CN101014317A - 含有免疫抑制剂的眼用乳剂 - Google Patents
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Abstract
眼用水包油型乳剂,其包含胶体颗粒,该胶体颗粒具有被界面膜包围的油核,所述乳剂含有免疫抑制剂、油和四丁酚醛,优选该油的至少50%是MCT。这样的乳剂在制造用于治疗眼睛的疾病状态,尤其是干眼病的药物中的用途。
Description
本发明涉及在含有油,并优选还含有四丁酚醛(tyloxapol)的特定介质中包含作为活性成分的免疫抑制剂的眼用组合物,优选眼用乳剂,并且该眼用组合物适合治疗眼睛疾病状态,特别适合治疗干眼病。
在本发明的含意中,干眼病涉及与眼睛干涩和/或泪液缺乏相关的任何疾病状态,包括但不限于与来自角膜表面的流体的病理蒸发相关的疾病状态,或者与有缺陷的泪液膜相关的疾病状态,或者更通常为由于不能充分产生泪液而造成的任何角膜干燥或结膜干燥,以及由此导致的诸如角膜炎或角膜上皮糜烂的疾病状态。例如干燥性角结膜炎(KCS)、特应性干躁性角膜结膜炎(AKC)和春季角结膜炎(VKC)均是干眼疾病。
环孢菌素(cyclosporin)是一大类具有诸如免疫抑制剂和抗炎应用的多种药物应用的肽化合物。环孢菌素包括环孢菌素A、B、C和D。最为广泛研究的环孢菌素是环孢菌素A及环孢菌素A衍生物。其它普通的免疫抑制剂是西罗莫司(sirolimus)或他克莫司(tacrolimus)及其衍生物。
已经描述了环孢菌素的水包油型眼用乳剂,并且Allergan以商标名Restasis将该乳剂商品化(0.05%环孢菌素眼用乳剂)。
美国专利第4,839,342号描述了环孢菌素在治疗免疫性干燥性角结膜炎(KCS)的用途,以及增加泪液缺乏眼睛中泪液产生的方法,特别针对患有免疫介导的泪腺功能异常的患者。该专利中公开的方法包括将含有的环孢菌素(优选环孢菌素A)与为橄榄油、花生油、蓖麻油或矿物油的药物赋形剂一起给药。
Shulin Ding和Orest Olejnik在1997年11月3日的AAPS年会上公开了展示板,该文献涉及使用0.1%至0.4%环孢菌素且环孢菌素/蓖麻油的重量比为0.08的基于蓖麻油的水包油型乳剂。该展示板公开了该油中环孢菌素A的最佳浓度为7.4%重量比,这低于环孢菌素在特定的油介质(vehicle)蓖麻油中的溶解度(10%重量比)。
WO 2005/032577描述了治疗人类眼睛的方法,其包括将含有低于0.1%环孢菌素并且具有低于0.08的环孢菌素/蓖麻油重量比的乳剂给药。
虽然以上引用的专利申请描述了其它的油类,环孢菌素在任何油介质中具有相同的行为对于本领域技术人员是并不明显的,因为其在所有油类中不具有相同的溶解度,并且环孢菌素在一种油性介质中的生物利用度并不给出关于其在另一种油介质中的生物利用度的信息。
乳剂是由两种不相混溶的液相组成的体系,将其中一相以微滴形式分散在另一相中,是通过第三种组分-乳化剂来稳定的体系。乳剂内在是不稳定的,因而乳化剂对于乳剂的最初形成和长期稳定性是必不可少的。
由于液滴的尺寸很小,亚微米或纳米乳剂可以呈现为透明,并且布朗运动防止了沉降或分层,因此提供了增加的稳定性。
当由于分层(密度差异)、奥斯特瓦尔德熟化(歧化)、絮凝(通过颗粒间碰撞而聚集)以及聚结(单独的液滴的融合)而导致相分离时,出现乳剂的不稳定性。重要的区别在于絮凝通常是可逆的,而聚结是不可逆的。液滴聚结的过程是乳剂随时间而粗化的正常行为,粗化是指液滴的平均粒度随着储存而增大。
较大聚集物的存在促使更快的分层,因此促进了聚结。这对于多分散系来说尤为真实,其中不同的分层速率产生了增加的液滴遇见率。因此,乳剂的液滴大小分布控制乳剂的性质,例如长期稳定性。
因此,除了药物含量均一性以外,单峰液滴总体还有益于提高稳定性,所述药物含量均一性对于正确的药物剂量给药的药物应用是必要的。
虽然诸如Restasis的现有技术中的制剂当前可以用于治疗难于治疗的疾病状态,但是已知现有技术中的制剂的生物利用度并不是最佳的,并且Restasis的一个已知的缺点例如是需要数周来获得完全的作用。此外,诸如Restasis的基于蓖麻油的环孢菌素乳剂呈现双峰液滴总体(Ding,AAPS 1997的摘要)。由于小油滴的聚结,预计这样的制剂具有减少的贮藏寿命。
因此,亟需使用具有至少相同的物理化学稳定性和改善的药物生物利用度的乳剂来治疗干眼疾病状态的其它解决方案。在本发明的意义上,生物利用度指在给药后,靶眼组织中可以检测到的药物的百分比。可以从药效学(对环孢菌素的生物反应的量化)或从药物代谢动力学(实际药物浓度的量化)来完成该药物的检测。
此外,患有干眼病的患者具有非常敏感的眼睛,并且本发明的目的是提供舒适感以及治疗的组合物。
本发明的目的是提供具有这些性质的眼用乳剂。因此,本发明的乳剂包含成分的组合,使它们可以适应稳定性和生物利用度的要求。
因此,本发明涉及眼用乳剂,其包含胶体颗粒,该胶体颗粒具有被界面膜包围的油核,所述乳剂在含有油和四丁酚醛的介质中包含至少一种免疫抑制剂,该免疫抑制剂优选选自环孢菌素、西罗莫司、他克莫司。
发明人惊讶地发现,使用从中选择的植物油MCT为含有环孢菌素的眼用乳剂提供了意想不到的稳定性和生物利用度。发明人还发现MCT更好地溶解了环孢菌素,这在本发明所述乳剂中(实施例1-6)所观察到的改善的环孢菌素的生物利用度中起作用。根据本发明的实施方案,MCT的量为乳剂的总油成分的至少50%重量比。根据优选实施方案,乳剂的油成分为100%的MCT。MCT的量为乳剂的0.5%至4%重量比时是有利的,优选0.9%至3%重量比,更优选2%重量比。
根据本发明的优选实施方案,四丁酚醛的量低于乳剂总重的1%重量比,优选0.01%至0.6%重量比。
发明人甚至更惊讶地发现,当与四丁酚醛组合时,关于免疫抑制剂的生物利用度,MCT提供更好的结果(实施例7)。发明人证实了在含有免疫抑制剂的本发明的眼用乳剂中四丁酚醛和MCT的协同效应,所述免疫抑制剂尤其是环孢菌素、西罗莫司或他克莫司。
最后,WO2005/032577描述了基于1.25%蓖麻油的乳剂,将环孢菌素的量由0.05%提高到0.1%(因此CsA/油之比由0.04提高至0.08)并没有改善治疗干眼病的总有效性。与该教导相反,发明人意外地发现,当增加本发明乳剂中免疫抑制剂的量时,增多的药物量转移至眼睛靶中(参见实施例8);这意味着,本发明的乳剂并不限于特定比例的免疫抑制剂/油。因此,本发明的乳剂可以增加待输送至靶点的药物的治疗量,因而增加了所使用的免疫抑制剂的治疗价值。
根据本发明的实施方案,所述乳剂还可以包含任何其它合适的油类组分,尤其是一种或多种选自橄榄、大豆、玉米、矿物、棉子、红花、芝麻的油类。根据本发明的优选实施方案,所述乳剂不含蓖麻油。
在本发明的第一实施方案中,所述乳剂是阴离子型的。根据优选实施方案,本发明的乳剂包含一种或多种选自下列的组分:磷脂类,胆酸及其衍生物,金属羧甲基纤维素,金属羧甲基羟乙基纤维素,金属羧甲基淀粉,金属羧甲基羟乙基淀粉,水解的聚丙烯酰胺和聚丙烯腈,肝素,葡胺多糖,透明质酸,硫酸软骨素,硫酸皮肤素,肽和多肽,藻酸,藻酸金属盐,一种或多种下列物质的均聚物和共聚物:丙烯酸和甲基丙烯酸、丙烯酸金属盐和甲基丙烯酸金属盐、乙烯基磺酸、乙烯基磺酸金属盐、诸如天冬氨酸、谷氨酸等氨基酸、氨基酸的金属盐、对苯乙烯磺酸、对苯乙烯磺酸金属盐、2-甲基丙烯酰基氧乙基磺酸、2-甲基丙烯酰基氧乙基磺酸金属盐、3-甲基丙烯酰基氧-2-羟丙基磺酸、3-甲基丙烯酰基氧-2-羟丙基磺酸金属盐、2-丙烯酰胺基-2-甲基丙磺酸、2-丙烯酰胺基-2-甲基丙磺酸金属盐、烯丙基磺酸、烯丙基磺酸金属盐等。
在本发明的第二实施方案中,所述乳剂是阳离子型的。在该实施方案中,优选阳离子剂的浓度为0.001%至0.1%重量比,优选0.002%至0.05%重量比并且更优选0.003%至0.03%重量比。该第二实施方案是特别优选的,因为发现所述乳剂的阳离子电荷改善了该乳剂中含有的环孢菌素的生物利用度。有利的是,本发明的含有环孢菌素的阳离子型眼用乳剂是水包油型乳剂,其包含胶体颗粒,该胶体颗粒具有被界面膜包围的油核,所述乳剂包含至少一种阳离子剂、至少一种非离子的表面活性剂,所述乳剂具有正的ζ电势。根据优选实施方案,本发明的阳离子型眼用乳剂满足如下所述的ζ电势稳定性试验A的要求:
试验A包括在热应力条件下测量所述乳剂ζ电势的稳定性。
在T=0天时,即乳剂一制备后就进行实验,测量所述乳剂的ζ电势,将所得的值称为Z0。在80℃下储存含有5至10ml乳剂的10ml有效容量并在氮气气氛下密封的(无气泡)玻璃小瓶(I型)。
随后在T=7天时,测量ζ电势Z7天。
然后在T=15天时,测量ζ电势Z15天。
然后计算值δA=Z7h-Z0或者Z15h-Z0。
对于ζ电势的每一次测量,如下进行操作:
通过在配有合适软件并用所提供的标准校准的诸如MalvernZetasizer 2000(Malvern Instruments,UK)装置中的电泳迁移率确定所述乳剂液滴表面的ζ电势。
如果需要,在双蒸馏水中稀释所述乳剂以便得到可以进行最佳颗粒检测的散射强度。在零差检测中,试样计数率应为100至1000KCps(如果使用外差检测,应该推导出参比束的作用)。在25℃下,使用150mV的恒压电池进行三次连续测量。通过Smoluchowsky方程,使用水的介电常数和粘度将电泳迁移率转化为ζ电势。测量值对应于三次所得数值的平均值。
应该考虑的是,如果δA低于测量的标准误差,优选低于10mV,并且更优选低于5mV,那么所述乳剂满足ζ电势稳定性试验A。
在本发明的优选实施方案中,本发明所述的乳剂含有环孢菌素A。有利的是,本发明所述乳剂含有0.01%至0.4%重量比的免疫抑制剂,优选含有0.05%至0.3%重量比的免疫抑制剂,该免疫抑制剂优选环孢菌素,更优选环孢菌素A。根据本发明的实施方案,所述乳剂包含他克莫司的量为0.01%至0.3%重量比的乳剂,优选包含0.05%至0.2%重量比的乳剂。根据本发明的另一实施方案,乳剂包含西罗莫司的量为该乳剂的0.01%至0.3%重量比,优选0.05%至0.2%重量比。
在本发明的另一优选实施方案中,免疫抑制剂与油的重量比为0.0125至0.1。在本发明的特别实施方案中,所述乳剂中免疫抑制剂与油的重量比为0.083至0.1。在本发明的另一特别实施方案中,所述乳剂中免疫抑制剂与油的重量比为0.0125至0.05。当本发明的乳剂是亚微米级时是有利的,并且在非常优选的实施方案中,本发明所述乳剂颗粒是单峰亚微米级,其意思是本发明的胶体颗粒是非常均一的,其大小等于或小于1μm,因为其具有多分散指数接近0.2,通常为0.1至0.15的液滴大小。ISO标准文件13321:1996 E中定义了多分散指数的计算。
优选本发明所述乳剂的胶体颗粒具有等于或小于1μm的粒度,优选等于或小于300nm,更优选100至250nm。
根据本发明的优选实施方案,本发明所述乳剂是阳离子型亚微米乳剂,并且不含有任何能够产生足量负电荷以影响该乳剂的正ζ电势的物质。在该实施方案中,优选所述乳剂不含有磷脂类。
本发明还涉及制备含有至少一种免疫抑制剂、MCT和四丁酚醛的乳剂的方法,所述免疫抑制剂选自环孢菌素、西罗莫司或他克莫司,所述环孢菌素优选环孢菌素A,所述方法包括剪切混合然后高压均化的步骤。
下列实施例描述了制造并使用本发明的最佳方式。给出这些实施例仅仅是为了提供如何制造并使用本发明的说明和指导,并且不旨在以任何方式限制本发明的范围。
实施例
在以下实施例中,使用了下列缩写:
MCT:中链甘油三酯(Sociétédes Oléagineux,France)
BAK:苯扎氯铵(Benzalkonium chloride)
CsA:环孢菌素A
克列莫佛(Cremophor):聚氧乙烯蓖麻油(Cremophor EL)(BASF,Germany)
Lipoid E80(卵磷脂)(Lipoid GMBH,Germany)
Lutrol(泊洛沙姆):Lutrol F68(BASF,Germany)
Pemulen TR-2(Noveon,US)
Phospholipon 90G(Natterman,Germany)
实施例1:本发明乳剂的制备
连续称量油相组分,然后在稍微加热下将其搅拌直至得到清澈并且稍微粘稠的相。连续称量水相组分,然后在稍微加热下将其磁力搅拌直至得到透明、澄清且流动的相。加热两相并通过在该油相中快速加入该水相来形成粗乳液并然后迅速将其加热至75℃。该乳液是白色的并且稍微透明。然后通过使用例如POLYTRON PT 6100来进行高剪切混合,随后冷却以降低该乳液的液滴大小。
通过在诸如微射流机(microfluidizer)(C5,Avestin)的合适设备中,通过若干连续循环的高压均化得到最终的乳剂。该最终的乳剂是乳状且非常流动的。然后将该乳剂温度降至25℃,测量其pH,然后使用0.1M HCl或0.1M NaOH溶液将pH调至6.0、7.0、8.0。使用高压灭菌器在121℃下进行20分钟的灭菌,或者使用0.22μm的滤膜过滤进行灭菌。
实施例2:本发明乳剂的表征
在水中稀释后,使用例如高性能粒度分析仪(High PerformanceParticle Sizer)(Malvern Instruments,UK)通过准弹性光散射来确定所述乳剂液滴的平均粒度。该仪器还可以用于确定多分散指数。在25℃下,在诸如Malvern Zetasizer 2000(Malvern Instruments,UK)的合适仪器中,在双蒸馏水中稀释200倍后测量电泳迁移率,并通过Smoluchowski方程将其转化为ζ电势。
通过经验证的HPLC-UV方法确定该乳剂中的CsA。
实施例3:含有CsA/油/四丁酚醛的本发明组合物
成分 | EM047 | EM048 | EM049 | EM050 | EM051 | EM052 | EM053 |
CsA | 0.25 | 0.025 | 0.05 | 0.05 | 0.2 | 0.2 | 0.1 |
MCT | 0.75 | 2 | 1 | 2 | 2 | 4 | 2 |
BAK | 0.02 | 0.02 | 0.02 | 0.02 | 0.02 | 0.02 | 0.02 |
四丁酚醛 | 0.12 | 0.3 | 0.16 | 0.3 | 0.3 | 0.3 | 0.3 |
泊洛沙姆 | 0.1 | 0.1 | 0.1 | 0.1 | 0.1 | 0.1 | 0.1 |
维生素E | 0.01 | 0.01 | 0.01 | 0.01 | 0.01 | 0.01 | 0.01 |
甘油 | 2.25 | 2.25 | 2.25 | 2.25 | 2.25 | 2.25 | 2.25 |
纯净水 | qs | qs | qs | qs | qs | qs | qs |
实施例4:本发明组合物的稳定性
方法:
在由高压灭菌器或过滤灭菌后并在80℃的加速稳定性试验中,通过测量物理化学参数来评价所述乳剂的稳定性,所述物理化学参数例如是小油滴大小、ζ电势和CsA含量。
结果:
乳剂 | EM047 | EM048 | EM049 | EM050 | EM051 | EM052 | EM053 | |
乳剂球径(nm) | T0 | 172 | 182 | 151 | 211 | 188 | 170 | 204 |
T7 | 188 | 193 | 173 | 212 | 195 | 201 | 211 | |
T14 | 194 | 200 | 177 | 221 | 206 | 195 | 226 | |
多分散指数 | T0 | 0.155 | 0.144 | 0.148 | 0.116 | 0.078 | 0.138 | 0.108 |
ζ电势(mV) | T0 | 20.9 | 19.6 | 25.0 | 17.9 | 20.1 | 28.4 | 23.5 |
T7 | 18.9 | 19.6 | 24.7 | 20.3 | 21.9 | 24.5 | 23.2 | |
T14 | 16.9 | 19.4 | 19.2 | 18.5 | 19.0 | 23.0 | ND | |
CsA(初始含量的%) | T0 | 100.0% | 100.0% | 100.0% | 100.0% | 100.0% | 100.0% | 100.0% |
T7 | 96.4% | 97.5% | 97.8% | 95.8% | 92.8% | 96.0% | 97.4% | |
T14 | 94.6% | 96.4% | 96.0% | 94.2% | 88.2% | 96.6% | 94.8% |
ND:未确定
结论:
通过本发明所述方法制备的基于MCT/四丁酚醛的乳剂在制备之后并在80℃下至少两周内是稳定的,所述方法包括剪切混合的步骤和随后的高压均化步骤。
实施例5:对比实施例-含有CsA/蓖麻油的组合物
EMCIC007 | EMCIC003 | Restasis | |||
成分 | %重量比 | 成分 | %重量比 | 成分 | %重量比 |
CsA | 0.2 | CsA | 0.2 | CsA | 0.05 |
蓖麻油 | 2.5 | 蓖麻油 | 2.5 | 蓖麻油 | 1.25 |
油胺 | 0.12 | 硬脂胺 | 0.12 | - | - |
Phospholipon90G | 0.5 | Lipoid E80 | 0.5 | 聚山梨酯80 | 1 |
Lutrol F68 | 0.42 | Lutro1 F68 | 0.42 | PemulenTR-2 | 0.05 |
甘油 | 2.25 | 甘油 | 2.25 | 甘油 | 2.2 |
纯净水 | qs | 纯净水 | qs | 纯净水 | qs |
实施例6:含有CsA/蓖麻油的乳剂的稳定性
方法:
与实施例1-4类似
结果:
乳剂 | EMCIC003 | Restasis | EMCIC007 | |
乳剂球径(nm) | T0 | 破乳后的乳剂 | 279 | 破乳后的乳剂 |
T7 | ND | 514(56%)和2467(43%) | ND | |
T14 | ND | 破乳后的乳剂 | ND | |
ζ电势(mV) | T0 | ND | -43.7 | ND |
T7 | ND | -41.6 | ND | |
T14 | ND | ND | ND | |
CsA(初始含量的%) | T0 | ND | 100.0% | ND |
T7 | ND | 55.3% | ND | |
T14 | ND | ND | ND |
ND:未确定
百分比表示使用散射光测量的相对总体。
结论:
在制备之后或在80℃下放置一周后,使用上述均化技术生产的CsA的蓖麻油乳剂是不稳定的。
实施例7:通过药物代谢动力学参数评价的本发明乳剂的有效性
方法:
将96只来自HYRNZ104品种的染色家兔随机分为每组48只动物的两个治疗组,每组再次被分为每组6只动物的8个亚组,对应8个时间点(0.33、0.66、1、2、4、8、12和24小时)。向动物的右眼中单次滴注上述的EM050或Restasis(Allergan,US)。在相应的时间点时,将动物安乐死并将结膜取样。使用HPLC-MS确定CsA的含量。
结果:
结论:
本发明所述的乳剂所显示的组织浓度至少与基于蓖麻油的市售乳剂Restasis所显示的组织浓度一样好。
实施例8:通过药物代谢动力学参数进行评价的本发明乳剂中CsA/油之比对其有效性的影响
方法:
将104只来自HYRNZ104品种的染色家兔随机分为每组48只动物的三个治疗组,每组再次被分为每组6只动物的8个亚组,对应8个时间点(O.33、0.66、1、2、4、8、12和24小时)。向动物的右眼中单次滴注上述的EM048、EM050或EM053(2%MCT乳剂中含0.025、0.05和O.1%重量比的CsA)。在对应的时间点时,将动物安乐死并将结膜取样。使用HPLC-MS确定CsA的含量。使用梯形法计算表示暴露于所述化合物下的动物的曲线下面积(AUC)。
结果:
结论:
本发明中描述的乳剂显示了CsA/油之比与结膜浓度之间的线性相关。由于临床有效性与CsA浓度相关,因此可以推测该特殊的介质由于提高了CsA的量,因而提供增加的治疗价值。
实施例9:本发明乳剂的眼睛耐受性
该研究的目的是确定在向白化兔右眼内连续28天每天多次眼睛局部给药后,本发明乳剂的眼睛耐受性(EM048、EM050和EMO53,参见前面实施例的组合物)。
方法:
该研究涉及每组10只新西兰White白化兔(5只雄性和5只雌性)。进行连续28天,每天4次的治疗(50□1眼部局部给药)。研究了全身的耐受性(体重、食物和水的消耗、全身外观、临床体征、血液学和血液生物化学)、眼睛耐受性(使用眼底镜、裂隙灯检查和眼睛组织学观察)以及尸体剖检(肉眼检查、主要器官重量)。还进行了关于体重和器官重量、食物或水的消耗数据以及血液学和生物化学参数的统计分析(MANOVA LSD试验)。
结果:
全身行为、食物或水的消耗、体重、器官重量未受治疗的影响。尸体剖检方面没有观察到由治疗引起的显著异常。眼睛及附件的眼科学观察和显微镜检查没有显示不良反应。眼睛的反应限于轻微的结膜发红,在该研究中的全部动物中均观察到该轻微的结膜发红并且在眼用产品的多次滴注后,在家兔中也普遍观察到了此反应。
结论:
本发明中描述的乳剂在长期局部给药后是良好耐受的。
Claims (19)
1.眼用水包油型乳剂,其包含胶体颗粒,所述胶体颗粒具有被界面膜包围的油核,所述乳剂含有免疫抑制剂、油和四丁酚醛。
2.如权利要求1所述的眼用水包油型乳剂,其可局部给药。
3.如权利要求1或2所述的眼用水包油型乳剂,其中所述油成分的至少50%是MCT。
4.如权利要求3所述的眼用水包油型乳剂,其中所述乳剂包含占所述乳剂总重的0.5%至4%的MCT。
5.如权利要求1-4中任一权利要求所述的眼用水包油型乳剂,其中所述免疫抑制剂选自环孢菌素、西罗莫司或他克莫司。
6.如权利要求1-5中任一权利要求所述的眼用水包油型乳剂,其中所述环孢菌素是或包括环孢菌素A。
7.如权利要求1-6中任一权利要求所述的眼用水包油型乳剂,其中所述免疫抑制剂的量为所述乳剂的0.01%至4%重量比,优选0.05%至0.3%重量比。
8.如权利要求1-7中任一权利要求所述的眼用水包油型乳剂,其中所述四丁酚醛的量低于所述乳剂总重的1%重量比,优选0.01%至0.6%重量比。
9.如权利要求1-8中任一权利要求所述的眼用水包油型乳剂,还含有一种或多种油类,所述油类选自橄榄、大豆、玉米、矿物、棉子、红花、芝麻。
10.如权利要求1-9中任一权利要求所述的眼用水包油型乳剂,其中所述乳剂是阴离子型的。
11.如权利要求1-10中任一权利要求所述的眼用水包油型乳剂,其中所述乳剂是阳离子型的。
12.如权利要求11所述的眼用水包油型乳剂,其中所含的阳离子剂为0.001%至0.1%重量比,优选0.002%至0.05%重量比,并且更优选0.003%至0.03%重量比。
13.如权利要求11或12所述的眼用水包油型乳剂,其中所述阳离子剂是苯扎氯铵。
14.如权利要求11-13中任一权利要求所述的眼用水包油型乳剂,其特征在于其满足ζ电势稳定性试验A的要求。
15.如权利要求1-14中任一权利要求所述的眼用水包油型乳剂,其中本发明乳剂的所述胶体颗粒具有等于或小于1μm的平均粒度,且其粒度的总体分布是单峰的。
16.如权利要求1-15中任一权利要求所述的眼用水包油型乳剂,其中本发明乳剂的所述胶体颗粒的平均粒度等于或小于1μm,优选等于或小于300nm,更优选100至250nm。
17.制备含有免疫抑制剂、油和四丁酚醛的眼用水包油型乳剂的方法,其包括向油相中加入水相,随后剪切混合,然后高压均化的步骤。
18.权利要求1-16中任一权利要求所述的眼用水包油型乳剂在药物制造中的用途,其中所述药物用于治疗眼睛的疾病状态,尤其是干眼病。
19.如权利要求18所述的眼用水包油型乳剂在制造用于治疗KCS、AKC或VKC的药物中的用途。
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