WO2008007932A1 - Complexe de chitosan contenant un groupe imidazole sensible au ph et procédé de préparation de ce dernier - Google Patents

Complexe de chitosan contenant un groupe imidazole sensible au ph et procédé de préparation de ce dernier Download PDF

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Publication number
WO2008007932A1
WO2008007932A1 PCT/KR2007/003447 KR2007003447W WO2008007932A1 WO 2008007932 A1 WO2008007932 A1 WO 2008007932A1 KR 2007003447 W KR2007003447 W KR 2007003447W WO 2008007932 A1 WO2008007932 A1 WO 2008007932A1
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WO
WIPO (PCT)
Prior art keywords
chitosan
chitosan complex
group
imidazole group
aggregates
Prior art date
Application number
PCT/KR2007/003447
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English (en)
Inventor
Sang Yoon Kim
Yong Woo Cho
Ick Chan Kwon
Kwang Meyung Kim
Dae Hyuk Moon
Original Assignee
University Of Ulsan Foundation For Industry Cooperation
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.)
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Publication date
Application filed by University Of Ulsan Foundation For Industry Cooperation filed Critical University Of Ulsan Foundation For Industry Cooperation
Publication of WO2008007932A1 publication Critical patent/WO2008007932A1/fr

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    • 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
    • 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
    • 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
    • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
    • 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
    • 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
    • A61K9/5192—Processes
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
    • C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
    • C08B37/0006—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid
    • C08B37/0024—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid beta-D-Glucans; (beta-1,3)-D-Glucans, e.g. paramylon, coriolan, sclerotan, pachyman, callose, scleroglucan, schizophyllan, laminaran, lentinan or curdlan; (beta-1,6)-D-Glucans, e.g. pustulan; (beta-1,4)-D-Glucans; (beta-1,3)(beta-1,4)-D-Glucans, e.g. lichenan; Derivatives thereof
    • C08B37/0027—2-Acetamido-2-deoxy-beta-glucans; Derivatives thereof
    • C08B37/003—Chitin, i.e. 2-acetamido-2-deoxy-(beta-1,4)-D-glucan or N-acetyl-beta-1,4-D-glucosamine; Chitosan, i.e. deacetylated product of chitin or (beta-1,4)-D-glucosamine; Derivatives thereof

Definitions

  • the present invention relates to a chitosan complex containing pH-sensitive imidazole group and a preparation method thereof.
  • DDS drug delivery systems
  • drugs are useful in increasing the selectivity of drugs which must be administered at low doses or are difficult to administer.
  • Physico- chemically or pharmacokinetically unusual properties of drugs to be administered such as high water solubility, high oil solubility or insolubility, require the use of special DDS.
  • drugs having special requirements for example, highly toxic drugs for single injection, unstable cytotoxic drugs, high clearance drugs, drugs apt to be inactivated in vivo, and drugs for topical application must be accompanied by suitable DDS.
  • Chitosan can be produced through the deacetylation of chitin, the second most abundant polysaccharide in nature after cellulose, and is a linear polysaccharide composed of 2-amino-2-deoxy- ⁇ -D-glucopyranose.
  • chitosan has primary amines in its backbone chain and thus finds useful applications in a variety of fields including environmental, agricultural, medicinal fields, etc. thanks to its unique characteristics. Superior in biocompatibility and biodegradability, chitosan is an intensive research target of great interest for use in gene and drug carriers, scaffolds for tissue engineering, and injectable hydrogel (Polym. Int. 1999, 48, 732-734).
  • nanotechnology is a field of applied science and technology covering a broad range of topics.
  • nanotechnology is intensively applied to nanoscale carriers for transferring therapeutically useful ingredients, such as chemical components, oligonucleic acid, siRNA, DNA, proteins, etc., into cells.
  • therapeutically useful ingredients such as chemical components, oligonucleic acid, siRNA, DNA, proteins, etc.
  • the nanoscale carriers release drugs within cells after passing through lipid bilayers of cell membranes via specific or general passages.
  • amphophilic macromolecules in an aqueous phase, form into micelles or self-aggregates to obtain stable interfacial energy as a result of interaction between hydrophobic blocks.
  • micelles of amphophilic macromolecules change in size, size distribution, rheology, and thermodynamic stability.
  • micelles having hydrophobic drugs entrapped therein have been used as carrier vesicles for the selective and effective transfer of drugs (Adv. Drug. Deliv. Rev. 2001, 47, 113-131).
  • a chitosan complex capable of forming nano self-aggregates in aqueous phases, comprising a water-soluble chitosan chain grafted with a pH-sensitive imidazole group.
  • a method for preparing a chitosan complex comprising reacting a pH-sensitive imidazole group with water-soluble chitosan to form an amide group therebetween.
  • the present invention provides a chitosan complex pH-sensitive containing imidazole group and a method for preparing the same.
  • the chitosan complex is superior in biocompatibility and biodegradability, and forms globular aggregates ranging in size from tens to hundreds of nanometers, which consist of hydrophilic glycol chitosan on the surface and hydrophobic histidine inside.
  • the chitosan complex can be loaded with various hydrophobic drugs, such as anticancer agents and genes, and can be labeled with traceable radioisotopes, so that it is useful as a drug delivery system, a scintigraphical tracer and a gene carrier.
  • FlG. 1 is a diagram illustrating the intracellular behavior of the chitosan complex according to the present invention
  • FlG. 2 is a graph showing the particle size distribution of nano self-aggregates of the chitosan complex according to an embodiment of the present invention, measured using dynamic light scattering (DLS);
  • DLS dynamic light scattering
  • FlG. 3 shows cell cycles of cancer cells, obtained by FACS (fluorescence activated cell sorting) when cancer cells are treated with a chitosan complex loaded with paclitaxel in accordance with an embodiment of the present invention
  • FlG. 4 provides photographs showing the selectivity of the chitosan complex of the present invention for tumors, obtained through nuclear scintigraphy with mice injected with a radiolabeled (1311) chitosan complex through the tail vein.
  • the present invention pertains to a chitosan complex containing a pH-dependent imidazole group, which can form into self- aggregates.
  • the formation of the chitosan complex of the present invention into self-aggregates is based on the presence of both a hydrophobic moiety and a hydrophilic moiety which are linked to each other via the linkage of the amino group of water-soluble chitosan to the carboxylic moiety of the pH-sensitive imidazole group.
  • Water-soluble glycol chitosan, chitosan oligomer, or acetylated chitosan may be used as the water-soluble chitosan.
  • the pH-sensitive imidazole group is substituted in an amount of 1 ⁇ 30% based on the number of moles of chitosan monomer in order to form self-aggregates optimal for entrapping drugs.
  • the chitosan complex containing a pH-sensitive imidazole group can form into globular self-aggregates in an aqueous phase.
  • the chitosan complex ranges in size from 50 nm to 500 nm in order to migrate to target cells.
  • the present invention pertains to a chitosan-nano-paclitaxel comprising a chitosan complex with paclitaxel entrapped therein, the chitosan complex, capable of forming into self-aggregates, consisting of a water-soluble chitosan chain grafted with a pH-sensitive imidazole.
  • the histidine group in the self-aggregate changes from hydrophobicity to hydrophilicity because the pH condition of the endosome is of acidity.
  • the paclitaxel entrapped therein is released. Therefore, the aggregate of the present invention with pH-sensitive imidazole groups introduced therein can solve the problem in which conventional aggregates, although able to enter cells, release drugs too slowly or with great difficulty.
  • Paclitaxel is entrapped at an efficiency of 30 - 95% in the chitosan complex. This increased entrapment efficiency leads to an increased anticancer effect of the chitosan nanoparticle.
  • any hydrophobic anticancer agent can be employed.
  • hydrophobic anticancer agents useful in the present invention include adriamycin, cis-platin, mitomycin-C, daunomycin, and 5-fluorouracil.
  • a typical micelle in aqueous solution forms an aggregate of amphiphilic molecules with the hydrophilic "head" regions in contact with the surrounding solvent, sequestering the hydrophobic tail regions in the micelle center [Adv. Drug Deliv. Rev., 1996, 21, 107].
  • micelles are widely used as drug delivery systems for effectively carrying hydrophobic anticancer agents.
  • the DDS based on self-aggregates of amphiphilic molecules exhibits highly sufficient selectivity for target cells with greatly reduced toxicity on normal cells and the sustained release of drugs, and thus can be applied to new paradigm therapy for serious diseases, such as cancer.
  • the chitosan complex containing a pH-sensitive imidazole in accordance with the present invention when entrapping an anticancer agent, shows higher selectivity for cancer tissues than do low molecular weight anticancer agents alone.
  • anticancer agents when delivered by the chitosan complex of the present invention, anticancer agents can accumulate in larger amounts in cancer tissues, resulting in more effective anticancer activity.
  • the chitosan complex with a hydrophilic chitosan backbone linked to pH-sensitive histidine spontaneously forms globular self-aggr egates, ranging in size from tens to hundreds nanometers, which can be used as target- directed carriers of anticancer agents and release the entrapped anticancer agents over a long period of time.
  • the present invention pertains to a method for preparing a chitosan complex, comprising linking a pH-sensitive imidazole group to water-soluble chitosan via an amide bond.
  • the amide bond between a water-soluble chitosan backbone and a pH-sensitive imidazole group may be further induced in the presence of l-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (hereinafter referred to as "EDC”) and N-hydrosuccinimide (hereinafter referred to as "NHS”).
  • EDC l-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride
  • NHS N-hydrosuccinimide
  • the examples of the pH-sensitive imidazole group useful in the present invention include histidine, N-acetyl histidine, and polyhistidine, but are not limited thereto.
  • chitosan complex For the preparation of the chitosan complex according to the present invention, water-soluble chitosan is dissolved in phosphate buffered saline. [51] Also, the pH-sensitive imidazole group, which is a histidine based compound, is dissolved in phosphate buffered saline. [52] The pH-sensitive imidazole group may be grafted to chitosan in an amount of 1-30 mol% based on the total number of moles of chitosan monomers in order for the chitosan complex to readily form self-aggregates.
  • the method may further comprise entrapping nano-paclitaxel within the core formed by the hydrophobic pH-sensitive imidazole group of the chitosan complex.
  • the chitosan complex of the present invention is useful as DDS.
  • a better understanding of the present invention may be obtained through the following examples which are set forth to illustrate, but are not to be construed as the limit of the present invention. [58]
  • Nano self-aggregates of chitosan complex containing an N-acetyl histidine were prepared in a manner similar to that of Example 1, with the exception that N-acetyl histidine in an amount of 5-30 moles per 100 moles of the glycol chitosan monomers was added to the same suspension as in Example 1, followed by the addition of EDC and NHS in an amount three times as large as that of N-acetyl histidine.
  • Nano self-aggregates of chitosan complex containing an N-acetyl histidine labeled with radioactive I were prepared in a manner similar to that of Example 3, with the exception that the chitosan complex of Example 2 was used.
  • the chitosan complex prepared in Example 2 was dissolved at a concentration of 1 mg/ml in a mixture solvent of heavy water (D O)/dimethylsulfoxide (d-6) (1/4, v/v) and analyzed with 1 H-NMR, followed by measuring the degree of substitution of N- acetyl histidine from the histidine characteristic peaks around 7 - 8 ppm and the C-2 hydrogen characteristic peaks of chitosan around 3.0 - 3.3 ppm.
  • D O heavy water
  • d-6 dimethylsulfoxide
  • the self-aggregates formed in aqueous phase at pH 7.4 were nano- sized. That is, the chitosan complex of the present invention can form nano-size self- aggregates in neutral aqueous phases.
  • Example 2 After the anticancer agent paclitaxel was loaded into the inside thereof, the nano self- aggregates of Example 2 were applied to a human lung cancer cell line (A549) and a human breast cancer cell line (MDA-MB231). In order to determine the anticancer effect of the nano self-aggregates, these cells were observed for change in cell cycle using FACS (fluorescence activated cell sorter). The results are shown in FIG. 3.
  • FACS fluorescence activated cell sorter
  • Example 2 The chitosan complex of Example 2 was labeled with an in-vivo traceable radioisotope as in Example 4 and injected into cancer cell-implanted mice via the tail vein.
  • the nano self-aggregates were observed for tumor selectivity through images acquired using a gamma camera.
  • the resulting nuclear scintigraphs are shown in FIG. 4.
  • the images of the radioisotope ( 131 I)-labeled nano self-aggregates, taken with a gamma camera, show the focal location of the radioisotope in cancer regions, demonstrating that the nano self-aggregates are highly selective for tumors and traceable in vivo.
  • the present invention provides a chitosan complex pH- sensitive containing imidazole group and a method for preparing the same.
  • the chitosan complex is superior in biocompatibility and biodegradability, and forms globular aggregates ranging in size from tens to hundreds of nanometers, which consist of hydrophilic glycol chitosan on the surface and hydrophobic histidine inside.
  • the chitosan complex can be loaded with various hydrophobic drugs, such as anticancer agents and genes, and can be labeled with traceable radioisotopes, so that it is useful as a drug delivery system, a scintigraphical tracer and a gene carrier.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Nanotechnology (AREA)
  • Optics & Photonics (AREA)
  • Physics & Mathematics (AREA)
  • Biomedical Technology (AREA)
  • Inorganic Chemistry (AREA)
  • Molecular Biology (AREA)
  • Biochemistry (AREA)
  • Materials Engineering (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Polymers & Plastics (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un complexe de chitosan contenant un groupe imidazole sensible au pH et un procédé de préparation de ce dernier. Le groupe amino du glycol chitosan est lié par une liaison amine à l'histidine de l'imidazole, qui est hydrophobe dans une plage neutre, mais hydrophile dans un milieu faiblement acide. Le complexe chitosan peut être chargé de divers médicaments hydrophobes, tels que des agents anticancéreux et des gènes, et marqué par des isotopes traçables, de manière que l'on peut l'utiliser comme système d'administration de médicament, comme traceur scintigraphique et comme porteur de gène.
PCT/KR2007/003447 2006-07-14 2007-07-16 Complexe de chitosan contenant un groupe imidazole sensible au ph et procédé de préparation de ce dernier WO2008007932A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
KR1020060066107A KR100831391B1 (ko) 2006-07-14 2006-07-14 ｐＨ 민감성 이미다졸 그룹을 함유한 키토산 복합체 및 그제조방법
KR10-2006-0066107 2006-07-14

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112618793A (zh) * 2020-12-31 2021-04-09 南方医科大学珠江医院 一种pH敏感的抗氧化纳米载体及其制备方法和应用

Families Citing this family (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR101319642B1 (ko) * 2009-12-16 2013-10-17 가톨릭대학교 산학협력단 ｐＨ 민감성 약물 전달용 나노 복합체 및 이의 제조방법
KR101586866B1 (ko) * 2010-04-14 2016-01-21 가톨릭대학교 산학협력단 약물 전달을 위한 ｐＨ-민감성 나노입자 및 이의 제조방법
KR101672231B1 (ko) * 2014-11-12 2016-11-04 한국과학기술연구원 인 제거용 키토산 복합체 및 이의 제조방법
KR102300092B1 (ko) * 2018-11-05 2021-09-09 가톨릭대학교 산학협력단 pH 민감성 탄소 나노입자, 이의 제조방법 및 이를 이용한 약물전달
KR102354429B1 (ko) * 2020-01-29 2022-01-21 중앙대학교 산학협력단 pH 민감성 히알루론산 공중합체 및 이를 이용한 약물전달체
CN111821509B (zh) * 2020-08-07 2022-04-19 北京邦塞科技有限公司 具有pH响应的智能化骨水泥载药微球、骨水泥及其制备方法、使用方法

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WO2005021514A1 (fr) * 2003-08-29 2005-03-10 The University Of Tokyo Nouvel acide amine non naturel analogue de l'histidine
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US5912000A (en) * 1994-09-23 1999-06-15 Zonagen, Inc. Chitosan induced immunopotentiation
WO2005021514A1 (fr) * 2003-08-29 2005-03-10 The University Of Tokyo Nouvel acide amine non naturel analogue de l'histidine
KR20050097189A (ko) * 2004-03-31 2005-10-07 재단법인서울대학교산학협력재단 이미다졸 링을 갖는 키토산 유도체를 이용한 유전자 전달체

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Publication number Priority date Publication date Assignee Title
CN112618793A (zh) * 2020-12-31 2021-04-09 南方医科大学珠江医院 一种pH敏感的抗氧化纳米载体及其制备方法和应用

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