CN114099505B - 一种眼用组合物及其制备方法与应用 - Google Patents
一种眼用组合物及其制备方法与应用 Download PDFInfo
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- CN114099505B CN114099505B CN202111562148.0A CN202111562148A CN114099505B CN 114099505 B CN114099505 B CN 114099505B CN 202111562148 A CN202111562148 A CN 202111562148A CN 114099505 B CN114099505 B CN 114099505B
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- Prior art keywords
- ophthalmic composition
- pranoprofen
- olopatadine
- naphazoline
- sodium
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- 239000000203 mixture Substances 0.000 title claims abstract description 82
- 238000002360 preparation method Methods 0.000 title claims abstract description 15
- CNIIGCLFLJGOGP-UHFFFAOYSA-N 2-(1-naphthalenylmethyl)-4,5-dihydro-1H-imidazole Chemical compound C=1C=CC2=CC=CC=C2C=1CC1=NCCN1 CNIIGCLFLJGOGP-UHFFFAOYSA-N 0.000 claims abstract description 66
- TVQZAMVBTVNYLA-UHFFFAOYSA-N Pranoprofen Chemical compound C1=CC=C2CC3=CC(C(C(O)=O)C)=CC=C3OC2=N1 TVQZAMVBTVNYLA-UHFFFAOYSA-N 0.000 claims abstract description 42
- 229960003101 pranoprofen Drugs 0.000 claims abstract description 42
- 229960005016 naphazoline Drugs 0.000 claims abstract description 33
- 229960004114 olopatadine Drugs 0.000 claims abstract description 33
- JBIMVDZLSHOPLA-LSCVHKIXSA-N olopatadine Chemical compound C1OC2=CC=C(CC(O)=O)C=C2C(=C/CCN(C)C)\C2=CC=CC=C21 JBIMVDZLSHOPLA-LSCVHKIXSA-N 0.000 claims abstract description 33
- 206010061218 Inflammation Diseases 0.000 claims abstract description 27
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 9
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- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 21
- 239000003889 eye drop Substances 0.000 claims description 18
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 8
- 238000000034 method Methods 0.000 claims description 8
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 7
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- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 claims description 6
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- 206010010741 Conjunctivitis Diseases 0.000 claims description 5
- 208000010217 blepharitis Diseases 0.000 claims description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- 229960002233 benzalkonium bromide Drugs 0.000 claims description 4
- KHSLHYAUZSPBIU-UHFFFAOYSA-M benzododecinium bromide Chemical compound [Br-].CCCCCCCCCCCC[N+](C)(C)CC1=CC=CC=C1 KHSLHYAUZSPBIU-UHFFFAOYSA-M 0.000 claims description 4
- 206010023332 keratitis Diseases 0.000 claims description 4
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
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- 239000001509 sodium citrate Substances 0.000 claims description 4
- 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 claims description 4
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 claims description 3
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- 206010022941 Iridocyclitis Diseases 0.000 claims description 3
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 3
- 201000004612 anterior uveitis Diseases 0.000 claims description 3
- 229960000686 benzalkonium chloride Drugs 0.000 claims description 3
- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 claims description 3
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- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 2
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 claims description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 2
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- 229930195725 Mannitol Natural products 0.000 claims description 2
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 claims description 2
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- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 2
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- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims description 2
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- 239000003795 chemical substances by application Substances 0.000 claims description 2
- ACYGYJFTZSAZKR-UHFFFAOYSA-J dicalcium;2-[2-[bis(carboxylatomethyl)amino]ethyl-(carboxylatomethyl)amino]acetate Chemical compound [Ca+2].[Ca+2].[O-]C(=O)CN(CC([O-])=O)CCN(CC([O-])=O)CC([O-])=O ACYGYJFTZSAZKR-UHFFFAOYSA-J 0.000 claims description 2
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 claims description 2
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- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 claims description 2
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- 239000004403 ethyl p-hydroxybenzoate Substances 0.000 claims description 2
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- NUVBSKCKDOMJSU-UHFFFAOYSA-N ethylparaben Chemical compound CCOC(=O)C1=CC=C(O)C=C1 NUVBSKCKDOMJSU-UHFFFAOYSA-N 0.000 claims description 2
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- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 2
- HELHAJAZNSDZJO-OLXYHTOASA-L sodium L-tartrate Chemical compound [Na+].[Na+].[O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O HELHAJAZNSDZJO-OLXYHTOASA-L 0.000 claims description 2
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Classifications
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- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/436—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4174—Arylalkylimidazoles, e.g. oxymetazolin, naphazoline, miconazole
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
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Abstract
本发明涉及一种眼用组合物,其包含普拉洛芬以及奥洛他定和/或萘甲唑啉。本发明还涉及该眼用组合物的制备方法,其包括如下步骤:将普拉洛芬、奥洛他定和/或萘甲唑啉、渗透压调节剂、pH调节剂、金属离子螯合剂、增稠剂、防腐剂与注射用水混合,得到所述眼用组合物。本发明还涉及该眼用组合物在制备用于治疗眼部炎症的药物中的应用,其中,所述眼部炎症包括由革兰氏阳性菌和/或革兰氏阴性菌感染导致的外眼和/或眼前节炎症。本发明提供的眼用组合物作为滴眼液不仅可提高患者眼部炎症的治疗效果,同时还可以避免用药后眼刺激、结膜充血和水肿等不利影响,从而增加患者的用药顺应性,缩短患者的恢复时间。
Description
技术领域
本发明属于医药技术领域,具体涉及一种眼用组合物及其制备方法与应用。
背景技术
普拉洛芬(Pranoprofen)滴眼液是丙酸类非类固醇抗炎药物普拉洛芬的滴眼剂,其作用机制为通过抑制体内环氧化酶(COX)活性而减少抑制***素的生物合成,用于外眼及眼前节炎症(眼睑炎、结膜炎、角膜炎、巩膜炎、浅层巩膜炎、虹膜睫状体炎、术后炎症等)的对症治疗。
现有的普拉洛芬滴眼液在用药后不良反应较多,主要表现为:刺激性强、结膜充血等,从而影响患者用药的顺应性,延长患者的恢复时间。
为了降低普拉洛芬滴眼液的用药刺激性和结膜充血等不良反应,研发人员对普拉洛芬滴眼液的配方进行了多种改进。CN112587479A公开了一种含有普拉洛芬的滴眼液及其制备方法,通过添加磺丁基醚-β-环糊精和玻璃酸钠,其中,普拉洛芬和磺丁基醚-β-环糊精协同作用,用于结膜炎、眼睑炎、角膜炎、巩膜炎等眼部炎症的对症治疗;同时,玻璃酸钠可明显缓解眼干燥症的疼痛、痒、烧灼感、异物感等临床症状,进而能够很好的缓解因眼睑炎、结膜炎等疾病所引起的充血,效果显著,该滴眼液稳定性好,不含防腐剂,减少了抗炎药物的用量,同时增强了抗炎效果,降低了对眼部的刺激性。CN108096298A公开了一种含有普拉洛芬的滴眼液,通过加入马齿笕提取物,马齿笕提取物与普拉洛芬协同作用,有利于提高充血缓解作用和水肿抑制作用,该滴眼液具有良好的充血缓解作用和水肿抑制作用,能够很好的缓解因眼睑炎、结膜炎等疾病所引起的充血,效果显著。
尽管上述现有技术在一定程度上降低了普拉洛芬滴眼液的用药刺激性和结膜充血等不良反应,但研发人员仍然致力于研究出性能更加优异、用药后不良反应更小的普拉洛芬滴眼液。
发明内容
针对现有技术中存在的缺陷,本发明的目的在于提供一种眼用组合物及其制备方法与应用。本发明提供的眼用组合物中包含普拉洛芬、奥洛他定和/或萘甲唑啉,其中,普拉洛芬和奥洛他定和/或萘甲唑啉的复合,使得该眼用组合物作为滴眼液不仅可提高患者眼部炎症的治疗效果,而且还能显著降低用药后出现的眼刺激、结膜充血和水肿等不利影响,从而增加患者的用药顺应性,缩短患者的恢复时间。
为达到以上目的,本发明第一方面提供了一种眼用组合物,其包含普拉洛芬以及奥洛他定和/或萘甲唑啉。
在本发明一些具体的实施方式中,所述普拉洛芬与所述奥洛他定的质量比为1:(0.01-15);和/或
所述普拉洛芬与所述萘甲唑啉的质量比为1:(0.01-10)。
在本发明一些优选的实施方式中,所述眼用组合物包含普拉洛芬、奥洛他定和萘甲唑啉,所述普拉洛芬、奥洛他定和萘甲唑啉的质量比为1:(0.05-15):(0.1-10)。更优选地,所述普拉洛芬、奥洛他定和萘甲唑啉的质量比为1:(0.05-5):(0.1-5)。进一步优选地,所述所述普拉洛芬、奥洛他定和萘甲唑啉的质量比为1:(1.25-3):(0.25-4)。
在本发明一些具体的实施方式中,以所述眼用组合物的总质量计,所述眼用组合物包含:
普拉洛芬 0.01wt%-1wt%;以及
奥洛他定 0.01wt%-0.15wt%;和/或
萘甲唑啉 0.01wt%-0.1wt%。
根据本发明,所述眼用组合物还包含渗透压调节剂、pH调节剂、金属离子螯合剂、增稠剂、防腐剂和注射用水中的一种或多种。
在本发明一些具体的实施方式中,以所述眼用组合物的总质量计,所述眼用组合物还包含:
根据本发明,所述渗透压调节剂包括氯化钠、甘露醇、氯化钾、甘油、山梨醇、葡萄糖和丙二醇中的一种或多种。
根据本发明,所述pH调节剂包括磷酸二氢钠、磷酸氢二钠、磷酸二氢钾、磷酸氢二钾、硼酸、硼砂、醋酸、醋酸钠、柠檬酸、柠檬酸钠、酒石酸、酒石酸钠、碳酸钠、碳酸钾、碳酸氢钠、碳酸氢钾、氢氧化钠、氢氧化钾、盐酸、磷酸、枸橼酸、枸橼酸钠和枸橼酸钾中的一种或多种。
根据本发明,所述金属离子螯合剂包括乙二胺四乙酸二钠、乙二胺四乙酸二钙和柠檬酸中的一种或多种。
根据本发明,所述增稠剂包括聚乙烯醇、聚乙烯吡咯烷酮、聚卡波非、泊洛沙姆、卡波姆、甲基纤维素和羟乙基纤维素中的一种或多种。
根据本发明,所述防腐剂包括苯扎氯铵、苯扎溴铵、尼泊金甲酯、尼泊金乙酯和山梨酸中的一种或多种。
本发明第二方面提供了一种根据本发明第一方面所述的眼用组合物的制备方法,其包括如下步骤:
将普拉洛芬、奥洛他定和/或萘甲唑啉、渗透压调节剂、pH调节剂、金属离子螯合剂、增稠剂、防腐剂与注射用水混合,得到所述眼用组合物。
在本发明一些优选的实施方式中,所述的眼用组合物的制备方法包括如下步骤:
S1,将普拉洛芬、奥洛他定和/或萘甲唑琳与注射用水混合,得到混合溶液I;
S2,向所述混合溶液I中加入渗透压调节剂、pH调节剂、金属离子螯合剂、增稠剂和防腐剂,再加入注射用水,得到混合溶液II;
S3,将所述混合溶液II经0.22μm滤膜过滤后,灌装,得到所述眼用组合物。
本发明第三方面提供了一种根据本发明第一方面所述的眼用组合物或根据本发明第二方面所述方法制备的眼用组合物在制备用于治疗眼部炎症的药物中的应用,其中,所述眼部炎症包括由革兰氏阳性菌和/或革兰氏阴性菌感染导致的外眼和/或眼前节炎症;所述外眼和/或眼前节炎症包含眼睑炎、结膜炎、角膜炎、巩膜炎、浅层巩膜炎、虹膜睫状体炎和术后炎症中的一种或多种。
根据本发明,所述药物为滴眼液。
与现有技术相比,本发明的有益效果在于:
本发明提供的眼用组合物中包含普拉洛芬以及奥洛他定和/或萘甲唑啉,其中普拉洛芬和奥洛他定和/或萘甲唑啉的复合能够抑制细菌性炎症因子(如:花生四稀酸代谢物等)的生成,从而缓解水肿、疼痛等炎症反应,使得该眼用组合物作为滴眼液不仅可提高患者眼部炎症的治疗效果,而且还能显著降低用药后出现的眼刺激、结膜充血和水肿等不利影响,从而增加患者的用药顺应性,缩短患者的恢复时间。
具体实施方式
为使本发明更加容易理解,以下结合具体实施例来详细说明本发明。应当理解,这些实施例仅起说明性作用,并不用于限定本发明。
实施例
眼用组合物的制备
实施例1
向配制罐中加入配制全量70wt%的注射用水,开启搅拌。在70℃的温度下,将处方量的普拉洛芬、奥洛他定和萘甲唑啉加入配制罐中搅拌溶解均匀后,向配制罐中加入处方量的渗透压调节剂(氯化钾)、pH调节剂(硼酸)、金属离子螯合剂(乙二胺四乙酸二钙)、增稠剂(聚乙烯吡咯烷酮)和防腐剂(苯扎氯铵),搅拌溶解均匀,再加入注射用水定容至全量,然后经0.22μm滤膜过滤,灌装,制得以眼用组合物的总质量计的如下组成的眼用组合物:
普拉洛芬、奥洛他定与萘甲唑啉的质量比为1:1.25:0.25。
实施例2
本实施例的眼用组合物的制备方法同实施例1,不同之处在于,不加入萘甲唑啉,制得以眼用组合物的总质量计的如下组成的眼用组合物:
普拉洛芬与奥洛他定的质量比为1∶1.5。
实施例3
本实施例的眼用组合物的制备方法同实施例1,不同之处在于,不加入奥洛他定,制得以眼用组合物的总质量计的如下组成的眼用组合物:
普拉洛芬与萘甲唑啉的质量比为1∶1。
实施例4
本实施例的眼用组合物的制备方法同实施例1,不同之处在于,制得以眼用组合物的总质量计的如下组成的眼用组合物:
普拉洛芬、奥洛他定与萘甲唑啉的质量比为1∶3∶4。
实施例5
本实施例的眼用组合物的制备方法同实施例1,不同之处在于,渗透压调节剂为氯化钠、金属离子螯合剂为羟乙基纤维素、防腐剂为苯扎溴铵,制得以眼用组合物的总质量计的如下组成的眼用组合物:
普拉洛芬、奥洛他定与萘甲唑啉的质量比为1∶5∶5。
实施例6
本实施例的眼用组合物的制备方法同实施例1,不同之处在于,渗透压调节剂为甘油、pH调节剂为磷酸、增稠剂为甲基纤维素,防腐剂为尼泊金甲酯,制得以眼用组合物的总质量计的如下组成的眼用组合物:
普拉洛芬、奥洛他定与萘甲唑啉的质量比为1∶0.05∶0.1。
实施例7
本实施例的眼用组合物的制备方法同实施例1,不同之处在于,渗透压调节剂为氯化钠、pH调节剂为枸橼酸、金属离子螯合剂为乙二胺四乙酸二钠、防腐剂为苯扎溴铵,制得以眼用组合物的总质量计的如下组成的眼用组合物:
普拉洛芬、奥洛他定与萘甲唑啉的质量比为1∶1.5∶0.5。
对比例1
本对比例的眼用组合物的制备方法同实施例1,不同之处在于,不加入奥洛他定和萘甲唑啉,制得以眼用组合物总质量计的如下组成的眼用组合物:
眼用组合物的质量属性考察
按照《中国药典》2020年版四部眼用制剂的质量要求,分别对实施例1-7和对比例1的各眼用组合物的性状、pH、渗透压摩尔浓度及澄清度与颜色进行考察,结果见表1所示。
表1不同眼用组合物的质量属性考察
从表1结果可知,本发明实施例1-7和对比例1的所有眼用组合物的质量属性均符合《中国药典》2020年版四部眼用制剂要求,溶液无色且澄清,pH与渗透压摩尔浓度均满足眼部的舒适度要求。眼用组合物作为滴眼液对动物眼部刺激性的评价
动物实验
采用Draize试验评价不同眼用组合物对眼的刺激性,具体如下:选择80只健康家兔,雌雄各半,体重2.0-2.5kg,随机分为8组,每组10只,剔除有眼睛刺激症状、角膜损伤和结膜损伤的家兔后,左眼滴入生理盐水(空白对照),右眼则分别滴入实施例1-7和对比例1的眼用组合物,滴加量均为0.05mL(1-2滴),然后轻合眼睑10s,停药1h后,观察眼局部刺激反应。另外,每日给药2次,连续给药7d、末次给药后24h,观察眼局部刺激反应。
根据“眼刺激反应分值评价标准”,见表2所示,将各组家兔的角膜、虹膜和结膜的刺激反应分值相加后,除以家兔数,即为各组最终分值(其中空白对照的最终分值为所有各组家兔左眼的角膜、虹膜和结膜的刺激反应分值相加后,除以家兔数),根据表3“刺激性评价”判定各组刺激情况,具体结果见表4。
表2眼刺激反应分值评价标准
表3刺激性评价
表4不同眼用组合物的眼刺激结果
组合物 | 1h后分值 | 7d后分值 |
空白对照 | 0.32±0.01 | 0.37±0.04 |
实施例1 | 0.72±0.01 | 1.29±0.05 |
实施例2 | 1.55±0.07 | 2.14±0.09 |
实施例3 | 1.69±0.09 | 2.25±0.11 |
实施例4 | 1.03±0.05 | 1.42±0.02 |
实施例5 | 1.23±0.03 | 1.71±0.05 |
实施例6 | 1.12±0.07 | 1.65±0.09 |
实施例7 | 1.25±0.05 | 1.72±0.06 |
对比例1 | 4.28±0.15 | 5.07±0.12 |
将各实施例与对比例1进行组间结果方差分析,根据表4结果可知,本发明实施例1-7的含有萘甲唑啉和/或奥洛他定的眼用组合物作为滴眼液对家兔的眼部刺激性明显低于对比例1的不含有萘甲唑啉和/或奥洛他定的眼用组合物,各实施例与对比例1的结果之间均具有显著性差异(p<0.05)。由此表明,普拉洛芬与奥罗他定和/或萘甲唑啉复用,能够减轻眼部的刺激性作用。用药7d后,实施例1-7的结果对眼部刺激性增加不明显(均表现为无刺激),且与用药1h后结果相较,结果无显著性差异(p>0.05),但对比例1对眼部的刺激性明显增加(表现为轻度刺激),且与用药1h后结果相较,结果具有显著性差异(p<0.05)。由此可见,与常规普拉洛芬滴眼液相比,本发明的含有萘甲唑啉和/或奥洛他定的眼用组合物作为普拉洛芬滴眼液对眼部无明显刺激作用。
眼用组合物作为滴眼液对动物眼部炎症的评价
动物实验
参考CN201711485565.3所述制造家兔眼部炎症模型的方法,取家兔80只,随机分为8组,每组10只,以0.1%花生四烯酸滴眼诱导动物眼左眼黏膜出现炎症后(充血或水肿),左眼滴入生理盐水(空白对照),右眼则分别滴入实施例1-7和对比例1的眼用组合物,滴加量均为0.05mL(1-2滴),然后轻合眼睑10s,停药1h后,采用裂隙灯观察各组动物充血及水肿程度。根据表5所示的患眼炎症评价标准,将各组使用不同眼用组合物后患眼的动物充血及水肿程度分值相加后,除以动物数,得到各组最终分值,具体结果见表6。
表5患眼炎症症状评价标准
表6不同眼用组合物的眼部炎症症状评价结果
根据表6结果可知,本发明实施例1-7的含有萘甲唑啉和/或奥洛他定的眼用组合物作为滴眼液对患眼的动物充血及水肿程度明显低于对比例1的不含有萘甲唑啉和/或奥洛他定的眼用组合物,将各实施例与对比例1进行组间结果方差分析,各实施例与对比例1的结果之间均具有显著性差异(p<0.05)。因此,本发明提供的眼用组合物具有良好的抗炎作用,可有效缓解炎症反应症状。
综上所述,本发明提供的眼用药物组合物通过普拉洛芬与萘甲唑啉和/或奥洛他定复用,不仅能够提升其对眼部炎症(外眼和/或眼前节炎症)的治疗效果,而且还可以减少普拉洛芬对眼部的刺激,提升患者用药的体验感。
本发明不局限于上述实施方式,对于本技术领域的普通技术人员来说,在不脱离本发明原理的前提下,还可以做出若干改进和润饰,这些改进和润饰也视为在本发明的保护范围之内。本说明书中未作详细描述的内容属于本领域专业技术人员公知的现有技术。
Claims (6)
1.一种眼用组合物,以所述眼用组合物的总质量计,其包含:
普拉洛芬 0.01wt%-1wt%;
奥洛他定 0.01wt%-0.15wt%;
萘甲唑啉 0.01wt%-0.1wt%;
渗透压调节剂 0.02wt%-2.59wt%;
pH调节剂 0.01wt%-0.63wt%;
金属离子螯合剂 0.01wt%-0.45wt%;
增稠剂 0.05wt%-1.37wt%;
防腐剂 0.02wt%-0.22wt%;以及
余量的注射用水;
所述普拉洛芬、奥洛他定和萘甲唑啉的质量比为1:1.25:0.25。
2.根据权利要求1所述的眼用组合物,其特征在于,所述渗透压调节剂包括氯化钠、甘露醇、氯化钾、甘油、山梨醇、葡萄糖和丙二醇中的一种或多种;
所述pH调节剂包括磷酸二氢钠、磷酸氢二钠、磷酸二氢钾、磷酸氢二钾、硼酸、硼砂、醋酸、醋酸钠、柠檬酸、柠檬酸钠、酒石酸、酒石酸钠、碳酸钠、碳酸钾、碳酸氢钠、碳酸氢钾、氢氧化钠、氢氧化钾、盐酸、磷酸、枸橼酸、枸橼酸钠和枸橼酸钾中的一种或多种;
所述金属离子螯合剂包括乙二胺四乙酸二钠、乙二胺四乙酸二钙和柠檬酸中的一种或多种;
所述增稠剂包括聚乙烯醇、聚乙烯吡咯烷酮、聚卡波非、泊洛沙姆、卡波姆、甲基纤维素和羟乙基纤维素中的一种或多种;
所述防腐剂包括苯扎氯铵、苯扎溴铵、尼泊金甲酯、尼泊金乙酯和山梨酸中的一种或多种。
3.一种根据权利要求1或2所述的眼用组合物的制备方法,其包括如下步骤:
将普拉洛芬、奥洛他定、萘甲唑啉、渗透压调节剂、pH调节剂、金属离子螯合剂、增稠剂、防腐剂与注射用水混合,得到所述眼用组合物。
4.一种根据权利要求1或2所述的眼用组合物或根据权利要求3所述方法制备的眼用组合物在制备用于治疗眼部炎症的药物中的应用,其中,所述眼部炎症为由革兰氏阳性菌和/或革兰氏阴性菌感染导致的外眼和/或眼前节炎症。
5.根据权利要求4所述的应用,其特征在于,所述外眼和/或眼前节炎症包含眼睑炎、结膜炎、角膜炎、巩膜炎、浅层巩膜炎、虹膜睫状体炎和术后炎症中的一种或多种。
6.根据权利要求4所述的应用,其特征在于,所述药物为滴眼液。
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