CN107753424A - 一种不含防腐剂的多剂量包装抗炎滴眼液及其制备方法 - Google Patents
一种不含防腐剂的多剂量包装抗炎滴眼液及其制备方法 Download PDFInfo
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- CN107753424A CN107753424A CN201711252577.1A CN201711252577A CN107753424A CN 107753424 A CN107753424 A CN 107753424A CN 201711252577 A CN201711252577 A CN 201711252577A CN 107753424 A CN107753424 A CN 107753424A
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- Prior art keywords
- eye drops
- sodium
- unit container
- inflammatory
- inflammatory eye
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- 239000003889 eye drop Substances 0.000 title claims abstract description 94
- 229940012356 eye drops Drugs 0.000 title claims abstract description 87
- 239000003755 preservative agent Substances 0.000 title claims abstract description 29
- 230000003110 anti-inflammatory effect Effects 0.000 title claims abstract description 28
- 230000002335 preservative effect Effects 0.000 title claims abstract description 28
- 238000002360 preparation method Methods 0.000 title claims abstract description 22
- 239000003814 drug Substances 0.000 claims abstract description 43
- -1 isotonic regulator Substances 0.000 claims abstract description 27
- 239000007788 liquid Substances 0.000 claims abstract description 26
- 239000002562 thickening agent Substances 0.000 claims abstract description 20
- 238000013329 compounding Methods 0.000 claims abstract description 14
- 239000002260 anti-inflammatory agent Substances 0.000 claims abstract description 11
- 229940124599 anti-inflammatory drug Drugs 0.000 claims abstract description 11
- 239000003002 pH adjusting agent Substances 0.000 claims abstract description 9
- 239000003381 stabilizer Substances 0.000 claims abstract description 9
- 239000000203 mixture Substances 0.000 claims abstract description 7
- 229940079593 drug Drugs 0.000 claims description 31
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 27
- 239000000243 solution Substances 0.000 claims description 27
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 24
- 239000002202 Polyethylene glycol Substances 0.000 claims description 20
- 229920001223 polyethylene glycol Polymers 0.000 claims description 20
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 18
- QXZGLTYKKZKGLN-UHFFFAOYSA-N 4-(2,5-dioxopyrrolidin-1-yl)oxy-4-oxobutanoic acid Chemical compound OC(=O)CCC(=O)ON1C(=O)CCC1=O QXZGLTYKKZKGLN-UHFFFAOYSA-N 0.000 claims description 15
- 239000004472 Lysine Substances 0.000 claims description 15
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 claims description 15
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- 239000008215 water for injection Substances 0.000 claims description 13
- 229910021538 borax Inorganic materials 0.000 claims description 10
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- 235000015165 citric acid Nutrition 0.000 claims description 9
- 239000011780 sodium chloride Substances 0.000 claims description 9
- 235000002639 sodium chloride Nutrition 0.000 claims description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 8
- 238000000034 method Methods 0.000 claims description 7
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- 229960005112 moxifloxacin hydrochloride Drugs 0.000 claims description 5
- IDIIJJHBXUESQI-DFIJPDEKSA-N moxifloxacin hydrochloride Chemical compound Cl.COC1=C(N2C[C@H]3NCCC[C@H]3C2)C(F)=CC(C(C(C(O)=O)=C2)=O)=C1N2C1CC1 IDIIJJHBXUESQI-DFIJPDEKSA-N 0.000 claims description 5
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- ULGZDMOVFRHVEP-RWJQBGPGSA-N Erythromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 ULGZDMOVFRHVEP-RWJQBGPGSA-N 0.000 claims description 4
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- 239000002253 acid Substances 0.000 claims description 4
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- VWDWKYIASSYTQR-UHFFFAOYSA-N sodium nitrate Chemical compound [Na+].[O-][N+]([O-])=O VWDWKYIASSYTQR-UHFFFAOYSA-N 0.000 claims description 4
- 230000001954 sterilising effect Effects 0.000 claims description 4
- 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 3
- 229930195725 Mannitol Natural products 0.000 claims description 3
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 3
- 235000011054 acetic acid Nutrition 0.000 claims description 3
- 150000001875 compounds Chemical class 0.000 claims description 3
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- 238000007789 sealing Methods 0.000 claims description 3
- RDEIXVOBVLKYNT-HDZPSJEVSA-N (2r,3r,4r,5r)-2-[(1s,2s,3r,4s,6r)-4,6-diamino-3-[(2r,3r,6s)-3-amino-6-[(1r)-1-aminoethyl]oxan-2-yl]oxy-2-hydroxycyclohexyl]oxy-5-methyl-4-(methylamino)oxane-3,5-diol;(2r,3r,4r,5r)-2-[(1s,2s,3r,4s,6r)-4,6-diamino-3-[(2r,3r,6s)-3-amino-6-(aminomethyl)oxan-2 Chemical compound OS(O)(=O)=O.O1C[C@@](O)(C)[C@H](NC)[C@@H](O)[C@H]1O[C@@H]1[C@@H](O)[C@H](O[C@@H]2[C@@H](CC[C@@H](CN)O2)N)[C@@H](N)C[C@H]1N.O1C[C@@](O)(C)[C@H](NC)[C@@H](O)[C@H]1O[C@@H]1[C@@H](O)[C@H](O[C@@H]2[C@@H](CC[C@H](O2)[C@@H](C)N)N)[C@@H](N)C[C@H]1N.O1[C@H]([C@@H](C)NC)CC[C@@H](N)[C@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](NC)[C@@](C)(O)CO2)O)[C@H](N)C[C@@H]1N RDEIXVOBVLKYNT-HDZPSJEVSA-N 0.000 claims description 2
- WWJBDSBGLBEFSH-UHFFFAOYSA-N 2-(4-methoxyphenyl)azepane Chemical compound C1=CC(OC)=CC=C1C1NCCCCC1 WWJBDSBGLBEFSH-UHFFFAOYSA-N 0.000 claims description 2
- WUWFMDMBOJLQIV-UHFFFAOYSA-N 7-(3-aminopyrrolidin-1-yl)-1-(2,4-difluorophenyl)-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid Chemical compound C1C(N)CCN1C(C(=C1)F)=NC2=C1C(=O)C(C(O)=O)=CN2C1=CC=C(F)C=C1F WUWFMDMBOJLQIV-UHFFFAOYSA-N 0.000 claims 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 claims description 2
- 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
- XAGMUUZPGZWTRP-ZETCQYMHSA-N LSM-5745 Chemical compound C([C@@H](N1C2=C(C(C(C(O)=O)=C1)=O)C=C1F)C)OC2=C1C1(N)CC1 XAGMUUZPGZWTRP-ZETCQYMHSA-N 0.000 claims description 2
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- 235000011613 Pinus brutia Nutrition 0.000 claims description 2
- 241000018646 Pinus brutia Species 0.000 claims description 2
- TVQZAMVBTVNYLA-UHFFFAOYSA-N Pranoprofen Chemical compound C1=CC=C2CC3=CC(C(C(O)=O)C)=CC=C3OC2=N1 TVQZAMVBTVNYLA-UHFFFAOYSA-N 0.000 claims description 2
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 2
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- RRNJROHIFSLGRA-JEDNCBNOSA-N acetic acid;(2s)-2,6-diaminohexanoic acid Chemical compound CC(O)=O.NCCCC[C@H](N)C(O)=O RRNJROHIFSLGRA-JEDNCBNOSA-N 0.000 claims description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 2
- 229960004099 azithromycin Drugs 0.000 claims description 2
- MQTOSJVFKKJCRP-BICOPXKESA-N azithromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)N(C)C[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 MQTOSJVFKKJCRP-BICOPXKESA-N 0.000 claims description 2
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- 229960002716 bromfenac sodium Drugs 0.000 claims description 2
- HZFGMQJYAFHESD-UHFFFAOYSA-M bromfenac sodium Chemical compound [Na+].NC1=C(CC([O-])=O)C=CC=C1C(=O)C1=CC=C(Br)C=C1 HZFGMQJYAFHESD-UHFFFAOYSA-M 0.000 claims description 2
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Abstract
本发明涉及一种滴眼液,具体涉及一种不含防腐剂的多剂量包装抗炎滴眼液,该滴眼液配方组成包括抗炎类药物、复配增稠剂、等渗调节剂、pH调节剂。该复配增稠剂可延长药物在角膜表层的滞留时间,从而在降低了抗炎类药物用量的同时增强了滴眼液的抗炎效果。本发明还提供了该滴眼液的制备方法。本发明的抗炎滴眼液不含防腐剂和稳定剂,大大降低了滴眼液对眼部的刺激,且采用Aptar装置瓶进行多剂量包装,避免了细菌侵入,降低了药品污染风险,延长了多剂量滴眼液的使用期限,避免了药品浪费,并使得产品更加安全可靠。
Description
技术领域
本发明涉及一种滴眼液,特别涉及一种不含防腐剂的多剂量包装抗炎滴眼液及其制备方法。
技术背景
近年来,由于受到环境污染、工作环境、用眼卫生等因素的影响,使干眼症或慢性结膜炎症状的眼病患者不断增多。而抗炎滴眼液作为一种眼科最常用且使用简单、方便的眼药制剂,成为很多人缓解眼睛炎症及其它不适症状的必需品。目前,抗炎滴眼液大多为多次使用的多剂量包装,多次重复使用。制剂一旦开封后,容易在使用和保存过程中被泪液及空气中的微生物污染,进而产生安全隐患。为了防止眼用制剂在开封后重复使用过程中被微生物二次污染,几乎所有的滴眼液处方中都添加了防腐剂。
防腐剂虽然在防止微生物污染方面有一定的积极意义,但其不良反应也逐步被人们所认识。近年来的一些研究显示,防腐剂可通过以下几种途径对眼表产生损伤:①破坏角膜上皮的微绒毛,使泪膜的稳定性降低;②对脂质层有类似去污剂的作用,使泪液蒸发加速;③减少结膜杯状细胞的密度,间接破坏泪膜稳定性;④降低角膜细胞的增长和活力,使角膜上皮屏障受损,延缓伤口愈合;⑤导致眼表炎性反应、结膜下纤维化等。具体表现为乳头状结膜炎、点状角膜病变、导致或加重干眼症状、过敏性睑缘结膜炎等多种眼表损害性疾病。防腐剂一方面会产生毒性,另一方面会抵消药物的治疗作用,另外,即使添加了防腐剂,也会因为防腐剂的种类、浓度、配伍及使用等因素,无法完全避免滴眼剂的细菌污染。因此,对于长期使用滴眼液的患者,防腐剂对眼表的潜在危害是不容忽视的。同时,滴眼液中的防腐剂和稳定剂也会造成对眼部的刺激,有损眼部健康。如果滴眼液对眼部刺激性较大,不仅会流泪,还会稀释药物,使药物在眼部停留时间变短,影响疗效。但是药物在眼部停留时间过长会对眼部造成阻碍,产生不良影响。
对于不含防腐剂的滴眼液,通常采用单剂量包装,但单剂量包装需“吹瓶-灌装-封口”三合一设备,该种设备需国外进口且造价高昂。另外,单剂量包装额外增加了包装数量,一次性或一天使用后丢弃,会造成更多的医疗垃圾。
为了降低滴眼液对眼部的刺激性,减少防腐剂对眼部的伤害,现有技术做了很多工作。CN103181892A公开了一种盐酸莫西沙星滴眼液及其制备方法,该滴眼液的pH值为6.0-8.0,优选pH值6.0-7.0,盐酸莫西沙星含量为0.5wt%,所述助剂为增稠剂、等渗调节剂、pH调节剂、注射用水。该发明不含防腐剂,全身副作用少,直接在眼部吸收,可快速被吸收到达病灶部位,迅速发挥治疗效果。CN104546696A公开了一种S-(-)-那氟沙星-L-精氨酸单剂量滴眼液及其制备方法,该滴眼液由活性成分S-(-)-那氟沙星-L-精氨酸、金属络合剂、渗透压调节剂、pH调节剂、增稠剂以及注射用水组成。该发明制得的滴眼液不含防腐剂,避免了由于防腐剂引起的潜在危险及对眼睛的毒副作用,并且具备高的稳定性。
发明内容
本发明的目的在于提供一种不含防腐剂的多剂量包装抗炎滴眼液及其制备方法,该抗炎滴眼液稳定性好,不含防腐剂和稳定剂,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,同时该抗炎滴眼液可多剂量包装使用,减少了医疗垃圾。
本发明的一个目的是提供一种不含防腐剂的多剂量包装抗炎滴眼液,该抗炎滴眼液配方组成及其含量包括:抗炎类药物0.001-0.01%(w/v),复配增稠剂1.0-5.0%(w/v),等渗调节剂0.5-3.0%(w/v),pH调节剂适量,余量为注射用水。
进一步地,所述的抗炎类药物选自:氯霉素、红霉素、阿奇霉素、妥布霉素、林可霉素、那他霉素、克拉霉素、盐酸林可霉素、硫酸新霉素、硫酸庆大霉素、硫酸链霉素、四环素、利福平、氧氟沙星、左氧氟沙星、盐酸左氧氟沙星、诺氟沙星、依诺沙星、盐酸环丙沙星、乳酸环丙沙星、盐酸洛美沙星、盐酸莫西沙星、加替沙星、盐酸贝西沙星、甲苯磺酸托氟沙星、甲磺酸帕珠沙星、氟比洛芬钠、普拉洛芬、吲哚美辛、双氯酚酸钠、奈帕芬胺、溴芬酸钠、酮咯酸氨丁三醇、醋酸氢化可的松、醋酸泼尼松、地塞米松磷酸钠、塞禾松、氟米龙中的一种或多种。
进一步地,所述的等渗调节剂选自:甘露醇、山梨醇、氯化钠、氯化钾、硫酸钠、硫酸钾、硝酸钠、硝酸钾、甘油、丙二醇、葡萄糖中的一种或多种。
进一步地,所述的pH调节剂选自:磷酸二氢钠、磷酸氢二钠、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、磷酸中的一种或多种。
进一步地,所述的复配增稠剂为水溶性聚乙二醇琥珀酰亚胺琥珀酸酯和三赖氨酸醋酸盐组合物。
进一步地,所述的复配增稠剂的浓度优选为2.0-4.0%(w/v)。
进一步地,水溶性聚乙二醇琥珀酰亚胺琥珀酸酯和三赖氨酸醋酸盐的质量比为10/1-40/1,优选为15/1-30/1。
本发明的另一个目的是提供一种不含防腐剂的多剂量包装抗炎滴眼液的制备方法,具体步骤如下:
(1)称取处方量的抗炎类药物、复配增稠剂、等渗调节剂、pH调节剂,加入适量注射用水,搅拌,调节pH范围为5.0-9.0,再进行定容;
(2)将步骤1所得的药物溶液过滤;
(3)将步骤2所得过滤后的药液热压灭菌;
(4)检验步骤3所得药液,灌装药液至滴眼液瓶中,封口,即得成品。
进一步地,步骤(1)中pH范围优选为5.4-6.8。
进一步地,步骤(2)中所述过滤过程为先经0.45μm微孔滤膜过滤,再经0.22μm微孔滤膜过滤。
进一步地,步骤(3)中所述的药液热压灭菌是在121℃下灭菌15-45min,冷却。
进一步地,步骤(4)中检验步骤3所得药液,合格后,在百级环境下,灌装药液至滴眼液瓶中。
进一步地,步骤(4)中所述的滴眼液瓶为Aptar装置瓶。
Aptar装置瓶通过以下原理有效避免细菌污染:①压力平衡系统:液体流出,空气进入;②通过弹簧的张力实现滴孔处的密封保护,以防止液体倒吸及细菌进人;③通过有效孔径为0.2μm的微孔滤膜对补偿进入装置的空气进行过滤除菌。在本发明中,所述的滴眼液瓶带有细菌滤过装置,所述的带有细菌滤过装置的滴眼液瓶即为Aptar装置瓶。
进一步地,所述抗炎滴眼液不含有防腐剂、稳定剂。
本发明中复配增稠剂是水溶性聚乙二醇琥珀酰亚胺琥珀酸酯和三赖氨酸醋酸盐组合物。聚乙二醇琥珀酰亚胺琥珀酸酯含有-NHS基团,-NHS基团具有亲电性,而三赖氨酸醋酸盐含有-NH2基团,-NH-有亲核性,将两种组分溶解在生理稀释剂中,通过混合搅拌引发官能团交联反应,在适宜的浓度下,它们会形成一种具有特殊增稠效果的粘合剂。本发明申请人经过大量的研究发现,水溶性聚乙二醇琥珀酰亚胺琥珀酸酯和三赖氨酸醋酸盐配合使用,在1.0-5.0%(w/v)的浓度下不仅可以起到增稠的效果,还具有稳定剂的作用。水溶性聚乙二醇琥珀酰亚胺琥珀酸酯和三赖氨酸醋酸盐在适宜的浓度,适宜的配比下,可以有效延长药物在角膜表层的滞留时间,调节药物的释放速率,改善滴眼液的流变学性质,大大降低了抗炎类药物的用量,以及对眼部的刺激性。
本发明中滴眼液采用Aptar装置瓶包装,可有效避免细菌侵入,降低药品污染风险,避免加入防腐剂,同时在水溶性聚乙二醇琥珀酰亚胺琥珀酸酯和三赖氨酸醋酸盐的作用下,使滴眼液达到一定的稠度,可以使其整滴的被挤出,避免半滴被挤出后回落入滴眼液瓶,造成对滴眼液的污染。
本发明与现有技术相比具有的有益效果为:
1、本发明的多剂量滴眼液不含防腐剂,可避免由防腐剂引起的潜在危险和对眼睛的毒副作用;
2、本发明的多剂量滴眼液含有的水溶性聚乙二醇琥珀酰亚胺琥珀酸酯和三赖氨酸醋酸盐组合物,可延长药物在角膜表层的滞留时间,调节药物的释放速率,改善滴眼液的流变学性质,从而在降低了抗炎类药物用量的同时增强了滴眼液的抗炎效果;
3、本发明的多剂量滴眼液含有的水溶性聚乙二醇琥珀酰亚胺琥珀酸酯和三赖氨酸醋酸盐协同作用可使滴眼液长期稳定保存、不变质,避免了向滴眼液中加入稳定剂。
4、本发明的多剂量滴眼液采用带细菌滤过装置的滴眼液瓶包装,可有效避免细菌侵入,降低药品污染风险,从而延长多剂量滴眼液的使用期限,避免药品浪费。
5、本发明的多剂量滴眼液组分简单,不含有防腐剂和稳定剂,大大降低了滴眼液对眼部的刺激。
具体实施方式
实施例1
处方
制备方法:
(1)精密称取上述配方中的加替沙星、氯化钠、复配增稠剂(水溶性聚乙二醇琥珀酰亚胺琥珀酸酯和三赖氨酸醋酸盐的质量比为19:1)、硼砂,加水300mL,搅拌溶解混合均匀后,用柠檬酸调节溶液pH至6.3,用注射用水定容至1000mL,得药物溶液;
(2)将步骤1所得的药物溶液经0.45μm微孔滤膜过滤1次,再经0.22μm微孔滤膜过滤1次;
(3)将步骤2所得的药液,采用热压灭菌法,于121℃下灭菌15min,冷却;
(4)检测步骤3所得药液,合格后,在百级环境下,灌装药液至带细菌滤过装置的滴眼液瓶中,每瓶10mL,然后封口,即得成品。
实施例2
处方
制备方法:
(1)精密称取上述配方中的地塞米松磷酸钠、复配增稠剂(水溶性聚乙二醇琥珀酰亚胺琥珀酸酯和三赖氨酸醋酸盐的质量比为10:1)、硼砂、甘露醇,加水300mL,搅拌溶解混合均匀后,用盐酸调节溶液pH至5.0,用注射用水定容至1000mL,得药物溶液;
(2)将步骤1所得的药物溶液经0.45μm微孔滤膜过滤1次,再经0.22μm微孔滤膜过滤1次;
(3)将步骤2所得的药液,采用热压灭菌法,于121℃下灭菌25min,冷却;
(4)检测步骤3所得药液,合格后,在百级环境下,灌装药液至带细菌滤过装置的滴眼液瓶中,每瓶10mL,然后封口,即得成品。
实施例3
处方
制备方法:
(1)精密称取盐酸莫西沙星、复配增稠剂(水溶性聚乙二醇琥珀酰亚胺琥珀酸酯和三赖氨酸醋酸盐的质量比为40:1)、甘油、硼砂,加水300mL,搅拌溶解混合均匀后,用醋酸调节溶液pH至9.0,再用注射用水定容至1000mL,得药物溶液;
(2)将步骤1所得的药物溶液经0.45μm微孔滤膜过滤1次,再经0.22μm微孔滤膜过滤1次;
(3)将步骤2所得的药液,采用热压灭菌法,于121℃下灭菌45min,冷却;
(4)检测步骤3所得药液,合格后,在百级环境下,灌装药液至带细菌滤过装置的滴眼液瓶中,每瓶10mL,然后封口,即得成品。
实施例4
处方
制备方法:
(1)精密称取上述配方中的加替沙星、氯化钠、复配增稠剂(水溶性聚乙二醇琥珀酰亚胺琥珀酸酯和三赖氨酸醋酸盐的质量比为10:1)、硼砂,加水300mL,搅拌溶解混合均匀后,用柠檬酸调节溶液pH至6.3,用注射用水定容至1000mL,得药物溶液;
(2)将步骤1所得的药物溶液经0.45μm微孔滤膜过滤1次,再经0.22μm微孔滤膜过滤1次;
(3)将步骤2所得的药液,采用热压灭菌法,于121℃下灭菌15min,冷却;
(4)检测步骤3所得药液,合格后,在百级环境下,灌装药液至带细菌滤过装置的滴眼液瓶中,每瓶10mL,然后封口,即得成品。
实施例5
处方
制备方法:
(1)精密称取上述配方中的加替沙星、复配增稠剂(水溶性聚乙二醇琥珀酰亚胺琥珀酸酯和三赖氨酸醋酸盐的质量比为40:1)、硼砂、氯化钠,加水300mL,搅拌溶解混合均匀后,用柠檬酸调节溶液pH至6.3,用注射用水定容至1000mL,得药物溶液;
(2)将步骤1所得的药物溶液经0.45μm微孔滤膜过滤1次,再经0.22μm微孔滤膜过滤1次;
(3)将步骤2所得的药液,采用热压灭菌法,于121℃下灭菌15min,冷却;
(4)检测步骤3所得药液,合格后,在百级环境下,灌装药液至带细菌滤过装置的滴眼液瓶中,每瓶10mL,然后封口,即得成品。
对比例1
处方
制备方法:
(1)精密称取上述配方中的加替沙星、氯化钠、水溶性聚乙二醇琥珀酰亚胺琥珀酸酯、硼砂,加水300mL,搅拌溶解混合均匀后,用柠檬酸调节溶液pH至6.3,用注射用水定容至1000mL,得药物溶液;
(2)将步骤1所得的药物溶液经0.45μm微孔滤膜过滤1次,再经0.22μm微孔滤膜过滤1次;
(3)将步骤2所得的药液,采用热压灭菌法,于121℃下灭菌15min,冷却;
(4)检测步骤3所得药液,合格后,在百级环境下,灌装药液至带细菌滤过装置的滴眼液瓶中,每瓶10mL,然后封口,即得成品。
对比例2
处方
制备方法:
(1)精密称取上述配方中的加替沙星、氯化钠、三赖氨酸醋酸盐、硼砂,加水300mL,搅拌溶解混合均匀后,用柠檬酸调节溶液pH至6.3,用注射用水定容至1000mL,得药物溶液;
(2)将步骤1所得的药物溶液经0.45μm微孔滤膜过滤1次,再经0.22μm微孔滤膜过滤1次;
(3)将步骤2所得的药液,采用热压灭菌法,于121℃下灭菌15min,冷却;
(4)检测步骤3所得药液,合格后,在百级环境下,灌装药液至带细菌滤过装置的滴眼液瓶中,每瓶10mL,然后封口,即得成品。
对比例3
处方
加替沙星 | 0.05g |
玻璃酸钠 | 20.0g |
氯化钠 | 8g |
硼砂 | 5.7g |
柠檬酸 | 适量 |
注射用水 | 定容至1000mL |
制备方法:
(1)精密称取上述配方中的加替沙星、玻璃酸钠、氯化钠、硼砂,加水300mL,搅拌溶解混合均匀后,用柠檬酸调节溶液pH至6.3,用注射用水定容至1000mL,得药物溶液;
(2)将步骤1所得的药物溶液经0.45μm微孔滤膜过滤1次,再经0.22μm微孔滤膜过滤1次;
(3)将步骤2所得的药液,采用热压灭菌法,于121℃下灭菌15min,冷却;
(4)检测步骤3所得药液,合格后,在百级环境下,灌装药液至带细菌滤过装置的滴眼液瓶中,每瓶10mL,然后封口,即得成品。
细菌污染对比
以实施例1所制备的用带细菌滤过装置的滴眼液瓶包装的滴眼液与用普通瓶包装的滴眼液做细菌污染对比。取新西兰大白兔(2.5-3.0kg)60只,雌雄不限,均分成2组。两种不同瓶装(各30瓶)的滴眼液开启后,给白兔按照常规点眼方法点眼,每天4次。在开启后3、7、14、21天,每瓶滴眼液取60μL加到增菌液中,标准循环扩增24h后,去增菌液样本在血琼脂平板培养基上用菌环划分离线,然后倒置放立于含有CO2和O2的37℃恒温箱中孵化48h。最后通过观察菌落在固体培养基上的生长形式、外形和聚落的大小,以及对菌落进行革兰氏染色判定有无细菌污染。
在21天的观察期间内,30瓶普通瓶装滴眼液中,第3天无污染情况出现,第7天有3瓶污染,第14天有5瓶污染,第21天有16瓶污染;而30瓶带细菌滤过装置的滴眼液均未出现污染情况。
药效学评价
以实施例1、实施例4、实施例5、对比例1、对比例2、对比例3所制备的滴眼液作为试验品,生理盐水作为对照品,进行药效学评价。取新西兰大白兔(2.5-3.0kg)36只,雌雄不限,均分成6组。
损伤型细菌性结膜炎模型的建立
感染菌悬液的制备:用0.9%氯化钠注射液将培养2天的金黄色葡萄球菌液稀释成5×109cfu.ml-1(采用标准比浊管确定)。
结膜损伤和结膜感染:用无菌6号针头与兔子上睑结膜划4mm×4mm“+”,以刚划破为宜,轻轻拉眼睑成小杯型,小心向结膜伤痕处滴入2滴感染菌悬液,轻轻复原眼睑,所有兔子的左右眼都按照同法进行结膜感染。
损伤型细菌性结膜炎的治疗
实验设置:每组6只兔子,每只兔子左眼和右眼分别滴入试验品和对照品。对感染结膜炎兔子连续用药7天,每天上、下午各一次,每次0.1mL,观察眼部流泪及分泌物情况,结膜充血和水肿状况。
观察指标及评分标准:体征(结膜、水肿、分泌物)根据病情情况分为无、轻度、中度、重度,分别记为0、1、2、3分。结膜充血分为:无充血为0分;睑结膜充血,色鲜红为1分;睑结膜及穹隆结膜充血,色介于鲜红与紫红为2分;睑结膜及球结膜充血,色紫红为3分。结膜水肿分为:无水肿为0分;可见结膜水肿为1分;水肿介于1-3分之间为2分;结膜水肿突出于眼球为3分。分泌物无为0分,较少为1分,较多为2分,甚多擦之即有为3分。
细菌性结膜炎的治疗效果
金黄色葡萄球菌感染24h后,呈紫红色,伴有明显水肿并使眼呈半闭合状,大量分泌物浸湿眼睑、睫毛和眼周围区域。具体治疗效果见表1和表2。
表1试验各组疗效计分表
表2试验各组疗效计分表
表1和表2中结果表明水溶性聚乙二醇琥珀酰亚胺琥珀酸酯和三赖氨酸醋酸盐配合使用达到了良好的抗炎效果,缺少任何一种物质的滴眼液的抗炎效果都大大降低。通过实施例1、实施例4和实施例5的数据还可以看出,水溶性聚乙二醇琥珀酰亚胺琥珀酸酯和三赖氨酸醋酸盐的配比对滴眼液的抗炎效果也有着重要的影响,只有在最佳的配比条件下,滴眼液的抗炎效果才能达到最佳。通过实施例1和对比例3可以看出,同使用玻璃酸钠相比,本发明复配增稠剂可以使滴眼液的抗炎效果更好。
稳定性比较
取由实施例1和对比例1-3所制备的滴眼液于40℃,相对湿度65%条件下放置6个月,于第1个月、2个月、3个月、6个月末分别取样一次进行检测,并与0月结果相比较,试验结果见表3:
表3稳定性试验结果
由表3的试验数据可知,水溶性聚乙二醇琥珀酰亚胺琥珀酸酯和三赖氨酸醋酸盐配合使用对滴眼液的稳定性还起到良好的效果。缺少任何一种物质,滴眼液的稳定性都将降低。
刺激性试验比较
取眼部检查无损伤的健康新西兰兔21只,按照体重随机分为7组,3只/组,第一组左眼给生理盐水作为对照,右眼给空白辅料滴眼液。第2-7组左眼也给生理盐水作为自身对照,右眼分别给实施例1、实施例4、实施例5、对比例1、对比例2、对比例3制备的滴眼液。将滴眼液滴于家兔眼结膜囊内,压迫鼻泪管,并使眼睛被动闭合,一天4次,每次1-2滴,连续滴眼14天,观察角膜、虹膜、结膜、水肿、分泌物的刺激情况,并进行记分,其记分方法如下。
眼部刺激反应分值标准
分值 | 0-3 | 4-8 | 9-12 | 13-16 |
评价 | 无刺激 | 轻微刺激 | 中度刺激 | 强度刺激 |
滴眼液刺激性实验结果表4刺激性实验结果
由表4可知,本发明的抗炎滴眼液不含防腐剂和稳定剂,对眼无刺激性。同时还可以看出复配增稠剂的组分、配比对眼部的刺激性也有着一定的影响。
以上所述仅为本发明的较佳实施例而已,并不用以限制本发明,凡在本发明的精神和原则之内,所作的任何修改、等同替换、改进等,均应包含在本发明的保护范围之内。
Claims (10)
1.一种不含防腐剂的多剂量包装抗炎滴眼液,其特征在于,所述抗炎滴眼液配方组成及其含量包括:抗炎类药物0.001-0.01%(w/v),复配增稠剂1.0-5.0%(w/v),等渗调节剂0.5-3.0%(w/v),pH调节剂适量,余量为注射用水。
2.根据权利要求1所述的多剂量包装抗炎滴眼液,其特征在于,所述的复配增稠剂为水溶性聚乙二醇琥珀酰亚胺琥珀酸酯和三赖氨酸醋酸盐组合物。
3.根据权利要求1所述的多剂量包装抗炎滴眼液,其特征在于,所述的复配增稠剂的浓度优选为2.0-4.0%(w/v)。
4.根据权利要求2所述的多剂量包装抗炎滴眼液,其特征在于,水溶性聚乙二醇琥珀酰亚胺琥珀酸酯和三赖氨酸醋酸盐的质量比为10/1-40/1,优选为15/1-30/1。
5.根据权利要求1所述的多剂量包装抗炎滴眼液,其特征在于,所述的抗炎类药物选自:氯霉素、红霉素、阿奇霉素、妥布霉素、林可霉素、那他霉素、克拉霉素、盐酸林可霉素、硫酸新霉素、硫酸庆大霉素、硫酸链霉素、四环素、利福平、氧氟沙星、左氧氟沙星、盐酸左氧氟沙星、诺氟沙星、依诺沙星、盐酸环丙沙星、乳酸环丙沙星、盐酸洛美沙星、盐酸莫西沙星、加替沙星、盐酸贝西沙星、甲苯磺酸托氟沙星、甲磺酸帕珠沙星、氟比洛芬钠、普拉洛芬、吲哚美辛、双氯酚酸钠、奈帕芬胺、溴芬酸钠、酮咯酸氨丁三醇、醋酸氢化可的松、醋酸泼尼松、地塞米松磷酸钠、塞禾松、氟米龙中的一种或多种。
6.根据权利要求1所述的多剂量包装抗炎滴眼液,其特征在于,所述的等渗调节剂选自:甘露醇、山梨醇、氯化钠、氯化钾、硫酸钠、硫酸钾、硝酸钠、硝酸钾、甘油、丙二醇、葡萄糖中的一种或多种。
7.根据权利要求1所述的多剂量包装抗炎滴眼液,其特征在于,所述的pH调节剂选自:磷酸二氢钠、磷酸氢二钠、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、磷酸中的一种或多种。
8.权利要求1所述的多剂量包装抗炎滴眼液的制备方法,其特征在于,步骤如下:
(1)称取处方量的抗炎类药物、复配增稠剂、等渗调节剂、pH调节剂,加入适量注射用水,搅拌,调节pH范围为5.0-9.0,再进行定容;
(2)将步骤1所得的药物溶液过滤;
(3)将步骤2所得过滤后的药液热压灭菌;
(4)检验步骤3所得药液,灌装药液至滴眼液瓶中,封口,即得成品。
9.根据权利要求8所述的多剂量包装抗炎滴眼液的制备方法,其特征在于,步骤(4)中所述的滴眼液瓶为Aptar装置瓶。
10.根据权利要求1所述的多剂量包装抗炎滴眼液,其特征在于,所述抗炎滴眼液不含有防腐剂、稳定剂。
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Address after: 100176 Beijing Daxing District Yizhuang Development Zone, Chuang Chuang thirteen Street 31 hospital, one open center 7 building. Applicant after: Beijing nukangda medicine Polytron Technologies Inc Address before: 100176 Beijing Daxing District Yizhuang Development Zone, Chuang Chuang thirteen Street 31 hospital, one open center 7 building. Applicant before: BEIJING NUOKANGDA PHARMACEUTICAL CO., LTD. |
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GR01 | Patent grant | ||
GR01 | Patent grant |