WO2024252335A1 - Nouvelle association de principes actifs d'origine végétale, compositions les contenant et utilisation en thérapeutique - Google Patents

Nouvelle association de principes actifs d'origine végétale, compositions les contenant et utilisation en thérapeutique Download PDF

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Publication number
WO2024252335A1
WO2024252335A1 PCT/IB2024/055559 IB2024055559W WO2024252335A1 WO 2024252335 A1 WO2024252335 A1 WO 2024252335A1 IB 2024055559 W IB2024055559 W IB 2024055559W WO 2024252335 A1 WO2024252335 A1 WO 2024252335A1
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Prior art keywords
gum
association
composition
pea proteins
use according
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Inventor
Miguel Angel Alonso Cohen
Sabrina CASELLA
Giulia BRAMATI
Bhavna KARNANI
Rossana SIDOTI
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Devintec Sagl
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Devintec Sagl
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    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • 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
    • A23L33/17—Amino acids, peptides or proteins
    • A23L33/185—Vegetable proteins
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • 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 OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/20—Reducing nutritive value; Dietetic products with reduced nutritive value
    • A23L33/21—Addition of substantially indigestible substances, e.g. dietary fibres
    • 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)
    • 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)
    • A61K36/48—Fabaceae or Leguminosae (Pea or Legume family); Caesalpiniaceae; Mimosaceae; Papilionaceae
    • 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)
    • A61K36/73—Rosaceae (Rose family), e.g. strawberry, chokeberry, blackberry, pear or firethorn
    • A61K36/736—Prunus, e.g. plum, cherry, peach, apricot or almond
    • 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
    • A61K38/168—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from plants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders

Definitions

  • the present invention relates to a new association of active ingredients of plant origin, to the pharmaceutical, nutraceutical and food compositions containing it and to the uses thereof in therapy, in particular for the treatment and prevention of autoimmune diseases, preferably autoimmune diseases whose physiopathology is associated with an alteration of the intestinal barrier, characterised by an increased permeability and dysbiosis.
  • autoimmune diseases preferably autoimmune diseases whose physiopathology is associated with an alteration of the intestinal barrier, characterised by an increased permeability and dysbiosis.
  • LPS lipopolysaccharides
  • anti-cyclic citrul linated peptide antibodies are detectable several years before the onset of the arthritis in humans, suggesting that rheumatoid arthritis (RA) originates in the mucosae, such as in the gut and the oral cavity.
  • autoimmune diseases such as lupus erythematosus and Sjogren's syndrome
  • lupus erythematosus and Sjogren's syndrome have been studied with the aim of understanding the link between alterations of intestinal permeability, microflora and the physiopathology of autoimmune diseases.
  • WO2021119810 discloses a system of oral administration comprising an active ingredient dispersed in a homogeneous dry mixture of a protein powder and a polysaccharide powder.
  • the protein powder can derive from legume proteins, whereas the polysaccharide powder comprises or consists of natural polysaccharides.
  • the protein/polysaccharide complex disclosed in WO2021119810 imparts gastric protection and/or modified release to an active ingredient dispersed therein and can be used in therapy. The therapeutic effect is thus mediated by the active ingredient present within the protein/polysaccharide complex.
  • autoimmune diseases use for the treatment of autoimmune diseases is not disclosed, nor is use for the treatment of diseases characterised by intestinal membrane damage and/or increased intestinal permeability and/or dysbiosis.
  • Carpentier Jeremy et al. “Complex coacervation of pea protein isolate and tragacanth gum: Comparative study with commercial polysaccharides", Innovative Food Science & Emerging Technologies, Vol. 69 (2021), discloses the ability of pea protein isolates (PPI) to form complex coacervates with tragacanth gum.
  • PPI pea protein isolates
  • the coacervate formation was compared to three other PPI-polysaccharide interaction models: arable gum and sodium alginate (known to form coacervates with PPI) and tara gum, a galactomannan.
  • autoimmune diseases use for the treatment of autoimmune diseases is not disclosed, nor is the use for the treatment of diseases characterized by intestinal membrane damage and/or increased intestinal permeability and/or dysbiosis.
  • the expression “diseases physiopathologically associated with intestinal membrane damage” is meant to indicate conditions characterised by structural and/or functional alterations or modifications of the intestinal membrane, which lead to the development of a disease.
  • physiopathologically associated is here meant to indicate that the aetiology of such diseases is at least partially connected with the presence of a non-intact intestinal membrane, preferably with an increased intestinal permeability and/or in the presence of dysbiosis.
  • diseases include or, alternatively, consist of:
  • lupus for example systemic lupus erythematosus -SLE
  • EU Regulation
  • FSMP food for special medical purposes
  • the invention relates to an association or combination of active ingredients of plant origin which comprises or, alternatively, consists of at least one active ingredient selected from the group comprising or, alternatively, consisting of:
  • the object of the present invention relates to an association of active ingredients of plant origin which comprises or, alternatively, consists of:
  • Prunus armeniaca gum or mixtures thereof, said association being for use in a method for the prevention and treatment of autoimmune diseases.
  • Said autoimmune diseases include or, alternatively, consist of:
  • lupus for example systemic lupus erythematosus -SLE
  • the association or combination of active ingredients of plant origin comprises, in addition to the components (i)-(iv), at least one further active ingredient selected from the group comprising or, alternatively, consisting of (v) pectin, (vi) acacia gum, (vii) xanthan gum, (viii) tara gum, (ix) guar gum, and (x) carrageenan, or mixtures thereof; preferably, said association or combination being for use in the treatment of autoimmune diseases; in particular, for the treatment of autoimmune diseases physiologically associated with intestinal membrane damage and/or increased intestinal permeability and/or dysbiosis.
  • the active ingredient (ii) present in the mixture (i) + (ii) + (iii) + (iv) can be replaced, in whole or in part, by at least one further active ingredient selected from the group comprising or, alternatively, consisting of (v) pectin, (vi) acacia gum, (vii) xanthan gum, (viii) tara gum, (ix) guar gum, and (x) carrageenan, or mixtures thereof; preferably, said association or combination being for use in the treatment of autoimmune diseases; in particular, for the treatment of autoimmune diseases physiologically associated with intestinal membrane damage and/or increased intestinal permeability and/or dysbiosis.
  • the active ingredient (iii) present in the mixture (i) + (ii) + (iii) + (iv) can be replaced, in whole or in part, by at least one further active ingredient selected from the group comprising or, alternatively, consisting of (v) pectin, (vi) acacia gum, (vii) xanthan gum, (viii) tara gum, (ix) guar gum, and (x) carrageenan, or mixtures thereof; preferably, said association or combination being for use in the treatment of autoimmune diseases; in particular, for the treatment of autoimmune diseases physiologically associated with intestinal membrane damage and/or increased intestinal permeability and/or dysbiosis.
  • the active ingredient (iv) present in the mixture (i) + (ii) + (iii) + (iv) can be replaced, in whole or in part, by at least one further active ingredient selected from the group comprising or, alternatively, consisting of (v) pectin, (vi) acacia gum, (vii) xanthan gum, (viii) tara gum, (ix) guar gum, and (x) carrageenan, or mixtures thereof; preferably, said association or combination being for use in the treatment of autoimmune diseases; in particular, for the treatment of autoimmune diseases physiologically associated with intestinal membrane damage and/or increased intestinal permeability and/or dysbiosis.
  • the invention relates to an association or combination of active ingredients of plant origin which comprises or, alternatively, consists of (i) pea proteins in combination or association with at least one other selected active ingredient of plant origin selected from the group comprising or, alternatively, consisting of: (ii) karaya gum, (iii) Prunus cerasus gum, and/or (iv) Prunus armeniaca gum, or mixtures thereof.
  • said association or combination of active ingredients of plant origin, or composition which comprises it, is for use in a method for the prevention and treatment of autoimmune diseases.
  • said autoimmune diseases are diseases physiopathologically associated with intestinal membrane damage and/or ad increased intestinal permeability and/or dysbiosis.
  • association or combination according to the invention, or a composition which comprises it is for use in a method for the prevention and treatment of autoimmune diseases physiopathologically associated with intestinal membrane damage, an increased intestinal permeability and/or dysbiosis.
  • said association or combination comprises or, alternatively, consists of: (i) pea proteins + (ii) karaya gum; or
  • the PP (i) are present, relative to the natural gums (ii) + (iii) + (iv), in an amount by weight comprised from 1 :5 to 5:1 , preferably from 1 :4 to 4: 1 , more preferably from 1 :3 to 3: 1 , even more preferably 1 : 1.
  • the PP (i) are present, relative to the natural gums (ii) + (iii) + (iv), in an amount by weight of about 4:3, for example 200 mg of PP and 150 mg of (ii) + (iii)+ (iv), in a weight ratio of 1 : 1 :1.
  • pea proteins (hereinafter indicated as PP) (or isolated pea proteins) (i) appear as a light cream-coloured powder, derived from Pisum sativum.
  • PP are reserve proteins mainly composed of albumin, legumin and vicilin (for example, globulin protein associated with legumin), besides being known as a source of essential amino acids and fibre and for being highly digestible.
  • PP are characterised by high solubility at an alkaline pH, minimal solubility at the isoelectric point and moderate solubility in an acidic environment.
  • globulins and vicilin impart gelling properties to the PP.
  • Plant protein-based products are approved as food additives according to the FDA (21 CFR ⁇ 170.3) and PP received Generally Recognized As Safe (GRAS) status in 2015 (GRN 608 Axiom Foods GRN 581 and GRN 788) after an assessment of absorption, distribution, excretion studies, bioavailability, toxicity and mutagenicity.
  • GRAS Generally Recognized As Safe
  • the PP according to the invention are high quality and non-GMO (genetically modified organisms).
  • one type of PP ⁇ Pisum sativum L) is isolated at least at 80% on a dry basis, preferably has a density of about 0.5 g/ml, is water soluble, gives rise to a solution having a pH value comprised from 6.5 to 8.5 and can have a particle size of 100% through 100 mesh.
  • 80% pea protein is obtained from golden or yellow peas by means of dry and liquid processes. In the dry phase, the pea shell is mechanically removed and ground. Subsequently, pea flour is obtained and, thanks to its properties of water solubility, the proteins are separated and collected by centrifugation.
  • Karaya gum (ii) is obtained as an exudate from Sterculia urens, a large bushy tree belonging to the family Sterculiaceae, and is well known as a food additive (for example with the number E-416).
  • the gum mainly consists of high molecular weight acetylated polysaccharides, which, by hydrolysis, yield galactose, rhamnose, and galacturonic acid together with a small amount of glucuronic acid.
  • Karaya gum appears as a fine powder, with a greyish pink colour and a slightly acetic flavour and odour.
  • Karaya gum has very low water solubility and produces solutions with a very low concentration ( ⁇ 0.02% in cold water and 0.06% in hot water), due to the acetyl groups in the structure of the gum.
  • the viscosity of karaya gum in 0.5% dispersions for example, has a value close to 120-400 centipoises (cPs) and in a 3% dispersion, for example, about 10000 cPs.
  • cPs centipoises
  • cPs centipoises
  • one type of karaya gum (ii) in powder form can be the one with CAS No 9000-36-6, EC 232-539-4.
  • Karaya gum is neither digested nor degraded by enteric microflora and is not absorbed by humans.
  • Prunus cerasus gum (ill) consists of branched polysaccharide chains containing various monosaccharides such as D-xylose, D-galactose, L-arabinose, L-rhamnose, D-mannose and D-glucuronic acid, which derives from glucose. In solution, Prunus cerasus shows a viscous behaviour rather than a tendency to form a gel.
  • one type of Prunus cerasus (ill) in the form of an extract can be the one with CAS No 89997-53-5, EC 289-688-3.
  • Prunus armeniaca L. gum belongs to the family Rosaceae.
  • the gum exudate obtained from branches of P. armeniaca trees is used as a food additive and possesses antioxidant capacities. Prunus armeniaca gum is used as a matrix for extended drug release and does not seem to exert bactericidal activity.
  • Prunus armeniaca (iv) in the form of an extract can be the one with CAS No 68650-44-2, EC 272-046-1.
  • association or combination (I) + (ii) + (ill) + (iv) can further comprise pectin (v).
  • Pectin consists mainly of partial methyl esters of polygalacturonic acid and their ammonium, sodium, potassium and calcium salts. It is obtained by extraction in an aqueous medium of strains of appropriate edible plant material, usually citrus fruits or apples. No organic precipitants are used for its extraction other than methanol, ethanol and propan-2-ol.
  • Pectin is preferably characterised by a galacturonic acid content of no less than 65% on an ash-free and anhydrous basis after washing with acid and alcohol. It appears in the form of a white, yellowish or brown powder, is soluble in water and insoluble in ethanol and gives rise to an opalescent colloidal solution.
  • the pectin (v) is sugar beet pectin.
  • An example of pectin extracted from sugar beet is the product Sugarbeetpectin E 440 sold by C.E. Roeper GmbH.
  • the association or combination (I) + (ii) + (ill) + (iv) can further comprise an acacia gum (vi).
  • Acacia gum (vi) is a natural gum also known as gum arable as it is extracted from two species of sub-Saharan acacia: Acacia Senegal and Acacia seyal.
  • Acacia gum consists mainly of complex carbohydrates and glycoproteins, which make it an emulsifier and a stabilising agent that is useful in various applications.
  • an acacia gum powder is used. It is insoluble in alcohol and 1g of powder in 2 ml of water forms a solution that flows easily and is acidic to litmus. The pH (25% solution in water) is comprised from 4.1 to 5.8.
  • one type of (vi) acacia gum in the form of a dried gummy exudate of trunks and branches of Acacia Senegal (Linne) Willdenow or of other related African species can be the one with a CAS No 9000-01-5, EC 232-519-5.
  • association or combination (I) + (ii) + (ill) + (iv) can further comprise a xanthan gum (vii).
  • Xanthan gum (vii) is a high molecular weight polysaccharide gum produced by fermentation in a pure culture with Xanthomonas campestris, purified by recovery with ethanol or isopropyl alcohol, dried and ground. It is prepared as a sodium, potassium or calcium salt. It is prepared in the form of a sodium, potassium or calcium salt and appears as a cream-coloured water-soluble powder. The viscosity (1% solution in 1 % KCI) is comprised from 1200 to 1600 mPas.
  • the xanthan gum that can be present in the association or combination of the invention has the CAS No 11138-66-2 EC 234-394-2.
  • association or combination (I) + (ii) + (ill) + (iv) can further comprise a tara gum (vii).
  • Tara gum (viii) consists mainly of high molecular weight polysaccharides, essentially galactomannan, and is produced by grinding the endosperm of the seed of the variety Caesalpinia spinosa (family Leguminosae). It appears as a powder that is white to yellow in colour. The viscosity (1%, 20 U/min, 10 min. 87°C) is 5000 mPas.
  • Tara gum E417 is well known as a food additive in powder form (for example, with the number E-417).
  • An example of the tara gum that can be present in the association or combination of the invention is the product CEROTA Tara Gum Type 5000, sold by C.E. Roeper GmbH.
  • association or combination (I) + (ii) + (ill) + (iv) can further comprise a guar gum (ix).
  • Guar gum (ix) is a gum consisting mainly of a high molecular weight hydrocolloidal polysaccharide.
  • the main constituent is a galactomannan, a trisaccharide formed by mannose and galactose units, specifically polymerised to form o-D-mannopyranosyl chains joined with a
  • Guar gum is obtained by grinding the endosperm of seeds of guar (Cyamopsis tetragonoloba), a herbaceous plant of the legume family, typical of India and Pakistan.
  • guar gum that can be present in the association or combination of the invention has the CAS No 9000-30-0 EC 232-536-8.
  • association or combination (I) + (ii) + (ill) + (iv) can further comprise a carrageenan (x).
  • Carrageenan (x) is a gelatine widely used in food, medicine and industry and consisting essentially of calcium, potassium sodium and magnesium salts of sulphate esters of polysaccharides which yield galactose and 3,6- an hydrogalactose by hydrolysis. It appears in the form of a yellowish to colourless powder and is practically odourless, with a particle size of about 160 microns. It is stable in a neutral or alkaline environment and insoluble in organic solvents.
  • the carrageenan (x) present in the association of the invention is kappa or iota carrageenan, more preferably kappa.
  • Kappa carrageenan forms strong, stiff gels in the presence of potassium ions and reacts with milk protein. It originates mainly from Kappaphycus alvarezii.
  • carrageenan that can be present in the association or combination according to the invention is the product CEROGEL Carrageenan RCK 580, sold by C.E. Roeper GmbH, which can have, for example, a pH (1.5% w/w at 60 °C) comprised from 8 to 11 , and a viscosity (1.5% w/w at 75°C, Spindle 2 60rpm. LVT Brookfield Viscometer) that has a minimum value of 20 - 70 mPas.
  • All the active ingredients of the association of the invention are preferably in solid form, more preferably in the form of a powder, or granules or flakes.
  • the Applicant has been able to observe that the association or combination of the invention has demonstrated to be effective in the prevention and treatment, preferably early treatment, of autoimmune diseases physiopathologically associated with intestinal membrane damage, preferably with an increased intestinal permeability and/or in the presence of dysbiosis.
  • Physiopathologically associated is here meant to indicate that the aetiology of such diseases is at least partially connected with the presence of a non-intact intestinal membrane, preferably with an increased intestinal permeability and/or in the presence of dysbiosis.
  • Such diseases include or, alternatively, consist of:
  • lupus for example systemic lupus erythematosus -SLE
  • association of the invention is preferably formulated in a pharmaceutical, nutraceutical or food composition.
  • the invention relates to a composition which comprises the association or combination of the present invention, together, optionally, with at least one conventional vehicle and/or excipient and/or a technological additive or excipient, said composition being for use in a method for the prevention and treatment of autoimmune diseases; preferably, for the treatment of autoimmune diseases physiopathologically associated with intestinal membrane damage, an increased intestinal permeability and/or dysbiosis.
  • composition of the present invention can be a pharmaceutical, nutraceutical or food composition which comprises the association of the invention, together, optionally, with at least one conventional vehicle and/or excipient (briefly, the composition(s) of the present invention).
  • composition of the invention is for oral use.
  • the association or combination of the present invention is present in the composition in an amount by weight comprised from 10% to 90%, preferably comprised from 25% to 75%, more preferably comprised from 40% to 60%, whereas said at least one conventional vehicle and/or excipient are present in an amount by weight comprised from 90% to 10%, preferably from 75% to 25%, more preferably comprised from 60% to 40% by weight, relative to the total weight of the composition.
  • the pea proteins (I) are present in the mixture (I) + (ii) + (ill) + (iv) in an amount by weight comprised from 40% to 70%, preferably comprised from 50% to 60%, relative to the total weight of the mixture.
  • the active ingredients (ii), (ill) and (iv) are present in the mixture (I) + (ii) + (ill) + (iv) in an amount by weight comprised from 30% to 60%, preferably comprised from 40% to 50%, relative to the total weight of the mixture.
  • the active ingredients (v), (vi), (vii), (viii), (ix) and (x) are present in the mixture (i) + (v) + (vi) + (vii) + (viii) + (ix) + (x) in an amount by weight comprised from 30% to 60%, preferably comprised from 40% to 50%, relative to the total weight of the mixture.
  • the active ingredients (v), (vi), (vii), (viii), (ix) and (x) are present in a weight ratio of 1 : 1 : 1 : 1 : 1 : 1 : 1 .
  • the individual to be treated with the composition of the invention is preferably a mammal, more preferably a human being.
  • composition of the invention is formulated for oral use, for example in the form of pharmaceutical, nutraceutical or food compositions, such as, for example, tablets, possibly coated, granules, fine granules, powders, hard capsules, soft capsules, syrups, emulsions, suspensions and solutions, suitable for oral administration.
  • pharmaceutical, nutraceutical or food compositions such as, for example, tablets, possibly coated, granules, fine granules, powders, hard capsules, soft capsules, syrups, emulsions, suspensions and solutions, suitable for oral administration.
  • the composition of the invention is in a solid oral form, preferably selected from tablets, capsules, powders and granules.
  • the tablets and the capsules can have a weight comprised from 200 mg to 1,200 mg, preferably from 400 mg to 1,000 mg, more preferably from 600 mg to 800 mg.
  • the types of pharmaceutical additives used to prepare the composition of the invention, the ratios of the additive contents relative to the active ingredient and the methods for preparing the pharmaceutical composition can be appropriately selected by the person skilled in the art.
  • Organic or inorganic substances, or solid or liquid substances can be used as excipients and vehicles, provided that they are pharmaceutical or food grade.
  • excipients used to prepare solid pharmaceutical compositions include, for example, lactose, sucrose, starch, talc, cellulose, dextrin, kaolin, calcium carbonate, stearic acid or magnesium stearate, lactose, polyethylene glycol, mannitol, sorbitol, chelating agents, anti-agglomerant agents, sweetening agents, preservative agents and flavouring agents.
  • liquid compositions for oral administration use can be made of a conventional inert diluent such as water or an oil, for example a vegetable oil.
  • the liquid composition can contain, in addition to the inert diluent, auxiliaries such as wetting agents, suspension agents, sweeteners, flavourings, colourings and preservatives.
  • auxiliaries such as wetting agents, suspension agents, sweeteners, flavourings, colourings and preservatives.
  • the liquid composition can be enclosed in capsules made of an absorbable material, such as gelatine.
  • the sweeteners can be one or more natural sugars, reduced as desired, such as, for example sucrose, dextrose, xylitol, mannitol or sorbitol, or a synthetic product, such as, for example, sodium saccharine, aspartame, acesulfame K or the sucralose. Acidifying agents can also be added.
  • flavouring agents are pharmaceutically acceptable flavours and tastes of synthetic oils or natural oils, the latter extracted from plants, flowers, fruits and combinations thereof, such as, for example, cinnamon, mint, anise, and citrus fruit leaves, bitter almonds, citrus fruits, in particular orange and/or lemon oils, linden, vanilla, chocolate and grapefruit.
  • chocolate, vanilla or eucalyptus flavourings and fruit essences in particular apple, pear, peach, strawberry, apricot, orange, lemon and grape, can also be advantageously used.
  • composition of the invention can also comprise other components, useful for the use according to the invention.
  • the mixtures and compositions subject-matter of the present invention are prepared using methods and equipment known to an expert in the nutraceutical or pharmaceutical sector.
  • the composition of the invention can be packaged in dosage units or in multidose packages, according to the conventional methods well known to the person skilled in the art.
  • composition of the invention is in the form of dosage units.
  • the invention relates to a pharmaceutical composition, a composition for a medical device as per Regulation (EU) 2017/745, a nutraceutical or food composition or food for special medical purposes (FSMP) for use according to the invention, which comprises or, alternatively, consists of:
  • said pharmaceutical composition, composition for a medical device as per Regulation (EU) 2017/745, nutraceutical or food composition or food for special medical purposes (FSMP) for use according to the invention comprises or, alternatively, consists of:
  • the natural gums (II) karaya gum, (ill) Prunus cerasus gum and (iv) Prunus armeniaca gum can for example be present, in said composition, in a weight ratio of 1 : 1 : 1 , for example 50 mg (ii) + 50 mg (iii) + 50 mg (iv); or also 75 mg (ii) + 50 mg (iii) + 50 mg (iv); or also 50 mg (ii) + 75 mg (iii) + 50 mg (iv); or also 50 mg (ii) + 50 mg (iii) + 75 mg (iv); or also 100 mg (ii) + 50 mg (iii) + 50 mg (iv); or also 50 mg (ii) + 100 mg (iii) + 50 mg (iv); or 50 mg (ii) + 50 mg (iii) + 100 mg (iv).
  • the active ingredients pectin (v), acacia gum (vi), xanthan gum (vii), tara gum (viii), guar gum (ix) and carrageenan (x) can for example be present in said association or combination in a weight ratio, for example, of 1 : 1 :1 : 1 :1 :1 , for example 25 mg (v) + 25 mg (vi) + 25 mg (vii) + 25 mg (viii) + 25 mg (ix) + 25 mg (x).
  • the invention relates to the association and the pharmaceutical or nutraceutical composition according to the invention for use in therapy.
  • the invention relates to the association and the pharmaceutical or nutraceutical composition according to the invention for use in the prevention and treatment, preferably early treatment, of diseases physiopathologically associated with intestinal membrane damage, preferably with an increased intestinal permeability and/or dysbiosis.
  • Such diseases are selected from the group comprising or, alternatively, consisting of:
  • lupus for example systemic lupus erythematosus
  • association of the invention and/or the composition comprising that association are advantageously used for the treatment of systemic lupus erythematosus.
  • association comprising pea proteins and one or more of the tested active ingredients (see examples 1 and 2) is capable of attenuating and/or treating damage to the intestinal membrane in a mouse model of systemic lupus erythematosus.
  • the association and compositions of the invention are well tolerated and do not give significant side effects.
  • association and compositions of the invention thus offer a natural, nontoxic, alternative solution to conventional therapies for the prevention and early treatment of autoimmune diseases aetiologically correlated with an altered intestinal permeability and/or with dysbiosis.
  • the invention relates to a method for the prevention and treatment, preferably the early treatment, of diseases physiopathologically associated with intestinal membrane damage, preferably with an increased intestinal permeability and dysbiosis, which comprises administering, to an individual in need thereof, an effective dose of the association and/or composition according to the invention.
  • Example 1 Evaluation of pea proteins combined with polysaccharides (ii) - (iv) on the intestinal characteristics of systemic lupus erythematosus (SLE) using an MRL/lpr genetic mouse model
  • the animals were fed on a complete standard diet in the form of pellets supplied by the authorised breeder. Filtered tap water from the local mains supply was provided ad libitum.
  • the pea proteins (PP), polysaccharides and various combinations thereof were administered orally once a day starting from 16 weeks of age until 18 weeks of age using an oral gavage.
  • the following doses were tested: 150 mg of polysaccharides (a total of 3: Prunus cerasus, Prunus armeniaca and karaya gum; preferably in a weight ratio of 1 :1 :1) and 200 mg of pea proteins, preferably with a PP content of at least 80% by weight.
  • the polysaccharides were tested individually and in three different combinations, such as, for example: Polysaccharide 1 + PP; Polysaccharide 2 + PP; Polysaccharide 3 + PP).
  • the dose administered to the animals was defined by suitable conversion of the dose envisaged for humans based on the proportion of body surface.
  • the vehicle was saline solution.
  • MRL/lpr female mice were used (3 weeks of age; 20-25 g; Jackson Laboratory, USA) and C57BL/6 female mice as control groups (CTR) (3 weeks of age; 20-25 g; Envigo, Italy).
  • CTR control groups
  • the animals were housed in a controlled environment (22 ⁇ 2 °C, 55 ⁇ 15% relative humidity, light/dark cycle of 12 hours) with a standard diet and water ad libitum.
  • the experimental protocols began when the animals reached sixteen weeks of age.
  • the experiments on the animals were conducted in compliance with Italian legislation on the protection of animals used for experimental purposes and other scientific purposes (Ministerial Degree 116192) and Directive 2010/63/EU, as amended by Regulation (EU) 2019/1010, as well as ARRIVE guidelines.
  • the MRL/lpr mouse is a genetic model that shares many pathological characteristics with SLE (Katzav A. et al., Treatment of MRL/lpr mice, a genetic autoimmune model, with the Ras inhibitor, farnesylthiosalicylate (PTS). Clin Exp Immunol. 2001 Dec;126(3):570-7); in fact, the MRL/lpr strains spontaneously develop characteristics similar to lupus with an onset of disease at around 8 weeks of age and an evolution of around 16 weeks. In this regard, it was verified that the natural compounds tested are effective in restoring the intestinal barrier damaged by the progression of lupus.
  • the oral treatments were administered for two weeks when both mouse strains (C57BL/6 and MRL/lpr) reached sixteen weeks of age.
  • the natural compounds are effective in restoring the intestinal barrier damaged by the progression of lupus.
  • mice were randomly divided into the following experimental groups, using the C57BL/6 strain for the CTR group and the MRL/lpr strain for the SLE group.
  • Group 2 CTR + PP: sixteen-week-old C57BL/6 mice to which PP was administered orally once a day for 2 weeks
  • Group 10 SLE + PP: sixteen-week-old MRL/lpr mice to which PP was administered orally once a day for 2 weeks
  • mice were sacrificed by cervical dislocation 2 weeks after treatment, when they had reached 18 weeks of age.
  • the blood was collected for biochemical analyses of inflammatory and autoimmune markers and for the FITC- dextran test.
  • the FITC-dextran method was used to measure intestinal permeability in the C57BL/6 and MRL/lpr animals.
  • the mice were fasted for 6 hours, after which FITC-dextran was administered by gavage (500 mg/kg of body weight, 125 mg/mL).
  • 100 piL of blood were collected from the caudal vein after 1 h and 4 h.
  • the blood was centrifuged at 12,000* g for 5 min at 4° C.
  • the plasma concentration of FITC-dextran was measured with a microplate reader. The values were compared with a standard curve created by diluting FITC-dextran diluted with phosphate-buffered saline (1 : 1, v/v).
  • cytokines such as IL-113, IL-6 and TNF-o were measured in serum at the end of the experiment.
  • lipocalin-2 (LCN2), an indicator of the severity of lupus, was measured with an ELISA test.
  • autoantibodies such as antinuclear antibodies (ANA) and antismooth muscle antibodies (ASMA) were also evaluated. All the ELISA tests were carried out following the instructions of the kit manufacturer.
  • the first preliminary results are very promising and indicate that the association and the composition comprising said association, both forming the subject matter of the present invention, could have valid application in the prevention and treatment of autoimmune diseases, for example where said autoimmune diseases are selected from those physiopathologically associated with intestinal membrane damage, or broadly, in the case of rheumatoid arthritis and psoriatic arthritis; lupus, preferably systemic lupus erythematosus and/or Sjogren's syndrome).
  • the Applicant has observed that the association of active ingredients (I), (ii), (ill) and (iv) is capable of attenuating and/or treating damage to the intestinal membrane, in particular in mice having autoimmune diseases in which such damage is present.
  • the animals were fed on a complete standard diet in the form of pellets supplied by the authorised breeder. Filtered tap water from the local mains supply was provided ad libitum.
  • the pea protein (PP), polysaccharides and various combinations thereof were administered orally once a day starting from 16 weeks of age until 18 weeks of age using an oral gavage.
  • the dose administered to the animals was defined by suitable conversion of the dose envisaged for humans based on the proportion of body surface.
  • the vehicle was saline solution.
  • mice were used (3 weeks of age; 20-25 g; Jackson Laboratory, USA) and C57BL/6 female mice as control groups (CTR) (3 weeks of age; 20-25 g; Envigo, Italy).
  • CTR control groups
  • the animals were housed in a controlled environment (22 ⁇ 2 °C, 55 ⁇ 15% relative humidity, light/dark cycle of 12 hours) with a standard diet and water ad libitum.
  • the experimental protocols began when the animals reached sixteen weeks of age.
  • the MRL/lpr mouse is a genetic model that shares many pathological characteristics with SLE (Katzav A. et al., Treatment of MRL/lpr mice, a genetic autoimmune model, with the Ras inhibitor, farnesylthiosalicylate (FTS). Clin Exp Immunol. 2001 Dec;126(3):570-7); in fact, the MRL/lpr strains spontaneously develop characteristics similar to lupus with an onset of disease at around 8 weeks of age and an evolution of around 16 weeks. In particular, the oral treatments were administered for two weeks when both mouse strains (C57BL/6 and MRL/lpr) reached sixteen weeks of age. In this regard, it was verified that the natural compounds are effective in restoring the intestinal barrier damaged by the progression of lupus.
  • mice were randomly divided into the following experimental groups, using the C57BL/6 strain for the CTR group and the MRL/lpr strain for the SLE group.
  • colon, kidney and liver tissues were embedded in paraffin, sectioned into 7pm thick slices and stained with H&E for microscopic analyses.
  • immunohistochemistry was used to analyse the function of the intestinal barrier by evaluating the TJs in the colon samples.
  • the paraffin-embedded tissue samples were sectioned (7 pm), deparaffinised and treated according to the immunohistochemical protocol.
  • the sections were incubated overnight at 4°C with the following primary antibodies: zonula occludens-1 (ZO-1) (Santa Cruz Biotechnology sc-33725, 1 : 100 in PBS, v/v) and anti-occludin (Santa Cruz Biotechnology sc-13).
  • the slices were then incubated with a secondary antibody (Vector Laboratories). Subsequently, the antigenantibody complexes were detected using an avidin-biotin complex detection system (Vectastain ABC Kit, Vector Laboratories) and a 3, 3' -diaminobenzidine (DAB) substrate kit (Vector Laboratories). The sections were examined using a Nikon Eclipse Ci-L microscope.
  • the FITC-dextran method was used to measure intestinal permeability in the C57BL/6 and MRL/lpr animals. Briefly, the mice were fasted for 6 hours, after which FITC-dextran was administered by gavage (500 mg/kg of body weight, 125 mg/mL). After 1 h and 4 h, 100 piL of blood were collected from the caudal vein. The blood was centrifuged at 12,000x g for 5 min at 4° C. The plasma concentration of FITC-dextran was measured with a microplate reader. The values were compared with a standard curve created by diluting FITC-dextran in untreated plasma diluted with phosphate-buffered saline (1 : 1, v/v).
  • cytokines such as IL-113, IL-6 and TNF-o were measured in serum.
  • lipocalin-2 (LCN2), an indicator of the severity of lupus, was measured with an ELISA test.
  • autoantibodies such as antinuclear antibodies (ANA) and anti-smooth muscle antibodies (ASMA) were also evaluated. All the ELISA tests were carried out following the instructions of the kit manufacturer.
  • the first results indicate that the association comprising pea proteins and one or more of the tested active ingredients (tara gum, guar gum, xanthan gum, acacia gum, sugar beet pectin, carrageenan) seems to be able to attenuate and/or treat damage to the intestinal membrane in mice having autoimmune diseases in which such damage and/or an increased intestinal permeability and/or dysbiosis is present, in particular in a mouse model of systemic lupus erythematosus.
  • the tested active ingredients tara gum, guar gum, xanthan gum, acacia gum, sugar beet pectin, carrageenan

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Abstract

La présente invention concerne une nouvelle association de principes actifs d'origine végétale, les compositions pharmaceutiques, nutraceutiques et alimentaires les contenant et leurs utilisations en thérapie, en particulier pour le traitement et la prévention de maladies auto-immunes dont la physiopathologie est associée à une perméabilité intestinale et à une dysbiose accrues.
PCT/IB2024/055559 2023-06-06 2024-06-06 Nouvelle association de principes actifs d'origine végétale, compositions les contenant et utilisation en thérapeutique Ceased WO2024252335A1 (fr)

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WO2017207223A1 (fr) * 2016-05-31 2017-12-07 Novintethical Pharma Sa Compositions pour le traitement de troubles intestinaux
WO2023110855A1 (fr) * 2021-12-14 2023-06-22 Devintec Sagl Compositions pour le traitement de l'arthrite auto-immune

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PL3937983T3 (pl) * 2019-12-17 2025-08-11 9286-3620 Québec Inc. Doustne systemy dostarczania oparte na tworzących się in situ koacerwatach białko/polisacharyd

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017207223A1 (fr) * 2016-05-31 2017-12-07 Novintethical Pharma Sa Compositions pour le traitement de troubles intestinaux
WO2023110855A1 (fr) * 2021-12-14 2023-06-22 Devintec Sagl Compositions pour le traitement de l'arthrite auto-immune

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
MA LONGHUAN ET AL: "Loss of Gut Barrier Integrity In Lupus", FRONTIERS IN IMMUNOLOGY, vol. 13, 20 June 2022 (2022-06-20), Lausanne, CH, XP093206980, ISSN: 1664-3224, Retrieved from the Internet <URL:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9250981/pdf/fimmu-13-919792.pdf> [retrieved on 20240920], DOI: 10.3389/fimmu.2022.919792 *
SCUDERI SARAH ADRIANA ET AL: "Efficacy of a Product Containing Xyloglucan and Pea Protein on Intestinal Barrier Function in a Partial Restraint Stress Animal Model", INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, vol. 23, no. 4, 1 February 2022 (2022-02-01), Basel, CH, pages 2269, XP093112052, ISSN: 1661-6596, [retrieved on 20231214], DOI: 10.3390/ijms23042269 *

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