引发剂包括但不限于：1-羟基环己基苯基酮、2，2-二乙氧基苯乙酮、2-羟基-2-甲基苯丙酮、2，2-二甲氧基-2-苯基苯乙酮、安息香乙醚、安息香异丁基醚、安息香甲醚、安息香、2-甲基二苯甲酮、3，4-二甲基二苯甲酮、3-羟基二苯甲酮、3-甲基二苯甲酮、4-(二乙氨基)二苯甲酮、4-苯甲酰基二苯基、4-羟基二苯甲酮、4-甲基二苯甲酮、二苯甲酮、苯甲酰基甲酸甲酯、米希勒酮、锍、碘、2-(4-甲氧基苯乙烯基)-4，6-二(三氯甲基)-1，3，5-三嗪、二苯基碘、对甲苯磺酸盐、N-羟基-5-降冰片烯-2，3-二甲酰亚胺全氟代-1-丁烷磺酸酯、N-羟基萘酰亚胺三氟甲磺酸盐、2-叔丁基蒽醌、9，10-菲醌、蒽醌-2-磺酸钠盐单水合物、樟脑醌、二苯基(2，4，6-三甲基苯甲酰基)氧化膦、10-甲基吩噻嗪、噻吨酮。
(ii)热引发剂
在另一种实施方案中，采用热活化的热引发剂替代上述紫外引发剂，通过加热单体水溶液的温度至期望温度而引发，直至聚合反应完成。
适宜的热引发剂包括但不限：过氧苯甲酸叔戊酯、4，4-偶氮二(4-氰基戊酸)、
2，2′-偶氮二异丁腈(AIBN)、过氧化苯甲酰、2，2-二(过氧化叔丁基)丁烷、1，1-二(过氧化叔丁基)环己烷、2，5-二(过氧化叔丁基)-2，5-二甲基己烷、2，5-二(过氧化叔丁基)-2，5-二甲基-3-己炔，二(1-(过氧化叔丁基)-1-甲基乙基)苯、1，1-二(过氧化叔丁基)-3，3，5-三甲基环己烷、氢过氧化叔丁基、过乙酸叔丁酯、过氧化叔丁基、过苯甲酸叔丁酯、过氧化叔丁基碳酸异丙酯、氢过氧化枯烯、过氧化环己酮、过氧化二枯基、过氧化月桂酰、过氧化2，4-戊二酮、过乙酸、过硫酸钾。加热溶液要达到的温度取决于单体和引发剂，聚合反应通过在液氮中快速冷却反应溶液而淬灭。
(iii)氧化还原引发剂
在另一种实施方案中，将氧化还原引发剂体系用于引发两性离子单体的聚合反应。氧化还原引发剂体系通常包括一对引发剂：氧化剂与还原剂。氧化还原引发过程被看作是在温和条件下有效生成自由基的最有效的单电子迁移反应。
适宜的氧化剂包括但不限于：过氧化物、过硫酸盐、过焦硫酸盐、过二磷酸盐、高锰酸盐、金属如Mn(III)、Ce(IV)、V(V)、Co(III)、Cr(VI)和Fe(III)的盐。
适宜的还原剂包括但不限于：诸如Fe(II)、Cr(II)、V(II)、Ti(III)、Cu(II)和Ag(I)的金属盐、硫的含氧酸、羟酸、醇、硫醇、酮、醛、胺和酰胺。
通过直接从氧化还原反应生成的自由基可以引发聚合反应。
具体实施方式
实施例1不含抑菌剂的滴眼液
将100克1，3-丙磺酸内酯加入1000毫升无水乙酸乙酯中，再加入80克1-乙烯基咪唑，在25℃反应7天，得到白色的1-乙烯基-3-(3-磺基丙基)咪唑鎓氢氧化物内盐沉淀。用无水乙酸乙酯反复冲洗，并在真空中干燥。
将100克1-乙烯基-3-(3-磺基丙基)咪唑鎓氢氧化物内盐和1.3克4，4’-偶氮双(4-氰基戊酸)混合，加入2000毫升去离子水搅拌溶解，然后倒入一密封容器，通氮气15分钟，在60℃水浴加热24小时，再加入5000毫升1M溴化钾溶液，在去离子水中透析，得到的琥珀色沉淀即为咪唑烷基磺酸两性离子聚合物。将其在110℃真空中加热干燥，并碾制成粉末。
配制100毫升含上述两性离子聚合物的滴眼液：
量取100毫升注射用水，准确称量氯化钠0.5克，加入搅拌至完全溶解；
准确称量0.5克上述两性离子聚合物，加入配制好的氯化钠溶液，搅拌至完全溶解；药液经过滤后装入玻璃瓶内。
实施例2不含抑菌剂的滴眼液
将120克丙烯酰胺丙基二甲基胺和200毫升丙酮以及阻聚剂加入三口烧瓶中，将50克1，3-丙基磺内酯和100毫升丙酮的混合物加入滴液漏斗中，在2小时内逐滴加入烧瓶中，55℃下反应24小时。3-(丙烯酰胺丙基二甲胺基)丙磺酸盐
以白色晶体析出，用大量丙酮和乙醚的混合液(体积比3∶1)反复冲洗，除去未反应原料，于55℃真空干燥。
称取50克丙烯酰胺和1.0克3-(丙烯酰胺丙基二甲胺基)丙磺酸盐单体于盛有500毫升0.5M氯化钠溶液的聚合瓶中，振荡使之完全溶解。氮气保护下加入30毫克偶氮二异丁腈，55℃恒温反应。反应结束后，用丙酮提纯，真空干燥，粉碎后得到白色粉末。
配制100毫升含上述两性离子聚合物的滴眼液：
量取100毫升注射用水，准确称量氯化钠0.5克，加入搅拌至完全溶解；
准确称量0.5克上述两性离子聚合物，加入配制好的氯化钠溶液，搅拌至完全溶解，既得。
实施例3
将500克甲基丙烯酸二甲氨乙酯和400克1，4-丁磺酸内酯，2.0克1，3-二硝基苯溶解在5000毫升乙腈中，在60℃回流反应36个小时，得到浅黄色糊状沉淀，在乙酸乙酯中清洗，得到固体沉淀，粉碎并过滤，在乙酸乙酯中洗涤三次，室温在真空中干燥48小时。将值得的粉末200克与500毫克偶氮二异丁腈和500克三氟乙醇混合，氮气保护下55℃恒温反应24小时。反应结束后，用丙酮提纯，真空干燥，粉碎后得到4-[N，N-二甲基-[2-(2-甲基丙-2-烯酰氧基)乙基]铵]丁烷-1-磺酸内盐白色粉末。
配制100毫升含上述两性离子聚合物的滴眼液：
量取100毫升注射用水，准确称量氯化钠0.5克，加入搅拌至完全溶解；
准确称量1.0克上述两性离子聚合物，加入配制好的氯化钠溶液，搅拌至完全溶解，既得。
实施例4
将1000克甲基丙烯酸二乙氨乙酯和400克1，3-丙磺酸内酯，2.0克1，3-二硝基苯溶解在10升乙腈中，在60℃回流反应24个小时，得到浅黄色糊状沉淀，在乙酸乙酯中清洗，得到固体沉淀，粉碎并过滤，在乙酸乙酯中洗涤三次，室温在真空中干燥48小时。将值得的粉末200克与500毫克偶氮二异丁腈和500克三氟乙醇混合，氮气保护下55℃恒温反应24小时。反应结束后，用丙酮提纯，真空干燥，粉碎后得到3-[N，N-二乙基-[2-(2-甲基丙-2-烯酰氧基)乙基]铵]丙烷-1-磺酸内盐白色粉末。
配制100毫升含上述两性离子聚合物的滴眼液：
量取100毫升注射用水，准确称量氯化钠0.5克，加入搅拌至完全溶解；
准确称量0.5克上述两性离子聚合物，加入配制好的氯化钠溶液，搅拌至完全溶解，既得。
实施例5
两性离子单体和聚合物的制备过程同实施例1。
配制100毫升含上述两性离子聚合物的滴眼液：
氯化钠0.5克，两性离子聚合物0.5克，L-谷氨酸钠0.2克，扎氯铵0.005克，丙二醇0.3克，薄荷醇0.01克。
顺次将上述成分溶解在100毫升注射用水中，并用磷酸盐缓冲剂调节pH值到6.0～7.8。
实施例6
两性离子单体和聚合物的制备过程同实施例2。
配制100毫升含上述两性离子聚合物的滴眼液：
氯化钠0.5克，两性离子聚合物0.5克，L-谷氨酸钠0.2克，扎氯铵0.005克，丙二醇0.3克，薄荷醇0.01克。
顺次将上述成分溶解在100毫升注射用水中，并用磷酸盐缓冲剂调节pH值到6.0～7.8。
实施例7
两性离子单体和聚合物的制备过程同实施例3。
配制100毫升含上述两性离子聚合物的滴眼液：
氯化钠0.5克，两性离子聚合物0.5克，L-谷氨酸钠0.2克，扎氯铵0.005克，丙二醇0.3克，薄荷醇0.01克。
顺次将上述成分溶解在100毫升注射用水中，并用磷酸盐缓冲剂调节pH值到6.0～7.8。
实施例8
两性离子单体和聚合物的制备过程同实施例4。
配制100毫升含上述两性离子聚合物的滴眼液：
氯化钠0.5克，两性离子聚合物0.5克，L-谷氨酸钠0.2克，扎氯铵0.005克，丙二醇0.3克，薄荷醇0.01克。
顺次将上述成分溶解在100毫升注射用水中，并用磷酸盐缓冲剂调节pH值到6.0～7.8。
以上所述仅是本发明的优选实施方式，应当指出，对于本技术领域的普通技术人员来说，在不脱离本发明技术原理的前提下，还可以做出若干改进和润饰，这些改进和润饰也应视为本发明的保护范围。
Claims (7)
1.一种滴眼液，其主要有效成分为两性离子聚合物，在滴入眼睛后形成亲水超滑层，增加眼泪粘度，延缓泪膜破裂时间，降低眼睛的摩擦，缓解疲劳。
2.如权利要求1中所述的滴眼液，其中两性离子聚合物的单体具有以下结构式：
B-L-Z
其中B选自以下基团：
其中R选自氢、取代的烷基或未取代的烷基；
L不存在或者为直链或支链的烷基，任选地含有一个或多个氧原子；
Z是两性离子基团，选自：
其中R1选自氢、取代的烷基或未取代的烷基；
其中R2，R3独立地选自氢、取代的烷基或未取代的烷基；
m是1-7的整数。
3.如权利要求1中所述的滴眼液，其中两性离子聚合物包含了一种或一种以上的单体。
4.如权利要求1中所述的滴眼液，其特征在于，含有渗透压调节剂，可选地渗透压调节剂包括但不限于氯化钠、氯化钾、氯化镁、氯化钙、乳酸钠、碳酸氢盐、磷酸钠、葡萄糖、甘露醇或硼酸中的一种或一种种以上的混合物。
5.如权利要求1中所述的滴眼液，其特征在于，含有抑菌剂，包括但不限于为羟苯甲酯、羟苯乙酯、羟苯丙酯、羟苯丁酯、苯扎氯铵、苯扎溴铵、聚季铵盐、醋酸氯己定、三氯叔丁醇、苯乙醇、硫柳汞、聚赖氨酸、硝酸苯汞或山梨酸中的一种或一种以上混合物。
6.如权利要求1中所述的滴眼液，其特征在于，含有黏度调节剂，包括但不限于玻璃酸钠、羟丙基甲基纤维素、羧甲纤维素钠、聚维酮、聚乙二醇、右旋糖酐、泊洛沙姆、卡波姆和甘油中的一种或一种种以上的混合物。
7.如权利要求1中所述的滴眼液，其特征在于，含有缓冲盐体系，包括但不限于磷酸二氢钠-磷酸氢二钠、碳酸氢钠-碳酸钠、枸橼酸钠-枸橼酸、醋酸钠-硼酸、硼酸-硼砂中的一种或一种以上的混合物。
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| CN102395378A (zh) * | 2009-02-18 | 2012-03-28 | 爱昂粒子科学有限责任公司 | 用于眼科和其他外用或局部应用的双功能共聚物 |
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| CN102395378A (zh) * | 2009-02-18 | 2012-03-28 | 爱昂粒子科学有限责任公司 | 用于眼科和其他外用或局部应用的双功能共聚物 |
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| WILLIAM G. GENSHEIMER ETAL: "Novel Formulation of Glycerin 1% Artificial Tears Extends Tear Film Break-Up Time Compared with Systane Lubricant Eye Drops", 《JOURNAL OF OCULAR PHARMACOLOGY AND THERAPEUTICS》 * |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN111840225A (zh) * | 2020-08-12 | 2020-10-30 | 王信 | 一种用于治疗青光眼的滴眼剂及其制备方法 |
| CN111840225B (zh) * | 2020-08-12 | 2021-09-14 | 陈丽娜 | 一种用于治疗青光眼的滴眼剂及其制备方法 |
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