WO2022259175A1 - Composition destinée à être utilisée dans la prévention et/ou le traitement de maladies ostéoarticulaires - Google Patents

Composition destinée à être utilisée dans la prévention et/ou le traitement de maladies ostéoarticulaires Download PDF

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Publication number
WO2022259175A1
WO2022259175A1 PCT/IB2022/055332 IB2022055332W WO2022259175A1 WO 2022259175 A1 WO2022259175 A1 WO 2022259175A1 IB 2022055332 W IB2022055332 W IB 2022055332W WO 2022259175 A1 WO2022259175 A1 WO 2022259175A1
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Prior art keywords
composition
aescin
osteoarthritis
sod
treatment
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PCT/IB2022/055332
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English (en)
Inventor
Umberto DI MAIO
Original Assignee
Neilos S.r.l.
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Application filed by Neilos S.r.l. filed Critical Neilos S.r.l.
Priority to EP22736362.9A priority Critical patent/EP4351589A1/fr
Publication of WO2022259175A1 publication Critical patent/WO2022259175A1/fr

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Classifications

    • 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
    • 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
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
    • 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
    • A61K31/737—Sulfated polysaccharides, e.g. chondroitin sulfate, dermatan sulfate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/77—Sapindaceae (Soapberry family), e.g. lychee or soapberry
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/43—Enzymes; Proenzymes; Derivatives thereof
    • A61K38/44—Oxidoreductases (1)
    • A61K38/446—Superoxide dismutase (1.15)
    • 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
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • 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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Y—ENZYMES
    • C12Y115/00—Oxidoreductases acting on superoxide as acceptor (1.15)
    • C12Y115/01—Oxidoreductases acting on superoxide as acceptor (1.15) with NAD or NADP as acceptor (1.15.1)
    • C12Y115/01001—Superoxide dismutase (1.15.1.1)

Definitions

  • composition for use in the prevention and/or treatment of osteoarticular diseases Composition for use in the prevention and/or treatment of osteoarticular diseases
  • the present invention relates to a composition of substances, preferably obtained from natural sources, effective in the prevention and/or treatment of osteoarticular diseases, such as rheumatoid arthritis, osteoarthritis, tendinopathies.
  • arthritis is used to indicate all disorders that affect the joints. In all cases patients suffer from pain and stiffness of the joints. There are about 100 different types of arthritis, the most common of which are rheumatoid arthritis and osteoarthritis.
  • Rheumatoid arthritis is an autoimmune disorder that primarily involves joints, which are swollen and painful.
  • the disease can also affect other parts of the organism, for example resulting in a decrease in the number of red blood cells, onset of inflammation around the heart and lungs, fever, and a general sense of fatigue. It is believed that this disease is due to a combination of genetic and environmental factors.
  • the primary mechanism entails activating the immune system with respect to the joints, which leads to inflammation and thickening of the joint capsule, also involving the bone and the cartilage.
  • the initial site of the disease is the synovial membrane, where there is an infiltration of the cells of the immune system. More specifically, rheumatoid arthritis is generally characterised by three successive stages: an initial stage due to non-specific inflammation, an amplification stage which regards T- cell activation, and lastly a final stage of chronic inflammation due to the release of pro-inflammatory cytokines such as interleukin-2, Y-interferon, tumour necrosis factor (TNF) and interleukin-6.
  • pro-inflammatory cytokines such as interleukin-2, Y-interferon, tumour necrosis factor (TNF) and interleukin-6.
  • the primary risk factors for rheumatoid arthritis are gene mutations that entail disorders in the regulation of immune response.
  • One of the gene mutations responsible for the aetiology of rheumatoid arthritis is located in the genes involved in the expression of the class 2 major histocompatibility complex (MHC) such as HLA DR4 .
  • MHC major histocompatibility complex
  • Other documented environmental factors are, for example, smoking habits.
  • Osteoarthritis is a degenerative joint disease that affects millions of people around the world primarily at the level of the hip, hand, and knee. It is known that the synovia, the bone, and the cartilage are the tissues most involved in the pathological mechanisms of osteoarthritis.
  • the cause of the disease is probably related to changes in the articular cartilage and bone homeostasis which lead to increased destructive processes.
  • osteoarthritis results in a change in the bone structure and degeneration of articular cartilage.
  • the subchondral bone becomes stiff, less capable of absorbing impact loads, resulting in increased stress on the cartilage.
  • the primary features of the disease include a progressive loss of cartilaginous tissue, hypertrophic changes in the bone, and formation of osteophytes which grow on the edges of the bones involved.
  • chondrocytes are known to be the cells responsible for balancing matrix synthesis and destruction processes, capable of regulating cytokines and growth factors. In osteoarticular degenerative processes, this balance is usually impaired. In patients with osteoarthritis, chondrocytes produce high levels of inflammatory cytokines such as interleukin l-b and tumour necrosis factor (TNF), which in turn reduce collagen synthesis and increase concentrations of catabolic mediators such as metalloproteases. Other pro-inflammatory substances such as interleukin-8 (IL-8) and interleukin-6 (IL-6), prostaglandin E2 and nitric oxide are simultaneously released. The increase in oxidising agents such as nitric oxide causes chondrocyte apoptosis and therefore degeneration of the matrix.
  • IL-8 interleukin-8
  • IL-6 interleukin-6
  • ROS reactive oxygen species
  • OH- hydroxyl radicals
  • Age is the main risk factor given that it is known that the tensile properties of articular cartilage decrease as age increases, leading to mechanical problems. Women normally show more pain and disability with respect to men. People with a high body mass index are at increased risk.
  • osteoarthritis The most common symptoms of osteoarthritis include chronic pain, due to an increase in concentration of excitatory amino acids - such as glutamate - at the sites of interest, which contributes to hyperalgesia and pain.
  • Another characteristic symptom is articular stiffness due to a decrease in the levels of phospholipids, surfactants responsible for reducing friction by ensuring optimal lubrication.
  • Tendinopathy is a chronic and degenerative disease of tendons, tissue structures which have the important task of connecting the muscles to the bones. Tendons are tissues that are rich in collagen and highly resistant to stretch. Unlike common tendinitis, tendinopathy is not of inflammatory origin, and it differs precisely in the fact that there is a degeneration of collagen. The disease mainly affects the Achilles tendon, rotator cuff tendon, patellar tendon and - lastly - femoral bicep tendon, but it may manifest itself in any tendon located in any region. Tendinopathy may be caused by various factors, such as for example an excessive strain or use of a certain part of the body, or it may be related to ageing or even lack of muscle tone. Therefore, the populations most at risk of contracting this disease are the elderly as well as sportsmen and sportswomen.
  • osteoarticular diseases The pharmacological treatments traditionally used in osteoarticular diseases are first and foremost analgesic drugs, which help to reduce the sensation of pain but which, clearly, do not offer anything other than symptomatic treatments.
  • Anti-inflammatory drugs of various kinds non-steroidal and steroidal which combat inflammatory processes that characterise the disease, are also used.
  • these drugs require numerous daily administrations to reach adequate therapeutic doses and often entail side effects, even severe, such as peptic ulcers or gastric perforation.
  • COX-2 selective NSAIDs such as for example celecoxib
  • paracetamol has fewer side effects, it is only recommended for mild or moderate forms of osteoarthritis .
  • composition characterised in that it comprises a synergistic combination of active substances, obtained from natural sources, the aforementioned combination having proved to be particularly effective against osteoarticular diseases.
  • extract is used to indicate any product related to a herb including all products derived from mechanical treatments (pulverisation, crushing, mixing and/or other methods) or from extract-based treatments (solvent extraction, distillation, and/or other specific methods) conducted on a drug.
  • the composition of the invention is as defined in the attached claim 1. Further characteristics and advantages of the invention are defined in the dependent claims. The claims are an integral part of the present description.
  • the synergistic composition of the present invention is useful for the treatment and prevention of osteoarticular diseases both in humans and animals.
  • the synergistic action occurs between aescin, chondroitin sulfate, and superoxide dismutase (SOD).
  • Aesculus Hippocastanum L. is a large tree known as horse chestnut or European horse chestnut, belonging to the family of Hippocastanaceae.
  • the herb consists of dried seeds, which contain not less than 3% triterpene glycosides.
  • the primary characteristic chemical constituents of the herb are collectively known as aescin, a name representing a mixture of acylated triterpene glycosides (saponins) whose aglycons are mainly protoescigenin and barringtogenol C. The difference between these aglycons is due to the presence of a hydroxyl at position C-24 of the molecule of protoescigenin.
  • All horse chestnut saponins have a trisaccharide group bound in position C-3 consisting of glucuronic acid which can be combined with glucose, galactose or xylose.
  • the two primary saponins both derived from protoescigenin, are esterified one at the position 21b with angelic acid and the other at the position 22a with acetic acid.
  • aescin which can be grouped into three fractions: b- aescin, which exclusively contains 22-O-acetyl compounds; cryptoescin, which exclusively contains 28- O-acetyl compounds; a-aescin, which is a mixture of b- aescin and cryptoescin.
  • Other herbal constituents include flavonoids (quercetin and kaempferol di- and tri-glycosides, which account for 0.3% of the herb), sterols, an essential oil and a significant amount of starch.
  • Aescin and the saponin fractions of the herb exert anti-inflammatory activity, demonstrated in several animal experiments: inhibition of albumin- or carrageenan-induced oedema in the rat paw or inhibition of dextran-induced exuding oedema in the rat skin; the mechanism on which this activity depends appears to be the inhibition of the prostaglandin synthetase enzyme, as shown by an in vitro experiment with a saponin fraction.
  • aescin can act at different levels in the pathway of glucocorticoids ending up stimulating their release or increasing the expression of the receptors, thereby stimulating the anti-inflammatory effect.
  • Chondroitin sulfate is a high molecular weight molecule belonging to the family of glycosaminoglycans, which play a key role in conferring structural support to the extracellular matrix. It is widely present in connective tissues and in particular in cartilages located at the articular level, conferring tensile strength, flexibility and a certain deformability. As a result of various events - whether physiological such as ageing or non-physiological, such as chronic inflammatory conditions, trauma to a certain extent - there can be obtained a decrease in the intraarticular content of chondroitin, and as a result lose standard articular capacity.
  • the LI questionnaire which is filled out by the patient and it allows to award a score to the pain, to the stiffness, to the difficulty in performing normal daily activities and maximum walking capacity
  • VAS which is used to measure perceived pain.
  • At the end of treatment there was a significant difference between the treated groups and the placebo, both in LI and in VAS.
  • Administration of 800 mg of chondroitin sulfate daily for 6 months showed to be capable of preventing loss of articular cartilage volume and significantly decrease subchondral lesions of the bone marrow. Therefore, showing a protection effect on articular degeneration.
  • ROS reactive oxygen species
  • Superoxide dismutase is a catalytic enzyme of crucial importance in cell protection against oxidative stress. In particular, it is responsible for transforming the superoxide radicals into species that are less harmful to the organism. It therefore plays a key role as an antioxidant by intervening in the regulation and maintenance of the oxidation state balance. The formation of the highly reactive and harmful superoxide radical belonging to the family of
  • ROSs occurs continuously in the organisms and most is produced as a secondary metabolite in mitochondria.
  • radicals may be caused by external stimuli such as ionising radiations or oxidative damage.
  • the most well-known natural source of SOD is melon (Cucumis Melo); raw materials - in which SOD is bound to proteins such as gliadin - capable of improving the bioavailability and therefore the therapeutic efficacy of the enzyme after oral administration, are available on the market.
  • the synergistic composition of the present invention is effective in the treatment and/or prevention of osteoarticular diseases.
  • the effectiveness of the composition stems from the following activities of the components:
  • Aescin preferably obtained from an extract of Aesculus hippocastanum, carries out an anti-edemigenic, vaso-protective and anti-inflammatory action;
  • Chondroitin sulfate plays a key role in articular well-being, conferring tensile strength, flexibility and a certain deformability.
  • Superoxide dismutase is an antioxidant and anti inflammatory agent.
  • the synergistic action occurs between aescin, chondroitin sulfate and superoxide dismutase (SOD).
  • aescin is administered in a daily dose comprised between 0.1 mg and 5000 mg, preferably between 0.5 and 2000 mg, and even more preferably between 1 and 1000 mg; chondroitin sulfate is administered in a daily dose comprised between 10 mg and 9000 mg, preferably between 20 mg and 7000 mg, even more preferably between 50 mg and 5000 mg; superoxide dismutase is administered in a daily dose comprised between 0.1 IU and 1000 IU preferably between 1 IU and 800 IU, even more preferably between 5 IU and 500 IU.
  • the dosage form may be a pharmaceutical composition or a dietary supplement or a medical device or a food for special medical purposes including the aforementioned active ingredients mixed to each other.
  • the preferred route of administration is oral or topical.
  • Pharmaceutical forms may be: capsules, tablets, granules, powders for suspension or solution, solutions, suspensions, syrups.
  • compositions with respect to the individual active ingredients are evaluated through experimental methods in vitro and/or in vivo.
  • cytokines TNF- a, IL-1, IL-4, IL-6, IL-8, IL-10, IL-17, INF-Y, COMP
  • a simple general inflammation model is the carrageenan-induced paw oedema model induced on mice or rats is used as in vivo test.
  • the injection of carrageenan into the paw of the animal determines an acute inflammatory reaction of the paw with onset of classical signs of inflammation; this reaction reaches its peak within 3 hours from inoculation.
  • This test allows to evaluate the ability of the active components of the present invention in reducing the oedema of the paw induced by the injection of carrageenan.
  • More complex methods which are used to evaluate osteoarticular diseases are, for example, the collagen- induced arthritis model, Freund's adjuvant-induced arthritis which allow to evaluate the effects of potential agents for the treatment of arthritis over an extended period of time.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Organic Chemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Rheumatology (AREA)
  • Natural Medicines & Medicinal Plants (AREA)
  • General Chemical & Material Sciences (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Molecular Biology (AREA)
  • Immunology (AREA)
  • Medical Informatics (AREA)
  • Biochemistry (AREA)
  • Biotechnology (AREA)
  • Botany (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Microbiology (AREA)
  • Mycology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Dermatology (AREA)
  • Alternative & Traditional Medicine (AREA)
  • General Engineering & Computer Science (AREA)
  • Genetics & Genomics (AREA)
  • Wood Science & Technology (AREA)
  • Zoology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Macromolecular Compounds Obtained By Forming Nitrogen-Containing Linkages In General (AREA)
  • Detergent Compositions (AREA)

Abstract

L'invention concerne une composition synergique de substances d'origine naturelle, particulièrement efficace dans le traitement et la prévention de maladies ostéoarticulaires, telles que la polyarthrite rhumatoïde, l'arthrose, et les tendinopathies. La composition de l'invention comprend la combinaison synergique d'aescine, de sulfate de chondroïtine et de superoxyde dismutase (SOD). La composition synergique selon la présente invention peut se présenter sous la forme d'une composition pharmaceutique, d'un complément alimentaire, d'un dispositif médical, d'un aliment utilisé à des fins médicales spécfiques et d'un produit cosmétique.
PCT/IB2022/055332 2021-06-08 2022-06-08 Composition destinée à être utilisée dans la prévention et/ou le traitement de maladies ostéoarticulaires WO2022259175A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP22736362.9A EP4351589A1 (fr) 2021-06-08 2022-06-08 Composition destinée à être utilisée dans la prévention et/ou le traitement de maladies ostéoarticulaires

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IT102021000014495A IT202100014495A1 (it) 2021-06-08 2021-06-08 "Composizione per l’uso nella prevenzione e/o nel trattamento di patologie osteoarticolari"
IT102021000014495 2021-06-08

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6326003B1 (en) * 1986-10-14 2001-12-04 Chiron Corporation Manganese superoxide dismutase cloning and expression in microorganisms
US20040234633A1 (en) * 2001-10-26 2004-11-25 Min-Young Kim Composition containing horse chestnut extract
JP2007254332A (ja) * 2006-03-22 2007-10-04 Kitasato Gakuen 免疫調整作用のあるメロン抽出物含有組成物
WO2008015007A2 (fr) * 2006-08-04 2008-02-07 Marinomed Biotechnologie Gmbh Utilisation d'escine

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6326003B1 (en) * 1986-10-14 2001-12-04 Chiron Corporation Manganese superoxide dismutase cloning and expression in microorganisms
US20040234633A1 (en) * 2001-10-26 2004-11-25 Min-Young Kim Composition containing horse chestnut extract
JP2007254332A (ja) * 2006-03-22 2007-10-04 Kitasato Gakuen 免疫調整作用のあるメロン抽出物含有組成物
WO2008015007A2 (fr) * 2006-08-04 2008-02-07 Marinomed Biotechnologie Gmbh Utilisation d'escine

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
BAUEROVA K ET AL: "Chondroitin sulfate effect on induced arthritis in rats", OSTEOARTHRITIS AND CARTILAGE, ELSEVIER, AMSTERDAM, NL, vol. 19, no. 11, 5 August 2011 (2011-08-05), pages 1373 - 1379, XP028312378, ISSN: 1063-4584, [retrieved on 20110816], DOI: 10.1016/J.JOCA.2011.08.006 *
GOEBEL K M ET AL: "Effect of intra-articular orgotein versus a corticosteroid on rheumatoid arthritis of the knees", AMERICAN JOURNAL OF MEDICINE, EXCERPTA MEDICA, INC, UNITED STATES, vol. 74, no. 1, 1 January 1983 (1983-01-01), pages 124 - 128, XP026335669, ISSN: 0002-9343, [retrieved on 19830101], DOI: 10.1016/0002-9343(83)91128-2 *
MAGHSOUDI HOSSEIN ET AL: "Evaluation of the effect of polyphenol of escin compared with ibuprofen and dexamethasone in synoviocyte model for osteoarthritis: an in vitro study", CLINICAL RHEUMATOLOGY, ACTA MEDICA BELGICA, BRUXELLES, BE, vol. 37, no. 9, 16 April 2018 (2018-04-16), pages 2471 - 2478, XP036570235, ISSN: 0770-3198, [retrieved on 20180416], DOI: 10.1007/S10067-018-4097-Z *
MARTEL-PELLETIER J ET AL: "Effects of chondroitin sulfate in the pathophysiology of the osteoarthritic joint: a narrative review", OSTEOARTHRITIS AND CARTILAGE, ELSEVIER, AMSTERDAM, NL, vol. 18, 1 June 2010 (2010-06-01), pages S7 - S11, XP027085012, ISSN: 1063-4584, [retrieved on 20100427] *
MCILWAIN H ET AL: "Intra-articular orgotein in osteoarthritis of the knee: A placebo-controlled efficacy, Safety, and dosage comparison", AMERICAN JOURNAL OF MEDICINE, EXCERPTA MEDICA, INC, UNITED STATES, vol. 87, 1 January 1989 (1989-01-01), pages 295 - 300, XP026539765, ISSN: 0002-9343, [retrieved on 19890101], DOI: 10.1016/S0002-9343(89)80154-8 *

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EP4351589A1 (fr) 2024-04-17

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