CN100441169C - 合成的无机纳米微粒作为载体在眼用和耳用的药物中的应用 - Google Patents

合成的无机纳米微粒作为载体在眼用和耳用的药物中的应用 Download PDF

Info

Publication number
CN100441169C
CN100441169C CNB028253639A CN02825363A CN100441169C CN 100441169 C CN100441169 C CN 100441169C CN B028253639 A CNB028253639 A CN B028253639A CN 02825363 A CN02825363 A CN 02825363A CN 100441169 C CN100441169 C CN 100441169C
Authority
CN
China
Prior art keywords
nanoparticle
compositions
eye
ear
synthetic
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.)
Expired - Fee Related
Application number
CNB028253639A
Other languages
English (en)
Other versions
CN1604770A (zh
Inventor
H·A·凯特尔森
D·L·梅多斯
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.)
Novartis AG
Original Assignee
Alcon Universal Ltd
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 Alcon Universal Ltd filed Critical Alcon Universal Ltd
Publication of CN1604770A publication Critical patent/CN1604770A/zh
Application granted granted Critical
Publication of CN100441169C publication Critical patent/CN100441169C/zh
Anticipated expiration legal-status Critical
Expired - Fee Related legal-status Critical Current

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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
    • 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
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • 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
    • 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
    • A61P27/16—Otologicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02—Inorganic compounds
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Epidemiology (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Ophthalmology & Optometry (AREA)
  • Immunology (AREA)
  • Pulmonology (AREA)
  • Communicable Diseases (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Oncology (AREA)
  • Inorganic Chemistry (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Silicates, Zeolites, And Molecular Sieves (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)

Abstract

本发明涉及无机材料的纳米微粒(例如合成的绿土粘土)在眼用和耳用药物组合物中的应用。纳米微粒被用作眼用和耳用药物的生物学惰性载体或储存库。纳变微粒还被用来改变组合物的流变性质，从而增强组合物的粘度或流动特性和/或延长组合物在眼睛或耳朵的停留时间。

Description

合成的无机纳米微粒作为载体在眼用和耳用的药物中的应用
发明背景
本发明涉及眼用和耳用药物输送，特别是，本发明涉及合成的无机纳米微粒作为惰性载体在眼用和耳用药物中的应用和这种基于本发明的药物组合物在眼睛和耳朵的局部施用。
许多不同类型的物质被用来作为载体向眼部施加眼科用药，例如，美国专利4271143，就报道了使用羧乙烯聚合物来实现这一目的。很多其他的有机聚合物也被用来作为眼科用药的载体。
由合成的或天然聚合物形成的纳米微粒在眼科组合物中的应用已经在很多科技出版物中公开，例如：
Kreuter，J.“纳米微粒”胶体药物传输系统，Jork Kreuter编辑，Marcel Dekker，纽约，纽约(美国)，第219页第5章(1994年)；
Gurny，R.“使用纳米微粒治疗眼睛”聚合的纳米微粒和微球 体，P.Guiot和P.Couverur编辑，Boca Raton，佛罗里达(美国)：CRC Press，第127页(1986年)；
Gurny，R.“延长活性药物传输系统在治疗青光眼中的初步探讨”Pharm Acta Helv.，第56卷第130页(1981年)；
Zimmer等，“微球体和纳米微粒在眼部传输系统中的应用”高级药 物传输综述，第16卷第1期，第61-73页(1995年)；
Galvo等，“一些胶束系统如纳米微粒、纳米微胶囊和纳米微乳作为眼部用药载体的体外评估比较”，J Pharm Sci，第85卷第5期，第530-536页(1996年5月)。
被用于本发明的纳米微粒并不是如上所引证的出版物所描述的合成的或天然的聚合物，本发明涉及无机纳米微粒的使用。应用于本发明的纳米微粒包括例如可水溶胀的粘土物质，一些相关的粘土的化学和物理性质的综述可在下文中找到。
Giese，R.F.and van Oss C.J.，“粘土和相关矿物的胶体和表面性质”，A.T.Hubbard，Marcel Dekker Inc.第105卷。
优选的纳米微粒是由简单的硅酸盐制备的合成的绿土粘土，下面的出版物将指出关于合成的粘土纳米微粒在药物组合物中的应用的背景：
Plaizier-Vercammen，“Laponite XLG，一种合成的纯的锂蒙脱石的流变性质”Phamazie，，第47卷第856页(1992年)；
Grandolini等，“象水滑石样的阴离子粘土嵌入抗炎剂的化合物：布洛芬的嵌入和体外释放”International Journal of Pharmaceutics，第220卷第1-2期，第23-32页(2001年6月4日)；
美国专利5585108(Ruddy等)，题目为“口服的胃肠道治疗剂和药学可接受的粘土的制剂”；
美国专利6177480B1(Tsuzuki等)描述了合成的粘土材料(如LaponiteTM)作为接触透镜的湿润剂以帮助表面活性剂来去除镜片上的脂类沉淀物；
美国专利6015816(Kostyniak等)描述了例如绿土粘土矿物的胶束微粒的改良方法，作为具有抗菌活性的配体作用物来控制细菌在材料上的生长；
美国专利6177480(Tsuzuki等)描述了合成的粘土材料(如LaponiteTM)作为接触透镜的湿润剂以帮助表面活性剂来去除镜片上的脂类沉淀物。
发明概述
本发明基于无机物料的纳米微粒在配制眼用的和耳用的药物组合物中的用途，特别的，这类组合物适于眼部的和耳部的局部组织应用。纳米微粒作为化学惰性载体或眼用或耳用药物的贮存库以及作为眼用或耳用组合物的一部分。
本发明确信比现有的使用有机聚合物作为眼部用药传输的效果要好。例如，应用于本发明的无机纳米微粒特别适合作为在需要控制释放药物的情况下作为药物传输剂。微粒提供了很高的表面积并且微粒在水介质中可以很好的分散为透明胶状或溶液的能力使得该微粒可提供优于现有传输剂的优势。
现在已经发现在很低浓度的水溶液中，纳米微粒可以很好的被分散并保持成透明溶液。由于纳米微粒的微小尺寸，本发明的组合物可以保持透明且不混浊，这对于眼用组合物来说很重要。同时还发现，微粒可以作为眼用和耳用药物的载体，而对于组合物中所含的抗微生物防腐剂的抗微生物活性没有影响。
除了作为眼用的和耳用药物的惰性载体以外，无机纳米微粒还为本发明组合物提供了很好的流变性质。
发明的详细描述
应用于本发明的纳米微粒是无机物质。微粒具有胶体的尺寸，大的表面积和很高的离子交换能力。在下文中将微粒一般称作无机纳米微粒。优选的是使用合成的无机纳米微粒。
应用于本发明的无机纳米微粒优选颗粒尺寸小于100纳米(“nm”)，但要大于1纳米，分布的标准误差不超过10％，纳米微粒的形状不限于球形，也可以是盘状、立方体的、椭球形的或其他微粒形态。微粒的表面积为30-1000平方米/克(m2/g)，在pH值范围为6.0-7.8时总体为负的表面电荷。
用于本发明的无机纳米微粒也可是表面改性的，这取决于所涉及组合物的特定形状和所需的稳定性。不同类型的纳米微粒可以被联合以优化制剂的性质。
用于本发明的无机纳米微粒优选由在水溶液中可溶胀的粘土制成。这类粘土在这里是指水合的。优选使用合成的水合粘土纳米微粒，因为它们可以商购、质纯，且这些材料的化学组成和物理性质明确。此外合成的粘土纳米微粒比自然存在的粘土形成的无机纳米微粒容易配制并形成为无色和透明胶状。
特别有用的合成无机纳米微粒包括可商购的商标名为Laponite(Southern Clay Products，Gonzales，Texas，USA)的合成绿土粘土。Laponite
Figure C0282536300062
是分层的水合硅酸镁，是由简单的硅酸盐制备而得的。可从以下的出版物中得到关于Laponite
Figure C0282536300063
的物理性质和功能的介绍：Laponite Technical Bulletin“Laponite-synthetic layeredsilicate-its chemistry，structure and relationship to naturalclays”L204/01g，其他的合成的硅酸镁铝是也可商购的商标名为OPTIGEL
Figure C0282536300064
SH(Sud-Chemie，Louisville，Kentucky)。
从天然的水合粘土中形成的无机纳米微粒可以单独或和合成粘土联合使用。合适的天然存在的粘土如aliettite，贝得石，膨润土，锂蒙脱石，高岭石，magadite，蒙脱石，绿脱石，皂石，锌蒙脱石，stevensite和铬岭石。
以下出版物可以看到有关各种类型的粘土纳米微粒的物理性质和这些材料可作为离子交换材料、粘度调节剂和成膜剂的进一步详细描述：
Gieseking，J.E.，“在蒙脱-蒙脱石-贝得石-绿脱石类的粘土矿物中的阳离子交换机制”，Soil Science，第47卷第1-14页(1939年)；
Theng，B.K.G.，“粘土聚合复合物的形成和性质”，Elsevier，Amsterdam，(1979年)；
H.van Olphen，“粘土胶体化学”，Krieger PublishingCompany，Florida，Second Edition(1991年)。
其他可替换或联合如上文所描述的粘土纳米微粒的无机纳米微粒材料的例子包括：沸石、水滑石、二氧化硅、氧化铝、二氧化铈、氧化钛和氧化锌。纳米尺寸的二氧化硅微粒例如由Nalco提供的Nalco115和1140，和EKA化学公司的NaAcol
Figure C0282536300066
级均可很好的被应用。基于其他金属的矿物氧化物也可商购。例如矿物氧化物(如氧化铝、二氧化铈、氧化钛和氧化锌)可购自Nanophase Technologies(Romeoville，Illinois，USA)商标为“Nano Tek
Figure C0282536300067
”具有明确的纳米直径。
如上所述，已经发现的上面提到的无机钠米微粒可以很好的作为眼用和耳用药物分子的载体和眼用和耳用组合物的其他组成成分。本发明应用纳米微粒作为各类药物活性剂的载体，如控制眼内压和治疗青光眼的制剂，神经保护剂，抗过敏剂，抗感染剂，抗炎剂，粘液促分泌素(mucosecretagogues)，angiostatic甾类化合物，疼痛缓解剂，充血缓和剂或收敛剂等等。
包括入本发明组合物的和通过本发明的方法施与的药物活性剂例如，但并不局限于这些：抗青光眼剂，如阿普尼定、布莫尼定、倍他洛尔、噻马洛尔、毛果芸香碱、碳酸酐酶抑制剂、前列腺素和5-羟色胺；多巴胺拮抗剂；抗感染剂，如莫西杀星(moxifloxacin)、加替杀星(gatifloxacin)、左氟星、环丙杀星和妥布霉素；非类固醇和类固醇类抗炎药，如利美索龙、地塞米松、泼尼松龙、氟甲缩松、lotoprednol、奈普生、双氯酚酸钠、舒洛芬和酮咯酸；蛋白质；生长因子，如表皮生长因子；粘液促分泌素，如15-HETE；神经保护剂、angiostatic甾类化合物，如阿奈可他(anecortave)乙酸盐；抗组胺药，如依美斯汀(emadine)；肥大细胞稳定剂，如奥洛他定(olopatadine)和免疫调节剂如环孢菌素。
用于本发明的特殊眼用或耳用组合物的无机纳米微粒的浓度依赖于组合物的物理形态(如溶液、分散体、悬浮液或凝胶)和其他本领域已知的因素。特定制剂的纳米微粒最理想的浓度可通过常规实验来确定，根据说明书和这里讨论的事项来进行。作为选定的实验结果，理想的浓度在不同制剂之间明显不同，一般是在0.000001-10w/v％，优选0.1-10w/v％这个范围内。分散的绿土粘土纳米微粒(如Laponite
Figure C0282536300071
)在本发明的组合物中的浓度从一种制剂到另一种制剂可以显著的变化，但是一般在0.1-1w/v％这个范围内，优选是0.3-0.5w/v％。
已经发现，如上所描述的无机纳米微粒在生理学pH条件下可以很好的分散在低浓度的缓冲水溶液中，保持透明溶液、分散体或凝胶状。在浓度至多10w/v％时，无机纳米微粒会形成透明无色的低粘度分散体。可是，如果和适当的盐和其它赋形剂联合，纳米微粒会形成透明的具有高剪切稀薄和触变性的凝胶。特别在浓度超过0.5w/v％时，微粒在适当的电解质条件下会成为透明凝胶，显示出具有润滑、成膜和粘弹性。
要形成这种凝胶的电解质条件多少依赖于所选的无机纳米微粒的微粒类型、所使用的浓度、缓冲剂或赋形剂的类型和其他本领域已知的因素等。但是最好的电解液条件是使用非常低水平的1∶1的电解质(如氯化钠)。本发明的凝胶组合物的理想浓度可以很容易地通过每一制剂的常规试验得到。但是一般的所需电解质的量在0.01-0.1w/v％范围。
在这里所描述的加入无机纳米微粒的水性眼用和耳用组合物具有重要的流变学变化，本发明的组合物典型的具有比不含有合成无机纳米微粒的相同组合物高数个数量级的粘性。本发明的组合物优选在高剪切率下具有小于5.0mPa*sec的粘度。更特别的，本发明的组合物在剪切率超过25sec-1下具有小于5.0mPa*sec的牛顿平台粘度，最优选粘度范围是0.1-1mPa*sec。
如上所讨论的由无机纳米微粒提供的改变的流变学性质被用于使本发明组合物在眼睛或耳朵的储留时间延长，或提高组合物的流动特性。
如本发明所述的眼用和耳用组合物除了上述合成无机纳米微粒和药物活性剂外可以包含各种辅助物质，如缓冲液和张力调节剂。如本发明所述的眼用和耳用组合物一般配制成无菌水溶液、悬浮液、分散体或凝胶。组合物必须配制成与眼部和耳部的组织相容。本发明所述的眼用的溶液、悬浮液和分散体的渗透压一般是200到400毫渗透压摩尔/公斤水。所有这些组合物具有生理学可接受的pH值。
如本发明所述被包装为多剂量产品的眼用和耳用组合物可包含一种或多种有效量的眼部可接受的杀虫剂以避免被诸如细菌和真菌类微生物所污染。用于此目的的杀虫剂被称为抗微生物防腐剂。
本发明对作为抗微生物防腐剂的杀虫剂没有限制。优选的杀虫剂包括：洗必泰、聚亚己基缩二胍聚合物(pHMB)、polyquaternium-1和氨基缩二胍，描述于美国专利申请序列号09/581952和相应的国际公开号(PCT)，WO99/32158，全部内容均被引入本申请作为参考，优选使用表面活性杀虫剂。
优选的抗微生物剂是polyquaternium-1和氨基缩二胍类，描述于美国专利申请序列号09/581952和相应的国际公开号(PCT)，WO99/32158，最优选的氨基缩二胍描述于美国专利申请序列号09/581952中，对应于PCT公开中“化合物I”，结构如下：
结构式
Figure C0282536300091
该化合物在后面用AL8496来表示。
防止眼用或耳用药物被微生物污染所需的抗微生物活性水平是本领域已知的，基于个人经验和官方公布标准，如美国药典制定的和其他国家相似的规定。用于此目的的抗微生物防腐剂的量在这里被称为“有效量”。
组合物还可含有一种或多种成分来增强组合物的抗微生物活性，如，硼酸盐/多元醇化合物的复合物(例如硼酸/丙二醇)，如美国专利6143799(Chowhan等)所述；小分子量的氨基醇(例如AMP)，如美国专利6319464B2(Asgharian)所述；或者是小分子量的氨基酸(例如甘氨酸)，如美国专利5741817(Chowhan等)中所述。如上所述专利的全部内容均被引入本申请作为参考。上面所引证的成分可以单独或联合抗微生物剂如polyquaternium-1使用。
本发明组合物根据如下实施例所述的代表性配方进一步描述。
实施例
下表提供的例子是含有利美索龙的眼科用药。该组合物用于治疗眼部炎症。表中所有的浓度均用重量/体积百分比来表示。
Figure C0282536300101
注：在室温下、未控制用Brookfield DVIII-ULA-转子测量。

Claims (8)

1.合成的无机纳米微粒在眼用或耳用药物中作为载体的应用，其中所述纳米微粒是由合成的水性粘土形成并具有：(a)颗粒尺寸小于100纳米但大于1纳米，分布的标准误差不超过10％；(b)表面积的范围在30到1000m2/g；和(c)在pH值为6.0到7.8之间有总体为负的表面电荷；并且纳米微粒在组合物中的浓度为0.000001到10w/v％。
2.如权利要求1的应用，其中纳米微粒在组合物中的浓度为0.1到10w/v％。
3.如权利要求1所述的应用，其中的合成的水性粘土是绿土粘土。
4.如权利要求1或2所述的应用，其中的纳米微粒选自沸石，水滑石，二氧化硅，氧化铝，二氧化铈，氧化钛和氧化锌。
5.眼用或耳用药物组合物，包括治疗有效量的眼用或耳用药物和足以运载药物的量的合成的无机纳米微粒，其中所述纳米微粒是由合成的水性粘土形成并具有：(a)颗粒尺寸小于100纳米但大于1纳米，分布的标准误差不超过10％；(b)表面积的范围在30到1000m2/g；和(c)在pH值为6.0到7.8之间有总体为负的表面电荷；并且纳米微粒在组合物中的浓度为0.000001到10w/v％。
6.如权利要求5的药物组合物，其中纳米微粒在组合物中的浓度为0.1到10w/v％。
7.如权利要求5所述的组合物，其中的合成的水性粘土是绿土粘土。
8.如权利要求5或6所述的组合物，其中的纳米微粒选自沸石，水滑石，二氧化硅，氧化铝，二氧化铈，氧化钛和氧化锌。
CNB028253639A 2001-12-21 2002-12-20 合成的无机纳米微粒作为载体在眼用和耳用的药物中的应用 Expired - Fee Related CN100441169C (zh)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US34298301P 2001-12-21 2001-12-21
US60/342,983 2001-12-21

Publications (2)

Publication Number Publication Date
CN1604770A CN1604770A (zh) 2005-04-06
CN100441169C true CN100441169C (zh) 2008-12-10

Family

ID=23344163

Family Applications (1)

Application Number Title Priority Date Filing Date
CNB028253639A Expired - Fee Related CN100441169C (zh) 2001-12-21 2002-12-20 合成的无机纳米微粒作为载体在眼用和耳用的药物中的应用

Country Status (19)

Country Link
US (2) US20050003014A1 (zh)
EP (1) EP1474109B1 (zh)
JP (1) JP2005514429A (zh)
KR (1) KR100990810B1 (zh)
CN (1) CN100441169C (zh)
AT (1) ATE478657T1 (zh)
AU (1) AU2002367029B2 (zh)
BR (1) BR0215238A (zh)
CA (1) CA2467763C (zh)
DE (1) DE60237475D1 (zh)
DK (1) DK1474109T3 (zh)
ES (1) ES2349235T3 (zh)
HK (1) HK1075001A1 (zh)
MX (1) MXPA04004919A (zh)
PL (1) PL211494B1 (zh)
PT (1) PT1474109E (zh)
SI (1) SI1474109T1 (zh)
WO (1) WO2003059194A2 (zh)
ZA (1) ZA200403666B (zh)

Families Citing this family (51)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
PL211494B1 (pl) 2001-12-21 2012-05-31 Alcon Zastosowanie syntetycznych, nieorganicznych nanocząstek jako nośników dla leków i kompozycja farmaceutyczna do oczu lub uszu
CA2467764A1 (en) * 2001-12-21 2003-07-24 Alcon, Inc. Inorganic nanoparticles to modify the viscosity and physical properties of ophthalmic and otic compositions.
MXPA04005227A (es) * 2001-12-21 2004-10-11 Alcon Inc Uso de nanoparticulas como portadores para biocidas en composiciones oftalmicas.
CA2549994A1 (en) 2002-12-18 2004-08-12 Hough Ear Institute Otologic nanotechnology
US7344491B1 (en) 2003-11-26 2008-03-18 Nanobiomagnetics, Inc. Method and apparatus for improving hearing
US8651113B2 (en) 2003-06-18 2014-02-18 Swr&D Inc. Magnetically responsive nanoparticle therapeutic constructs and methods of making and using
US7723311B2 (en) 2003-06-18 2010-05-25 Nanobiomagnetics, Inc. Delivery of bioactive substances to target cells
EP2112196A1 (en) * 2008-04-25 2009-10-28 Nederlandse Organisatie voor toegepast- natuurwetenschappelijk onderzoek TNO A liquid composition comprising polymer chains and particles of an inorganic material in a liquid
US20100098768A1 (en) * 2008-10-16 2010-04-22 Clarkson University Method of neuroprotection from oxidant injury using metal oxide nanoparticles
US8822663B2 (en) 2010-08-06 2014-09-02 Moderna Therapeutics, Inc. Engineered nucleic acids and methods of use thereof
US20130295012A1 (en) 2010-08-30 2013-11-07 President And Fellows Of Harvard College Shear controlled release for stenotic lesions and thrombolytic therapies
EP2625189B1 (en) 2010-10-01 2018-06-27 ModernaTX, Inc. Engineered nucleic acids and methods of use thereof
JP2014511687A (ja) 2011-03-31 2014-05-19 モデルナ セラピューティクス インコーポレイテッド 工学操作された核酸の送達および製剤
US9464124B2 (en) 2011-09-12 2016-10-11 Moderna Therapeutics, Inc. Engineered nucleic acids and methods of use thereof
HUE057725T2 (hu) 2011-10-03 2022-06-28 Modernatx Inc Módosított nukleozidok, nukleotidok és nukleinsavak és ezek felhasználása
HRP20220717T1 (hr) 2011-12-16 2022-07-22 Modernatx, Inc. Modificirani pripravci mrna
US10501512B2 (en) 2012-04-02 2019-12-10 Modernatx, Inc. Modified polynucleotides
CA2868391A1 (en) 2012-04-02 2013-10-10 Stephane Bancel Polynucleotides comprising n1-methyl-pseudouridine and methods for preparing the same
US9283287B2 (en) 2012-04-02 2016-03-15 Moderna Therapeutics, Inc. Modified polynucleotides for the production of nuclear proteins
AU2013243947A1 (en) 2012-04-02 2014-10-30 Moderna Therapeutics, Inc. Modified polynucleotides for the production of proteins
US9572897B2 (en) 2012-04-02 2017-02-21 Modernatx, Inc. Modified polynucleotides for the production of cytoplasmic and cytoskeletal proteins
KR101415221B1 (ko) * 2012-08-07 2014-07-09 한국표준과학연구원 무기 나노입자를 유효성분으로 함유하는 혈관 신생 관련 질환의 예방 및 치료용 조성물
ES2921623T3 (es) 2012-11-26 2022-08-30 Modernatx Inc ARN modificado terminalmente
EP2971010B1 (en) 2013-03-14 2020-06-10 ModernaTX, Inc. Formulation and delivery of modified nucleoside, nucleotide, and nucleic acid compositions
US8980864B2 (en) 2013-03-15 2015-03-17 Moderna Therapeutics, Inc. Compositions and methods of altering cholesterol levels
WO2015034925A1 (en) 2013-09-03 2015-03-12 Moderna Therapeutics, Inc. Circular polynucleotides
WO2015034928A1 (en) 2013-09-03 2015-03-12 Moderna Therapeutics, Inc. Chimeric polynucleotides
EP3052521A1 (en) 2013-10-03 2016-08-10 Moderna Therapeutics, Inc. Polynucleotides encoding low density lipoprotein receptor
CL2013003807A1 (es) * 2013-12-31 2014-07-11 Univ Santiago Chile Dispositivos de tubos pequeños de silicona que contienen nanopartículas y micropartículas de zeolitas como agentes de liberación prolongada y controlada, cargadas con 2-metoxiestradiol y suspendidas en un medio oleoso que también contiene 2-metoxiestradiol.
US20170204152A1 (en) 2014-07-16 2017-07-20 Moderna Therapeutics, Inc. Chimeric polynucleotides
US20170210788A1 (en) 2014-07-23 2017-07-27 Modernatx, Inc. Modified polynucleotides for the production of intrabodies
EP3179982B1 (en) * 2014-07-28 2023-07-19 Sun Pharma Advanced Research Company Ltd Method of increasing bioavailability and/or prolonging ophthalmic action of a drug
MY189159A (en) 2015-07-06 2022-01-29 Regeneron Pharma Multispecific antigen-binding molecules and uses thereof
KR101748120B1 (ko) * 2015-07-13 2017-06-16 서울대학교산학협력단 나노입자-유리체 기반 단백질 복합체를 유효성분으로 포함하는 혈관신생억제용 조성물 및 이의 용도
SI3394093T1 (sl) 2015-12-23 2022-05-31 Modernatx, Inc. Metode uporabe liganda OX40, ki kodira polinukleotid
US20190241658A1 (en) 2016-01-10 2019-08-08 Modernatx, Inc. Therapeutic mRNAs encoding anti CTLA-4 antibodies
WO2017190079A1 (en) 2016-04-28 2017-11-02 Regeneron Pharmaceuticals, Inc. Methods of making multispecific antigen-binding molecules
WO2018053273A1 (en) 2016-09-15 2018-03-22 University Of Pittsburgh - Of The Commonwealth System Of Higher Education Shear-thinning therapeutic composition, and related methods
AU2018270111B2 (en) 2017-05-18 2022-07-14 Modernatx, Inc. Polynucleotides encoding tethered interleukin-12 (IL12) polypeptides and uses thereof
BR112019025888A2 (pt) 2017-06-07 2020-06-30 Regeneron Pharmaceuticals, Inc. polinucleotídeo que codifica uma proteína terapêutica multidomínio, vetor de terapia gênica, proteína terapêutica multidomínio recombinante, método de expressão, métodos para reduzir o acúmulo de glicogênio em um tecido em um paciente em necessidade, para reduzir o acúmulo de glicogênio em um tecido em um paciente em necessidade epara tratar a deficiência enzimática em um paciente em necessidade e/ou tolerar o paciente à enzima para a qual é deficiente, anticorpo anti-cd63 ou fragmento de ligação a antígeno, e, composição farmacêutica
SG11202007363TA (en) 2018-02-07 2020-08-28 Regeneron Pharma Methods and compositions for therapeutic protein delivery
CN109045305B (zh) * 2018-07-31 2021-12-10 东华大学 一种tpgs修饰的锂皂石纳米颗粒的制备方法
CA3125511A1 (en) 2019-02-08 2020-08-13 Curevac Ag Coding rna administered into the suprachoroidal space in the treatment of ophthalmic diseases
EP3851097A1 (en) * 2020-01-15 2021-07-21 Universidad De Zaragoza Controlled release formulations
WO2022023559A1 (en) 2020-07-31 2022-02-03 Curevac Ag Nucleic acid encoded antibody mixtures
EP4215212A4 (en) 2020-09-17 2024-04-24 Restore Vision Inc COMPOSITION FOR THE TREATMENT OR PREVENTION OF DISEASES, DISORDERS OR CONDITIONS ASSOCIATED WITH ENDOPLASTIC RETICULUM STRESS OR ALL-TRANS-RETINOAL
AU2021353913A1 (en) 2020-09-29 2023-06-01 Oxford University Innovation Limited Stroke treatment
TW202346348A (zh) 2022-01-10 2023-12-01 美商再生元醫藥公司 作為基因治療所遞送之bbb靶向的gaa在龐貝氏症小鼠模型中治療cns及肌肉
WO2023220603A1 (en) 2022-05-09 2023-11-16 Regeneron Pharmaceuticals, Inc. Vectors and methods for in vivo antibody production
WO2024026474A1 (en) 2022-07-29 2024-02-01 Regeneron Pharmaceuticals, Inc. Compositions and methods for transferrin receptor (tfr)-mediated delivery to the brain and muscle
WO2024098002A1 (en) 2022-11-04 2024-05-10 Regeneron Pharmaceuticals, Inc. Calcium voltage-gated channel auxiliary subunit gamma 1 (cacng1) binding proteins and cacng1-mediated delivery to skeletal muscle

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US627124A (en) * 1899-06-20 Fan attachment for sewing-machines
US5212162A (en) * 1991-03-27 1993-05-18 Alcon Laboratories, Inc. Use of combinations gelling polysaccharides and finely divided drug carrier substrates in topical ophthalmic compositions
US6177480B1 (en) * 1998-03-27 2001-01-23 Menicon Co., Ltd. Agent for contact lenses
CN1313755A (zh) * 1998-08-24 2001-09-19 宝洁公司 含胃肠道药物的口服粘膜粘附组合物
CN1491102A (zh) * 2001-02-15 2004-04-21 株式会社三和化学研究所 新的眼科用组合物

Family Cites Families (53)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3947573A (en) 1969-12-01 1976-03-30 Burton, Parsons And Company, Inc. Opthalmic solution
US3884826A (en) * 1973-07-20 1975-05-20 Barnes Hind Pharm Inc Thixotropic cleaning agent for hard contact lenses
US3974125A (en) * 1974-09-27 1976-08-10 Exxon Research And Engineering Company Higher dialkyl dimethyl ammonium clay gelling agents for unsaturated polyester compositions
US4127423A (en) * 1977-09-13 1978-11-28 Burton, Parsons And Company, Inc. Contact lens cleaning solution
US4120949A (en) 1977-10-05 1978-10-17 Cooper Laboratories, Inc. Ophthalmic solution
US4271143A (en) * 1978-01-25 1981-06-02 Alcon Laboratories, Inc. Sustained release ophthalmic drug dosage
US4394179A (en) * 1979-06-25 1983-07-19 Polymer Technology Corporation Abrasive-containing contact lens cleaning materials
US4374745A (en) * 1981-08-13 1983-02-22 Barnes-Hind Pharmaceuticals, Inc. Cleaning compositions
US4940701A (en) * 1984-01-25 1990-07-10 Beecham Group P.L.C. Topical drug release system
GB8401965D0 (en) * 1984-01-25 1984-02-29 Beecham Group Plc Composition
US4738851A (en) * 1985-09-27 1988-04-19 University Of Iowa Research Foundation, Inc. Controlled release ophthalmic gel formulation
EP0217440A1 (en) * 1985-09-27 1987-04-08 The Procter & Gamble Company Stable aqueous pharmaceutical suspensions
US4804539A (en) * 1986-07-28 1989-02-14 Liposome Technology, Inc. Ophthalmic liposomes
IL80298A (en) 1986-10-14 1993-01-31 Res & Dev Co Ltd Eye drops
US4847078A (en) * 1987-01-14 1989-07-11 Arseco, Inc. Storage stable topical composition having moisture control agent
EP0292551A1 (en) * 1986-12-08 1988-11-30 Arseco, Inc. A storage stable topical composition
BR8707615A (pt) 1986-12-24 1989-10-03 Alcon Lab Inc Composicao para limpeza de lentes de contato e processo para sua utilizacao
US4891043A (en) * 1987-05-28 1990-01-02 Board Of Trustees Of The University Of Illinois System for selective release of liposome encapsulated material via laser radiation
US4923699A (en) * 1988-06-03 1990-05-08 Kaufman Herbert E Eye treatment suspension
US5037647A (en) * 1988-09-15 1991-08-06 Alcon Laboratories, Inc. Aqueous antimicrobial opthalmic solutions comprised of quaternary ammonium compound, citric acid, citrate and sodium chloride
US5674504A (en) * 1989-07-12 1997-10-07 L'oreal Cosmetic composition in the form of an aqueous gel containing in suspension spheroids of a non-hydrophilic, lipoidal substance
US5185152A (en) * 1990-01-10 1993-02-09 Peyman Gholam A Method and apparatus for controlled release drug delivery to the cornea and anterior chamber of the eye
JP2536806B2 (ja) * 1991-03-27 1996-09-25 アルコン ラボラトリーズ インコーポレイテッド ゲル化多糖類と微粉砕された薬剤担体とを組み合わせた局部眼科用組成物
EP0546728A3 (en) * 1991-12-13 1993-09-08 Alcon Laboratories Inc Physiological tear compositions and methods for their preparation
US5139782A (en) * 1991-12-23 1992-08-18 Uop Facial cleansing mineral compositions
US5505953A (en) * 1992-05-06 1996-04-09 Alcon Laboratories, Inc. Use of borate-polyol complexes in ophthalmic compositions
KR100295030B1 (ko) * 1992-07-13 2001-09-17 겜마 아키라 피부외용조성물
US5532224A (en) * 1993-12-22 1996-07-02 Alcon Laboratories, Inc. Contact lens cleaning composition containing polyalklene oxide modified siloxanes
AU3070395A (en) * 1994-07-22 1996-02-22 Alcon Laboratories, Inc. Use of low molecular weight amino acids in ophthalmic compositions
US5585108A (en) * 1994-12-30 1996-12-17 Nanosystems L.L.C. Formulations of oral gastrointestinal therapeutic agents in combination with pharmaceutically acceptable clays
JP3719609B2 (ja) * 1995-12-21 2005-11-24 アルコン ラボラトリーズ，インコーポレイテッド 緑内障および眼虚血の治療のための特定のイソキノリンスルホニル化合物の使用
JP3736916B2 (ja) 1996-02-19 2006-01-18 株式会社サンコンタクトレンズ 含水性ソフトコンタクトレンズの消毒用組成物とその用途
US6015816A (en) * 1996-02-29 2000-01-18 The Research Foundation Of State University Of New York Antimicrobial compositions
US6180093B1 (en) * 1996-09-20 2001-01-30 Bausch & Lomb Incorporated Method and composition for rewetting contact lenses and relieving eye dryness
US5811580A (en) * 1996-12-04 1998-09-22 The Lubrizol Corporation Process for the preparation of N-hydrocarbyl-substituted amides via the ritter reaction using solid clay catalysts
US6319464B1 (en) * 1996-12-13 2001-11-20 Alcon Manufacturing, Ltd. Use of low molecular weight amino alcohols in ophthalmic compositions
US5858346A (en) * 1997-05-09 1999-01-12 Allergan Compositions and methods for enhancing contact lens wearability
CA2296080C (en) * 1997-07-29 2005-02-01 Alcon Laboratories, Inc. Ophthalmic compositions containing galactomannan polymers and borate
ID24946A (id) 1997-11-12 2000-08-31 Bausch & Lomb Perawatan lensa kontak dengan larutan berair yang terdiri dari alkali karbonat
ZA9811445B (en) 1997-12-19 1999-08-16 Alcon Lab Inc Aminobiguanides and the use thereof to disinfect contact lenses and preserve pharmaceutical compositions.
US6319513B1 (en) * 1998-08-24 2001-11-20 The Procter & Gamble Company Oral liquid mucoadhesive compounds
FR2783419B1 (fr) 1998-09-18 2002-07-12 Oreal Utilisation a ph acide de silicates mixtes en tant qu'agents tenseurs dans des compositions cosmetiques anti-rides
ES2228467T3 (es) 1999-02-03 2005-04-16 Biosante Pharmaceuticals, Inc. Particulas terapeuticas de fosfato calcico y metodos de fabricacion y su uso.
US6333054B1 (en) * 1999-10-21 2001-12-25 Amuchina S.P.A. Topical, non-cytotoxic, antimicrobial hydrogel with thixotropic properties
JP2001240547A (ja) * 2000-02-29 2001-09-04 Lion Corp 花粉症抑制剤
PE20020146A1 (es) * 2000-07-13 2002-03-31 Upjohn Co Formulacion oftalmica que comprende un inhibidor de ciclooxigenasa-2 (cox-2)
WO2003011351A2 (en) 2001-08-02 2003-02-13 Johnson & Johnson Vision Care, Inc. Antimicrobial lenses and methods of their use
PL211494B1 (pl) 2001-12-21 2012-05-31 Alcon Zastosowanie syntetycznych, nieorganicznych nanocząstek jako nośników dla leków i kompozycja farmaceutyczna do oczu lub uszu
CA2467764A1 (en) * 2001-12-21 2003-07-24 Alcon, Inc. Inorganic nanoparticles to modify the viscosity and physical properties of ophthalmic and otic compositions.
US7217853B2 (en) * 2002-05-24 2007-05-15 Corium International, Inc. Composition for cushions, wound dressings and other skin-contacting products
EP1534202B1 (en) * 2002-06-05 2009-03-11 University Of Florida Research Foundation, Inc. Ophthalmic drug delivery system
US20050181015A1 (en) * 2004-02-12 2005-08-18 Sheng-Ping (Samuel) Zhong Layered silicate nanoparticles for controlled delivery of therapeutic agents from medical articles
US20060193787A1 (en) * 2005-01-31 2006-08-31 Si-Shen Feng Nanoparticle-based drug delivery system

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US627124A (en) * 1899-06-20 Fan attachment for sewing-machines
US5212162A (en) * 1991-03-27 1993-05-18 Alcon Laboratories, Inc. Use of combinations gelling polysaccharides and finely divided drug carrier substrates in topical ophthalmic compositions
US6177480B1 (en) * 1998-03-27 2001-01-23 Menicon Co., Ltd. Agent for contact lenses
CN1313755A (zh) * 1998-08-24 2001-09-19 宝洁公司 含胃肠道药物的口服粘膜粘附组合物
CN1491102A (zh) * 2001-02-15 2004-04-21 株式会社三和化学研究所 新的眼科用组合物

Also Published As

Publication number Publication date
US20050003014A1 (en) 2005-01-06
US8257745B2 (en) 2012-09-04
ES2349235T3 (es) 2010-12-29
JP2005514429A (ja) 2005-05-19
WO2003059194A2 (en) 2003-07-24
HK1075001A1 (en) 2005-12-02
EP1474109A2 (en) 2004-11-10
PL211494B1 (pl) 2012-05-31
CA2467763C (en) 2011-09-13
KR20040072669A (ko) 2004-08-18
DE60237475D1 (de) 2010-10-07
AU2002367029A1 (en) 2003-07-30
EP1474109B1 (en) 2010-08-25
EP1474109A4 (en) 2006-03-29
PL374262A1 (en) 2005-10-03
ATE478657T1 (de) 2010-09-15
ZA200403666B (en) 2005-07-27
CN1604770A (zh) 2005-04-06
PT1474109E (pt) 2010-10-25
AU2002367029B2 (en) 2008-10-02
WO2003059194A3 (en) 2004-05-13
US20110274760A1 (en) 2011-11-10
DK1474109T3 (da) 2010-10-25
MXPA04004919A (es) 2004-08-11
KR100990810B1 (ko) 2010-10-29
SI1474109T1 (sl) 2010-11-30
BR0215238A (pt) 2005-05-31
CA2467763A1 (en) 2003-07-24

Similar Documents

Publication Publication Date Title
CN100441169C (zh) 合成的无机纳米微粒作为载体在眼用和耳用的药物中的应用
AU2002367030B2 (en) Inorganic nanoparticles to modify the viscosity and physical properties of ophthalmic and otic compositions
JP5354239B2 (ja) ピロキシカム−無機物複合体を含む経皮投与組成物及びこれを利用したパッチシステム
DE69926377T2 (de) Orale flüssige mucoadhäsive zusammensetzungen
EP2467132B1 (en) Core stabilized microcapsules, method of their preparation and uses thereof
JP4787165B2 (ja) 表面安定剤としてペプチドを有するナノ粒子組成物
US20100172993A1 (en) Particles for delivery of active ingredients, process of making and compositions thereof
US8097270B2 (en) Use of nanoparticles as carriers for biocides in ophthalmic compositions
CN1129400A (zh) 维生素e生育酚衍生物在眼科组合物中的应用
CZ286596A3 (en) Eye preparation with reduced viscosity
EA036306B1 (ru) Стабилизированные силикатные композиции и их применение в качестве антиперспирантных композиций
JP2594877B2 (ja) 抗菌力が向上した目薬組成物
Hong et al. Functional nanomaterials and their potential applications in antibacterial therapy
JPH0710776A (ja) ゲル化多糖類と微粉砕された薬剤担体とを組み合わせた局部眼科用組成物および薬剤含有の該組成物を目に送達する方法
Godge et al. Formulation Perspectives in Topical Antifungal Drug Therapy: A Review
Tripathi et al. Development of brimonidine niosomes laden contact lenses for extended release and promising delivery system in glaucoma treatment
CN118076340A (zh) 眼用药物组合物及其用途
Jawahar et al. Nanoclay: A Novel Drug Delivery System for Improved Oral Bioavailability
AU2002367028B2 (en) Use of nanoparticles as carriers for biocides in ophthalmic compositions
Ahmed et al. SEMISOLID DOSAGE FORM: TOPICAL GEL FORMULATION A

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
REG Reference to a national code

Ref country code: HK

Ref legal event code: DE

Ref document number: 1075001

Country of ref document: HK

C14 Grant of patent or utility model
GR01 Patent grant
REG Reference to a national code

Ref country code: HK

Ref legal event code: GR

Ref document number: 1075001

Country of ref document: HK

CF01 Termination of patent right due to non-payment of annual fee

Granted publication date: 20081210

Termination date: 20171220

CF01 Termination of patent right due to non-payment of annual fee