WO2011100984A1 - Gelatin, a curcumin drug carrier system - Google Patents

Gelatin, a curcumin drug carrier system Download PDF

Info

Publication number
WO2011100984A1
WO2011100984A1 PCT/EG2010/000008 EG2010000008W WO2011100984A1 WO 2011100984 A1 WO2011100984 A1 WO 2011100984A1 EG 2010000008 W EG2010000008 W EG 2010000008W WO 2011100984 A1 WO2011100984 A1 WO 2011100984A1
Authority
WO
WIPO (PCT)
Prior art keywords
curcumin
natural
novel
gelatin
conjugate
Prior art date
Application number
PCT/EG2010/000008
Other languages
French (fr)
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/EG2010/000008 priority Critical patent/WO2011100984A1/en
Publication of WO2011100984A1 publication Critical patent/WO2011100984A1/en

Links

Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K47/00Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50Medicinal 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
    • A61K47/51Medicinal 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
    • A61K47/62Medicinal 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
    • A61K47/64Drug-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
    • A61K47/6435Drug-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 the peptide or protein in the drug conjugate being a connective tissue peptide, e.g. collagen, fibronectin or gelatin
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00Drugs for genital or sexual disorders; Contraceptives
    • A61P15/10Drugs for genital or sexual disorders; Contraceptives for impotence
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00Drugs for disorders of the metabolism
    • A61P3/08Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics

Abstract

Curcumin is a water insoluble component of turmeric, the yellow spice from the rhizome 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 a wide variety of medical conditions. The World Health Organization approved its use as non-toxic food additive and a potentially safe drug. Oral administration is well tolerated, but bioavailability is very low. Less than 1% of the curcumin makes its way to the bloodstream, where the liver rapidly destroys most of it. 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. Accordingly, based on the successful application of our previous "Patent Pending PCT/EG2008/000044" filed on 20/11/2008 under "Long Acting Conserved Natural Functional Groups Curcumin", the need for the present development looked urgent through the use of several other protein carrier systems for curcumin. The successful clinical application of a globular carrier protein system for curcumin has been internationally published in the Journal of International Society for Sexual Medicine and is available online since Oct. 19 2009 12:02PM, under "Novel Water-soluble Curcumin Derivative Mediating Erectile Signaling".

Description

GELATIN , A CURCUMIN DRUG CARRIER SYSTEM

Technical Field

This invention relates to the synthesis of a novel curcumin-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. The use of 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.

The 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 arid experimental animal models. In addition, the novel derivatives are intended to be used as natural health food additives and as food colorants.

Such novel protein curcumin carrier derivatives with their improved properties are intended to be submitted to testing in medical studies in experimental animal models to try to get better medicinal effects that were not achievable with natural curcumin. Highly controlled clinical trails on volunteer consented humans in internationally accredited clinical research centers will follow based on the terms and rules internationally approved for such purposes. Background Art

Curcumin, l,7-Bis(4-hydroxy-3-methoxyphenyI)-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.

Oral administration of 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 urcumin actually makes its way to the bloodstream, where the liver rapidly destroys most of it.

Mixing of Bioperine with curcumin is one of the most famous solutions to counteract this problem. 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.

In general three different approaches were used to improve curcumin bioavailability; namely: additives, microemulsions and chemical derivatives, but none proved to overcome the problem. 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).

On the other hand, no protein carriers for curcumin, based on covalent conjugation of curcumin to a carrier protein were previously reported. Some other reported systems made use of the natural curcumin-protein interactions. Obviously such 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.

Accordingly, based on one of the successful applications of our previous "Patent Pending PCT/EG2008/000044" filed on 20/11/2008 by the same first author; REZQ, El-Sayed Ameen Mahmoud et al., under "Long Acting Conserved Natural Functional Groups Curcumin", the need looked urgent to develop several other protein carrier systems for curcumin. The successful clinical application of a globular carrier protein system for curcumin has been internationally published in the Journal of International Society for Sexual Medicine and is available online since Oct. 19 2009 12:02PM, under "Novel Water-soluble Curcumin Derivative Mediating Erectile Signaling". Highly trustful of the originality of the scientific research hypothesis and the results outcome, the "Journal Editorial Board" didn't ask for the disclosure of the invention.

The same "Patent Pending PCT/EG2008/000044" has also been granted a national project fund of L.E. 1,000,000 From the Academy of Scientific Research and Technology of Egypt, once again, without asking for the disclosure of the invention. The project entitled "Development of a Novel Drug of Herbal Origin for Management of Erectile Dysfunction and Diabetes Mellitus" under ID: 634, the Science and Technology Fund (STDF). Disclosure of Invention

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-gelatin as a glutinous 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. Diazotized 4-minobenzoic acid was added dropwise to an equivalent concentration, (0.85 mEq) of curcumin, (I) dissolved in ethanol/lN NaOH at pH 11.0 with continuous stirring at 5°C. The solution was acidified with IN HC1 to pH 2.0 at which derivative (II) l,7-bis(5-carboxyphenylazo-4-hydroxy-3-methoxyphenyl)-l,6- heptadiene-3,5-dione was precipitated. The precipitate was centrifuged and redissolved in ethanol/lN NaOH at pH 11.0 again. After repeating the acid and base cycle twice, the crude derivative (II) was chromatographed on a column of silica gel. Reduced pressure and temperature evaporation of the elution solvent gave a derivative of about 98% purity as checked by TLC.

The curcumin-gelatin conjugate (III), of this invention was synthesized in a medium of 1% NaCl/l,4-dioxane/lN NaOH solution of pH 8-10, at 5°C with continuous stirring, by adding previously cooled to 5°C, 0.1 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. One per cent gelatin solution in 0.5N NaOH was added to the foregoing mixture at 5°C, pH 8-10 with continuous stirring for 1 hr until the intermediate azopseudourea has been completely conjugated to gelatin as was evident by the complete disappearance of the original red color of the l,7-bis(5-carboxyphenylazo-4- hydroxy-3-methoxyphenyl)-l,6-heptadiene-3,5-dione, (II) solution, after which the mixture was centrifuged off, acidified to pH 5.1, salted out with either solid NaCl or ammonium sulphate, recentrifuged, redissolved then dialyzed for 24 hr at 5°C against 0.5M sodium carbonate, pH 8.2 until any color no longer appears in dialysis solution. A final dialysis is performed against bi-distilled water for 24 hours at 5°C, after which the protein conjugate (III) was lyophilized. The novel curcumin derivatives (II) and (III) were characterized by IR Spectroscopy, GC/MS, NMR, EM, TLC, Gel Filtration, Continuous Flow Electrophoresis and Isoelectric Focusing whenever applicable.

Claims

Claims
We claim the following:
1- The synthesis of a novel covalently linked drug carrier system of gelatin-curcumin conjugate with conserved natural functional chemical groups of curcumin, of free water solubility, easy digestibility, and free intestinal absorption.
2- According to claim (1) we claim higher curcumin bioavailability and longer serum half-life for on oral administration of the novel gelatin-curcumin conjugate.
3- According to claims (1&2) we claim the novel derivative to convey 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.
4- According to claims (1,2&3) the novel gelatin-curcumin conjugate is intended to be used as therapeutic protein-curcumin carrier system, as a natural health food additives and as a food colorant.
5- We also claim the synthesis of a novel intermediate essential for the synthesis of the novel gelatin-curcumin conjugate.
6- According to claim (4&5) we claim the use of the claimed curcumin derivatives in medical studies in experimental animals for treatment from some acute and chronic illnesses e.g. erectile dysfunction, diabetes mellitus, osteoporosis, cancer and all other illnesses reported to be treated or benefited from natural curcumin treatment.
The novel gelatin curcumin carrier system derivatives with their improved properties are intended to be submitted to testing in medical studies in experimental animal models to try to get better medicinal effects that were not achievable with natural curcumin.
7- According to claims (1-6) we claim the successful conversion of natural pure water insoluble curcumin to a novel, water soluble conserved natural functional group derivatives, with no change to its original active functional natural molecular chemical groups necessary for full biochemical, physiological and pharmacological potencies previously reported for natural curcumin. The novel curcumin derivatives were characterized by IR Spectroscopy, GC/MS, NMR, EM, TLC, Gel Filtration, Continuous Flow Electrophoresis and Isoelectric Focusing whenever applicable.
PCT/EG2010/000008 2010-02-17 2010-02-17 Gelatin, a curcumin drug carrier system WO2011100984A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
PCT/EG2010/000008 WO2011100984A1 (en) 2010-02-17 2010-02-17 Gelatin, a curcumin drug carrier system

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/EG2010/000008 WO2011100984A1 (en) 2010-02-17 2010-02-17 Gelatin, a curcumin drug carrier system

Publications (1)

Publication Number Publication Date
WO2011100984A1 true WO2011100984A1 (en) 2011-08-25

Family

ID=42313974

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EG2010/000008 WO2011100984A1 (en) 2010-02-17 2010-02-17 Gelatin, a curcumin drug carrier system

Country Status (1)

Country Link
WO (1) WO2011100984A1 (en)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4368208A (en) * 1981-04-13 1983-01-11 Mccormick & Company, Inc. Water-soluble curcumin complex
WO2007098504A1 (en) * 2006-02-24 2007-08-30 Emory University Prodrugs of curcumin analogs
DE102007041625A1 (en) * 2007-09-03 2009-03-05 Sinn, Hannsjörg, Dr. New gelatine-drug conjugates

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4368208A (en) * 1981-04-13 1983-01-11 Mccormick & Company, Inc. Water-soluble curcumin complex
WO2007098504A1 (en) * 2006-02-24 2007-08-30 Emory University Prodrugs of curcumin analogs
DE102007041625A1 (en) * 2007-09-03 2009-03-05 Sinn, Hannsjörg, Dr. New gelatine-drug conjugates

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
MOHAMED TALAAT ABDEL AZIZ ET AL: "Novel Water-soluble Curcumin Derivative Mediating Erectile Signaling", JOURNAL OF SEXUAL MEDICINE, BLACKWELL PUBLISHING LTD., OXFORD, GB LNKD- DOI:10.1111/J.1743-6109.2009.01543.X, 19 October 2009 (2009-10-19), pages 1 - 10, XP002576728, ISSN: 1743-6095, [retrieved on 20091019] *
SNEHARANI ATHAHALLI H ET AL: "Interaction of alpha(S1)-Casein with Curcumin and Its Biological Implications", JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY, AMERICAN CHEMICAL SOCIETY, US LNKD- DOI:10.1021/JF902464P, vol. 57, no. 21, 1 November 2009 (2009-11-01), pages 10386 - 10391, XP002576727, ISSN: 0021-8561, [retrieved on 20091016] *

Similar Documents

Publication Publication Date Title
Wu et al. Deer antler base as a traditional Chinese medicine: a review of its traditional uses, chemistry and pharmacology
Ngoh et al. Enzyme-assisted extraction and identification of antioxidative and α-amylase inhibitory peptides from Pinto beans (Phaseolus vulgaris cv. Pinto)
JP5538611B2 (en) Maillard reaction inhibitor
CA2467805C (en) Novel chromium (iii) alpha amino acid complexes
Eddouks et al. Inhibition of endogenous glucose production accounts for hypoglycemic effect of Spergularia purpurea in streptozotocin mice
ES2373937T3 (en) Gastro-intestinal administration systems.
Petersson et al. Dietary nitrate increases gastric mucosal blood flow and mucosal defense
Mukherjee et al. Vanadium—an element of atypical biological significance
US8420132B2 (en) Synergistic anti-inflammatory and antioxidant dietary supplement compositions
Breiner et al. Hybrids of amino acids and acetylenic DNA-photocleavers: optimising efficiency and selectivity for cancer phototherapy
US6368617B1 (en) Dietary supplement
Sheeba et al. Effect of Cardiospermum halicacabum on ethanol-induced gastric ulcers in rats
TWI233353B (en) Therapeutic or preventive agents containing polyphenols
US8686053B2 (en) Alginic acid with low molecular weight, its salts, uses, preparative methods, pharmaceutical compositions and foods
JP2011068680A (en) Curcuminoid composition exhibiting synergistic inhibition on expression and/or activity of cyclooxygenase-2
US6224871B1 (en) Dietary supplement for nutritionally promoting healthy joint function
ES2402215T5 (en) Suspension containing hydronium stabilized colloidal silicic acid nanoparticles, formulation obtained from said diluted suspension, powder obtained from said dehydrated suspension, compositions obtained from said powder, preparation and use
JP2009500433A (en) Rain complex, preparation method thereof and use for diabetes nephrotic drug, intestinal adhesion drug, osteoarthritis drug
Kshirsagar et al. Anti-inflammatory and antiarthritic activity of anthraquinone derivatives in rodents
JP4419390B2 (en) Inflammatory disease treatment and prevention agent
JPH11500725A (en) Use of piperine as a bioavailability enhancer
Qiu et al. ACPI conjugated gold nanorods as nanoplatform for dual image guided activatable photodynamic and photothermal combined therapy in vivo
Ai et al. Preparation and biological activities of chitosan from the larvae of housefly, Musca domestica
NO334407B1 (en) A method for producing a sterile lyophilized powder consisting of nanoparticles of paclitaxel and human serum albumin
ES2270070T3 (en) Iron-dextrine compound for the treatment of iron deficiency anemia.

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 10704894

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase in:

Ref country code: DE

WWE Wipo information: entry into national phase

Ref document number: 8081/DELNP/2012

Country of ref document: IN

122 Ep: pct application non-entry in european phase

Ref document number: 10704894

Country of ref document: EP

Kind code of ref document: A1