EP4355347A1 - Zusammensetzung zur prävention und/oder behandlung von entzündlichen erkrankungen - Google Patents

Zusammensetzung zur prävention und/oder behandlung von entzündlichen erkrankungen

Info

Publication number
EP4355347A1
EP4355347A1 EP22737531.8A EP22737531A EP4355347A1 EP 4355347 A1 EP4355347 A1 EP 4355347A1 EP 22737531 A EP22737531 A EP 22737531A EP 4355347 A1 EP4355347 A1 EP 4355347A1
Authority
EP
European Patent Office
Prior art keywords
extract
composition
composition according
inflammatory
treatment
Prior art date
Legal status (The legal status 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 status listed.)
Pending
Application number
EP22737531.8A
Other languages
English (en)
French (fr)
Inventor
Umberto DI MAIO
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Neilos SRL
Original Assignee
Neilos SRL
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 Neilos SRL filed Critical Neilos SRL
Publication of EP4355347A1 publication Critical patent/EP4355347A1/de
Pending legal-status Critical Current

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Classifications

    • 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)
    • A61K36/22—Anacardiaceae (Sumac family), e.g. smoketree, sumac or poison oak
    • 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)
    • A61K36/53—Lamiaceae or Labiatae (Mint family), e.g. thyme, rosemary or lavender
    • A61K36/537—Salvia (sage)
    • 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
    • A61K38/46—Hydrolases (3)
    • A61K38/48—Hydrolases (3) acting on peptide bonds (3.4)
    • A61K38/4873—Cysteine endopeptidases (3.4.22), e.g. stem bromelain, papain, ficin, cathepsin H
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

  • composition for the prevention and/or treatment of inflammatory diseases “Composition for the prevention and/or treatment of inflammatory diseases”
  • the present invention relates to a composition containing a combination of an extract of Mangifera indica, bromelain and an extract of Salvia officinalis useful for the prevention and/or treatment of inflammatory diseases.
  • composition is particularly effective due to the synergistic action of its components.
  • Inflammation also known as phlogosis, is the ensemble of changes and variations that occur in a specific region or in a wider area of the body following damage. It is an adaptive response usually triggered by noxious stimuli or conditions. Physical agents such as trauma or heat, chemical agents such as acid substances, or still biological agents such as bacteria and viruses may play a role in the genesis of pro-inflammatory conditions. Therefore, it is appreciated as an important defence mechanism in case of tissue damage or during infections, which acts with the aim of restoring homeostasis. Inflammation, in general, is a predominantly acute and local reaction but in various cases can become chronic and affect larger and larger areas of the body.
  • the pivotal points of inflammation are five and are defined as calor, increased temperature of the affected area caused by increased vascularization, tumor, swelling of the affected area due to the formation of exudate following vasodilation, rubor, redness resulting from hyperaemia, dolor, a painful sensation triggered by the stimulation of sensory endings by the inflammatory agent or by the components of the inflammatory response, and finally, the functio laesa, which consists in the functional impairment of the affected area. Inflammation may be induced by either endogenous or exogenous factors.
  • Microbial factors that induce inflammation are PAMPs (Pathogen- Associated Molecular Patterns) and virulence factors, whereas non-microbial factors include allergens, irritants, foreign bodies, and toxic compounds.
  • endogenous inflammation inducers are signals produced by stressed and damaged cells, or by tissues with impaired function.
  • Inflammation mediators are divided into 7 groups according to their biochemical properties into: vasoactive amines, vasoactive peptides, lipid mediators, fragments forming part of the complement system, cytokines, chemokines, and proteolytic enzymes.
  • Lipid mediators derive from the phospholipids of the cell membrane and have arachidonic acid as the main component, which can be metabolized by cyclooxygenases (COX-1 and COX-2) into prostaglandins, thereby acting as an important algesic agent and fever inducer, or be metabolized by lipoxygenases into leukotrienes and lipoxins.
  • COX-1 and COX-2 cyclooxygenases
  • Fragments forming part of the complement system act by promoting granulocyte and monocyte recruitment and induce mast cell degranulation.
  • Pro-inflammatory cytokines such as TNF-a, IL-6, IL-1 and many others are produced by several cell types, particularly mast cells and macrophages, and are important in the inflammatory response as they are involved in endothelial and leukocyte activation.
  • Chemokines on the other hand, control leukocyte extravasation and chemotaxis.
  • proteolytic enzymes have different roles ranging from the body's defence to tissue remodelling.
  • the inflammatory response may go out of control and may turn from a defence, homeostasis-restoring mechanism into a cause triggering or even exacerbating a disease.
  • NSAIDs Non- Steroidal Anti-Inflammatory Drugs
  • COX-1 and COX-2 Two isoforms of the COX enzyme
  • This mechanism prevents the formation of prostaglandins and thromboxane, which are major pro-inflammatory factors.
  • prolonged use of this class of drugs is accompanied by non-negligible side effects, the most frequent of which are at the gastrointestinal and cardiovascular levels.
  • SAIDs Steoidal Anti-Inflammatory Drugs
  • glucocorticoids also known as glucocorticoids.
  • Anti-inflammatory activity is mediated through various mechanisms of action, but the major mechanism of action is thought to be cytokine-induced gene transcription inhibition.
  • SAIDs can enter the cell and bind the cytoplasmic steroid receptor; subsequently, this complex migrates within the nucleus and recognizes and binds specific sequences on the DNA. This prevents NF- kB and AP-1 transcription factors from acting.
  • glucocorticoids are widely used in the treatment of inflammatory and autoimmune chronic diseases, their use is related to annoying and in some cases serious side effects such as carbohydrate metabolism alteration, osteoporosis, menstrual abnormalities, hyperlipidemia, decreased GH secretion, and they also have important interactions with other classes of drugs.
  • the side effects are usually directly proportional to the duration of treatment and the dosage used.
  • New drugs designated as monoclonal antibodies or more simply biologies, can act and inhibit the diverse activities of the various pro-inflammatory agents in a highly selective manner. However, even these are not free from side effects, indeed the major side effect consists precisely in reducing the body’s defences against other noxious stimuli and infections.
  • Inflammation therefore occurs in a wide range of diseases that can affect all areas of the body.
  • osteoarthritis One of the classic diseases associated with a high inflammatory state is osteoarthritis. After a trauma, the classic signs of inflammation are easily visible and detectable within the tissues and in the synovial fluid of the joints. If inflammation, which initially plays an important role in optimal healing, does not resolve on its own, it can be an important risk factor for the development of post-traumatic osteoarthritis. In addition, inflammation can lead to progressive cartilage degeneration and subsequent development of chronic post- injury symptoms.
  • the urogenital tract is also often subject to inflammatory states, especially with advancing age. Frequently, the pro-inflammatory state is associated with infections caused by bacteria and viruses, but also with a wide range of non-infectious processes. The most common inflammatory processes are vulvovaginitis, metritis, endometritis, prostatitis, epididymitis, orchitis. These are all diseases which, if not treated properly and correctly, can lead to infertility.
  • inflammation plays a major role in various fields, whether in the case of infections, systemic diseases, or damage caused by a physical agent. Inflammation is the basis of stomatitis, which is a widespread inflammation of the oral cavity, but periodontitis, gingivitis and canker sores can also occur. Furthermore, the role of inflammation in the case of tooth extraction is not to be underestimated, as pain and swelling are important limiting factors for this procedure.
  • extract in the context of this description, means any product referable to a plant drug including all products derived from mechanical treatments (pulverization, grinding, mixing and/or other methods) or extractive treatments (solvent extraction, distillation, and/or other specific methods) performed on a drug.
  • the object of the present invention is a composition containing a combination of an extract of Mangifera indica, bromelain and an extract of Salvia officinalis useful for the prevention and/or treatment of inflammatory diseases in both humans and animals, and in particular osteo articular, urogenital, dental, and gynecological inflammatory diseases.
  • MANGIFERA INDICA MANGIFERA INDICA
  • Mangifera indica known by the common name of mango, is a tree belonging to the Anacardiaceae family, native to India but now cultivated in all tropical areas of the world. Since ancient times, it has been used in Ayurvedic and indigenous medicine, and different pharmacological properties are attributed to the different parts of the tree.
  • mango is one of the most famous and used tropical fruits, second only to bananas. It contains mangiferin, a glycosidic xanthone, which is attributed with high antioxidant activity, ability to inhibit lipid peroxidation, immunomodulation, and cardiotonic, hypotensive, anti-degenerative and hypoglycemic activities.
  • the seeds are used to treat asthma and as astringents. Inhalation of smoke from the burning of leaves is used to treat upper respiratory tract diseases.
  • the bark has astringent abilities and is used in diphtheria and rheumatism, and is believed to have a tonic action on the mucous membranes.
  • mangiferin has been shown to have the ability to suppress the activation of the transcription factor NF-kB, which in turn controls the production of pro-inflammatory cytokines.
  • NSAIDs non-steroidal anti inflammatory drugs
  • the athletes were divided into two groups, one was given the supplement (140 mg containing mangiferin in a quantity greater than or equal to 60% + 140 mg quercetin), while the other was given a placebo.
  • the supplement or placebo was administered one hour before the competition, and then one tablet was administered every 8 h for the next 24 h.
  • the group receiving the supplement exhibited a decrease in pain sensation, less muscle damage caused by physical exercise and also improved muscle recovery.
  • Bromelain is the generic name for a family of proteolytic enzymes containing the sulfhydryl group. However, the beneficial effects of bromelain are also attributable to the constituents that are not part of the proteolytic fraction such as peroxidase, acid phosphatase, various protein inhibitors, and organic calcium.
  • Oral absorption is high, especially bromelain is absorbed intact, and the plasma peak is approximately one hour after administration. However, the proteolytic activity is rapidly inactivated.
  • anti-inflammatory activity is mainly due to its ability to inhibit bradykinin formation at the site of inflammation through action on the kinin-kallikrein system, and it is also able to limit fibrin production, thus decreasing the intermediates of the coagulation cascade.
  • bromelain had the ability to significantly decrease the production of prostaglandins and substance P, two important mediators of the inflammatory and pain response. Bromelain was already effective at a dose of 10 mg/kg. In addition, the above study also assessed the activity of bromelain in vitw, however, it had no effect, indeed the value of substance P increased. This shows that bromelain does not act directly on these mediators, but implicitly, resulting in a decrease in the two inflammatory markers.
  • bromelain by acting as a signalling molecule appears to have the ability to intervene in and affect different cell signalling cascades, many of which are involved in cell survival.
  • a mouse carcinogenesis model showed that treatment with 1 mg/animal of bromelain caused increased regulation of p53 and Bax, two important transcription factors involved in the apoptosis process, and subsequent activation of caspase 3 and caspase 9 with concomitant decrease in Bcl-2.
  • bromelain at a dose of 5 mg/ml demonstrated the ability to decrease platelet activity and aggregation in blood samples taken from 10 healthy, non-smoking male volunteers (Glaser et ah).
  • bromelain when administered orally at a dose of 60 mg/kg was assessed in a mouse laser-induced thrombosis model. Under these conditions, bromelain showed the ability to significantly inhibit the formation of thrombi in rat mesenteric vessels. The above in vitro and in vivo scientific evidence was later also confirmed in clinical studies. Bromelain has actually been shown to be effective in treating inflammatory diseases.
  • Salvia officinalis is a perennial aromatic plant belonging to the Laminaceae family and is widely spread throughout the world, although it is native to the Middle east and the Mediterranean area.
  • the aerial parts of S. officinalis have been commonly used for centuries for food purposes and in traditional medicine.
  • Asian and Latin American popular medicine it has been widely used for a long time as a remedy in the treatment of different diseases such as ulcers, rheumatism, tremors, gout, vertigo, inflammation, and diarrhoea.
  • S. officinalis is used to treat moderate dyspepsia such as gastroesophageal reflux or the sense of swelling, excessive sweating, age-related cognitive decline, and inflammation of the upper respiratory tract and skin.
  • Oxidative stress plays a pivotal role in the early stages and progression of several diseases.
  • High oxidative stress occurs when the production of reactive oxygen species (ROS) through the mitochondrial electron transport chain, NAPDH oxidase activity and xanthine oxidase activity exceeds the antioxidant activity of catalase (CAT), glutathione peroxidase (GPx), and superoxide dismutase (SOD).
  • ROS reactive oxygen species
  • CAT catalase
  • GPx glutathione peroxidase
  • SOD superoxide dismutase
  • Natural substances with antioxidant activity can protect cells from excessive ROS production and possibly prevent tissue damage caused by high oxidative stress.
  • the extract when administered orally at a dose of 10, 30 and 100 mg/kg was shown to significantly decrease leukocyte and plasma extravasation induced by acetic acid administration. Furthermore, in the formalin test, the extract showed a significant decrease in pain both in the initial phase, known as neurological pain, and in the subsequent phase, known as inflammatory pain.
  • camosol at a dose of 10 mg/kg and ursolic acid/oleanic acid at a dose of 30 mg/kg significantly inhibited the inflammatory phase induced by the formalin test and the nociceptive and mechanical pain caused by cinnamaldehyde.
  • the S. officinalis extract and specifically camosic acid and camosol, can inhibit the production of prostaglandins by selective inhibition of mPGES-1 (microsomal Prostaglandin E Synthase- 1) with an IC50 value of 5.0 mM.
  • mPGES-1 microsomal Prostaglandin E Synthase-1
  • the treatment consisted of taking one tablet per day for 2 months. At the end of the study, a significant decrease in physical and psychological symptoms in premenstrual pain was achieved in the group treated with the product obtained from S. officinalis.
  • the composition object of the present invention contains the combination of an extract of Mangifera indica, bromelain and an extract of Salvia officinalis in admixture with a suitable pharmaceutically acceptable carrier.
  • Suitable pharmaceutically acceptable carriers are those commonly known to those skilled in the art for the preparation of pharmaceutical compositions for oral administration such as solutions, suspensions, powders or granules, tablets, capsules, pellets.
  • such pharmaceutically acceptable carriers may consist of binders, diluents, lubricants, glidants, disintegrants, solubilisers (wetting agents), stabilizers, dyes, anti-caking agents, emulsifiers, thickeners and gelling agents, coating agents, humectants, sequestrants, sweeteners.
  • diluents can be: magnesium carbonate, microcrystalline cellulose, starch, lactose, sucrose; mainly used lubricants are magnesium stearate, stearic acid, sodium stearyl fumarate.
  • Colloidal silica and magnesium silicate may be mentioned as glidants, cross-linked polyvinylpyrrolidones and sodium starch glycolate may be mentioned as disintegrants, surfactants such as TWEEN or sodium lauryl sulphate may be mentioned as solubilisers, and all classes of preservatives (sorbic acid and derivatives, benzoic acid and derivatives, parabens), antioxidants (ascorbic acid and derivatives, tocopherol), acidifiers (phosphoric acid, tartaric acid) may be mentioned as stabilizers.
  • preservatives sorbic acid and derivatives, benzoic acid and derivatives, parabens
  • antioxidants ascorbic acid and derivatives, tocopherol
  • acidifiers phosphoric acid, tartaric acid
  • Thickeners and gelling agents can be carrageenan, pectins, starches; coating agents include, e.g., waxes and derivatives; anti-caking agents include calcium or magnesium carbonate; humectants include sorbitol, mannitol; sequestrants include EDTA and derivatives; dyes include aspartame, potassium acesulfame.
  • the composition object of the present invention is preferably a solid, liquid or semi-solid composition for oral use, still more preferably powder or granules, a capsule, a tablet, an aqueous solution, a suspension, a buccal powder, a pellet.
  • composition object of the present invention contains an extract of Mangifera indica, bromelain and an extract of Salvia officinalis.
  • the extract of Mangifera indica is present in an amount between 1 mg and 5000 mg, preferably between 5 mg and 4000 mg, still more preferably between 10 mg and 2000 mg.
  • Bromelain is present in an amount between 5 mg and 10000 mg, preferably between 10 mg and 7000 mg, still more preferably between 20 mg and 5000 mg.
  • the extract of Salvia officinalis is present in an amount between 1 mg and 5000 mg, preferably between 5 mg and 4000 mg, still more preferably between 10 mg and 2000 mg.
  • the composition object of the present invention is particularly effective in the prevention and/or treatment of inflammatory diseases.
  • compositions object of the present invention are particularly effective in the prevention and/or treatment of inflammatory diseases, in particular at the osteoarticular, urogenital, dental and gynecological levels.
  • compositions object of the present invention are particularly effective in the prevention and/or treatment of osteoarthritis, arthritis, arthrosis, vulvovaginitis, metritis, mastitis, endometritis, prostatitis, epididymitis, orchitis, periodontitis, gingivitis, canker sores, stomatitis, inflammation following dental procedures, soft tissue inflammation.
  • the composition object of the present invention simultaneously allows:
  • a further object of the present invention is a composition containing the combination of an extract of Mangifera indica, bromelain and an extract of Salvia officinalis in admixture with a suitable pharmaceutically acceptable carrier for use in the prevention and/or treatment of inflammatory diseases.
  • the composition can be a medical device, a food supplement, a nutraceutic, dietetic and nutritional composition, a food product, a beverage, a nutraceutic product, a medicament, a medicated food, a pharmaceutical composition, a food for special medical purposes, a complementary feed, a complete feed, a feed intended for particular nutritional purposes, or a medicated feed.
  • the extract of Mangifera indica has a strong anti-inflammatory activity by inhibiting the NfKB factor and a good antioxidant activity.
  • Bromelain provides anti-inflammatory efficacy, prevents the phosphorylation and degradation of IKB-a related to the activity of NfKb, and inhibits bradykinin activity.
  • the extract of Salvia officinalis acts by inhibiting 5-LOX and mPGES-1, ensuring anti-inflammatory activity.
  • the synergistic activity of the aforementioned active ingredients is investigated through the use of in vitro and/or in vivo tests capable of assessing the anti-inflammatory and antioxidant activity of the compositions according to the present invention and/or of comparative compositions. Tests and experimental models known in the literature are used for the evaluation of these activities.
  • cytokines characterizing the inflammatory process (such as, for example, TNF-a, IL-1, IL-4, IL-6, IL-8, IL-10, IL-17, INF-Y, COMP) during inflammatory processes induced by LPS or another pro-inflammatory agent.
  • WBA Whole Blood Assay
  • PBMC Peripheral Blood Mononuclear Cells
  • doses per dosage unit of the active components of the compositions object of the present invention are now provided for illustrative purposes.
  • Daily doses are intended to be administered in a suitable oral dosage form and divided into one or more dosage units.
  • EXAMPLE 2 powder or granules for oral solution/suspension
  • compositions are prepared according to conventional techniques.

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  • Health & Medical Sciences (AREA)
  • Natural Medicines & Medicinal Plants (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Biotechnology (AREA)
  • Mycology (AREA)
  • Microbiology (AREA)
  • Medical Informatics (AREA)
  • Botany (AREA)
  • Alternative & Traditional Medicine (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Immunology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines Containing Plant Substances (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
EP22737531.8A 2021-06-16 2022-06-15 Zusammensetzung zur prävention und/oder behandlung von entzündlichen erkrankungen Pending EP4355347A1 (de)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IT102021000015704A IT202100015704A1 (it) 2021-06-16 2021-06-16 “Composizione per la prevenzione e/o il trattamento di affezioni flogistiche”
PCT/IB2022/055541 WO2022264058A1 (en) 2021-06-16 2022-06-15 Composition for the prevention and/or treatment of inflammatory diseases

Publications (1)

Publication Number Publication Date
EP4355347A1 true EP4355347A1 (de) 2024-04-24

Family

ID=77711295

Family Applications (1)

Application Number Title Priority Date Filing Date
EP22737531.8A Pending EP4355347A1 (de) 2021-06-16 2022-06-15 Zusammensetzung zur prävention und/oder behandlung von entzündlichen erkrankungen

Country Status (3)

Country Link
EP (1) EP4355347A1 (de)
IT (1) IT202100015704A1 (de)
WO (1) WO2022264058A1 (de)

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CU22846A1 (es) * 1998-12-29 2003-04-28 Ct De Quimica Farmaceutica Composiciones farmacéuticas y nutricionales a partir de extractos de mangifera indica l
EP1208849B1 (de) * 2000-11-28 2015-10-28 URSAPHARM Arzneimittel GmbH Verwendung von Bromelain zur adjuvanten Therapie der Wundheilung
IT201800006474A1 (it) * 2018-06-20 2019-12-20 Composizione per l’uso nella prevenzione e/o nel trattamento di patologie osteoarticolari.

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Publication number Publication date
IT202100015704A1 (it) 2022-12-16
WO2022264058A1 (en) 2022-12-22

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