WO2018167655A1 - Sirop laxatif - Google Patents

Sirop laxatif Download PDF

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Publication number
WO2018167655A1
WO2018167655A1 PCT/IB2018/051649 IB2018051649W WO2018167655A1 WO 2018167655 A1 WO2018167655 A1 WO 2018167655A1 IB 2018051649 W IB2018051649 W IB 2018051649W WO 2018167655 A1 WO2018167655 A1 WO 2018167655A1
Authority
WO
WIPO (PCT)
Prior art keywords
syrup
mannitol
laxative
fructooligosaccharides
gum
Prior art date
Application number
PCT/IB2018/051649
Other languages
English (en)
Inventor
Maurizio Danilo CATANESE
Renato VALSASINA
Giulia DAL MORO
Stefano Cecchi
Original Assignee
Pharmaxima S.R.L.
Alebehr Italia S.R.L.
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 Pharmaxima S.R.L., Alebehr Italia S.R.L. filed Critical Pharmaxima S.R.L.
Publication of WO2018167655A1 publication Critical patent/WO2018167655A1/fr

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Classifications

    • 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
    • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
    • 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
    • A61K31/7004—Monosaccharides having only carbon, hydrogen and oxygen atoms
    • 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
    • A61K31/702—Oligosaccharides, i.e. having three to five saccharide radicals attached to each other by glycosidic linkages

Definitions

  • the present invention relates to a laxative syrup which offers a satisfactory balance of palatability, calorie intake, viscosity, and efficacy for the treatment of intestinal constipation. It has therefore been proved to be particularly suitable not only for adults, but also for children and the elderly.
  • Laxatives can be divided in bulk-forming laxatives, contact laxatives, emollient laxatives, and osmotic laxatives.
  • Laxatives can be useful in patients with haemorrhoids, with drug-induced constipation, after anthelmintic therapy, and prior to surgical and radiological procedures.
  • Contact laxatives increase intestinal motility, but can lead to abdominal cramps and are contraindicated in the event of intestinal obstruction. Furthermore, prolonged use of contact laxatives may cause colonic atony and hypocalcaemia.
  • contact laxatives are bisacodyl, senna, dantron, docusate, glycerine and picosulphate.
  • Emollient laxatives such as Vaseline oil, are useful for oral administration, provide lubrication, and stimulate intestinal motility.
  • Vaseline oil has disadvantages, such as irritation in the event of prolonged use thereof, granulomatous reactions following absorption of small amounts thereof, lipid pneumonia, and interference with the absorption of fat-soluble vitamins.
  • Osmotic laxatives retain fluids in the intestine through an osmotic mechanism.
  • osmotic laxatives are magnesium hydroxide and lactulose.
  • Magnesium hydroxide allows a rapid intestinal discharge, but its use must be occasional. In patients with renal impairment, magnesium accumulation can be observed.
  • Lactulose is a semi-synthetic disaccharide which is not absorbed in the gastroenteric tract. It is contraindicated in people suffering from galactosemia. Furthermore, lactulose is particularly sweet and causes nausea in patients prescribed with doses ranging from 10 to 20 ml at a time.
  • the object of the present invention is therefore to provide a product which effectively treats intestinal constipation, while also overcoming the drawbacks of conventional laxatives.
  • the present invention relates to a process for preparing the laxative syrup.
  • the present invention relates to the use of said laxative syrup to treat intestinal constipation.
  • the laxative syrup of the invention has surprisingly proved to be highly effective for the treatment of intestinal constipation, while also offering optimal tolerability by the body, even over long periods of administration, in addition to a satisfactory balance of palatability and calorie intake.
  • the invention therefore relates to a laxative syrup comprising mannitol and fructooligo s accharides .
  • Mannitol (or D-(-)-mannitol), which is often also known as mannite, is a chiral alditol with six hydroxyl groups in the aliphatic chain, consisting of six saturated carbon atoms. Said substance is easily found in nature, in algae and fungi, and its name originates from the word 'manna' (i.e. the sap of the ash tree) from which it can be obtained.
  • Fructooligosaccharides also known as oligofructose or oligofructans, are short- chain fructans (oligosaccharides) found in various plant species, in which they act as energy reserves.
  • G Glucose
  • F Fructose
  • n number of Fructose molecules.
  • the molecules with a degree of polymerisation ranging from 3 to 10 are known as fructooligosaccharides.
  • the combination of mannitol and fructooligosaccharides allows to obtain a laxative syrup, which is not only effective in the treatment of intestinal constipation, but also features optimal tolerability by the body, even over prolonged periods of administration, in addition to a satisfactory balance of palatability and calorie intake.
  • the syrup of the invention advantageously does not contain sucrose, however resulting in a pleasant taste. This is particularly significant as conventional laxative syrups can contain sucrose levels of up to 60%.
  • mannitol and fructooligosaccharides are preferably in a weight ratio of 15 : 1 to 1 : 1.
  • mannitol is in an amount greater than fructooligosaccharides.
  • mannitol and fructooligosaccharides are preferably in a weight ratio of 10: 1 to 2: 1.
  • mannitol and fructooligosaccharides are in a weight ratio of 7: 1 to 3: 1.
  • mannitol is in the syrup in a concentration of up to 1000 mg/ml.
  • mannitol is in the syrup in a concentration of 100-800 mg/ml, more preferably of 300-500 mg/ml.
  • fructooligosaccharides are in the syrup in a concentration of up to 200 mg/ml.
  • fructooligosaccharides are in the syrup in a concentration of 50-120 mg/ml, more preferably of 70-90 mg/ml.
  • mannitol and fructooligosaccharides are the only active ingredients for the treatment of intestinal constipation to be present in the laxative syrup of the invention.
  • the laxative syrup of the invention preferably further comprises water.
  • water is the only solvent present in the laxative syrup.
  • the laxative syrup of the invention can also comprise pharmaceutically acceptable excipients, such as antioxidants, emulsifiers, tonicity regulators, preservatives, flavourings, sweeteners, thinners, glidants, colourings, binders, adsorbents, buffers, and mixtures thereof.
  • pharmaceutically acceptable excipients such as antioxidants, emulsifiers, tonicity regulators, preservatives, flavourings, sweeteners, thinners, glidants, colourings, binders, adsorbents, buffers, and mixtures thereof.
  • pharmaceutically acceptable excipient should be understood as a compound or mixture which should generally not cause an adverse response in a patient, nor should it significantly inhibit the action the laxative action of the syrup.
  • Suitable excipients may be xanthan gum, guar gum, tara gum, locust bean gum, fenugreek gum, gum arabic, acacia gum, alginic acid, sodium alginate, propylene glycol alginate, calcium carboxymethylcellulose, sodium carboxymethylcellulose, ethyl cellulose, gelatin, ethyl cellulose, hydroxyethylcellulose, hydroxypropylcellulose, polydextrose, carrageenan, methylcellulose, sucrose, sorbitol, xylitol, dextrose, fructose, maltitol, sodium alginate, tragacanth gum, hydroxypropyl methylcellulose, potassium sorbate, sodium benzoate, sucralose, maltodextrin, magnesium carbonate, magnesium stearate, natural starch, partially hydrolysed starch, lactose, calcium phosphate, calcium carbonate, calcium sulphate, silica, colloidal silica, precipitated
  • said pharmaceutically acceptable excipients comprise xanthan gum, guar gum, tara gum, locust bean gum, fenugreek gum, gum arabic, acacia gum, alginic acid, sodium alginate, propylene glycol alginate, tragacanth gum, or a mixture thereof.
  • said pharmaceutically acceptable excipients comprise xanthan gum, guar gum, tara gum, locust bean gum, fenugreek gum, gum arabic, acacia gum, tragacanth gum, or a mixture thereof.
  • said pharmaceutically acceptable excipients comprise xanthan gum.
  • compositions wherein said pharmaceutically acceptable excipients also comprise potassium sorbate, sodium benzoate, or a mixture thereof.
  • the syrup of the invention comprises up to 100 mg/ml of pharmaceutically acceptable excipients.
  • the pharmaceutically acceptable excipients are in the syrup in a concentration of 20-60 mg/ml, more preferably of 30-50 mg/ml.
  • the laxative syrup of the invention does not comprise preservatives.
  • the pH of the syrup of the invention is 4 to 6, more preferably 4.5 to 5.5.
  • the density of the syrup of the invention is preferably 1.0-1.5 g/ml, more preferably 1.1- 1.3 g/ml.
  • the laxative syrup according to the invention is in the form of a unit dose.
  • said unit dose comprises up to 15 g of mannitol.
  • said unit dose comprises 2-14 g of mannitol, more preferably 3-13 g of mannitol.
  • said unit dose comprises up to 5 g of fructooligosaccharides.
  • said unit dose comprises 0.1-4 g of fructooligosaccharides, more preferably 0.5-3 g of fructooligosaccharides.
  • the laxative syrup of the invention comprises:
  • the laxative syrup of the invention comprises:
  • fructooligosaccharides
  • the laxative syrup of the invention consists essentially of mannitol, fructooligosaccharides, and water.
  • the expression "consists essentially of” means that mannitol and fructooligosaccharides are the only active ingredients for the treatment of intestinal constipation to be present in the solution according to the invention, while further components or excipients do not interfere with the laxative action and are water-miscible and -soluble.
  • the laxative syrup of the invention consists of mannitol, fructooligosaccharides, water, and pharmaceutically acceptable excipients.
  • the present invention relates to a process for preparing the laxative syrup as described above.
  • the preparation process comprises the following steps:
  • the present invention also relates to a laxative syrup comprising mannitol.
  • mannitol is the only active ingredient for the treatment of intestinal constipation to be present in the laxative syrup of the invention.
  • mannitol is in the syrup in a concentration of up to 1000 mg/ml.
  • mannitol is in the syrup in a concentration of 100-800 mg/ml, more preferably 300-500 mg/ml.
  • the laxative syrup of the invention further comprises water.
  • the water is the only solvent present in the laxative syrup.
  • the laxative syrup of the invention further comprises pharmaceutically acceptable excipients, as described above.
  • said excipients comprise xanthan gum, guar gum, tara gum, locust bean gum, fenugreek gum, gum arabic, acacia gum, alginic acid, sodium alginate, propylene glycol alginate, tragacanth gum, or a mixture thereof.
  • said pharmaceutically acceptable excipients comprise xanthan gum, guar gum, tara gum, locust bean gum, fenugreek gum, gum arabic, acacia gum, tragacanth gum, or a mixture thereof.
  • said pharmaceutically acceptable excipients comprise xanthan gum.
  • compositions wherein said pharmaceutically acceptable excipients also comprise potassium sorbate, sodium benzoate, or a mixture thereof.
  • the syrup of the invention comprises up to 100 mg/ml of pharmaceutically acceptable excipients.
  • the pharmaceutically acceptable excipients are in the syrup in a concentration of 20-60 mg/ml, more preferably 30-50 mg/ml.
  • the laxative syrup of the invention does not comprise preservatives.
  • the syrup of the invention has a pH of 4-6, more preferably 4.5-5.5.
  • the density of the syrup of the invention is preferably 1.0-1.5 g/ml, more preferably 1.1- 1.3g/ml.
  • the laxative syrup of the invention is in the form of a unit dose. It should also be understood that all aspects identified as preferred and advantageous for the laxative syrup and the components thereof should be deemed to be equally preferred and advantageous also for these embodiments containing mannitol.
  • This stable mannitol solution can be obtained by a process comprising the following steps:
  • excipients comprising xanthan gum, guar gum, tara gum, locust bean gum, fenugreek gum, gum arabic, acacia gum, alginic acid, sodium alginate, propylene glycol alginate, tragacanth gum, or a mixture thereof,
  • said pharmaceutically acceptable excipients comprise xanthan gum, guar gum, tara gum, locust bean gum, fenugreek gum, gum arabic, acacia gum, tragacanth gum, or a mixture thereof.
  • said pharmaceutically acceptable excipients comprise xanthan gum.
  • compositions wherein said pharmaceutically acceptable excipients also comprise potassium sorbate, sodium benzoate, or a mixture thereof.
  • Step 2) is preferably carried out under stirring at a temperature of 60-80°C, until a homogenous mixture is obtained.
  • Step 3) involves the addition of mannitol to the mixture obtained in step 2).
  • the mixture obtained in step 2) is allowed to cool to 30-50°C before mannitol is added.
  • Step 4) involves cooling the mixture obtained in step 3), preferably by using a cooling jacket, until room temperature is reached (i.e. 20-25°C, more preferably 22-25°C). Step 4) is preferably carried out with the mixture under stirring.
  • the resulting syrup has a pH of 4-6, more preferably of 4.5- 5.5. Particularly preferred are those embodiments wherein the pH is 5.
  • the overall amount of water used in the process is sufficient to achieve a final syrup density of 1.0-1.5 g/ml, preferably 1.1-1.3 g/ml. Particularly preferred are those embodiments wherein the density is 1.15 g/ml.
  • Said process may also be carried out for the preparation of a laxative syrup comprising both mannitol and fructooligosaccharides.
  • the latter may be added together with mannitol in step 3).
  • the present invention relates to the use of the laxative syrup described above for the treatment of intestinal constipation.
  • the laxative syrup of the invention is not only effective for the treatment of intestinal constipation, but also features optimal tolerability by the body, even over prolonged periods of administration, in addition to a satisfactory balance of palatability and calorie intake.
  • the syrup of the invention advantageously does not contain sucrose, however resulting in a pleasant taste.
  • the laxative syrup of the invention is particularly recommended for administration to children, pregnant women, and the elderly.
  • the laxative syrup of the invention is administered via oral, buccal, or sublingual route. More preferably, the laxative syrup of the invention is administered via oral route.
  • the laxative syrup of the invention is administered in doses of 0.5-50 ml per day, more preferably 5-40 ml per day. It should be understood that all the possible combinations of the preferred aspects of the components of the syrup, the unit doses, the preparation, and the uses of said syrup are described herein and therefore are also preferred.
  • a laxative syrup was prepared having the following composition for 2 ml of laxative syrup:
  • a laxative syrup was prepared having the following composition:
  • a laxative syrup was prepared having the following composition:
  • a laxative syrup was prepared having the following composition:
  • flavouring and citric acid were added until the mixture reached a pH of 5.0, and a density of 1.15 g/ml.
  • the resulting syrup contained mannitol stably dissolved therein.
  • Example 5 The resulting syrup contained mannitol stably dissolved therein.
  • a laxative syrup was prepared having the following composition:
  • flavouring and citric acid were added until the mixture reached a pH of 5.0, and a density of 1.15 g/ml.
  • the resulting syrup contained mannitol stably dissolved therein.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Epidemiology (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Molecular Biology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicinal Preparation (AREA)

Abstract

L'invention concerne un sirop laxatif qui offre un équilibre satisfaisant de sapidité, d'absorption de calories, de viscosité et d'efficacité. Il est donc particulièrement adapté non seulement aux adultes, mais aussi aux enfants et aux personnes âgées.
PCT/IB2018/051649 2017-03-14 2018-03-13 Sirop laxatif WO2018167655A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IT102017000028220A IT201700028220A1 (it) 2017-03-14 2017-03-14 Sciroppo lassativo
IT102017000028220 2017-03-14

Publications (1)

Publication Number Publication Date
WO2018167655A1 true WO2018167655A1 (fr) 2018-09-20

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ID=59521443

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2018/051649 WO2018167655A1 (fr) 2017-03-14 2018-03-13 Sirop laxatif

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IT (1) IT201700028220A1 (fr)
WO (1) WO2018167655A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IT202100002204A1 (it) * 2021-02-02 2022-08-02 Foodar Advanced Res S R L Composizione per il trattamento della disfagia

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA607149A (en) * 1960-10-18 S. Cardaciotto Paul Laxative syrups containing di-n-octyl sulfosuccinate salts
EP0423771A2 (fr) * 1989-10-17 1991-04-24 Hershey Foods Corporation Utilisation de L-sucres pour la fabrication de compositions laxatives
WO2017040860A1 (fr) * 2015-09-01 2017-03-09 Colonaryconcepts Llc Formulations de laxatifs et leur fabrication

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA607149A (en) * 1960-10-18 S. Cardaciotto Paul Laxative syrups containing di-n-octyl sulfosuccinate salts
EP0423771A2 (fr) * 1989-10-17 1991-04-24 Hershey Foods Corporation Utilisation de L-sucres pour la fabrication de compositions laxatives
WO2017040860A1 (fr) * 2015-09-01 2017-03-09 Colonaryconcepts Llc Formulations de laxatifs et leur fabrication

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IT202100002204A1 (it) * 2021-02-02 2022-08-02 Foodar Advanced Res S R L Composizione per il trattamento della disfagia

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Publication number Publication date
IT201700028220A1 (it) 2018-09-14

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