[go: up one dir, main page]

CN110063938A - 阳离子化透明质酸修饰的类脂质囊泡及其制备和应用 - Google Patents

阳离子化透明质酸修饰的类脂质囊泡及其制备和应用 Download PDF

Info

Publication number
CN110063938A
CN110063938A CN201910308271.6A CN201910308271A CN110063938A CN 110063938 A CN110063938 A CN 110063938A CN 201910308271 A CN201910308271 A CN 201910308271A CN 110063938 A CN110063938 A CN 110063938A
Authority
CN
China
Prior art keywords
hyaluronic acid
vesicle
cationized hyaluronic
modified
drug
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.)
Pending
Application number
CN201910308271.6A
Other languages
English (en)
Inventor
甘莉
刘阳
张华�
王亚男
杨金龙
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.)
Fubicheng Shanghai Pharmaceutical Technology Co ltd
Kewpie Corp
Original Assignee
Shanghai Institute of Technology
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 Shanghai Institute of Technology filed Critical Shanghai Institute of Technology
Priority to CN201910308271.6A priority Critical patent/CN110063938A/zh
Publication of CN110063938A publication Critical patent/CN110063938A/zh
Priority to JP2021561011A priority patent/JP7504125B2/ja
Priority to EP20791862.4A priority patent/EP3957300B1/en
Priority to US17/604,347 priority patent/US20220192980A1/en
Priority to KR1020217036847A priority patent/KR20220002955A/ko
Priority to ES20791862T priority patent/ES3041497T3/es
Priority to PCT/CN2020/082905 priority patent/WO2020211653A1/zh
Pending 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
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/047—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates having two or more hydroxy groups, e.g. sorbitol
    • 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
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/07—Retinol compounds, e.g. vitamin A
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
    • A61K31/355—Tocopherols, e.g. vitamin E
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • 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
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
    • A61K38/13—Cyclosporins
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/28—Steroids, e.g. cholesterol, bile acids or glycyrrhetinic acid
    • 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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • 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
    • A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
    • 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
    • A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/56—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • A61K47/61—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule the organic macromolecular compound being a polysaccharide or a derivative thereof
    • 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
    • A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6905—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a colloid or an emulsion
    • A61K47/6907—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a colloid or an emulsion the form being a microemulsion, nanoemulsion or micelle
    • 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
    • A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6905—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a colloid or an emulsion
    • A61K47/6911—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a colloid or an emulsion the form being a liposome
    • A61K47/6915—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a colloid or an emulsion the form being a liposome the form being a liposome with polymerisable or polymerized bilayer-forming substances, e.g. polymersomes
    • 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—Synthetic bilayered vehicles, e.g. liposomes or liposomes with cholesterol as the only non-phosphatidyl surfactant
    • A61K9/1271—Non-conventional liposomes, e.g. PEGylated liposomes or liposomes coated or grafted with polymers
    • A61K9/1272—Non-conventional liposomes, e.g. PEGylated liposomes or liposomes coated or grafted with polymers comprising non-phosphatidyl surfactants as bilayer-forming substances, e.g. cationic lipids or non-phosphatidyl liposomes coated or grafted with polymers
    • 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—Synthetic bilayered vehicles, e.g. liposomes or liposomes with cholesterol as the only non-phosphatidyl surfactant
    • A61K9/1271—Non-conventional liposomes, e.g. PEGylated liposomes or liposomes coated or grafted with polymers
    • A61K9/1273—Polymersomes; Liposomes with polymerisable or polymerised bilayer-forming substances
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
    • A61K9/5107—Excipients; Inactive ingredients
    • A61K9/5123—Organic compounds, e.g. fats, sugars
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
    • A61K9/5107—Excipients; Inactive ingredients
    • A61K9/513—Organic macromolecular compounds; Dendrimers
    • A61K9/5146—Organic macromolecular compounds; Dendrimers obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyamines, polyanhydrides
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
    • A61K9/5107—Excipients; Inactive ingredients
    • A61K9/513—Organic macromolecular compounds; Dendrimers
    • A61K9/5161—Polysaccharides, e.g. alginate, chitosan, cellulose derivatives; Cyclodextrin
    • 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

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Dispersion Chemistry (AREA)
  • Ophthalmology & Optometry (AREA)
  • Molecular Biology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Nanotechnology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Immunology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Inorganic Chemistry (AREA)
  • Physics & Mathematics (AREA)
  • Biomedical Technology (AREA)
  • Optics & Photonics (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

本发明提供了一种阳离子化透明质酸修饰的类脂质囊泡，其特征在于，包括载药囊泡，所述的载药囊泡的表面修饰有阳离子化透明质酸，所述的载药囊泡包括囊泡膜以及被囊泡膜所包裹的疏水药物，所述的囊泡膜包含非离子表面活性剂和边缘活性剂。

Description

阳离子化透明质酸修饰的类脂质囊泡及其制备和应用
技术领域
本发明属于药物制剂技术领域，具体涉及一种阳离子化透明质酸修饰的类脂质囊泡、制备方法及其应用。
背景技术
眼，是可以感知光线提供视觉的器官，是传递信息的门户，是我们获取大部分信息的源泉。大脑中大约80％的记忆和知识都是通过眼睛来获取的。目前，由各种原因引起的眼部疾病呈上升趋势，全球每年受眼部疾病困扰的人口高达2 亿人以上。眼局部用药是治疗眼部疾病的主要方式之一。但是由于角膜屏障，鼻泪管引流以及药物本身的理化性质等使药物的跨膜转运受到限制。
环孢素、叶黄素、酮康唑、α-生育酚和地塞米松棕榈酸酯等亲脂性大分子药物。亲脂性可能有助于其渗透生物膜，但是大分子量阻碍其穿过生物膜。此外，可以注意到高脂溶性可以确保其通过角膜上皮，但是进一步通过高亲水性的角膜基质受到阻碍，因此必须制定药物递送策略，以最大限度地提高生物利用度。此外，眼表给药后暴露于眼睛的各种生理机制，例如反射性眨眼，泪膜更新和泪液周转，会导致其剂量的部分损失。因此，分子量大、水溶性差、在眼表有限的保留时间是这些药物生物利用度低的主要原因，通常低于5％。此外，安全性和耐受性是眼部应用产品的重要考虑因素。
用于眼科制剂的囊泡药物递送系统包括脂质体和类脂质体，可以将亲水性药物包封于水性核心，将疏水性药物包封于双层膜中，以保护药物免受生物环境的影响并控制药物的释放时间。通过防止泪液中酶的眼部代谢，囊泡系统还可以延长在角膜表面的作用时间。类脂质体具有类似于脂质体的优势，如生物相容性和生物可降解性。此外，使用非离子表面活性剂代替磷脂，使其相较于脂质体来说具有较低的生产成本和化学稳定性。弹性类脂质囊泡是在类脂质体中加入边缘活性剂(如吐温80)，可以增加囊泡的弹性，使其能够通过浓度梯度造成的压力挤压较小的孔径，从而增加了角膜渗透性。
延长药物眼表保留时间的方法还有使用粘膜粘附聚合物作为滴眼剂的载体，例如壳聚糖，羧甲基纤维素，硫酸软骨素和透明质酸等。透明质酸(HA)是人体玻璃体液的天然成分，并且已广泛用于眼科药物递送。最近，已有许多基于 HA或其衍生物的产品用于治疗干眼症。含有季铵基团的阳离子化透明质酸 (CHA)已被用于修复剂，皮肤改性剂和头发化妆品，并且由于其吸附性能而显示出比阴离子透明质酸更好的保湿性。该特点使其具有了眼部应用的潜力。
发明内容
为了克服现有技术的不足，本发明的目的在于开发一种阳离子化透明质酸修饰的类脂质囊泡，用于药物的眼表递送。
为了达到上述目的，本发明提供了一种阳离子化透明质酸修饰的类脂质囊泡，其特征在于，包括载药囊泡，所述的载药囊泡的表面修饰有阳离子化透明质酸，所述的载药囊泡包括囊泡膜以及被囊泡膜所包裹的疏水药物，所述的囊泡膜包含非离子表面活性剂和边缘活性剂。
优选地，所述的疏水药物为环孢素、叶黄素、酮康唑、α生育酚和地塞米松棕榈酸酯中的至少一种。
优选地，所述的非离子表面活性剂包括但不限于司盘40、司盘60、司盘80、泊洛沙姆121或泊洛沙姆123。
优选地，所述的边缘活性剂包括但不限于吐温20、吐温40、吐温80、胆酸钠、聚氧乙烯月桂醚35或聚氧乙烯蓖麻油EL。
优选地，所述的阳离子化透明质酸修饰的类脂质囊泡的粒径为200-310nm， zeta电位为-10～-30mV，粘度为1～12mPa·s。
优选地，所述的非离子表面活性剂和边缘活性剂的重量比在60：40～90：10 之间。
优选地，所述的非离子表面活性剂与疏水药物的重量比在20：1～4：1之间。
上述的阳离子化透明质酸修饰的类脂质囊泡的制备方法包括但不限于薄膜水化法、逆相蒸发法和有机溶剂挥发法。
本发明还提供了上述的阳离子化透明质酸修饰的类脂质囊泡的制备方法，其特征在于，包括：将含有非离子表面活性剂和疏水药物的乙醇溶液注入65-75℃的含有边缘活性剂和甘油的水溶液中，搅拌使乙醇挥发，得到载药囊泡分散液，将载药囊泡分散液逐滴加入阳离子化透明质酸的等渗溶液中，搅拌，得到阳离子化透明质酸修饰的类脂质囊泡分散液。
优选地，所述的等渗溶液为生理盐水溶液或2.5％甘油水溶液。
优选地，所述的阳离子化透明质酸的修饰浓度0.05％～0.15％w/v(即100mL 阳离子化透明质酸修饰的类脂质囊泡分散液中含有0.05～0.15g阳离子化透明质酸)
本发明还提供了上述的阳离子化透明质酸修饰的类脂质囊泡在制备治疗眼部疾病的药物中的应用。
本发明中的阳离子透明质酸与载药囊泡之间包括但不限于静电吸附与氢键连接。
与现有技术相比，本发明的有益效果在于：
(1)本发明中制备得到的类脂质囊泡，其中非离子表面活性剂具有较好的稳定性，不易氧化，眼部刺激性低；使用边缘活性剂，可以增加囊泡的弹性，使其能够通过浓度梯度造成的压力挤压较小的孔径，从而增加了角膜渗透性。
(2)本发明中，使用阳离子化透明质酸修饰载体，既延长了载体的眼表作用时间，又增强了载体的角膜渗透能力。
(3)本发明中，区别于市售乳剂，未使用蓖麻油、防腐剂、阳离子表面活性剂，类脂质囊泡为胶体溶液，眼表滴注给药不会产生刺激性，具有良好的患者依从性，适合长期使用。
(4)本发明具有眼表作用时间延长、角膜渗透和角膜残留增加，眼表无刺激，生物利用度增强的特点，是一种具有潜力的眼部药物递送系统。
(5)本发明实验表明，该囊泡具有良好的环孢素包封效果，与市售乳剂相比，具有良好的角膜渗透能力和角膜残留量，并且在急性与长期刺激实验中均为表现出刺激性。此外，在干眼动物模型中，通过Schirmer泪液分泌测试、泪液蕨样结晶检查、病理切片分析发现动物的肝炎症状得到明显的改善。
(6)本发明将疏水性药物包封于双层或多层膜中，以保护药物免受生物环境的影响并控制药物的释放时间；在类脂质囊泡中加入边缘活性剂，可以增加囊泡的弹性，使其能够通过浓度梯度造成的压力挤压较小的孔径，从而增加了角膜渗透性；阳离子透明质酸增加载体粘膜黏附性，进一步提高角膜渗透能力，同时具有一定的角膜润湿效果。
附图说明
图1：环孢素载药类脂质囊泡(SVs)以及阳离子化透明质酸修饰的类脂质囊泡(CHASVs)透射电镜图。
图2：角膜渗透(a)和角膜水化(b)实验结果。
图3：急性(A)和长期(B)刺激性实验结果。
图4：Schirmer泪液分泌测试实验结果。
图5：泪液蕨样结晶检查实验结果。
图6：组织学分析结果。
具体实施方式
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。此外应理解，在阅读了本发明讲授的内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。
以下实施例中所用到的各原料均为市售产品。
以下实施例中使用的阳离子化透明质酸为日本丘比HYLOVEILTM-P。
实施例1-3
一种具有形变能力的类脂质囊泡的制备方法：
精密称取0.4g非离子表面活性剂司盘60和0.075g疏水药物(环孢素)将其溶解在12.5mL无水乙醇中，水浴超声1min并加热到70℃使其溶解完全，得到含非离子表面活性剂和疏水药物的乙醇溶液。
水相：将边缘活性剂吐温20(司盘60与吐温20的用量比见表1)和2.5％甘油溶解在100mL水中，得到溶有边缘活性剂和甘油的水溶液；
量取100mL溶有边缘活性剂的水溶液于70℃恒温搅拌，调节转速 800rpm/min。
用注射器吸取已完全溶解的含非离子表面活性剂和疏水药物的乙醇溶液，将针头放于溶有边缘活性剂和甘油的水溶液的液面下，以1ml/min的速度匀速将溶液完全注入到溶有边缘活性剂和甘油的水溶液中，继续搅拌约半小时使乙醇挥发。使用超滤杯，采用截留分子量为100kDa的膜，对形成的囊泡进行等体积超滤10 次，除去乙醇和游离药物。将所得的阳离子化透明质酸修饰的类脂质囊泡用等渗水溶液(2.5％甘油水溶液)定容至100mL，室温下水浴超声3min使囊泡分散，得到分散液。
通过粒度仪测粒径、zeta、PDI，通过高效液相色谱法(色谱条件：用十八烷基硅烷键合硅胶为填充剂(色谱柱为Diamonsil Plus C18，150mm×4.6mm，5μm)；以乙腈-甲醇-水(62：5：33)为流动相；以甲醇为稀释剂；检测波长为210nm；柱温为70℃。)测药物含量和包封率。将类脂质囊泡挤出通过100nm孔径的聚碳酸酯膜过滤器，并测量挤膜前后的粒径，根据变形指数，来评价囊泡弹。变形指数计算为：D＝j/t(rv/rp)2；其中，D：变形指数(ml/s)，j：挤出量(ml)，t：挤出时间(s)，rv：挤出后囊泡大小(nm)，rp：滤膜孔径(nm)。
使用司盘60和吐温20分别作为非离子表面活性剂和边缘活化剂进行实验。
表1
边缘活性剂的加入增加了膜流动性，弹性囊泡可以通过基于膜弯曲能量的水梯度的影响，挤压自身通过胞间区域，从上表可见实施例2表现出最高变形指数。实施例3药物含量较低，可能是由于边缘活性剂增加了脂质两层的流动性，从而导致了双分子层内药物的泄露。
实施例4-28
一种具有形变能力的类脂质囊泡的制备：
类似实施例2，区别在于，使用不同的非离子表面活性剂和边缘活性剂制备类脂质囊泡。
表2
实施例29-32
一种载药类脂质囊泡的制备方法：
类似于实施例10，区别在于，使用不同药脂比制备疏水药物(环孢素)载药的类脂质囊泡，通过包封率和放置稳定性(4℃放置两周，测泄露率＝(两周前包封率-两周后包封率))，筛选合适的药脂比。
表3
比较各实施例，随包封药物量的增加，类脂质囊泡粒径增加，两周的药物泄露增加，实施例31相较而言，载药量较高且较稳定，能够形成均匀稳定的双重或多层纳米囊泡，如图1(a)。
实施例33-37
一种载药类脂质囊泡的制备方法：
使用实施例31环孢素类脂质囊泡的处方，分别使用叶黄素、酮康唑、α生育酚、地塞米松棕榈酸酯进行载药，且不使用超滤除杂质，测药物的包封率。表4
实施例38-42
一种阳离子透明质酸修饰的环孢素类脂质囊泡，包括载药囊泡，所述的载药囊泡的表面修饰有阳离子化透明质酸，所述的载药囊泡包括囊泡膜以及被囊泡膜所包裹的环孢素，所述的囊泡膜包含非离子表面活性剂和边缘活性剂。
按实施例33的方法制备环孢素载药类脂质囊泡分散液，将分散液逐滴加入 2％阳离子化透明质酸(CHA)的等渗溶液(2.5％甘油水溶液)中，在环境温度下磁力搅拌1小时，得到阳离子化透明质酸修饰的类脂质囊泡(CHASVs)分散液。测各载体的粒径、pH、zeta电位、表面张力、接触角，并使用流变仪在环境温度下测定粘度。剪切速率由0s-1逐渐增加到300s-1。
表4
通过JEM-2100型透射电镜对各载体进行观察，从图1(a)中可以看出在不添加胆固醇的情况下，非离子表明面活性剂司盘60和吐温80能够自组装形成双层或多层囊泡。从1(b)图中可以看出阳离子化透明质酸在SVs周围形成了一层形态不规则的包衣壳。阳离子化透明质酸可能通过较弱的静电吸附和氢键作用结合到类脂质囊泡表面。增加CHA的修饰量，载体的粒径和PDI增大。然而，透明质酸是玻璃体固有处方且可以用作增稠剂，增加透明质酸的量虽然不能进一步修饰，但是可以分散于类脂质囊泡胶体溶液中增加制剂的粘度。
应用实施例
应用本发明实施例38(SVs)、40(0.075％w/vCHA修饰SVs)和42(0.15％w/v CHA修饰SVs)所得分散液作为样品进行体外角膜渗透与角膜残留、眼部耐药性和体内药效学评价考察。
1.阳离子化透明质酸修饰类脂质囊泡角膜促渗及角膜残留
1.1角膜渗透：耳缘静脉注射空气处死家兔，取出眼球，分离角膜。将新鲜立体角膜小心固定在扩散池的供给池与接收池之间，角膜的上皮层面向供给池。配制谷胱甘肽-碳酸氢钠林格溶液(GBR)作为扩散介质。GBR溶液由两部分溶液组成：一部分含有12.4g/L氯化钠、0.716g/L氯化钾、0.233g/L二水合磷酸二氢钠及4.908g/L碳酸氢钠；另一部分含有0.174g/L无水氯化钙、0.349g/L六水合氯化镁、1.8g/L葡萄糖及0.184g/L氧化型谷胱甘肽。上述两溶液低温贮存，临用前等量混合。供给池和接收池内各加入37℃含2％SDS的GBR溶液(谷胱甘肽-碳酸氢钠林格溶液)7ml。系统平衡10min后，实验组撤掉供给池中的溶液，换成样品溶液。控制水域循环37℃，并向GBR溶液缓慢鼓入O2/CO2(95％:5％) 混合气体。于试验开始后的30min、60min、90min、120min、150min、180min、 240min和300min从接收池取样200μl，并立即补充等体积37℃预热的GBR溶液，以保持扩散池内体积不变。取样品20μl用HPLC测定。计算各取样点样品浓度(μg/ml),通过下式计算累积透过量Qn(μg)与表观渗透系数Papp(cm/s)：
其中，C0为供给池初始药物浓度(μg·cm-3)，A为有效透过面积(cm2)，ΔQn/Δt 可由累积透过量-时间曲线稳态部分的斜率(μg·min-1)求得、Ci为第i次取样测定的浓度，n为取样次数、V0为接收池液体体积，V为取样体积，Cn为第n次取样样品浓度。
1.2角膜水化程度：试验后，计算角膜水化值H：其中，mb为角膜透过部分在透过实验结束时的湿重，即透过实验后，将角膜边缘用于固定的巩膜环剪除，将角膜称重，记为mb；然后将此角膜于40℃下干燥至恒重，记为ma。
1.3角膜残留：离体角膜渗透实验结束后，将所用角膜取下冲洗，晾干后准确称重，放入玻璃匀浆管中，加甲醇1ml，匀浆，离心，取上清液，进HPLC测定，色谱条件同含量测定项。角膜药物标准曲线制备：将空白角膜加入不同浓度环孢素的甲醇溶液1ml，匀浆，离心，取上清液，HPLC测定。
表4
实验结果如表4和图2所示，弹性囊泡SVs由于添加边缘活性剂增加了囊泡弹性，角膜透过大于类脂质体。使用阳离子化透明质酸修饰后，角膜透过显著增加，且修饰量越高，透过率越高，说明了CHA能够显著提高药物的角膜透过。SVs实验组角膜中CsA残留较大，可能是由于囊泡浸润机制，先被角膜表面吸收，然后被包裹的药物运输到角膜上皮细胞膜，再被动扩散运输。与SVs相比， CHA修饰的囊泡角膜中药物的残留量显著增加，且随CHA修饰量的增加而增加，说明CHA能够进一步促进制剂与角膜的接触融合，与上文接触角降低，利于铺展润湿结果一致。此外，各制剂孵育过的离体角膜水化值测定结果与空白组不存在显著性差异(P>0.05)，表明离体实验中所采用的制剂对角膜无损坏作用。综上，SVs和CHASVs是具有潜力的眼部药物递送系统。
2.阳离子透明质酸修饰的类脂质囊泡在体耐受性研究
家兔固定于兔台，双眼分别于结膜囊处滴入样品100μl，闭合眼睑使药物分布均匀。急性刺激性：家兔双眼连续给药3次，每次间隔5min，最后一次给药 30min后检查眼部各项指标。长期刺激性：家兔双眼每天给药5次，连续7天。最后一次给药2h后，按Draize眼刺激性评分标准，检查眼部各项指标。
实验结果如图3所示，(a)为未给药组，(b)为SVs组，(c)0.075％w/v CHASVs 组，(d)0.15％w/v CHASVs组。急性刺激实验中，以为给药组对照，SVs组和 CHASVs组均未显示出发炎、水肿等现象。在长期实验中，各组Draize眼刺激性评分也均为0，说明SVs和CHASVs长期给药无刺激，适合眼部的长期给药。
3.阳离子透明质酸修饰的类脂质囊泡的体内药效学评价
3.1干眼症动物模型的诱导
为了诱发干眼症，将1％硫酸阿托品溶液灌注到兔子的双眼中。上午9点，下午2点和晚上7点，在家兔两眼的下结膜囊中滴注50μL硫酸阿托品溶液。连续灌注五天。
3.2给药方案
上午9点，下午2点和晚上7点，每次给予硫酸阿托品溶液5分钟后，滴注 50μL样品溶液，持续治疗五天。Schirmer撕裂测试检测泪液基础分泌值，光学显微镜观察泪液蕨样结晶，组织学分析观察杯状细胞。
3.3Schirmer泪液分泌测试
Schirmer泪液分泌测试(LST)检测泪液基础分泌情况。向眼内滴表面麻醉剂，吸去眼部的多余泪液后，取5×35mm有刻度的试纸，一端反折5mm，轻轻放入被测眼下结膜囊的中外1/3处，5min后取出滤纸，测量湿长，一般10-30mm/5min为正常。小于5mm可以诊断为泪液缺乏；6-10mm可疑分泌减少，大于10mm为正常。如果不足5分钟滤纸就全湿，则记录全湿的时间。
实验结果如图4所示，以家兔眼为研究对象，采用不同方法治疗干眼症。空白组与健康组相比，兔眼泪液分泌量突然下降且STT评分低于10，说明干眼症诱导成功。经NS治疗后得分无明显提高。经SVs和CHASVs治疗后，家兔泪液分泌明显提高，说明干眼症状有所改善。STT结果也显示CHASVs对干眼症抑制作用的改善与CHA修饰量有关，当CHA修饰浓度增加到0.15％w/v时，泪液分泌状况与健康组无显著差异。
3.4泪液蕨样结晶检查
用于检查泪液形状与泪腺分泌功能。用毛细管吸取泪湖泪液滴于载玻片上，室温干燥10min后，在光学显微镜下放大400倍观察结晶情况。评价标准：按泪液蕨样结晶的完整性、均匀性和分支状态分为4型：Ⅰ型分Ⅰa和Ⅰb型，Ⅰa 型蕨样分支粗大、浓密，Ⅰb型分支较细小，存在间隙；Ⅱ型蕨样分支小，视野空白，雪花结晶；Ⅲ型结晶少，无蕨样分支形成；Ⅳ型仅见串珠样粘液。Ⅰ型为正常结晶，其余为异常结晶。
实验结果如图5所示，(a)为健康组，(b)为干眼症组，(c)为生理盐水治疗组，(d)为SVs治疗组，(e)为0.075％w/v CHASVs治疗组，(f)为0.15％w/v CHASVs治疗组。硫酸阿托品诱导组中泪液蕨样结晶为Ⅱ型，泪液蕨样分支小且不完全形成，反映了干眼症的成功诱导。经生理盐水处理的组泪液蕨样形态无明显改善。SVs治疗组蕨样结晶为Ⅰb型，分支较细小，存在间隙。经CHASVs 治疗后，蕨样分支粗大、浓密，恢复为Ⅰa型。结果表明，SVs可改善泪腺分泌功能，修饰CHA后可取得更好的治疗效果。
3.5组织学分析
给药后空气栓塞致死家兔，摘取眼球，甲醛固定，石蜡包埋，病理组织切片，苏木素-伊红染色，进行显微镜检查，观察各表皮细胞与基底细胞形态是否正常，有无炎症性细胞(嗜曙红细胞、嗜中性粒细胞、肥大细胞和淋巴细胞)的浸润及组织形态改变以及结膜杯状细胞密度和上皮形态。
实验结果如图6所示，(a)为健康组，(b)为干眼症组，(c)为生理盐水治疗组，(d)为SVs治疗组，(e)为0.075％w/v CHASVs治疗组，(f)为0.15％w/v CHASVs治疗组。人结膜杯状细胞是黏蛋白的主要来源，对维持正常的眼表功能起着重要作用。黏蛋白分泌减少可能使泪膜不稳定，导致眼表润滑不良。因此，杯状细胞的数量是反映眼表健康的一个关键指标。CsA可增加干眼症患者球结膜杯状细胞密度。从图6可以看出，与健康组相比，硫酸阿托品诱导组结膜杯状细胞数量明显减少，反映了干眼症的成功诱导。与生理盐水组相比，CsA给药组结膜杯状细胞数量均有所增加，说明眼表功能有所改善。因此，所有制剂均可通过局部给药靶向到眼表，抑制干眼症。CHA修饰后，杯状细胞数量显著增加，说明CHA可提高CsA的生物利用度。因此，阳离子化透明质酸修饰的类脂质囊泡是一种具有潜力的眼部药物递送系统。

Claims (10)

1.一种阳离子化透明质酸修饰的类脂质囊泡，其特征在于，包括载药囊泡，所述的载药囊泡的表面修饰有阳离子化透明质酸，所述的载药囊泡包括囊泡膜以及被囊泡膜所包裹的疏水药物，所述的囊泡膜包含非离子表面活性剂和边缘活性剂。
2.如权利要求1所述的阳离子化透明质酸修饰的类脂质囊泡，其特征在于，所述的疏水药物为环孢素、叶黄素、酮康唑、α生育酚和地塞米松棕榈酸酯中的至少一种。
3.如权利要求1所述的阳离子化透明质酸修饰的类脂质囊泡，其特征在于，所述的非离子表面活性剂包括司盘40、司盘60、司盘80、泊洛沙姆121或泊洛沙姆123。
4.如权利要求1所述的阳离子化透明质酸修饰的类脂质囊泡，其特征在于，所述的边缘活性剂包括吐温20、吐温40、吐温80、胆酸钠、聚氧乙烯月桂醚35或聚氧乙烯蓖麻油。
5.如权利要求1所述的阳离子化透明质酸修饰的类脂质囊泡，其特征在于，所述的阳离子化透明质酸修饰的类脂质囊泡的粒径为200-310nm，zeta电位为-10～-30mV，粘度为1～12mPa·s。
6.如权利要求1所述的阳离子化透明质酸修饰的类脂质囊泡，其特征在于，所述的非离子表面活性剂和边缘活性剂的重量比在60：40～90：10之间。
7.如权利要求1所述的阳离子化透明质酸修饰的类脂质囊泡，其特征在于，所述的非离子表面活性剂与疏水药物的重量比在20：1～4：1之间。
8.权利要求1-7中任一项所述的阳离子化透明质酸修饰的类脂质囊泡的制备方法，其特征在于，包括：将含有非离子表面活性剂和疏水药物的乙醇溶液注入65-75℃的含有边缘活性剂和甘油的水溶液中，搅拌使乙醇挥发，得到载药囊泡分散液，将载药囊泡分散液逐滴加入阳离子化透明质酸的等渗溶液中，搅拌，得到阳离子化透明质酸修饰的类脂质囊泡分散液。
9.如权利要求8所述的阳离子化透明质酸修饰的类脂质囊泡的制备方法，其特征在于，所述的阳离子化透明质酸的修饰浓度0.05％～0.15％w/v。
10.权利要求1-7中任一项所述的阳离子化透明质酸修饰的类脂质囊泡在制备治疗眼部疾病的药物中的应用。
CN201910308271.6A 2019-04-17 2019-04-17 阳离子化透明质酸修饰的类脂质囊泡及其制备和应用 Pending CN110063938A (zh)

Priority Applications (7)

Application Number Priority Date Filing Date Title
CN201910308271.6A CN110063938A (zh) 2019-04-17 2019-04-17 阳离子化透明质酸修饰的类脂质囊泡及其制备和应用
JP2021561011A JP7504125B2 (ja) 2019-04-17 2020-04-02 カチオン化ヒアルロン酸修飾ニオソーム小胞及びその製造並びに使用
EP20791862.4A EP3957300B1 (en) 2019-04-17 2020-04-02 Cationic hyaluronic acid modified lipoid vesicle and preparation and application thereof
US17/604,347 US20220192980A1 (en) 2019-04-17 2020-04-02 Cationic hyaluronic acid coated spanlastics and preparation and application thereof
KR1020217036847A KR20220002955A (ko) 2019-04-17 2020-04-02 양이온화 히알루론산 수식된 리포이드 베시클 및 그 제조와 응용
ES20791862T ES3041497T3 (en) 2019-04-17 2020-04-02 Cationic hyaluronic acid modified lipoid vesicle and preparation and application thereof
PCT/CN2020/082905 WO2020211653A1 (zh) 2019-04-17 2020-04-02 阳离子化透明质酸修饰的类脂质囊泡及其制备和应用

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201910308271.6A CN110063938A (zh) 2019-04-17 2019-04-17 阳离子化透明质酸修饰的类脂质囊泡及其制备和应用

Publications (1)

Publication Number Publication Date
CN110063938A true CN110063938A (zh) 2019-07-30

Family

ID=67367921

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201910308271.6A Pending CN110063938A (zh) 2019-04-17 2019-04-17 阳离子化透明质酸修饰的类脂质囊泡及其制备和应用

Country Status (7)

Country Link
US (1) US20220192980A1 (zh)
EP (1) EP3957300B1 (zh)
JP (1) JP7504125B2 (zh)
KR (1) KR20220002955A (zh)
CN (1) CN110063938A (zh)
ES (1) ES3041497T3 (zh)
WO (1) WO2020211653A1 (zh)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020211653A1 (zh) * 2019-04-17 2020-10-22 艾伟拓（上海）医药科技有限公司 阳离子化透明质酸修饰的类脂质囊泡及其制备和应用

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IL313997A (en) 2022-01-04 2024-08-01 Renovion Inc Aqueous solution including glutathione salt
CN115487143B (zh) * 2022-11-16 2023-02-03 成都普什制药有限公司 一种玻璃酸钠滴眼液及其制备方法

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101316864A (zh) * 2005-12-01 2008-12-03 株式会社资生堂 阳离子化透明质酸
CN101715457A (zh) * 2007-04-24 2010-05-26 丘比株式会社 阳离子化透明质酸和/或其盐及其制法、及使用其的毛发改善剂、角质层修复剂、皮肤改善剂和化妆品
JP2016108285A (ja) * 2014-12-08 2016-06-20 ワミレスコスメティックス株式会社 カチオン化ベシクル及びその組成物
CN107485603A (zh) * 2017-08-02 2017-12-19 中国药科大学 一种自组装的透明质酸－难溶性前药包覆的包载活性药物的脂质体纳米给药系统及其制备方法
CN107556402A (zh) * 2017-10-18 2018-01-09 重庆工商大学 阳离子化透明质酸及其制备方法
CN108451908A (zh) * 2018-06-15 2018-08-28 上海应用技术大学 一种透明质酸修饰的阳离子类脂质体、制备方法及其应用

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070172520A1 (en) * 2005-11-18 2007-07-26 University Of South Florida Immunotargeting of Nonionic Surfactant Vesicles
KR20100043748A (ko) * 2008-10-21 2010-04-29 (주)네오팜 탄성 리포좀 및 이를 함유하는 피부외용제 조성물
TWI522115B (zh) * 2013-10-09 2016-02-21 綠祚生技有限公司 The delivery of the active ingredient and its application
CN110063938A (zh) * 2019-04-17 2019-07-30 上海应用技术大学 阳离子化透明质酸修饰的类脂质囊泡及其制备和应用

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101316864A (zh) * 2005-12-01 2008-12-03 株式会社资生堂 阳离子化透明质酸
CN101715457A (zh) * 2007-04-24 2010-05-26 丘比株式会社 阳离子化透明质酸和/或其盐及其制法、及使用其的毛发改善剂、角质层修复剂、皮肤改善剂和化妆品
JP2016108285A (ja) * 2014-12-08 2016-06-20 ワミレスコスメティックス株式会社 カチオン化ベシクル及びその組成物
CN107485603A (zh) * 2017-08-02 2017-12-19 中国药科大学 一种自组装的透明质酸－难溶性前药包覆的包载活性药物的脂质体纳米给药系统及其制备方法
CN107556402A (zh) * 2017-10-18 2018-01-09 重庆工商大学 阳离子化透明质酸及其制备方法
CN108451908A (zh) * 2018-06-15 2018-08-28 上海应用技术大学 一种透明质酸修饰的阳离子类脂质体、制备方法及其应用

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
SHILPA KAKKAR等: ""Spanlastics—A novel nanovesicular carrier system for ocular delivery"", 《INTERNATIONAL JOURNAL OF PHARMACEUTICS》 *
YANG LIU等: ""Cationized hyaluronic acid coated spanlastics for cyclosporine A ocular delivery: Prolonged ocular retention, enhanced corneal permeation and improved tear production"", 《INTERNATIONAL JOURNAL OF PHARMACEUTICS》 *
YANMEI QIN等: ""Hyaluronic acid-modified cationic niosomes for ocular gene delivery: improving transfection efficiency in retinal pigment epithelium"", 《JOURNAL OF PHARMACY AND PHARMACOLOGY》 *
刘阳: ""阳离子化透明质酸修饰的眼部药物递送系统的研究"", 《中国优秀硕士学位论文全文数据库 工程科技I辑》 *
秦艳梅: ""透明质酸修饰的阳离子类脂质体作为眼底基因递送载体的研究"", 《中国优秀硕士学位论文全文数据库》 *
陆彬主编: "《药物新剂型与新技术 第2版》", 31 July 2005, 人民卫生出版社 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020211653A1 (zh) * 2019-04-17 2020-10-22 艾伟拓（上海）医药科技有限公司 阳离子化透明质酸修饰的类脂质囊泡及其制备和应用

Also Published As

Publication number Publication date
KR20220002955A (ko) 2022-01-07
ES3041497T3 (en) 2025-11-12
JP2022529918A (ja) 2022-06-27
EP3957300A1 (en) 2022-02-23
EP3957300A4 (en) 2022-12-21
EP3957300B1 (en) 2025-09-10
WO2020211653A1 (zh) 2020-10-22
US20220192980A1 (en) 2022-06-23
JP7504125B2 (ja) 2024-06-21

Similar Documents

Publication Publication Date Title
Li et al. Montmorillonite/chitosan nanoparticles as a novel controlled-release topical ophthalmic delivery system for the treatment of glaucoma
Jain et al. Formulation and investigation of pilocarpine hydrochloride niosomal gels for the treatment of glaucoma: intraocular pressure measurement in white albino rabbits
Natarajan et al. Nanomedicine for glaucoma: liposomes provide sustained release of latanoprost in the eye
Pitkanen et al. Permeability of retinal pigment epithelium: effects of permeant molecular weight and lipophilicity
Choi et al. The efficiency of cyclosporine A-eluting contact lenses for the treatment of dry eye
Bessone et al. Neuroprotective effect of melatonin loaded in ethylcellulose nanoparticles applied topically in a retinal degeneration model in rabbits
WO2012021107A2 (en) A liposomal formulation for ocular drug delivery
EP3957300B1 (en) Cationic hyaluronic acid modified lipoid vesicle and preparation and application thereof
Alambiaga-Caravaca et al. Development, characterization, and ex vivo evaluation of an insert for the ocular administration of progesterone
Guo et al. Antioxidant nanoemulsion loaded with latanoprost enables highly effective glaucoma treatment
Chen et al. Therapeutic nanocoating of ocular surface
Xiong et al. Liposome–trimethyl chitosan nanoparticles codeliver insulin and siVEGF to treat corneal alkali burns by inhibiting ferroptosis
Tártara et al. Improvement of acetazolamide ocular permeation using ascorbyl laurate nanostructures as drug delivery system
Li et al. Efficiency co-delivery of ellagic acid and oxygen by a non-invasive liposome for ameliorating diabetic retinopathy
Zou et al. Multifunctional cerium oxide nanozymes with high ocular surface retention for dry eye disease treatment achieved by restoring redox balance
Kaul et al. Investigating nanostructured liquid crystalline particles as prospective ocular delivery vehicle for tobramycin sulfate: Ex vivo: And: In vivo: Studies
Wei et al. Antioxidant carbon dots nanozyme loaded in thermosensitive in situ hydrogel system for efficient dry eye disease treatment
Sun et al. Topical ophthalmic liposomes dual-modified with penetratin and hyaluronic acid for the noninvasive treatment of neovascular age-related macular degeneration
JP2014122244A (ja) 真菌感染症を治療するための新規な製剤
Zafar et al. Formulation of carteolol chitosomes for ocular delivery: Formulation optimization, ex-vivo permeation, and ocular toxicity examination
Liu et al. Wettability and contact angle affect precorneal retention and pharmacodynamic behavior of microspheres
Hao et al. Silk Fibroin Formed Bioadhesive Ophthalmic Gel for Dry Eye Syndrome Treatment
Gonzalez Cela Casamayor et al. A novel osmoprotective liposomal formulation from synthetic phospholipids to reduce in vitro hyperosmolar stress in dry eye treatments
Zhou et al. RGD-Functionalized Ginsenoside Rg3 Liposomes for Alleviating Oxidative Stress and Choroidal Neovascularization in Age-Related Macular Degeneration
hui-hui et al. Novel ophthalmic timolol meleate liposomal-hydrogel and its improved local glaucomatous therapeutic effect in vivo

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
TA01 Transfer of patent application right

Effective date of registration: 20200414

Address after: 200122 block a, 27th floor, Huadu building, No. 838, Zhangyang Road, Pudong New Area, Shanghai

Applicant after: Ai Weituo (Shanghai) Pharmaceutical Science and Technology Co., Ltd.

Address before: 200235 Xuhui District, Caobao Road, No. 120,

Applicant before: SHANGHAI INSTITUTE OF TECHNOLOGY

TA01 Transfer of patent application right
TA01 Transfer of patent application right

Effective date of registration: 20200917

Address after: A506, 5 / F, building 1, No. 1976, Gaoke Middle Road, Pudong New Area, Shanghai 201210

Applicant after: FUBICHENG (SHANGHAI) PHARMACEUTICAL TECHNOLOGY Co.,Ltd.

Address before: 200122 block a, 27th floor, Huadu building, No. 838, Zhangyang Road, Pudong New Area, Shanghai

Applicant before: Ai Weituo (Shanghai) Pharmaceutical Science and Technology Co.,Ltd.

TA01 Transfer of patent application right
TA01 Transfer of patent application right

Effective date of registration: 20211101

Address after: 201210 a506, 1976 Gaoke Middle Road, Pudong New Area, Shanghai

Applicant after: FUBICHENG (SHANGHAI) PHARMACEUTICAL TECHNOLOGY CO.,LTD.

Applicant after: KEWPIE Corp.

Address before: 201210 a506, 5th floor, building 1, 1976 Gaoke Middle Road, Pudong New Area, Shanghai

Applicant before: FUBICHENG (SHANGHAI) PHARMACEUTICAL TECHNOLOGY CO.,LTD.

TA01 Transfer of patent application right