WO2013026113A1 - Utilisation de chondroïtine sulfate fucosylée, composition pharmaceutique et méthode pour la prévention et/ou le traitement d'une métastase cancéreuse - Google Patents

Utilisation de chondroïtine sulfate fucosylée, composition pharmaceutique et méthode pour la prévention et/ou le traitement d'une métastase cancéreuse Download PDF

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Publication number
WO2013026113A1
WO2013026113A1 PCT/BR2012/000275 BR2012000275W WO2013026113A1 WO 2013026113 A1 WO2013026113 A1 WO 2013026113A1 BR 2012000275 W BR2012000275 W BR 2012000275W WO 2013026113 A1 WO2013026113 A1 WO 2013026113A1
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WO
WIPO (PCT)
Prior art keywords
chondroitin sulfate
prevention
treatment
cancer metastasis
fucosylated chondroitin
Prior art date
Application number
PCT/BR2012/000275
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English (en)
Inventor
Mauro Sergio Gonçalves PAVÃO
Original Assignee
S.A Delta Do Prata
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Filing date
Publication date
Application filed by S.A Delta Do Prata filed Critical S.A Delta Do Prata
Publication of WO2013026113A1 publication Critical patent/WO2013026113A1/fr

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Classifications

    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/726—Glycosaminoglycans, i.e. mucopolysaccharides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis

Definitions

  • the invention concerns the use of sulfated polysaccharides, specifically fucosylated chondroitin sulfates, from holothuroidea, or sea cucumbers, in the preparation of a medicament useful for prevention and/or treatment of cancer metastasis in the animal body.
  • Sulfated polysaccharides constitute a complex group of macromolecules known to possess a wide range of important biological properties. These anionic polymers are widespread in nature, occurring in a great variety of organisms. For instance, in marine algae the carrageenans and fucoidans are composed mainly of sulfated galactose and fucose, respectively. In the animal kingdom, sulfated glycosaminoglycans abound in vertebrate tissues. Invertebrate species are also a rich source of sulfated polysaccharides with novel structures.
  • Anticoagulant and antithrombotic activities are among the most widely studied properties of sulfated polysaccharides.
  • the anticoagulant glycosaminoglycan heparin is an important therapeutic agent used in the prophylaxis and treatment of thrombosis; dermatan sulfate is also an anticoagulant, although of lower potency than heparin.
  • a chemically sulfated xylan from beechwood, pentosan polysulfate, has been available for many years as an anticoagulant polysaccharide.
  • Sulfated fucans from brown seaweed have anticoagulant activity due to the ability to potentiate inhibition of thrombin by antithrombin or heparin cofactor II.
  • FCS fucosylated chondroitin sulfate
  • FCS is an anti-thrombotic agent, with oral administration ("Fucosylated chondroitin sulfate as a new oral antithrombotic agent", Thromb Haemost 2006; 96: 822- 9), and an anti-metastatic agent ("Selectin blocking activity of a fucosylated chondroitin sulfate glycosaminoglycan from sea cucumber : Effect on tumor metastasis and neutrophil recruitment” , The Journal of biological chemistry 2007, vol. 282, no20, pp. 14984-
  • the prior art brings indication that FCS is active against cancer metastasis.
  • the patent document US 5, 989,592. discloses a method for inhibiting the complement pathway in a mammal after administering an effective dose of a composition containing an active principle selected from isolated sea cucumber (phylum Echinodermata , class Holothuroidea) body wall, isolated sea cucumber epithelial layer, isolated sea cucumber flower, sea cucumber fucosylated chondroitin sulfate, combinations thereof, active derivatives thereof or combinations of active derivatives thereof.
  • an active principle selected from isolated sea cucumber (phylum Echinodermata , class Holothuroidea) body wall, isolated sea cucumber epithelial layer, isolated sea cucumber flower, sea cucumber fucosylated chondroitin sulfate, combinations thereof, active derivatives thereof or combinations of active derivatives thereof.
  • the most preferable daily dose of the active is 25 mg/kg of body weight, a value randomly intercalated between purportedly preferable range values of 1 and 1,000 mg/kg of body weight.
  • the active being the isolated sea cucumber body wall, the isolated epithelial layer, the isolated flower or fucosylated chondroitin sulfate from the body wall, with respect to the daily dose.
  • FCS prepared according to example n° 10 - but there are only 9 examples, so the ambiguity keeps one from precisely understanding what is actually being disclosed.
  • FCS in vitro effect of FCS on enzymes, particularly C5a, that allegedly would be involved in physiological mechanisms related to a series of diseases, among which cancer cell metastasis.
  • FCS is likely to have anti-metastatic effects on mammals. Despite no hard evidence in that sense, other than just unsupported allegations, it seems likely that oral administration of FCS would also cause that effect, at least to some extent - a technical person with the common knowledge in the art would be led to accept that effective oral forms (a) would have to contain larger amounts of FCS, as compared to injected amounts, (b) would have to observe the amount generally accepted as safe for sulfated polysaccharides (around 1200 mg/day or around 17mg/kg/day, see for instance HATHCOCK JN & SHAO A. 2007. Risk assessment for glucosamine and chondroitin sulfate. Regul Toxicol Pharmacol. 47 (1) : 78-83. ) .
  • FCS effective anti-metastatic amount for safe oral administration is surprisingly small, not foreseeable based only on prior art teaching, with all the benefits that this new knowledge brings: lesser amounts of an active compound in the body of the patient, therefore with less possibility of side effects or toxic effects, besides more economical to the patient.
  • FCS The oral administration of FCS facilitates its use in a chronic way, and its mechanism of action (inhibition of the formation of microemboli, comprised of circulating tumoral cells and platelets) does not interfere with chemoterapics already in use, making it adequate as an adjuvant medicament. Its combination with other chemoterapics is apt to increase the survival and quality of life of patients once metastasis is decisive for such prognostics .
  • FCS does not increase the bleeding in animal models and is not known to be associated with hemorrhagic events, increasing its potential for chronic use. Additionally, in the small doses as utilized in the present invention, chondroitin does not present side effects .
  • a first aspect of this invention is, therefore, the use of low oral daily doses of FCS in the prevention and/or treatment of cancer metastasis, from 0.01 to 20 mg/kg of body weight, by itself or as an adjuvant.
  • FCS can be used along with another or other known anti-metastatic compounds, so as to obtain complementary effects, based on the fact that different compounds may act in the body through different mechanisms .
  • the invention concerns the use of FCS in the manufacture of a low oral dose composition useful in the prevention and/or treatment of cancer metastasis .
  • the invention concerns an oral composition and/or oral medicament comprising an effective amount of FCS in the prevention and/or treatment of cancer metastasis, from 0.1 to about 20 mg per kg of body weight of fucosylated chondroitin sulfate and pharmaceutically acceptable excipients.
  • Typical excipients include diluents, binders or granulating agents, glidants (flow aids) and lubricants to ensure efficient tableting; desintegrantes to promote tablet break-up in the digestive tract; sweeteners or flavors to enhance taste; and pigments to- make the tablets visually attractive.
  • a polymer coating may be applied to make the tablet smoother and easier to swallow, to enhance the tablet's appearance, to control the release rate of the active principle for instance as a powder or granules, or to make it more resistant to the environment (extending its shelf life) .
  • Excipients for such formulations are not per se part of the invention, as they are well-known in the art, for instance as disclosed in Remington's Pharmaceutical Sciences, 18th ed. , Mack Publishing Co., Easton, Pa (1990).
  • Adequate oral formulations are under the form of tablets, coated tablets, pills, capsules, powders, granules, fine granules, solutions, emulsions and suspensions.
  • Particular formulations of the invention are unit dosage forms comprising FCS - unit dosage forms, as known to one skilled in the art, are typically solid or liquid, and contain a specific dosage, for instance a minimum dosage for daily administration of the . active compound .
  • the FCS is nanoencapsulated with microparticules of acrylic compounds, for example with the product commercialized by Evonik Industries under the tradename Eudragit.
  • the invention concerns a method of prevention and/or treatment of cancer metastasis comprising administering to a mammal daily oral dose of about 0.1 to about 20 mg per kg of body weight of fucosylated chondroitin sulfate, particularly 0.05 - 20 mg/kg of body weight .
  • the term "sea cucumber” refers to any species of the Phylum Echinodermata, Class Holothuroidea, such as species of the genera Actinopyga (e.g., A. lacanora, L. echinites) , Cucumaria (e.g., C. frondosa, C. echinata, C. chronh. ielmi) , Eupentacta (e.g., E. quinquesemita) , Halodeima (e.g., H.
  • Actinopyga e.g., A. lacanora, L. echinites
  • Cucumaria e.g., C. frondosa, C. echinata, C. chronh. ielmi
  • Eupentacta e.g., E. quinquesemita
  • Halodeima e.g., H.
  • Holothuria e.g., H. pervicax, H. atra, H. edulis, H. scabra, H. monoacaria, H. leucospilota
  • Leptosynapta e.g., L. inhaerens
  • Ludwigothuria e.g., L. grisea
  • Microthele e.g., M. nobilis
  • Molpadia e.g., M. musculus
  • Parastichopus e.g., P. nigripunctatus
  • Paracaudina e.g., P.
  • PBS phosphate-buffered saline

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Oncology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Dermatology (AREA)
  • Molecular Biology (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne l'utilisation de polysaccharides sulfatés, en particulier des chondroïtine sulfates fucosylées, provenant d'holoturoïdea, ou concombres de mer, dans la préparation d'un médicament utile pour la prévention et/ou le traitement d'une métastase cancéreuse dans le corps animal.
PCT/BR2012/000275 2011-08-19 2012-08-06 Utilisation de chondroïtine sulfate fucosylée, composition pharmaceutique et méthode pour la prévention et/ou le traitement d'une métastase cancéreuse WO2013026113A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
BRPI1103783-0 2011-08-19
BRPI1103783-0A BRPI1103783A2 (pt) 2011-08-19 2011-08-19 uso de sulfato de condroitina fucosilada, composiÇço farmacÊutica oral e mÉtodo de prevenÇço e / ou tratamento de metÁstase de cÂncer

Publications (1)

Publication Number Publication Date
WO2013026113A1 true WO2013026113A1 (fr) 2013-02-28

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PCT/BR2012/000275 WO2013026113A1 (fr) 2011-08-19 2012-08-06 Utilisation de chondroïtine sulfate fucosylée, composition pharmaceutique et méthode pour la prévention et/ou le traitement d'une métastase cancéreuse

Country Status (2)

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BR (1) BRPI1103783A2 (fr)
WO (1) WO2013026113A1 (fr)

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2217322C (fr) * 1996-10-03 2005-01-04 Coastside Bio Resources Inhibition de la voie d'activation du complement au moyen de fractions de holothuries
US20070231332A1 (en) * 2006-03-31 2007-10-04 Board Of Trustees Of The University Of Arkansas Inhibition of Cancer Metastasis

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2217322C (fr) * 1996-10-03 2005-01-04 Coastside Bio Resources Inhibition de la voie d'activation du complement au moyen de fractions de holothuries
US20070231332A1 (en) * 2006-03-31 2007-10-04 Board Of Trustees Of The University Of Arkansas Inhibition of Cancer Metastasis

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
ATHANASIA P: ASIMAKOPOULOU ET AL.: "The Biological Role of Chondroitin Sulfate in Cancer and Chondroitin-based Anticancer Agents", IN VIVO, vol. 22, 2008, pages 385 - 390 *
BEHJATOLAH MONZAVI-KARBASSI ET AL.: "Chondroitin sulfate glycosaminoglycans as major P-selectin ligands on metastatic breast cancer cell lines", INT. J. CANCER, vol. 120, 2007, pages 1179 - 1191 *
CARLA Y. PUMPHREY ET AL.: "Carbodiimide-modified Glycosaminoglycans: A New Class of Anticancer Agents That Inhibit Cancer Cell Proliferation and Induce Apoptosis", CANCER RESEARCH, vol. 62, 2002, pages 3722 - 3728 *
FUCHUAN LI ET AL.: "Involvement of Highly 'Sulfated Chondroitin Sulfate in the Metastasis of the Lewis Lung Carcinoma Cells", JOURNAL OF BIOLOGICAL CHEMISTRY, vol. 283, no. 49, 2008 *
JOHN N. HATHCOCK ET AL.: "Risk assessment for glucosamine and chondroitin sulfate", REGULATORY TOXICOLOGY AND PHARMACOLOGY, vol. 47, 2007, pages 78 - 83 *
LUBOR BORSIG ET AL.: "Selectin Blocking Activity of a Fucosylated Chondroitin Sulfate Glycosaminoglycan from Sea Cucumber - Effect on Tumor Metastasis and Neutrophil Recruitment", THE JOURNAL OF BIOLOGICAL CHEMISTRY, vol. 282, no. 20, 2007, pages 14984 - 14991 *

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