CN104758249A - 用于眼药物递送的稳定的脂质体制剂 - Google Patents

用于眼药物递送的稳定的脂质体制剂 Download PDF

Info

Publication number
CN104758249A
CN104758249A CN201410204720.XA CN201410204720A CN104758249A CN 104758249 A CN104758249 A CN 104758249A CN 201410204720 A CN201410204720 A CN 201410204720A CN 104758249 A CN104758249 A CN 104758249A
Authority
CN
China
Prior art keywords
liposome
latanoprost
liposomal formulation
preparation
stable liposomal
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
CN201410204720.XA
Other languages
English (en)
Other versions
CN104758249B (zh
Inventor
苏布拉马尼亚·文卡特拉曼
贾亚加内什·V·纳塔拉詹
蒂娜·豪登
弗雷迪·博埃
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Health Service Co Ltd Of Singapore
Nanyang Technological University
Singapore Health Services Pte Ltd
Original Assignee
Health Service Co Ltd Of Singapore
Nanyang Technological University
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Health Service Co Ltd Of Singapore, Nanyang Technological University filed Critical Health Service Co Ltd Of Singapore
Publication of CN104758249A publication Critical patent/CN104758249A/zh
Application granted granted Critical
Publication of CN104758249B publication Critical patent/CN104758249B/zh
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/557—Eicosanoids, e.g. leukotrienes or prostaglandins
    • A61K31/5575—Eicosanoids, e.g. leukotrienes or prostaglandins having a cyclopentane, e.g. prostaglandin E2, prostaglandin F2-alpha
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0048—Eye, e.g. artificial tears
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/127—Liposomes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/06—Antiglaucoma agents or miotics

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Ophthalmology & Optometry (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Dispersion Chemistry (AREA)
  • Emergency Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

一种用于眼药物递送的稳定的脂质体制剂。该制剂含有包括至少一个脂质双层的脂质体，该脂质双层含有卵磷脂；以及被包覆在该脂质体内的前列腺素F2α。本发明还提供一种以该制剂来治疗眼疾病的方法。

Description

用于眼药物递送的稳定的脂质体制剂
技术领域
本发明涉及用于眼药物递送的稳定的脂质体制剂。
背景技术
眼睛内的眼内压(intraocular pressure，IOP)是通过睫状体所生成的水状液的连续流予以维持。过多的流体经由巩膜小梁网(trabecular meshwork)流出眼睛。如果流出物被阻塞，则水状液在眼睛内部积累而导致增加的IOP与眼高压。眼高压会损害视神经，导致视神经病变及不可逆地视觉受损。此病况被称为青光眼(glaucoma)，影响超过全世界六千万人，并且为第二大致盲原因。增加的IOP是青光眼的关键可改变的危险因子。
传统用于眼高压及青光眼病患的治疗包括眼手术以及局部眼药水滴注。这些治疗方式有缺点。例如，并非所有病患为眼手术的候选者。再者，虽然局部眼药水一般被认为是有效的，病患长期遵守滴注安排是主要问题。假如病患不遵守适当的眼药水滴注安排，局部眼高压与青光眼无法妥善被控制。
局部眼药水含有用于控制IOP的药物，这些药物典型地通过降低眼睛所产生的流体、增加流体流出，或通过这两种机制来作用。前列腺素类似物[如拉坦前列腺素(latanoprost)]是强效药物，其可通过增加房水经由葡萄膜巩膜路径(uveoscleral pathway)外流来降低IOP。
典型地，只有5％经由眼药水施用至角膜上皮的游离药物成功地穿过角膜。因此，到达水状液的药物的量通常低于治疗有效的浓度。这迫使反复的施用。再者，该药物的大量部分经由结膜囊(conjunctival sac)进入循环而引起非所需的全身性副作用。
作为局部眼药水的替代，持续释放IOP-降低药物的结膜下注射(subconjunctival injection)可以被用来直接递送药物至作用位点。这样的递送模式解决了病患不遵守滴注安排及低效率的穿过角膜的药物传送的问题。
对于用于结膜下注射的稳定的药物制剂，且需最低频率的施用以长期稳定控制IOP，存在有需要。
发明内容
为解决用于眼内压的改善的疗法的需求，一种用于眼递送的稳定的脂质体制剂被提供。该制剂包含含有至少一个脂质双层的脂质体，该脂质双层含有卵磷脂。该制剂还含有被包覆在该脂质体内的前列腺素F2α。此外，该脂质体具有低于2μm的直径。
还被提供的是，一种通过施用上面所描述的制剂来治疗眼疾病的方法。
本发明的一个或多个实施方式的细节阐明于附图以及以下说明中。本发明的其他特征、目的以及优点将从详细说明以及权利要求中变得明显。所有在此被引述的参考文献以其整体被并入本案以作为参考数据。
附图说明
下面的详细说明参照所附附图，其中：
图1是拉坦前列腺素从棕榈酰基油酰基卵磷脂(palmitoyl oleoylphosphatidyl choline，POPC)脂质体中相对于时间的累积释放的图形；
图2A是针对含有蛋卵磷脂(egg phosphatidyl choline，eggPC)的脂质体及含有POPC的脂质体，在脂质体中剩余的拉坦前列腺素的起始量的百分比相对于时间的图形；
图2B是在4℃储存下，脂质体大小相对于时间的图形；
图3是在被包覆在含有POPC的脂质体内的拉坦前列腺素的单一结膜下注射之后，眼内压相对于天数的图形。
具体实施方式
如上面所提，一种用于眼递送的稳定的脂质体制剂被提供。该制剂包括含有至少一个脂质双层的脂质体，该脂质双层含有卵磷脂。在一个实施方式中，该脂质体是单层囊泡(unilamellar vesicle)。在一个优选实施方式中，该卵磷脂是棕榈酰基油酰基卵磷脂(POPC)。
该制剂还含有被包覆在该脂质体内的前列腺素F2α。该前列腺素F2α可为拉坦前列腺素、比马前列腺素(bimatoprost)、曲伏前列腺素(travoprost)或卡前列素(carboprost)。在一个优选实施方式中，该前列腺素F2α是拉坦前列腺素。
前列腺素F2α相对于POPC的摩尔比可为0.01∶1至0.5∶1。在一个实施方式中，该摩尔比为0.01∶1至0.35∶1。在一个优选实施方式中，该稳定的脂质体制剂包括摩尔比为0.01∶1至0.175∶1的拉坦前列腺素与POPC。此外，该脂质体可被配制成包括介于2与25wt％之间的前列腺素F2α。
该脂质体可具有低于2μm的直径。在一个实施方式中，该脂质体的直径是100nm至300nm，例如100nm、150nm、200nm、250nm及300nm。在一个优选实施方式中，该直径为100nm。这些纳米大小的装载有药物的脂质体可以随着时间缓慢地释放前列腺素F2α。
在一个实施方式中，上面所描述的脂质体制剂可以是用于结膜下注射的预先组成的、实时可注射的水性制剂。
还落在本发明的范畴的是一种用于治疗眼疾病的方法，其依赖于施用上面所描述的脂质体制剂。该眼疾病可为眼高压或青光眼。优选地，该疾病是青光眼。在一个实施方式中，该脂质体制剂通过结膜下注射而被施用。
施用上面所描述的脂质体制剂可以在注射后一小时显著地降低IOP。更具体地，施用该脂质体制剂致使IOP相较于治疗前IOP降低至少30％(例如30％、40％及50％)。有利地，在单一注射之后，IOP维持被降低的历时长达4至6个月。
如上面所提，所注射的脂质体制剂可以缓慢地释放前列腺素F2α(例如拉坦前列腺素)超过数个月。例如，在该脂质体内的药物的50％初始量可以在注射该制剂至眼睛内之后的10天内被释放。优选地，该药物的65％在注射的28天内被释放。抗青光眼药物的慢性局部施用通常会诱发眼表面疾病。该脂质体的缓释特征免除每天施用这些药物的需要，由此降低或消除伴随的副作用。
典型地，不稳定的药物在-20℃或更低的温度下冻干或冷冻，以避免活性随着时间丧失。特别是，冻干或冷冻装载有药物的脂质体的持续释放制剂会不利地影响该药物释放图形，致使在该药物有效性上不可预期的变异性。
有利地，该脂质体制剂是稳定的历时相当长期的时间。例如，该制剂可以在4℃下储存历时多达6个月(例如1、2、3、4、5及6个月)，而无脂质体的聚集或从该脂质体中损失药物。因此，该脂质体制剂可以在4℃下储存在小瓶中历时长期间，继而可以直接地从该小瓶中立即被注射。
不用进一步详细阐述，可以相信的是，基于上面的详细说明，本领域技术人员可以利用本发明达至其最大程度。在下面的具体实施例仅要被解释为例示说明，而非以任何方式限制本公开内容的剩余部分。
实施例1：制备用于药物释放研究的大单层囊泡(large unilamellar vesicles，LUV)
一种薄膜水合技术被用来配制用于药物释放速率的装载有拉坦前列腺素的POPC脂质体。简言之，POPC被称重并且溶于氯仿∶甲醇(2∶1v/v)溶剂混合物中。拉坦前列腺素(在乙腈中的2mg/ml储备溶液)以药物∶脂质摩尔比为0.175∶1而被加入至该脂质溶剂混合物中并且维持在40℃下。该溶剂混合物被加入至一个旋转蒸发器中的圆底烧瓶内，该旋转蒸发器被连结至维持在40℃的水浴。该烧瓶在低压下以100rpm旋转历时1小时以移除溶剂，由此形成薄的装载有药物的脂质膜。等张的磷酸盐缓冲液(PBS)(150mM、pH5.5)被加入至此膜，以形成多层囊泡(multilamellar vesicles，MLV)。这些MLV经由聚碳酸酯滤器(0.2μm-0.08μm)挤压10次。该挤压致使形成具有大小分布为0.09-0.12μm的直径的LUV。
实施例2：制备用于药物稳定性研究的LUV
装载有药物的LUV还被制备用于稳定性研究。POPC被溶于PBC(在pH6.7下)中，并在室温下以恒定的搅拌历时2小时以形成MLV。这些MLV使用3个一起堆叠在实验台挤压机上的80nM大小的聚碳酸酯膜挤压3-5次，以形成POPC LUV。拉坦前列腺素被溶于乙醇中，且所形成的溶液(维持于50℃的水浴中的圆底烧瓶内)在氮气气流下进行干燥以形成薄的药物膜。该药物膜在室温下用这些POPC LUV进行水合历时2-3小时，直到在该烧瓶壁上没有油滴被观察到。为0.175∶1的拉坦前列腺素∶POPC摩尔比被用来制备装载有药物的LUV。装载有拉坦前列腺素的POPC LUV在室温下使用0.2μm注射过滤器进行灭菌过滤，并且储存于4℃下直到分析。相似的方法被用来制备装载有拉坦前列腺素的eggPC脂质体。
实施例3：装载有药物的POPC脂质体的表征
药物释放研究通过下述方式执行：将如在上面实施例1中描述所制得的装载有拉坦前列腺素的POPC脂质体对PBS(在pH7.4下)进行透析，并且通过HPLC量测所释放的拉坦前列腺素的量。结果显示于图1中。超过28天时期，大约65％的拉坦前列腺素从该装载有拉坦前列腺素的POPC脂质体中以时间-依赖的方式被释放。
这些装载有拉坦前列腺素的POPC脂质体的物理特征基本上如在Venkatraman等人的国际申请公开案第2012/021107号中所描述的来进行测量，其内容以其整体被并入此处以作为参考数据。
如在上面实施例2描述所制得的装载有拉坦前列腺素的POPC脂质体的稳定性被测量，并且与相似的装载有拉坦前列腺素的eggPC脂质体进行比较。这些脂质体储存于4℃下的稳定性被评估历时为6-9个月的期间。稳定性通过量测这些脂质体的平均大小以及通过HPLC量测在这些脂质体中的拉坦前列腺素浓度来进行评估。结果被描绘于图2A与图2B中。如图2A所示，显著的拉坦前列腺量随着时间从eggPC脂质体丧失，这表示拉坦前列腺素的起始量在储存于4℃下3个月之后有45％降低。意外地，没有可测量的拉坦前列腺素量从POPC脂质体丧失，甚至在储存于4℃下6个月之后。至于粒子大小，在图2B中所描绘的结果显示装载有拉坦前列腺素的eggPC脂质体的平均大小在储存于4℃下9个月的期间逐步地变小。再次意外地，装载有拉坦前列腺素的POPC脂质体没有可测量的变化，甚至于4℃下6个月之后。特别是，在装载有药物的脂质体的大小上的变化将显著地改变该药物的释放动力学。
实施例4：拉坦前列腺素脂质体制剂的活体内活性
在上面所描述的拉坦前列腺素脂质体制剂的效力在青光眼的动物模型[即，具有眼高压(被定义为IOP＞18mm Hg)的长尾猕猴]中被测试。动物研究按照视觉与眼科学研究协会所认可的动物在眼科与视觉上的研究的使用规定来执行。再者，Singhealth新加坡的实验动物管理评鉴及认证协会的动物伦理委员会的准则也被遵行。
这些猕猴通过含有克他明(ketamine)(5-10mg/kg体重)及乙酰丙嗪马来酸酯(acepromazine maleate)(0.25mg/kg体重)的混合物的肌肉内注射连同硫酸阿托平(atropine sulfate)(0.125mg/kg体重)的皮下注射而被麻醉。它们的气道、呼吸及脉搏在所有步骤期间被监测。一至两滴的1％利多卡因(xylocaine)被用来作为局部麻醉以降低这些动物在结膜下注射期间可能的不适。这些动物的瞳孔以2.5％盐酸脱羟肾上腺素(phenylephrinehydrochloride)及1％托吡卡胺(tropicamide)滴剂(Alcon Laboratories，French's Forest，NSW，Australia)予以扩张。
装载有拉坦前列腺素的POPC脂质体通过在上面实施例2所描述的技术来进行制备。具有起始药物/脂质摩尔比为0.175∶1的拉坦前列腺素脂质体(100μl)通过结膜下注射而被导入至三只动物的双眼内。IOP在注射之前及注射之后的每天与每周间隔被测量。
这些猴子在IOP测量之前以克他明(5-10mg/kg体重)稍微予以麻醉。再一次，一至两滴的1％利多卡因被用来作为局部麻醉以降低这些涉入的动物在测量步骤期间可能的不适。IOP使用经校正的眼压计(XL，Reichert Technologies，Depew，NY)来测量。IOP在注射之前被监测历时3天，以及在注射之后被监测历时120天。结果被显示于图3中。单一的结膜下注射致使在注射后的第一天在眼内压的初始的快速下降。该降低的IOP在注射后持续稳定历时至少120天。
其他实施方式
在本详细说明所公开的所有特征可以任何组合而被结合。在本详细说明的各个特征可由提供相同、等效或相似目的备选特征置换。因此，除非另外明确表明，所公开的各个特征仅为总体系列的等效或相似特征的实例。
从上面的详细说明，本领域技术人员可以简单地查明本发明的必要特征，并且在不背离其精神及范畴的情况下，可以完成本发明的各式各样的变化与修饰以使其适合于各式各样的使用与状况。因此，其他实施方式也落入所附权利要求的范围内。

Claims (17)

1.一种用于眼递送的稳定的脂质体制剂，所述制剂包含包括至少一个脂质双层的脂质体，所述脂质双层含有卵磷脂；以及被包覆在所述脂质体内的前列腺素F2α，其中所述脂质体具有低于2μm的直径。
2.根据权利要求1所述的稳定的脂质体制剂，其中所述卵磷脂是棕榈酰基油酰基卵磷脂(POPC)。
3.根据权利要求2所述的稳定的脂质体制剂，其中所述前列腺素F2α是拉坦前列腺素、比马前列腺素、曲伏前列腺素或卡前列素。
4.根据权利要求3所述的稳定的脂质体制剂，其中所述前列腺素F2α是拉坦前列腺素。
5.根据权利要求4所述的稳定的脂质体制剂，其中所述制剂具有的拉坦前列腺素对POPC的摩尔比为0.01∶1至0.5∶1。
6.根据权利要求5所述的稳定的脂质体制剂，其中所述拉坦前列腺素对POPC的摩尔比为0.01∶1至0.175∶1。
7.根据权利要求5所述的稳定的脂质体制剂，其中所述脂质体具有100nm至300nm的直径。
8.根据权利要求6所述的稳定的脂质体制剂，其中所述脂质体具有100nm至300nm的直径。
9.一种用于治疗眼疾病的方法，所述方法包括对有需要的个体的眼睛施用根据权利要求1所述的制剂。
10.根据权利要求9所述的方法，其中所述眼疾病是眼高压或青光眼。
11.根据权利要求10所述的方法，其中所述制剂经由结膜下注射施用。
12.一种用于治疗眼疾病的方法，所述方法包括对有需要的个体的眼睛施用根据权利要求7所述的制剂。
13.根据权利要求12所述的方法，其中所述眼疾病是眼高压或青光眼。
14.根据权利要求13所述的方法，其中所述制剂经由结膜下注射施用。
15.一种用于治疗眼疾病的方法，所述方法包括对有需要的个体的眼睛施用根据权利要求8所述的制剂。
16.根据权利要求15所述的方法，其中所述眼疾病是眼高压或青光眼。
17.根据权利要求16所述的方法，其中所述制剂经由结膜下注射施用。
CN201410204720.XA 2014-01-07 2014-05-15 用于眼药物递送的稳定的脂质体制剂 Active CN104758249B (zh)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US14/149,159 US9956195B2 (en) 2014-01-07 2014-01-07 Stable liposomal formulations for ocular drug delivery
US14/149,159 2014-01-07

Publications (2)

Publication Number Publication Date
CN104758249A true CN104758249A (zh) 2015-07-08
CN104758249B CN104758249B (zh) 2019-08-23

Family

ID=50112787

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201410204720.XA Active CN104758249B (zh) 2014-01-07 2014-05-15 用于眼药物递送的稳定的脂质体制剂

Country Status (9)

Country Link
US (1) US9956195B2 (zh)
EP (1) EP2891484B1 (zh)
JP (1) JP6463902B2 (zh)
KR (1) KR102315264B1 (zh)
CN (1) CN104758249B (zh)
ES (1) ES2676213T3 (zh)
HK (1) HK1206254A1 (zh)
TW (1) TWI630925B (zh)
WO (1) WO2015105458A1 (zh)

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014039012A1 (en) * 2012-09-06 2014-03-13 Nanyang Technological University Hyaluronic acid-based drug delivery systems
US20190133931A1 (en) * 2016-04-19 2019-05-09 Nanyang Technological University Subconjunctival depot forming formulations for ocular drug delivery
US11452703B2 (en) 2020-05-21 2022-09-27 Peregrine Ophthalmic PTE LTD. Methods and compositions for reducing adipocyte numbers

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6015716A (en) * 1996-07-12 2000-01-18 The Liposome Company, Inc. Detection of endotoxin levels in liposomes, lipid bilayers and lipid complexes
US20040224010A1 (en) * 2002-11-15 2004-11-11 Optime Therapeutics, Inc. Ophthalmic liposome compositions and uses thereof
US20060246145A1 (en) * 2004-04-30 2006-11-02 Allergan, Inc. Methods for treating ocular conditions with cyclic lipid containing microparticles
CN101049504A (zh) * 2007-04-05 2007-10-10 广州立恩生物科技有限公司 一种脂质体药物载体及其制备方法
US20100310637A1 (en) * 2007-10-11 2010-12-09 Muhammad Abdulrazik Composition and method for the treatment or prevention of glaucoma and ocular hypertension
WO2011098578A2 (en) * 2010-02-12 2011-08-18 Bioneer A/S Liposome system for ocular administration
WO2012021107A2 (en) * 2010-08-12 2012-02-16 Nanyang Technological University A liposomal formulation for ocular drug delivery

Family Cites Families (60)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5925375A (en) 1987-05-22 1999-07-20 The Liposome Company, Inc. Therapeutic use of multilamellar liposomal prostaglandin formulations
AU617678B2 (en) 1987-05-22 1991-12-05 Liposome Company, Inc., The Prostaglandin-lipid formulations
US4938965A (en) 1987-07-22 1990-07-03 Her Majesty The Queen In Right Of Canada, As Represented By The Minister Of National Defence Of Her Majesty's Canadian Government Ocular delivery of prophylactic agents
SE8703854D0 (sv) 1987-10-07 1987-10-07 Pharmacia Ab Prostaglandinderivat for behandling av glaukom eller okuler hypertension
JP2602964B2 (ja) 1989-10-16 1997-04-23 裕 水島 プロスタグランジン類縁体およびその脂肪乳剤
US5478819A (en) 1993-06-23 1995-12-26 Simo Tarpila Phospholipid composition and use thereof
US6773719B2 (en) 1994-03-04 2004-08-10 Esperion Luv Development, Inc. Liposomal compositions, and methods of using liposomal compositions to treat dislipidemias
CA2247270A1 (en) 1996-02-26 1997-08-28 Daiichi Pharmaceutical Co., Ltd. Liposome and liposome dispersion
US5997899A (en) 1996-10-01 1999-12-07 Skyepharma Inc. Method for producing liposomes with increased percent of compound encapsulated
WO1998043616A1 (en) 1997-03-31 1998-10-08 University Of Iowa Research Foundation Glycosylceramide-containing liposomes
BR9913955A (pt) 1998-09-25 2001-06-12 Alcon Lab Inc Composição oftalmológica confortável e de liberação sustentada e método para terapia ocular
WO2003030818A2 (en) 2001-10-05 2003-04-17 Pichit Suvanprakorn Active agents using liposome beads
US6864239B2 (en) 2002-03-27 2005-03-08 Theratechnologies Inc. Methods and compounds for prevention and treatment of elevated intraocular pressure and related conditions
CN100591333C (zh) 2002-08-23 2010-02-24 参天制药株式会社 以拉坦前列素为有效成分的稳定的滴眼液
JP2006516027A (ja) 2002-12-02 2006-06-15 ジェンベク、インコーポレイティッド 眼関連障害の治療用材料および治療方法
EA008496B1 (ru) 2002-12-20 2007-06-29 Чакшу Рисерч, Инк. Офтальмологический препарат для профилактики и лечения болезненных состояний глаз
EP1643971A2 (en) 2003-05-22 2006-04-12 Neopharm, Inc. Liposomal formulations comprising a combination of two or more active agents
US20050054723A1 (en) 2003-05-27 2005-03-10 Johan Stjernschantz Method for the treatment of glaucoma and ocular hypertension with prostaglandin analogues without melanogenic side effect
EP1667705A1 (en) 2003-10-03 2006-06-14 Allergan, Inc. Compositions and methods comprising prostaglandin-related compounds and trefoil factor family peptides for the treatment of glaucoma with reduced hyperemia
WO2005094790A1 (es) 2004-04-02 2005-10-13 Italfarmaco, S.A. Formulaciones liposomales
PT1759702E (pt) 2004-05-26 2009-04-13 Arturo Jimenez Bayardo Método de preparação de uma solução oftálmica de latanoprost e a solução assim produzida
ATE401054T1 (de) 2004-06-04 2008-08-15 Camurus Ab Flüssige depotformulierungen
CA2578064C (en) 2004-08-23 2015-10-13 Sylentis S.A.U. Treatment of eye disorders characterized by an elevated intraocular pressure by sirnas
AU2005279308B2 (en) * 2004-09-03 2012-05-03 Creabilis Therapeutics S.R.L. Protease resistant human and non-human HMGB1 Box-A mutants and their therapeutic/diagnostic use
SI1797109T1 (sl) 2004-09-09 2016-07-29 Yeda Research And Development Co., Ltd. Zmesi polipeptidov, sestavki, ki jih vsebujejo, in postopki za njihovo pripravo ter njihove uporabe
DE602004017477D1 (de) 2004-11-09 2008-12-11 Novagali Pharma Sa Öl-in-Wasser-Emulsion mit niedriger Konzentration des kationischen Mittels und positivem Zetapotential
US20060188481A1 (en) 2005-02-22 2006-08-24 Saitama Medical School Methods for prophylactically or therapeutically treating an animal for an ocular-related disorder
US7851504B2 (en) 2005-03-16 2010-12-14 Allergan, Inc. Enhanced bimatoprost ophthalmic solution
ES2389500T3 (es) 2005-03-31 2012-10-26 Asahi Glass Company, Limited Agente protector para una célula neuronal retiniana que contiene un derivado de prostaglandina F2 alfa como ingrediente activo
US20070026061A1 (en) 2005-05-25 2007-02-01 Nahid Ali Liposomal formulation and use thereof
US9539202B2 (en) 2006-04-28 2017-01-10 Universidad Complutense De Madrid Formulation of liposomal vesicles in aqueous solutions with lachrymal film characteristics
WO2008120249A1 (en) 2007-03-30 2008-10-09 Sifi S.P.A. Pharmaceutical formulations based on apolar and polar lipids for ophthalmic use
EP1985298A1 (en) 2007-04-24 2008-10-29 Azad Pharma AG Ophtalmic oil-in-water emulsions containing prostaglandins
AU2008289552B2 (en) 2007-08-16 2014-10-09 The Schepens Eye Research Institute, Inc. Therapeutic compositions for treatment of inflammation of ocular and adnexal tissues
WO2009051670A2 (en) 2007-10-12 2009-04-23 Resolvyx Pharmaceuticals, Inc. Oxylipin compounds for the treatment of ophthalmic conditions
WO2009107753A1 (ja) 2008-02-29 2009-09-03 財団法人 名古屋産業科学研究所 後眼部到達用リポソーム及び後眼部疾患用医薬組成物
ITRM20080182A1 (it) 2008-04-07 2009-10-08 Medivis S R L Preparato oftalmico a base di dorzolamide e latanoprost per il trattamento topico del glaucoma.
CN102123713A (zh) 2008-05-09 2011-07-13 Qlt栓塞输送公司 治疗青光眼和眼高血压的活性剂的持续释放递送
EP2127638A1 (en) 2008-05-30 2009-12-02 Santen Pharmaceutical Co., Ltd Method and composition for treating ocular hypertension and glaucoma
CN102105118A (zh) 2008-06-24 2011-06-22 Qlt栓塞输送公司 青光眼的联合治疗
US20100104654A1 (en) 2008-10-27 2010-04-29 Allergan, Inc. Prostaglandin and prostamide drug delivery systems and intraocular therapeutic uses thereof
MX2011007804A (es) 2009-01-23 2011-12-06 Quadra Logic Tech Inc Suministro de liberación sostenida de uno o más agentes.
CN102395401B (zh) 2009-02-12 2015-08-19 因赛普特有限责任公司 经由水凝胶塞的药物递送
US20100247606A1 (en) 2009-03-25 2010-09-30 Allergan, Inc. Intraocular sustained release drug delivery systems and methods for treating ocular conditions
EP3318264A1 (en) 2009-08-24 2018-05-09 Stealth Peptides International, Inc. Methods ans compositions for preventing or treating opthalmic conditions
EP2478906A4 (en) 2009-09-17 2013-02-20 Senju Pharma Co AQUEOUS OPHTHALMIC DROPS THAT CONTAIN LATANOPROST, AND A METHOD OF INHIBITING ADSORPTION OF LATANOPROST ON A RESIN
US20110070294A1 (en) 2009-09-23 2011-03-24 Javeri Indu Methods for the Administration of Drugs Using Liposomes
WO2011053801A2 (en) 2009-10-30 2011-05-05 Intratus, Inc. Methods and cosmetic preparations for the sustained delivery of therapeutic agents to the eye
WO2011106702A2 (en) 2010-02-25 2011-09-01 The Johns Hopkins University Sustained delivery of therapeutic agents to an eye compartment
US20110294730A1 (en) 2010-05-31 2011-12-01 Shantha Totada R Method of treating glaucoma and intraocular hypertension
AU2011327785A1 (en) 2010-11-08 2013-03-07 Healor Ltd. Buffered ophthalmic compositions and methods of use thereof
CA2860453C (en) 2011-01-24 2020-04-28 Inceptum Research & Therapeutics, Inc. Compositions comprising a prostaglandin for treating neuropsychiatric conditions
EP2750660B1 (en) 2011-08-29 2016-10-12 Mati Therapeutics Inc. Sustained release delivery of active agents to treat glaucoma and ocular hypertension
US9974685B2 (en) 2011-08-29 2018-05-22 Mati Therapeutics Drug delivery system and methods of treating open angle glaucoma and ocular hypertension
EP2841104A1 (en) 2012-04-24 2015-03-04 Allergan, Inc. Prostaglandin and vasoconstrictor pharmaceutical compositions and methods of use
CA2872338C (en) 2012-05-03 2021-09-14 Qlt Inc. Drug delivery system and methods of treating open angle glaucoma and ocular hypertension
WO2014039012A1 (en) 2012-09-06 2014-03-13 Nanyang Technological University Hyaluronic acid-based drug delivery systems
US9750636B2 (en) 2012-10-26 2017-09-05 Forsight Vision5, Inc. Ophthalmic system for sustained release of drug to eye
EP2950782B1 (en) 2013-01-31 2017-12-27 Icon Bioscience, Inc. Sustained release formulations for the treatment of intraocular pressure or glaucoma
EP2978409B1 (en) 2013-03-27 2018-01-10 Comprehensive Drug Enterprises Ltd Ophthalmic composition, method for preparing the same, and use of the same

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6015716A (en) * 1996-07-12 2000-01-18 The Liposome Company, Inc. Detection of endotoxin levels in liposomes, lipid bilayers and lipid complexes
US20040224010A1 (en) * 2002-11-15 2004-11-11 Optime Therapeutics, Inc. Ophthalmic liposome compositions and uses thereof
US20060246145A1 (en) * 2004-04-30 2006-11-02 Allergan, Inc. Methods for treating ocular conditions with cyclic lipid containing microparticles
CN101049504A (zh) * 2007-04-05 2007-10-10 广州立恩生物科技有限公司 一种脂质体药物载体及其制备方法
US20100310637A1 (en) * 2007-10-11 2010-12-09 Muhammad Abdulrazik Composition and method for the treatment or prevention of glaucoma and ocular hypertension
WO2011098578A2 (en) * 2010-02-12 2011-08-18 Bioneer A/S Liposome system for ocular administration
WO2012021107A2 (en) * 2010-08-12 2012-02-16 Nanyang Technological University A liposomal formulation for ocular drug delivery

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
JAYAGANESH V NATARAJAN，等: "Nanomedicine for glaucoma: liposomes provide sustained release of latanoprost in the eye", 《INTERNATIONAL JOURNAL OF NANOMEDICINE》 *
SHARON M.K. DAVIDSON，等: "Association and release of prostaglandin E from liposomes", 《BIOCHIMICA ET BIOPHYSICA ACTA》 *
冯玉荣，等: "《临床护理技术操作规范》", 31 May 2011, 河南科学技术出版社 *
叶萍仙，等: "脂质体携载前列腺素E1抑制血小板功能降低心肌梗死面积", 《中华心血管病杂志》 *
童桥，等: "糖和膜脂的相互作用——脂质体稳定性的研究", 《生理科学进展》 *
陈孝治，等: "《药物处方手册 第二版》", 30 June 2012, 湖南科学技术出版社 *

Also Published As

Publication number Publication date
CN104758249B (zh) 2019-08-23
EP2891484A1 (en) 2015-07-08
US9956195B2 (en) 2018-05-01
JP6463902B2 (ja) 2019-02-06
ES2676213T3 (es) 2018-07-17
JP2015129107A (ja) 2015-07-16
HK1206254A1 (zh) 2016-01-08
EP2891484B1 (en) 2018-04-11
TW201526924A (zh) 2015-07-16
KR102315264B1 (ko) 2021-10-20
WO2015105458A1 (en) 2015-07-16
TWI630925B (zh) 2018-08-01
US20150190359A1 (en) 2015-07-09
KR20150082078A (ko) 2015-07-15

Similar Documents

Publication Publication Date Title
Subrizi et al. Design principles of ocular drug delivery systems: importance of drug payload, release rate, and material properties
CN103200931B (zh) 用于眼后节疾病治疗的液体药物组合物
Ranta et al. Barrier analysis of periocular drug delivery to the posterior segment
KR20190100283A (ko) 건성 안 질환 치료용 안구 조성물
CN109803650A (zh) 包含大麻素受体结合配体的组合物
Daull et al. A comparative study of a preservative-free latanoprost cationic emulsion (Catioprost) and a BAK-preserved latanoprost solution in animal models
EP2968139B1 (en) Microemulsion topical delivery platform
Singh et al. The challenges of ophthalmic drug delivery: a review
Loftsson Topical drug delivery to the retina: obstacles and routes to success
CN107454841A (zh) 内皮素受体拮抗剂的局部眼用制剂及其用途
JP2017519813A (ja) 局所製剤およびその使用
KR20200136403A (ko) 티몰롤을 포함하는 약제학적 조성물
CN104758249A (zh) 用于眼药物递送的稳定的脂质体制剂
Zhang et al. A novel eyes topical drug delivery system: CsA-LNC for the treatment of DED
Qi et al. Challenges and strategies for ocular posterior diseases therapy via non-invasive advanced drug delivery
Rupenthal Sector overview: ocular drug delivery technologies: exciting times ahead
WO2018011705A1 (en) Liposome-based eye drops and use thereof for in vivo evaluation of the drug efficacy of medical and surgical anti-glaucoma therapy
Chen et al. Breaking barriers: Nanomedicine-based drug delivery for cataract treatment
Tyagi et al. Novel technology and future prospects of ocular drug delivery
CN110022856A (zh) 用于降低眼压的眼用组合物
Desai et al. Factors Affecting Intra-ocular Bioavailability of Drugs
Faria et al. Recent advances and strategies for nanocarrier-mediated topical therapy and theranostic for posterior eye disease
Garrigue et al. A comparative study of latanoprost-cationic emulsion (Catioprost) and latanoprost aqueous solution (Xalatan) in preclinical efficacy and safety models
EP4260845A1 (en) Preservative-free ophthalmic pharmaceutical emulsion and its application
Urtti Nanostructures Overcoming the Ocular Barrier: Drug Delivery Strategies

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
REG Reference to a national code

Ref country code: HK

Ref legal event code: DE

Ref document number: 1206254

Country of ref document: HK

C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
GR01 Patent grant
GR01 Patent grant
REG Reference to a national code

Ref country code: HK

Ref legal event code: WD

Ref document number: 1206254

Country of ref document: HK