CN113712909A - 一种复方地夸磷索四钠滴眼液及其制备方法 - Google Patents
一种复方地夸磷索四钠滴眼液及其制备方法 Download PDFInfo
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- diquafosol tetrasodium
- tetrasodium
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- 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 abstract description 30
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- A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
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Abstract
本发明公开了一种复方地夸磷索四钠滴眼液,包含如下的组分:地夸磷索四钠2‑8%(w/v)、玻璃酸钠0.02‑0.3%(w/v)、甘油0.1‑3%(w/v)、防腐剂、渗透压调节剂及水,本发明所公开的复方地夸磷索四钠滴眼液滴眼液处方简单,刺激性低,效果良好,稳定性佳,有一定的治疗优势。
Description
技术领域
本发明涉及一种复方地夸磷索四钠滴眼液及其制备方法。
背景技术
[地夸磷索四钠是白色结晶粉末。它易溶于水,易溶于甲酰胺,不溶于甲醇,难溶于乙醇。其药理学作用机制为1. 通过作用于P2Y2受体的杯状细胞的膜和结膜上皮细胞,从而提高细胞内钙离子浓度,Diquafosol钠促进粘蛋白和水的分泌。2.泪液分泌促进作用,包括粘蛋白
(1)在(大鼠和兔)正常动物,并从结膜细胞促进黏液分泌和眼泪Diquafosol钠单一灌输的分泌。(2) 在大鼠干眼模型,并通过Diquafosol钠单次滴眼促进泪液分泌。另外,粘蛋白在结膜组织的量增加了反复滴眼。3.改善角膜上皮障碍,在4周的重复灌注以浓度依赖性方式提高6倍,在大鼠干眼症模型角膜上皮病症表明在1%或更高的最大效果。另外,在1%的2周重复滴注,显示最大的改善,每天在6次以上.适应症:本品用于干眼症 。
地夸磷索为P1,P4-二(尿苷-5’)四磷酸 (P1,P4-di(uridine-5’)tetraphosphate)或亦被称作Up4U的嘌呤受体激 动剂,如日本专利第3652707号公报(专利文献1)中所公开的那样, 已知其具有促进泪液分泌的作用。此外,Cornea,23(8),784-792(2004) (非专利文献1)中记载了通过滴眼给予含有地夸磷索四钠盐的滴眼 液,干眼症患者的角膜上皮障碍得到了改善。实际上,在日本,含 有浓度为3%(w/v)的地夸磷索四钠盐的滴眼液已被用作干眼症治 疗药物(商品名:DIQUAS(注册商标)滴眼液3%)。
目前国内临床上用于干眼症的品种,约有14个,这些产品为:1.玻璃酸钠滴眼液(透明质酸钠滴眼剂);2.重组牛碱性成纤维细胞生长因子眼用凝胶;3.聚乙烯醇滴眼液;4.聚乙二醇滴眼液;5.羧甲基纤维素钠滴眼液;6.复方羟丙甲纤维素滴眼液;7.维生素A棕榈酸酯眼用凝胶;8.复方右旋糖酐70滴眼液(含右旋糖酐70与羟丙甲纤维素E4M);9.右旋糖酐70甘油滴眼液(含右旋糖酐70、羟丙甲纤维素60RT4000和甘油);10.右旋糖酐70滴眼液;11.卡波姆眼用凝胶、卡波姆滴眼液;12.羟糖甘滴眼液;13.氯化钠滴眼液;14.复方氯化钠滴眼液。这些产品有的是单方制剂有的是复方制剂,但从临床上来比较复方制剂效果要优于单方制剂,我们发明的这个复方制剂就是地夸磷索四钠与玻璃酸钠的复方制剂。
发明内容
本发明要解决的技术问题是提供一种效果非常好的治疗干眼症制剂,地夸磷索四钠滴眼液滴眼液,该滴眼液成分简单,成本较低,刺激性低,粘度大,药物在眼内的停留时间长,稳定性好,效果良好。
为解决上述技术问题,本发明公开了一种地夸磷索四钠滴眼液,其包含如下的组分:地夸磷索四钠2-8%(w/v)、玻璃酸钠0.05-0.3%(w/v)、甘油0.1-1%(w/v)、苯扎氯铵0.02%渗透压调节剂及水。
优选包含如下的组分:地夸磷索四钠3-6%(w/v)、玻璃酸钠0.06-0.13%(w/v)、甘油0. 5-0.1%(w/v)、苯扎氯铵0.06%,渗透压调节剂及水。
所述渗透压调节剂优选为为氯化钠、甘露醇、甘油中的一种或多种。
更优选包含如下的组分:地夸磷索四钠35%(w/v)、玻璃酸钠0.08%(w/v)、甘油0.1%(w/v)、氯化钠0.4%及余量的水。或包含如下的组分:地夸磷索四钠3%(w/v)、玻璃酸钠0.1%(w/v)、甘油0.1%(w/v)、苯扎氯铵0.02%及余量的水。
本发明所公开的地夸磷索四钠滴眼液可采用如下步骤制备:a.称取玻璃酸钠、甘油及渗透压调节剂加入用水总量的3/5–4/5溶胀,得备用液,备用液中加入地夸磷索四钠混合溶解定容至用水总量,得药液;b.在A级环境下,将步骤a所得药液经0.22–0.45μm微孔滤膜过滤1至5次;分装即得。步骤a所得的备用液中加入地夸磷索四钠前优选热压灭菌。
本发明所公开的地夸磷索四钠滴眼液中加入了玻璃酸钠和甘油。玻璃酸钠具有非牛顿流体特性和极好的生物相容性,其稀溶液和泪液相似,具有与生物泪液相同的黏滞性和伸缩性,并可覆盖痛觉感觉器,且具有保湿润滑、抗炎和促修复等作用,可缓解药物所致的眼局部刺激,并可形成网状透气膜,不影响角膜细胞氧的代谢,使患者感觉舒适。甘油的安全性值得肯定,常作为化妆品的保湿剂和溶剂使用,对人的粘膜和皮肤无刺激作用,在保湿方面,由于丁二醇是小分子保湿成份,所以抓水比例很小,地夸磷索四钠,玻璃酸钠与甘油在一定的组成比例下配比,很低的浓度即有较好的抑菌及物理增稠作用,不需要再添加抑菌剂即完全满足眼用制剂的抑菌效力要求,并延长药物在眼表的停留时间,使药物局限在眼内,不易流入口、鼻腔,减少了口、鼻腔对药物的吸收。另外,由于玻璃酸钠的加入,减少了眼局部刺激,可不致结膜毛细血管扩张,进一步减少了药物从外周血管的消除,从而减少了全身毒副作用,增强了针对眼部的疗效。并且,地夸磷索四钠,玻璃酸钠与甘油的组合具有良好的稳定性,不需要再添加额外的稳定剂,即可长期存放。因此,本发明所公开的地夸磷索四钠滴眼液滴眼液处方简单,刺激性低,效果良好,稳定性佳,有一定的治疗优势。
具体实施方式
以下通过具体实施例再对本发明的上述内容作进一步的详细说明。但不应将此理解为本发明上述主题的范围仅局限于以下的实例。在不脱离本发明上述技术思想的情况下,根据本领域普通技术知识和惯用手段做出的各种替换或变更,均应包括在本发明的范围内。
实施例1
处方:
物料组成处方配比地夸磷索四钠30g玻璃酸钠1.0g甘油1g甘露醇5.0g、苯扎氯铵0.2水定容至1000ml
制备方法:a.称取玻璃酸钠、甘油及甘露醇加入650ml水中溶胀,得备用液,备用液中加入地夸磷索四钠混合溶解定容至1000ml,得药液;b.在A级环境下,将步骤a所得药液经0.45μm微孔滤膜过滤;分装即得。
实施例2
处方:
物料组成处方配比地夸磷索四钠30g,玻璃酸钠1.0g甘油1g 氯化钠8.0g、苯扎氯铵0.2水定容至1000ml
制备方法:a.称取玻璃酸钠、甘油及氯化钠加入700ml水中溶胀,得备用液,备用液中加入地夸磷索四钠混合溶解定容至1000ml,得药液;b.在A级环境下,将步骤a所得药液经0.22μm微孔滤膜过滤;分装即得。
实施例3
处方:
物料组成处方配比地夸磷索四钠30g玻璃酸钠0.8g甘油2.0g氯化钠3.0g、苯扎氯铵0.2水定容至1000ml
制备方法:a.称取玻璃酸钠、甘油及氯化钠加入700ml水中溶胀,得备用液,备用液中加入地夸磷索四钠混合溶解定容至1000ml,得药液;b.在A级环境下,将步骤a所得药液经0.45μm微孔滤膜过滤;分装即得。
实施例4
处方:
物料组成处方配比地夸磷索四钠30g玻璃酸钠1g甘油1.0g氯化钠5.0g、苯扎氯铵0.5水定容至1000ml
制备方法:a.称取玻璃酸钠、甘油及氯化钠加入700ml水中溶胀,得备用液,备用液中加入地夸磷索四钠混合溶解定容至1000ml,得药液;b.在A级环境下,将步骤a所得药液经0.22μm微孔滤膜过滤;分装即得。
实施例5
处方:
物料组成处方配比地夸磷索四钠30g玻璃酸钠0.8g甘油1.0g氯化钠5.0g、苯扎氯铵0.5水定容至1000ml
制备方法:a.称取玻璃酸钠、甘油及甘油加入750ml水中溶胀,得备用液,备用液中加入地夸磷索四钠混合溶解定容至1000ml,得药液;b.在A级环境下,将步骤a所得药液经0.22μm微孔滤膜过滤;分装即得。
对比组别采用相同制备方法制备,处方如下
对比例1对比例2对比例3对比例4地夸磷索四钠5.0g5.0g5.0g5.0g玻璃酸钠0.8g0.8g甘油2.0g氯化钠6.0g4.0g3.0g4.0g甘油1.0g三氯叔丁醇2.0g水定容至1000ml定容至1000ml定容至1000ml定容至1000ml
本发明以上实施例所制备的地夸磷索四钠滴眼液的分析测试结果如下:
(1)以上实施例及对比例所制备的地夸磷索四钠滴眼液进行抑菌效力检查(参照《中国药典》2015年版四部通则1121抑菌效力检查法测定),以上实施例所制备的地夸磷索四钠滴眼液抑菌效力均达到A标准,优于对比例。
(2)实施例3,4所制备的地夸磷索四钠滴眼液与参比制剂(地夸磷索四钠,5ml:24.4mg,可乐必妥日本参天制药株式会社)及对比例样品作为试药,进行了高频次长周期的兔眼刺激性实验,试验方法如下:采用成年新西兰大白兔同体自身对照,每组选用家兔5只,实验前24h内在裂隙灯显微镜下对每只家兔作双眼检查(包括使用荧光素钠检查),并记录角膜、虹膜及结膜情况。因为滴眼液的使用剂,每次将试药0.1mL滴入左侧眼结膜囊内,右侧用0.9%生理盐水作对照,轻合眼睑10s,每天滴眼12次,每次间隔1h,连续使用14d,在每日给药前以及最后一次给药后的1、2、4、24、48、72h观察眼部情况,并按表2进行眼刺激反应评分,按表2的要求将每个观察时间点每只家兔的眼角膜、虹膜、结膜和分泌物的刺激反应分值相加得总积分,再将同组的积分总和除以观察时间点数,即可得到其眼刺激性反应的平均分值。试验结果显示以上实施例所制备的地夸磷索四钠滴眼液刺激性略小于于参比制剂,远小于对比例。
(3)稳定性结果显示:实施例样品置于高温40℃,湿度75%条件放置,0、6月对比外观性状,地夸磷索四钠含量,运动粘度。实施例1~5的稳定性皆较好。
Claims (7)
1.一种地夸磷索四钠滴眼液,其特征在于,包含如下的组分:地夸磷索四钠2-8%(w/v)、玻璃酸钠0.05-0.3%(w/v)、甘油0.1-1%(w/v)、苯扎氯铵0.01~0.1%,渗透压调节剂及水。
2.如权利要求1所述的地夸磷索四钠滴眼液,其特征在于,包含如下的组分:地夸磷索四钠0.3-0.6%(w/v)、玻璃酸钠0.08-0.12%(w/v)、甘油0. 5-1.0%(w/v)、苯扎氯铵0.01~0.1%,渗透压调节剂及水。
3.如权利要求1或2所述的地夸磷索四钠滴眼液,其特征在于,所述渗透压调节剂为氯化钠、甘露醇、甘油中的一种或多种。
4.如权利要求2所述的地夸磷索四钠滴眼液,其特征在于,包含如下的组分:地夸磷索四钠3%(w/v)、玻璃酸钠0.1%(w/v)、甘油1%(w/v)、氯化钠0.4%,苯扎氯铵0.02%及余量的水。
5.如权利要求2所述的地夸磷索四钠滴眼液,其特征在于,包含如下的组分:地夸磷索四钠3%(w/v)、玻璃酸钠0.08%(w/v)、甘油0.5%(w/v)、苯扎氯铵0.1%及余量的水。
6.如权利要求1所述的地夸磷索四钠滴滴眼液的制备方法,其特征在于包括以下步骤:
a.称取玻璃酸钠、甘油及渗透压调节剂加入用水总量的3/5–4/5溶胀,得备用液,备用液中加入地夸磷索四钠混合溶解定容至用水总量,得药液;
b.在A级环境下,将步骤a所得药液经0.22–0.45μm微孔滤膜过滤1至5次;分装即得。
7.如权利要求6所述的地夸磷索四钠滴滴眼液的制备方法,其特征在于步骤a所得的备用液中加入地夸磷索四钠前热压灭菌。
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