WO2020242410A1 - Compositions pharmaceutiques comprenant de l'acide ursodésoxycholique en tant que substance active - Google Patents

Compositions pharmaceutiques comprenant de l'acide ursodésoxycholique en tant que substance active Download PDF

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Publication number
WO2020242410A1
WO2020242410A1 PCT/TR2020/050265 TR2020050265W WO2020242410A1 WO 2020242410 A1 WO2020242410 A1 WO 2020242410A1 TR 2020050265 W TR2020050265 W TR 2020050265W WO 2020242410 A1 WO2020242410 A1 WO 2020242410A1
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WO
WIPO (PCT)
Prior art keywords
pharmaceutical composition
ursodeoxycholic acid
composition according
pharmaceutical compositions
gall
Prior art date
Application number
PCT/TR2020/050265
Other languages
English (en)
Inventor
Ece Pembecioglu
Alpay CEYLAN
Gozde INCEOGLU
Sibel GULIYEV
Original Assignee
Vefa Ilac San. Ve Tic. A.S.
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 Vefa Ilac San. Ve Tic. A.S. filed Critical Vefa Ilac San. Ve Tic. A.S.
Publication of WO2020242410A1 publication Critical patent/WO2020242410A1/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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2009—Inorganic compounds
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • 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 pharmaceutical compositions comprising ursodeoxycholic acid as active substance.
  • Ursodeoxycholic acid (Formula I) is a gall acid formed naturally in the body.
  • the chemical formula of ursodeoxycholic acid is C24 I40O4 and the chemical structure thereof is 3alpha,7beta-Dihydroxy-5beta-colan-24-oic acid and the molecular weight thereof is 392.6 g/mole.
  • Ursodeoxycholic acid is crystallized powder which has white color or a color similar to white color. Practically, it does not dissolve in water, it freely dissolves in alcohol and glacial acetic acid and it less dissolves in chloroform and it slightly dissolves in ether.
  • Gall acids form the basic component of gall and they are synthesized from cholesterol in liver and they are responsible for carrying and absorption of oil in diet and vitamins which dissolve in oil.
  • the gall acids synthesized in liver are named as primary gall acids (colic acid and cenodeoxycolic acid). Gall acids are released to intestine in gall. By means of the hydroxylation of primary gall acids in the intestine by the intestinal bacteria, secondary gall acids (deoxycolic acid and litholic acid) are formed.
  • Ursodeoxycholic acid (UDCA) is formed as a result of 7b epimerization of cenodeoxycolic acid in the intestine and forms 1 -3% of gall acid pool. A big part of gall acids is absorbed through terminal ileum and carried again to the liver and excreted to the gall.
  • Gall acids are conjugated with glycine and taurine in the plasma or are provided in a bonded manner with the plasma proteins and intra-cellular proteins, and the free form is under 5%. Since more than 5% of gall acids are in free form, toxicity occurs. Bonding of hydroxyl group in different positions and in different numbers with the cholesterol determines that the gall acid is hydrophobic or hydrophilic. Hydrophobicity is responsible for toxicity. The hydrophobicity characteristic exists in respectively decreasing amounts in lithocolic acid, deoxycolic acid, cenodeoxycolic acid, colic acid and ursodeoxycholic acid. Gall acids are used in diseases of duodenogastric reflux and gall stone for a long time. In the recent times, as the pharmacological characteristics of gall acids are examined and as related studies are made, the role of gall acids in the treatment of colestatic liver diseases which has auto-immune component has been shown and gall acids have been used frequently in a clinical manner.
  • Ursodeoxycholic acid is a gall acid which is naturally produced in the body. In patients whose gall bladder functions are active, ursodeoxycholic acid is used for melting non-radio-opaque cholesterol gall stones and for melting stone fragments which occur after gall stone fragmentation. Ursodeoxycholic acid can also be effective in treatment of cystic fibrosis associated with hepatobiliary disease in babies and children; it is used for eliminating liver functions and disease symptoms in primary biliary cirrhosis (I. and II. period).
  • Ursodeoxycholic acid exists in small amounts in normal human gall and suppresses hepatic synthesis and excretion of cholesterol and absorption through the intestines. Thus, it shows its effect by decreasing cholesterol excretion from the liver and by decreasing cholesterol ingredient of both gall and gall stones depending on decreasing fractional absorption of cholesterol through the intestines. In order to observe the effect thereof against gall stones, it must be used for months, and in some patients, gall stones may not dissolve completely. In pharmaceutical compositions comprising ursodeoxycholic acid which need long duration usage, formulations must be developed which will increase compliancy of the patient to this long-duration treatment.
  • the present invention relates to pharmaceutical compositions comprising ursodeoxycholic acid, for eliminating the above mentioned disadvantages and for bringing new advantages to the related technical field.
  • An object of the present invention is to provide pharmaceutical compositions comprising 750 mg ursodeoxycholic acid in unit dose.
  • the present invention relates to pharmaceutical compositions comprising 750 mg ursodeoxycholic acid.
  • the patients will not have to use two different tablets, for instance, 250 mg and 500 mg, and the compliancy of the patients to the treatment will increase. This is going to indirectly increase the chance of healing in patients.
  • the number of tablets in the package decreases and easiness is provided in the packaging process.
  • a preferred embodiment of the present invention relates to pharmaceutical compositions comprising binder, dispersant, lubricant besides 750 mg ursodeoxycholic acid.
  • a preferred embodiment of the present invention relates to pharmaceutical compositions comprising Povidon K30, microcrystalline cellulose, crospovidon, talc and magnesium stearate besides 750 mg ursodeoxycholic acid.
  • An embodiment of the present invention relates to pharmaceutical compositions comprising Povidon K30 between 1 -10%, microcrystalline cellulose between 5-30%, crospovidon between 1 -5%, talc between 1 -5% and magnesium stearate between 0.2-5% by weight proportion in total tablet weight besides 750 mg ursodeoxycholic acid.
  • the subject matter pharmaceutical composition comprises 750 mg ursodeoxycholic acid, 40.50 mg Povidon K30, 195 mg microcrystalline cellulose, 34.50 mg crospovidon, 15 mg talc and 15 mg magnesium stearate.
  • the subject matter pharmaceutical compositions can be in dosage forms which are suitable for oral intake, for instance, can be in tablet, capsule, oral drop, effervescent tablet form. In a particularly preferred embodiment of the present invention, the subject matter pharmaceutical compositions are in tablet form.
  • compositions prepared in tablet form according to the present invention and comprising 750 mg ursodeoxycholic acid in unit dose, can be coated by means of a suitable coating solution.
  • compositions When the subject matter pharmaceutical compositions are prepared in tablet form, they can have a notched form. Thus, the patient can easily take half-dose drug when required.
  • the present invention relates to pharmaceutical compositions comprising 750 mg ursodeoxycholic acid in unit dose for usage in cirrhosis treatment, in melting of gall stones, in treatment of pregnancy intra-hepatic cholestasis, in treatment of hepatobiliary diseases associated with cystic fibrosis or in elimination of the symptoms resulting from these diseases.
  • the present invention relates to usage of pharmaceutical compositions comprising 750 mg ursodeoxycholic acid in preparation of a drug to be used in cirrhosis treatment, in melting of gall stones, in treatment of pregnancy intra-hepatic cholestasis, in treatment of hepatobiliary diseases associated with cystic fibrosis or in elimination of the symptoms resulting from these diseases.
  • compositions comprising 750 mg ursodeoxycholic acid in unit dose is explained with references to examples without forming any restrictive effect only in order to make the subject more understandable.
  • Example 1 Recipe for pharmaceutical compositions comprising 750 mg ursodeoxycholic acid in unit dose
  • 250 mg and 500 mg tablet formulas are used as reference, which exist in the known state of the art, in the in vitro dissolution tests realized, since in the world, there is no tablet which comprises the subject matter 750 mg ursodeoxycholic acid. Said dissolution tests have been realized by means of“multiple doses” study.

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  • Health & Medical Sciences (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)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Inorganic Chemistry (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

La présente invention concerne des compositions pharmaceutiques comprenant de l'acide ursodésoxycholique en tant que substance active.
PCT/TR2020/050265 2019-05-28 2020-04-03 Compositions pharmaceutiques comprenant de l'acide ursodésoxycholique en tant que substance active WO2020242410A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
TR2019/08144A TR201908144A2 (tr) 2019-05-28 2019-05-28 Etken madde olarak ursodeoksi̇koli̇k asi̇t i̇çeren farmasöti̇k bi̇leşi̇mler
TR2019/08144 2019-05-28

Publications (1)

Publication Number Publication Date
WO2020242410A1 true WO2020242410A1 (fr) 2020-12-03

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ID=73553848

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/TR2020/050265 WO2020242410A1 (fr) 2019-05-28 2020-04-03 Compositions pharmaceutiques comprenant de l'acide ursodésoxycholique en tant que substance active

Country Status (2)

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TR (1) TR201908144A2 (fr)
WO (1) WO2020242410A1 (fr)

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008130234A1 (fr) * 2007-04-19 2008-10-30 Disphar International B.V. Composition à dose élevée d'acide ursodésoxycholique
WO2015142178A1 (fr) * 2014-03-20 2015-09-24 Disphar International B.V. Composition d'acide biliaire à solubilité améliorée

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008130234A1 (fr) * 2007-04-19 2008-10-30 Disphar International B.V. Composition à dose élevée d'acide ursodésoxycholique
WO2015142178A1 (fr) * 2014-03-20 2015-09-24 Disphar International B.V. Composition d'acide biliaire à solubilité améliorée

Also Published As

Publication number Publication date
TR201908144A2 (tr) 2020-12-21

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