WO2020018049A2 - Lipid nanoparticles loaded with ceranib-2 as anticancer agents - Google Patents
Lipid nanoparticles loaded with ceranib-2 as anticancer agents Download PDFInfo
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- WO2020018049A2 WO2020018049A2 PCT/TR2019/050338 TR2019050338W WO2020018049A2 WO 2020018049 A2 WO2020018049 A2 WO 2020018049A2 TR 2019050338 W TR2019050338 W TR 2019050338W WO 2020018049 A2 WO2020018049 A2 WO 2020018049A2
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- lipid nanoparticles
- lipid
- ceranib
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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
- A61K9/48—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
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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
- A61K31/33—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
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- 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.
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- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
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- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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- Biomedical Technology (AREA)
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Abstract
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.
Description
LIPID NANOPARTICLES LOADED WITH CERANIB-2 AS ANTICANCER AGENTS
Technical Field
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.
Background of the Invention
Acid ceramidase is an enzyme and bioactive lipid which is responsable 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, for instance, 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. Likewise, WO 2013/178576 A1 discloses different acid ceramidase inhibitors for treatment of cancer.
The inventors, however, noted that there is still a need in prior art for acid ceramidase inhibitors formulated in a specific media that provide easy penetration through the cell membrane and increase bioavailibility, which in turn, require less amount of medicament for the achievement of the desired effect in treatment of cancer.
For this purpose, the present invention provides ceranib-2 molecules incorporated into lipid nanoparticles 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 (!]:
Formula (I)
Conventional anticancer agents generally act systemically and cause cell death besides tumours. 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.
Detailed Description of the Invention In one aspect, 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.
It is noted that 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. Those skilled in the art would appreciate that 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. In one embodiment, 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.
Accordingly, in another aspect, 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 of the pre-emulsion at a temperature above the melting point of the lipid material,
recrystallizing the nanoemulsion and obtaining the lipid nanoparticles loaded with Ceranib-2.
In preferred embodiments, 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.
Example 1
Human A549 lung adenocarcinoma cells were inoculated on a 96-well cell culture plate such that 5x103 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. The color change was evaluated in HTX Synergy (Bio-Tek, USA] plate reader at a wavelength of 570 nm. The experiment was repeated three times. Viability values for each dose were calculated based on the control group from the absorbances obtained from MTT results and given as percentages.
Example 2
The same protocol of the experiment was repeated by using MCF-7 and colon cancer cell lines. Results
It was observed that 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.
Claims
1. Lipid nanoparticles loaded with therapeutically effective amount of ceranib-2 for use in treatment of cancer.
2. Lipid nanoparticles for use according to claim 1 wherein the lipid material is selected from the group consisting of triglycerides, fatty acids, waxes and steroids.
3. Lipid nanoparticles for use according to claim 2 wherein the lipid material comprises Compritol 888 ATO which is a blend of esters of behenic acid with glycerol.
4. Lipid nanoparticles for use according to claim 1 wherein the particle size of the nanoparticles ranges from 10 to 1000 nm.
5. Lipid nanoparticles for use according to claim 1 wherein the cancer is breast cancer, lung cancer or colon cancer.
6. Lipid nanoparticles for use according to claim 1 wherein the cancer is breast cancer.
7. Lipid nanoparticles for use according to claim 1 wherein the lipid nanoparticles are produced with a method comprising the steps of: preparing a pre-emulsion by melting a lipid material, adding an emulsifier and dispersing Ceranib-2 therein,
homogenization of the pre-emulsion at a temperature above the melting point of the lipid material,
recrystallizing the nanoemulsion and obtaining the lipid nanoparticles loaded with Ceranib-2.
8. Lipid nanoparticles for use according to claim 7 wherein the homogenization is carried out in a high pressure homogenizer.
9. Lipid nanoparticles for use according to claim 7 wherein the temperature of the homogenization is set at 5-10°C above the melting point of the lipid material.
10. Lipid nanoparticles for use according to claim 7 wherein the emulsifier is Tween 80.
11. A pharmaceutical composition comprising lipid nanoparticles loaded with therapeutically effective amount of ceranib-2 for use in treatment of cancer.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP19812871.2A EP3806831A2 (en) | 2018-06-18 | 2019-05-16 | Lipid nanoparticles loaded with ceranib-2 as anticancer agents |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| TR201808578 | 2018-06-18 | ||
| TR2018/08578 | 2018-06-18 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| WO2020018049A2 true WO2020018049A2 (en) | 2020-01-23 |
| WO2020018049A3 WO2020018049A3 (en) | 2020-02-27 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/TR2019/050338 WO2020018049A2 (en) | 2018-06-18 | 2019-05-16 | Lipid nanoparticles loaded with ceranib-2 as anticancer agents |
Country Status (2)
| Country | Link |
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| EP (1) | EP3806831A2 (en) |
| WO (1) | WO2020018049A2 (en) |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2003005965A2 (en) | 2001-07-11 | 2003-01-23 | Musc Foundation For Research Development | Modulators of ceramidase and methods of use based thereon |
| WO2013178576A1 (en) | 2012-05-28 | 2013-12-05 | Fondazione Istituto Italiano Di Tecnologia | Acid ceramidase inhibitors and their use as medicaments |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20180369211A1 (en) * | 2015-06-25 | 2018-12-27 | Lysosomal Therapeutics Inc. | Methods and compositions for treating neurodegenerative disorders |
| TR201702500A2 (en) * | 2017-02-20 | 2017-07-21 | Anadolu Ueniversitesi | THE USE OF SERANIB-2 IN THE TREATMENT OF LUNG CANCER AND BREAST CANCER |
-
2019
- 2019-05-16 WO PCT/TR2019/050338 patent/WO2020018049A2/en unknown
- 2019-05-16 EP EP19812871.2A patent/EP3806831A2/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2003005965A2 (en) | 2001-07-11 | 2003-01-23 | Musc Foundation For Research Development | Modulators of ceramidase and methods of use based thereon |
| WO2013178576A1 (en) | 2012-05-28 | 2013-12-05 | Fondazione Istituto Italiano Di Tecnologia | Acid ceramidase inhibitors and their use as medicaments |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2020018049A3 (en) | 2020-02-27 |
| EP3806831A2 (en) | 2021-04-21 |
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