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WO2015080396A1 - Composition anticancéreuse pour administration orale, contenant un dérivé de botuline pégylé - Google Patents

Composition anticancéreuse pour administration orale, contenant un dérivé de botuline pégylé Download PDF

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Publication number
WO2015080396A1
WO2015080396A1 PCT/KR2014/010677 KR2014010677W WO2015080396A1 WO 2015080396 A1 WO2015080396 A1 WO 2015080396A1 KR 2014010677 W KR2014010677 W KR 2014010677W WO 2015080396 A1 WO2015080396 A1 WO 2015080396A1
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Prior art keywords
oral administration
formula
anticancer composition
cancer
anticancer
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English (en)
Korean (ko)
Inventor
정봉열
방성식
유민지
배근원
정민욱
정인화
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Humedix Co Ltd
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Humedix Co Ltd
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    • 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
    • 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
    • A61K47/59—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 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
    • A61K47/60—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 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to an anticancer drug composition for oral administration comprising a PEGylated betulin derivative. More specifically, the present invention relates to an anticancer composition for oral administration comprising a pegylated betulin derivative which has excellent anticancer effect against various carcinomas and is particularly useful for the treatment of cancer as a drug with significantly improved oral absorption.
  • Betulin and betulinic acid are known to have apoptosis potency.
  • Apoptosis refers to the destruction or suicide of cells in eukaryotic cells, and is a basic intracellular process for maintaining homeostasis of an individual, including controlling the normal development of an animal, or removing unnecessary or abnormal cells.
  • Apoptosis occurs in response to various external and internal stimuli, with the progression of apoptosis, such as cytoplasmic breakdown, blebbing of cell membranes, changes in the cytoskeleton, cell contraction, chromosome condensation and DNA fragmentation. Distinctive changes occur and, if not activated, cells divide indefinitely and form tumors.
  • Betulin represented by the following formula (2) is a lupine-based natural 5-ring triterpene alcohol, betulinol and loop-20 (29) -ene-3 ⁇ , 28-diol (lup). -20 (29) -ene-3 ⁇ , 28-diol). Betulin is present in many bark of tree species, especially in the bark of Betula sp., And methods for separating betulin by extraction from birch bark are known.
  • betulinic acid represented by the following formula (3) is isolated by extraction from the cork of the birch ( Betula sp.) Bark or Quercus suber L., or to the direct oxidation of It is known that it can be prepared by the methods.
  • betulin (2) was oxidized in the presence of a chromium (VI) catalyst according to the Jones oxidation method disclosed in US Pat. No. 6,280,778 to obtain betunic acid. It is then reported that betulinic acid (3) can be obtained by selective reduction of the obtained beturonic acid with sodium borohydride.
  • U. S. Patent No. 5,804, 575 also discloses another method for preparing betulinic acid comprising protecting the 3- ⁇ -hydroxy group of betulin by acetylation and then oxidizing.
  • betulin derivatives are a kind of natural biosynthesis produced by plants having a pentacyclic triterpenoid structure, first isolated from evergreen (Ziziphus mauritiana), and are known to be particularly abundant in the bark of white birch. It is known to have an effect of selectively acting on melanoma or neuroectoderm-derived cancer cells to kill cancer cells.
  • These anticancer actions of betulin derivatives are known to be through various mechanisms, such as reducing the permeability of mitochondria or deactivating mitochondria, such as cytochrome-C release into the cytoplasm, active oxygen formation, or caspase activation.
  • betulin derivatives have been shown to block the activity of HIV-1, showing the possibility of being used as an antiviral agent, and has been reported to be effective in other infectious diseases such as bacteria and malaria.
  • betulin derivatives have been reported to have NO production inhibitory activity by interferon- ⁇ , interest in the anti-inflammatory action of betulin is also increasing.
  • Betulin derivatives have been studied in addition to the various physiological activities mentioned above, but researches on anticancer agents using them are particularly active due to their excellent anticancer effects based on cell death.
  • EP 1309605 and 1124842 disclose that betulin derivatives have inhibitory effects against various malignant tumor cell lines such as sarcomas, oral cancers, breast cancers, lung cancers, colon cancers and the like.
  • betulin and its derivatives known to date have problems in the development and commercialization of oral anticancer drugs due to solubility in water and absorption into the body.
  • the present inventors have tried to solve the problems of the oral absorption rate of the betulin and its derivatives, as a result, the pegylated betulin derivatives of the general formula (1) is found that the oral absorption is significantly improved and has an excellent anticancer effect and the present invention It was completed.
  • X, X ', Y, R 1 and n are as defined in the specification.
  • an object of the present invention relates to an anticancer composition for oral administration comprising a pegylated betulin derivative of Formula 1 or a pharmaceutically acceptable salt thereof having an excellent anticancer effect and particularly having improved oral absorption.
  • the present invention relates to an anticancer composition for oral administration comprising a compound of Formula 1 or a pharmaceutically acceptable salt thereof.
  • X is CH 2 or CO
  • Y is NR 3 , NH, O, S or -OCO,
  • R 1 , R 2 and R 3 are each independently an alkyl group of C 1 -C 6 ,
  • n is an integer of 0-800, Preferably it is 10-400, More preferably, it is 40-200.
  • the C 1 -C 6 alkyl group means a straight or branched hydrocarbon having 1 to 6 carbon atoms, for example methyl, ethyl, n-propyl, i-propyl, n-butyl, i- Butyl, s-butyl, t-butyl, n-pentyl, n-hexyl, and the like.
  • Pegylated betulin derivatives of the present invention include compounds represented by the following Formulas 1a and 1b.
  • X ', Y, R 1 and n in Formula 1a are as defined in Formula 1.
  • X ', Y, R 1 and n are as defined in Formula 1.
  • the polyethylene glycol derivative (5) disclosed in Scheme 2 is an intermediate for single pegylation, and is commercially available or known methods [Ref. Sandler and Karo, Polymer Synthesis , Academic Press, New York, Vol. 3, PP 138-161] may be prepared by ring-opening polymerization of ethylene glycol.
  • the PEGylated betulin derivative (6) of the present invention can be prepared by reacting the betulin (2) and methoxy polyethylene glycol propionic acid.
  • the PEGylated betulinic acid derivative (8) of the present invention is acetylated betulinic acid (3) to obtain 3- ⁇ -acetoxybutulinic acid (7), and then the polyethylene of Scheme 2 It can be prepared by reacting with a glycol derivative (5).
  • the pegylated betulinic acid derivative (8) may be deacetylated to prepare another pegylated betulinic acid derivative (9).
  • the anticancer agent compositions of the present invention are not limited thereto, but may be useful for treating various cancers such as prostate cancer, lung cancer, breast cancer, colon cancer, kidney cancer, liver cancer or glioblastoma. It is preferably useful for the inhibition or treatment of prostate cancer.
  • an anticancer composition containing the compound of the present invention or a pharmaceutically acceptable salt thereof as an active ingredient is administered orally (dose or inhalation). That is, the anticancer composition of the present invention may be administered by formulating in oral form of tablets, capsules, dragees or film coating tablets, solutions or suspensions.
  • a diluent for example, lactose, dextrose, sucrose, cellulose, corn starch or potato starch
  • a suspending agent for example, Silica, talc, stearic acid, magnesium or calcium stearate and / or polyethylene glycol
  • binders e.g. starch, arabic gum, gelatin methylcellulose, carboxymethylcellulose or polyvinyl pyrrolidone
  • disintegrants e.g. Starch, alginic acid, alginate or sodium starch glycolate
  • lecithin polysorbates, laurylsulfate
  • pharmacologically inert substances generally used in pharmaceuticals It may contain.
  • agents can be prepared by known methods, for example by means of mixing, granulating, tableting, dragging or film-coating processes.
  • the active ingredient when formulated in liquid dispersions for oral administration such as syrups, emulsions and suspensions, the active ingredient may contain natural gums, agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose or polyvinyl alcohol. .
  • the content of a compound of the present invention or a pharmaceutically acceptable salt thereof in the preparation of the medicament depends on the form of the medicament, but is preferably in a concentration of 0.01 to 100% by weight.
  • the dosage of the anticancer agent of the present invention varies in a wide range depending on the type of mammal including the person to be treated, the extent of the disease and the judgment of the doctor. In general, however, in the case of oral administration, 0.01 to 50 mg of the active ingredient may be administered per 1 kg of body weight per day.
  • the daily dosages described above can be used one at a time or dividedly, and can be arbitrarily changed depending on the extent of the disease and the judgment of the physician.
  • Pegylated betulin derivatives according to the present invention can be effectively used as a novel anticancer agent, maximize the efficacy by improving solubility and oral absorption through pegylation can be an effective treatment for various carcinomas.
  • it has excellent stability and has both water-soluble and fat-soluble properties, so it can be easily used for various formulation development and complex development.
  • the betulin derivatives can be easily used in the formulation development to maximize the convenience of medication by significantly improving oral absorption through pegylation.
  • FIG. 1 is a graph showing changes in tumor size for 21 days upon repeated oral administration of betulinic acid and BA-mPEG samples to PC-3 xenograft mice of Test Example 3 according to the present invention.
  • Figure 2 is a graph showing the tumor weight of the last day of 21 days when repeated oral administration of betulinic acid, BA-mPEG samples to PC-3 xenograft mice of Test Example 3 according to the present invention.
  • Figure 3 is a photograph showing the tumor size of the last day 21 days after repeated oral administration of betulinic acid, BA-mPEG samples to PC-3 xenograft mice of Test Example 3 according to the present invention.
  • p-toluenesulfonylchloride (p-toluenesulfonyl) in a solution of 10 g (4.975 mmol) of ⁇ -methoxy- ⁇ -hydroxypoly (ethylene glycol) (MeO-PEG (2K) -OH) dissolved in 300 ml of dry dichloromethane. chloride) 2.46 g (13 mmol), 2 ml (15 mmol) of triethylamine, and 0.18 g (15 mmol) of 4-dimethylaminopyridine were added thereto and stirred at room temperature for 5 hours.
  • the reaction solution was diluted with 1 L of dichloromethane, washed sequentially with 800 ml of 1N aqueous hydrochloric acid solution, saturated sodium bicarbonate and saturated sodium chloride aqueous solution, and the organic layer was dried over anhydrous magnesium sulfate and filtered and concentrated under reduced pressure.
  • the resulting mixture was subjected to silica gel column chromatography with methanol and dichloromethane (1:30) to give 10.5 g (4.976 mmol) of the title compound (4) as a white solid.
  • Example 1-2 ⁇ -methoxy- ⁇ -aminopoly (ethylene glycol) (MeO-PEG (2K) -NH 2 Manufacture of 5
  • the reaction solution was diluted with 100 ml of dichloromethane, washed with 300 mL of 0.1 N aqueous hydrochloric acid solution, and then the separated organic layer was washed with 300 mL of saturated aqueous sodium hydrogen carbonate solution. Then, the organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting mixture was precipitated by adding 400 ml of diethyl ether. The precipitate was filtered while washing sufficiently with diethyl ether to give 20.3 g of the title compound (6) as a white solid.
  • the reaction solution was diluted with 500 ml of dichloromethane, washed sequentially with 5000 ml of 1N aqueous hydrochloric acid solution, saturated sodium bicarbonate and saturated sodium chloride aqueous solution, and the organic layer was dried over anhydrous magnesium sulfate and filtered and concentrated under reduced pressure.
  • the resulting mixture was subjected to silica gel column chromatography with methanol and dichloromethane (1:30) to give 2.4 g (0.968 mmol) of the title compound (8) as a white solid.
  • SNU354 was distributed by the Korea Cell Line Bank, and the remaining cell lines used in the experiment were purchased from ATCC. All cell lines were used within 10 passages. Cell lines were cultured containing RPMI1640 and 10% calf serum.
  • Test Example 1-2 Human-derived Cancer Cell Line
  • Samples were dissolved 30 mM using DMSO and diluted again 30, 10, 3, 1, 0.3, 0.1, 0.03 mM.
  • the diluted stock solution was diluted 1000-fold at each dose using RPMI-1640 culture media, and then each sample was treated with final 30, 10, 3, 1, 0.3, 0.1, and 0.03 uM.
  • Test Example 1-4 Measurement method and result of cell growth inhibition activity
  • the loading of cancer cell lines was applied differently depending on the growth rate of the cell line.
  • the working solution was treated to a final concentration of 30, 10, 3, 1, 0.3, 0.1, 0.03 (uM).
  • the drug-treated plate was fixed by adding 50 ⁇ l / well in 50% TCA. The plate was fixed for 60 minutes at 4 °C and then washed 4 to 5 times with tap water (tap water). After washing, the plate was dried, and 100 ⁇ l / well of SRB solution (0.4% sulforhodamine B in 1% acetic acid) was added and left for 30 minutes.
  • Unbound dyeing reagent was washed by adding 0.1% acetic acid, and after drying, the dyeing reagent was dissolved by adding 100 ⁇ l / well of 10 mM Tris Base (pH 10.5). Absorbance was measured at 540 nm using a Versa max microplate reader (Molecular Devices), and the measured absorbance was calculated as a percentage of the solvent treated group. The GI 50 value of the test material was calculated using Graphpad prism v4.0 software.
  • Table 1 shows the GI 50 values of the two betulin derivatives and the comparative substances for eight human-derived cancer cell lines.
  • Test Example 2 Evaluation of anticancer drug efficacy by repeated oral administration in PC-3 xenograft model of human-derived prostate cancer
  • PC-3 prostate cancer
  • Test Example 2-2 Cancer Cell Culture
  • the cells were thawed and thawed in the liquid nitrogen and then cultured. Culture of the cells was incubated for a suitable period of time in a CO 2 incubator (Forma, USA) at a temperature of 37 °C and 5% CO 2 concentration.
  • a CO 2 incubator Forma, USA
  • SPF Specific pathogen free nude mouse of BALB / C strain, 5w, female
  • Test Example 2-5 Test Substance
  • Test Example 2-7 Preparation and Administration Method of Sample
  • Betulinic acid was dissolved at concentrations of 0.5, 2 mg / ml and 3.13, 12.52 mg / ml (molecular weight considerations) using EtOH 10% + [20% HPBCD (in distilled water) 90% solvent, respectively.
  • mPEG was used after dissolving at a concentration of 2.925, 11.7 mg / ml and 4.285, 17.14 mg / ml (considering molecular weight) using sterile distilled water, respectively.
  • mice were orally administered to the mice five times a week at 0.2 ml per 20 g (days 0-4, 7-11, 14-18).
  • Positive control substance Dox.hcl
  • mice were orally administered to the mice five times a week at 0.2 ml per 20 g (days 0-4, 7-11, 14-18).
  • Positive control substance Dox.hcl
  • mice were orally administered to the mice five times a week at 0.2 ml per 20 g (days 0-4, 7-11, 14-18).
  • Positive control substance Dox.hcl
  • mice was dissolved in physiological saline at the concentration of 0.2 mg / ml, and then in mice every 10 days with 10 ml / kg fluid (days 0, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20) repeated intraperitoneal administration.
  • Test Example 2-8 Observation and Inspection Items
  • Test Example 2-8-1 General Symptoms and Weight Change
  • the average tumor size of each group from 56.6 mm 3 to 21 days was measured in three directions using a vernier caliper, and then expressed as a formula of length X width X height / 2.
  • Test Example 2-8-3 Last Day Autopsy (Tumor Weighing, Photography, Fixation)
  • mice On day 21 after the start of drug administration, mice were killed by CO 2 gas, and tumors were separated and weighed on a chemical balance. After taking pictures, the tumors were fixed in formalin.
  • Test Example 2-8-4 Statistical Test Method
  • Test Example 2-9 Results of Anticancer Drug Evaluation by Repeated Oral Administration
  • Test Example 2-9-1 General Symptoms and Weight Change
  • PC-3 tumors were excised and weighed 21 days after the initiation of drug administration and showed 2.2% and 6.3% for betulinic acid and BA-mPEG 20 mg / kg, respectively; Tumor weight reductions of 1.2% and 42.0% (p ⁇ 0.001) were noted. Positive control (Dox.hcl) had a tumor weight reduction of 60.8% (p ⁇ 0.001) (Table 2, Figure 2).
  • ⁇ ⁇ t Vt-Vo, Measurement of the tumor volume (Vt), Initial tumor volume (Vo)
  • the new oral anticancer drugs containing pegylated betulin derivatives according to the present invention have confirmed excellent efficacy with a PC-3 xenograft model, a hormone refractory prostate cell line.
  • the efficacy of cell-based analysis was confirmed through experiments on various representative carcinomas including prostate cancer, and can be widely used as a novel oral anticancer agent related to apoptosis.

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Abstract

La présente invention concerne une composition anticancéreuse destinée à une administration par voie orale, contenant un dérivé de botuline pégylé.
PCT/KR2014/010677 2013-11-27 2014-11-07 Composition anticancéreuse pour administration orale, contenant un dérivé de botuline pégylé Ceased WO2015080396A1 (fr)

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KR1020130145568A KR101531821B1 (ko) 2013-11-27 2013-11-27 페길레이션된 베튤린 유도체를 포함하는 경구 투여용 항암제 조성물
KR10-2013-0145568 2013-11-27

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109988217A (zh) * 2019-03-18 2019-07-09 南通大学 白桦醇衍生物及其制备方法与应用

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20010080507A (ko) * 1998-11-18 2001-08-22 추후보정 신규한 베툴린산 유도체, 그의 제조 방법 및 암 성장억제제로서의 그의 용도
JP2004517045A (ja) * 2000-08-18 2004-06-10 ザ ボード オブ トラスティーズ オブ ザ ユニバーシティ オブ イリノイ 癌およびｈｉｖの治療用ベツリン酸誘導体のプロドラッグ
KR100578382B1 (ko) * 2004-07-16 2006-05-11 나재운 항암제의 전달체용 수용성 키토산 나노입자 및 그 제조방법
JP2009530405A (ja) * 2006-03-23 2009-08-27 アドバンスト ライフ サイエンシズ インコーポレイテッド 合成五環性トリテルペノイド、ならびにベツリン酸およびベツリンの誘導体
KR20100109618A (ko) * 2009-04-01 2010-10-11 주식회사 페라온 페길레이션된 베튤린 유도체 및 그를 포함하는 화장료 조성물

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20010080507A (ko) * 1998-11-18 2001-08-22 추후보정 신규한 베툴린산 유도체, 그의 제조 방법 및 암 성장억제제로서의 그의 용도
JP2004517045A (ja) * 2000-08-18 2004-06-10 ザ ボード オブ トラスティーズ オブ ザ ユニバーシティ オブ イリノイ 癌およびｈｉｖの治療用ベツリン酸誘導体のプロドラッグ
KR100578382B1 (ko) * 2004-07-16 2006-05-11 나재운 항암제의 전달체용 수용성 키토산 나노입자 및 그 제조방법
JP2009530405A (ja) * 2006-03-23 2009-08-27 アドバンスト ライフ サイエンシズ インコーポレイテッド 合成五環性トリテルペノイド、ならびにベツリン酸およびベツリンの誘導体
KR20100109618A (ko) * 2009-04-01 2010-10-11 주식회사 페라온 페길레이션된 베튤린 유도체 및 그를 포함하는 화장료 조성물

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109988217A (zh) * 2019-03-18 2019-07-09 南通大学 白桦醇衍生物及其制备方法与应用
CN109988217B (zh) * 2019-03-18 2021-07-13 南通大学 白桦醇衍生物及其制备方法与应用

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KR101531821B1 (ko) 2015-06-24

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