WO2017170564A1 - Formulation nanoparticulaire pour le traitement de maladies cancéreuses - Google Patents

Formulation nanoparticulaire pour le traitement de maladies cancéreuses Download PDF

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WO2017170564A1
WO2017170564A1 PCT/JP2017/012669 JP2017012669W WO2017170564A1 WO 2017170564 A1 WO2017170564 A1 WO 2017170564A1 JP 2017012669 W JP2017012669 W JP 2017012669W WO 2017170564 A1 WO2017170564 A1 WO 2017170564A1
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cancer
compound according
optionally substituted
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笠井　均
良卓 小関
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国立大学法人東北大学
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • 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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
    • 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
    • A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/22—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains four or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J43/00—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton

Definitions

  • the present invention relates to a drug used for the treatment of cancer diseases, particularly a compound in which a water-soluble and hardly absorbable drug 10-hydroxy 7-ethylcamptothecin (SN-38) and a fat-soluble organic acid are bound,
  • the present invention relates to a nanoparticle, a method for producing a nanoparticulate preparation for treating cancer diseases by nanoparticulating the compound, and a nanoparticulate preparation for treating cancer diseases.
  • camptothecin An anticancer drug, camptothecin, and its specific derivatives are known. Many of camptothecin and its derivatives are extremely insoluble in water, which limits the clinical use of this drug. Water-soluble camptothecin derivatives include 9-dimethylaminomethyl-10-hydroxycamptothecin (Topotecan), 7-[(4-methylpiperazino) methyl] -10,11-ethylenedioxycamptothecin, 7-[(4- Methylpiperazino) methyl] -10,11-methylenedioxycamptothecin, and 7-ethyl-10- [4- (1-piperidino) -1-piperidino] carbonyloxycamptothecin (CPT-11). Among these, CPT-11 (Irinotecan / Camptosar, registered trademark) was approved for use in humans by the US Food and Drug Administration in June 1996.
  • Patent Document 1 it was found in Patent Document 1 by Miyasaka et al. In 1984 that the active body of CPT-11 is 10-hydroxy-7-ethylcamptothecin (SN-38).
  • SN-38 is not directly administered to human cancer patients because of its poor water solubility.
  • SN-38 is further metabolized to form inactivated glucuronide species.
  • NK012 which is a preparation obtained by polymerizing SN-38 into a polymer micelle, has been developed, there are various problems with micellized nanoparticles, and their practical application is questioned.
  • nanoparticles of poorly soluble drugs are produced by mechanically pulverizing coarse particles with a ball mill or the like.
  • a poorly soluble drug is often used as an aqueous suspension drug in which the drug is dispersed in water.
  • Aqueous suspension drugs have the property that nanoparticulate drug components dispersed in water stay in the body, and are therefore effective for exerting their effects locally or over a long period of time.
  • it is used as an oral preparation, an external preparation for skin, an external preparation for nasal cavity, an external preparation for ophthalmology and the like.
  • An aqueous suspension drug is usually produced by dispersing a drug pulverized into nanoparticles into water using a surfactant or the like.
  • the particle size of the drug obtained by pulverization is relatively large, and the variation in particle size is also large, so that a large particle component settles due to long-term storage and rapid changes in the environment such as temperature. There's a problem.
  • the quality of the aqueous suspension drug is likely to vary, and even if the drug is manufactured by the same manufacturing method, the retention time is too short to be effective. There is also a problem that side effects may occur due to the time being too long. Therefore, a method for obtaining drug nanoparticles having a small particle size and a narrow particle size distribution has been demanded.
  • Patent Document 2 discloses a conjugate-based antifungal or antibacterial prodrug formed by coupling an antifungal or antibacterial agent with at least one linker and / or carrier. Yes.
  • a fatty acid, a surfactant, a polymer, or the like is used as the carrier, there are problems such as safety and practical application.
  • Patent Document 3 discloses a cholesterol-modified cancer therapeutic compound, a bile acid-modified cancer therapeutic compound, a bile acid derivatized modified cancer therapeutic compound, an emulsion, a microemulsion, a micelle preparation containing these compounds, these And a method for administration of the compounds and preparations and a method for treating cancer using these compounds and preparations.
  • micellar nanoparticles have various problems and their practical application is questioned.
  • the present inventors have intensively studied the development of a new DDS having SN-38 as a medicinal ingredient.
  • the present inventors have surprisingly found that SN-38 ester derivatives in which a specific fat-soluble organic acid is introduced into the 10-position hydroxy group of SN-38 are effective for producing nanopharmaceuticals and have excellent cancer. It was found to show cell growth inhibitory activity.
  • the present inventor has completed the present invention based on this finding.
  • the present invention solves the above problems by providing the inventions described in [1] to [24] below.
  • X is a hydroxy group, an optionally substituted alkyl group, an optionally substituted alkoxy group or an optionally substituted acyloxy group, and a carbon atom between the 5-position and 6-position of the cholesterol skeleton— The compound according to [1], wherein the carbon bond is a double bond. [4] The compound according to [3], wherein X is a hydroxy group. [5] The compound according to [3], wherein X is an acyloxy group. [6] The compound according to [5], wherein the acyloxy group is an alkylcarbonyloxy group. [7] The alkylcarbonyloxy group is an acetyloxy group, [6] Compound described in 1.
  • [16] [14] or [15] which is obtained by injecting a solution in which the compound according to any one of [1] to [13] is dissolved in water into a water-miscible organic solvent.
  • the manufacturing method of the nanoparticle of description [17] [1] A pharmaceutical composition comprising the compound according to any one of [13]. [18] [14] A pharmaceutical composition comprising the nanoparticle according to [15]. [19] [1] A therapeutic agent for cancer diseases comprising the compound according to any one of [13]. [20] [14] or a therapeutic agent for cancer diseases comprising the nanoparticle according to [15]. [21] The therapeutic agent for cancer disease according to [19] or [20], wherein the cancer disease is a solid tumor.
  • the solid tumor is esophageal cancer, stomach cancer, colon cancer, colon cancer, rectal cancer, pancreatic cancer, liver cancer, laryngeal cancer, lung cancer, prostate cancer, bladder cancer, breast cancer, uterine cancer or ovarian cancer.
  • Therapeutic agent for cancer diseases [23] [1] The nanoparticulate preparation for cancer disease treatment according to any one of [13]. [24] [14] or an injection containing the nanoparticle according to [15].
  • alkyl group means a saturated aliphatic hydrocarbon group, for example, a linear or branched alkyl group having 1 to 20 carbon atoms, for example, a methyl group, an ethyl group, a propyl group, an isopropyl, unless otherwise specified.
  • alkoxy group refers to an (alkyl) -O— group having 1 to 20 carbon atoms in which the alkyl portion has the above-mentioned meaning, for example, methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group, sec -C 1 -C 6 alkoxy groups such as butoxy, isobutoxy, tert-butoxy, pentyloxy, isopentyloxy, hexyloxy, isohexyloxy, etc. It is not a thing.
  • acyloxy group examples include alkylcarbonyloxy group, alkoxycarbonyloxy group, carbamoyloxy group, alkylcarbamoyloxy group, alkylsulfinyloxy group, alkylsulfonyloxy group and the like.
  • Alkylcarbonyloxy group means an (alkyl) -C ( ⁇ O) —O— group having 1 to 20 carbon atoms in which the alkyl portion has the above-mentioned meaning, for example, an acetoxy group or a propionyloxy group A 1 to C 6 alkylcarbonyloxy group may be mentioned, but is not limited thereto.
  • Alkoxycarbonyloxy group refers to an (alkyl) -O—C ( ⁇ O) —O— group having 1 to 20 carbon atoms in which the alkoxy moiety has the above meaning, such as a methoxycarbonyloxy group, ethoxy carbonyloxy group, propoxycarbonyl group, C 1 ⁇ C 6 alkoxy such as butoxycarbonyl group - is carbonyl group) can be mentioned, but not limited thereto.
  • Alkylcarbamoyloxy group refers to an (alkyl) -NH—C ( ⁇ O) —O— group having 1 to 20 carbon atoms in which the alkyl moiety has the above meaning, for example, methylcarbamoyloxy group, ethyl A C 1 -C 6 alkylcarbamoyloxy group such as a carbamoyloxy group), but is not limited thereto.
  • Alkylsulfinyloxy group means an (alkyl) -SO—O— group having 1 to 20 carbon atoms in which the alkyl moiety has the above-mentioned meaning, for example, methylsulfinyloxy group, ethylsulfinyloxy group, propylsulfinyl group Examples thereof include, but are not limited to, C 1 -C 6 alkylsulfinyloxy groups such as oxy group and isopropylsulfinyloxy group.
  • Alkylsulfonyloxy group means an (alkyl) -SO 2 —O— group having 1 to 20 carbon atoms in which the alkyl moiety has the above-mentioned meaning, for example, methylsulfonyloxy group, ethylsulfonyloxy group, propyl Examples thereof include, but are not limited to, a C 1 -C 6 alkylsulfonyloxy group such as a sulfonyloxy group and an isopropylsulfonyloxy group.
  • the alkyl group which may be substituted, the alkoxy group which may be substituted or the acyloxy group which may be substituted may be substituted or unsubstituted.
  • the substituent may be substituted at any substitutable position, and preferably the substituent is a halogen, a hydroxy group, a cyano group, a nitro group, or the like.
  • the anti-cancer active ingredient SN-38 is chemically bonded with a fat-soluble organic acid (hydrophobic molecule) to improve the cell membrane affinity and permeability of the ingredient, and to efficiently form nanoparticles in the reprecipitation method. By urging, the function of the drug for treating cancer containing such a medicinal ingredient can be remarkably improved.
  • the fat-soluble organic acid any substance known to those skilled in the art can be used.
  • cholesterols such as cholesterol
  • various derivatives such as hydrogenated dihydrocholesterol (for example, colanic acid or cholenoic acid), hinokitiol Organic acid derivatives (for example, hinokitiol glutaric acid), esters or salts with various fatty acids, and hydrophobic amino acids and hydrophobic peptides.
  • a typical example of the fat-soluble organic acid is an organic acid represented by the formula (4) or the formula (5).
  • X is a hydrogen atom, a hydroxy group, an optionally substituted alkyl group, an optionally substituted alkoxy group or an optionally substituted acyloxy group, the 5-position of the cholesterol skeleton and The carbon-carbon bond between the 6 positions is a single bond or a double bond.
  • n represents an integer of 1 to 20, preferably an integer of 1 to 6, and more preferably 3.
  • a suitable representative example of the fat-soluble organic acid is a compound in which X is a hydrogen atom, and the carbon-carbon bond between the 5-position and the 6-position of the cholesterol skeleton is a single bond.
  • X is a hydroxy group, an optionally substituted alkyl group, an optionally substituted alkoxy group or an optionally substituted acyloxy group, and a cholesterol skeleton.
  • Examples of the carbon-carbon bond between the 5-position and 6-position of the compound include a double bond.
  • X is preferably a hydroxy group or an acyloxy group (eg, alkylcarbonyloxy), more preferably an acetyloxy group.
  • Examples of the fat-soluble organic acid include the following, but are not limited thereto.
  • photographed with the scanning electron microscope of the SN-38 hinokitiol derivative nanoparticle of this invention is shown.
  • photographed with the scanning electron microscope of the SN-38 colanic acid derivative nanoparticle of this invention is shown.
  • photographed with the scanning electron microscope of the surface modified SN-38 colanic acid derivative nanoparticle by the albumin of this invention is shown.
  • the result of the in-vitro anticancer activity test of SN-38 derivative nanoparticles of the present invention and irinotecan is shown.
  • the result of the in-vivo anticancer activity test of SN-38 colanic acid derivative nanoparticles surface-modified with albumin and irinotecan is shown.
  • Synthesis of compounds of formula (1), formula (2) and formula (3) of the present invention The compounds of formula (1), formula (2) and formula (3) of the present invention are prepared by methods known to those skilled in the art. Can be manufactured. For example, SN-38 ester is produced by dehydrating condensation of SN-38 or a derivative thereof and a fat-soluble organic acid such as colanic acid, cholenic acid, hinokitiol or a derivative thereof in the presence of a base and a solvent. Can do.
  • SN-38 ester is produced by dehydrating condensation of SN-38 or a derivative thereof and a fat-soluble organic acid such as colanic acid, cholenic acid, hinokitiol or a derivative thereof in the presence of a base and a solvent. Can do.
  • the aromatic tertiary amine is an aniline in which a fatty acid chain having 1 to 6 carbon atoms is substituted on the nitrogen atom (for example, N, N-dimethylaniline, N, N-diethylaniline, etc.)
  • nitrogen-containing heterocyclic compounds such as pyridines (specifically, pyridine, N, N-dimethylaminopyridine (DMAP), N, N-diethylaminopyridine, etc.), diazines (specifically, 1,2-diazine, 1,3-diazine, 1,4-diazine, etc.),
  • solvents for the preparation of SN-38 esters include suitable solvents such as methylene chloride, ethylene dichloride (EDC), tetrahydrofuran, ethyl acetate, dimethylformamide (DMF) or dimethoxyethane (DME). .
  • suitable solvents such as methylene chloride, ethylene dichloride (EDC), tetrahydrofuran, ethyl acetate, dimethylformamide (DMF) or dimethoxyethane (DME).
  • the reaction temperature for producing the SN-38 ester can be arbitrarily selected within the temperature range below the boiling point of the solvent, but a range of 0 to 60 ° C. can be exemplified as a preferable reaction temperature. More preferably, it is 20 to 30 ° C.
  • the reaction time of the reaction is not unambiguous because it is affected by the reaction conditions (for example, the type and amount of the compound and solvent used, reaction temperature, etc.), it is usually 1 to 24 hours.
  • the compound of formula (1) is first dissolved in an organic solvent which is a good solvent.
  • the organic solvent can be appropriately selected as long as it can dissolve the compound of the formula (1) and is miscible with water.
  • Specific examples of the organic solvent include, but are not limited to, acetone, tetrahydrofuran, dioxane, acetonitrile, methanol, ethanol, propanol, N-methylpyrrolidone, dimethyl sulfoxide, and the like. Or can be used in combination.
  • acetone, tetrahydrofuran, ethanol and dimethyl sulfoxide are particularly preferable from the viewpoints of solubility and safety.
  • the concentration of the compound of formula (1) of the present invention in the organic solvent is a large factor that affects the particle size of the produced nanoparticles, the concentration is appropriately changed according to the desired particle size.
  • the dissolution concentration is usually adjusted to about 0.1 to 15% by mass, but nanoparticles having an average particle size of 10 to 200 nm are used. Is prepared using a solution of around 0.5% by mass.
  • an organic solvent solution of a compound of formula (1) (hereinafter simply referred to as an organic solvent solution) is injected into water which is a poor solvent, nanoparticles of the compound of formula (1) in a state dispersed in water are generated.
  • an organic solvent solution of a compound of formula (1)
  • the solubility to the water of the compound of Formula (1) becomes lower than original SN-38.
  • the compound of formula (1) crystallizes more rapidly in water than the original SN-38, resulting in nanoparticles with smaller particle size and particle size distribution.
  • the amount of water into which the organic solvent solution is injected is usually 10 times or more based on the volume of the compound of the formula (1) of the present invention. There is no particular upper limit, but if there is too much water, the concentration of the nanoparticles of the compound of formula (1) will become thin and it will be necessary to concentrate, so it is usually 100 times or less.
  • the particle size of the produced nanoparticles also changes, so the formula obtained by keeping the water constant at a specific temperature during the injection of the organic solvent solution
  • the particle size of the nanoparticles of the compound (1) can be controlled. For example, when water at a low temperature is used, the particle size of the nanoparticles of the compound of formula (1) tends to increase. Usually, the temperature is controlled in the range of ⁇ 20 ° C. to 60 ° C. according to the desired particle size.
  • the injection of the organic solvent solution is performed in a short time in agitated water in order to prevent variation in particle size.
  • an aqueous dispersion in which the crystallized or nanoparticulated compound of formula (1) is uniformly dispersed in water can be obtained.
  • the obtained nanoparticles of the compound of the formula (1) can be used as an aqueous suspension medicine while being dispersed in water, and can be obtained as a fine particle powder by performing a solid-liquid separation operation such as filtration. It can also be separated.
  • an organic solvent added as a good solvent improves the safety of the drug.
  • Removed There is no restriction
  • nanoparticles of the compound of formula (1) having a very small particle size and a narrow particle size distribution can be obtained, such as the temperature of water, the type of good solvent, the amount added, etc. It is possible to produce nanoparticles of the compound of the formula (1) having a large particle size while maintaining a narrow particle size distribution by controlling the average particle size by changing the production conditions. Nanoparticles of the compound of formula (1) having a diameter of about 10 nm to 200 nm can be produced.
  • the compound of the formula (1) is hydrolyzed in the living body to the original form of the drug SN-38 by the change of pH when passing through the living body and the action of an enzyme such as esterase. Therefore, since it functions as SN-38 itself in a living body, it is possible to ensure the drug efficacy and safety of the nanoparticles of the compound of formula (1) of the present invention.
  • the manufacturing method of the nanoparticle of the compound of Formula (2) and Formula (3) of this invention is based on said manufacturing method of the compound nanoparticle of Formula (1) of this invention.
  • the size of the nanoparticles needs to be 10 nm or more in order to suppress renal excretion.
  • the average particle size of the nanoparticles of the present invention is preferably 10 to 200 nm, and more preferably 10 to 100 nm.
  • the present invention relates to various therapeutic pharmaceutical compositions containing the above-mentioned nanoparticulate preparation for cancer treatment.
  • Such pharmaceutical compositions include any pharmaceutical formulation known to those skilled in the art, depending on various conditions such as the subject of administration, administration route, application, form, and type and amount of the drug included.
  • Various other buffers, adjuvants, additives, and the like that are allowed can be appropriately contained.
  • the tumor to be treated with the nanoparticulate preparation for cancer disease treatment of the present invention is not particularly limited but is a solid tumor, specifically, esophageal cancer, stomach cancer, colon cancer, colon cancer, rectal cancer, pancreatic cancer. Liver cancer, laryngeal cancer, lung cancer, prostate cancer, bladder cancer, breast cancer, uterine cancer or ovarian cancer.
  • Target sites include tumor cells, tissues, organs or organs and their interiors.
  • the nanoparticulate preparation for cancer disease treatment of the present invention is prepared, for example, in a parenteral, oral, transdermal, nasal or pulmonary administration form.
  • compositions of the invention containing pharmaceutically acceptable excipients can be prepared by any of the well-known dispensing techniques including mixing excipients with drugs or therapeutic agents.
  • parenteral for example, it can be formulated as a sterile aqueous solution for injection administration.
  • the pharmaceutical composition according to the present invention comprises, for example, neoplasms derived from epithelial cells (epithelial carcinoma) such as brain cancer, bone cancer, basal cell carcinoma, adenocarcinoma, esophageal cancer, small intestine cancer and gastric cancer, colon cancer, liver cancer, bladder Benign or malignant including cancers such as cancer, pancreatic cancer, ovarian cancer, cervical cancer, lung cancer, breast cancer, skin cancer, prostate cancer, renal carcinoma and other known cancers that affect epithelial cells throughout the body Useful for prevention, amelioration and / or treatment of tumor / neoplasm.
  • Cancers for which the compositions of the invention are considered particularly useful are gastrointestinal cancers, particularly colorectal cancer, lung cancer, especially small cell lung cancer, cervical cancer and pancreatic cancer.
  • composition according to the present invention is administered to obtain a therapeutic effect
  • the individual dose at which the composition according to the present invention is administered to obtain a therapeutic effect will of course depend on the individual administration environment including, for example, age, weight, patient status, route of administration and the like.
  • Individual dosing schedules can be tailored to a particular subject based on their individual needs and the professional judgment of the person who supervises the administration of the composition.
  • the daily dose of the composition of the present invention is generally 1 to 1000 mg / m 2 body surface area, preferably 10 to 500 mg / m 2 body for parenteral administration, specifically bolus or intravenous administration by infusion. Surface area.
  • the dose may be administered at one time, or may be divided into several portions at various time intervals.
  • a specific example of a suitable schedule for parenteral administration is 6 weeks of administering 125 mg / m 2 body surface area over 90 minutes by intravenous infusion on the first day of each week from week 1 to week 4. Dosing schedule. In another treatment regimen, parenteral administration of 350 mg / m 2 body surface area is given intravenously over 90 minutes every 3 weeks.
  • SN-38 glutarate 50 mg, 0.0987 mmol
  • hinokitiol 16.2 mg, 0.0987 mmol
  • EDC 37.8 mg, 0.197 mmol
  • DMAP 1.2 mg, 0.00987 mmol
  • Saturated aqueous ammonium chloride solution was added to the reaction solution to stop the reaction, and the mixture was transferred to a separatory funnel. After extraction with chloroform, the chloroform layer was washed with water and a saturated aqueous sodium chloride solution.
  • the chloroform layer was dehydrated with anhydrous magnesium sulfate, filtered with absorbent cotton, and then the solvent was distilled off under reduced pressure. And it refine
  • purified by the silica gel column chromatography which made the developing solvent chloroform / methanol 100/1-30/1. The color of the purified crystals was pale yellow, and SN-38 hinokitiol derivative (56.3 mg, 0.0863 mmol) was obtained in a yield of 87%.
  • SN-38 (80.6 mg, 0.205 mmol) and colanic acid (77.4 ng, 0.215 mmol) were added to a two-necked eggplant-shaped flask and dissolved in 10 ml of dehydrated CH 2 Cl 2 .
  • EDC 84.9 mg, 0.443 mmol
  • DMAP 5.5 mg, 0.0450 mmol
  • the reaction solution was transferred to a separatory funnel, chloroform was added, and the mixture was washed with a saturated aqueous ammonium chloride solution, water, and an aqueous sodium chloride solution.
  • the chloroform layer was dehydrated with anhydrous magnesium sulfate, filtered with absorbent cotton, and then the solvent was distilled off under reduced pressure. And it refine
  • purified by the silica gel column chromatography which made the developing solvent chloroform / methanol 100/1. The color of the purified crystals was pale yellow, and SN-38 colanic acid derivative (149 mg, 0.203 mmol) was obtained in a yield of 99%.
  • TBS-cholenic acid was synthesized based on the description in known literature (T. A. Spencer at al., Journal of Medicinal Chemistry 2001, 44, 886-897.).
  • SN-38 50 mg, 0.127 mmol
  • TBS-cholenic acid 62.3 mg, 0.127 mmol
  • EDC 48.7 mg, 0.254 mmol
  • DMAP 1.6 mg, 0.0127 mmol
  • Saturated aqueous ammonium chloride solution was added to the reaction solution to stop the reaction, and the mixture was transferred to a separatory funnel. After extraction with chloroform, the chloroform layer was washed with water and a saturated aqueous sodium chloride solution.
  • the chloroform layer was dehydrated with anhydrous magnesium sulfate, filtered with absorbent cotton, and then the solvent was distilled off under reduced pressure. And it refine
  • purified by the silica gel column chromatography which made the developing solvent chloroform / methanol 100/1. The color of the purified crystals was pale yellow, and SN-38 cholate TBS protector (38.4 mg, 0.0445 mmol) was obtained in a yield of 35%.
  • the chloroform layer was dehydrated with anhydrous magnesium sulfate, filtered with absorbent cotton, and then the solvent was distilled off under reduced pressure. And it refine
  • purified by the silica gel column chromatography which made the developing solvent chloroform / methanol 100/1. The color of the purified crystals was pale yellow, and SN-38 cholate derivative (27.0 mg, 0.0360 mmol) was obtained in a yield of 81%.
  • Acetylcholenic acid was synthesized based on the description in known literature (Y.YShen at al., Journal of Fluorine Chemistry 2002, 113, 13-15.).
  • SN-38 (84.7 mg, 0.216 mmol) and acetylcholenoic acid (108 mg, 0.259 mmol) were added to the eggplant-shaped flask, and dehydrated CH 2 Cl 2 was dissolved in 2.2 ml.
  • EDC 82.8 mg, 0.254 mmol
  • DMAP 2.6 mg, 0.0216 mmol
  • Saturated aqueous ammonium chloride solution was added to this solution to stop the reaction, and the solution was transferred to a separatory funnel. After extraction with chloroform, the chloroform layer was washed with water and a saturated aqueous sodium chloride solution.
  • the chloroform layer was dehydrated with anhydrous magnesium sulfate, filtered with absorbent cotton, and then the solvent was distilled off under reduced pressure. And it refine
  • purified by the silica gel column chromatography which made the developing solvent chloroform / methanol 100/1. The color of the purified crystals was light yellow, and SN-38 acetylcholenic acid derivative (136 mg, 0.0445 mmol) was obtained in a yield of 80%.
  • Method for producing nanoparticles 100 ⁇ L of a SN-38 derivative THF solution prepared to 10 mM was injected into 10 ml of water at room temperature using a syringe to obtain an aqueous dispersion of SN-38 derivative nanoparticles.
  • a dialysis membrane fractionated molecular weight: 12,000-14,000
  • an aqueous dispersion of nanoparticles (10 mL) is placed in a beaker containing 100 mL of distilled water and distilled twice every 5 hours.
  • the water in the nanoparticle dispersion was removed by exchanging water.
  • the final concentration became 0.1 mM by adjusting the volume of the nanoparticle dispersion in the dialysis membrane to 10 mL.
  • the particle size was as follows. SN-38 hinokitiol derivative 200 nm SN-38 colanic acid derivative 50 nm SN-38 cholenoic acid derivative 50 nm SN-38 acetylcholenic acid derivative 50 nm
  • Human hepatoma cell line HepG2 was seeded in a 96-well plate at 2 ⁇ 10 4 cells / well.
  • the irinotecan and SN-38 derivative nanoparticle dispersion was added to the HepG2 cell culture so as to be 0.01 to 10 ⁇ M.
  • the cells were cultured for 48 hours, and cell viability was measured by a colorimetric method using Cell Counting Kit-8 (manufactured by DOJINDO) and a microplate reader (manufactured by BIO-RAD).
  • DOJINDO Cell Counting Kit-8
  • BIO-RAD microplate reader
  • the SN-38 colanic acid derivative nanoparticle dispersion and the irinotecan solution were prepared in physiological saline so that the amounts of SN-38 were 10 mg and 1 mg, respectively, with respect to 1 kg of mouse body weight.
  • Administration was performed 5 times at a frequency of once every two days, and the change in tumor volume over time was evaluated.
  • the SN-38 colanic acid derivative nanoparticle dispersion (1 mg / kg) showed the same level of activity as compared with the case where 10 times the amount of irinotecan solution (10 mg / kg) was administered. It was.
  • Nanoparticles of the invention according to the present application show remarkable anticancer activity, and unlike micelles containing surfactant as a constituent requirement, they do not make surfactant a constituent requirement, so practical use and safety are expected. .

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  • Engineering & Computer Science (AREA)
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Abstract

L'objet de la présente invention est de fournir un nouveau mode d'administration ayant SN-38 en tant que composant médicinal. L'invention concerne un excellent dérivé d'ester SN-38 ayant une activité inhibitrice de la prolifération des cellules cancéreuses qui est efficace dans la production de nanomédicaments.
PCT/JP2017/012669 2016-03-28 2017-03-28 Formulation nanoparticulaire pour le traitement de maladies cancéreuses WO2017170564A1 (fr)

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CN116178474A (zh) * 2023-03-02 2023-05-30 湖南省中医药研究院 一种喜树碱修饰的胆固醇及其制备方法和应用

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