CN114246935B - 含有环孢素的组合物及其在制备治疗干眼症药物中的应用 - Google Patents
含有环孢素的组合物及其在制备治疗干眼症药物中的应用 Download PDFInfo
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Abstract
本发明公开了一种含有环孢素的组合物及其在制备治疗干眼症药物中的应用,含有环孢素的药物组合物为由载体中链脂肪酸甘油三酯和环孢素组成的溶液,动物试验证明,所述的含有环孢素的药物组合物,对于干眼症有良好的治疗效果,能够用于治疗干眼症。本发明促进环孢素向眼睛角膜和结缔组织中渗透,延长其保留时间,在保持药物有效浓度的同时减少对眼睛的剌激。本发明的目的还可避免在局部给药后可能出现的视力模糊的问题。本发明还涉及环孢素滴眼液的绿色生产工艺,降本增效,且能延长在应用前的保质期。
Description
技术领域
本发明涉及环孢素制剂及其应用。
背景技术
干眼症,也称为干燥性角膜结膜炎,是由多因素和复杂原因引起的泪液质或量或流体动力学异常,导致泪膜稳定性下降,并伴有眼部不适和/或眼表组织病变特征的多种疾病的总称,可导致严重的眼表免疫炎症和其它眼表疾病,包括角膜表面磨损、丝状角膜炎和角膜溃疡等并发症,最终导致角膜混浊和视力丧失。
干眼症患病率因地区不同而不同。根据流行病学研究《干眼临床诊疗专家共识2013年》,在中国干眼症发病率大约在21-30%,其中蒸发过强型干眼症患者占大部分的比例。国内干眼症患者就诊率较低,并且可用的治疗方案有限。目前国内最常用的治疗方案为人工泪液和激素,大多数患者未能获得满意的治疗效果。
环孢素(cyclosprine)又称环孢多肽A;环孢灵;环孢霉素A;赛斯平;山地明;环孢素A;新山地明;是由11个氨基酸组成的环状多肽,是土壤中一种真菌的活性代谢物。1978年英国首次将环孢素应用于临床肾移植,此后环孢素又用于肝、心、肺、胰腺、骨髓等器官的移植,均取得令人满意的效果,明显提高病人的生存率。1984年环孢素进入我国,形成了"环孢素+硫唑嘌呤+激素"的三联免疫抑制方案,大大提高了移植存活率,同时也使移植术后急性排斥反应的发生率大幅下降。环孢素作为一种强效免疫抑制剂,近年来人们对它的研究越来越多,发现它还可用来治疗干眼症、血液病及抗寄生虫病等。
目前,用于治疗干眼症的环孢素滴眼液中,美国已上市的产品包括艾尔建的(0.05%,乳剂)和太阳制药的CEQUATM(0.09%,纳米胶束水溶液);欧洲已上市的产品包括参天制药的IkervisTM(0.1%,阳离子纳米乳剂)。2020年6月22日,兴齐眼药0.05%环孢素滴眼液(Ⅱ)/>获批上市;康哲药业发布公告,已与太阳制药就用于治疗干眼症的0.09%环孢素滴眼液签订许可协议,产品于2020年6月30日获得中国国家药品监督管理局签发的临床试验通知书,同意开展增加干燥性角膜结膜炎患者泪液分泌的临床试验,即0.09%环孢素滴眼液治疗干燥性角膜结膜炎的安全性和有效性的随机、双盲、安慰剂对照、多中心临床研究。
由于环孢素在水中几乎不溶,已上市的环孢素滴眼液均采用有机溶剂和或表面活性剂增溶,常有短暂的烧灼感、刺痛或流泪等刺激性。
中链脂肪酸甘油三酯(Medium Chain Triglycerides,MCT)是以椰子油或棕榈油为原料,经水解、分馏、酯化、精炼等化学处理得到的甘油三酸酯,脂肪酸为中链脂肪酸。药用MCT是由饱和脂肪酸甘油三酸酯(主要为辛酸和癸酸)组成的混合物,用于多种药物制剂如:口服制剂,注射用制剂和局部用制剂。在口服给药制剂中,MCT可作为制剂的基质,如:口服乳剂、微乳、自乳化系统、溶液剂或混悬剂。研究表明,MCT还可作为小肠吸收促进剂、胶囊剂的填充剂和糖衣片以及片剂中的润滑剂和抗黏附剂。注射制剂中,MCT应用在脂肪乳剂、溶液型和混悬液型注射剂等静脉注射产品。MCT还与长链甘油酸三酯并用于全营养输液治疗法中。在化妆品和局部制剂中,MCT作为软膏剂、乳膏剂以及液态乳剂的组分之一。在直肠给药中,MCT用在含有不稳定组分的栓剂中。在治疗方面,MCT可作为营养剂。由于MCT比长链甘油三酯更容易吸收,它可以用在脂肪吸收较差的疾患,如组织囊纤维化的治疗,每克MCT可提供35kJ(8.3kcal)的热量。虽然MCT与长链甘油三酯相类似,但它在药物制剂中的应用具有独特的优点。例如在皮肤表面易于涂抹,不阻碍皮肤的通气,穿透性好,具有良好的润肤性和美容效果,在皮肤表面不形成可见的薄膜,相容性和溶解性好,抗氧性稳定。
发明内容
本发明的目的在于提供一种含有环孢素的组合物及其在治疗干眼症中的应用,以克服现有技术存在的缺陷。
所述的含有环孢素的组合物,为由载体中链脂肪酸甘油三酯和环孢素组成的溶液;
所述的中链脂肪酸甘油三酯,英文名称为Medium Chain Triglycerides,简称MCT;优选的,组合物中环孢素的浓度为0.05%-2%,重量百分比;
进一步优选的,组合物中环孢素的浓度为0.05%-1%,重量百分比;
更优选的,组合物中环孢素的浓度为0.05%-0.1%,重量百分比;
优选的,所述中链脂肪酸包含8至10个碳原子的脂肪酸;
优选的,所述中链脂肪酸为辛酸或癸酸中的一种或其混合物;
所述的环孢素组合物不含有超过0.2μm的微粒,不含有任何有机溶剂、表面活性剂和防腐剂;
动物试验证明,所述的含有环孢素的组合物,对于干眼症有良好的治疗效果,能够用于治疗干眼症,所述的药物组合物为滴眼液。
本发明人发现,环孢素在中链脂肪酸甘油三酯中易溶,为避免有机溶剂和表面活性剂对眼睛的粘膜和角膜产生剌激性,在处方中零添加有机溶剂、表面活性剂和防腐剂,可在常温下将环孢素溶解于中链脂肪酸甘油三酯中,过滤除菌。
本发明的有益效果是:
促进环孢素向眼睛角膜和结缔组织中渗透,延长其保留时间,在保持药物有效浓度的同时减少对眼睛的剌激,减少每天滴眼的次数和治疗的持续时间。本发明的目的还可避免在局部给药后可能出现的视力模糊的问题。本发明还涉及环孢素滴眼液的绿色生产工艺,降本增效,且能延长在应用前的保质期。
为了对本发明的特性以及优点和结果进行更全面的说明,现在非限制性地给出一些制备本发明组合物的实施例。
附图说明
图1为泪膜破裂时间。
图2为角膜荧光素钠染色评分。
具体实施方式
根据中国药典,采用反相HPLC法测定了环孢素在3种来源中链甘油三酸酯中的溶解度,结果见表1,环孢素在中链脂肪酸甘油三酯中易溶,在室温和冰箱冷藏条件下均有10%(w/w)以上的溶解度。
表1 MCT中环孢素的溶解度
实施例1
MCT来源:德国Cremer(812N,批号:190910)。
处方:
环孢素 2.0g
MCT 98g
称取MCT 98g,加入2.0g环孢素粉末,常温搅拌下使环孢素完全溶解。在常温无菌环境中用0.2μm的聚醚砜膜进行过滤除菌,得澄清透明溶液,以单剂量或多剂量聚丙烯瓶包装,避光,15-25℃保存。
溶液经0.2μm的聚醚砜膜过滤,故不含有超过0.2μm的微粒。
测得溶液的黏度为35.4mPa.s(20℃),密度为0.940g/cm3(20℃),折光率为1.445(20℃)。因正常人泪液的折射率约为1.33(20℃),密度约为1.0g/cm3(20℃),滴眼液的密度和折射率值与泪液相似,因而在使用该组合物时,发生视力模糊的风险可以减至最低。
实施例2
MCT来源:新兴(铁岭)药业(批号:180401/2/01)。
处方:
环孢素 1.0g
MCT 99g
具体制法与实施例1类同。
溶液经0.2μm的聚醚砜膜过滤,故不含有超过0.2μm的微粒。
测得溶液的黏度为21.8mPa.s(20℃),密度为0.938g/cm3(20℃),折光率为1.443(20℃)。
实施例3
MCT来源:广州白云山汉方现代药业(批号:A30190402)。
处方:
环孢素 0.1g
MCT 99.9g
具体制法与实施例1类同。
溶液经0.2μm的聚醚砜膜过滤,故不含有超过0.2μm的微粒。
测得溶液的黏度为24.9mPa.s(20℃),密度为0.935g/cm3(20℃),折光率为1.447(20℃)。
实施例4
MCT来源:德国Cremer(812N,批号:190910)。
处方:
环孢素 0.05g
MCT 99.95g
具体制法与实施例1类同。
溶液经0.2μm的聚醚砜膜过滤,故不含有超过0.2μm的微粒。
测得溶液的黏度为32.1mPa.s(20℃),密度为0.935g/cm3(20℃),折光率为1.449(20℃)。
实施例5
用Babl/c小鼠角膜干燥症模型探讨环孢素MCT滴眼液改善角膜干燥症的效果。
动物每天使用0.2%的苯扎氯铵滴眼,早晚各一次,持续14天造模。造模后记录泪膜破裂时间并进行角膜荧光素钠染色实验和评分。
造模后给予溶剂MCT和实施例4(0.05%,溶液剂)滴眼治疗,并以进口环孢素滴眼液(0.05%,乳剂)为阳性对照。每天2次,两次间隔6小时,连续给药6天。
第2、4、6天给药后1小时,记录泪膜破裂时间并进行角膜荧光素钠染色实验评分,结果见图1,图2。
结果显示:MCT能延长模型动物泪膜破裂时间,环孢素MCT滴眼液(0.05%,溶液剂)能在延长模型动物泪膜破裂时间的同时减轻角膜干燥症所致的角膜损伤,药效优于市售环孢素滴眼液(0.05%,乳剂)。
实施例6
进行与中国药典2015年版四部通则1121的抗菌效力检查法相似的抗微生物防腐有效性试验。向中链脂肪酸甘油三酯培养皿中接种大肠埃希菌、铜绿假单胞菌、金黄色葡萄球菌、白色念珠菌以及黑曲霉,在约22.5℃下培养,结果见表2。观察到在24小时和48小时内菌落总数(cfu)的含量没有增加而是实质上降低。显然,中链脂肪酸甘油三酯不支持微生物生长,而是以如同加入有效量的抗微生物防腐剂同样的方式抑制微生物生长。
表2防腐有效性试验
。
Claims (6)
1.含有环孢素的组合物,其特征在于,为由载体中链脂肪酸甘油三酯和环孢素组成的溶液;
组合物中环孢素的浓度为0.05%-0.1%,重量百分比。
2.根据权利要求1所述的含有环孢素的组合物,其特征在于,所述中链脂肪酸为包含8至10个碳原子的脂肪酸。
3.根据权利要求2所述的含有环孢素的组合物,其特征在于,所述中链脂肪酸为辛酸或癸酸中的一种或其混合物。
4.根据权利要求1所述的含有环孢素的组合物,其特征在于,其中,所述的环孢素组合物不含有超过0.2μm的微粒,不含有任何有机溶剂、表面活性剂和防腐剂。
5.权利要求1~4任一项所述的含有环孢素的组合物在制备治疗干眼症药物中的应用。
6.根据权利要求5所述的应用,其特征在于,所述的药物组合物为滴眼液。
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