CN109381708A - 一种***-多肽纳米颗粒滴眼液及其制备方法 - Google Patents

一种***-多肽纳米颗粒滴眼液及其制备方法 Download PDF

Info

Publication number
CN109381708A
CN109381708A CN201811184013.3A CN201811184013A CN109381708A CN 109381708 A CN109381708 A CN 109381708A CN 201811184013 A CN201811184013 A CN 201811184013A CN 109381708 A CN109381708 A CN 109381708A
Authority
CN
China
Prior art keywords
nano particle
fffe
dexamethasone
dex
polypeptide
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
CN201811184013.3A
Other languages
English (en)
Inventor
李星熠
师帅
***
陈浩
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.)
Wenzhou Medical University
Original Assignee
Wenzhou Medical 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 Wenzhou Medical University filed Critical Wenzhou Medical University
Publication of CN109381708A publication Critical patent/CN109381708A/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
    • 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
    • A61K47/6921—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 particulate, a powder, an adsorbate, a bead or a sphere
    • A61K47/6927—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 particulate, a powder, an adsorbate, a bead or a sphere the form being a solid microparticle having no hollow or gas-filled cores
    • A61K47/6929—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 particulate, a powder, an adsorbate, a bead or a sphere the form being a solid microparticle having no hollow or gas-filled cores the form being a nanoparticle, e.g. an immuno-nanoparticle
    • 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
    • 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
    • A61K47/62—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 a protein, peptide or polyamino acid
    • A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
    • 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
    • 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]

Landscapes

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

Abstract

本发明公开了一种***‑多肽纳米颗粒滴眼液，其特征是：包括***‑丁二酸‑多肽化学键合物（Dex‑SA‑FFFE）和水溶液，所述Dex‑SA‑FFFE化合物发生自组装形成纳米颗粒。本发明还涉及上述***‑多肽纳米颗粒滴眼液的制备方法。本发明采用多肽化学修饰***药物分子，使其能在水溶液中发生自组装，获得Dex‑SA‑FFFE纳米颗粒，具有制备简单、药物装载量高、无需药物载体等优点；同时由于纳米颗粒的小尺寸效应，使得制备的Dex‑SA‑FFFE纳米颗粒能显著提高药物穿透角膜屏障的能力，提高药物生物利用度。

Description

一种***-多肽纳米颗粒滴眼液及其制备方法
技术领域
本发明涉及一种***-多肽纳米颗粒滴眼液。本发明还涉及上述***-多肽纳米颗粒滴眼液的制备方法。
背景技术
***作为一种强效的甾体类抗炎药物，被广泛的应用于眼科炎症的治疗。由于其水溶性差，眼科临床通常使用的制剂为***磷酸钠滴眼液。该滴眼液局部给药后，***以磷酸盐的形式存在，难以透过亲脂性的角膜上皮层进入眼球内部，导致药物生物利用度，需要频繁给药，才能达到有效药物治疗浓度。因而，如何通过合适的药物制剂设计和给药途径的创新来提高***在眼科炎症治疗中的疗效，同时降低其毒副作用是目前该领域研究的热点与难题。
发明内容
鉴于背景技术的不足，本发明所要解决的技术问题是提供一种***-多肽纳米颗粒滴眼液，该滴眼液能显著提高药物穿透角膜屏障的能力。本发明所要解决的技术问题还包括提供一种更加简便的上述***-多肽纳米颗粒滴眼液的制备方法。
为此，本发明是采用如下技术方案来实现的：
***-多肽纳米颗粒滴眼液，其特征是：包括***-丁二酸-多肽化学键合物（Dex-SA-FFFE）和水溶液，所述Dex-SA-FFFE化合物发生自组装形成纳米颗粒。
本发明还提供了上述***-多肽纳米颗粒滴眼液的制备方法，
包括以下步骤：a、采用多肽苯丙氨酸-苯丙氨酸-苯丙氨酸-谷氨酸FFFE对***进行修饰，获得***-丁二酸-多肽化学键合物Dex-SA-FFFE；b、***-丁二酸-多肽化学键合物在水溶液中，通过加热-冷却诱导，使得Dex-SA-FFFE化合物发生自组装形成纳米颗粒。
本发明采用多肽化学修饰***药物分子，使其能在水溶液中发生自组装，获得Dex-SA-FFFE纳米颗粒，具有制备简单、药物装载量高、无需药物载体等优点；同时由于纳米颗粒的小尺寸效应，使得制备的Dex-SA-FFFE纳米颗粒能显著提高药物穿透角膜屏障的能力，提高药物生物利用度。
附图说明
图1为本发明的提供的多肽化学键合物（Dex-SA-FFFE的化学结构图。
图2为本发明提供的3% Dex-SA-FFFE纳米颗粒的（A）显微形貌和（B）粒径分布图。
具体实施方式
下面结合附图和实施例对本发明进行详细介绍
参照图1所示，实例1： (以磷酸盐缓冲溶液（PBS; pH=7.4）为溶液，制备1% Dex-SA-FFFE纳米颗粒):
准确称取10mg Dex-SA-FFFE化合物，分散于0.8mL磷酸盐缓冲溶液（PBS; pH=7.4）中，加入0.2mL氢氧化钠水溶液（1当量），加热体系至90℃，溶液变澄清状态，获得1% Dex-SA-FFFE纳米颗粒。
参照图1所示，实例2 ：以磷酸盐缓冲溶液（PBS; pH=7.4）为溶液，制备2% Dex-SA-FFFE纳米颗粒
准确称取20mg Dex-SA-FFFE化合物，分散于0.8mL磷酸盐缓冲溶液（PBS; pH=7.4）中，加入0.2mL氢氧化钠水溶液（1当量），加热体系至90℃，溶液变澄清状态，获得2% Dex-SA-FFFE纳米颗粒。
参照图1、图2所示，实例3(以磷酸盐缓冲溶液（PBS; pH=7.4）为溶液，制备3% Dex-SA-FFFE纳米颗粒):
准确称取30mg Dex-SA-FFFE化合物，分散于0.8mL磷酸盐缓冲溶液（PBS; pH=7.4）中，加入0.2mL氢氧化钠水溶液（1当量），加热体系至90℃，溶液变澄清状态，获得3% Dex-SA-FFFE纳米颗粒。
参照图1所示，实例4(以磷酸盐缓冲溶液（PBS; pH=7.4）为溶液，制备4% Dex-SA-FFFE纳米颗粒):
准确称取40mg Dex-SA-FFFE化合物，分散于0.8mL磷酸盐缓冲溶液（PBS; pH=7.4）中，加入0.2mL氢氧化钠水溶液（1当量），加热体系至90℃，溶液变澄清状态，获得4% Dex-SA-FFFE纳米颗粒。

Claims (5)

1.一种***-多肽纳米颗粒滴眼液，其特征是：包括***-丁二酸-多肽化学键合物（Dex-SA-FFFE）和水溶液，所述Dex-SA-FFFE化合物发生自组装形成纳米颗粒。
2.一种权利要求1所述***-多肽纳米颗粒滴眼液的制备方法，其特征是：包括以下步骤：a、采用多肽苯丙氨酸-苯丙氨酸-苯丙氨酸-谷氨酸FFFE对***进行修饰，获得***-丁二酸-多肽化学键合物Dex-SA-FFFE；b、***-丁二酸-多肽化学键合物在水溶液中，通过加热-冷却诱导，使得Dex-SA-FFFE化合物发生自组装形成纳米颗粒。
3.根据权利2所述的***-多肽纳米颗粒滴眼液的制备方法，其特征是：将所述Dex-SA-FFFE 分散于磷酸盐缓冲溶液中, 再加入氢氧化钠的溶液中，R然后加热至90—150℃，待溶液完全澄清，冷却至室温，获得Dex-SA-FFFE纳米颗粒。
4.根据权利2所述的***-多肽纳米颗粒滴眼液的制备方法，其特征是：将30mgDex-SA-FFFE 分散于1mL磷酸盐缓冲溶液（PBS,pH=7.4）中, 加入1当量的氢氧化钠（1mM）的溶液中，加热至90—150℃，待溶液完全澄清，获得Dex-SA-FFFE纳米颗粒。
5.根据权利要求1或2或3或4所述的，其特征是：所述***-丁二酸-多肽化学键合物Dex-SA-FFFE的化学结构为：。
CN201811184013.3A 2018-07-18 2018-10-11 一种***-多肽纳米颗粒滴眼液及其制备方法 Pending CN109381708A (zh)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201810791212 2018-07-18
CN2018107912124 2018-07-18

Publications (1)

Publication Number Publication Date
CN109381708A true CN109381708A (zh) 2019-02-26

Family

ID=65427445

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201811184013.3A Pending CN109381708A (zh) 2018-07-18 2018-10-11 一种***-多肽纳米颗粒滴眼液及其制备方法

Country Status (1)

Country Link
CN (1) CN109381708A (zh)

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103044523A (zh) * 2012-12-13 2013-04-17 济南向惠医药技术有限公司 ***-rgd多肽缀合物，其制备方法及应用
CN104211762A (zh) * 2013-06-05 2014-12-17 首都医科大学 饱和脂肪链醇，***和His-Gly-Lys的缀合物，其制备，纳米结构及应用
CN105585611A (zh) * 2014-10-20 2016-05-18 北京益生康华医药技术有限公司 八肽修饰的***,其制备,纳米结构和应用
CN105585612A (zh) * 2014-10-20 2016-05-18 北京益生康华医药技术有限公司 八肽修饰的***、制备、纳米结构和应用
US20170240680A1 (en) * 2014-10-15 2017-08-24 University Of Connecticut Bio-reducible self-assembled liquid crystalline block copolymer for drug delivery
CN107375939A (zh) * 2017-07-19 2017-11-24 中国药科大学 用于治疗真菌感染的两性霉素b多肽类水凝胶载药体系

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103044523A (zh) * 2012-12-13 2013-04-17 济南向惠医药技术有限公司 ***-rgd多肽缀合物，其制备方法及应用
CN104211762A (zh) * 2013-06-05 2014-12-17 首都医科大学 饱和脂肪链醇，***和His-Gly-Lys的缀合物，其制备，纳米结构及应用
US20170240680A1 (en) * 2014-10-15 2017-08-24 University Of Connecticut Bio-reducible self-assembled liquid crystalline block copolymer for drug delivery
CN105585611A (zh) * 2014-10-20 2016-05-18 北京益生康华医药技术有限公司 八肽修饰的***,其制备,纳米结构和应用
CN105585612A (zh) * 2014-10-20 2016-05-18 北京益生康华医药技术有限公司 八肽修饰的***、制备、纳米结构和应用
CN107375939A (zh) * 2017-07-19 2017-11-24 中国药科大学 用于治疗真菌感染的两性霉素b多肽类水凝胶载药体系

Similar Documents

Publication Publication Date Title
Romero et al. Development of cationic nanocrystals for ocular delivery
H Muller et al. 20 years of lipid nanoparticles (SLN & NLC): present state of development & industrial applications
Trivedi et al. Local delivery of biodegradable pirfenidone nanoparticles ameliorates bleomycin-induced pulmonary fibrosis in mice
Chang et al. Liposomal dexamethasone–moxifloxacin nanoparticle combinations with collagen/gelatin/alginate hydrogel for corneal infection treatment and wound healing
Nguyen et al. Chitosan-coated nano-liposomes for the oral delivery of berberine hydrochloride
Al-Ghananeem et al. Intranasal drug delivery of didanosine-loaded chitosan nanoparticles for brain targeting; an attractive route against infections caused by AIDS viruses
Pourshahab et al. Preparation and characterization of spray dried inhalable powders containing chitosan nanoparticles for pulmonary delivery of isoniazid
CN104350063B (zh) 疏水性治疗剂的制剂、其制备方法及应用
Sun et al. pH-sensitive poly (lactide-co-glycolide) nanoparticle composite microcapsules for oral delivery of insulin
Gökçe et al. Cyclosporine a-loaded solid lipid nanoparticles: ocular tolerance and in vivo drug release in rabbit eyes
Banerjee et al. Comparative study of oral lipid nanoparticle formulations (LNFs) for chemical stabilization of antitubercular drugs: physicochemical and cellular evaluation
Zhang et al. Novel multiple agents loaded PLGA nanoparticles for brain delivery via inner ear administration: in vitro and in vivo evaluation
DK2813229T3 (en) System for administration of ophthalmic medication containing phospholipid and cholesterol
Tang et al. Development and evaluation of a dry powder formulation of liposome-encapsulated oseltamivir phosphate for inhalation
Wang et al. Chitosan-modified cholesterol-free liposomes for improving the oral bioavailability of progesterone
KR102268710B1 (ko) 글루코코르티코스테로이드의 나노미립자를 함유하는 수성 현탁액제
JP7055820B2 (ja) 化学塞栓療法剤
JP2015508787A (ja) 活性化合物を取り込んだナノ粒子の製造プロセス
Suresh et al. Nanocarriers for ocular delivery for possible benefits in the treatment of anterior uveitis: focus on current paradigms and future directions
Elnaggar et al. Phytochylomicron as a dual nanocarrier for liver cancer targeting of luteolin: in vitro appraisal and pharmacodynamics
CN104491867B (zh) 一种壳聚糖包裹载药蒙脱石的新型给药***的制备方法
Alai et al. Novel lansoprazole-loaded nanoparticles for the treatment of gastric acid secretion-related ulcers: in vitro and in vivo pharmacokinetic pharmacodynamic evaluation
Urimi et al. Formulation development and upscaling of lipid nanocapsules as a drug delivery system for a novel cyclic GMP analogue intended for retinal drug delivery
WO2015165373A1 (zh) 一种注射用前列地尔脂肪乳及其制备方法
CN111346060A (zh) 一种释药速度可控的乙基纤维素掩味微球及其制备

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
RJ01 Rejection of invention patent application after publication

Application publication date: 20190226

RJ01 Rejection of invention patent application after publication