US20060166931A1 - Clathrates of butylphtualide with cyclodextrin or its derivatives, a process for their preparation and the use thereof - Google Patents

Clathrates of butylphtualide with cyclodextrin or its derivatives, a process for their preparation and the use thereof Download PDF

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Publication number
US20060166931A1
US20060166931A1 US10/524,653 US52465305A US2006166931A1 US 20060166931 A1 US20060166931 A1 US 20060166931A1 US 52465305 A US52465305 A US 52465305A US 2006166931 A1 US2006166931 A1 US 2006166931A1
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United States
Prior art keywords
cyclodextrin
butylphthalide
inclusion complex
derivatives
solution
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Abandoned
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US10/524,653
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English (en)
Inventor
Zhan-qi Niu
Kai Zhao
Wen-juan Liu
Gui-rong Zhou
Chao Liu
Rong-duan Wang
Hong-zhong Yuan
Wen-min Guo
Sui-chao Yan
Min Bai
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SHIJIAZHUANG PHARMA GROUP ZHONGQI PHARMACEUTICAL TECHNOLOGY (SHIJIAZHUANG) Co Ltd A Corp OF PR CHINA
Original Assignee
SHIJIAZHUANG PHARMA GROUP ZHONGQI PHARMACEUTICAL TECHNOLOGY (SHIJIAZHUANG) Co Ltd A Corp OF PR CHINA
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Application filed by SHIJIAZHUANG PHARMA GROUP ZHONGQI PHARMACEUTICAL TECHNOLOGY (SHIJIAZHUANG) Co Ltd A Corp OF PR CHINA filed Critical SHIJIAZHUANG PHARMA GROUP ZHONGQI PHARMACEUTICAL TECHNOLOGY (SHIJIAZHUANG) Co Ltd A Corp OF PR CHINA
Assigned to SHIJIAZHUANG PHARMA. GROUP ZHONGQI PHARMACEUTICAL TECHNOLOGY (SHIJIAZHUANG) CO., LTD. A CORPORATION OF P.R. CHINA reassignment SHIJIAZHUANG PHARMA. GROUP ZHONGQI PHARMACEUTICAL TECHNOLOGY (SHIJIAZHUANG) CO., LTD. A CORPORATION OF P.R. CHINA ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: BAI, MIN, GUO, WEN-MIN, LIU, CHAO, LIU, WEN-JUAN, NIU, ZHAN-QI, WANG, RONG-DUAN, YAN, SUI-CHAO, YUAN, HONG-ZHONG, ZHAO, KAI, ZHOU, GUI-RONG
Publication of US20060166931A1 publication Critical patent/US20060166931A1/en
Priority to US12/200,130 priority Critical patent/US7678776B2/en
Abandoned legal-status Critical Current

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Classifications

    • 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
    • C08B37/0009—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid alpha-D-Glucans, e.g. polydextrose, alternan, glycogen; (alpha-1,4)(alpha-1,6)-D-Glucans; (alpha-1,3)(alpha-1,4)-D-Glucans, e.g. isolichenan or nigeran; (alpha-1,4)-D-Glucans; (alpha-1,3)-D-Glucans, e.g. pseudonigeran; Derivatives thereof
    • C08B37/0012—Cyclodextrin [CD], e.g. cycle with 6 units (alpha), with 7 units (beta) and with 8 units (gamma), large-ring cyclodextrin or cycloamylose with 9 units or more; Derivatives thereof
    • C08B37/0015—Inclusion compounds, i.e. host-guest compounds, e.g. polyrotaxanes
    • 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
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
    • 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
    • A61K47/6949—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 inclusion complexes, e.g. clathrates, cavitates or fullerenes
    • A61K47/6951—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 inclusion complexes, e.g. clathrates, cavitates or fullerenes using cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • 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
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/87—Benzo [c] furans; Hydrogenated benzo [c] furans
    • C07D307/88—Benzo [c] furans; Hydrogenated benzo [c] furans with one oxygen atom directly attached in position 1 or 3

Definitions

  • the present invention relates to pharmaceutical compositions. More particularly, it relates to the inclusion complexes of butylphthalide, which is D,L-mixed or levorotary, with cyclodextrin or its derivatives, to a process for their preparation and the use thereof.
  • Butylphthalide is a water insoluble oily compound with the following formula:
  • Butylphtualide can be obtained by extraction from natural celery seed oil or by chemical synthesis, as described in Chinese patent application No. 99109673.8 and the prior reference: Junshan Yang, Yalun Su, Chinese Pharmaceutical Bulletin, 1984, 31; 671, which realized the availability of butylphthalide.
  • the pharmaceutical formulations are required to release active agents quickly and exert therapeutic effects rapidly when they are used to treat ischemia-induced diseases or thrombosis.
  • the formulations for treating acute disease are administrated by intravenous instillation.
  • the butylphthalide can only be formulated into soft capsules for oral administration because of its oily characteristics. Therefore, solubility problem of the butylphthalide must be resolved firstly in order to obtain injectable dosage forms.
  • the present invention intends to provide inclusion complexes of butylphthalide with cyclodextrin or its derivatives, a process for their preparation and the use thereof.
  • it is complexed with cyclodextrin or its derivatives, wherein the butylphthalide is D,L-mixed or levorotary, and the inclusion complexes may be used to prepare various clinically applicable solid and liquid formulations.
  • An inclusion complex of butylphthalide with cyclodextrin or its derivatives comprises butylphthalide and cyclodextrin or its derivatives, wherein the molar ratio of butylphthalide to cyclodextrin or its derivatives is in the range of 1:1-10.
  • the butylphthalide mentioned above comprises D,L-mixed or levorotatory butylphthalide.
  • the cyclodextrin mentioned above is selected from the group consisting of ⁇ -cyclodextrin, ⁇ -cyclodextrin, and ⁇ -cyclodextrin.
  • the derivatives of cyclodextrin mentioned above are selected from the group consisting of hydroxyethyl- ⁇ -cyclodextrin, hydroxypropyl- ⁇ -cyclodextrin, dihydroxypropyl- ⁇ -cyclodextrin, methyl- ⁇ -cyclodextrin, glucose cyclodextrin, maltose cyclodextrin, meltotriose cyclodextrin, carboxymethyl cyclodextrin, and sulfonylalkyl cyclodextrin.
  • hydroxypropyl- ⁇ -cyclodextrin is preferred.
  • a solution with a concentration of 5-60% is prepared by adding cyclodextrin or its derivatives into a suitable solvent vehicle.
  • a liquid inclusion complex of butylphthalide with cyclodextrin or its derivatives is obtained by adding butylphthalide into the above solution, stirring to provide a clear and transparent solution without oil drops, wherein the molar ratio of butylphthalide to cyclodextrin or its derivatives is in the range of 1:1 to 1:10.
  • the process mentioned above may further comprise drying the liquid inclusion complex of butylphthalide with cyclodextrin or its derivatives at the temperature of 40-80° C. to obtain a solid inclusion complex of butylphthalide with cyclodextrin or its derivatives.
  • the process mentioned above may also comprise concentrating the liquid inclusion complex of butylphthalide with cyclodextrin or its derivatives until the concentration of cyclodextrin or its derivatives is 10-15% (W/V), cooling the solution for, e.g. about 12 hours to obtain white precipitate, filtering, and drying at 40-80° C., to obtain a solid inclusion complex of butylphthalide with cyclodextrin or its derivatives.
  • a process for preparing the inclusion complex of butylphthalide with cyclodextrin or its derivatives comprises placing cyclodextrin or its derivatives into a colloid mill or mortar, adding an appropriate amount of suitable solvent vehicle, and stirring the mixture to provide a paste; adding butylphthalide into the paste described above, grinding for about 1-5 hours to provide a homogenous and viscous paste, then filtering the paste, and drying at 40-80° C. to obtain a solid inclusion complex of butylphthalide with cyclodextrin or its derivatives, wherein the molar ratio butylphthalide to cyclodextrin or its derivatives is in the range of 1:1-10.
  • a process for preparing the inclusion complex of butylphthalide with cyclodextrin or its derivatives comprises adding cyclodextrin or its derivatives into a suitable solvent vehicle to obtain a solution with a concentration of 5-60%, dissolving the butylphthalide into an appropriate amount of ethanol with purity of 99%, mixing the two solutions, stirring, and drying to obtain a solid inclusion complex of butylphthalide with cyclodextrin or its derivatives, wherein the molar ratio butylphthalide to cyclodextrin or its derivatives is in the range of 1:1-10.
  • the drying method mentioned above may be any drying method, such as direct drying, spray drying, or freeze-drying.
  • solvent vehicles examples include water, ethanol, methanol, propanol, isopropanol, ethylene glycol, propylene glycol, glycerin, or acetone, or the mixture of any two or more above-mentioned solvent vehicles, wherein water is preferred.
  • Such liquid inclusion complex of butylphthalide with cyclodextrin or its derivatives may be directly used to produce liquid formulations, such as infusion, injection, injectable powder, liquids for oral administration, syrup, and the like;
  • the solid inclusion complex of butylphthalide with cyclodextrin or its derivatives may be used to produce solid formulations, such as tablets, capsules, granules, dispersible tablets, and the like.
  • cyclodextrin or its derivatives could trap the butylphthalide into their tubular structure to generate an inclusion complex of butylphthalide with cyclodextrin or its derivatives, thereby improving the water-solubility of butylphthalide.
  • the active ingredient butylphthalide in the form of inclusion complexes can be directly applied in solid or liquid dosage forms. Limitations such as poor water-solubility, disability to be directly applied in solid, especially injectable dosage forms can be overcome.
  • Cyclodextrin or its derivatives are water-soluble pharmaceutical excipients with little toxicity.
  • the inclusion complexes of butylphthalide with cyclodextrin or its derivatives prepared thereby are suitable to be formulated into various liquid and solid dosage forms.
  • the inclusion complexes have the advantages such as good water-solubility and little vascular irritation.
  • the solubility of inclusion complex of butylphthalide with hydroxypropyl-o-cyclodextrin in water at 25° C. is 924 mg/100 ml.
  • the inclusion complex is particularly applicable for preparing liquid dosage forms.
  • the present invention overcomes the limitation that butylphthalide cannot be used to prepare liquid formulations. Due to the fact that the water-solubility is improved, the resulting solid dosage forms have the advantages such as rapid disintegration, good solubility and high bioavailability, which is more applicable for clinical use.
  • vascular irritation assay using inclusion complex of butylphthalide with hydroxypropyl- ⁇ -cyclodextrin is provided as follows:
  • test group Eight rabbits were divided into two groups, namely, test group and control group.
  • test group 2.45 g/kg of the inclusion complex together with 40 ml of 5% glucose were instilled via the marginal ear vein of a rabbit at the rate of 1.5 ml/min. The administration was once per day and lasted for 3 days.
  • control group 10% acetic acid was administrated into the ear vein on one side and 5% glucose injection was instilled into the rabbit ear on the opposite side serving as negative control. The administration lasted for 3 days. Results showed that there was no topical abnormity in the test group after 3 days, similar to the negative control of 5% glucose injection. However, topical hyperaemia, thickening, and exudation were observed after 10% acetic acid injection.
  • the assay suggests that instillation of the inclusion complex has little vascular irritation, and that the inclusion complex can be used to produce injectable dosage forms.
  • hydroxypropyl- ⁇ -cyclodextrin is preferably used as trapping agent.
  • suitable solvent vehicle for dissolving cyclodextrin or its derivatives is water.
  • the inclusion complex is prepared by
  • the solid inclusion complex is prepared by
  • the solid inclusion complex is prepared by
  • the lyophilized injectable powder is prepared by
  • the saline infusion of the inclusion complex is prepared by
  • the glucose infusion of the inclusion complex is prepared by
  • the sterile injectable powder is prepared by
  • the complexation process is conducted by

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
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  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
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  • Chemical Kinetics & Catalysis (AREA)
  • Nanotechnology (AREA)
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  • Polymers & Plastics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Crystallography & Structural Chemistry (AREA)
  • Biochemistry (AREA)
  • Materials Engineering (AREA)
  • General Engineering & Computer Science (AREA)
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  • Biophysics (AREA)
  • Biotechnology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Polysaccharides And Polysaccharide Derivatives (AREA)
US10/524,653 2002-08-21 2002-08-21 Clathrates of butylphtualide with cyclodextrin or its derivatives, a process for their preparation and the use thereof Abandoned US20060166931A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
US12/200,130 US7678776B2 (en) 2002-08-21 2008-08-28 Inclusion complexes of butylphthalide with cyclodextrin or its derivatives, a process for their preparation and the use thereof

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/CN2002/000579 WO2004018444A1 (fr) 2002-08-21 2002-08-21 Clathrates de phtalide butylique associe a de la cyclodextrine ou a ses derives, procede de preparation desdites compositions et leur utilisation

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US12/200,130 Continuation US7678776B2 (en) 2002-08-21 2008-08-28 Inclusion complexes of butylphthalide with cyclodextrin or its derivatives, a process for their preparation and the use thereof

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US12/200,130 Expired - Lifetime US7678776B2 (en) 2002-08-21 2008-08-28 Inclusion complexes of butylphthalide with cyclodextrin or its derivatives, a process for their preparation and the use thereof

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US (2) US20060166931A1 (fr)
EP (1) EP1535916B1 (fr)
JP (1) JP4378755B2 (fr)
AT (1) ATE489972T1 (fr)
AU (1) AU2002327307B8 (fr)
BR (1) BR0215848A (fr)
CA (1) CA2494157C (fr)
DE (1) DE60238510D1 (fr)
DK (1) DK1535916T3 (fr)
ES (1) ES2355133T3 (fr)
NO (1) NO20050629L (fr)
WO (1) WO2004018444A1 (fr)

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070112065A1 (en) * 2003-10-10 2007-05-17 Shijiazhuang Pharma. Group Zhongqi Pharmaceutical Use of l-butylphthalide in the manufacture of medicaments for prevention and treatment of cerebral infarct
US20070134316A1 (en) * 2003-12-05 2007-06-14 Shijiazhuang Pharma. Group Zhongqi Pharmaceutical Technology (Shijiazhuang) Co., Ltd. Soft capsule of butylphthalide and a process for preparing the same
US10463614B2 (en) 2005-12-16 2019-11-05 Shijiazhuang Pharma Group Nbp Pharmaceutical Co. Butylphthalide intravenous emulsion and application thereof
CN110548004A (zh) * 2018-05-30 2019-12-10 成都施贝康生物医药科技有限公司 一种稳定的丁苯酞大容量注射液及其制备方法
CN112386571A (zh) * 2020-12-04 2021-02-23 成都施贝康生物医药科技有限公司 一种稳定的丁苯酞氯化钠注射液、其制备方法及用途
CN114685410A (zh) * 2020-12-26 2022-07-01 四川汇宇制药股份有限公司 一种丁苯酞的制备方法
WO2023165094A1 (fr) * 2022-03-04 2023-09-07 中国医学科学院药用植物研究所 Composé diester d'acide hydroxypentyl benzoïque, son procédé de préparation et son utilisation

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JP2008502607A (ja) * 2004-06-18 2008-01-31 石薬集団中奇制薬技術（石家庄）有限公司 痴呆の予防および治療におけるＬ−ｎ−ブチルフタリドの適用
CN100361656C (zh) * 2004-08-27 2008-01-16 石药集团中奇制药技术（石家庄）有限公司 丁苯酞自乳化释药体系及其制备方法和应用
CN101342152B (zh) * 2007-07-10 2010-10-13 石药集团中奇制药技术（石家庄）有限公司 丁苯酞片及其制备方法
CN107970208B (zh) * 2012-06-27 2021-01-19 石药集团中奇制药技术（石家庄）有限公司 一种丁苯酞注射液及其制备方法
CN103784424B (zh) * 2012-10-30 2018-04-27 石药集团中奇制药技术（石家庄）有限公司 一种丁苯酞经皮贴剂及其制备方法
CN105616375B (zh) * 2013-03-06 2018-08-28 贵州贵安新区协生元医药科技有限公司 消旋2-(α-羟基戊基)苯甲酸盐片及其制备方法
CN105380908B (zh) * 2015-12-09 2018-08-10 河北大学 一种丁苯酞药物复合物及其制备方法和缓释制剂
CN108553412B (zh) * 2018-05-14 2019-10-29 田普森 一种含丁苯酞与增溶剂药物组合物
CN111743892A (zh) * 2019-03-26 2020-10-09 石家庄以岭药业股份有限公司 丁苯酞衍生物在制备治疗心梗或其相关疾病药物中的应用
CN112999175B (zh) * 2021-04-26 2021-08-03 奥信阳光(北京)药业科技有限公司 一种丁苯酞口服冻干粉及其制备方法和用途

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CN1086942C (zh) * 1998-12-18 2002-07-03 中国医学科学院药物研究所 丁基苯酞在制备抗血栓形成及抗血小板聚集药物中的应用
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US4727064A (en) * 1984-04-25 1988-02-23 The United States Of America As Represented By The Department Of Health And Human Services Pharmaceutical preparations containing cyclodextrin derivatives

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070112065A1 (en) * 2003-10-10 2007-05-17 Shijiazhuang Pharma. Group Zhongqi Pharmaceutical Use of l-butylphthalide in the manufacture of medicaments for prevention and treatment of cerebral infarct
US8598225B2 (en) 2003-10-10 2013-12-03 Cspc Zhongqi Pharmaceutical Technology (Shijiazhuang) Co., Ltd. Use of L-butylphthalide in the manufacture of medicaments for treatment of cerebral infarct
US20070134316A1 (en) * 2003-12-05 2007-06-14 Shijiazhuang Pharma. Group Zhongqi Pharmaceutical Technology (Shijiazhuang) Co., Ltd. Soft capsule of butylphthalide and a process for preparing the same
US10463614B2 (en) 2005-12-16 2019-11-05 Shijiazhuang Pharma Group Nbp Pharmaceutical Co. Butylphthalide intravenous emulsion and application thereof
CN110548004A (zh) * 2018-05-30 2019-12-10 成都施贝康生物医药科技有限公司 一种稳定的丁苯酞大容量注射液及其制备方法
CN112386571A (zh) * 2020-12-04 2021-02-23 成都施贝康生物医药科技有限公司 一种稳定的丁苯酞氯化钠注射液、其制备方法及用途
CN114685410A (zh) * 2020-12-26 2022-07-01 四川汇宇制药股份有限公司 一种丁苯酞的制备方法
WO2023165094A1 (fr) * 2022-03-04 2023-09-07 中国医学科学院药用植物研究所 Composé diester d'acide hydroxypentyl benzoïque, son procédé de préparation et son utilisation
US12403116B2 (en) 2022-03-04 2025-09-02 Chinese Academy Of Medical Sciences Institue Of Medicinal Plant Development Hydroxypentyl benzoic acid diester compound, and preparation method and pharmaceutical application thereof

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AU2002327307B2 (en) 2009-02-12
JP2006500367A (ja) 2006-01-05
WO2004018444A1 (fr) 2004-03-04
DK1535916T3 (da) 2011-03-14
BR0215848A (pt) 2005-06-21
ATE489972T1 (de) 2010-12-15
DE60238510D1 (de) 2011-01-13
US20080318898A1 (en) 2008-12-25
AU2002327307B8 (en) 2009-02-26
EP1535916A1 (fr) 2005-06-01
EP1535916B1 (fr) 2010-12-01
US7678776B2 (en) 2010-03-16
CA2494157A1 (fr) 2004-03-04
EP1535916A4 (fr) 2006-09-20
CA2494157C (fr) 2010-10-12
AU2002327307A1 (en) 2004-03-11
NO20050629L (no) 2005-03-17
HK1074200A1 (en) 2005-11-04
JP4378755B2 (ja) 2009-12-09
ES2355133T3 (es) 2011-03-23

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