CN110893190A - 一种复方洛索洛芬滴眼剂及其制备方法 - Google Patents
一种复方洛索洛芬滴眼剂及其制备方法 Download PDFInfo
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- CN110893190A CN110893190A CN201911221077.0A CN201911221077A CN110893190A CN 110893190 A CN110893190 A CN 110893190A CN 201911221077 A CN201911221077 A CN 201911221077A CN 110893190 A CN110893190 A CN 110893190A
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- loxoprofen
- sodium
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- eye drops
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Abstract
一种复方洛索洛芬滴眼剂及其制备方法,按其重量份包括以下组分:洛索洛芬钠1份;玻璃酸钠0.05~1份;依地酸二钠0.02~0.2份;氯化钠4.5份,黄芩苷1‑2份;本发明的有益效果在于:具有良好的眼内穿透性,眼内生物利用度较高,渗透力强、靶向作用强、毒副作用小优点;适用于治疗及预防非感染性炎症引起的外眼及眼前节疾病以及术后炎症;原料易得,成本低,可以实现工业化大规模生产,具有显著的经济效益。
Description
技术领域
本发明涉及一种治疗非感染性炎症的眼科药物制剂,尤其涉及一种复方洛索洛芬滴眼剂及其制备方法。
背景技术
炎症是宿主组织对损伤的血管和细胞反应的表现形式。物理或化学的原因可能会造成组织损伤,譬如病原体入侵、缺血、过敏或不恰当(自身免疫)运作的免疫机制。此时花生四烯酸从细胞膜磷脂中释放出来,在环氧化酶的催化下形成环内过氧化物(PGG2和PGH2),再通过异构酶的作用转化成***素(PGE2、PGF2、PGD2),而***素是目前所知天然物质中最强有力的眼部致炎物质,在眼部可导致血-房水屏障受损,从而使蛋白质及多种细胞、毒素、免疫复合体等成分渗透到房水中,导致眼组织发生炎性反应,充血、水肿、瘙痒和疼痛。非甾体抗炎药(NSAIDS)具有抗炎、解热、镇痛作用,并且无糖皮质激素类药物易导致较多严重不良反应的缺点,目前已成为眼科临床中一类重要抗炎药。其滴眼液用于眼外伤,激光手术和白内障手术后的消炎及术中抑制缩瞳作用,取得良好效果。
发明内容
综上所述,本发明有必要提供一种复方洛索洛芬滴眼剂,按其重量份包括以下组分:
洛索洛芬钠 1份;
玻璃酸钠 1份;
依地酸二钠 0.02~0.2份;
氯化钠 0.45份;
黄芩苷 1-2份
所述洛索洛芬钠占滴眼液浓度为0.5~5 mg/ml。
优选的:所述滴眼液还包括渗透压调节剂和pH调节剂,所述滴眼液还包括抑菌剂,且所述抑菌剂与洛索洛芬钠的质量分数比为洛索洛芬钠:抑菌剂=1∶0.004,所述滴眼液还包括增稠剂,增稠剂与洛索洛芬钠的质量分数比为洛索洛芬钠:增稠剂=1∶1。
上述方案中:所述抑菌剂为硫柳汞、季铵盐类、杜米芬、冼必泰、三氯叔丁醇、尼泊金类、山梨酸中的一种或多种。
上述方案中:所述增稠剂为甲基纤维素、玻璃酸钠、聚乙烯醇、聚乙烯吡咯烷酮中的一种或多种。
一项所述的复方洛索洛芬滴眼剂的制备方法:
步骤1)、用玻璃酸钠、依地酸二钠和氯化钠溶解洛索洛芬钠,备用;
步骤2)、将增稠剂用注射用水分散放冷,再加入抑菌剂,搅匀过滤,加入至步骤1)所得的洛索洛芬钠溶液;
步骤3)、用注射用水溶解pH调节剂,缓慢添加步骤2)所得的洛索洛芬钠溶液中,调节pH值为6即停止;
步骤4)、用注射用水溶解渗透压调节剂,缓慢添加步骤3)所得溶液中,调节渗透压摩尔浓度至300mOsmol/kg即停止添加;
步骤5)、加注射用水定容,使得滴眼液中洛索洛芬钠的浓度为0.5~5mg/ml,过滤,分装;
步骤6)、加入黄芩苷,即得。
本发明的有益效果:目前,眼科常用的NSAIDS包括0.1%的普拉洛芬滴眼液、0.1%的双氯芬酸钠滴眼液、0.5%及0.4%的酮咯酸氨丁三醇滴眼液、0.03%的氟比洛芬钠滴眼液、1.0%的苏洛芬钠滴眼液、奈帕芬胺、溴芬酸钠、吲哚美辛等滴眼液等。单方洛索洛芬滴眼剂是丙酸类前体型非甾体抗炎药(NSAIDs),口服后在体内代谢成trans-OH型药物,与环氧化酶结合掩盖了环氧化酶的活性中心,从而阻断了该酶催化的花生四烯酸转化为***素的代谢过程,而发挥镇痛、消炎作用。
相较单方洛索洛芬滴眼剂,本发明的复方洛索洛芬滴眼剂,眼内各主要组织内的洛索洛芬钠浓度都比较高,尤其以结膜、角膜及虹膜中浓度最高,说明本发明的复方洛索洛芬滴眼剂眼内穿透性好,浓度高,用于治疗眼内非感染性疾病完全可以达到有效的治疗浓度。
本发明复方洛索洛芬滴眼剂的疗效明显优于单方洛索洛芬滴眼剂,且作用时间长。各组药物治疗眼EB外渗量均低于生理盐水治疗眼,复方洛索洛芬滴眼剂抑制率为60.52% ±16.40%,,显著高于单方洛索洛芬滴眼剂组37.82%±18.35%, P=0.028)。由此可见,复方洛索洛芬滴眼剂具有良好的抗炎作用。
具体实施方式
下面结合一些具体实施方式对本发明所述的一种复方洛索洛芬滴眼剂及其制备方法。具体实施例为进一步详细说明本发明,非限定本发明的保护范围。
本发明所用的特征均来自市售。
对比例所用普拉洛芬滴眼液:药品准字号:H20030026
首先将按表格1所示配方备料;
步骤1)、用玻璃酸钠、依地酸二钠和氯化钠溶解洛索洛芬钠,备用;
步骤2)、将增稠剂用注射用水分散放冷,再加入抑菌剂,搅匀过滤,加入至步骤1)所得的洛索洛芬钠溶液;
步骤3)、用注射用水溶解pH调节剂,缓慢添加步骤2)所得的洛索洛芬钠溶液中,调节pH值为6即停止;
步骤4)、用注射用水溶解渗透压调节剂,缓慢添加步骤3)所得溶液中,调节渗透压摩尔浓度至300mOsmol/kg即停止添加;
步骤5)、加注射用水至100ml,过滤,分装,即得单方洛索洛芬滴眼剂;
具体如下:
表1 滴眼液的原料及配比情况
实施例 | 洛索洛芬钠 | 玻璃酸钠 | 依地酸二钠 | 氯化钠 | 抑菌剂 | 增稠剂 | 注射用水 |
1 | 0.2g | 0.05-0.2g | 0.005g-0.2g | 0.9g | 0.0004 g | 0.2 g | 加至100ml |
抑菌剂用硫柳汞、季铵盐类、杜米芬、冼必素、三氯叔丁醇、尼泊全类、山梨酸中一种或多种,增稠剂用甲基纤维素、玻璃酸钠、聚乙烯醇,聚乙烯或洛索洛芬钠中一种或多种,pH调节剂为氢氧化钠溶液和/或盐酸溶液;渗透压调节剂为氯化钠和/或甘露醇,用以调节溶液渗透压摩尔浓度。
将实施例1所制得的滴眼液进行药学实验。
实验例1 滴眼液的药代动力学
新西兰兔左右眼同时给药,给药剂量为50μL。分别于给药后20、40、60、80、100、120、150、210、270、360、480 min抽取房水30μl检测;房水样品经LC-MS测定,结果见表4:
表2:新西兰兔眼部单剂量给予实施1滴眼液和普拉洛芬滴眼液的主要药代动力学参数
Parameters | 0.1%的普拉洛芬滴眼液 | 实施例4 |
药峰时间(min) | 54.00±10.20 | 35.00±15.44 |
药物半衰期(min) | 80.13±12.02 | 63.52±9.68 |
一级消除速率(min-1) | 0.01±0.001 | 0.02±0.01 |
时间曲线下面积(μg·min·ml-1) | 6025.50±1258.11 | 3689.54±1644.00 |
积分法计算曲线下面积(μg·min·ml-1) | 6095.50±1104.50 | 3698.66±1675.68 |
稳态最大血药浓度(μg·ml-1) | 47.44±10.25 | 37.54±11.39 |
稳态最小血药浓度(μg·ml-1) | 3.1±0.45 | 1.55±0.95 |
平均稳态血药浓度(μg·ml-1) | 10.84±1.54 | 10.75±2.56 |
生物利用度(%) | 93.5%±7.6% | 97.8%±4.7% |
组织样本的制备:单剂量给药后用气体栓塞方法处死动物,然后用刀片刮除角膜上皮,生理盐水冲洗结膜囊,抽取房水,用棉签吸干结膜囊的水分,用显微剪取部分球结膜、角膜、虹膜、视网膜、玻璃体和巩膜,然后用生理盐水冲洗,滤纸吸干水分后放在1.5ml试管中,盖上盖子,尽快放在电子天平称重,然后转移到8ml玻璃试管中,加二氯甲烷5ml,用显微剪充分粉碎组织。用离心机离心10分钟后,取底层二氯甲烷4.5ml于另一试管中,用氮气吹干。封闭试管口,于4℃保存。实验表明,洛索洛芬钠广泛分布于眼内各主要组织,以结膜、角膜及虹膜中浓度最高。给药后眼部主要组织的洛索洛芬钠分布浓度见表5-6。
表3:新西兰兔给予实施例1后眼组织中洛索洛芬钠的浓度
组织 | 60min | 120min | 240min |
结膜(μg/g) | 667.140±214.2 | 534.13±69.76 | 446.42±129.32 |
角膜(μg/g) | 625.53±134.10 | 539. 60±117.36 | 321.24±23.14 |
虹膜(μg/g) | 396.21±77.16 | 211.22±35.50 | 153.51±51.45 |
视网膜(μg/g) | 181.56±41.30 | 115.91±36.12 | 39.56±6.14 |
玻璃体(μg/g) | 7.84±1.87 | 6.50±1.22 | 5.47±1.02 |
巩膜(μg/g) | 79.67±16.07 | 66.26±6.99 | 50.96±8.56 |
表4:新西兰兔给予普拉洛芬滴眼液后眼组织中洛索洛芬钠的浓度
组织 | 60min | 120min | 240min |
结膜(μg/g) | 658.20±226.11 | 409.52±92.46 | 312.11±196.27 |
角膜(μg/g) | 608.55±202.44 | 503.20±185.20 | 297.44±30.44 |
虹膜(μg/g) | 277.50±123.61 | 100.22±54.50 | 101.11±97.64 |
视网膜(μg/g) | 140.25±67.14 | 99.11±28.40 | 20.44±7.05 |
玻璃体(μg/g) | 4.13±2.10 | 3.50±2.05 | 2.53±1.14 |
巩膜(μg/g) | 66.44±26.57 | 49.44±13.94 | 19.10±20.24 |
结果表明,本发明的洛索洛芬钠滴眼液,眼内各主要组织内的洛索洛芬钠浓度都比较高,尤其以结膜、角膜及虹膜中浓度最高,说明本发明的洛索洛芬钠滴眼液眼内穿透性更好,浓度高,用于治疗眼内非感染性疾病完全可以达到有效的治疗浓度。
实施例1对葡萄膜炎的抗炎作用实验
取健康成年雌性大白兔30只,随机分为4组:实施例1滴眼液组,正常对照组,模型对照组,双氯芬酸钠滴眼液组。
每组兔全部自右耳缘静脉抽取血清于-20℃保存。随即行右眼前房穿刺:10 g/L丁卡因表面麻醉兔眼后,于3点方位角膜缘以1ml注射器穿刺入前房,抽取房水0.2 ml于-20℃保存。用牛血清白蛋白(bovine serum albumin,BSA)(Sigma)作异体抗原,玻璃体、耳缘静脉2次注射法诱导实验性葡萄膜炎动物模型。方法:精确称量4~8℃保存的BSA粉剂4g,用无菌注射用水100 ml充分溶解为40g/L BSA溶液。10g/L 丁卡因表面麻醉兔左眼后,于左眼角膜缘外5mm、3点方位处进针,垂直眼球壁刺入眼球中央5mm,注入40g/L BSA 10g/L溶液0.25ml。1周后再精确称量4~8℃保存的BSA粉剂2g,用注射用水100ml充分溶解为20g/LBSA 10g/L溶液,各兔自左耳缘静脉注入20g/L BSA 2.5ml。1周后造模完成。此时用聚光电筒和裂隙灯观察:所有兔双眼均逐渐出现不同程度的眼前段炎症表现:前房闪辉,前房积脓,前房纤维素性渗出,瞳孔缩小,虹膜充血,为造模成功。
造模成功后,分别滴/涂实施例1滴眼液、双氯芬酸钠滴眼液,正常对照组和模型对照组予以等量生理盐水。分别于制模前、制模后5d、给药后5d、10d,停药后5d用聚光电筒和裂隙灯观察兔眼前段的变化。
每组兔对眼前段炎症记分,虹膜充血为0~2分,瞳孔缩小为0~2分,纤维素渗出为0~2分,前房积脓为0~2分,共计8分。制膜前各组兔眼均无眼前段炎症,制模后5d均出现明显的眼前段炎症,给实施例1滴眼液后5d,眼前段炎症开始缓解,部分痊愈,给药后10d眼前段炎症完全消失;模型对照组的眼前段炎症无明显改变,双氯芬酸钠滴眼液组眼前段炎症评分高于实施例1滴眼液组,实施例1滴眼液的疗效明显优于双氯芬酸钠滴眼液,而且没有刺激性、滴眼较舒适、顺应性较好,双氯芬酸钠滴眼液有强烈刺激性,可以引起结膜充血、流泪等不良反应。
实验表明,本发明所述的滴眼液对注射牛血清蛋白而引起的家兔实验性葡萄膜炎具有抗炎作用。
实施例1滴眼液对急性结膜水肿的抗炎作用实验
取健康SD大鼠40只,随机分为4组:实施例1滴眼液组,双氯芬酸钠滴眼液组。各组均用花生四烯酸制成大鼠实验性急性结膜水肿模型。制膜前各组兔眼均无眼前段炎症,制膜前60,45,30,15 min 及制膜后15,30 min各组1只眼给药,对侧眼为生理盐水。用聚光电筒和裂隙灯观察兔眼前段炎症的变化。结果表明,实施例1组可以抑制花生四烯酸而引起的大鼠实验性急性结膜水肿,但实施例1滴液眼的疗效明显优于双氯芬酸钠滴眼液,而且副作用较少。
实验表明,本发明所述的滴眼液对花生四烯酸而引起的大鼠实验性急性结膜水肿具有明显的抗炎作用。
实施例1滴眼液对过敏性结膜炎的抗炎作用实验
取雄性Wistar大鼠40只,随机分为4组:实施例1滴眼液组,双氯芬酸钠滴眼液组。各组预先腹腔注射卵清蛋白致敏液(100μg 卵清蛋白及20mg硫酸铝钾溶于1ml磷酸盐缓冲液,pH7.4),两周后以10%卵清蛋白液(溶于磷酸盐缓冲液) 10μl滴眼攻击,引起结膜速发型过敏反应。攻击前15min以1mol·l-1DL-二巯苏糖醇20μl作眼部预处理,临攻击时静脉注射Evans 蓝(EB) 溶液(约2mg/100g);攻击前60,45,30,15 min 及攻击后15,30 min各组1只眼给药,对侧眼为生理盐水。攻击后1h处死所有动物,测定各眼EB渗出量,进行比较,计算药物抑制率。结果表明,各组药物治疗眼EB外渗量均低于生理盐水治疗眼,实施例1滴眼液组和双氯芬酸钠组显示统计学有显著意义,实施例1滴眼液抑制率为57.65% ±12.47%,显著高于双氯芬酸钠滴眼液(30.21%±23.16%, P=0.028)。显示本发明所述的滴眼液具有良好的抗过敏作用。
实验表明,本发明所述的滴眼液对于抗体抗血清引起的实验性过敏性结膜炎也具有明显的抗炎作用。
发明人还对实施例1和双氯芬酸钠滴眼液进行了药效学验证,其对葡萄膜炎、急性结膜水肿、过敏性结膜炎等非感染性炎症的治疗效果与对比例相比,没有明显差异,甚至效果更优。本发明所述的滴眼液不含防腐剂,用于治疗及预防非感染性炎症效果更好,安全性更高。
实施例2,在实施例1成分的基础上加入0.2g的黄芩苷得出复方洛索洛芬滴眼剂。黄芩苷: 为唇形科植物黄芩 Scutellaria baicalensis Georgi 的干燥根的提取物,。为淡黄色粉末,无臭,味苦。分子式C21H18O11及分子量为446.35。黄芩苷具有很好的抗炎抗菌作用:1.抗炎抗***反应:本品对豚鼠离体气管过敏性收缩及整体动物过敏性气喘有缓解作用,并与麻黄碱有协同作用。有微弱的抗组织胺作用,可使组织胺与SRS-A的释放减少,对组织胺引起的被动全身过敏(PSA)、被动皮肤过敏(PCA)及皮肤反应有抑制作用。能抑制过敏性水肿及炎症,并能降低小鼠耳毛细血管的通透性,尚能防止低气压引起的小鼠肺出血。2、抗菌:为黄芩抗菌成分之一,含3%本品的眼药水临床用于治疗沙眼,疗效与治疗沙眼较好的药物利福平相似。
比较实施例1和实施例2:单方洛索洛芬和复方洛索洛芬滴眼剂的药代动力学比较:
比较洛索洛芬滴眼剂与添加了黄芩苷的复方洛索洛芬滴眼剂的药代动力学,复方洛索洛芬滴眼剂除添加了黄芩苷作为药效辅料外,其他配方与单方洛索洛芬滴眼液相同。
新西兰兔左右眼同时给药,给药剂量为50μL。分别于给药后20、40、60、80、100、120、150、210、270、360、480 min抽取房水30μl检测;房水样品经LC-MS测定,结果见下表:
新西兰兔眼部单剂量给予单方洛索洛芬滴眼剂和复方洛索洛芬滴眼剂的主要药代动力学参数,表5
Parameters | 复方洛索洛芬滴眼剂 | 洛索洛芬滴眼剂 |
药峰时间(min) | 56.00±14.20 | 38.00±12.44 |
药物半衰期(min) | 79.46±13.02 | 65.62±10.87 |
一级消除速率(min-1) | 0.01±0.001 | 0.02±0.01 |
时间曲线下面积(μg·min·ml-1) | 6010.50±1428.11 | 3789.54±1754.00 |
积分法计算曲线下面积(μg·min·ml-1) | 6086.50±1124.50 | 3895.66±1975.66 |
稳态最大血药浓度(μg·ml-1) | 45.44±11.25 | 39.54±12.33 |
稳态最小血药浓度(μg·ml-1) | 2.7±0.65 | 1.67±1.04 |
平均稳态血药浓度(μg·ml-1) | 10.74±2.54 | 10.65±3.26 |
生物利用度(%) | 95.8%±8.7% | 92.5%±6.6% |
组织样本的制备:单剂量给药后用气体栓塞方法处死动物,然后用刀片刮除角膜上皮,生理盐水冲洗结膜囊,抽取房水,用棉签吸干结膜囊的水分,用显微剪取部分球结膜、角膜、虹膜、视网膜、玻璃体和巩膜,然后用生理盐水冲洗,滤纸吸干水分后放在1.5ml试管中,盖上盖子,尽快放在电子天平称重,然后转移到8ml玻璃试管中,加二氯甲烷5ml,用显微剪充分粉碎组织。用离心机离心10分钟后,取底层二氯甲烷4.5ml于另一试管中,用氮气吹干。封闭试管口,于4℃保存。实验表明,洛索洛芬钠广泛分布于眼内各主要组织,以结膜、角膜及虹膜中浓度最高。给药后眼部主要组织的洛索洛芬钠分布浓度见表2-3。
表6:新西兰兔给予复方洛索洛芬滴眼剂后眼组织中洛索洛芬钠的浓度
组织 | 60min | 120min | 240min |
结膜(μg /g) | 657.140±254.2 | 524.13±79.56 | 439.42±149.32 |
角膜(μg /g) | 615.53.±144.10 | 536. 60±127.36 | 304.24±47.14 |
虹膜(μg /g) | 385.21±98.16 | 203.22±24.50 | 147.51±57.45 |
视网膜(μg /g) | 171.56±50.30 | 109.91±47.12 | 33.56±10.14 |
玻璃体(μg /g) | 7.44±2.87 | 5.60±1.12 | 4.47±1.26 |
巩膜(μg /g) | 77.67±19.07 | 64.56±8.97 | 46.96±12.56 |
表7:新西兰兔给予单复方洛索洛芬滴眼剂后眼组织中洛索洛芬钠的浓度
组织 | 60min | 120min | 240min |
结膜(μg /g) | 654.20±246.11 | 413.52±89.46 | 319.11±189.27 |
角膜(μg /g) | 613.55±210.44 | 506.20±187.60 | 287.44±50.44 |
虹膜(μg /g) | 287.50±116.61 | 110.22±34.50 | 107.11±87.54 |
视网膜(μg /g) | 150.25±57.14 | 89.11±34.20 | 18.44±9.11 |
玻璃体(μg /g) | 4.04±2.20 | 3.60±2.11 | 2.11±1.40 |
巩膜(μg /g) | 65.44±28.77 | 47.44±18.44 | 20.10±17.44 |
结果表明,本发明的复方洛索洛芬滴眼剂,眼内各主要组织内的洛索洛芬钠浓度都比较高,尤其以结膜、角膜及虹膜中浓度最高,说明本发明的复方洛索洛芬滴眼剂眼内穿透性好,浓度高,用于治疗眼内非感染性疾病完全可以达到有效的治疗浓度。
二、复方洛索洛芬滴眼剂与单方洛索洛芬滴眼剂的药效学比较
复方洛索洛芬滴眼剂为眼部无菌性炎症有较好疗效的药物,主要用于治疗葡萄膜炎、急性结膜水肿、过敏性结膜炎等非感染性炎症,故考察其对兔实验性葡萄膜炎的疗效。
取健康成年雌性大白兔30只,随机分为4组:单方洛索洛芬滴眼剂组,复方洛索洛芬滴眼剂组、空白对照组、模型组。每组兔全部自右耳缘静脉抽取血清于-20℃保存。随即行右眼前房穿刺:10 g/L丁卡因表面麻醉兔眼后,于3点方位角膜缘以1ml注射器穿刺入前房,抽取房水0.2 ml于-20℃保存。用牛血清白蛋白(bovine serum albumin,BSA)(Sigma)作异体抗原,玻璃体、耳缘静脉2次注射法诱导实验性葡萄膜炎动物模型。方法:精确称量4~8℃保存的BSA粉剂4g,用无菌注射用水100 ml充分溶解为40g/L BSA溶液。10g/L 丁卡因表面麻醉兔左眼后,于左眼角膜缘外5mm、3点方位处进针,垂直眼球壁刺入眼球中央5mm,注入40g/L BSA 10g/L溶液0.25ml。1周后再精确称量4~8℃保存的BSA粉剂2g,用注射用水100ml充分溶解为20g/L BSA 10g/L溶液,各兔自左耳缘静脉注入20g/L BSA 2.5ml。1周后造模完成。此时用聚光电筒和裂隙灯观察:所有兔双眼均逐渐出现不同程度的眼前段炎症表现:前房闪辉,前房积脓,前房纤维素性渗出,瞳孔缩小,虹膜充血,为造模成功。
造模成功后,分别滴本发明单方洛索洛芬滴眼剂和,复方洛索洛芬滴眼剂,正常对照组和模型对照组予以等量生理盐水。分别于制模前、制模后5d、给药后5d、10d,停药后5d用聚光电筒和裂隙灯观察兔眼前段的变化。
每组兔对眼前段炎症记分,虹膜充血为0~2分,瞳孔缩小为0~2分,纤维素渗出为0~2分,前房积脓为0~2分,共计8分。制膜前各组兔眼均无眼前段炎症,制模后5d均出现明显的眼前段炎症,给药2组滴眼液后5d,眼前段炎症开始缓解,部分痊愈,给药后10d眼前段炎症完全消失;模型对照组的眼前段炎症无明显改变。
结果表明,本发明复方洛索洛芬滴眼剂的疗效明显优于单方洛索洛芬滴眼剂,且作用时间长。各组药物治疗眼EB外渗量均低于生理盐水治疗眼,复方洛索洛芬滴眼剂抑制率为60.52% ±16.40%,,显著高于单方洛索洛芬滴眼剂组37.82%±18.35%, P=0.028)。由此可见,复方洛索洛芬滴眼剂具有良好的抗炎作用。
以上所述仅为本发明的实施例,并非因此限制本发明的专利范围,凡是利用本发明说明书内容所作的等效结构或等效流程变换,或直接或间接运用在其他相关的技术领域,均同理包括在本发明的专利保护范围内。
Claims (5)
1.一种复方洛索洛芬滴眼剂,按其重量份包括以下组分:
洛索洛芬钠 1份;
玻璃酸钠 0.05~1份;
依地酸二钠 0.02~0.2份;
氯化钠 4.5份;
其特征在于,还加入1-2份黄芩苷。
2.如权利要求1所述的复方洛索洛芬滴眼剂,其特征在于:
所述滴眼液还包括渗透压调节剂和pH调节剂,所述滴眼液还包括抑菌剂,且所述抑菌剂与洛索洛芬钠的质量分数比为洛索洛芬钠:抑菌剂=1∶0.004,所述滴眼液还包括增稠剂,增稠剂与洛索洛芬钠的质量分数比为洛索洛芬钠:增稠剂=1∶1。
3.如权利要求2所述的复方洛索洛芬滴眼剂,其特征在于:
所述抑菌剂为硫柳汞、季铵盐类、杜米芬、冼必泰、三氯叔丁醇、尼泊金类、山梨酸中的一种或多种。
4.如权利要求2所述的复方洛索洛芬滴眼剂,其特征在于:
所述增稠剂为甲基纤维素、玻璃酸钠、聚乙烯醇、聚乙烯吡咯烷酮中的一种或多种。
5.如权利要求1-4任一项所述的复方洛索洛芬滴眼剂的制备方法:
步骤1)、用玻璃酸钠、依地酸二钠和氯化钠溶解洛索洛芬钠,备用;
步骤2)、将增稠剂用注射用水分散放冷,再加入抑菌剂,搅匀过滤,加入至步骤1)所得的洛索洛芬钠溶液;
步骤3)、用注射用水溶解pH调节剂,缓慢添加步骤2)所得的洛索洛芬钠溶液中,调节pH值为6即停止;
步骤4)、用注射用水溶解渗透压调节剂,缓慢添加步骤3)所得溶液中,调节渗透压摩尔浓度至300mOsmol/kg即停止添加;
步骤5)、加注射用水定容,使得滴眼液中洛索洛芬钠的浓度为0.5~5mg/ml,过滤,分装即得单方洛索洛芬滴眼剂;
步奏6)、加入黄芩苷即得复方洛索洛芬滴眼剂。
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Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN103006847A (zh) * | 2013-01-08 | 2013-04-03 | 山东施尔明眼科医院 | 一种治疗葡萄膜炎的滴眼液及其制备方法 |
CN103040986A (zh) * | 2013-01-08 | 2013-04-17 | 山东施尔明眼科医院 | 一种治疗葡萄膜炎的眼用凝胶及其制备方法 |
CN106880590A (zh) * | 2017-03-10 | 2017-06-23 | 广州奥博医药科技有限公司 | 一种前体型非甾体抗炎滴眼液及其制备方法 |
CN106913518A (zh) * | 2017-03-10 | 2017-07-04 | 广州奥博医药科技有限公司 | 一种前体型非甾体抗炎眼用凝胶及其制备方法 |
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Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN103006847A (zh) * | 2013-01-08 | 2013-04-03 | 山东施尔明眼科医院 | 一种治疗葡萄膜炎的滴眼液及其制备方法 |
CN103040986A (zh) * | 2013-01-08 | 2013-04-17 | 山东施尔明眼科医院 | 一种治疗葡萄膜炎的眼用凝胶及其制备方法 |
CN106880590A (zh) * | 2017-03-10 | 2017-06-23 | 广州奥博医药科技有限公司 | 一种前体型非甾体抗炎滴眼液及其制备方法 |
CN106913518A (zh) * | 2017-03-10 | 2017-07-04 | 广州奥博医药科技有限公司 | 一种前体型非甾体抗炎眼用凝胶及其制备方法 |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN115531305B (zh) * | 2022-10-21 | 2023-11-07 | 福建汇天生物药业有限公司 | 一种洛索洛芬钠口服溶液剂及其制备方法 |
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