EP4392041A1 - Composition for the prevention and/or treatment of gastric and esophageal diseases - Google Patents
Composition for the prevention and/or treatment of gastric and esophageal diseasesInfo
- Publication number
- EP4392041A1 EP4392041A1 EP22776992.4A EP22776992A EP4392041A1 EP 4392041 A1 EP4392041 A1 EP 4392041A1 EP 22776992 A EP22776992 A EP 22776992A EP 4392041 A1 EP4392041 A1 EP 4392041A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- honey
- gastric
- composition
- hyaluronic acid
- composition according
- 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
Links
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- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
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Abstract
The present invention relates to a composition for oral use comprising hyaluronic acid and/or Salts thereof, an extract of Prunus dulcis and optionally honey, for the treatment of gastric and esophageal diseases, in particular of the gastroesophageal reflux disease.
Description
Composition for the prevention and/or treatment of gastric and esophageal diseases"
FIELD OF THE INVENTION
The present invention relates to a composition for oral use comprising hyaluronic acid and/or salts thereof , an extract of Prunus dul ci s and optionally honey for the treatment of gastric and esophageal diseases , in particular of the gastroesophageal reflux disease .
Such invention is based upon the synergic action of the above-mentioned active principles .
STATE OF ART
Under gastroesophageal reflux "the unvoluntary and unconscious passage of a portion of the gastric content in the esophagus , without involving the gastric and abdominal muscles" is meant . The esophagus is a 25-30 cm long channel connecting the mouth with the stomach, along its path it is possible to detect two sphincter structures : the first one between hypopharynx and esophageal cervical tract (Upper Esophageal Sphincter, UES ) , the second one , Lower Esophageal Sphincter ( LES ) , at the level of esophagus-gastric j unction . The latter is a high- pressure area representing the main anti-reflux structure , thanks to its locali zation between the intrathoracic negative pressure and the intra
abdominal positive pressure area . Then, under normal conditions , an increase in the abdominal pressure has an impact at the LES level by preventing the ingested material from returning into esophagus . Under physiological conditions LES is closed and it is released for a period of time of about 3-10 seconds after swallowing .
Other anatomical structures , apart from LES , contributing to keep the anti-reflux barrier are :
• His angle , acute angle formed between esophagus and gastric fundus ;
• the phrenico-esophageal ligament ;
• the diaphragmatic collar, consisting of diaphragm beams , which arranging like a scarf around the esophagus throttle the lumen thereof during the inspiratory phase .
To the pathogenesis of the gastroesophageal reflux disease ( GERD) several factors belong, such as for example :
1 . Insuf ficient anti-reflux barrier of the lower esophageal sphincter which has the purpose o f preventing mechanically the gastric j uices from flowing again into the esophagus .
2 . Delay in the gastric emptying, due to anatomical anomalies or functional alterations : ( i ) anatomical anomalies : stenosis of pylorus ( it is the
stomach's terminal region, adjusting the passage of the gastric content into the duodenum) : (ii) functional alterations: motor alterations of fundus (region responsible for emptying the liquids)
3. Insufficient mechanism of esophageal clearing, which has the purpose of minimizing the contact between esophageal mucosa and gastric juices acting both through esophageal peristalsis and through neutralization of the acid residues thanks to saliva.
4. Gastric hyperacidity.
5. Aggressivity of the gastric content which flows again into the esophagus, due to the action of the hydrochloric acid.
6. Duodenal-gastric reflux with passage in the stomach of pancreatic-biliary secretions which, in case of gastroesophageal reflux, can determine more severe lesions.
Among other predisposing factors there is smoke, incorrect dietary-behavioural habits (abundant meals, food rich in fats, caffeine) , drugs, pregnancy and obesity can exacerbate GERD. Even hiatal hernia (passage of a stomach portion inside the thorax, through a hole in the diaphragm called esophageal hiatus) is often associated to GERD and it can contribute to the prolonged exposure to the gastroduodenal content. Generally, the esophageal
hiatus ' walls are well adherent to esophagus , but it may happen that the anchoring structures of the lower portion of esophagus lose tone , by favouring the going back of a small stomach portion in the thorax .
Whatever the cause may be , the frequent and repeated contact of the gastric material regurgitated with the gastric mucosa exerts on the latter a harmful action which is the more serious the longer the contact time is and the lower the reflux pH is . The persistent phlogistic action due to the esophageal mucosa becomes over time responsible for the inflammatory reaction which can evolve in ulcerations , in stenos is and in the so- called columnar metaplasia ( or Barret epithelium, most important single risk factor for developing esophageal adenocarcinoma ) . The considered typical symptoms are represented by the retrosternal heartburn ( defined by the patient as burning sensation beginning at the stomach or at the lower portion of the thorax and which goes back towards the neck) and by regurgitation (perception of liquid with bitter and acid taste inside the oral cavity) , symptoms the speci ficity thereof for GERD is equal to 89 and 95% , respectively . Frequent , but less speci fic, symptoms are odynophagia, dysphagia, eructations , epigastric pain, swelling, digestive di f ficulty . Some of these symptoms characteri ze
functional dyspepsia diagnosis and it is known that
+1 between 10% and 17% of patients requesting medical intervention due to dyspepsia have GERD.
GERD is one of the pathological conditions most frequently encountered by gastroenterologists.
From a study on the prevalence of the disease it was found that GERD has a prevalence of 10-20% in the Western countries against only 5% found in Asia; in particular a greater number of cases was found in North America then in North Europe and South Europe.
Scientific studies demonstrate that the disease symptoms have a strong impact on the quality of life since the persistent reflux symptoms, even during the treatment with inhibitors of the protonic pump for example, are associated to a reduced physical and mental well-being.
Since it is a chronic disease, the conventional treatment is almost always long lasting and, depending upon gravity, it consists in changes in the life style (eliminating chocolate, caffeine, alcohol, cigarette smoke, weight loss, etcetera) , pharmacological treatments, surgical therapy.
The classes of drugs commonly used in GERD include: antiacid drugs, antagonist of H2 receptor of histamine and protonic pump inhibitors (PPI) , prokinetic agents.
The antiacids are over-the-counter drugs of fering a quick relief of symptoms of the disease but they are not able to induce a curative ef fect in the erosive esophagitis . These drugs include carbonates or bicarbonates which reduce the stomach acidity by reacting with the hydrochloric acid by releasing carbon dioxide .
The antagonist H2 drugs such as ranitidine , famotidine , cimetidine , guarantee a temporary relie f of the symptoms although with a slower time of onset than the antiacids . The use for prolonged time periods is not recommended since the patients could develop tolerance within 1-2 weeks and however the ef fect of these drugs is not of curative type . The PPI drugs (pantoprazole , lansoprazole , omeprazole , etcetera ) represent the standard treatment in the gastroesophageal reflux diseases , in fact the number of prescriptions of such drugs has doubled over the last 10 years . Often such prescriptions are associated to those of anti-inflammatory drugs o f steroid or not steroid nature . The action mechanism of PPI s includes blocking the protonic pump at the level of the parietal cells of the stomach; this APTasic hydrogen/potassium pump determines the release of hydrochloric acid in the stomach lumen .
With respect to the antagonist H2 drugs , these drugs have a quicker ef fect and above all they exert a
curative ef fect on the esophagus lesions . The side ef fects mostly found in the treatment with PPI are nausea, diarrhea, headache , insomnia and anaphylactic reactions .
The prokinetic agents , such as cisapride or metoclopramide , activate the receptors of serotonin or dopamine capable of increasing the esophageal or gastric peristalsis . These drugs have a slow action onset , a short duration and they have no curative ef fect on the disease . Moreover, they have di f ferent side ef fects such as tremors , dyskinesia, fatigue and increase in adverse events at heart level therefore their use is quite limited in the GERD treatment .
Apart from the traditional pharmacological remedies , even alginates are used for the symptomatic treatment of GERD . Alginates , such as alginate sodium, are natural polysaccharides which, when in contact with the gastric environment , precipitate by forming, in few minutes , a low- density gel . The ph variation triggered by the bicarbonates and carbonates , almost always present too in the formulations on the market , release carbon dioxide which is trapped inside the alginate gel , by making it to float on the gastric content . The alginate gel forms in the stomach portion near the gastroesophageal j unction, exactly where the acid
pocket develops . In this way the going back of acid from the stomach to the esophageal channel is blocked or strongly reduced .
The purpose of the present invention is to provide a composition alternative to those known in the state of known art useful in the treatment for treating gastric and esophageal diseases , in particular the gastroesophageal reflux disease . SUMMARY OF THE INVENTION
The present invention is based upon the search for and identi fication of a new combination of active principles exerting the synergic action, strengthened with the various components of the combination the invention relates to .
The present invention relates to compositions comprising or consisting of a mixture of hyaluronic acid and/or salts thereof and an extract of Prunus dul ci s and optionally honey . The present invention further relates to such compositions for use in the treatment of gastric and esophageal diseases , in particular of gastroesophageal reflux disease .
The present invention provides in a single composition the following advantages :
- hyaluronic acid and/or salts thereof provide an essential component of the extracellular matrix of fundamental importance in the repairing processes , its capability of favouring the cellular
turnover and repairing the damages to the mucosae induced by the gastric pathologies .
- The extract o f Prunus dul ci s is capable of adhering to the mucosae with hydrating and soothing ef fect by favouring at the same time the physiological digestion process ; honey, i f present , guarantees an antiinflammatory action .
Other advantages and features of the present invention will result evident from the following detailed description .
DETAILED DESCRIPTION OF THE INVENTION
The present invention describes a composition comprising as main active ingredients Hyaluronic acid and/or salts thereof and an extract of Prunus dul ci s ; the composition can optionally include even honey .
The hyaluronic acid is an important component of the synovial liquid and of the extracellular matrix . Chemically it is a natural polymer consisting of alternated residues of hyaluronic acid and n-acetyl- d-glucosamine and it belongs to the class of substances known as glycosaminoglycans ( GAGs ) . In this class of compounds it represents the structurally simplest compound, the only one not covalently bound to a protein and not sul fonate core .
Fibroblasts are the main cells which release hyaluronic acid in the extracellular matrix.
It takes part in important physiological processes: repair and regeneration of wounds, morphogenesis and structural organization of the matrix itself. The biological role of the hyaluronic acid is strictly correlated to its hydrophilic and hydrodynamic properties, which allow it to keep water and then perform an important structural role in cells.
The molar mass can reach up to 107 Da and, thanks to its viscoelastic and rheologic properties, it is an interesting component for use in different medical applications. Hyaluronic acid with high or low molecular weight could be used. The term hyaluronic acid with high molecular weight describes a hyaluronic acid having a molecular weight comprised between 1.0 million of Daltons to about 4.0 MDa . For example, the high molecular weight of hyaluronic acid could have a molecular weight of about 2.0 MDa. In another example, it can have a molecular weight of about 2.8 MDa. The term hyaluronic acid with low molecular weight describes a hyaluronic acid having a molecular weight lower than about 1.0 MDa. Hyaluronic acid with low molecular weight can have a molecular weight comprised between about 200,000 Da (0.2 MDA) to less
than about 1 . 0 MDa, for example , between about 300 , 000 Da ( 0 . 3 MDa ) to about 750 , 000 Da ( 0 . 75 MDA) .
The topic application of hyaluronic acid for example allows to treat aphtha of the oral mucosa with a quick remission of the symptoms thanks to its recogni zed anti-inflammatory properties .
By intra-articular inj ection route , it is used in patients with knee osteoarthritis , by ocular route instead it is used in ophthalmic preparations especially in eyedrops for the dry eye syndrome thanks to its lubricating action .
Relatively to the present invention, the hyaluronic acid is particularly interesting for its hydrating and soothing protecting action on mucosae of the gastroesophageal tract . Moreover, its local anti-inflammatory action allows a quick relief of symptoms linked to the burning caused by the contact of the hydrochloric acid with tissues . The capability of the compound of acting on prostaglandin, metalloproteinase and other inflammation mediators is known in literature . The hyaluronic acid and the salts thereof represent valid bioactive principles for the preparation o f pharmaceutical , nutraceutical , dermo-cosmetic products or medical devices for the treatment of the gastroesophageal reflux thanks to their hydrating,
protective and regenerating action on the tissues of the gastrointestinal mucosa.
The almond tree (Prunus dulcis) is an important fruit tree originating in central Asia, currently produced all over the world. The fruit seed is known as almond constituting the edible portion, it is a seed formed by two big cotyledons coated with a brown peel and protected by an external shell with an intermediate shell.
The main substances found in the fruit, apart from water, are lipidic fraction (40-67%) , followed by a protein fraction, carbohydrates, minerals and vitamins. The oil extracted from almonds mainly consists of Monounsaturated fatty acids (MUFA) which associate to the reduction in LDL cholesterol. The protein fraction consists of Globulins and Albumins; the main free amino acids are the glutamic acid and the aspartic acid, followed by arginine. The total content of carbohydrates varies from 14% to 28%. The almonds are characterized by a low content of soluble sugars, in a range from 2.6% to 7.9%, most sugars are not reducing and the sucrose represents more than 90% of the total sugars. As far as the content in minerals are concerned, specifically for the macro minerals, potassium is the main element followed by phosphorus, whereas among the micro elements, those mostly present are sodium, chlorine,
iron, copper, zinc and manganese . Vitamin E , in particular a-tocopherol showing a strong antioxidant activity, is the most abundant one in the almond oil ; moreover, the almond fruit is a good source of Vitamin Bl , B2 , B6 and Niacin . Moreover, several polyphenols ( about 312 mg/ 100 g of fruit ) were identi fied; the most abundant ones are hydrolysable tannins , pro-anthocyanidins and flavonoids .
Several studies showed anti-oxidant and scavenger activity of the free radicals for the almond extracts ; the presence of huge amounts of phenolic compounds can be attributed to the antioxidant activities . The intestinal mucosa is vulnerable to oxidative stress due to constant exposure to the reactive oxygen species (ROS ) generated by the lumen content . The oxidative stress can cause cellular damages directly or through alteration of signalling routes . In an in vivo study, inflammatory intestinal colitis was induced in mice which subsequently were treated with extracts of almonds . The treatment reduced the appearance of diarrhea and weight loss ; this was associated to a signi ficant reduction in the activity of myeloperoxidase in colon . Moreover, it reduced the release of pro-inflammatory cytokines , the appearance of i-NOS , nitrotyrosine and BARB in colon
and it reduced the up-regulation of ICAM- 1 and the expression of P-selectin (Mandalari , 2011 ) .
The polyphenols extracted from almond have a potential antimicrobic activity, in particular it was demonstrated that they are active towards Li steria monocytogenes and Staphyl ococcus aureus, whereas Salmonell a enteri ca and Heli cobacter pyl ori demonstrated to be sensitive to the extracts of the almond peels . The prebiotic ef fects of the almond extracts were studied in vitro by using mixed faecal bacterial cultures and it was found that , after digestion of almonds , the populations of Bi fidobacteria and rectal Eubacterium increased signi ficantly . These results were confirmed even in in-vivo and clinical studies , where it was demonstrated that after 6 weeks of treatment the Bi fidobacterium spp . and Lactobacillus spp . populations in the faecal samples increased signi ficantly, whereas Escherichia coli remained stable and Clostridum perfringens was signi ficantly removed . These changes in intestinal bacterial population induce variations in the activity o f enzymes , in particular the activity of 0- galactosidase increases , and the activity of 0- glucuronidase , nitroreductase and azoreductase reduces ; the reduction in the activity of
glycosidase can induce a failure in the metabolism of the not absorbed carbohydrates , like the one shown in the ulcer colitis and in Crohn disease . The intestinal microbiota improvement induces beneficial ef fects for the human health, such as the activation of the immune response , the production of bacteriocins , nutritional and physical competition with pathogens and the maintenance of an acid environment .
The anti-inflammatory potential of almonds was studied through a randomi zed study on subj ects who consumed almonds with respect to a placebo group . After the treatment period, the levels of E- selectin, adhesion molecule involved in the inflammation process , resulted to be signi ficantly lower in the group who used almonds with respect to placebo . According to the authors , the antiinflammatory ef fects could be attributed mainly to the high content of monounsaturated fatty acids (MUFA) , which was considered responsible for the decrease in the levels of E-selectin and reactive C protein .
Honey is a substance containing about 200 di f ferent components , mainly sugars and water, and other substances like proteins , organic acids ,
vitamins and minerals, phenolic compounds and volatile compounds.
The monosaccharides, glucose and fructose represent about 75% of the sugars found in honey, followed by 10-15% of disaccharides; sugars are responsible for properties like energy value, viscosity, hygroscopicity and granulometry.
The protein content varies based upon the production species, for example honey from Apis mellifera has a protein content going from 0.2 to 1.6%, but it varies even based upon the different storage conditions. In honey, proline represents SOOS! of amino acids, it was used as criterion for evaluating honey ripening and, in some cases, of adulteration with sugar. All honeys have a light acidity, due to the presence of about 0.57% of organic acids.
Honey includes small amounts of vitamins, especially the vitamin complex B; the content of minerals in honey varies from 0.04%, in light honeys, to 0.2% in dark honeys. Potassium is the most abundant element, generally corresponding to one third of the total mineral content which can be found in honey, whereas in reduced amounts it contains sodium, iron, copper, manganese, calcium and magnesium.
The main functional components of honey are flavonoids. They can significantly contribute to the total antioxidant activity of honey, bringing beneficial effects for the human health (Alvarez- Suarez, 2012 ) .
The antioxidant activity of the flavonoids in most cases depends upon the number and position of the hydroxyl groups and other substituents, and upon the glycosylation of flavonoids. In honey there are complex mixtures of volatile compounds, responsible for the taste of honey, of different chemical families, belonging to monoterpenes, sesquiterpenes, benzene derivatives, and reduced content of alcohols, esters, fatty acids, ketones and aldehydes (Da Silva, 2016) .
Honey is historically used to treat various affections in the traditional medicine of various cultures. Classically, it is used to favour healing of wounds, due to various causes such as burns, diabetic ulcers or still scars after surgical operations and to avoid possible development of bacterial infections in the latter.
For this reason, over the last years, honey, its composition, and its biological effects have been extensively studied and tested.
From the performed researches a huge amount of scientific evidence was obtained, supporting the use
of honey in this application field, above all by demonstrating the action mechanisms therethrough it succeeds in performing a positive biological ef fect on healing wounds i f applied topically .
In particular, it was clari fied that honey does not act simply through a mechanical-physical ef fect linked to the properties of the latter, which make it , among other things , an ideal compound as material for covering wounds , but it acts al so through various biological activities due to the presence of bioactive substances , which can intervene and improve the healing process .
When it is applied topically over a wound, honey impacts positively on the wound environment and on the healing process thanks to its physical properties , since honey generally has an acid pH around 3 . 2-4 . 5 and it is well known that an acid environment in the wounds favours the release of oxygen from hemoglobin, thus increasing the amount of oxygen available inside the wound . Additionally, the acid environment disadvantages the activity of the proteolytical enzymes , by consequently decreasing the degradation of the extracellular matrix, fundamental for the tissue repair process .
As said previously, honey has a very high content of sugars , this confers the substance a high osmolarity, which results to be positive in healing
wounds . This because , through the osmotic ef fect induced by the application of honey, water is drawn from the wound and, consequently, the accumulation of liquids and the formation of oedema are avoided . Moreover, the sugars even draw water from the bacterial cells present inside the wound, thus by avoiding the growth and the formation of bacterial colonies . This , at least until there is an excessive dilution of honey .
Additionally, it is important to consider that due to the high viscosity a protective barrier above the inj ured skin, almost impenetrable by external agents , is created .
However, as said previously, the important activity performed by honey in the damage prevention and in healing can be attributed only partially to the physical properties of the substance . In fact , more and more studies attribute anti-bacterial , anti-inflammatory and immunomodulating activities to the various components found inside honey .
The anti-inflammatory activity has an additional important role in honey action mechanism . Thi s because there is a reduction in oedema and exudate , pain calming and reducing ef fect .
In particular, various clinical studies evaluated honey ef fectiveness in improving burns , by
comparing its activity with that of silver sul fadiazine , which acted as positive control .
Honey application decreased the levels of the inflammatory markers , decreased the levels of malondialdehyde , and reduced the number of inflammatory cells present in biopsies of wounds .
Additionally, in order to demonstrate that the ef fect is directly caused by an anti-inflammatory action and not by a secondary ef fect due to the antibacterial activity, various studies were performed on animal models in which the wound was produced and maintained under aseptic conditions , and even under these conditions honey demonstrated its antiinflammatory activity .
Moreover, honey demonstrated to be ef fective as anti-inflammatory agent , i f applied on the mucosa in which a damage was present , induced by radiotherapy, and j ust as ef fectively it decreased the inflammatory conditions when applied on the rat ophthalmic mucosa, in which a corneal abrasion or a keratitis induced by endotoxin was present .
This by now well established and recogni zed anti-inflammatory activity generally is attributed to the existing phenolic compounds , compounds which have the capability of inhibiting the production of pro-inflammatory cytokines such as for example TNF- a .
Thanks to the anti-inflammatory and antibacterial biological activities which were attributed to it and which were demonstrated, and thanks to the physical-chemical properties , allowing it to create a protective mechanical barrier on the mucosa, it is plausible thinking that honey could be an important weapon to fight the symptoms of the gastroesophageal reflux, since it could both create the mechanical barrier ef fect , and then avoid the contact between mucosa and the highly acid gastric content , and explicate an anti-inflammatory and soothing ef fect , and then bring an additional advantage and decrease the symptoms associated to the disease .
The inventors have observed that most synergic action among the di f ferent active ingredients is present with the following concentrations , meant as amounts per dosage unit :
- hyaluronic acid and/or the salts thereof are present in a concentration by weight comprised from 1 mg to 2000 mg, preferably from 5 mg to 1500 mg;
- the extract of Prunus dul ci s is in a quantity by weight comprised from 0 . 5 mg to 5000 mg, preferably from 1 mg to 3500 mg;
- honey, i f present , is present in a quantity by weight comprised between 1 mg and 4000 mg, preferably from 5 mg to 2500 mg .
The compositions according to the present invention can be formulated under any form and route of administration and associated to any other component, in a variety of ways, preferably they will be formulated for oral use for example as capsules, soft capsules, tablets, pills, gelatines, powders or granules, solutions, suspensions, gels, syrups, elixirs. Such excipients can be selected for example among those usually known in the state of art and include, without being limiting thereto: a) carriers, such as for example sodium citrate and calcium phosphate, b) fillers such as for example starch, lactose, microcrystalline cellulose, sucrose, glucose, mannitol and colloidal silica, c) humectants, such as for example glycerol, d) disintegrating agents, such as alginates, calcium carbonate, starches, derivatives of starch, of cellulose and of polyvinylpyrrolidone, silicates and sodium carbonate, e) binders such as carboxymethylcellulose, alginates, gelatine, polyvinylpyrrolidone, sucrose, polymeric derivatives of cellulose, starch derivatives, f) retarding agents such as paraffin, cellulose polymers, esters of fatty acids, g) absorption accelerators, such as compounds of quaternary ammonium, h) wetting agents and surfactants such as cetyl alcohol and glycerol monostearate, i)
adsorbents, such as Benthic clays and kaolin, k) lubricants such as talcum, calcium stearate, magnesium stearate, polyethylene glycol, sodium lauryl sulfate, sodium stearyl fumarate, j) glidants such as talcum, colloidal silica.
The forms of solid dosage, such as tablets, capsules, soft capsules, gelatines, pills and granules, could be coated with enteric, gastric coatings or coatings of other type known in the state of art. They can include matting agents and they can be of the type to allow the release of the active ingredients only or preferably in a certain tract of the intestine, in case, in delayed way. Substances which can allow such delayed use include, but they are not limited thereto, polymers and waxes.
The soft capsules could house the antioxidant active substances in liquid form alone or in solutions, suspensions or emulsions of the active substances in a liquid solvent. The soft capsules could be characterized by a casing qualitatively similar to that of the hard ones, but thicker and softer .
Liquid forms suitable to an oral administration for example are emulsions, solutions, prepared or extemporary suspensions, syrups and elixirs. Excipients suitable to the formulations according to the present invention in liquid forms for oral use
include, but they are not limited thereto, diluents such as water or other solvents, solubilizing agents and emulsifiers selected among ethyl alcohol, polyalcohols, propylene glycol, glycerol, polyethylene glycol and sorbitan esters. These formulations can even include sweeteners and flavourings .
The compositions will be for example a medical device, food supplement, a nutraceutical, dietary and nutritional composition, food product, a beverage, a nutraceutical product, a medicament, medicated food, food for special medical purposes, food. The compositions will be mainly intended to be used by human beings, but they could also be used on animals .
The combination of the above-mentioned active ingredients could be used formulated in one single composition according to the various above-described embodiments or in a kit containing the different separated ingredients, for example in single compositions as capsules, pills, tablets for sequential or contemporary administration of the different ingredients.
The above-described compositions and kits could be used/ administered/ taken for the treatment of gastric and esophageal diseases, in particular of the gastroesophageal reflux disease.
EXAMPLES
Some not limiting examples of daily dosages of the combination of active ingredients used in the compositions of the present invention are shown hereinafter .
EXAMPLE 1
EXAMPLE 2
EXAMPLE 3
EXAMPLE 4
Experimental data
The authors of the present invention have observed that the simultaneous administration of the active ingredients selected thereby provides a more ef fective treatment of the gastroesophageal reflux disease in the subj ects requiring it , with respect to a therapy providing the administration of the single active principles .
The synergic action of the single components is evaluated by in vitro or in vivo methods .
In vitro tests are for example the study of the viscosity depending upon temperature or other applicable parameters apt to demonstrate any improvement ef fect attributed to the synergy of the three components .
The synergic activity of the components can be evaluated in vitro through muco-adhesion tests performed on cells ( for example on epithelial cells of mucosa ) or by means of other validated methods
( for example tilted plane with mucin) .
On speci fic cellular model ( for example gastric cells ) it is possible to evaluate the antioxidant , anti-inflammatory activity of the composition the present invention relates to .
In vivo methods used to evaluate the anti-reflux ef fect of the formulation with respect to the single components are : gastric emptying, and/or reflux esophagitis , and/or gastric secretion, and/or gastric ulcer . The evaluation of such parameters is performed after administration of the single components , and association thereof , to animals .
The gastric emptying is performed on mice or rats thereto a suspension of phenol red in carboxymethylcellulose is administered . After about 20 minutes the animals are sacri ficed in atmosphere saturated with CO2 and the stomach is collected, which is positioned in a test tube of physiological solution . To each test tube an amount of NaOH i s added to develop the maximum colour intensity . Subsequently, the spectrophotometric analysis ( 560 nm) is performed and the percentage of gastric emptying is obtained from the following formula : 100 x ( l-[amount of phenol red present in the stomach after 20 minutes ) / ( amount of phenol red present in the stomach at time 0] ) .
Reflux esophagitis and the gastric secretion are induced by leaving free access to water to animals and fasting for 24 hours ; subsequently the animals are anestheti zed, the abdomen open and pylorus is tied . After about 4 hours from the surgical procedure the mice are sacri ficed in atmosphere saturated with CO2 and the stomach and esophagus are collected with the purpose of evaluating : the esophageal and gastric macroscopic damage , the esophageal and gastric inflammation level (myeloperoxidase activity) , volume of the gastric content , pH and total acidity . Formalin is used as reference drug administered at a dose of 40 mg/Kg .
Claims
1. A composition for oral use comprising hyaluronic acid and/or salts thereof and an extract of Prunus dulcis.
2. The composition according to claim 1, comprising honey.
3. The composition according to claims 1 or 2, in a form selected from capsule, soft capsule, tablet, pill, gelatine, powder, granule, emulsion, solution, suspension, gel, syrup.
4. The composition according to any one of claims 1 to 3, wherein: hyaluronic acid and/or Salts thereof are present in a quantity by weight comprised from 1 mg to 2000 mg, preferably from 5 mg to 1500 mg per dosage unit;
- the extract of Prunus dulcis is present in a quantity by weight comprised from 0.5 mg to 5000 mg, preferably from 1 mg to 3500 mg per dosage unit.
5. The composition according to any one of the preceding claims, wherein honey is present in a quantity by weight comprised between 1 mg and 4000 mg, preferably from 5 mg to 2500 mg per dosage unit.
6. The composition according to any one of claims from 1 to 5, wherein said composition is a medical device, a food supplement, a nutraceutical, dietary and nutritional composition, a food product, a
30 beverage, a nutraceutical product, a medicament, medicated food or food for special medical purposes.
7. The composition according to any one of claims
1 to 6 for use for the treatment of gastric and esophageal diseases both in man and animals.
8. The composition for use according to claim 7, wherein said disease is the gastroesophageal reflux.
9. A kit comprising hyaluronic acid and/or Salts thereof, an extract of Prunus dulcis and optionally honey .
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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IT102021000021992A IT202100021992A1 (en) | 2021-08-27 | 2021-08-27 | Composition for the prevention and/or treatment of gastric and oesophageal pathologies |
PCT/IB2022/057974 WO2023026231A1 (en) | 2021-08-27 | 2022-08-25 | Composition for the prevention and/or treatment of gastric and esophageal diseases |
Publications (1)
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EP4392041A1 true EP4392041A1 (en) | 2024-07-03 |
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EP22776992.4A Pending EP4392041A1 (en) | 2021-08-27 | 2022-08-25 | Composition for the prevention and/or treatment of gastric and esophageal diseases |
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EP (1) | EP4392041A1 (en) |
IT (1) | IT202100021992A1 (en) |
WO (1) | WO2023026231A1 (en) |
Family Cites Families (10)
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LT2543357T (en) * | 2011-07-07 | 2018-06-11 | Holy Stone Healthcare Co.,Ltd. | Composition for use in treating and preventing inflammation related disorder |
TWI446915B (en) * | 2011-07-12 | 2014-08-01 | Holy Stone Healthcare Co Ltd | Composition for use in treating and preventing mucosa related disease |
KR20180081508A (en) * | 2015-10-01 | 2018-07-16 | 에이팜 에스.알.엘. | Combinations of glycosaminoglycans and antacids and compositions thereof |
CN105495441A (en) * | 2015-12-18 | 2016-04-20 | 合肥市包河区大圩花果园武鸡繁育场 | Digestion aiding high-calcium sandwich fresh ginger buccal tablet and preparation method thereof |
ITUA20161822A1 (en) * | 2016-03-18 | 2017-09-18 | Indena Spa | USEFUL COMPOSITIONS IN THE PREVENTION AND / OR IN THE TREATMENT OF ORAL CABLE PATHOLOGIES, OF THE FIRST AIRWAYS AND OF THE ESOFAGO |
IT201600101413A1 (en) * | 2016-10-10 | 2018-04-10 | Sofar Swiss S A | Liquid composition for use in the treatment of gastroesophageal reflux |
IT201600121617A1 (en) * | 2016-11-30 | 2018-05-30 | Nekkar Lab Srl | COMPOSITION FOR THE TREATMENT OF GASTROESOFAGEO REFLUX |
CN108114047A (en) * | 2016-11-30 | 2018-06-05 | 邓炳章 | A kind of Chinese medicine composition for treating reflux esophagitis |
IT201900024958A1 (en) * | 2019-12-20 | 2021-06-20 | Neilos S R L | Composition for the protection of the gastrointestinal mucosa and for the prevention and treatment of associated pathologies |
CN111202233A (en) * | 2020-01-15 | 2020-05-29 | 安徽本草怡堂生物科技有限公司 | Black sesame pill containing milk calcium and preparation method thereof |
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2021
- 2021-08-27 IT IT102021000021992A patent/IT202100021992A1/en unknown
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2022
- 2022-08-25 WO PCT/IB2022/057974 patent/WO2023026231A1/en active Application Filing
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IT202100021992A1 (en) | 2023-02-27 |
WO2023026231A1 (en) | 2023-03-02 |
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