WO2006105725A1 - Association de la luteoline et d’un agent chimiotherapeutique pt - Google Patents

Association de la luteoline et d’un agent chimiotherapeutique pt Download PDF

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Publication number
WO2006105725A1
WO2006105725A1 PCT/CN2006/000587 CN2006000587W WO2006105725A1 WO 2006105725 A1 WO2006105725 A1 WO 2006105725A1 CN 2006000587 W CN2006000587 W CN 2006000587W WO 2006105725 A1 WO2006105725 A1 WO 2006105725A1
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WIPO (PCT)
Prior art keywords
luteolin
tumor
rhinoceros
cisplatin
platinum
Prior art date
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PCT/CN2006/000587
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English (en)
Chinese (zh)
Inventor
Yixin Wu
Original Assignee
Shanghai Gloriayx Biopharmaceuticals Co., Ltd
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 Gloriayx Biopharmaceuticals Co., Ltd filed Critical Shanghai Gloriayx Biopharmaceuticals Co., Ltd
Publication of WO2006105725A1 publication Critical patent/WO2006105725A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/243—Platinum; Compounds thereof
    • 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
    • A61K31/28—Compounds containing heavy metals
    • 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 
    • 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
    • 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
    • A61K31/555—Heterocyclic compounds containing heavy metals, e.g. hemin, hematin, melarsoprol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • chemotherapeutic drugs such as vincristine, cisplatin, methotrexate, cyclophosphamide, 5-fluorouracil (5-Fu) can produce local pain, venous thromboembolism, myelosuppression, and gastrointestinal reactions. , peripheral neuropathy and other toxic side effects.
  • cisplatin is clinically used in combination with 5-Fu, bleomycin or epipodophyllotoxin to treat esophageal cancer.
  • “Synergistic Effect” refers to the sum of the effects of the two drugs when they are used in combination with the two drugs when they are used alone. According to the principle of medium effect (Joseph R. Bertino, Ting-Chao Chou, Chemotherapy: Synergism and Antagonism, Encyclopedia of Cancer, 1996, Academic Press, Inc.), the effect of the combination of the two drugs can be achieved through the "combination index” (Combination) Index, CI) to judge:
  • mice are: mouse melanoma cell line B16, mouse fibrosarcoma cell line M5076 and other solid tumors. (solid tumor) tumor strain; mouse leukemia cell line L1210 and other blood tumor tumor strains. Therefore, those skilled in the art often use a certain tumor tumor strain as an in vivo test mode for transplanted tumors: For example, a mouse animal test using mouse melanoma cell line B16 is used as an animal test for solid tumors. Mode; Mouse animal test of mouse leukemia cell line L1210 was used as an in vivo test mode for blood line tumors. It is judged whether the substance to be tested has an antitumor effect by combining the results of the test in vitro and in vivo.
  • the present invention relates to the use of luteolin or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of tumors in combination with a platinum-based chemotherapeutic drug, including cisplatin, oxaliplatin and carboplatin. '
  • a second aspect of the invention relates to an antitumor pharmaceutical composition
  • an antitumor pharmaceutical composition comprising luteolin and a platinum chemotherapeutic agent.
  • pharmaceutically acceptable salts includes various inorganic or organic acid salts such as hydrochlorides, hydrobromides, phosphates, sulfates, citrates, lactates, tartrates, maleates, fumarates, Mandelic acid salts and oxalates; various inorganic or organic base salts such as sodium hydroxide, trishydroxymethylaminoglycol (TRIS, tromethane) and N-methyl-glucosamine.
  • inorganic or organic acid salts such as hydrochlorides, hydrobromides, phosphates, sulfates, citrates, lactates, tartrates, maleates, fumarates, Mandelic acid salts and oxalates
  • various inorganic or organic base salts such as sodium hydroxide, trishydroxymethylaminoglycol (TRIS, tromethane) and N-methyl-glucosamine.
  • the technical content of the references cited in the present invention is incorporated herein by reference in its entirety.
  • the luteolin of the present invention can be extracted from plants such as honeysuckle and chrysanthemum.
  • the luteolin of the present invention can also be obtained commercially or by conventional synthetic techniques in the art or by the action of microorganisms.
  • Chemicals for isolating or synthesizing the luteolin of the present invention include solvents, reagents, catalysts, protecting group agents, deprotecting group agents.
  • the separation and synthesis may also include the step of adding or removing a suitable protecting group to ultimately obtain the desired luteolin.
  • the present invention relates to a method of treatment using a combination of two components, luteolin and a platinum chemotherapeutic drug including, but not limited to, cisplatin, oxaliplatin or carboplatin.
  • the two components can be administered simultaneously or sequentially, or the luteolin and a platinum chemotherapeutic agent can be formulated into a pharmaceutical composition in a pharmaceutically acceptable carrier.
  • the ingredients of the pharmaceutical composition may be administered separately or together in any convenient form for parenteral or parenteral administration.
  • Formulations for enteral administration include, but are not limited to, capsules, tablets, emulsions, aqueous suspensions, colloidal solutions, solutions, microcapsules, pills, troches, granules, powders.
  • bland fixed oils are often used as a vehicle for solvents or suspending agents, and thus a variety of mild, fixed oils including synthetic mono- or diglycerides are suitable.
  • Fatty acids such as oleic acid and its glyceride derivatives (such as olive oil or castor oil, especially its polyoxyethylene derivatives) and the like can be used to prepare the injection.
  • the oil solution or suspension may also contain a long chain ethanol diluent or dispersant or carboxymethyl cellulose or similar other dispersing agents which are commonly used in the preparation of pharmaceutically acceptable emulsions and/or suspending agents.
  • Surfactants commonly used in other formulations such as Tweens or Spans and/or other similar emulsifiers or bioavailability enhancers and the like are also useful in the preparation of the formulations of the present invention.
  • compositions of the present invention can be formulated as a suppository for rectal administration by mixing the pharmaceutical compositions of the present invention with a suitable non-irritating excipient which is solid at room temperature and liquid at the rectal temperature.
  • a suitable non-irritating excipient which is solid at room temperature and liquid at the rectal temperature.
  • excipients include, but are not limited to, cocoa butter, beeswax, and polyethylene.
  • the topical preparation (e.g., ointment) of the pharmaceutical composition of the present invention can be directly used for the affected area.
  • Such weekly preparations contain the active ingredient and a pharmaceutically acceptable carrier including, but not limited to, mineral oil, liquid petroleum, white petroleum, propylene glycol, polyoxyethylene or polyoxypropylene compound, emulsified wax or water.
  • a pharmaceutically acceptable carrier including, but not limited to, mineral oil, liquid petroleum, white petroleum, propylene glycol, polyoxyethylene or polyoxypropylene compound, emulsified wax or water.
  • the pharmaceutical composition of the present invention can also be formulated as a lotion or an oil. Suitable carriers include, but are not limited to, mineral oil, sorbitol monostearate, polysorbate 60, cetyl ester, hexadecanol, 2-octadecyl alcohol, benzyl alcohol or water.
  • the pharmaceutical composition of the present invention can also be formulated into an enema or the like for local administration in the rectum.
  • Topical transdermal patches are also within the scope of the invention.
  • the pharmaceutical compositions of the present invention may also be administered by nasal spray or inhalation, i.e., using benzyl alcohol or other preservatives, absorption enhancers, fluorocarbons, and/or other solubilizing or dispersing agents, according to conventional methods in the art.
  • a salt solution was prepared.
  • the pharmaceutical compositions of the invention may also be administered by implantation.
  • the effect of the sustained release of the pharmaceutical composition of the present invention in the body of the administered subject can be achieved by the implantation method.
  • implant administration can also be administered in local tissue and organ localization (Negrin et al., Biomaterials 22 (6): 563, 2001).
  • Timed release techniques can also be used in the administration of the pharmaceutical compositions of the present invention, such as Timed release capsules based on polymer technology, sustained release techniques and formulation encapsulation techniques (eg, polymers and liposomes).
  • Patches are also included within the scope of the present invention. It includes a base layer (e.g., a polymer, cloth, yarn, and bandage) and a pharmaceutical composition of the present invention. One side of the base layer may be provided with a protective layer to prevent active ingredients Outflow.
  • the patch may further contain a binder for fixation, which may be a natural or synthetic substance which temporarily adheres to the skin when it comes into contact with the skin of the subject to be administered.
  • the adhesive can be waterproof.
  • the "pharmaceutically acceptable carrier” does not impair the pharmaceutical activity of the pharmaceutical composition of the present invention, and its effective amount, i.e., the amount which can function as a pharmaceutical carrier, is not toxic to the human body.
  • “Pharmaceutically acceptable carrier” includes, but is not limited to, ion exchange materials, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems (SEDDS) such as d-alpha-vitamin E polyethylene glycol 1000 succinate, Surfactants for pharmaceutical preparations such as Tweens or other similar polymerization media, serum proteins such as human serum albumin, buffer substances such as phosphate, glycine, sorbic acid, potassium sorbate, saturated glycerides of saturated vegetable fatty acids , water, salt, electrolytes such as protamine, dihydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, silica gel, magnesium silicate, and the like.
  • Polyvinylpyrrolidone, cellulosic material, polyvinyl alcohol, sodium carboxymethylcellulose, polyacrylate, ethylene-polyoxyethylene-block polymer and lanolin, cyclodextrin such as ⁇ -, ⁇ - and ⁇ a cyclodextrin or a chemically modified derivative thereof such as a hydroxyalkyl cyclodextrin such as 2- and 3-hydroxypropyl- ⁇ -cyclodextrin or other soluble derivative or the like can be used to promote the pharmaceutical composition of the present invention Drug delivery.
  • the synergistic effective range (molar ratio) of luteolin contained in the pharmaceutical composition of the present invention and a platinum-based chemotherapeutic drug including, but not limited to, cisplatin, oxaliplatin or carboplatin has passed through a suitable in vitro The test ( « w7w assay) was verified.
  • the usual dosages and routes of administration of cisplatin, carboplatin and oxaliplatin are as follows: Cisplatin 15-35 mg / m 2 (body surface area) for several days of continuous use, also 70-100 Single dose of mg/m2; carboplatin 300-400 mg/m2 for single-dose or fractional daily administration; oxaliplatin 85-135 mg/m2 for single use.
  • Cisplatin 15-35 mg / m 2 body surface area
  • carboplatin 300-400 mg/m2 for single-dose or fractional daily administration
  • oxaliplatin 85-135 mg/m2 for single use.
  • the exact amount of any ingredient in the composition used can be determined during clinical actual use depending on the potency of the compound employed, the age, weight, physical condition of the patient, and the sensitivity of the patient.
  • MTT assay was continued after 72 hours of incubation. It was stained with tetrazolium salt (MTT) and calculated for single use. The inhibition rate of HepG2 proliferation by using luteolin and cisplatin was analyzed by CalcuSyn statistical software and combined drug index value (CI) method.
  • Human lung cancer cell line A549 was suspended in a cell culture medium containing 10% (small) bovine fetal serum, and seeded at 5 x 10 3 /well in a 96-well cell culture dish. After 24 hours of cultivation, luteolin was added and mixed with cisplatin at different molar ratios to the culture. Final concentration: luteolin 0.3-20 ( ⁇ g/ml, cisplatin: 0.3-3 g/mL) After further incubation for 72 hours, MTT assay was performed. The tetrazolium salt (MTT) method was used to stain and calculate the single use and association. The inhibition rate of A549 proliferation with luteolin and cisplatin was analyzed by CalcuSyn statistical software and combined drug index value (CI) method.
  • CI drug index value
  • Table 4 shows that luteolin showed good synergy when the molar ratio of cisplatin to luteolin was 1:2.5, 1:5, 1:10 when combined with cisplatin (CDDP) in the treatment of HCT116. effect.
  • Example 5 Synergistic effect of luteolin on cisplatin (CDDP) against esophageal cancer
  • the human esophageal cancer cell line TE2 was suspended in a cell culture medium containing 10% (small) bovine fetal serum, and seeded at 5 x 10 3 /well in a 96-well cell culture dish. After 24 hours of cultivation, luteolin was added and mixed with cisplatin at different molar ratios to the culture. Final concentration: luteolin 0.3-20 ( ⁇ g/ml, cisplatin: 0.3-3 g/ml. MTT assay was continued after 72 hours of incubation. It was stained with tetrazolium salt (MTT) and calculated for single use. The inhibition rate of HE2 proliferation in combination with luteolin and cisplatin was analyzed by CalcuSyn statistical software and combined drug index value (CI) method.
  • CI drug index value
  • Rhinoceros luteolin
  • Table 5 shows that luteolin showed a good synergy when the molar ratio of cisplatin to luteolin was 1:2.5, 1:5, 1:10 when combined with cisplatin (CDDP) in the case of TE2. effect.
  • mice were inoculated subcutaneously under the testicular female C57BL/6 (body weight of about 20 g) with 2 ⁇ 10 ⁇ cells/only.
  • the rats were randomized on the second day after inoculation and started to be administered at 0.1 ml/10 g body weight.
  • Luteolin Shaanxi Huike Plant Development Co., Ltd.
  • anti-tumor test was grouped with cisplatin (product of Sigma) in different administration modes such as single administration and combined administration.
  • the tumor inhibition rate is determined according to the calculation formula;
  • test results are shown in Table 6: Animal test results of transplanted B16 melanoma when administered alone or in combination with cisplatin Group dosing schedule Weight of tumor weight (g) Tumor inhibition rate Animal mg/kg Decrease mean SD%
  • Wood rhinoceros 40 68.67 ⁇ 2.7
  • Rhinoceros 40 95 ⁇ 2.9 0.332
  • Rhinoceros luteolin
  • oliplatin oxaliplatin
  • CI ⁇ 1 When CI ⁇ 1 , it is synergistic, CI - 1 is additive; when CI > 1, it is antagonistic.
  • Table 7-9 shows that there is a good combination index in the vicinity of this concentration ratio (1:5 ⁇ 1:15), which can clearly indicate that luteolin and oxaliplatin are in the human colorectal cancer cell line HCT116.
  • Example 8 Synergistic effect of luteolin on oxaliplatin against transplanted tumor
  • mice were inoculated subcutaneously under the testicular female C57BL/6 (body weight of about 20 g) with 2 ⁇ 10 ⁇ cells/only.
  • the rats were randomized on the second day after inoculation and started to be administered at 0.1 ml/10 g body weight.
  • Luteolin Shaanxi Huike Plant Development Co., Ltd.
  • oxaliplatin product of Sigma
  • the tumor weight inhibition rate was calculated and statistical (t-test) treatment was performed. And calculate the Q value according to the Jin's formula.
  • MTT tetrazolium salt
  • Table 11 A549 cell proliferation inhibition rate when luteolin alone and combined with carboplatin, and the combination index
  • CI ⁇ 1 When CI ⁇ 1 , it is synergistic, CI - 1 is additive; when CI > 1, it is antagonistic.
  • Table 16 shows that the molar ratio of the IC50 of the uranium pair and the luteolin to the A549 cell line is about (1:1), which is shown in the vicinity of this concentration ratio (1:2 to 2:1).
  • a good combination drug index can clearly indicate that carboplatin and luteolin have a good combined effect on human lung cancer cell line A549.
  • Example 10 Antitumor synergistic effect of luteolin combined with carboplatin on transplanted tumors
  • mice were inoculated subcutaneously under the control of female C57BL/6 (body weight of about 20 g) at 2 ⁇ 10 6 cells/only.
  • the rats were randomized on the second day after inoculation and started to be administered at a dose of 0.1 ml/lOg.
  • Luteolin Shaanxi Huike Plant Hair Development Co., Ltd.
  • anti-tumor test was grouped with carboplatin (Sigma product) by separate administration, combined administration and other different administration methods. There were 10 experimental animals in each group. The body weight of the animals was measured before administration, and the body weight of the animals was weighed on the 15th day after the test, and the tissue was removed and weighed.
  • the tumor inhibition rate was determined according to the formula; the tumor inhibition rate - (1 - treatment group tumor weight / blank control group tumor weight) X 100% calculation of tumor weight inhibition rate and statistical (t test) treatment. And calculate the Q value according to the Jin's formula.
  • the test results are shown in Table 12.
  • Rhinoceros luteolin

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  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Inorganic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne une composition pharmaceutique contenant de la lutéoline et l’un des agents chimiothérapeutiques Pt comprenant du cisplatine, du carboplatine et de l’oxaliplatine. L’association à base de lutéoline et d’agents chimiothérapeutiques Pt exerce un effet synergique dans le traitement de la tumeur et peut être utilisée pour la fabrication d'un médicament destiné à traiter ladite tumeur.
PCT/CN2006/000587 2005-04-05 2006-04-03 Association de la luteoline et d’un agent chimiotherapeutique pt WO2006105725A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN200510024881 2005-04-05
CN200510024881.1 2005-04-05

Publications (1)

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WO2006105725A1 true WO2006105725A1 (fr) 2006-10-12

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2482855C2 (ru) * 2008-03-27 2013-05-27 Тайхо Фармасьютикал Ко., Лтд. Противоопухолевое средство, включающее производное цитидина и карбоплатин
CN113116925A (zh) * 2021-04-23 2021-07-16 上海市第一人民医院 通关藤苷h与顺铂组合物及其应用
WO2021170001A1 (fr) * 2020-02-25 2021-09-02 华东理工大学 Cristal eutectique de médicament à base d'oxaliplatine-flavonoïde, son procédé de préparation et son utilisation

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH10298098A (ja) * 1997-04-23 1998-11-10 Oriza Yuka Kk リポキシゲナーゼ阻害剤
WO2001058410A2 (fr) * 2000-02-11 2001-08-16 Musc Foundation For Research Development Procede permettant de traiter le cancer du colon par administration d'apigenine, de luteoline, de diosmetine et de chrysine
US20030166583A1 (en) * 2002-02-22 2003-09-04 Oliver Yoa-Pu Hu Dermal cytochrome P450 1A inhibitors and enhancers
TW581687B (en) * 2000-08-21 2004-04-01 You-Pu Hu Agent for inhibiting/promoting activities of Cytochrome P450 1A (CYP1A)

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH10298098A (ja) * 1997-04-23 1998-11-10 Oriza Yuka Kk リポキシゲナーゼ阻害剤
WO2001058410A2 (fr) * 2000-02-11 2001-08-16 Musc Foundation For Research Development Procede permettant de traiter le cancer du colon par administration d'apigenine, de luteoline, de diosmetine et de chrysine
TW581687B (en) * 2000-08-21 2004-04-01 You-Pu Hu Agent for inhibiting/promoting activities of Cytochrome P450 1A (CYP1A)
US20030166583A1 (en) * 2002-02-22 2003-09-04 Oliver Yoa-Pu Hu Dermal cytochrome P450 1A inhibitors and enhancers

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
MA C., SHAN DONG ZHONG YI ZA ZHI, vol. 20, no. 3, March 2001 (2001-03-01), pages 172 - 173 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2482855C2 (ru) * 2008-03-27 2013-05-27 Тайхо Фармасьютикал Ко., Лтд. Противоопухолевое средство, включающее производное цитидина и карбоплатин
WO2021170001A1 (fr) * 2020-02-25 2021-09-02 华东理工大学 Cristal eutectique de médicament à base d'oxaliplatine-flavonoïde, son procédé de préparation et son utilisation
CN113116925A (zh) * 2021-04-23 2021-07-16 上海市第一人民医院 通关藤苷h与顺铂组合物及其应用

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