[go: up one dir, main page]

EP4469034A1 - Composition for treating esophageal reflux - Google Patents

Composition for treating esophageal reflux

Info

Publication number
EP4469034A1
EP4469034A1 EP22709370.5A EP22709370A EP4469034A1 EP 4469034 A1 EP4469034 A1 EP 4469034A1 EP 22709370 A EP22709370 A EP 22709370A EP 4469034 A1 EP4469034 A1 EP 4469034A1
Authority
EP
European Patent Office
Prior art keywords
composition according
carnosine
composition
treatment
mucoadhesive matrix
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
EP22709370.5A
Other languages
German (de)
French (fr)
Inventor
Davide NENZIONI
Giovanna BARON
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.)
Adventia Pharma SL
Metis Healthcare Srl
Original Assignee
Adventia Pharma SL
Metis Healthcare 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 Adventia Pharma SL, Metis Healthcare Srl filed Critical Adventia Pharma SL
Publication of EP4469034A1 publication Critical patent/EP4469034A1/en
Pending legal-status Critical Current

Links

Classifications

    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/194—Carboxylic acids, e.g. valproic acid having two or more carboxyl groups, e.g. succinic, maleic or phthalic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4172—Imidazole-alkanecarboxylic acids, e.g. histidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/734—Alginic acid
    • 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
    • A61K36/02—Algae
    • A61K36/05—Chlorophycota or chlorophyta (green algae), e.g. Chlorella
    • 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)
    • A61K36/33—Cactaceae (Cactus family), e.g. pricklypear or Cereus
    • 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)
    • A61K36/60—Moraceae (Mulberry family), e.g. breadfruit or fig
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/006—Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/0065—Forms with gastric retention, e.g. floating on gastric juice, adhering to gastric mucosa, expanding to prevent passage through the pylorus

Definitions

  • the present invention applies to the medical and pharmaceutical fields , and in particular, it relates to a new composition for treating and curing esophageal reflux .
  • GERD GastroEsophageal Refl ux Di sease
  • the condition is pathological when episodes of heartburn and acid regurgitation occur frequently .
  • the main drug treatments include the use of antacids (basal bolus) or gastroprotectants , which are characterized by a rapid effect, but are not able to cure the disease or the lesions caused by the latter.
  • Antacids are based on salts such as sodium bicarbonate, magnesium oxide, aluminum hydroxide, or combinations thereof.
  • H2 blockers and proton pump inhibitors which are slower but more effective .
  • Some marketed products comprise a polymer base, typically sodium alginate, and an antacid salt, e.g., sodium bicarbonate or calcium carbonate, and act by reducing gastric acidity and forming a foam floating on the gastric contents which mechanically prevents reflux.
  • a polymer base typically sodium alginate
  • an antacid salt e.g., sodium bicarbonate or calcium carbonate
  • Polaprezinc which comprises zinc and carnosine and acts as a gastroprotectant by protecting the gastric mucosa but without blocking or healing the damage produced by acid reflux .
  • a composition comprising a buf fer system and a mucoadhesive matrix is surprisingly useful for treating gastroesophageal reflux (GERD) .
  • GERD gastroesophageal reflux
  • Figure 1 shows the results of the tests on pH variation .
  • Figure 2 shows the results of tests on the proteolytic action of reconstituted gastric fluid measured under fluorescence .
  • Figure 3 shows the results of comparison tests with known products for treating gastroesophageal reflux .
  • a first obj ect of the present invention is represented by a composition comprising a buf fer system and a mucoadhesive matrix for medical use in the treatment and prevention of gastroesophageal reflux .
  • the buf fer system is the citric acid/citrate system .
  • composition described further comprises carnosine .
  • carnos ine can be replaced by an analogue compound thereof .
  • a second obj ect is represented by a composition comprising a buf fer system and a mucoadhesive matrix .
  • the composition described further comprises carnosine .
  • carnos ine can be replaced by an analogue compound thereof .
  • the present invention describes a formulation comprising the described composition .
  • a fourth obj ect of the invention is represented by a method for the treatment and prevention of gastroesophageal reflux .
  • the present invention describes a method for the treatment and prevention in a subj ect in need thereof of the rebound ef fect caused by a treatment for the gastroesophageal reflux using gastric acid secretion inhibitor drugs or antacid drugs or compositions .
  • composition comprising a buf fer system and a mucoadhesive matrix for medical use .
  • such a medical use is for the treatment and prevention of the gastroesophageal reflux .
  • the buf fer system is represented by the citric acid/citrate system; for example , citrate trihydrate can be used .
  • the buffer system is a citric acid/sodium citrate system.
  • the buffer system comprises acid/salt in ratios between 1:3- 1:6.
  • the citric acid/sodium citrate buffer system comprises acid/salt in a ratio of about 1:5.
  • the mucoadhesive matrix can comprise one or more components.
  • such components can comprise mucopolysaccharides and polysaccharides, both independently of each other, of plant or animal origin or from microorganisms.
  • At least one component is mucopolysaccharides.
  • such mucopolysaccharides are from Opuntia ficus indica.
  • mucopolysaccharides from tamarind (Tamarindus indica)
  • jackfruit Artocarpus heterophyllus Lam.
  • seaweed can be used.
  • a further component can be alginate, e.g., sodium alginate.
  • the composition described further comprises carnosine.
  • carnosine can be replaced by a compound which is a structurally or functionally analogue compound thereof .
  • said analogue is a compound selected from the group comprising : anserine (N- p-alanyl-l-methylhistidine ) , balenine (N- p-alanyl-3-methylhistidine ) , homocarnosine (N-4-aminobutyryl-histidine ) , N-acetyl-carnosine , carcinine ( p-alanylhistamine ) , Gly-His , carnosinamide .
  • carnosine (or an analog thereof such as one of the compounds described above ) is included in an amount of about 0 . 2 - 1 % and preferably of about 0 . 4 - 0 . 6% (by weight/total weight of the composition) .
  • composition of the present patent application is also described for medical use the treatment and prevention of the rebound ef fect caused by a treatment for gastroesophageal reflux .
  • such a treatment causing the rebound ef fect is a treatment using gastric acid secretion inhibitor drugs or antacid drugs or compositions .
  • gastric acid secretion inhibitor drugs comprise : proton pump inhibitors , H2 blockers .
  • proton pump inhibitors comprise: omeprazole, esomeprazole, lansoprazole, rabeprazole, pantoprazole .
  • H2 blockers comprise: famotidine, ranitidine .
  • Antacid drugs instead comprise, for example, salts or mixtures of salts selected from sodium bicarbonate, magnesium oxide, aluminum hydroxide, or mixtures thereof.
  • such a treatment causing the rebound effect is a treatment which precedes or is concomitant with the treatment with the composition of the invention.
  • composition comprising a buffer system and a mucoadhesive matrix.
  • the buffer system is the citric acid/citrate system; for example, citrate trihydrate can be used.
  • the buffer system is a citric acid/sodium citrate system.
  • the buffer system comprises acid/salt in ratios between 1:3- 1:6.
  • the citric acid/sodium citrate buffer system comprises acid/salt in a ratio of about 1:5.
  • the mucoadhesive matrix can comprise one or more components.
  • such components can comprise mucopolysaccharides and polysaccharides, both independently of each other, of plant or animal origin or from microorganisms.
  • such mucopolysaccharides are from Opuntia ficus indica.
  • mucopolysaccharides from tamarind (Tamarindus indica)
  • jackfruit Artocarpus heterophyllus Lam.
  • seaweed can be used.
  • such mucopolysaccharides can be included in an amount of about 0.05-0.07% (weight/ total weight of the composition) .
  • a further component can be alginate, e.g., sodium alginate.
  • the further component possibly sodium alginate, may be included in an amount of about 2-2.5% (weight/ total weight of the composition) .
  • the mucoadhesive component enables the composition to form a coating on the mucosal walls of the esophagus.
  • the composition described further comprises carnosine.
  • carnosine is replaced by a compound which is a structurally or functionally analogue compound thereof .
  • said analogue is a compound selected from the group comprising: anserine (N-p-alanyl-l-methylhistidine) , balenine (N- p-alanyl-3-methylhistidine ) , homocarnosine (N-4-aminobutyryl-histidine ) , N-acetyl-carnosine, carcinine ( p-alanylhistamine ) , Gly-His, carnosinamide .
  • carnosine (or an analog thereof such as one of the compounds described above) is included in an amount of about 0.2- 1% and preferably of about 0.4-0.6% (by weight/total weight of the composition) .
  • composition of the invention can further comprise sweeteners or sugar substitutes, e.g., selected from sucrose, fructose.
  • composition described further comprises one or more of: preservatives, stabilizers, flavorings.
  • the further components are selected from those allowed for pharmaceutical use in the preparation of oral compositions.
  • the composition described is in liquid or gel form.
  • composition described can contain up to 90%, preferably up to 92% and more preferably up to about 95- 96% by weight of water.
  • the formulation is portioned into individual doses, e.g., sachets, having a volume of about 10 ml.
  • the formulation can be in the form of powder, granules, or tablets.
  • such a method comprises the step of administering to a subject in need thereof a pharmaceutically effective amount of a composition as described above.
  • a method for the treatment or prevention in a subject in need thereof of the rebound effect caused by a treatment for gastroesophageal reflux using gastric acid secretion inhibitors or antacid drugs or compositions .
  • such a method comprises the step of administering to a subject in need thereof a pharmaceutically effective amount of a composition as described above.
  • said subject in need thereof is a subject who has finished or is currently taking a treatment for gastroesophageal reflux therapy.
  • such a treatment comprised or comprises taking gastric acid secretion inhibitor drugs or antacid drugs or compositions.
  • gastric acid secretion inhibitor drugs comprise: proton pump inhibitors, H2 blockers.
  • proton pump inhibitors comprise: omeprazole, esomeprazole, lansoprazole, rabeprazole, pantoprazole .
  • H2 blockers comprise: famotidine, ranitidine .
  • Antacid drugs instead comprise, for example, salts or mixtures of salts selected from sodium bicarbonate, magnesium oxide, aluminum hydroxide, or mixtures thereof.
  • composition according to the invention is prepared, comprising :
  • composition described above can comprise 0.4-0.6% carnosine or an analogue compound thereof.
  • the mucopolysaccharides can be mucopolysaccharides of Opuntia ficus indica.
  • the graph in figure 1 shows the trend of the pH value of a solution containing deionized water (H2O) , carnosine, citric acid, and citric acid+citrate following the addition of increasing volumes of reconstituted gastric juice, containing 0.1 M HC1.
  • H2O deionized water
  • the analyses were carried out using an automatic titrator .
  • the band indicates the pH range for which the proteolytic activity of pepsin is maximum .
  • the buf fering action of the citrate+carnosine mixture allows neutrali zing about 20 ml of HC1 before the pH is reduced to acid values being compatible with the activation of pepsin .
  • the left panel (A) in Figure 2 shows the proteolytic action of the reconstituted gastric j uice (pepsin in HC1 ) measured under fluorescence .
  • a probe-labelled protein is used, which emits fluorescence only following the proteolytic reaction .
  • the protein was inserted into a mucin matrix to mimic the esophageal mucosa .
  • the increase in fluorescence units indicates the activation of the proteolytic process .
  • the black dotted line indicates the kinetics of the proteolytic process on the mucin matrix functionali zed with the fluorescent protein to which the reconstituted gastric fluid has been added .
  • composition according to the present invention When a composition according to the present invention is added to the matrix ( grey line with squares ) followed by the reconstituted gastric fluid, a signi ficant delay in proteolytic activity is observed, which demonstrates the action of the composition in neutrali zing the proteolytic activity of the gastric j uice on the mucin matrix .
  • the addition of the composition of the invention prior to the addition of the reconstituted gastric fluid mimics a preventive situation (the product is taken before the reflux occurs ) .
  • the right panel (B ) shows the therapeutic action of the composition of the invention (the reconstituted gastric fluid is first added to the mucin matrix labelled with the fluorescent protein, followed by the composition of the invention) .
  • the ef fect of neutrali zing the proteolytic activity due to the composition of the invention is very apparent .
  • composition of the invention inhibits the proteolytic action of the reconstituted gastric juice, as a therapy and prevention for reflux.
  • Figure 3 shows the effect of adding the composition of the invention and two known anti-GERD products with a basic composition (reference products 1 and 2) to a volume of reconstituted gastric fluid. Both of the known products cause an important increase in the pH value from 2 to 5-6, whereas the composition of the invention maintains the pH value of the gastric juice.
  • compositions and formulations described do not alter the contents of hydrogen ions of the gastric juice due to the neutralization; as a result, they do not modify the acid production of the stomach and therefore do not reduce the proteolytic activity in the stomach during digestion.
  • composition of the invention does not alter the electrolytic balance, especially with reference to sodium, which is important for subjects suffering from hypertension, for example, and magnesium. Moreover, since the product is not basic in nature and is not absorbed, it does not cause systemic alkalosis .
  • the product of the invention which has a pH of about 6 per se , is however surprisingly able to increase the pH of the gastric j uice present at the esophageal level to values which are incompatible with the activity of pepsin .
  • the product selectively removes the proteolytic action at esophageal level without however altering the composition of the gastric fluid, thus preventing the rebound effect .

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Natural Medicines & Medicinal Plants (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Biotechnology (AREA)
  • Alternative & Traditional Medicine (AREA)
  • Botany (AREA)
  • Mycology (AREA)
  • Microbiology (AREA)
  • Medical Informatics (AREA)
  • Nutrition Science (AREA)
  • Physiology (AREA)
  • Inorganic Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Molecular Biology (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The present invention relates to a composition for treating and curing esophageal reflux.

Description

Composition for treating esophageal reflux
DESCRIPTION
Technical field of the invention
The present invention applies to the medical and pharmaceutical fields , and in particular, it relates to a new composition for treating and curing esophageal reflux .
Background art
The acronym GERD ( GastroEsophageal Refl ux Di sease) refers to a condition af fecting a signi ficant part of the European population, estimated to be up to 10-20% .
There are various causes , including anatomical and physiological factors (hormonal causes or pregnancy) , the intake of some drugs , diet , and li festyle .
The condition is pathological when episodes of heartburn and acid regurgitation occur frequently .
In the most severe stage , erosions of the esophageal wall , ulcers , or narrowings can occur, also due to the proteolytic activity of pepsin, an enzyme contained in gastric j uice and responsible for damaging the esophageal mucosa following reflux .
While the correction of some habits can solve milder cases , treatment with drugs is required for more severe situations .
The main drug treatments include the use of antacids (basal bolus) or gastroprotectants , which are characterized by a rapid effect, but are not able to cure the disease or the lesions caused by the latter.
Antacids are based on salts such as sodium bicarbonate, magnesium oxide, aluminum hydroxide, or combinations thereof.
Otherwise, drugs are used which are able to reduce the production of acid in the stomach: H2 blockers and proton pump inhibitors, which are slower but more effective .
However, such drugs suffer from the so-called rebound effect, whereby, once the efficacy has finished, they produce an increase in acid secretion of the stomach, with a potential worsening of conditions.
Some marketed products comprise a polymer base, typically sodium alginate, and an antacid salt, e.g., sodium bicarbonate or calcium carbonate, and act by reducing gastric acidity and forming a foam floating on the gastric contents which mechanically prevents reflux.
Another known product is Polaprezinc, which comprises zinc and carnosine and acts as a gastroprotectant by protecting the gastric mucosa but without blocking or healing the damage produced by acid reflux .
Summary of the invention The authors of the present invention have found that a composition comprising a buf fer system and a mucoadhesive matrix is surprisingly useful for treating gastroesophageal reflux ( GERD) .
Brief description of the drawings
Figure 1 shows the results of the tests on pH variation .
Figure 2 shows the results of tests on the proteolytic action of reconstituted gastric fluid measured under fluorescence .
Figure 3 shows the results of comparison tests with known products for treating gastroesophageal reflux .
Obj ect of the invention
A first obj ect of the present invention is represented by a composition comprising a buf fer system and a mucoadhesive matrix for medical use in the treatment and prevention of gastroesophageal reflux .
In a preferred aspect of the invention, the buf fer system is the citric acid/citrate system .
In one aspect of the invention, the composition described further comprises carnosine .
In an alternative aspect , carnos ine can be replaced by an analogue compound thereof .
A second obj ect is represented by a composition comprising a buf fer system and a mucoadhesive matrix . According to one aspect of the invention, the composition described further comprises carnosine .
In an alternative aspect , carnos ine can be replaced by an analogue compound thereof .
In a third obj ect , the present invention describes a formulation comprising the described composition .
A fourth obj ect of the invention is represented by a method for the treatment and prevention of gastroesophageal reflux .
In a fi fth obj ect , the present invention describes a method for the treatment and prevention in a subj ect in need thereof of the rebound ef fect caused by a treatment for the gastroesophageal reflux using gastric acid secretion inhibitor drugs or antacid drugs or compositions .
Detailed description of the invention
According to a first obj ect of the invention, there is described a composition comprising a buf fer system and a mucoadhesive matrix for medical use .
In a preferred aspect of the invention, such a medical use is for the treatment and prevention of the gastroesophageal reflux .
For the purposes of the present invention, the buf fer system is represented by the citric acid/citrate system; for example , citrate trihydrate can be used . In particular, the buffer system is a citric acid/sodium citrate system.
For the purposes of the present invention, the buffer system comprises acid/salt in ratios between 1:3- 1:6.
The citric acid/sodium citrate buffer system comprises acid/salt in a ratio of about 1:5.
For the purposes of the present invention, the mucoadhesive matrix can comprise one or more components.
More in particular, such components can comprise mucopolysaccharides and polysaccharides, both independently of each other, of plant or animal origin or from microorganisms.
According to a preferred aspect, at least one component is mucopolysaccharides.
According to a particularly preferred aspect, such mucopolysaccharides are from Opuntia ficus indica.
Alternatively, mucopolysaccharides from tamarind (Tamarindus indica) , jackfruit (Artocarpus heterophyllus Lam. ) or seaweed can be used.
According to another preferred aspect, a further component can be alginate, e.g., sodium alginate.
According to a particular aspect of the invention, the composition described further comprises carnosine.
According to an alternative aspect of the present invention, carnosine can be replaced by a compound which is a structurally or functionally analogue compound thereof .
For the purposes of the present invention, said analogue is a compound selected from the group comprising : anserine (N- p-alanyl-l-methylhistidine ) , balenine (N- p-alanyl-3-methylhistidine ) , homocarnosine (N-4-aminobutyryl-histidine ) , N-acetyl-carnosine , carcinine ( p-alanylhistamine ) , Gly-His , carnosinamide .
For the purposes of the present invention, carnosine ( or an analog thereof such as one of the compounds described above ) is included in an amount of about 0 . 2 - 1 % and preferably of about 0 . 4 - 0 . 6% (by weight/total weight of the composition) .
According to a particular aspect of the invention, the composition of the present patent application is also described for medical use the treatment and prevention of the rebound ef fect caused by a treatment for gastroesophageal reflux .
In a particular aspect , such a treatment causing the rebound ef fect is a treatment using gastric acid secretion inhibitor drugs or antacid drugs or compositions .
In particular, such gastric acid secretion inhibitor drugs comprise : proton pump inhibitors , H2 blockers . For example, proton pump inhibitors comprise: omeprazole, esomeprazole, lansoprazole, rabeprazole, pantoprazole .
For example, H2 blockers comprise: famotidine, ranitidine .
Antacid drugs (basal bolus) instead comprise, for example, salts or mixtures of salts selected from sodium bicarbonate, magnesium oxide, aluminum hydroxide, or mixtures thereof.
In another particular aspect, such a treatment causing the rebound effect is a treatment which precedes or is concomitant with the treatment with the composition of the invention.
According to a second object of the invention, there is described a composition comprising a buffer system and a mucoadhesive matrix.
For the purposes of the present invention, the buffer system is the citric acid/citrate system; for example, citrate trihydrate can be used.
In particular, the buffer system is a citric acid/sodium citrate system.
For the purposes of the present invention, the buffer system comprises acid/salt in ratios between 1:3- 1:6.
The citric acid/sodium citrate buffer system comprises acid/salt in a ratio of about 1:5.
For the purposes of the present invention, the mucoadhesive matrix can comprise one or more components.
More in particular, such components can comprise mucopolysaccharides and polysaccharides, both independently of each other, of plant or animal origin or from microorganisms.
According to a particularly preferred aspect, such mucopolysaccharides are from Opuntia ficus indica.
Alternatively, mucopolysaccharides from tamarind (Tamarindus indica) , jackfruit (Artocarpus heterophyllus Lam. ) or seaweed can be used.
For the purposes of the present invention, such mucopolysaccharides can be included in an amount of about 0.05-0.07% (weight/ total weight of the composition) .
According to another preferred aspect, a further component can be alginate, e.g., sodium alginate.
For the purposes of the present invention, the further component, possibly sodium alginate, may be included in an amount of about 2-2.5% (weight/ total weight of the composition) .
Advantageously, the mucoadhesive component enables the composition to form a coating on the mucosal walls of the esophagus. According to a particular aspect of the invention, the composition described further comprises carnosine.
According to an alternative aspect of the present invention, carnosine is replaced by a compound which is a structurally or functionally analogue compound thereof .
For the purposes of the present invention, said analogue is a compound selected from the group comprising: anserine (N-p-alanyl-l-methylhistidine) , balenine (N- p-alanyl-3-methylhistidine ) , homocarnosine (N-4-aminobutyryl-histidine ) , N-acetyl-carnosine, carcinine ( p-alanylhistamine ) , Gly-His, carnosinamide .
For the purposes of the present invention, carnosine (or an analog thereof such as one of the compounds described above) is included in an amount of about 0.2- 1% and preferably of about 0.4-0.6% (by weight/total weight of the composition) .
The composition of the invention can further comprise sweeteners or sugar substitutes, e.g., selected from sucrose, fructose.
In one aspect of the invention, the composition described further comprises one or more of: preservatives, stabilizers, flavorings.
The further components are selected from those allowed for pharmaceutical use in the preparation of oral compositions.
According to the present invention, the composition described is in liquid or gel form.
The composition described can contain up to 90%, preferably up to 92% and more preferably up to about 95- 96% by weight of water.
In one aspect of the invention, the formulation is portioned into individual doses, e.g., sachets, having a volume of about 10 ml.
Alternatively, the formulation can be in the form of powder, granules, or tablets.
According to a third object of the invention, a method for the treatment and prevention of gastroesophageal reflux is described.
In particular, such a method comprises the step of administering to a subject in need thereof a pharmaceutically effective amount of a composition as described above.
According to a fourth object of the invention, a method is described for the treatment or prevention in a subject in need thereof of the rebound effect caused by a treatment for gastroesophageal reflux using gastric acid secretion inhibitors or antacid drugs or compositions .
In particular, such a method comprises the step of administering to a subject in need thereof a pharmaceutically effective amount of a composition as described above.
For the purposes of the present invention, said subject in need thereof is a subject who has finished or is currently taking a treatment for gastroesophageal reflux therapy.
In particular, such a treatment comprised or comprises taking gastric acid secretion inhibitor drugs or antacid drugs or compositions.
In particular, such gastric acid secretion inhibitor drugs comprise: proton pump inhibitors, H2 blockers.
For example, proton pump inhibitors comprise: omeprazole, esomeprazole, lansoprazole, rabeprazole, pantoprazole .
For example, H2 blockers comprise: famotidine, ranitidine .
Antacid drugs (basal bolus) instead comprise, for example, salts or mixtures of salts selected from sodium bicarbonate, magnesium oxide, aluminum hydroxide, or mixtures thereof.
The invention will be further described with reference to the following non-limiting examples of the present invention . EXAMPLE 1
A composition according to the invention is prepared, comprising :
The composition described above can comprise 0.4-0.6% carnosine or an analogue compound thereof.
The mucopolysaccharides can be mucopolysaccharides of Opuntia ficus indica.
EXAMPLE 2 pH value
The graph in figure 1 shows the trend of the pH value of a solution containing deionized water (H2O) , carnosine, citric acid, and citric acid+citrate following the addition of increasing volumes of reconstituted gastric juice, containing 0.1 M HC1.
The analyses were carried out using an automatic titrator . The band indicates the pH range for which the proteolytic activity of pepsin is maximum .
The addition of the HC1 solution to water causes a rapid reduction in pH .
The addition of HC1 to a carnosine solution results in the partial neutrali zation thereof .
A similar ef fect is observed for the solution containing citrate , whereas the ef fect is signi ficantly greater in the case of the citrate+carnosine mixture .
In this case , the buf fering action of the citrate+carnosine mixture allows neutrali zing about 20 ml of HC1 before the pH is reduced to acid values being compatible with the activation of pepsin .
The results demonstrate how the carnosine/citrate mixture is optimal for neutrali z ing the acidity caused by reflux and deactivating the proteolytic action of the gastric j uice at the esophageal mucosa .
EXAMPLE 3
Proteolytic activity
The left panel (A) in Figure 2 shows the proteolytic action of the reconstituted gastric j uice (pepsin in HC1 ) measured under fluorescence . A probe-labelled protein is used, which emits fluorescence only following the proteolytic reaction . The protein was inserted into a mucin matrix to mimic the esophageal mucosa . The increase in fluorescence units indicates the activation of the proteolytic process . The black dotted line indicates the kinetics of the proteolytic process on the mucin matrix functionali zed with the fluorescent protein to which the reconstituted gastric fluid has been added . When a composition according to the present invention is added to the matrix ( grey line with squares ) followed by the reconstituted gastric fluid, a signi ficant delay in proteolytic activity is observed, which demonstrates the action of the composition in neutrali zing the proteolytic activity of the gastric j uice on the mucin matrix . The addition of the composition of the invention prior to the addition of the reconstituted gastric fluid mimics a preventive situation ( the product is taken before the reflux occurs ) .
The right panel (B ) shows the therapeutic action of the composition of the invention ( the reconstituted gastric fluid is first added to the mucin matrix labelled with the fluorescent protein, followed by the composition of the invention) . As can be observed, in this case the ef fect of neutrali zing the proteolytic activity due to the composition of the invention is very apparent .
The two tests demonstrate that the composition of the invention inhibits the proteolytic action of the reconstituted gastric juice, as a therapy and prevention for reflux.
EXAMPLE 4
Comparison with known products
Figure 3 shows the effect of adding the composition of the invention and two known anti-GERD products with a basic composition (reference products 1 and 2) to a volume of reconstituted gastric fluid. Both of the known products cause an important increase in the pH value from 2 to 5-6, whereas the composition of the invention maintains the pH value of the gastric juice.
From the description provided above, the several advantages offered by the present invention will be apparent to those skilled in the art.
In particular, the compositions and formulations described do not alter the contents of hydrogen ions of the gastric juice due to the neutralization; as a result, they do not modify the acid production of the stomach and therefore do not reduce the proteolytic activity in the stomach during digestion.
The composition of the invention does not alter the electrolytic balance, especially with reference to sodium, which is important for subjects suffering from hypertension, for example, and magnesium. Moreover, since the product is not basic in nature and is not absorbed, it does not cause systemic alkalosis .
In fact, the product of the invention, which has a pH of about 6 per se , is however surprisingly able to increase the pH of the gastric j uice present at the esophageal level to values which are incompatible with the activity of pepsin .
Therefore , the product selectively removes the proteolytic action at esophageal level without however altering the composition of the gastric fluid, thus preventing the rebound effect .
-k 'k 'k

Claims

CLAIMS composition comprising a buf fer system and a mucoadhesive matrix for medical use in the treatment and prevention of the gastroesophageal reflux . he composition comprising a buf fer system and a mucoadhesive matrix for medical use in the treatment and prevention of the rebound ef fect caused by a treatment for gastroesophageal reflux using gastric acid secretion inhibitor drugs or antacid drugs or compositions . he composition for medical use according to the preceding claim, wherein said gastric acid secretion inhibitor drugs comprise : proton pump inhibitors , H2 blockers . he composition according to the preceding claim, wherein said mucoadhesive matrix comprises one or more components . he composition according to claim 4 , wherein said mucoadhesive matrix comprises mucopolysaccharides . he composition according to claim 4 or 5 , wherein said mucoadhesive matrix comprises mucopolysaccharides from Opuntia fi cus indi ca, Tamarindus indi ca, Artocarpus heterophyll us Lam . r or seaweed . he composition according to any one of the preceding claims , wherein said mucoadhesive matrix further comprises a further polymer component . he composition according to the preceding claim, wherein said further polymer component is represented by sodium alginate . he composition according to any one of claims 1 to
8 , wherein said buf fer system comprises a combination of citric acid and citrate . . The composition according to any one of the preceding claims , further comprising carnosine . . The composition according to the preceding claim, wherein said carnosine is substituted by a carnosine compound analogue . . The composition according to the preceding claim, wherein said carnosine analogue is a compound selected from the group comprising : anserine (N- p- alanyl-l-methylhistidine ) , balenine (N- p-alanyl-3- methylhistidine ) , homocarnosine (N-4-aminobutyryl- histidine ) , N-acetyl-carnosine , carcinine ( p- alanylhistamine ) , Gly-His , carnosinamide . . The composition according to any one of the preceding claims , further comprising one or more of : preservatives , stabili zers , flavorings , sweeteners , sugar substitutes .
. The composition according to any one of the preceding claims in liquid or gel form . . The composition according to the preceding claim having a volume of about 10 ml . . A composition comprising a buf fer system and a mucoadhesive matrix . . The composition according to the preceding claim, wherein said mucoadhesive matrix comprises one or more components . . The composition according to claim 16 or 17 , wherein said mucoadhesive matrix comprises mucopolysaccharides . . The composition according to any one of claims 16 to 18 , wherein said mucoadhesive matrix comprises mucopolysaccharides from Opuntia fi cus indi ca, Tamarindus indi ca, Artocarpus heterophyll us Lam . , or seaweed . . The composition according to any one of claims 16 to 19 , wherein said mucoadhesive matrix comprises a further polymer component . . The composition according to any one of claims 16 to 20 , wherein said further polymer component is sodium alginate .
. The composition according to any one of claims 16 to 21, wherein said buffer system comprises a combination of citric acid and citrate. . The composition according to any one of claims 16 to 22, further comprising carnosine. . The composition according to the preceding claim, wherein said carnosine is substituted by a carnosine analogue. . The composition according to the preceding claim, wherein said carnosine analogue is a compound selected from the group comprising: anserine (N-p- alanyl-l-methylhistidine ) , balenine (N- p-alanyl-3- methylhistidine ) , homocarnosine (N-4-aminobutyryl- histidine) , N-acetyl-carnosine, carcinine (p- alanylhistamine) , Gly-His, carnosinamide . . The composition according to any one of claims 16 to 25, further comprising one or more of: preservatives, stabilizers, flavorings, sweeteners, sugar substitutes. . A method for the treatment and prevention of the gastroesophageal reflux comprising the step of administering to a subject in need thereof a pharmaceutically effective amount of a composition according to any one of claims 16 to 26. A method for the treatment and prevention of the rebound ef fect caused by a treatment for gastroesophageal reflux therapy comprising the step of administering to a subj ect in need thereof a pharmaceutically ef fective amount of a composition according to any one of claims 16 to 26 . The method according to the preceding claim, wherein said subj ect in need thereof is a subj ect who has finished a treatment for gastroesophageal reflux therapy with gastric acid secretion inhibitor drugs or antacid drugs or compositions . The method according to the preceding claim, wherein said gastric acid secretion inhibitor drugs comprise : proton pump inhibitors , H2 blockers . The method according to the preceding claim, wherein said antacid drugs are drugs comprising a salt selected from the group comprising sodium bicarbonate , magnesium oxide , aluminum hydroxide , or combinations thereof .
EP22709370.5A 2022-01-24 2022-01-24 Composition for treating esophageal reflux Pending EP4469034A1 (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/IB2022/050584 WO2023139414A1 (en) 2022-01-24 2022-01-24 Composition for treating esophageal reflux

Publications (1)

Publication Number Publication Date
EP4469034A1 true EP4469034A1 (en) 2024-12-04

Family

ID=80684926

Family Applications (1)

Application Number Title Priority Date Filing Date
EP22709370.5A Pending EP4469034A1 (en) 2022-01-24 2022-01-24 Composition for treating esophageal reflux

Country Status (2)

Country Link
EP (1) EP4469034A1 (en)
WO (1) WO2023139414A1 (en)

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2208500A1 (en) * 2009-01-16 2010-07-21 Bionap S.r.L. Compositions for the treatment of gerd (gastroesophageal reflux disease)
ITUB20159732A1 (en) * 2015-12-22 2017-06-22 S I I T S R L Servizio Int Imballaggi Termosaldanti ORAL COMPOSITIONS FOR THE TREATMENT OF GASTROESOPHAGEAL REFLUX DISEASE
US20210085596A1 (en) * 2018-02-19 2021-03-25 Food Technology and Design, LLC, DBA FoodPharma Compositions for oral mucoadhesive dosage forms

Also Published As

Publication number Publication date
WO2023139414A1 (en) 2023-07-27

Similar Documents

Publication Publication Date Title
JP6141891B2 (en) Method for treating esophageal disorder and composition for treatment
CN101869709A (en) Composite of peptic ulcer resisting medicaments and preparation method thereof
WO1998015196A1 (en) Compositions for postgastrectomic mineral supply
US7087649B2 (en) Methods for preventing and treating diseases and conditions associated with cellular stress
CN101068535A (en) Oral composition for absorbing phosphorus-containing compounds
US20070202058A1 (en) Compositions for treating gastric reflux
CN1919170A (en) Colloid pectin bismuth dry suspensoid and its preparing process
WO2005105058A1 (en) Sustained-releasing injectable formulation for the treatment or prevention of bone-related diseases comprising bisphorenate-containing polymeric microparticles
JP2024525096A (en) Method for neutralizing stomach acid using alginate, polylysine, and a seed preservative
JP2005533833A (en) Liquid dosage forms of non-enteric acid labile drugs
EP4469034A1 (en) Composition for treating esophageal reflux
CN113905619B (en) Sodium exhaust particles
EA012261B1 (en) Pharmaceutical compositions comprising a proton pump inhibitor and a prokinetic agent
JP2012111773A (en) Medicinal composition for improving oral absorption
JP2007503427A (en) Composition for treating medical conditions requiring suppression of gastric acid secretion
EP2806880B2 (en) Pharmaceutical composition as a substance for antireflux antacid drug
BRPI0615770A2 (en) bisphosphonate formulation
US20050063980A1 (en) Gastric raft composition
CN103263415A (en) Levo pantoprazole sodium composition for injection and preparation method thereof
CN107397734A (en) A kind of 2-Propen-1-amine polymer with(chloromethyl)oxirane carbonate tablet of stabilization and preparation method thereof
MacLaren A review of stress ulcer prophylaxis
CN107106602B (en) Hepatic fibrosis improving agent
WO1992022305A1 (en) Therapeutic composition for sustained release of magnesium
EP1992345A1 (en) Synergic combination of h2-receptor inhibitors, inert silicone and a hydroxymagnesium aluminate complex
JP7499028B2 (en) Internal pharmaceutical composition

Legal Events

Date Code Title Description
STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: UNKNOWN

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE INTERNATIONAL PUBLICATION HAS BEEN MADE

PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: REQUEST FOR EXAMINATION WAS MADE

17P Request for examination filed

Effective date: 20240617

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR

DAV Request for validation of the european patent (deleted)
DAX Request for extension of the european patent (deleted)