EP3806831A2 - Nanoparticules lipidiques chargées de ceranib -2, utilisées en tant qu'agents anticancéreux - Google Patents

Nanoparticules lipidiques chargées de ceranib -2, utilisées en tant qu'agents anticancéreux

Info

Publication number
EP3806831A2
EP3806831A2 EP19812871.2A EP19812871A EP3806831A2 EP 3806831 A2 EP3806831 A2 EP 3806831A2 EP 19812871 A EP19812871 A EP 19812871A EP 3806831 A2 EP3806831 A2 EP 3806831A2
Authority
EP
European Patent Office
Prior art keywords
lipid nanoparticles
lipid
ceranib
cancer
use according
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
EP19812871.2A
Other languages
German (de)
English (en)
Inventor
Mehtap KUTLU
Gökhan KUS
Engin ULUKAYA
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Anadolu Universitesi
Original Assignee
Anadolu Universitesi
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 Anadolu Universitesi filed Critical Anadolu Universitesi
Publication of EP3806831A2 publication Critical patent/EP3806831A2/fr
Pending legal-status Critical Current

Links

Classifications

    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
    • A61K9/5107—Excipients; Inactive ingredients
    • A61K9/5123—Organic compounds, e.g. fats, sugars
    • 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
    • A61K31/4704—2-Quinolinones, e.g. carbostyril
    • 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 ceranib-2 formulations for use in treatment of cancer. More particularly, the present invention pertains to lipid nanoparticles comprising ceranib-2 as a medicament for treatment of cancer, such as breast cancer, lung cancer and colon cancer.
  • Acid ceramidase is an enzyme and bioactive lipid which is responsible for the degradation of ceramide into sphingosine and free fatly acids within lysosomes. It mediates cell proliferation differentiation, apoptosis, adhesion and migration.
  • Acid ceramidase inhibitors in general, are proposed for treatment of various diseases including neurodegenarative diseases, endometriosis, Parkinson's disease, obesity, diabetes and cancer. Recently, anticancer activity of the acid ceramidase inhibitors has attracted particular attention of the researchers.
  • WO 03/005965 A2 discloses inhibitors of mitochondrial ceramidase for the prevention and treatment of diseases associated with cell overproliferation and sphingolipid signal transduction including cancer, cardiovascular diseases, and inflammation.
  • WO 2013/178576 A1 discloses different acid ceramidase inhibitors for treatment of cancer.
  • Ceranib-2 is an acid ceramidase inhibitor known with the chemical name of 3-[3-(4-methoxyphenyl)-l-oxo-2-propen-l-yl]-4-phenyl-2(lH)-quinolinone having the general Formula (!]:
  • Chemoterapeutic agents particularly have considerable damages to healthy cells and tissues of cancer patients.
  • Ceranib-2 having the general formula above is noted to be effective for inhibiting proliferation of cancer cells in the course of ceramide dependent apoptosis. Therefore, Ceranib-2 has been advantageously selected as an anticancer agent, and it is basically aimed to improve its bioavailibility at lower doses. This objective is currently achieved by providing lipid nanoparticles of Ceranib-2 for use in treatment of cancer.
  • the present invention provides ceranib-2 containing lipid nanoparticles for use in treatment of cancer.
  • the inventors discovered that ceranib-2 as formulated with lipid nanoparticles are advantageous in several aspects.
  • lipid nanoparticles as mentioned above enhance the penetration through the membrane of cancer cells and therefore bioavailability of the drug increases to the satisfactory level. This in turn provides the advantage that lower doses of ceranib-2, being less toxic, can be used for obtaining the desired anticancer activity.
  • ceranib-2 being less toxic
  • the molecule entrapped in lipid nanoparticles would be more stable and safe because of the lipid coating which is biodegradable.
  • the lipid material as used in the current invention can be selected from the group consisting of triglycerides, fatty acids, waxes and steroids.
  • the lipid as mentioned herein comprises a mixture of triglycerides and fatly acids. More particularly, the lipid material comprises Compritol 888 ATO which is a blend of esters of behenic acid with glycerol.
  • the lipid nanoparticles comprising ceranib-2 according to the present invention can be prepared by a suitable homogenization method that may provide a lipid coating on Ceranib-2 particles.
  • the lipid nanoparticles according to the present invention can be prepared by way of a homogenization method such as high shear homogenization, hot homogenization and cold homogenization.
  • Ceranib-2 is noted to be less lipophilic such that it forms colloids in lipid with inferior homogeneity. Therefore, the inventors have noted that a specific hot homogenization method would be preferable in order to obtain the desired homogeneity.
  • the present invention provides a method for preparing lipid nanoparticles as identified above comprising the steps of; preparing a pre-emulsion by melting a lipid material, adding an emulsifier and dispersing Ceranib-2 therein,
  • homogenization is carried out in a high pressure homogenizer.
  • the temperature of the homogenization can be set at 5-10 °C above the melting point of the lipid material.
  • the particle size of the lipid nanoparticles according to the present invention may typically range from 10 to 1000 nm.
  • the particle size can be arranged by modifying certain parameters such as temperature, pressure and rotation speed and duration of the homogenizer, and also the particular type of the emulsifying agent.
  • Human A549 lung adenocarcinoma cells were inoculated on a 96-well cell culture plate such that 5x10 3 cells were provided in each well. The cells inoculated to the plate were incubated at 37°C in a 5% carbon dioxide media. A549 cells were incubated with ceranib-2 lipid nanoparticles for 24 hours with ceranib-2 concentrations of 1-65 mM. At the end of the procedure 20 pL of MTT dye (5 mg/mL] was added into each well and further incubated at 37°C for 2 hours. After the incubation, the liquid phase in each well was discharged and 200 pL of DMSO was added in order to dissolve the formazan salts produced by the cells followed by leaving the media for 10 minutes.
  • MTT dye 5 mg/mL
  • ceranib-2 lipid nanoparticles were effective for inhibiting of cell proliferation of both groups. Cytotoxicity tests have revealed that inhibition of cell proliferation was observed starting from the lowermost dose of ceranib-2. This was more prominent on MCF-7 cells.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Engineering & Computer Science (AREA)
  • Epidemiology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Physics & Mathematics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Biomedical Technology (AREA)
  • Nanotechnology (AREA)
  • Optics & Photonics (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

La présente invention concerne des formulations de ceranib-2 destinées à être utilisées dans le traitement du cancer. Plus particulièrement, la présente invention concerne des nanoparticules lipidiques comprenant de la ceranib-2 en tant que médicament pour le traitement du cancer, tel que le cancer du sein, le cancer du poumon et le cancer du côlon.
EP19812871.2A 2018-06-18 2019-05-16 Nanoparticules lipidiques chargées de ceranib -2, utilisées en tant qu'agents anticancéreux Pending EP3806831A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
TR201808578 2018-06-18
PCT/TR2019/050338 WO2020018049A2 (fr) 2018-06-18 2019-05-16 Nanoparticules lipidiques chargées de ceranib -2, utilisées en tant qu'agents anticancéreux

Publications (1)

Publication Number Publication Date
EP3806831A2 true EP3806831A2 (fr) 2021-04-21

Family

ID=68732033

Family Applications (1)

Application Number Title Priority Date Filing Date
EP19812871.2A Pending EP3806831A2 (fr) 2018-06-18 2019-05-16 Nanoparticules lipidiques chargées de ceranib -2, utilisées en tant qu'agents anticancéreux

Country Status (2)

Country Link
EP (1) EP3806831A2 (fr)
WO (1) WO2020018049A2 (fr)

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050043534A1 (en) 2001-07-11 2005-02-24 Alicja Bielawska Modulators of ceramidase and methods of used based thereon
ITMI20120921A1 (it) 2012-05-28 2013-11-29 Fond Istituto Italiano Di Tec Nologia 45 Inibitori della ceramidasi acida e loro usi come medicamenti
EP3313387A4 (fr) * 2015-06-25 2019-02-20 Lysosomal Therapeutics Inc. Méthodes et compositions pour le traitement de troubles neurodégénératifs
TR201702500A2 (tr) * 2017-02-20 2017-07-21 Anadolu Ueniversitesi Serani̇b-2?ni̇n akci̇ğer kanseri̇ ve meme kanseri̇ni̇n tedavi̇si̇nde kullanimi

Also Published As

Publication number Publication date
WO2020018049A3 (fr) 2020-02-27
WO2020018049A2 (fr) 2020-01-23

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