WO2011100983A1 - Caséine en tant que nouveau système de véhicule de médicament de curcumine - Google Patents

Caséine en tant que nouveau système de véhicule de médicament de curcumine Download PDF

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Publication number
WO2011100983A1
WO2011100983A1 PCT/EG2010/000007 EG2010000007W WO2011100983A1 WO 2011100983 A1 WO2011100983 A1 WO 2011100983A1 EG 2010000007 W EG2010000007 W EG 2010000007W WO 2011100983 A1 WO2011100983 A1 WO 2011100983A1
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WO
WIPO (PCT)
Prior art keywords
curcumin
natural
novel
casein
conjugate
Prior art date
Application number
PCT/EG2010/000007
Other languages
English (en)
Inventor
El-Sayed Ameen Mahmoud Rezq
Mohammad Talaat Abdel-Aziz Mansour
Abdulrahman Labeed Al-Malki
Original Assignee
El-Sayed Ameen Mahmoud Rezq
Mohammad Talaat Abdel-Aziz Mansour
Abdulrahman Labeed Al-Malki
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 El-Sayed Ameen Mahmoud Rezq, Mohammad Talaat Abdel-Aziz Mansour, Abdulrahman Labeed Al-Malki filed Critical El-Sayed Ameen Mahmoud Rezq
Priority to PCT/EG2010/000007 priority Critical patent/WO2011100983A1/fr
Publication of WO2011100983A1 publication Critical patent/WO2011100983A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/105—Plant extracts, their artificial duplicates or their derivatives
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L5/00—Preparation or treatment of foods or foodstuffs, in general; Food or foodstuffs obtained thereby; Materials therefor
    • A23L5/40—Colouring or decolouring of foods
    • A23L5/42—Addition of dyes or pigments, e.g. in combination with optical brighteners
    • A23L5/43—Addition of dyes or pigments, e.g. in combination with optical brighteners using naturally occurring organic dyes or pigments, their artificial duplicates or their derivatives
    • 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
    • A61K47/62—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 a protein, peptide or polyamino acid
    • A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2250/00—Food ingredients
    • A23V2250/20—Natural extracts
    • A23V2250/21—Plant extracts
    • A23V2250/2112—Curcumin, turmeric

Definitions

  • This invention relates to the synthesis of a novel curcumiri-protein conjugate as drug carrier system conserving the natural functional groups necessary for curcumin biochemical, physiological and pharmacological functionalities originally possessed by natural curcumin.
  • the novel compound will be submitted to testing in a wide range of variable clinical, pharmaceutical, health food products and as a general natural food colorant.
  • the invention also relates to a novel intermediate essential for the synthesis of the abovementioned curcumin-protein conjugate, that bears and serves, at the same time, most of the abovementioned functionalities of the novel product, except the presence of the protein carrier property with all of the other properties related to it, such as the slow intestinal absorption with all its relevant consequences.
  • protein carriers for several other drugs has been proved to be highly valuable tools as drug delivery systems that carry some specific drugs to sites within the body not reachable or difficult to reach with the proper therapeutic concentration by the drug by itself.
  • novel derivatives relate to conveying lacking essential properties on natural curcumin such as; free water solubility, easy digestibility, free intestinal absorption, higher and longer serum half-life and improved original biochemical, physiological and pharmacological potencies of natural curcumin towards certain pre-studied therapeutic effects in humans and experimental animal models.
  • novel derivatives are intended to be used as natural health food additives and as food colorants.
  • Curcumin, l,7-Bis(4-hydroxy-3-methoxyphenyl)-l,6-heptadiene-3,5-dione is a is water insoluble component of turmeric, a yellow spice from the rhizomes of the herb Curcuma longa L. (Zingiberaceae), that is widely used as a food flavoring and coloring agent.
  • Curcumin has a long history of medicinal use for the treatment of a wide variety of medical conditions; The World Health Organization approved its use as non-toxic food additive and a potentially safe drug.
  • curcumin is well tolerated, but its bioavailability is very low. However, when curcumin is used as a supplement, it is absorbed quickly but does not stay in the body for long.
  • the cell lining of the intestine are equipped with enzymes that convert curcumin into other substances, and also equipped with molecular pumps that pump curcumin and its byproducts out of the intestinal lining back into the intestine. Less than 1% of the curcumin actually makes its way to the bloodstream, where the liver rapidly destroys most of it.
  • Bioperine is a blend from black and long pepper, when used as an additive; it enhances the absorption of curcumin from the gastrointestinal tract. But for people who have medical conditions, or who are taking other supplements or drugs, all kinds of risks are elevated as such substances are known to interact with various drugs used to treat several medical conditions.
  • additives such as Piperine, (from black pepper), Quercetin (from various plants) and Genistein (from soy) were used to inhibit the natural pumps that expel curcumin out of the intestinal and/or other cells.
  • Microemulsions e.g. natural oils such as peppermint oil, different surfactants such as lecithin, monoolein, Tween-20 were used to facilitate intestinal curcumin absorption in larger amounts.
  • Chemical derivatives e.g., tetrahydro curcumin, demethoxy curcumin, tetrahydrodemethoxy curcumin, bisdemethoxy curcumin, tetrahydro bisdemethoxy curcumin, hexahydrocurcumin, acetate, phosphate, gluconate, etc. were used with the aim to try to avoid the abovementioned action of the intestinal enzymes/pumps and liver enzymes.
  • a serious drawback was that all such chemical derivatives were made through the use of the curcumin natural functional chemical groups required for full biological activity, (biochemical, physiological and pharmacological potencies).
  • curcumin carrier protein interactions are subject to several dissociating factors, starting and not ending with the gastrointestinal tract.
  • a suitable protein carrier system covalently linked to curcumin with conserved natural curcumin functional chemical groups, of free water solubility, easy digestibility, free intestinal absorption, long serum half-life should help getting the utmost possible beneficial effects of this historical, albeit promising treatment for several acute and chronic illnesses. Additionally, the protein-curcumun conjugate could be used as health food additive and a natural food colorant.
  • Curcumin, l,7-bis(4-hydroxy-3-methoxyphenyl)-l,6-heptadiene-3,5-dione (I) was coupled to diazotized 4-aminobenzoic acid for the synthesis of the novel compound l,7-bis(5-carboxyphenylazo-4-hydroxy-3-methoxyphenyl)-l,6-heptadiene-3,5-dione (II), which in turn was utilized for the synthesis of the novel curcumin-casein micellar conjugate (III), through the use of l-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride, EDC. Both compounds (II) and (III) represent the novel embodiment of this invention.
  • Nitrous acid was generated by the addition of a solution of 0.85 mEq of sodium nitrite to an excess of IN HC1 with continuous stirring in ice bath. The reaction was maintained at a temperature of 5°C. A solution of 0.85 mEq of 4-aminobenzoic acid in IN HC1 chilled to 5°C was prepared with continuous stirring in ice bath for 20 minutes; the pH of 1.0 was never exceeded. The 4-aminobenzoic acid solution was then added slowly to the cold freshly prepared nitrous acid with continuous stirring in ice bath at5°C.
  • the curcumin-casein conjugate (III), of this invention was synthesized in a medium of 1% NaCl/l,4-dioxane/lN NaOH solution ofpH 8-10, at 5°C with continuous stirring, by adding previously cooled to 5°C, 0.1M solution of l-ethyl-3-(3- dimethylaminopropyl) carbodiimide hydrochloride, EDC to the equivalent concentration of purified crystalline l,7-bis(5-carboxyphenylazo-4-hydroxy-3- methoxyphenyl)-l,6-heptadiene-3,5-dione, (II) in the same medium with continuous stirring.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical & Material Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Diabetes (AREA)
  • Polymers & Plastics (AREA)
  • Food Science & Technology (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Nutrition Science (AREA)
  • Mycology (AREA)
  • Endocrinology (AREA)
  • Rheumatology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Molecular Biology (AREA)
  • Emergency Medicine (AREA)
  • Hematology (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Epidemiology (AREA)
  • Gynecology & Obstetrics (AREA)
  • Reproductive Health (AREA)
  • Botany (AREA)
  • Medicinal Preparation (AREA)
  • Obesity (AREA)

Abstract

La curcumine est un composant insoluble dans l'eau du curcuma, l'épice jaune provenant du rhizome de la plante Curcuma longa L. (Zingiberaceae), qui est largement utilisée en tant qu'agent aromatisant et colorant alimentaire. La curcumine a une longue histoire d'utilisation médicinale pour une grande variété d'affections médicales. L'Organisation mondiale de la santé a approuvé son utilisation en tant qu'additif alimentaire non toxique et médicament potentiellement sûr. Son administration orale est bien tolérée, mais sa biodisponibilité est très faible. Moins de 1 % de la curcumine atteint la circulation sanguine, où le foie détruit rapidement la majeure partie de celui-ci. Un système de véhicule protéique adapté lié de façon covalente à la curcumine avec des groupes chimiques fonctionnels de curcumine naturelle conservés, aisément soluble dans l'eau, aisément digestible, librement absorbé dans l'intestin, de longue demi-vie sérique devrait contribuer à tirer les plus grands effets bénéfiques possibles de ce traitement historique, mais prometteur pour plusieurs maladies aiguës et chroniques. De plus, le conjugué protéine-curcumine pourrait être utilisé en tant qu'additif diététique et colorant alimentaire naturel. En conséquence, sur la base de l'application réussie de notre « brevet en instance PCT/EG2008/000044 » précédent, déposé le 20/11/2008 sous le titre « Long Acting Conserved Natural Functional Groups Curcumin », la nécessité du présent développement paraissait urgente par l'utilisation de plusieurs autres systèmes de véhicule protéique pour la curcumine. L'application clinique réussie d'un système de véhicule protéique globulaire pour la curcumine a été internationalement publiée dans le Journal of International Society for Sexual Medicine et est disponible en ligne depuis le 19 octobre 2009 12h02, sous le titre « Novel Water-soluble Curcumin Derivative Mediating Erectile Signaling ».
PCT/EG2010/000007 2010-02-17 2010-02-17 Caséine en tant que nouveau système de véhicule de médicament de curcumine WO2011100983A1 (fr)

Priority Applications (1)

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PCT/EG2010/000007 WO2011100983A1 (fr) 2010-02-17 2010-02-17 Caséine en tant que nouveau système de véhicule de médicament de curcumine

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PCT/EG2010/000007 WO2011100983A1 (fr) 2010-02-17 2010-02-17 Caséine en tant que nouveau système de véhicule de médicament de curcumine

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2968070A4 (fr) * 2013-03-15 2016-10-26 Glanbia Nutritionals Ireland Ltd Produit et procédé pour améliorer une biodisponibilité de composés thérapeutiques
EP3544632A4 (fr) * 2016-11-23 2020-11-18 John Robert Chancey Procédés de fabrication et d'utilisation de polyphénols complexés avec une protéine, un peptide, un acide aminé, un polysaccharide, un disaccharide ou un monosaccharide
CN117337989A (zh) * 2023-12-04 2024-01-05 东北农业大学 一种基于pH偏移负载姜黄素的纳米颗粒及其制备方法

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4999205A (en) * 1989-08-17 1991-03-12 Kalamazoo Holdings, Inc. Curcumin complexed on water-dispersible substrates
EP1103266A2 (fr) * 1999-11-26 2001-05-30 Basf Aktiengesellschaft Formulations de curcumine

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4999205A (en) * 1989-08-17 1991-03-12 Kalamazoo Holdings, Inc. Curcumin complexed on water-dispersible substrates
EP1103266A2 (fr) * 1999-11-26 2001-05-30 Basf Aktiengesellschaft Formulations de curcumine

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
"Development of a Novel Drug of Herbal Origin for Management of Erectile Dysfunction and Diabetes Mellitus", SCIENCE AND TECHNOLOGY FUND, vol. 634
ANAND PREETHA ET AL: "Bioavailability of curcumin: Problems and promises", MOLECULAR PHARMACEUTICS, vol. 4, no. 6, November 2007 (2007-11-01), pages 807 - 818, XP002576835, ISSN: 1543-8384 *
MOHAMED TALAAT ABDEL AZIZ ET AL: "Novel Water-soluble Curcumin Derivative Mediating Erectile Signaling", J. SEX. MED., 19 October 2009 (2009-10-19), XP002576728, DOI: 10.1111/j.1743-6109.2009.01543.x *
SAHU A ET AL: "Fluorescence study of the curcumin-casein micelle complexation and its application as a drug nanocarrier to cancer cells", BIOMACROMOLECULES 200810 US LNKD- DOI:10.1021/BM800683F, vol. 9, no. 10, October 2008 (2008-10-01), pages 2905 - 2912, XP002576834, ISSN: 1525-7797 *
SNEHARANI ATHAHALLI H ET AL: "Interaction of alpha(S1)-Casein with Curcumin and Its Biological Implications", JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY, vol. 57, no. 21, November 2009 (2009-11-01), pages 10386 - 10391, XP002576727, ISSN: 0021-8561 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2968070A4 (fr) * 2013-03-15 2016-10-26 Glanbia Nutritionals Ireland Ltd Produit et procédé pour améliorer une biodisponibilité de composés thérapeutiques
EP3544632A4 (fr) * 2016-11-23 2020-11-18 John Robert Chancey Procédés de fabrication et d'utilisation de polyphénols complexés avec une protéine, un peptide, un acide aminé, un polysaccharide, un disaccharide ou un monosaccharide
CN117337989A (zh) * 2023-12-04 2024-01-05 东北农业大学 一种基于pH偏移负载姜黄素的纳米颗粒及其制备方法

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