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)

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• 1995
  • 1995-12-27 IT IT95MI002763A patent/IT1282943B1/it active IP Right Grant
• 1996
  • 1996-12-26 WO PCT/FR1996/002083 patent/WO1997024125A2/fr not_active Ceased
  • 1996-12-26 EP EP96944084A patent/EP0920320A2/de not_active Ceased
  • 1996-12-26 AU AU13803/97A patent/AU1380397A/en not_active Abandoned
  • 1996-12-26 US US09/091,706 patent/US5955456A/en not_active Expired - Fee Related
  • 1996-12-26 CA CA002240266A patent/CA2240266A1/en not_active Abandoned
  • 1996-12-26 JP JP9524071A patent/JP2000509013A/ja active Pending

Non-Patent Citations (1)

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