WO2020214125A1 - Émulsion lipidique solide comprenant de la curcumine et de la pipérine et son utilisation - Google Patents

Émulsion lipidique solide comprenant de la curcumine et de la pipérine et son utilisation Download PDF

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Publication number
WO2020214125A1
WO2020214125A1 PCT/TR2020/050322 TR2020050322W WO2020214125A1 WO 2020214125 A1 WO2020214125 A1 WO 2020214125A1 TR 2020050322 W TR2020050322 W TR 2020050322W WO 2020214125 A1 WO2020214125 A1 WO 2020214125A1
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WO
WIPO (PCT)
Prior art keywords
cancer
cholesterol
curcumin
emulsome
triglyceride
Prior art date
Application number
PCT/TR2020/050322
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English (en)
Inventor
Fikrettin Sahin
Zeynep İŞLEK
Bilun DEMIR
Zeynep BOLAT
Elif Nur YILMAZ
Mehmet Hikmet ÜÇIŞIK
Original Assignee
Istanbul Medipol Universitesi
Yeditepe 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 Istanbul Medipol Universitesi, Yeditepe Universitesi filed Critical Istanbul Medipol Universitesi
Publication of WO2020214125A1 publication Critical patent/WO2020214125A1/fr

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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
    • A61K9/10—Dispersions; Emulsions
    • A61K9/127—Liposomes
    • 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
    • A61K31/12—Ketones
    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4525—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with oxygen as a ring hetero atom
    • 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

Definitions

  • the present invention is related to solid lipid emulsion formulations (emulsomes) and their usage for treatment of neoplastic diseases.
  • Curcumin constitutes the main material of the turmeric plant and pipeline constitutes the main material of black pepper.
  • Various therapeutic effects of these two natural active compounds have been known ever since ancient civilizations. Their usage has been examined particularly in the recent years in modern medicine applications and found effective against certain disease models such as various types of cancer and Alzheimer’s disease.
  • curcumin major compound of turmeric extract
  • curcumin cannot be used in therapeutic applications, as it is not sufficiently soluble and instable in water (it rapidly decomposes into subcomponents). Curcumin has low body absorption and even if used in high doses (for example 8-10mg per day) curcumin remains in the blood much lower concentrations than required for providing therapeutic effects. Due to this situation curcumin cannot be delivered to the unhealthy tissue in sufficient amounts.
  • curcumin and pipeline have been previously tested for their synergic effects.
  • certain problems have arisen such as low drug loading content, undesired toxicity and side effects (due to the organic solvent and surfactants used in the preparation of the formulation), low stability rate, inadequate cellular ingestion, rapid drug release problem and high economic costs.
  • the invention owners aim to overcome these problems present in the prior art and introduce a curcumin-piperine formulation that is an alternative to the present formulations.
  • the invention is related to emulsomes that are composed of phospholipid layers surrounding a triglyceride solid core inside which curcumin and piperine are distributed and serve to the usage of said emulsomes for treating neoplastic diseases.
  • the present invention is related to pharmaceutical formulations comprising curcumin and piperine, characterized in that it is in the form of an emulsome formed of; a core derived of trygliceride layers of phospholipid having cholesterol or ester derivatives both in the core and the outer layer.
  • curcumin and piperine formulations that have been formulated inside emulsomes having the above mentioned characteristics were advantageous in that (i) they did not have a toxic effect as they did not contain organic solvents or surfactants; (ii) they allowed high amounts of curcumin and piperine to be loaded into the structure; (iii) they provided prolonged effect of curcumin and piperine by increasing the release time due to their specific solid phase character; and (iv) they allowed the preparation of curcumin and piperine formulations whose release or absorption properties have been modified and that are targeted by the bonding of various molecules such as protein, polymer and various targeting ligands, etc., as the phospholipids that form the outer surface of the emulsomes are structures that can be modified.
  • the triglyceride derivatives that form the core of the emulsome formulations that comprise curcumin and pipeline suitable to the invention are selected from the group of fat that is solid at 25 °C temperature or is in liquid crystal form, natural, double digit, unbranched triglycerides such as tricaprin, trilaurin, trimyristin, tripalmitin and tristearin, mono unsaturated fatty acids, and partially hydrogenated vegetable oils.
  • tripalmitin or in other words triglyceride palmitate is used as the triglyceride derived material that forms the core of the emulsome formulations that comprise curcumin and piperine.
  • the phospholipids that form the outer surface of the emulsome formulations comprising curcumin and piperine can be selected from the group formed of phospholipids that form the outer surface of said formulations, natural phospholipids such as soy lecithin, egg lecithin, phosphatidyl glycerol, phosphatidylinositol, phosphatidylethanolamine, phosphatidic acid, sphingomyelin, diphosphatidyl glycerol, phosphatidyl serine, phosphatidylcholine, cardiolipin or synthetic phospholipids such as dimyristoyl phosphatidyl glycerol, dimyristoyl phosphatidylcholine, 1,2-dipalmitoyl-rac- glycero-3 -phosphatidylcholine (DPPC) or lecithin's and phospholipid that are hydrogenated or partially hydrogenated.
  • 1,2-phospholipids such as soy lecithin,
  • the cholesterol available in the core and the outer layer of the emulsome formulations that comprise curcumin and piperine is selected from the group of cholesterol, palmitoyl cholesterol, and oleoyl cholesterol.
  • the percentage by weight of the triglyceride, phospholipid and cholesterol derivatives that form the emulsome structure (triglyceride:phospholipid:cholesterol) in an embodiment of the invention is between 17: 1 : 1 and 21 :3 : 1, preferably between 18: 1.5: 1 and 20:2: 1.
  • the present invention is related to pharmaceutical formulations in emulsome form, comprising curcumin and piperine, characterized in that it is formed of;
  • DPPC l,2-dipalmitoyl-rac-glycero-3 -phosphatidylcholine
  • the percentage by weight of the triglyceride palmitate, l,2-dipalmitoyl-rac-glycero-3- phosphatidylcholine (DPPC) and cholesterol that form the emulsome structure (triglyceride palmitate:DPPC:cholesterol) in an embodiment of the invention is between 17: 1 : 1 and 21 :3: 1, preferably between 18: 1.5: 1 and 20:2: 1.
  • the present invention is particularly related to pharmaceutical formulations in emulsome form, comprising curcumin and piperine, characterized in that it is formed of; a core derived of trygliceride palmitate an outer layer formed of l,2-dipalmitoyl-rac-glycero-3 -phosphatidylcholine (DPPC) having cholesterol both in the core and the outer layer wherein the triglyceride palmitate:DPPC:cholesterol ratio is between 17: 1 : 1 and 21 :3: 1, preferably 18: 1.5: 1 and 20:2: 1.
  • DPPC l,2-dipalmitoyl-rac-glycero-3 -phosphatidylcholine
  • An embodiment of the invention is related to a method for preparing emulsomes that comprise curcumin and piperine suitable to the invention, wherein said method comprises; - dissolving of triglyceride, phospholipid and cholesterol derivatives in an organic solvent, preferably in chloroform dissolving of curcumin and piperine in an organic solvent, preferably in chloroform
  • the emulsome formulation comprising curcumin and piperine obtained according to a preferred embodiment of the invention, is subjected to a sonication bath, filtering (extrusion) or homogenization process in order to ensure that the particle size distribution of the emulsomes that form the formulation are homogenous.
  • the organic solvent, preferably chloroform used in said method can be removed at room temperature or at a temperature between 40-60°C.
  • the invention is related to using emulsome formulations comprising curcumin and piperine as a medicine for treating neoplastic diseases.
  • neoplastic diseases used within the scope of the invention related to a physiological condition, for example cancer, which is characterized with malign tumors or uncontrolled cell growth.
  • neoplastic disease and “cancer” can be used interchangeably with each other. Cancer examples although not limited with these, comprise carcinomas, lymphomas, blastoma sarcomas and leukemia.
  • Carcinoma as used herein expresses a type of cancer formed of epithelium cells.
  • Lymphoma as used herein describes a cancer type developed from lymphocytes.
  • Blastoma as used herein describes a cancer type progressing from precursor cells also known as blast cells.
  • Sarcoma refers to the type of cancer resulting from altered cells of mesenchymal origin.
  • Leukemia as used herein, expresses the type of cancer that is induced in the bone marrow and causes the formation of high number of abnormal white blood cells.
  • cancer types comprises breast cancer, prostate cancer, colorectal cancer, skin cancer, small cell lung cancer, non-small cell lung cancer, mesothelioma, gastrointestinal cancer, pancreatic cancer, glioblastoma, vulva cancer, cervical cancer, endometrial carcinoma, ovarian cancer, liver cancer, hepatoma , bladder cancer, kidney cancer, salivary gland carcinoma, thyroid cancer and various head and neck cancers.
  • Example 1 Preparation of emulsomes comprising curcumin and piperine
  • Table 1 Components that form the emulsome and amounts thereof
  • Tripalmitin, DPPC and cholesterol amounts given in Table 1, are dissolved in chloroform.
  • curcumin and piperine are also dissolved in chloroform. The obtained two mixtures are combined and the chloroform that is used as the solvent is removed under low pressure at 60 °C.
  • Cell viability is determined by means of an MTS cell viability technique following the processing of HCT116 cells with emulsomes that are loaded with curcumin and piperine. In an analysis carried out using 96 well plates, 10 thousand cells have been cultured per well for the HCT116 cell line. After the settling of the cells were observed, they were treated separately with emulsome loaded with 2,8 mM piperine and emulsome loaded with 25 pM curcumin. Cells that were not treated have been used as negative control. Following 24, 48, and 72 hour treatments, the cells were processed with MTS (“CellTiter96 AQueousOne Solution Cell Proliferation Assay“) colorimetric cell agent ( Figure 1).
  • MTS CellTiter96 AQueousOne Solution Cell Proliferation Assay“

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Physics & Mathematics (AREA)
  • Biomedical Technology (AREA)
  • Nanotechnology (AREA)
  • Optics & Photonics (AREA)
  • Dispersion Chemistry (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 d'émulsions lipidiques solides (émulsomes) et l'utilisation desdits émulsomes pour le traitement de maladies néoplasiques.
PCT/TR2020/050322 2019-04-16 2020-04-15 Émulsion lipidique solide comprenant de la curcumine et de la pipérine et son utilisation WO2020214125A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
TR2019/05678A TR201905678A2 (tr) 2019-04-16 2019-04-16 Kurkumi̇n ve pi̇peri̇n doğal bi̇leşenleri̇ni̇ i̇hti̇va eden kati li̇pi̇t emulsi̇yonlarinin tedavi̇ amaçli uygulamalari
TR2019/05678 2019-04-16

Publications (1)

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WO2020214125A1 true WO2020214125A1 (fr) 2020-10-22

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112972377A (zh) * 2021-03-04 2021-06-18 复旦大学附属中山医院青浦分院 一种姜黄素和胡椒碱复方自微乳制剂及其制备方法和应用
WO2023129413A1 (fr) * 2021-12-31 2023-07-06 Ingredient Fusion, Llc Procédé de complexation moléculaire, formulation et fabrication pour un meilleur apport en nutriments

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5662932A (en) * 1993-05-18 1997-09-02 Pharmos Corporation Solid fat nanoemulsions
EP2228062A1 (fr) * 2009-03-11 2010-09-15 Velleja Research SRL Compositions comprenant un complexe phospholipide-curcumin de la pipérine en tant qu'agent chimiosensibilisateur
US20150110866A1 (en) * 2012-05-22 2015-04-23 Harold Gordon Cave Complexes and compositions containing curcumin
WO2017095138A1 (fr) * 2015-11-30 2017-06-08 Gil Medical Center Complexe de nanoparticules lipidiques contenant de la curcumine comprenant des ginsénosides
EP3409275A1 (fr) * 2017-06-01 2018-12-05 Neilos S.r.l. Composition destinée à la prévention et/ou le traitement des maladies associées à l'inflammation et/ou a l'hyperalgésie

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5662932A (en) * 1993-05-18 1997-09-02 Pharmos Corporation Solid fat nanoemulsions
EP2228062A1 (fr) * 2009-03-11 2010-09-15 Velleja Research SRL Compositions comprenant un complexe phospholipide-curcumin de la pipérine en tant qu'agent chimiosensibilisateur
US20150110866A1 (en) * 2012-05-22 2015-04-23 Harold Gordon Cave Complexes and compositions containing curcumin
WO2017095138A1 (fr) * 2015-11-30 2017-06-08 Gil Medical Center Complexe de nanoparticules lipidiques contenant de la curcumine comprenant des ginsénosides
EP3409275A1 (fr) * 2017-06-01 2018-12-05 Neilos S.r.l. Composition destinée à la prévention et/ou le traitement des maladies associées à l'inflammation et/ou a l'hyperalgésie

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
"INCORPORATION OF CURCUMIN IN LIPID BASED DELIVERY SYSTEMS AND ASSESSMENT OF ITS BIOACCESSIBILITY", 1 October 2012, article KAVITAKUMARI H SOLANKI: "INCORPORATION OF CURCUMIN IN LIPID BASED DELIVERY SYSTEMS AND ASSESSMENT OF ITS BIOACCESSIBILITY", XP055122498 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112972377A (zh) * 2021-03-04 2021-06-18 复旦大学附属中山医院青浦分院 一种姜黄素和胡椒碱复方自微乳制剂及其制备方法和应用
WO2023129413A1 (fr) * 2021-12-31 2023-07-06 Ingredient Fusion, Llc Procédé de complexation moléculaire, formulation et fabrication pour un meilleur apport en nutriments

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