[go: up one dir, main page]

WO2009005258A2 - Conjugués d'héparine et procédés associés - Google Patents

Conjugués d'héparine et procédés associés Download PDF

Info

Publication number
WO2009005258A2
WO2009005258A2 PCT/KR2008/003731 KR2008003731W WO2009005258A2 WO 2009005258 A2 WO2009005258 A2 WO 2009005258A2 KR 2008003731 W KR2008003731 W KR 2008003731W WO 2009005258 A2 WO2009005258 A2 WO 2009005258A2
Authority
WO
WIPO (PCT)
Prior art keywords
acid
heparin
residue
composition
bile acid
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.)
Ceased
Application number
PCT/KR2008/003731
Other languages
English (en)
Other versions
WO2009005258A3 (fr
Inventor
Youngro Byun
E Sak Lee
Ok-Cheol Jeon
Sang Yoon Kim
Rang-Woon Park
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.)
MEDIPLEX CORP
Mediplex Corp Korea
Original Assignee
MEDIPLEX CORP
Mediplex Corp Korea
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 MEDIPLEX CORP, Mediplex Corp Korea filed Critical MEDIPLEX CORP
Priority to EP08778410A priority Critical patent/EP2173359A2/fr
Publication of WO2009005258A2 publication Critical patent/WO2009005258A2/fr
Publication of WO2009005258A3 publication Critical patent/WO2009005258A3/fr
Anticipated expiration legal-status Critical
Ceased 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/726—Glycosaminoglycans, i.e. mucopolysaccharides
    • A61K31/727—Heparin; Heparan
    • 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
    • C08B37/006—Heteroglycans, i.e. polysaccharides having more than one sugar residue in the main chain in either alternating or less regular sequence; Gellans; Succinoglycans; Arabinogalactans; Tragacanth or gum tragacanth or traganth from Astragalus; Gum Karaya from Sterculia urens; Gum Ghatti from Anogeissus latifolia; Derivatives thereof
    • C08B37/0063—Glycosaminoglycans or mucopolysaccharides, e.g. keratan sulfate; Derivatives thereof, e.g. fucoidan
    • C08B37/0075—Heparin; Heparan sulfate; Derivatives thereof, e.g. heparosan; Purification or extraction methods thereof
    • C08B37/0081—Reaction with amino acids, peptides, or proteins
    • 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
    • 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
    • A61K47/54—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 compound
    • A61K47/55—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 compound the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug, i.e. a dimer, oligomer or polymer of pharmacologically or therapeutically active compounds
    • A61K47/551—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 compound the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug, i.e. a dimer, oligomer or polymer of pharmacologically or therapeutically active compounds one of the codrug's components being a vitamin, e.g. niacinamide, vitamin B3, cobalamin, vitamin B12, folate, vitamin A or retinoic 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
    • A61K47/50—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
    • A61K47/54—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 compound
    • A61K47/554—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 compound the modifying agent being a steroid plant sterol, glycyrrhetic acid, enoxolone or bile 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
    • A61K47/50—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
    • 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
    • A61K47/66—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 the modifying agent being a pre-targeting system involving a peptide or protein for targeting specific cells
    • 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
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
    • C08L5/00—Compositions of polysaccharides or of their derivatives not provided for in groups C08L1/00 or C08L3/00
    • C08L5/10—Heparin; Derivatives thereof

Definitions

  • FIG. 5 illustrates a scheme for synthesis of JV-deoxycholylethylenediamine from aDOCA.
  • FIG. 6 illustrates a scheme for synthesis of a heparin-DOCA conjugate from N- deoxycholylethylenediamine and heparin.
  • the bile acid residue may be selected, for example, from the group consisting of residues of cholic acid, deoxycholic acid, chenodeoxycholic acid, lithocholic acid, ursocholic acid, ursodeoxycholic acid, isoursodeoxycholic acid, lagodeoxycholic acid, glycocholic acid, taurocholic acid, glycodeoxycholic acid, glycochenodeoxycholic acid, dehydrocholic acid, hyocholic acid, and hyodeoxycholic acid.
  • ⁇ means an amount of a heparin conjugate that is nontoxic but sufficient to provide the desired effect and performance at a reasonable benefit/risk ratio attending any cancer treatment.
  • n is about 1 to about 10.
  • the heparin can comprise heparin of any type, such as unfractionated heparin, high molecular weight heparin, low molecular weight heparin, heparin fragment, recombinant heparin, heparin analogs, heparin sulfate, and sulfonated polysaccharides containing heparin activity, and the like.
  • the spacers, S 1 and S 2 are independently selected from the group consisting of alkyl chains, polyethylene glycol, an ethylene diamine residue, and the like.
  • the targeting moiety may comprise a folic acid residue, a cRGD residue, and the like.
  • the second spacer-targeting moiety is bonded to the previously described heparin-spacer-bile acid conjugate or heparin-spacer-bile acid analog conjugate to result in the heparin-spacer-bile acid-spacer-targeting moiety conjugate or heparin-spacer-bile acid analog-spacer-targeting moiety conjugate.
  • the ultra-violet circular dichroism (CD) spectrum of proteins can predict important characteristics of their secondary structure. CD spectra can be readily used to estimate the fraction of a molecule that is in the alpha-helix conformation, the beta-sheet conformation, the beta-turn conformation, or some other (e.g., random coil) conformation. Jasco J-715 Circular Dichroism (Jasco, Japan) was used for making the determination.
  • HTlO (5 mg/kg) inhibited tumor growth about 71% compared with the control, while HTlO (1 mg/kg) inhibited tumor growth about 63%, and bevacizumab inhibited tumor growth about 74%.
  • HTlO nor LMWH administered at 0.5 mg/kg were effective in inhibiting tumor growth.
  • FIGS. 12-14 show synthesis of a cRGD-HT conjugate.
  • 50 mg of cRGDyK peptide was dissolved in DMF (10 ml) and then methyl-N-succinimidyl adipate (MSA, 32 mg) was added. After stirring for 12 h at room temperature, phenyl ester was added to the reaction mixture and stirring was continued for 6 h to protect the carboxyl group of the cRGDyK peptide.
  • the reaction mixture was precipitated with a 3-fold excess of water to remove any unreacted reagents, and the precipitate was washed with water and then dried in vacuo.
  • the folylethylamine (folate-NH 2 ) was precipitated by the addition of excess acetonitrile, and the precipitate was filtered and washed with diethyl ether before trying under vacuum to get yellow powder.
  • This product was added to HL (100 mg), dissolved in 20 ml of formamide, and activated by EDAC (3.38 mg) with 5 ⁇ l of N, N - diisopropylethylamine (DIEA) for 12 h.
  • the unreacted folate-NH 2 was removed by dialysis (MWCO 2000).
  • the final product, FHL was obtained by lyophilization at a yield of 91%.
  • the folate content in FHL was determined by quantitative UV spectrophotometry at 365 nm.
  • the anti-coagulation activity of FHL was measured by Fxa chromogenic assay (COATEST®eparin, Milan, Italy).

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Medicinal Chemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Organic Chemistry (AREA)
  • Polymers & Plastics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nanotechnology (AREA)
  • Biochemistry (AREA)
  • Crystallography & Structural Chemistry (AREA)
  • Medical Informatics (AREA)
  • General Engineering & Computer Science (AREA)
  • Biotechnology (AREA)
  • Biophysics (AREA)
  • Materials Engineering (AREA)
  • Cell Biology (AREA)
  • Botany (AREA)
  • Dermatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention porte sur des conjugués d'héparine et sur des procédés de production et d'utilisation. L'un desdits conjugués comprend une composition dans laquelle un acide biliaire est lié à l'héparine par l'intermédiaire du carbone 3 de l'acide biliaire, un espaceur pouvant être interposé entre l'acide biliaire et l'héparine. Dans un autre mode de réalisation, un fragment de ciblage est lié au conjugué d'héparine/acide biliaire par l'intermédiaire d'un espaceur. Dans encore un autre mode de réalisation, l'héparine est liée par covalence à un fragment sulfoné tel qu'un résidu de trisulfonate de naphtalène. L'invention porte également sur une méthode de traitement du cancer consistant à administrer à un patient le nécessitant un conjugué d'héparine.
PCT/KR2008/003731 2007-06-29 2008-06-27 Conjugués d'héparine et procédés associés Ceased WO2009005258A2 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP08778410A EP2173359A2 (fr) 2007-06-29 2008-06-27 Conjugués d'héparine et procédés associés

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US82459407A 2007-06-29 2007-06-29
US11/824,594 2007-06-29

Publications (2)

Publication Number Publication Date
WO2009005258A2 true WO2009005258A2 (fr) 2009-01-08
WO2009005258A3 WO2009005258A3 (fr) 2009-02-26

Family

ID=40226647

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/KR2008/003731 Ceased WO2009005258A2 (fr) 2007-06-29 2008-06-27 Conjugués d'héparine et procédés associés

Country Status (3)

Country Link
EP (1) EP2173359A2 (fr)
KR (1) KR101027161B1 (fr)
WO (1) WO2009005258A2 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011018496A3 (fr) * 2009-08-13 2011-05-19 Leibniz-Institut für Polymerforschung Dresden e. V. Procédé pour modifier et fonctionnaliser des saccharides
US20210355155A1 (en) * 2020-05-15 2021-11-18 Brigham Young University Cationic steroidal antimicrobial compounds with urethane linkages

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR101313894B1 (ko) 2011-04-08 2013-10-01 경북대학교 산학협력단 신규한 탈황산화된 헤파린-담즙산 유도체를 포함하는 염증성 질환의 예방 및 치료용 조성물
KR101702251B1 (ko) 2012-11-29 2017-02-02 에스티팜 주식회사 신규한 소포 수송에 이용하기 위한 담즙산 올리고머 결합체 및 이의 용도
KR20210122492A (ko) * 2020-04-01 2021-10-12 에스티팜 주식회사 항암 요법을 위한 헤파린-담즙산 올리고머 컨쥬게이트

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR100378109B1 (ko) * 2000-10-24 2003-03-29 주식회사 메디프렉스 소수성 다중복합 헤파린 결합체, 그의 제조방법 및 용도
FR2864091B1 (fr) 2003-12-19 2006-04-07 Ethypharm Sa Derive amphiphile d'heparine forme par couplage de l'heparine avec un acide biliaire

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011018496A3 (fr) * 2009-08-13 2011-05-19 Leibniz-Institut für Polymerforschung Dresden e. V. Procédé pour modifier et fonctionnaliser des saccharides
US20210355155A1 (en) * 2020-05-15 2021-11-18 Brigham Young University Cationic steroidal antimicrobial compounds with urethane linkages
CN116209448A (zh) * 2020-05-15 2023-06-02 布莱阿姆青年大学 阳离子甾族抗微生物化合物和制造此类化合物的方法
US12030912B2 (en) * 2020-05-15 2024-07-09 Brigham Young University Cationic steroidal antimicrobial compounds with urethane linkages

Also Published As

Publication number Publication date
EP2173359A2 (fr) 2010-04-14
KR101027161B1 (ko) 2011-04-05
KR20090003128A (ko) 2009-01-09
WO2009005258A3 (fr) 2009-02-26

Similar Documents

Publication Publication Date Title
US8088753B2 (en) Heparin conjugates and methods
CN103751795B (zh) 透明质酸‑抗肿瘤药偶联物及复合纳米粒组合物的制备和应用
Pasut et al. PEG-epirubicin conjugates with high drug loading
AU2006274992B2 (en) Antitumoral bioconjugates of hyaluronic acid or its derivatives obtained by indirect chemical conjugation
EP0640622A1 (fr) Derive de polysaccharide et vehicule de medicament
CN108524919A (zh) 用于改进的药物递送的载体
JPWO1994019376A1 (ja) 多糖誘導体および薬物担体
CA2257233A1 (fr) Procede de fabrication de complexes medicamenteux
WO2008136536A1 (fr) Gel hybride comprenant un dérivé de l'acide hyaluronique réticulé chimiquement, et composition pharmaceutique l'utilisant
Sargazi et al. Hyaluronic acid/polyethylene glycol nanoparticles for controlled delivery of mitoxantrone
TWI888483B (zh) 玻尿酸衍生物、醫藥組合物及玻尿酸衍生物－藥物結合體
WO2009005258A2 (fr) Conjugués d'héparine et procédés associés
Warrier et al. Novel derivatives of arabinogalactan, pullulan & lactobionic acid for targeting asialoglycoprotein receptor: Biomolecular interaction, synthesis & evaluation
KR101201473B1 (ko) 자기 조립형 약물 및 세포 전달체의 제조 방법 및 이에 의해 제조된 자기 조립형 약물 및 세포 전달체
Wang et al. A novel biomimetic chitosan-based nanocarrier with suppression of the protein-nanocarrier interactions
Yang et al. A hyaluronic acid–camptothecin nanoprodrug with cytosolic mode of activation for targeting cancer
Duan et al. Fabrication of tumor-targeting composites based on the triple helical β-glucan through conjugation of aptamer
CN105860057B (zh) 基于疏水功能性小分子‑亲水聚氨基酸的生物可降解聚合物及其制备方法和应用
CN109908084A (zh) 一种铂交联喜树碱前药胶束纳米药物及其制备方法和应用
WO2009145594A2 (fr) Vecteur d'administration de médicament
CN106749517B (zh) 一种含多肽靶向因子的多糖衍生物及其制备方法
WO2022068927A1 (fr) Composition de squelette de cyclodextrine à double greffe d'héparine-polypeptide ciblant les poumons, son procédé de préparation et son utilisation
US20090170195A1 (en) Curcumin-hyaluronan compounds
Long et al. Preparation and evaluation of water-soluble chondroitin sulfate-curcumin conjugate
CN114870031B (zh) 一种cd44靶向的紫杉烷类纳米晶体及其制备方法与应用

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 08778410

Country of ref document: EP

Kind code of ref document: A2

NENP Non-entry into the national phase

Ref country code: DE

WWE Wipo information: entry into national phase

Ref document number: 2008778410

Country of ref document: EP