WO2019026047A1 - Composition destinée à être utilisée dans la prévention et/ou le traitement de maladies gastriques ou gastro-œsophagiennes - Google Patents

Composition destinée à être utilisée dans la prévention et/ou le traitement de maladies gastriques ou gastro-œsophagiennes Download PDF

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Publication number
WO2019026047A1
WO2019026047A1 PCT/IB2018/055866 IB2018055866W WO2019026047A1 WO 2019026047 A1 WO2019026047 A1 WO 2019026047A1 IB 2018055866 W IB2018055866 W IB 2018055866W WO 2019026047 A1 WO2019026047 A1 WO 2019026047A1
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composition
gastric
gastroesophageal
stomach
antacid
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PCT/IB2018/055866
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English (en)
Inventor
Umberto DI MAIO
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Neilos S.r.l.
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Priority to EP18762395.4A priority Critical patent/EP3661533A1/fr
Publication of WO2019026047A1 publication Critical patent/WO2019026047A1/fr

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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)
    • A61K36/88—Liliopsida (monocotyledons)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/06—Aluminium, calcium or magnesium; Compounds thereof, e.g. clay
    • A61K33/10—Carbonates; Bicarbonates
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Y—ENZYMES
    • C12Y304/00—Hydrolases acting on peptide bonds, i.e. peptidases (3.4)
    • C12Y304/22—Cysteine endopeptidases (3.4.22)
    • C12Y304/22002—Papain (3.4.22.2)
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Y—ENZYMES
    • C12Y304/00—Hydrolases acting on peptide bonds, i.e. peptidases (3.4)
    • C12Y304/22—Cysteine endopeptidases (3.4.22)
    • C12Y304/22004—Bromelain (3.4.22.4)
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Y—ENZYMES
    • C12Y304/00—Hydrolases acting on peptide bonds, i.e. peptidases (3.4)
    • C12Y304/22—Cysteine endopeptidases (3.4.22)
    • C12Y304/22014—Actinidain (3.4.22.14)

Definitions

  • the present invention relates to a composition of substances preferably obtained from natural sources, which is effective in the prevention and/or treatment of gastric or gastroesophageal diseases selected from the group consisting of heartburn, dyspepsia, and gastroesophageal reflux disease.
  • Heartburn can arise spontaneously or following ingestion of irritating foods or particular drugs. It is generally associated with reflux, which brings gastric or duodenal material in contact with a dysfunctional esophagus. In the absence of a diagnosis of hiatal hernia or aerophagia, heartburn is to be considered as a functional disorder. If heartburn is secondary to diseases such as reflux oesophagitis, it usually appears daily and any factor capable of facilitating reflux, such as leaning forward, causes the appearance of the disorder. Hindered gastric emptying and nocturnal decubitus can increase heartburn.
  • Gastric secretion is a process dependent on neuronal (acetylcholine), paracrine (histamine), and endocrine (gastrin) factors. These factors act on the receptors M3, H2, CCK2, respectively, mainly located on the membrane of gastric parietal cells.
  • HISTAMINE It binds to the histaminergic receptors of parietal cells. Histamine, by interacting with the H2 receptor, in synergy with gastrin stimulates the release of hydrochloric acid and pepsin.
  • ACETYLCHOLINE It stimulates parietal cells and chief cells, thus increasing the secretory activity of the stomach, and also increases smooth muscle contraction.
  • dyspepsia refers to a series of episodic or persistent symptoms, mainly perceived at the upper part of the abdomen. Dyspepsia can be associated with a sense of heaviness and anorexia.
  • Prokinetic-acting drugs They act through several pharmacological mechanisms of action. They lead to an increase in the frequency of movement of the stomach, thereby increasing the gastric emptying rate.
  • Antacids They react with the hydrochloric acid present in the stomach, increasing the pH of the stomach contents and preventing damage to the esophageal mucosa in case of reflux.
  • Gastroesophageal reflux refers to unintentional and unconscious passage of part of the stomach contents into the esophagus, with no participation of the stomach and abdomen muscles.
  • the esophagus is a 25-30 cm long canal, which connects the mouth with the stomach; two sphincter structures can be identified along its length: the first between the hypopharynx and the cervical portion of the esophagus (Upper Esophageal Sphincter, UES), the second, i.e. the Lower Esophageal Sphincter (LES), at the esophagus-stomach junction.
  • UES Upper Esophageal Sphincter
  • LES Lower Esophageal Sphincter
  • the latter is a high-pressure area representing the main anti-reflux structure, due to its location between the negative-pressure intra-thoracic area and the positive-pressure intra-abdominal area.
  • the diaphragm collar consisting of diaphragm bundles, which, by placing itself like a scarf around the esophagus, squeezes the lumen thereof during the inspiratory phase.
  • GERD GERD
  • esophageal hiatus the extension of a portion of the stomach inside the thorax, through a hole in the diaphragm called the esophageal hiatus
  • GERD gastroduodenal contents
  • the walls of the esophageal hiatus adhere closely to the esophagus, but it can happen that the anchoring structures of the lower portion of the esophagus lose tone, thus favouring the ascent of a small part of the stomach into the thorax.
  • the frequent and repeated contact of the regurgitated gastric material with the esophageal mucosa exerts thereon a damaging action that is all the more serious the longer the contact time and the lower the pH of the reflux.
  • the persistent phlogistic action affecting the esophageal mucosa leads to an inflammatory reaction that can evolve into ulcerations, stenosis and so-called columnar metaplasia (or Barrett's epithelium, the single most important risk factor for the development of esophageal adenocarcinoma).
  • Antacids are over-the-counter drugs that offer rapid relief to the symptoms of the disease, but are not able to induce a curative effect in erosive esophagitis. These drugs contain carbonates or bicarbonates or other basic salts that reduce the acidity of the stomach by reacting with hydrochloric acid and releasing carbon dioxide.
  • H 2 antagonist drugs - such as ranitidine, famotidine, cimetidine - provide temporary relief of symptoms, although with a slower onset time than antacids. Use for prolonged periods of time is not recommended as patients may develop tolerance within 1 -2 weeks, and in any case the effect of these drugs is not curative.
  • alginates are also used for the symptomatic treatment of GERD.
  • Alginates such as sodium alginate, are natural polysaccharides, which upon contact with the gastric environment precipitate forming a low-density gel in minutes.
  • Bicarbonates and carbonates almost always present in commercially available alginate formulations, release carbon dioxide, which is trapped inside the alginate gel that is able to float on the gastric contents.
  • the alginate gel is formed in the portion of the stomach close to the gastroesophageal junction, right where the acid pocket develops. In this way, the ascent of acid from the stomach to the esophageal canal is blocked or greatly reduced.
  • composition of the invention is as defined in appended claim 1. Further features and advantages of the invention are defined in the dependent clauns. The claims form an integral part of the present specification. A detailed description of some preferred embodiments of the invention is provided hereinafter.
  • the synergistic composition of the present invention is a supplement useful for the treatment and prevention of gastric and gastroesophageal diseases, preferably heartburn, dyspepsia, and/or gastroesophageal reflux disease.
  • gastric and gastroesophageal diseases preferably heartburn, dyspepsia, and/or gastroesophageal reflux disease.
  • the synergistic action takes place between the antacid, the extract from a plant of the genus Musa, and the protease enzyme.
  • the antacid present in the composition of the invention is any chemical compound commonly known as an effective antacid, i.e. a compound that is capable of reacting with the hydrochloric acid present in the gastric acids, thus raising the pH of the stomach, thereby reducing potential damage to the gastric and esophageal mucosa that could result from contact with the acid.
  • the antacid is preferably a pharmaceutically acceptable basic salt, more preferably selected from the group consisting of carbonates, bicarbonates, citrates, hydroxides, metal oxides, trisilicates and any combination thereof.
  • Catecholamines such as norepinephrine, dopamine, serotonin, tryptophan and pectin were isolated from the pulp and the peel of M. sapientum and M. paradisiaca fruits. Flavonoids and derivatives (leucocyanidin, quercetin), sitosterol, sitoindosides, triterpenes, celluloses, hemicelluloses, amino acids, etc. were also found.
  • Extracts from M. sapientum fruits thanks to the presence of several compounds, mainly including the flavonoid leucocyanidin derivative and pectin, could be used as adjuvants in the treatment of diseases associated with acid hypersecretion or in case of poor digestion for the protection of gastric mucosal integrity.
  • the digestive enzyme in the composition of the present invention is a protease enzyme capable of breaking the peptide bonds in proteins, thus reducing them into peptides that can be absorbed by the body.
  • the kiwi fruit is known for its various pharmacological properties, for its high content of vitamin C and, in particular, for the protease enzyme actinidain, which has been shown to be capable of promoting digestion and gastric emptying.
  • actinidain was suggested to be involved in the defence of the kiwi fruit from pathogens. Numerous studies have shown that the rate and extent of digestion of proteins taken in with the diet have the ability to change the stomach emptying rate (SER).
  • Actinidain has also been shown to be able to degrade different types of proteins including beef muscle proteins, collagen, casein, and increase the digestive effect of pepsin at the gastric level.
  • actinidain promotes protein digestion and consequently increases the stomach emptying rate: this reduces the frequency of reflux episodes, with consequent reduction of the damage to the esophageal mucosa.
  • Papain is obtained from the fruit of the Carica papaya, which belongs to the small Caricaceae family.
  • the fruit, the leaves, and the latex extracted from the fruit are widely used because of their various pharmacological properties.
  • the main chemical compound extracted from the fruit is papain, a proteolytic enzyme used as an active ingredient and as a reagent in the food and leather industry.
  • papain there are several other chemical compounds in the C. papaya extract, such as vitamins, proteins, fibres, carbohydrates, minerals, carpaine, carposide, and the enzyme myrosine.
  • Papain is a cysteine protease and belongs to a protein family provided with various activities including the endopeptidase, aminopeptidase, and dipeptidyl peptidase activities.
  • Cys-25, Asn-175 and His- 159 constituting the catalytic triad, are present within the active site of the enzyme.
  • Asn-175 changes the orientation of the imidazole ring of His- 159, which deprotonates the cysteine Cys-25; this allows the formation of a powerful nucleophile that is able to attack the peptide bond and form a thioether intermediate, which in turn is attacked by a water molecule that completes the hydrolysis reaction.
  • Papain does not have high selectivity of action, although hydrolysis catalysed by this enzyme preferentially occurs at a peptide bond between a hydrophobic amino acid residue (Ala, Val, Leu, He, Phe, Tip, Tyr) and an arginine or lysine residue.
  • a hydrophobic amino acid residue Al, Val, Leu, He, Phe, Tip, Tyr
  • this enzyme in the composition of the invention is based on its ability to hydrolyze the peptide bonds of proteins taken in with the diet. This allows a greater digestion rate and consequently a greater stomach emptying rate.
  • actinidain another cysteine protease isolated from kiwi. Given the similarity of the two enzymes, it is expected that both are able to contribute to increasing the digestion rate of proteins taken in with the diet. This should lead to fewer problems of dyspepsia and gastroesophageal reflux.
  • Bromelain is a mixture of proteolytic enzymes contained in the fruit and the stem of pineapples (Ananas comosiis L. Men.). Bromelain also contains peroxidases, acid phosphatases, protease inhibitors. Its uses include the use in food supplements as a digestive aid thanks to its proteolytic action. Different titres are used to indicate the activity of bromelain, the most used are the following:
  • bromelain standardized to 2000 MCU would correspond to 1200 GDU, the daily dose is between 200-2000 mg.
  • the dose of bromelain is often divided into 4 times/day.
  • the present composition may be used for the treatment of gastric and esophageal diseases, in particular heartburn and gastroesophageal reflux disease.
  • the effectiveness of the composition is derived from the following component activities:
  • Bicarbonates are capable of neutralizing gastric acidity by reacting with hydrochloric acid. In this way, they protect the mucous membranes from any acid-induced damage.
  • the extract from the plant of the genus Musa thanks to its content of chemical compounds such as pectin, phosphatidylcholine and leucocyanidin, has mucoprotettive and antiulcerogenic activities.
  • the digestive enzymes by degrading the proteins, lead to an increased stomach emptying rate. In this way, they reduce the contact of the acid with the gastric mucosa and the frequency of gastroesophageal reflux episodes, thereby preventing any injury that may result from the contact of the acid with the gastric and esophageal mucosa.
  • the synergistic action takes place between the antacid, preferably carbonate and/or bicarbonate, the extract from a plant of the genus Musa, and at least one digestive enzyme, preferably actinidain, papain and/or bromelain.
  • the antacid is administered in an amount comprised between 10 mg and 500 mg, for example by administration of a dosage form in which the antacid is present at a concentration comprised between 5% and 90% w/w, more preferably in an amount comprised between 10% and 80% by weight based on the total weight of the composition;
  • the extract from the plant of the genus Musa is administered in an amount comprised between 20 mg and 4000 mg, for example by administration of a dosage form in which the extract is present at a concentration comprised between 2% and 90% w/w, more preferably in an amount comprised between 5% and 85% by weight based on the total weight of the composition;
  • the at least one digestive enzyme which is preferably selected from actinidain, papain and/or bromelain, is administered in an amount comprised between 0.1 mg and 300 mg, for example by administration of a dosage form in which the enzyme is present at a concentration by weight ranging between 0.1% and 40% w/w, more preferably in an amount comprised between
  • the dosage form may be a pharmaceutical composition or a supplement including the above-mentioned active ingredients mixed together, or may be a kit-of-parts for the simultaneous or sequential administration of the above-mentioned active ingredients.
  • a preferred embodiment consists of a kit-of- parts, in which the active principles are formulated into two separate sachets, so as to ensure greater flexibility in the administration of the formulation itself.
  • the digestive enzymes are administered immediately after meals, while the antacids are administered on an empty stomach, when its pH is lowered. This mode of administration maximizes the effectiveness of the combination of active principles according to the invention against gastric and gastroesophageal diseases.
  • the extract from the fruit of the plant of the genus Musa in this embodiment is administered together with the antacids, however administration with the at least one digestive enzyme is also contemplated.
  • gastric secretion volume of gastric contents, pH and total acidity
  • mice Male ICR-strain mice weighing 20-25 g supplied by the company Charles River were used. The animals, housed in temperature-controlled rooms (temperature of 23 ⁇ 2°C, humidity 50 ⁇ 2%, 12-hour light-dark cycles), had free access to water and food, which consisted of a standard diet supplied by the company Mucedola Mangimi (Settimo Milanese, Italy). All experiments were performed in observance of Legislative Decree no. 1 16 of 27 January 1992 and according to the guidelines of the Council of the European Union (86/609/EEC and 2010/63/EU).
  • Gastric emptying was evaluated with the method described by Smits and Lefebvre ( 1996) [4], For determining the gastric emptying, the animals were orally administered a marker (0.2 ml/mouse of a suspension containing 50 mg of phenol red in 100 ml of 1.5% carboxymethylcellulose). Twenty minutes later, the animals were sacrificed in a C0 2 saturated atmosphere and the stomach was removed. The stomach was positioned inside a test tube containing 4 ml of normal saline; after 20 seconds of stirring, 2 ml of 1 M NaOH were added to each test tube in order to obtain the maximum colour intensity. Spectrophotometric analysis (560 nm) was carried out on 1 ml of this solution. The percentage of gastric emptying was calculated according to the following formula:
  • mice Four hours after the surgical procedure (the time required to cause submaximal injury of the esophageal mucosa) [6], the mice were sacrificed in a C0 2 saturated atmosphere and the esophagus and stomach were removed for assessing: 1) macroscopic esophageal and gastric damage, 2) degree of esophageal and gastric inflammation (myeloperoxidase activity), and 3) characteristic parameters of gastric secretion (volume of the gastric contents, pH and total acidity).
  • the esophagus (opened longitudinally) and stomach (opened along the greater curvature) were spread out on a polystyrene support and analysed with the aid of a microscope for the detection of mucosal injury. Mucosal damage was determined by using a scoring scale that takes into account the severity and extent of hyperaemia and haemorrhagic erosions.
  • MPO myeloperoxidase activity
  • the supernatants were incubated with NaPP (sodium phosphate buffer pH 5.5) and 16 mM TMB (tetramethylbenzidine) followed, after a five-minute incubation at room temperature, by addition of H2O2 diluted in NaPP.
  • the reaction was quenched with 2M cold acetic acid and 1 ml of the reaction solution was spectrophotometrically read at a wavelength ( ⁇ ) of 650- 655 nm. The values obtained were compared to a standard MPO curve and the results expressed as U/ml of MPO.

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Abstract

La présente invention concerne une composition synergique de substances naturelles, qui est particulièrement efficace dans le traitement et la prévention de maladies gastriques ou gastro-œsophagiennes. La composition selon l'invention comprend la combinaison synergique d'au moins un antiacide, d'un extrait d'un fruit d'une plante du genre Musa et d'au moins une enzyme digestive de protéase. La composition synergique selon la présente invention peut se présenter sous la forme d'une composition pharmaceutique ou d'un complément alimentaire, ou sous la forme d'un kit de pièces.
PCT/IB2018/055866 2017-08-04 2018-08-03 Composition destinée à être utilisée dans la prévention et/ou le traitement de maladies gastriques ou gastro-œsophagiennes WO2019026047A1 (fr)

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EP18762395.4A EP3661533A1 (fr) 2017-08-04 2018-08-03 Composition destinée à être utilisée dans la prévention et/ou le traitement de maladies gastriques ou gastro- sophagiennes

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IT102017000090582A IT201700090582A1 (it) 2017-08-04 2017-08-04 Composizione per l’uso nella prevenzione e/o nel trattamento di disturbi gastrici o gastroesofagei.
IT102017000090582 2017-08-04

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IT201900024958A1 (it) * 2019-12-20 2021-06-20 Neilos S R L Composizione per la protezione della mucosa gastro-intestinale e per la prevenzione e il trattamento di patologie ad essa associate

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999003486A1 (fr) * 1997-07-15 1999-01-28 Warner-Lambert Company Combinaison d'antiacide et de papaine
CA2656220A1 (fr) * 2006-06-28 2008-01-03 Lycored Ltd. Compositions et procedes destines au traitement et a la prevention d'un reflux gastro-oesophagien pathologique
EP2208500A1 (fr) * 2009-01-16 2010-07-21 Bionap S.r.L. Compositions pour le traitement de GERD (maladie de reflux gastrooesophagien)
EP3124048A1 (fr) * 2015-07-30 2017-02-01 Neilos S.r.l. Composöe orale destinöe au traitement des maladies ou affections gastro-oesophagiennes

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999003486A1 (fr) * 1997-07-15 1999-01-28 Warner-Lambert Company Combinaison d'antiacide et de papaine
CA2656220A1 (fr) * 2006-06-28 2008-01-03 Lycored Ltd. Compositions et procedes destines au traitement et a la prevention d'un reflux gastro-oesophagien pathologique
EP2208500A1 (fr) * 2009-01-16 2010-07-21 Bionap S.r.L. Compositions pour le traitement de GERD (maladie de reflux gastrooesophagien)
EP3124048A1 (fr) * 2015-07-30 2017-02-01 Neilos S.r.l. Composöe orale destinöe au traitement des maladies ou affections gastro-oesophagiennes

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
ARCH.INT.PHARMACODYN. 1964, vol. 149, no. 3, 1964, pages 393 - 400 *
BEST R ET AL: "THE ANTI ULCEROGENIC ACTIVITY OF THE UNRIPE PLANTAIN BANANA MUSA-SPP", BRITISH JOURNAL OF PHARMACO, WILEY-BLACKWELL, UK, vol. 82, no. 1, 1 January 1984 (1984-01-01), pages 107 - 116, XP009150633, ISSN: 0007-1188 *
DATABASE EMBASE [online] ELSEVIER SCIENCE PUBLISHERS, AMSTERDAM, NL; 1964, SANYAL A K ET AL: "Studies on peptic ulceration. I. Role of banana in fhenylbutazone induced ulcers", XP002780537, Database accession no. EMB-0008618024 *
MOHAN KUMAR ET AL: "Healing effects of Musa sapientum var. paradisiaca in diabetic rats with co-occurring gastric ulcer: cytokines and growth factor by PCR amplification", BMC COMPLEMENTARY AND ALTERNATIVE MEDICINE, BIOMED CENTRAL LTD., LONDON, GB, vol. 13, no. 1, 5 November 2013 (2013-11-05), pages 305, XP021166136, ISSN: 1472-6882, DOI: 10.1186/1472-6882-13-305 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IT201900024958A1 (it) * 2019-12-20 2021-06-20 Neilos S R L Composizione per la protezione della mucosa gastro-intestinale e per la prevenzione e il trattamento di patologie ad essa associate
WO2021124306A1 (fr) * 2019-12-20 2021-06-24 Neilos S.r.l. Composition pour la protection de la muqueuse gastro-intestinale et pour la prévention et le traitement de maladies associées à celle-ci

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EP3661533A1 (fr) 2020-06-10

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