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EP0920320A2 - Injectable pharmaceutical composition comprising ursodesoxycholic acid or tauroursodesoxycholic acid, a strong base and tromethamol - Google Patents

Injectable pharmaceutical composition comprising ursodesoxycholic acid or tauroursodesoxycholic acid, a strong base and tromethamol

Info

Publication number
EP0920320A2
EP0920320A2 EP96944084A EP96944084A EP0920320A2 EP 0920320 A2 EP0920320 A2 EP 0920320A2 EP 96944084 A EP96944084 A EP 96944084A EP 96944084 A EP96944084 A EP 96944084A EP 0920320 A2 EP0920320 A2 EP 0920320A2
Authority
EP
European Patent Office
Prior art keywords
acid
composition according
strong base
ursodeoxycholic acid
trometamol
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.)
Ceased
Application number
EP96944084A
Other languages
German (de)
French (fr)
Inventor
Tiziano Prato
Anna Giulia Rusticali
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.)
Sanofi Aventis France
Sanofi Aventis SpA
Original Assignee
Sanofi SA
Sanofi Winthrop SpA
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 Sanofi SA, Sanofi Winthrop SpA filed Critical Sanofi SA
Publication of EP0920320A2 publication Critical patent/EP0920320A2/en
Ceased legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
    • 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
    • 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
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics

Definitions

  • the present invention relates to a new pharmaceutical composition based on ursodeoxycholic acid as such or conjugated with taurine.
  • the invention relates to an injectable formulation of ursodeoxycholic acid or tauroursodeoxycholic acid to be administered intravenously, in particular by slow infusion.
  • Ursodeoxycholic acid and tauroursodeoxycholic acid are drugs widely used in therapy as litholytics and in the treatment of various hepatic pathologies, such as hepatic cholestasis and primary biliary cirrhosis. It has now been found that the action of these drugs is particularly useful also in the treatment of liver pathologies in patients for whom oral administration is impossible or difficult.
  • no injectable pharmaceutical formulation based on ursodeoxycholic acid or tauroursodeoxycholic acid is marketed, their preparation presenting problems due to the physicochemical properties of these active ingredients.
  • Ursodeoxycholic acid is a weak acid practically insoluble in water; its solubility increases greatly in the presence of strong bases such as soda and potash.
  • Aqueous solutions consisting only of ursodeoxycholic acid and a strong base are however not suitable for intravenous administration since even a small variation in the amount of strong base in the preparation leads to a consequent variation in the pH of the solution for injection which is often incompatible with intravenous administration.
  • Tauroursodeoxycholic acid unlike ursodeoxycholic acid, is a strong acid, soluble in water, with a pKa of about 1.4. This high acidity is incompatible with intravenous administration; in this case also, one can resort to the addition of bases in the solution but the problems of the variation of the pH mentioned above are however not solved.
  • ursodeoxycholic and tauroursodeoxycholic acids are detergent compounds and, for this reason, when added to an aqueous solution such as solution for intravenous infusion, cause foaming. It has now been found that the addition of trometamol ((tris-hydroxymethyl) - aminomethane) to an aqueous solution containing ursodeoxycholic acid or tauroursodeoxycholic acid and strong bases, leads to stable solutions, well buffered and suitable for intravenous administration.
  • trometamol significantly decreases the formation and persistence of the foam which forms in the solution for intravenous infusion following the addition of the above preparation.
  • the present invention therefore relates to an injectable aqueous composition which comprises ursodeoxycholic acid or tauroursodeoxycholic acid, a strong base compatible with intravenous administration and trometamol.
  • the water used is suitable for injections.
  • the formulation according to the invention comprises an amount of active principle, ursodeoxycholic acid or tauroursodeoxycholic acid, of between 1 and 30% (w / v), preferably between 5 and 20% (w / v), for example 10% (w / v).
  • the strong base compatible with intravenous administration is preferably sodium or potassium hydroxide; such bases are used in an amount stoichiometrically equivalent with respect to the acid used.
  • Trometamol is added in an amount of 0.01 - 2% (w / v), preferably in an amount of about 0.1% (w / v).
  • the formulation according to the invention advantageously consists of an aqueous solution which comprises from 5 to 15% (w / v) of active principle (ursodeoxycholic acid or tauroursodeoxycholic acid), a stoichiometrically equivalent amount of strong base (sodium or potassium hydroxide ) and from 0.05 to 0.2% (w / v) of trometamol, ursodeoxycholic acid being the preferred active ingredient.
  • active principle ursodeoxycholic acid or tauroursodeoxycholic acid
  • strong base sodium or potassium hydroxide
  • the aqueous injectable formulation which is the subject of the present invention preferably contains approximately 10% (w / v) of ursodeoxycholic acid, approximately 1% (w / v) of sodium hydroxide and approximately 0.1% (w / v) of trometamol.
  • the formulation of the present invention is prepared by mixing the various components separately in distilled water and then bringing together the solutions / suspensions obtained. The solution is therefore properly filtered to remove any residues and sterilized.
  • the solution is subdivided into ampoules or single-dose vials, optionally by operating under a nitrogen atmosphere, and, when used, diluted in the solution for intravenous infusion to be administered. by slow infusion. If it is desired in any case to use multi-dose containers, it might be advisable to add a bactericidal agent to the composition.
  • a particularly advantageous solution for intravenous infusion is the physiological solution (usual, containing 0.9% sodium chloride).
  • Physiological solutions for intravenous infusions containing the above composition are also an object of the present invention. More particularly, the invention also relates to a composition for intravenous infusions which comprises physiological solution, ursodeoxycholic acid or tauroursodeoxycholic acid, a strong base compatible with intravenous administration in an amount stoichiometrically equivalent with respect to the acid employed. , and trometamol. According to another of its aspects, the present invention relates to the use of ursodeoxycholic acid or tauroursodeoxycholic acid for the preparation of injectable formulations suitable for the treatment of hepatic pathologies of patients for whom the administration of oral medication is impossible.
  • Said formulations are useful in subjects having undergone a transplant (for example liver, heart, marrow, kidney) for combating the hepatotoxic effects of the drugs which are normally administered following the transplant intervention; in subjects with hepatic impairment; in subjects whose feeding is carried out entirely parenterally; in subjects who have undergone a massive intestinal resection which provides for a prolonged fast; in newborns and children with hepatic cholestasis.
  • a transplant for example liver, heart, marrow, kidney
  • the duration of treatment by slow intravenous infusion of ursodeoxycholic acid or tauroursodeoxycholic acid, preferably administered by the formulation which is the subject of the invention varies according to the pathologies to be treated. In general, such a duration varies from 1 to 30 days, advantageously from 3 to 10 days, preferably from 5 to 7 days. If necessary, several treatment cycles can be carried out.
  • the daily dose of active ingredient to be administered naturally varies according to the age and weight of the patient, as well as according to the type and severity of the pathology to be treated.
  • the daily dose of active principle to be administered according to the present invention (expressed in mg of acid) is between 2 and 30 mg / kg of body weight, advantageously between 4 and 20 mg / kg, preferably between 8 and 15 mg / kg.
  • the daily dose is between 500 and 2000 mg.
  • Unit doses can therefore contain from 100 to 2000 mg of active ingredient
  • Such unit doses after suitable dilution in solution for intravenous infusion, can be administered 1 or more times a day, as needed.
  • the unit doses contain 250 or 500 mg of active principle (expressed in mg of acid), in volumes of 2.5 and 5 ml respectively.
  • active principle expressed in mg of acid
  • the ampoules thus obtained are capable of being diluted in a physiological solution and administered by slow infusion.

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  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Engineering & Computer Science (AREA)
  • Epidemiology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)
  • Exhaust Silencers (AREA)
  • Steroid Compounds (AREA)

Abstract

Injectable aqueous composition comprising ursodesoxycholic acid or tauroursodesoxycholic acid, a strong base compatible with intravenous injection and tromethamol.

Description

COMPOSITION PHARMACEUTIQUE INJECTABLE CONTENANT L'ACIDE URSODESOXYCHOLIQUE OU L'ACIDE TAUROURSODESOXYCHOLIQUE, UNE BASE FORTE ET DU TROMETAMOLINJECTABLE PHARMACEUTICAL COMPOSITION CONTAINING URSODESOXYCHOLIC ACID OR TAUROURSODESOXYCHOLIC ACID, A STRONG BASE AND TROMETAMOL
La présente invention concerne une nouvelle composition pharmaceutique à base d'acide ursodésoxycholique en tant que tel ou conjugué avec la taurine. En particulier, l'invention concerne une formulation injectable d'acide ursodésoxycholique ou d'acide tauroursodésoxycholique à administrer par voie intraveineuse, notamment par perfusion lente.The present invention relates to a new pharmaceutical composition based on ursodeoxycholic acid as such or conjugated with taurine. In particular, the invention relates to an injectable formulation of ursodeoxycholic acid or tauroursodeoxycholic acid to be administered intravenously, in particular by slow infusion.
L'acide ursodésoxycholique et l'acide tauroursodésoxycholique sont des médicaments largement utilisés en thérapie en tant que litholytiques et dans le traitement de différentes pathologies hépatiques, telles que la choléstase hépatique et la cirrhose biliaire primitive. On a maintenant trouvé que l'action de ces médicaments est particulièrement utile également dans le traitement des pathologies hépatiques chez les patients pour lesquels l'administration par voie orale est impossible ou difficile. Actuellement aucune formulation pharmaceutique injectable à base d'acide ursodésoxycholique ou d'acide tauroursodésoxycholique n'est commercialisée, leur préparation présentant des problèmes dus aux propriétés physico-chimiques de ces principes actifs.Ursodeoxycholic acid and tauroursodeoxycholic acid are drugs widely used in therapy as litholytics and in the treatment of various hepatic pathologies, such as hepatic cholestasis and primary biliary cirrhosis. It has now been found that the action of these drugs is particularly useful also in the treatment of liver pathologies in patients for whom oral administration is impossible or difficult. Currently, no injectable pharmaceutical formulation based on ursodeoxycholic acid or tauroursodeoxycholic acid is marketed, their preparation presenting problems due to the physicochemical properties of these active ingredients.
L'acide ursodésoxycholique est un acide faible pratiquement insoluble dans l'eau; sa solubilité augmente beaucoup en présence de bases fortes telles que la soude et la potasse. Des solutions aqueuses constituées uniquement d'acide ursodésoxycholique et d'une base forte ne sont cependant pas convenables pour l'administration par voie intraveineuse puisque même une petite variation de la quantité de base forte dans la préparation conduit à une conséquente variation du pH de la solution à injecter qui est souvent incompatible avec l'administration intraveineuse.Ursodeoxycholic acid is a weak acid practically insoluble in water; its solubility increases greatly in the presence of strong bases such as soda and potash. Aqueous solutions consisting only of ursodeoxycholic acid and a strong base are however not suitable for intravenous administration since even a small variation in the amount of strong base in the preparation leads to a consequent variation in the pH of the solution for injection which is often incompatible with intravenous administration.
L'acide tauroursodésoxycholique, contrairement à l'acide ursodésoxycholique, est un acide fort, soluble dans l'eau, avec pKa d'environ 1,4. Cette forte acidité est incompatible avec l'administration intraveineuse; dans ce cas aussi, on peut recourir à l'adjonction de bases dans la solution mais les problèmes de la variation du pH mentionnés ci-dessus ne sont cependant pas résolus.Tauroursodeoxycholic acid, unlike ursodeoxycholic acid, is a strong acid, soluble in water, with a pKa of about 1.4. This high acidity is incompatible with intravenous administration; in this case also, one can resort to the addition of bases in the solution but the problems of the variation of the pH mentioned above are however not solved.
En outre, les acides ursodésoxycholique et tauroursodésoxycholique sont des composés détergents et, pour cette raison, lorsqu'ils sont ajoutés à une solution aqueuse telle que la solution pour perfusion intraveineuse, provoquent la formation d'une mousse. On a maintenant trouvé que l'addition de trométamol ((tris-hydroxyméthyl)- aminométhane) à une solution aqueuse contenant de l'acide ursodésoxycholique ou de l'acide tauroursodésoxycholique et des bases fortes, conduit à des solutions stables, bien tamponnées et convenables pour l'administration intraveineuse.In addition, ursodeoxycholic and tauroursodeoxycholic acids are detergent compounds and, for this reason, when added to an aqueous solution such as solution for intravenous infusion, cause foaming. It has now been found that the addition of trometamol ((tris-hydroxymethyl) - aminomethane) to an aqueous solution containing ursodeoxycholic acid or tauroursodeoxycholic acid and strong bases, leads to stable solutions, well buffered and suitable for intravenous administration.
En outre, on a observé que l'adjonction de trométamol diminue de façon suφrenante la formation et la persistance de la mousse qui se forme dans la solution pour perfusion intraveineuse suite à l'addition de la préparation ci-dessus.In addition, it has been observed that the addition of trometamol significantly decreases the formation and persistence of the foam which forms in the solution for intravenous infusion following the addition of the above preparation.
La présente invention a donc pour objet une composition aqueuse injectable qui comprend l'acide ursodésoxycholique ou l'acide tauroursodésoxycholique, une base forte compatible avec l'administration par voie intraveineuse et le trométamol.The present invention therefore relates to an injectable aqueous composition which comprises ursodeoxycholic acid or tauroursodeoxycholic acid, a strong base compatible with intravenous administration and trometamol.
Selon la présente invention, l'eau utilisée est convenable pour les préparations injectables.According to the present invention, the water used is suitable for injections.
La formulation selon l'invention comprend une quantité de principe actif, l'acide ursodésoxycholique ou l'acide tauroursodésoxycholique, comprise entre 1 et 30% (p/v), de préférence entre 5 et 20% (p/v), par exemple 10% (p/v).The formulation according to the invention comprises an amount of active principle, ursodeoxycholic acid or tauroursodeoxycholic acid, of between 1 and 30% (w / v), preferably between 5 and 20% (w / v), for example 10% (w / v).
La base forte compatible avec l'administration par voie intraveineuse est de préférence l'hydroxyde de sodium ou de potassium; de telles bases sont utilisées en quantité stoechiométriquement équivalente par rapport à l'acide employé.The strong base compatible with intravenous administration is preferably sodium or potassium hydroxide; such bases are used in an amount stoichiometrically equivalent with respect to the acid used.
Le trométamol est ajouté à raison de 0,01 - 2% (p/v), de préférence à raison d'environ 0,1 % (p/v).Trometamol is added in an amount of 0.01 - 2% (w / v), preferably in an amount of about 0.1% (w / v).
La formulation selon l'invention est constituée avantageusement par une solution aqueuse qui comprend de 5 à 15% (p/v) de principe actif (acide ursodésoxycholique ou acide tauroursodésoxycholique), une quantité stoechiométriquement équivalente de base forte (hydroxyde de sodium ou de potassium) et de 0,05 à 0,2 % (p/v) de trométamol, l'acide ursodésoxycholique étant le principe actif préféré.The formulation according to the invention advantageously consists of an aqueous solution which comprises from 5 to 15% (w / v) of active principle (ursodeoxycholic acid or tauroursodeoxycholic acid), a stoichiometrically equivalent amount of strong base (sodium or potassium hydroxide ) and from 0.05 to 0.2% (w / v) of trometamol, ursodeoxycholic acid being the preferred active ingredient.
La formulation aqueuse injectable objet de la présente invention contient de préférence environ 10% (p/v) d'acide ursodésoxycholique, environ 1% (p/v) d'hydroxyde de sodium et environ 0,1 % (p/v) de trométamol.The aqueous injectable formulation which is the subject of the present invention preferably contains approximately 10% (w / v) of ursodeoxycholic acid, approximately 1% (w / v) of sodium hydroxide and approximately 0.1% (w / v) of trometamol.
La formulation de la présente invention est préparée en mélangeant séparément les différents composants dans de l'eau distillée et en réunissant après les solutions/suspensions obtenues. La solution est donc convenablement filtrée pour éliminer des résidus éventuels et stérilisée.The formulation of the present invention is prepared by mixing the various components separately in distilled water and then bringing together the solutions / suspensions obtained. The solution is therefore properly filtered to remove any residues and sterilized.
De préférence, avant la stérilisation, effectuée dans un autoclave, la solution est subdivisée dans des ampoules ou flacons mono-dose, éventuellement en opérant sous atmophère d'azote, et, lors de son utilisation, diluée dans la solution pour perfusion intraveineuse à administrer par perfusion lente. Au cas où on souhaiterait de toute façon utiliser des récipients multi-dose, il pourrait être opportun d'ajouter à la composition un agent bactéricide. Une solution pour perfusion intraveineuse particulièrement avantageuse est la solution physiologique (usuelle, contenant 0,9 % de chlorure de sodium).Preferably, before sterilization, carried out in an autoclave, the solution is subdivided into ampoules or single-dose vials, optionally by operating under a nitrogen atmosphere, and, when used, diluted in the solution for intravenous infusion to be administered. by slow infusion. If it is desired in any case to use multi-dose containers, it might be advisable to add a bactericidal agent to the composition. A particularly advantageous solution for intravenous infusion is the physiological solution (usual, containing 0.9% sodium chloride).
Des solutions physiologiques pour perfusions intraveineuses contenant la composition ci-dessus, sont également un objet de la présente invention. Plus particulièrement, l'invention concerne également une composition pour perfusions intraveineuses qui comprend de la solution physiologique, l'acide ursodésoxycholique ou l'acide tauroursodésoxycholique, une base forte compatible avec l'administration intraveineuse en quantité stoechiométriquement équivalente par rapport à l'acide employé, et du trométamol. Selon un autre de ses aspects, la présente invention a pour objet l'utilisation de l'acide ursodésoxycholique ou de l'acide tauroursodésoxycholique pour la préparation de formulations injectables convenables pour le traitement des patholo¬ gies hépatiques de patients pour lesquels l'administration de médicaments par voie orale est impossible. Lesdites formulations sont utiles chez les sujets ayant subi une greffe (par exemple foie, coeur, moelle, rein) pour combattre les effets hépatotoxiques des médicaments qui sont normalement administrés suite à l'intervention de greffe; chez les sujets atteint d'insuffisance hépatique; chez les sujets dont la nourriture est effectué entièrement par voie parentérale; chez les sujets qui ont subi une résection massive intestinale qui prévoie un jeûne prolongé; chez les nouveaux-nés et les enfants atteints de choléstase hépatique.Physiological solutions for intravenous infusions containing the above composition are also an object of the present invention. More particularly, the invention also relates to a composition for intravenous infusions which comprises physiological solution, ursodeoxycholic acid or tauroursodeoxycholic acid, a strong base compatible with intravenous administration in an amount stoichiometrically equivalent with respect to the acid employed. , and trometamol. According to another of its aspects, the present invention relates to the use of ursodeoxycholic acid or tauroursodeoxycholic acid for the preparation of injectable formulations suitable for the treatment of hepatic pathologies of patients for whom the administration of oral medication is impossible. Said formulations are useful in subjects having undergone a transplant (for example liver, heart, marrow, kidney) for combating the hepatotoxic effects of the drugs which are normally administered following the transplant intervention; in subjects with hepatic impairment; in subjects whose feeding is carried out entirely parenterally; in subjects who have undergone a massive intestinal resection which provides for a prolonged fast; in newborns and children with hepatic cholestasis.
La durée du traitement par perfusion intraveineuse lente d'acide ursodésoxycholique ou d'acide tauroursodésoxycholique, administré de préférence par la formulation objet de l'invention, varie en fonction des pathologies à traiter. En général, une telle durée varie de 1 à 30 jours, avantageusement de 3 à 10 jours, de préférence de 5 à 7 jours. Si nécessaire, on peut effectuer plusieurs cycles de traitement.The duration of treatment by slow intravenous infusion of ursodeoxycholic acid or tauroursodeoxycholic acid, preferably administered by the formulation which is the subject of the invention, varies according to the pathologies to be treated. In general, such a duration varies from 1 to 30 days, advantageously from 3 to 10 days, preferably from 5 to 7 days. If necessary, several treatment cycles can be carried out.
La dose journalière de principe actif à administrer varie naturellement selon l'âge et le poids du patient, ainsi que selon le type et la gravité de la pathologie à traiter. En général la dose journalière de principe actif à administrer selon la présente invention (exprimée en mg d'acide) est comprise entre 2 et 30 mg/kg de poids du coφs, avantageusement entre 4 et 20 mg/kg, de préférence entre 8 et 15 mg/kg. Pour un adulte ayant une constitution normale, la dose journalière est comprise entre 500 et 2000 mg. Les doses unitaires peuvent donc contenir de 100 à 2000 mg de principe actifThe daily dose of active ingredient to be administered naturally varies according to the age and weight of the patient, as well as according to the type and severity of the pathology to be treated. In general, the daily dose of active principle to be administered according to the present invention (expressed in mg of acid) is between 2 and 30 mg / kg of body weight, advantageously between 4 and 20 mg / kg, preferably between 8 and 15 mg / kg. For an adult with a normal constitution, the daily dose is between 500 and 2000 mg. Unit doses can therefore contain from 100 to 2000 mg of active ingredient
(exprimée en mg d'acide). De telles doses unitaires, après une convenable dilution dans la solution pour perfusion intraveineuse, peuvent être administrées 1 ou plusieurs fois par jour, selon le besoin.(expressed in mg of acid). Such unit doses, after suitable dilution in solution for intravenous infusion, can be administered 1 or more times a day, as needed.
Selon un aspect préféré, les doses unitaires contiennent 250 ou 500 mg de principe actif (exprimée en mg d'acide), dans des volumes respectivement de 2,5 et 5 ml. L'exemple qui suit illustre mieux l'invention.According to a preferred aspect, the unit doses contain 250 or 500 mg of active principle (expressed in mg of acid), in volumes of 2.5 and 5 ml respectively. The example which follows better illustrates the invention.
Exemple 1Example 1
COMPOSITION INJECTABLE A BASE D'ACIDE URSODESOXYCHOLIQUE A 10% - Ampoules contenant 250 mg d'acide ursodésoxycholiqueINJECTABLE COMPOSITION BASED ON 10% URSODESOXYCHOLIC ACID - Ampoules containing 250 mg of ursodeoxycholic acid
A une suspension de 200 g d'acide ursodésoxycholique dans 1300 ml d'eau distillée, on ajoute 20 g d'hydroxyde de sodium dissous dans 200 ml d'eau distillée etTo a suspension of 200 g of ursodeoxycholic acid in 1300 ml of distilled water, 20 g of sodium hydroxide dissolved in 200 ml of distilled water are added and
2 g de trométamol dissous dans 50 ml d'eau distillée. On ajoute éventuellement au mélange ainsi obtenu quelques gouttes d'une solution aqueuse d'hydroxyde de sodium IN jusqu'à ce qu'il devienne limpide. On dilue avec de l'eau distillée q.s.p.2 g of trometamol dissolved in 50 ml of distilled water. Optionally, a few drops of a 1N aqueous sodium hydroxide solution are added to the mixture thus obtained until it becomes clear. Dilute with distilled water q.s.p.
® jusqu'à 2000 ml. On filtre à travers une membrane Millipore HAWP 0,45 μ + prê¬ filtre Millipore AP25. On répartit la solution obtenue, en opérant sous atmosphère d'azote, dans 800 ampoules de verre neutre blanc pour injectables en versant 2,5 ml de solution par ampoule. On stérilise les ampoules dans un autoclave à 121 *C pendant 30 minutes.® up to 2000 ml. It is filtered through a Millipore HAWP 0.45 μ membrane + prê¬ Millipore AP25 filter. The solution obtained is distributed, operating under a nitrogen atmosphere, in 800 ampoules of white neutral glass for injections by pouring 2.5 ml of solution per ampoule. The ampoules are sterilized in an autoclave at 121 ° C for 30 minutes.
Les ampoules ainsi obtenues sont aptes à être diluées dans une solution physiologique et administrés par perfusion lente.The ampoules thus obtained are capable of being diluted in a physiological solution and administered by slow infusion.
Exemple 2Example 2
COMPOSITION INJECTABLE A BASE D'ACIDE URSODESOXYCHOLIQUE A 10% - Ampoules contenant 500 mg d'acide ursodésoxycholiqueINJECTABLE COMPOSITION BASED ON 10% URSODESOXYCHOLIC ACID - Ampoules containing 500 mg of ursodeoxycholic acid
En opérant comme décrit dans l'exemple 1 mais en versant 5 ml de solution dans 400 ampoules on obtient la composition du titre. By operating as described in Example 1 but by pouring 5 ml of solution into 400 ampoules, the title composition is obtained.

Claims

REVENDICATIONS
I. Composition aqueuse injectable qui comprend l'acide ursodésoxycholique ou l'acide tauroursodésoxycholique, une base forte compatible avec l'administration par voie intraveineuse et du trométamol. I. Aqueous injectable composition which includes ursodeoxycholic acid or tauroursodeoxycholic acid, a strong base compatible with intravenous administration and trometamol.
2. Composition selon la revendication 1 caractérisée en ce que le principe actif est présent en quantité comprise entre 1 et 30% (p/v), de préférence entre 5 et 20% (p/v), par exemple 10% (p/v). 2. Composition according to claim 1 characterized in that the active principle is present in an amount between 1 and 30% (w / v), preferably between 5 and 20% (w / v), for example 10% (w / v).
3. Composition selon la revendication 1 caractérisée en ce que la base forte est l'hydroxyde de sodium ou de potassium. 3. Composition according to claim 1 characterized in that the strong base is sodium or potassium hydroxide.
4. Composition selon la revendication 3 caractérisée en ce que la base forte est présente en quantité stoechiométriquement équivalente au principe actif.4. Composition according to claim 3 characterized in that the strong base is present in an amount stoichiometrically equivalent to the active principle.
5. Composition selon la revendication 1 caractérisée en ce que le trométamol est présent à raison de 0,01 - 2% (p/v), de préférence à raison d'environ 0,1 % (p/v).5. Composition according to claim 1 characterized in that the trometamol is present in an amount of 0.01 - 2% (w / v), preferably in an amount of about 0.1% (w / v).
6. Composition selon la revendication 1 caractérisée en ce qu'elle comprend de 5 à 15% (p/v) d'acide ursodésoxycholique, une quantité stoechiométriquement équivalente de base forte (hydroxyde de sodium ou de potassium) et de 0,05 à 0,2% (p/v) de trométamol.6. Composition according to claim 1 characterized in that it comprises from 5 to 15% (w / v) of ursodeoxycholic acid, a stoichiometrically equivalent amount of strong base (sodium or potassium hydroxide) and from 0.05 to 0.2% (w / v) trometamol.
7. Composition selon la revendication 6 caractérisée en ce qu'elle comprend environ 10% (p/v) d'acide ursodésoxycholique, environ 1% (p/v) d'hydroxyde de sodium et environ 0,1 % (p/v) de trométamol.7. Composition according to claim 6 characterized in that it comprises approximately 10% (w / v) of ursodeoxycholic acid, approximately 1% (w / v) of sodium hydroxide and approximately 0.1% (w / v ) of trometamol.
8. Composition selon la revendication 7 caractérisée en ce qu'elle est subdivisée en doses unitaires contenant 250 ou 500 mg d'acide ursodésoxycholique.8. Composition according to claim 7 characterized in that it is subdivided into unit doses containing 250 or 500 mg of ursodeoxycholic acid.
9. Utilisation de l'acide ursodésoxycholique ou de l'acide tauroursodésoxycholique pour la préparation de formulations injectables convenables pour le traitement des pathologies hépatiques chez les patients pour lesquels l'administration de médicaments par voie orale est impossible.9. Use of ursodeoxycholic acid or tauroursodeoxycholic acid for the preparation of injectable formulations suitable for the treatment of hepatic pathologies in patients for whom the administration of oral medications is impossible.
10. Utilisation selon la revendication 9 pour la préparation de formulations injectables convenables pour le traitement des effets hépatotoxiques des médicaments qui sont normalement administrés suite à l'intervention de greffe chez les sujets ayant subi une greffe.10. Use according to claim 9 for the preparation of injectable formulations suitable for the treatment of hepatotoxic effects of drugs which are normally administered following transplant intervention in subjects having undergone a transplant.
II. Utilisation selon la revendication 9 pour la préparation de formulations injectables convenables pour le traitement des pathologies hépatiques chez les sujets atteints d'insuffisance hépatique; chez les sujets dont la nourriture est effectué entièrement par voie parentérale; chez les sujets qui ont subi une résection massive intestinale qui prévoit un jeûne prolongé; chez les nouveaux- nés et les enfants atteints de choléstase hépatique. II. Use according to claim 9 for the preparation of injectable formulations suitable for the treatment of hepatic pathologies in subjects suffering from hepatic insufficiency; in subjects whose feeding is carried out entirely parenterally; in subjects who have undergone a massive intestinal resection which provides for a prolonged fast; in newborns and children with hepatic cholestasis.
EP96944084A 1995-12-27 1996-12-26 Injectable pharmaceutical composition comprising ursodesoxycholic acid or tauroursodesoxycholic acid, a strong base and tromethamol Ceased EP0920320A2 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
IT95MI002763A IT1282943B1 (en) 1995-12-27 1995-12-27 INJECTABLE PHARMACEUTICAL COMPOSITION__A BASED ON URSODEXOXICOL CO OR TAUROURSODEXOXICOLIC ACID
ITMI952763 1995-12-27
PCT/FR1996/002083 WO1997024125A2 (en) 1995-12-27 1996-12-26 Injectable pharmaceutical composition comprising ursodesoxycholic acid or tauroursodesoxycholic acid, a strong base and tromethamol

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EP0920320A2 true EP0920320A2 (en) 1999-06-09

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US (1) US5955456A (en)
EP (1) EP0920320A2 (en)
JP (1) JP2000509013A (en)
AU (1) AU1380397A (en)
CA (1) CA2240266A1 (en)
IT (1) IT1282943B1 (en)
WO (1) WO1997024125A2 (en)

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US6596762B2 (en) 2001-05-17 2003-07-22 The Regents Of The University Of Colorado Antioxidant compositions and use for treatment of hepatic steatosis and steatohepatitis
TWI232102B (en) * 2001-07-17 2005-05-11 Shionogi & Co A pharmaceutical formulation for injection
US9295677B2 (en) 2008-02-26 2016-03-29 Qing Bile Therapeutics Inc. Polyhydroxylated bile acids for treatment of biliary disorders
WO2021099973A1 (en) 2019-11-22 2021-05-27 Shilpa Medicare Limited Injectable compositions of ursodeoxycholic acid
MX2022009182A (en) * 2020-01-28 2022-08-17 Shilpa Medicare Ltd Method for administration of ursodeoxycholic acid.
JPWO2022173043A1 (en) * 2021-02-15 2022-08-18
TW202412751A (en) * 2022-08-09 2024-04-01 日商參天製藥股份有限公司 Aqueous pharmaceutical composition containing UDCA or salt thereof

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US4649155A (en) * 1983-07-22 1987-03-10 Hoffmann-La Roche Inc. Injectable solutions
GB8706313D0 (en) * 1987-03-17 1987-04-23 Health Lab Service Board Treatment & prevention of viral infections
US5863550A (en) * 1993-03-31 1999-01-26 Tokyo Tanabe Company Limited Cholestasis ameliorant

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JP2000509013A (en) 2000-07-18
CA2240266A1 (en) 1997-07-10
ITMI952763A0 (en) 1995-12-27
AU1380397A (en) 1997-07-28
WO1997024125A3 (en) 1997-10-16
IT1282943B1 (en) 1998-04-02
US5955456A (en) 1999-09-21
ITMI952763A1 (en) 1997-06-27
WO1997024125A2 (en) 1997-07-10

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